PYRIDYL AMIDE Cav 3 CHANNEL MODULATORS

Abstract

The present invention provides novel compounds, or pharmaceutically acceptable salts thereof, which are modulators of Cav3 channels, and are associated with abnormal Cav3 channel function or activity. The invention is also directed to pharmaceutical compositions comprising these compounds or pharmaceutically acceptable salts thereof. The invention further relates to methods of treating or preventing disorders, diseases and conditions associated with abnormal function or activity of Cav3 channels by administering the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions disclosed herein. The invention also relates to compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions disclosed herein for use in methods of treating or preventing disorders, diseases and conditions associated with abnormal function or activity of Cav3 channels.

Description

PYRIDYL AMIDE Cav3 CHANNEL MODULATORSRELATED APPLICATIONS

[0001] The present application is related to, and claims priority from, EP 24180875.7 filed on 07 June 2024 (07.06.2025), the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The present invention provides novel compounds, or pharmaceutically acceptable salts thereof, which are modulators of T-type calcium channels (Cav3). These compounds, or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of disorders, diseases and conditions that are associated with abnormal Cav3 channel function. The invention is also directed to pharmaceutical compositions comprising these compounds or pharmaceutically acceptable salts thereof. The invention further relates to methods of treating or preventing disorders, diseases and conditions associated with abnormal function or activity of Cav3 channels by administering the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions disclosed herein.

[0003] The invention also relates to compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions disclosed herein for use in methods of treating or preventing disorders, diseases and conditions associated with abnormal function or activity of Cav3 channels. The invention also relates to uses of compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions disclosed herein in the treatment or prevention of disorders, diseases and conditions associated with abnormal function or activity of Cav3 channels. The invention also relates to uses of compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions disclosed herein in the manufacture of medicaments for treating or preventing disorders, diseases and conditions associated with abnormal function or activity of Cav3 channels.BACKGROUND TO THE INVENTION

[0004] Cav3 channels are low-threshold voltage-dependent channels that modulate physiological and pathological rhythms in the brain (Park et al., 2010; Park et al., 2013). A unique and discriminating property of Cav3 channels is their ability to activate upon small depolarizations of the membrane, at relatively low voltages, allowing a surge of calcium entry into excitable cells that leads to further membrane depolarization, activation of additional ionchannel subtypes, and initiation of an action potential. Under conditions of normal neuronal firing, after opening, the channels then rapidly shut (Miwa et al., 2011; Cain et al., 2010) and enter the prolonged inactivated state (Feltz et al., 2004) during which time they cannot respond to any new stimuli. The existence of this inactivated state allows Cav3 to act as a brake, preventing the neuron from becoming too excitable.

[0005] Cav3 channels are known to be associated with several diseases and conditions, such as epilepsy, movement disorders, psychiatric disorders, pain, or cancer.

[0006] Numerous genetic and pharmacological studies have validated Cav3 channels as therapeutic targets for absence epilepsy / absence seizures. Absence seizures, a type of generalized onset seizure, are sudden relatively brief lapses of consciousness associated with a lack of voluntary movements and distinctive spike-wave discharges (SWD) at 2.5 to 4 Hz on EEG. These seizures are clinically characterized by a transient alteration of consciousness, with or without other clinical signs, and associated EEG with diffuse SWDs of variable duration, usually between 3 and 30 seconds.

[0007] Absence seizures normally have an age of onset during childhood or adolescence and are present in several idiopathic generalized epilepsies (IGE) syndromes - a category of disorders defined by strict clinical and EEG criteria proposed by the International League Against Epilepsy (I LAE) classification of epileptic syndromes (Scheffer, 2017) - including childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE). In CAE, typical absence seizures are the hallmark seizure type (present in all patients), occur very frequently (up to 30 or 40 per day), and have an age of onset between 4 and 10 years with a peak at 5 to 7 years (Berg, 2000; Jallon, 2001 ; Fisher, 2005). In JAE, typical absence seizures are normally longer in duration (lasting up to 45 seconds) and less frequent (sometimes occurring a few times daily or less than daily), compared with CAE (Loiseau, 1995). Moreover, the age of onset of JAE is later compared to CAE, with most cases beginning between 10 and 17 years (Loiseau, 1995). JAE is also distinguished from CAE by a more common incidence of generalized tonic-clonic seizures (GTCS), which eventually occur in approximately 90% of JAE patients (Trinka 2004). The long-term prognoses for CAE and JAE are thought to be similar, with remission rates in only approximately half of patients (Trinka, 2004). For JAE, it is believed that less than half of patients achieve seizure freedom despite polytherapy and many require life-long treatment. Although CAE has a better overall prognosis than JAE, one quarter to one third of patients will not achieve seizure freedom after 1st-line and 2nd-line anti-seizure medications (Cnaan et al., 2007; Glauser et al., 2010). Absence seizures are also present in developmental and epileptic encephalopathies (DEEs) with onset in childhood, such as Lennox-Gastaut Syndrome(LGS). In LGS, atypical absence seizures are often frequent and consist of periods of impaired awareness (Specchio, 2021). They may begin and end gradually, which differentiates them from the sudden start and stop of a typical absence seizure. They may be challenging to identify with confidence due to their gradual onset and offset in a patient with underlying cognitive impairment.

[0008] Both CAE and JAE are generalized epilepsy syndromes that are part of a group of epileptic disorders collectively referred to as IGE. Idiopathic generalized epilepsies have a strong underlying genetic basis; that is, the underlying cause is most likely due to a hereditary predisposition, and they occur in patients with otherwise normal physical and mental states. The genes encoding voltage-gated Cav3 channels (CACNA1G, CACNA1H, and CACNA1 I), the GABA-A receptor subunits (GABRG2 and GABRG3), and the voltagegated P / Q type calcium channels (CACNA1A) have all been implicated in the etiology of these IGE syndromes (Guilhoto, 2017; Kang and Macdonald, 2016; Pearl, 2018). They have also been implicated in the etiology of developmental and epileptic encephalopathy (DEE) and neurodevelopmental disorders (Ghaleb et al, 2021).

[0009] There are substantial data to support that Cav3 channels mediate the abnormal oscillatory rhythms that generate the generalized ~3 Hz SWDs that are the hallmark of absence seizures (Marescaux and Vergnes 1995; Danober 1998; Futatsugi and Riviello 1998; for review, see Carney and Jackson 2014). Isoforms of Cav3 (Cav3.1, Cav3.2, and Cav3.3) are expressed throughout the CNS including the thalamo cortical circuitry where they mediate neuronal burst firing and the generation of SWDs (Cain and Snutch, 2013; Chen, 2014). Mouse studies have shown Cav3 to be both necessary and sufficient to drive absence seizures in vivo (Kim, 2001; Ernst, 2009). Human genetics and functional studies have shown that many Cav3 mutations isolated from patients with CAE lead to gain of function through changes in channel gating and / or expression (Chen, 2004; Khosravani, 2004; Vikto, 2005; Peloquin, 2006; Vikto, 2007). Together, these findings delineate a key role for Cav3 mediated bursting of thalamic neurons as a pathological driver of absence seizure activity.

[0010] Several approved antiepileptic drugs including ethosuximide and zonisamide are known to produce blockade of Cav3 channels, however lack of potency and selectivity limit their therapeutic window and effectiveness. Given these limitations, a more potent, selective Cav3 modulator has the potential to achieve a higher level of target engagement and seizure control with less off-target side effects than existing nonselective agents.

[0011] Compounds that inhibit Cav3 channels, and uses of such compounds, are described in in Giordanetto et al, "T-type calcium channels inhibitors: a patent review,"Expert Opin. Ther. Pat., 2011 , 21, 85-101 , W02004035000, W09304047, W02006098969, W02009009015, W02007002361 , W02007002884, W02007120729, W02009054982, W02009054983, W02009054984, US20090270413, W02008110008, WO2009146539, W02009146540, US8, 133,998, WO2010083264, W02006023881, W02006023883, W02005007124, W02005009392, US2005245535, W02007073497, W0200707852, W02008033447, W02008033456, W02008033460, W02008033464, W02008033465, W02008050200, W02008117148, W02009056934, EP1568695, W02008007835, KR754325, US7319098, US20100004286, EP1757590, KR2009044924, US2010094006, W02009035307, US20090325979, KR75758317, W02008018655, US20080293786, and LIS20100056545, each of which is incorporated herein by reference in its entirety.

[0012] Novel compounds according to the invention are selective Cav3 channel modulators with potency against all 3 Cav3 isoforms. These compounds show improved Cav3 channel modulation and inhibition, significantly improved half-life and significantly improved brain penetration. These properties may correspond to clinically meaningful improvements and improved potency. The compounds also exhibit reduced CYP inhibition in comparison to known compounds, which may lead to the reduction of adverse drug-drug interactions (DDIs).

[0013] The present invention has been devised in light of these considerations.BRIEF SUMMARY OF THE INVENTION

[0014] At its most general, the present invention relates to compounds of Formula IA and Formula IB, and pharmaceutically acceptable salts thereof.Formula IA Formula IB

[0015] In a first aspect of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0016] In a second aspect of the invention, there is provided a compound of Formula I A, or a pharmaceutically acceptable salt thereof.

[0017] In a third aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of Formula I A or Formula IB, or a pharmaceutically acceptablesalt thereof, optionally wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier.

[0018] In a fourth aspect of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0019] In a fifth aspect of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels.

[0020] In a sixth aspect of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing seizures.

[0021] In a seventh aspect of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method of treating epilepsy.

[0022] In an eighth aspect of the invention, there is provided a compound of Formula I A or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method of treating a movement disorder.

[0023] In a ninth aspect of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method of treating a psychiatric disorder.

[0024] In a tenth aspect of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing pain.

[0025] In an eleventh aspect of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer.

[0026] In a twelfth aspect of the invention, there is provided a method of treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels, wherein the method comprises administering to a patient a therapeutically effective amount of a compound of Formula I A or Formula IB, or a pharmaceutically acceptable salt thereof.

[0027] In a thirteenth aspect of the invention, there is provided a method of treating or preventing seizures, wherein the method comprises administering to a patient atherapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0028] In a fourteenth aspect of the invention, there is provided a method of treating epilepsy, wherein the method comprises administering to a patient a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0029] In a fifteenth aspect of the invention, there is provided a method of treating a movement disorder, wherein the method comprises administering to a patient a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0030] In a sixteenth aspect of the invention, there is provided a method of treating a psychiatric disorder, wherein the method comprises administering to a patient a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0031] In a seventeenth aspect of the invention, there is provided a method of treating or preventing a sleep disorder, wherein the method comprises administering to a patient a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0032] In an eighteenth aspect of the invention, there is provided a method of treating or preventing pain, wherein the method comprises administering to a patient a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0033] In a nineteenth aspect of the invention, there is provided a method of treating or preventing cancer, wherein the method comprises administering to a patient a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0034] In a twentieth aspect of the invention, there is provided a use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in the treatment or prevention of a disease, disorder or condition associated with abnormal function or activity of Cav3 channels.

[0035] In a twenty-first aspect of the invention, there is provided a use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels.

[0036] In a twenty-second aspect of the invention, there is provided a process of preparing a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0037] In a twenty-third aspect of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, which is obtained by or obtainable by the process of the eleventh aspect of the invention.

[0038] These and other aspects and embodiments of the invention are described in further detail below.BRIEF SUMMARY OF THE DRAWINGS

[0039] The present invention is described with reference to the figures listed below:

[0040] Figure 1 illustrates variation of the holding potential prior to the test pulses, as used in the voltage protocol for the evaluation of the test article effects on the steady-state inactivation of Cav3 in Example 3.

[0041] Figure 2 is a time course showing the number of SWDs recorded in GAERS after a single oral dose of test compound (the compound of Formula IA) or vehicle recorded over a 48 hr period (24 hr before dosing; 25 hr after dosing) as described in Example 7 (Study 1). The 12 hr dark cycle is shaded, the light cycle is unshaded. Data are presented as mean ± SEM in 1-hour bins. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: *p < 0.05.

[0042] Figure 3 shows the number of SWDs recorded in GAERS after a single oral dose of test compound (the compound of Formula IA), vehicle or positive control (ethosuximide) recorded over the first 3 hours post-dose (A, left) and the first 12 hours post-dose (B, right) as described in Example 7 (Study 1). Data are presented as mean ± SEM. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: ***p < 0.001, ****p <0.0001.

[0043] Figure 4 is a time course showing the average duration of SWD per hour after a single oral does of test compound (the compound of Formula 1A) or vehicle recorded over a 48 hr period (24 hr before dosing; 25 hr after dosing) as described in Example 7 (Study 1). The 12 hr dark cycle is shaded, the light cycle is unshaded. Data are presented as mean ± SEM in 1-hour bins. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: *p < 0.05.

[0044] Figure 5 shows the average duration of remaining SWDs after a single oral dose of test compound (the compound of Formula IA), vehicle or positive control (ethosuximide) recorded over the first 3 hours post-dose (A, left) and the first 12 hours post-dose (B, right)as described in Example 7 (Study 1). Data are presented as mean ± SEM. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: ***p < 0.001, ****p <0.0001.

[0045] Figure 6 is a time course showing the total time in SWD in second per hour after a single oral does of test compound (the compound of Formula 1A) or vehicle recorded over a 48 hr period (24 hr before dosing; 25 hr after dosing) as described in Example 7 (Study 1). The 12 hr dark cycle is shaded, the light cycle is unshaded. Data are presented as mean ± SEM in 1-hour bins. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: *p < 0.05.

[0046] Figure 7 shows the total time in SWD (in seconds) after a single oral dose of test compound (the compound of Formula IA), vehicle or positive control (ethosuximide) recorded over the first 3 hours post-dose (A, left) and the first 12 hours post-dose (B, right) as described in Example 7 (Study 1). Data are presented as mean ± SEM. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: ***p < 0.001, ****p <0.0001.

[0047] Figure 8 is a time course showing the number of SWDs recorded in GAERS after a single oral dose of test compound (the compound of Formula IA) or vehicle recorded over a 48 hr period post-dose as described in Example 7 (Study 2). The 12 hr dark cycles (hours 0 to 12 and 24 to 36) are shaded and the light cycles (hours 12 to 24 and 36 to 48) are unshaded. Data are presented as mean ± SEM in 4-hour bins. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: *p < 0.05.

[0048] Figure 9 shows the number of SWDs recorded in GAERS after a single oral dose of test compound (the compound of Formula IA) or vehicle recorded over the first 12 hours post-dose (A, left) and the first 24 hours post-dose (B, right) as described in Example 7 (Study 2). Data are presented as mean ± SEM. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: ****p <0.0001.

[0049] Figure 10 shows the average duration of remaining SWDs after a single oral dose of test compound (the compound of Formula IA) or vehicle recorded over the first 12 hours post-dose (A, left) and the first 24 hours post-dose (B, right) as described in Example 7 (Study 1). Data are presented as mean ± SEM. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: ***p < 0.001, ****p <0.0001.

[0050] Figure 11 is a time course showing the total time in SWD in second per 4-hour bin after a single oral dose of test compound (the compound of Formula 1 A) or vehicle recorded over a 48 hr period post-dose as described in Example 7 (Study 2). The 12 hr dark cycle isshaded, the light cycle is unshaded. Data are presented as mean ± SEM in 4-hour bins. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: *p < 0.05.

[0051] Figure 12 shows the total time in SWD (in seconds) after a single oral dose of test compound (the compound of Formula IA) or vehicle recorded over the first 12 hours postdose (A, left) and the first 24 hours post-dose (B, right) as described in Example 7 (Study 2). Data are presented as mean ± SEM. The significance against the vehicle group (Dunnett post-hoc analysis) is indicated as follows: ****p <0.0001.DETAILED DESCRIPTION OF THE INVENTION

[0052] The present invention provides compounds of Formula IA and Formula IB, or pharmaceutically acceptable salts thereof.Formula IA Formula IB

[0053] In some embodiments, the compound is of Formula IA or is a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the compound is of Formula IB or is a pharmaceutically acceptable salt thereof.

[0055] In preferred embodiments, the compound is of Formula IA or is a pharmaceutically acceptable salt thereof.

[0056] Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.

[0057] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. Where compounds contain an sp2nitrogen atom (-N=), for example in a heteroaryl group, it may be convenient to prepare, purify, and / or handle the corresponding N-oxide (-N(^O)=), also denoted as -N+(O-)=).

[0058] Accordingly, compounds of Formula IA or Formula IB may be provided in the form of an N-oxide. For example, quinoline may be substituted to give quinoline N-oxide; pyridine to give pyridine N-oxide; benzofurazan to give benzofurazan N-oxide (also known as benzofuroxan).

[0059] In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0060] The compounds according to the invention can be in any appropriate form.

[0061] In some embodiments, the compounds can be in the form of a base (e.g., a free base form of the compound).

[0062] In some embodiments, the compounds can be in the form of a salt (e.g., a salt form of the compound), particularly a pharmaceutically acceptable salt.

[0063] In embodiments where the compounds are in the form of a pharmaceutically acceptable salt, the salt can be any appropriate salt. This can include a salt formed with any appropriate acid (e.g., hydrochloric acids, citric acids, hydrobromic acids, maleic acids, phosphoric acids, sulfuric acids, fumaric acids, and tartaric acids). For example, compounds according to the invention can be provided as a hydrochloride salt. In some embodiments, the compounds can be deuterated.Other Aspects and Embodiments

[0064] Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.

[0065] Various further aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure.

[0066] Where used, “and / or” is to be taken as a specific disclosure of each of the relevant components or features alone as well as a specific disclosure of the combination of thecomponents or features. For example, “A and / or B” is to be taken as specific disclosure of each of i) A, ii) B, and iii) A and B, just as if each were set out individually.

[0067] Unless context dictates otherwise, the descriptions and definitions of the features set out above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments which are described.Definitions

[0068] The following definitions are provided in order to aid understanding of the invention.

[0069] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs, taking into account the context provided by the present disclosure.

[0070] For the terms "e.g." and "such as," and grammatical equivalents thereof, the phrase "and without limitation" is understood to follow unless explicitly stated otherwise.

[0071] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0072] The term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value).

[0073] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, i.e. as "including, but not limited to". The term “consist of’ and variations thereof, such as “consists of” and “consisting of” are to be construed in a closed sense. For the avoidance of doubt, the open interpretations of the term ’’comprise” (and variations thereof) include within them the closed interpretations given by “consisting of” (and variations thereof).

[0074] The term "compound" includes all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless the context indicates otherwise. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0075] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0076] The present application also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins, and Handbook of Pharmaceutical Excipients, 9th edition, 2020, pub. Pharmaceutical Press, each of which is incorporated herein by reference in its entirety.

[0077] The terms "individual" or "patient," used interchangeably, refer to (e.g., as a subject of the treatment) any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0078] The phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0079] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0080] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results. For purposes of the present invention, beneficial or desired results include, but are not limited to, alleviation of a symptom and / or diminishment of the extent of a symptom associated with a disease, disorder or condition. “Treatment” or “treating” includes one or more of the following: a) inhibiting the disease, disorder or condition (e.g., decreasing one or more symptoms resulting from the disease, disorder or condition, and / or diminishing the extent of the disease, disorder or condition); b) slowing or arresting the development of one or more symptoms associated with the disease, disorder or condition (e.g., stabilizing the disease, disorder or condition, delaying the worsening or progression of the disease,disorder or condition); and c) relieving the disease, disorder or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0081] As used herein, "prevention" or "preventing" refers to a regimen that protects against the onset of the disease, disorder or condition such that the clinical symptoms of the disease do not develop. Thus, "prevention" relates to administration of a therapy (e.g., administration of a therapeutic substance) to a patient before signs of the disease are detectable in the patient. The patient may be an individual at risk of developing the disease, disorder or condition, such as an individual who has one or more risk factors known to be associated with development or onset of the disease, disorder or condition. Where the treatment of a disease, condition or disorder in a subject or patient is disclosed, the same method is also disclosed for the prevention of said disease, condition or disorder in the subject or patient.

[0082] As used herein, “Cav3” and “Cav3 channels” are used interchangeably to refer to T- type calcium channels.

[0083] As used herein, “function” of, for example, Cav3 channels, refers to the ability of that specific entity to perform its associated purpose or effect, i.e. for Cav3 channels, function refers to the ability of Cav3 channels to regulate the flow of calcium into cells, for example in response to changes in membrane potential.

[0084] As used herein, “activity” of for example, Cav3 channels, refers to the capacity of that specific entity to achieve a defined effect, i.e. for Cav3 channels, activity refers to the capacity of Cav3 channels to regulate the flow of calcium into cells, for example in response to changes in membrane potential. For Cav3 channels, activity can be measured using the patch clamp techniques, such as the protocol used in Example 3 of this application. Other suitable methods of measuring such activity are known in the art and may also be used.

[0085] As used herein, “abnormal” refers to a variance from an accepted normal level of function or activity. In biological settings, such as referring to abnormal function or activity of Cav3, the abnormal condition may result in pathological symptoms.

[0086] As used herein, “modulation” or “modulating” is used to refer to a change (e.g. an increase or a decrease) in the activity or the function of, for example, Cav3 channels. A change in activity can be from 1% to 100%, 5% to 100%, 20 to 100%, 50% to 100%, 70% to 100% of the original value, for example the change can be 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%. In the case of Cav3 channels, modulation may refer to state or use dependent binding, or slowing recovery from inactivation.

[0087] As used herein, “inhibition” or “inhibiting” is used to refer to a decrease in the activity or an impairment in the function of, for example, Cav3 channels. A decrease in activity can be from 1% to 100%, 5% to 100%, 20 to 100%, 50% to 100%, 70% to 100% of the original value, for example the decrease can be 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%. For Cav3 channels, inhibition can be measured by comparing the activity of the channel in the presence or absence of a test compound using the patch clamp technique, such as described in Example 3 of this application. Other suitable methods of measuring such activity are known in the art and may also be used.

[0088] Reference to “T3P”, a registered trademark, in this application, corresponds to propanephosphonic acid anhydride.

[0089] As used herein, “refractory”, when used in the context of, for example, “refractory seizures” or “refractory absence seizures”, is used to refer to the failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.Synthetic processes

[0090] Compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

[0091] Processes of preparing compounds, or pharmaceutically acceptable salts thereof, according to the invention can be performed according to any suitable process. The reactions for preparing compounds as described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

[0092] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC MS Purification: Improved Compound Specific Method Optimization" Blom, et al., J. Combi. Chem. 2004, 6(6) 874-883) and normal phase silica chromatography (Still et al., J. Org. Chem., 1978, 43(14), 2923-25).

[0093] In Schemes 1 and 2 shown below, the carboxylic acid starting materials are commercially available, for example from Apollo Scientific, with CAS numbers: 1839048-23- 5 and 1211578-68-5. The amine starting material referred to in Schemes 1 and 2 shown below, (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine, may be prepared using the method described in Example 16 of WO 2007 / 120729 A2, the contents of which are incorporated herein by reference.

[0094] The invention provides a process of preparing compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof. In some embodiments, the process comprises reacting either 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid or 2-(3- (pentafluoro- A6-sulfanyl)phenyl)acetic acid, in combination with (R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethan-1 -amine.

[0095] In some embodiments, the process comprises preparing a solution of either 2-(4- (pentafluoro-A6-sulfanyl)phenyl)acetic acid or 2-(3-(pentafluoro- A6-sulfanyl)phenyl)acetic acid, in combination with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine, in a solvent. Any suitable solvent may be used. For example, a hydrocarbon solvent, an ester solvent, or an ether solvent may be used. A solvent may also be DMF (dimethylformamide), NMP (N-Methyl-2-pyrrolidone), DCM (dichloromethane) or ethyl acetate. In some embodiments, the solvent is an ester solvent. In some embodiments, the solvent is ethyl acetate.

[0096] In some embodiments, the invention provides a process of preparing a compound of Formula I A, or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the process comprises reacting 2-(4-(pentafluoro-A6- sulfanyl)phenyl)acetic acid in combination with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1 -amine. In some embodiments, 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid is converted into the analogous acyl chloride or mixed anhydride prior to the reaction with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine.

[0098] In some embodiments, the process comprises preparing a solution of 2-(4- (pentafluoro-A6-sulfanyl)phenyl)acetic acid and (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine in a solvent Any suitable solvent may be used. For example, a hydrocarbon solvent, an ester solvent, or an ether solvent may be used. A solvent may also be DMF (dimethylformamide), NMP (N-Methyl-2-pyrrolidone), DCM (dichloromethane) or ethyl acetate. In some embodiments, the solvent is an ester solvent. In some embodiments, the solvent is ethyl acetate. In some embodiments, the molar ratio of the starting amount of2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid:(R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine is about 1.05:1.

[0099] In some embodiments, the process comprises cooling the solution of 2-(4- (pentafluoro-A6-sulfanyl)phenyl)acetic acid and (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine. Suitable methods of cooling a reaction are known in the art, such as using a jacket reaction vessel with a temperature control system. In some embodiments, the solution is cooled to a temperature between -10 °C and 40 °C, such as a temperature between -10 °C and 20 °C; for example, the solution may be cooled to 0 °C.

[0100] In some embodiments, the process comprises adding a base to the cooled solution. Any suitable base may be used. For example, the base is a tertiary amine. In some embodiments, the base is triethylamine. In some embodiments, the base is added in excess to the initial amount of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine added to the first solution. In some embodiments, the molar ratio of the initial amount of (R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethan-1-amine added to the first solution, to the amount of the base added in this step, is between 1 :1.05 to 1:5, such as about 1:3.

[0101] In some embodiments, after the addition of the base, the process comprises the slow addition of a peptide coupling agent, such as HATLI (Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), HBTLI (Hexafluorophosphate Benzotriazole Tetramethyl Uronium), HCTU (O-(1 H-6-Chlorobenzotriazole-1-yl)-1,1 ,3,3-tetramethyluronium hexafluorophosphate), T3P (defined above), EDC (1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide), HCI / DMAP (4-Dimethylaminopyridine) / HOBt (Hydroxybenzotriazole), DIC (N,N'-Diisopropylcarbodiimide) or DCC (N,N'- Dicyclohexylcarbodiimide) / HOBt, PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate), BOP (benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate), or GDI (Carbonyldiimidazole) and a base In some embodiments, the peptide coupling agent is T3P. In some embodiments, the peptide coupling agent is at a concentration of 50% weight sol. in an appropriate solvent such as EtOAc. In some embodiments, the molar ratio of the initial amount of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine added to the first solution, to the amount of the peptide coupling agent added in this step, is about 1:1 to 1:2, such as 1:1.5.

[0102] In some embodiments, the process comprises agitating the reaction for a suitable time, such as for an hour or less (for example, an hour), at a suitable temperature, such as at room temperature. Methods of agitating the solution are known in the art, such as stirring the reaction mixture. In some embodiments, the process comprises quenching the reaction mixture with an appropriate quenching solution, such as saturated sodium bicarbonate solution.

[0103] In some embodiments, the process comprises extracting the compound from the reaction mixture. Any suitable method may be used to extract the compound. In some embodiments, the process comprises extracting the aqueous phase with a solvent, such as ethyl acetate, DCM, TBME, diethyl ether, 2-methylTHF, heptane, cyclohexane. In some embodiments, the process comprises extracting the aqueous phase with ethyl acetate. In some embodiments, the process comprises washing the organic phase with reagents, such as water or brine. In some embodiments, the process comprises drying the organic phase. Any suitable method can be used to dry the organic phase. In some embodiments, the process comprises drying the compound using a hydrophobic phase separator.

[0104] In some embodiments, the process comprises purifying the compound. The compound may be purified by any suitable method. In some embodiments, the process comprises purifying the compound using silica gel flash chromatography. Any suitable solvent can be used in the chromatography. In some embodiments, the process comprises purifying the compound using silica gel flash chromatography using 0% to 60% ethyl acetate in heptane.

[0105] In some embodiments, the invention provides a process of preparing a compound of Formula IB, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the process comprises reacting 2-(3-(pentafluoro-A6- sulfanyl)phenyl)acetic acid in combination with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1 -amine. In some embodiments, 2-(3-(pentafluoro-A6-sulfanyl)phenyl)acetic acid is converted into the analogous acyl chloride or mixed anhydride prior to the reaction with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine.

[0107] In some embodiments, the process comprises preparing a solution of 2-(3- (pentafluoro-A6-sulfanyl)phenyl)acetic acid and (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine in a solvent. Any suitable solvent may be used. For example, a hydrocarbon solvent, an ester solvent, or an ether solvent may be used. A solvent may also be DMF (dimethylformamide), NMP (N-Methyl-2-pyrrolidone), DCM (dichloromethane) or ethyl acetate. In some embodiments, the solvent is an ester solvent. In some embodiments, the solvent is ethyl acetate. In some embodiments, the molar ratio of the starting amount of2-(3-(pentafluoro-A6-sulfanyl)phenyl)acetic acid:(R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine is about 1:1.

[0108] In some embodiments, the process comprises cooling the solution of 2-(3- (pentafluoro-A6-sulfanyl)phenyl)acetic acid and (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine. Suitable methods of cooling a reaction are known in the art, such as by placing the reaction vessel into an ice / water bath (optionally further containing sodium chloride). In some embodiments, the solution is cooled a temperature between -10 °C and 40 °C, such as a temperature between -10 °C and 20 °C; for example, the solution may be cooled to 0 °C.

[0109] In some embodiments, the process comprises the addition of a base, such as triethylamine, to the cooled solution. Any suitable base may be used. For example, the base is a tertiary amine. In some embodiments, the base is triethylamine. In some embodiments, the base is added in excess to the initial amount of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine added to the first solution. In some embodiments, the molar ratio of the initial amount of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine added to the first solution, to the amount of the base added in this step, is between 1:1.05 to 1:5, such as about 1:1.25.

[0110] In some embodiments, after the addition of the base, the process comprises the slow addition of a peptide coupling agent, such as HATLI (Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), HBTLI (Hexafluorophosphate Benzotriazole Tetramethyl Uronium), HCTU (O-(1 H-6-Chlorobenzotriazole-1-yl)-1,1 ,3,3-tetramethyluronium hexafluorophosphate), T3P (defined above), EDC (1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide), HCI / DMAP (4-Dimethylaminopyridine) / HOBt(Hydroxybenzotriazole), DIC (N,N'-Diisopropylcarbodiimide) or DCC (N,N'- Dicyclohexylcarbodiimide) / HOBt, PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate), BOP (benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate), or GDI (Carbonyldiimidazole) and a base In some embodiments, the peptide coupling agent is T3P. In some embodiments, the peptide coupling agent is at a concentration of 50% weight sol. in an appropriate solvent such as EtOAc. In some embodiments, the molar ratio of the initial amount of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine added to the first solution, to the amount of the peptide coupling agent added in this step, is about 1:1 to 1:2, such as 1:1.1.

[0111] In some embodiments, the process comprises agitating the reaction for a suitable time, such as overnight, at a suitable temperature, such as at room temperature. Methods of agitating the solution are known, such as stirring the reaction mixture. In some embodiments, the process comprises diluting the reaction mixture with an appropriate solvent, such as ethyl acetate.

[0112] In some embodiments, the compound is extracted from the reaction mixture. Any suitable method may be used to extract the compound. In some embodiments, the process comprises extracting the aqueous phase with a solvent, such as ethyl acetate, DCM, TBME, diethyl ether, 2-methylTHF, heptane, cyclohexane. In some embodiments, the process comprises extracting the aqueous phase with ethyl acetate. In some embodiments, the process comprises washing the reaction mixture with reagents, such as water or brine. In some embodiments, the process comprises drying the reaction mixture. Any suitable method can be used to dry the organic phase. In some embodiments, the process comprises drying the reaction mixture over sodium bicarbonate.

[0113] In some embodiments, the process comprises purifying the compound. The compound may be purified by any suitable method. In some embodiments, the process comprises purifying the compound using silica gel flash chromatography. Any suitable solvent can be used in the chromatography. In some embodiments, the process comprises using silica gel flash chromatography with using 5% to 50% ethyl acetate in heptane.

[0114] Characterisation of compounds of the invention may be carried out using1H NMR,19F NMR, LCMS (liquid chromatography-mass spectrometry) and / or UPLC-MS (ultra performance liquid chromatography-mass spectrometry).1H NMR and19F NMR spectra can be recorded on a Bruker Avance Neo 500 (operating at 500 MHz and 471 MHz, respectively) or a Bruker Avance 500 (operating at 500 MHz and 471 MHz, respectively), and are reported relative to residual solvent peak for1H NMR (52.50 in DMSO; 5 7.26 in CDCI3) and against CFCh for19F NMR (5 0.00 in DMSO)

[0115] LCMS may be performed according to any suitable method. One such method may make use of a suitable instrument such as a Shimadzu LCMS system, and a suitable column, such as the Waters SunFire C18 column, 100A, 5 pm, 4.6 mm X 50 mm, with a suitable flow rate such as 2.0 ml / min.

[0116] LCMS Method refers to a method of carrying out LCMS which is defined as follows:Instrument: Shimadzu LCMS systemColumn: Waters SunFire C18 50*4.6mm 5um 2.6min Column Temperature: 40 °CMobile Phase A : 0.03% TFA in H2O; Mobile Phase B : 0.03% TFA in ACNFlow Rate: 2.0 ml / min Gradient: 5% B hold for 0.2min, increase to 95 % B within 1.40 min, hold at 95 % B for 0.9 min, then back to 5% B within 0.01 min.

[0117] UPLC-MS may be performed according to any suitable method. One such method may make use of a suitable instrument such as UPLC Waters H-class QDa and PDA or UPLC Waters Premier QDa and PDA, and a suitable column, such as the ACQUITY UPLC BEH C18 Column, 130A, 1.7 pm, 2.1 mm X 50 mm or ACQUITY Premier BEH C18, 130A, 1.7 pm, 2.1 x 100 mm MVK, with a suitable Flow Rate such as 0.6 mL / min.

[0118] Such methods may make use of a suitable first and second mobile phase, such as a Mobile Phase A - 0.1% ammonium hydroxide in water: acetonitrile (95:5) and a Mobile Phase B - acetonitrile: 0.1% ammonium hydroxide in water (95:5), Mobile Phase: A - 0.1% formic acid in water: acetonitrile (95:5), Mobile Phase B - acetonitrile: 0.1% formic acid in water (95:5), or Mobile Phase: A - 0.1% formic acid in water, Mobile Phase B - acetonitrile.

[0119] Such methods may make use of a suitable gradient such as: 0.0 / 5, 0.1 / 5, 3.0 / 95, 4.5 / 95, 4.6 / 5, 5.0 / 5 (time(min) / %B); or 0.0 / 5, 0.1 / 5, 8.5 / 95, 9.2 / 95, 9.3 / 5, 10.0 / 5 (time(min) / %B).

[0120] Method A refers to a method of carrying out UPLC-MS which is defined as follows:Instrument: UPLC Waters H-class QDa and PDA,Column: ACQUITY UPLC BEH C18 Column, 130A, 1.7 pm, 2.1 mm X 50 mm,Mobile Phase: A - 0.1% formic acid in water: acetonitrile (95:5), Mobile Phase B - acetonitrile: 0.1% formic acid in water (95:5),Flow Rate: 0.6 mL / min, Gradient (time(min) / %B): 0.0 / 5, 0.1 / 5, 3.0 / 95, 4.5 / 95, 4.6 / 5,5.0 / 5.

[0121] Method B refers to a method of carrying out UPLC-MS which is defined as follows:Instrument: LIPLC Waters H-class QDa and PDA,Column: ACQUITY UPLC BEH C18 Column, 130A, 1.7 pm, 2.1 mm X 50 mm,Mobile Phase: A - 0.1% ammonium hydroxide in water: acetonitrile (95:5), Mobile Phase B - acetonitrile: 0.1% ammonium hydroxide in water (95:5),Flow Rate: 0.6 mL / min, Gradient (time(min) / %B): 0.0 / 5, 0.1 / 5, 3.0 / 95, 4.5 / 95, 4.6 / 5, 5.0 / 5.

[0122] Method C refers to a method of carrying out UPLC-MS which is defined as follows:Instrument: UPLC Waters H-class QDa and PDA, Column: ACQUITY UPLC BEH C18 Column, 130A, 1.7 pm, 2.1 mm X 50 mm, Mobile Phase: A - 0.1% ammonium hydroxide in water: acetonitrile (95:5), Mobile Phase B - acetonitrile: 0.1% ammonium hydroxide in water (95:5),Flow Rate: 0.6 mL / min, Gradient (time(min) / %B): 0.0 / 5, 0.1 / 5, 8.5 / 95, 9.2 / 95, 9.3 / 5, 10.0 / 5.

[0123] Method D refers to a method of carrying out UPLC-MS which is defined as follows:Instrument: UPLC Waters Premier QDa and PDA, Column: ACQUITY Premier BEH C18, 130A, 1.7 pm, 2.1 x 100 mm MVK, Mobile Phase: A - 0.1% formic acid in water, Mobile Phase B - acetonitrile, Flow Rate: 0.6 mL / min, Gradient (time(min) / %B): 0.0 / 5, 0.1 / 5, 8.5 / 95, 9.2 / 95, 9.3 / 5, 10.0 / 5.

[0124] It will be appreciated by one skilled in the art that the processes described herein are not the exclusive means by which compounds provided herein may be synthesized and that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds provided herein. The person skilled in the art knows how to select and implement appropriate synthetic routes. Suitable synthetic methods of starting materials, intermediates and products may be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd Edition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry(Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

[0125] The invention provides a compound obtained or obtainable by the methods set out above. In some embodiments, the invention provides a compound obtained or obtainable by reacting either 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid or 2-(3-(pentafluoro- A6- sulfanyl)phenyl)acetic acid, in combination with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1 -amine. In preferred embodiments, the invention provides a compound obtained or obtainable by reacting 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid with (R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethan-1 -amine.

[0126] In some embodiments, the invention provides a compound obtained or obtainable by a method comprising preparing a solution of 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid or 2-(3-(pentafluoro- A6-sulfanyl)phenyl)acetic acid, in combination with (R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethan-1-amine in a solvent. In some embodiments, such a method comprises cooling the solution. In some embodiments, such a method comprises the addition of a base, optionally in excess to the initial amount of (R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethan-1-amine added to the first solution. In some embodiments, after the addition of the base, such a method comprises the slow addition of a peptide coupling agent. In some embodiments, the reaction mixture is then agitated. In some embodiments, such a method comprises extracting such a compound. In some embodiments, such a method comprises drying such a compound. In some embodiments, such a method comprises purifying such a compound.Methods of UseIn vitro methods

[0127] The present application further provides methods of modulating or inhibiting the function or activity of Cav3 channels. In some embodiments, the method is an in vitro method.

[0128] In some embodiments, the method comprises modulating or inhibiting the function or activity of Cav3 channels in a cell sample or tissue sample, comprising contacting the cell sample or tissue sample with a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0129] Such cell or tissue samples can be taken from a subject. The term "subject," refers to any animal, including mammals. Example subjects include, but are not limited to, mice, rats, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. Preferably, the subject is a human. The method may comprise taking a sample from a subject by any suitable method, such as by biopsy.

[0130] In some embodiments, the method comprises modulating or inhibiting the function or activity of one or more isoforms of Cav3 channels in a cell sample or tissue sample, comprising contacting the cell sample or tissue sample with a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the isoform is Cav3.1, Cav3.2, Cav3.3, or any combination thereof. In one embodiment, the isoform is Cav3.1. In one embodiment, the isoform is Cav3.2. In one embodiment, the isoform is Cav3.3. In some embodiments, the function or activity of all of the isoforms of the Cav3 channels is modulated or inhibited.Methods of modulating or inhibiting Cav3 in a subject

[0132] The present application further provides a method of treating a disease, condition or disorder in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a patient.

[0133] The present application further provides a method of modulating or inhibiting the function or activity of Cav3 channels in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a patient.

[0134] In some embodiments, the method comprises modulating or inhibiting the function or activity of one or more isoforms of Cav3 channels in the subject.

[0135] In some embodiments, the isoform is Cav3.1, Cav3.2, Cav3.3, or any combination thereof. In one embodiment, the isoform is Cav3.1. In one embodiment, the isoform is Cav3.2. In one embodiment, the isoform is Cav3.3. In some embodiments, the activity of all of the isoforms of the Cav3 channels is modulated or inhibited.

[0136] The present application further provides a method of treating a disease associated with abnormal function or activity of Cav3 channels. In some embodiments, the method comprises administering to the patient a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0137] The methods of treatment provided by the invention may also be expressed in terms of the use of the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, in these methods.

[0138] For instance, the invention provides such compounds and pharmaceutically acceptable salts thereof for use in any method of treating a disease in a patient in need of such treatment defined herein. The invention also provides the use of such compounds and pharmaceutically acceptable salts thereof for treating a disease in a subject in need of such treatment according to any method herein. The invention also provides the use of such compounds and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease in a patient in need of such treatment according to any method herein.

[0139] In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of a psychiatric disorder; a movement disorder; a sleep disorder; pain; cancer; seizures, such as absence seizures; and epilepsy, such as epilepsy with absence seizures. In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of a psychiatric disorder; a movement disorder; a sleep disorder; pain; seizures, such as absence seizures; and epilepsy, such as epilepsy with absence seizures.

[0140] In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of essential tremor; Parkinson’s tremor; dystonia(s); spinocerebellar ataxia; epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE);Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE); photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); febrile seizures (FS); autism spectrum disorder; ADHD; amyotrophic lateral sclerosis; chronic pain syndrome; schizophrenia; addiction; neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy; and inflammatory pain, such as IBS inflammatory pain. In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of essential tremor; Parkinson’s tremor; dystonia(s); spinocerebellar ataxia; epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy(IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE); photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); febrile seizures (FS); autism spectrum disorder; ADHD; amyotrophic lateral sclerosis; chronic pain syndrome; schizophrenia; addiction; neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy; and inflammatory pain, such as IBS inflammatory pain.

[0141] In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is absence seizures.

[0142] In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS). In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE);Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).

[0143] In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of epilepsy with absence seizures, such as idiopathic generalized epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE).

[0144] In some embodiments, the disease, disorder or condition is associated with abnormal function or activity of Cav3.1, Cav3.2 or Cav3.3 channels, or any combination thereof, in the patient. In one embodiment, the disease, disorder or condition is associated with abnormal function or activity of Cav3.1 channels. In one embodiment, the disease, disorder or condition is associated with abnormal function or activity of Cav3.2 channels. Inone embodiment, the disease, disorder or condition is associated with abnormal function or activity of Cav3.3 channels. In some embodiments, the disease, disorder or condition is associated with abnormal function or activity of all of the types of Cav3 channels in the patient.

[0145] In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3.1 channels, is selected from the group consisting of tremor, such as essential tremor, MS tremor or dystonic tremor; dystonia(s); epilepsy with absence seizures; idiopathic generalized epilepsy (IGE), such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); cerebellar ataxia; and autism spectrum disorder.

[0146] In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3.2 channels, is selected from the group consisting of idiopathic generalized epilepsy (IGE), such as childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE) juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE); generalized epilepsy with febrile seizures plus (GEFS+); febrile seizures (FS); photosensitive epilepsy; autism spectrum disorder; familial and primary aldosteronism; a neuromuscular disorder; and chronic pain syndrome. In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3.2 channels, is selected from the group consisting of idiopathic generalized epilepsy (IGE), such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE) or juvenile myoclonic epilepsy (JME); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE); generalized epilepsy with febrile seizures plus (GEFS+); febrile seizures (FS); photosensitive epilepsy; autism spectrum disorder; familial and primary aldosteronism; a neuromuscular disorder; and chronic pain syndrome.

[0147] In some embodiments, the disease, disorder or condition associated with abnormal function or activity of Cav3.3 channels, is selected from the group consisting of neurodevelopmental disorders with and without seizures; sleep disorders; childhood absence epilepsy (CAE); schizophrenia; ADHD; anxiety disorders; and autism spectrum disorder.Seizures

[0148] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful in methods of treating seizures or conditions associated with seizure.

[0149] In some embodiments, the present invention is directed towards a method for treating seizures, or certain conditions associated with seizure, wherein the methodcomprises administering to a patient, wherein said patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0150] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) seizures, or certain conditions associated with seizure.

[0151] In some embodiments, the present invention is directed towards compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, for use in methods for treating seizures, or certain conditions associated with seizure.

[0152] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof for treating seizures, or certain conditions associated with seizure. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof in a method of manufacturing a medicament for treating seizures, or certain conditions associated with seizure.

[0153] In some embodiments, the type of seizure is selected from selected from focal onset seizure (focal seizure), generalised onset seizure (generalised seizure), and seizure with unknown onset (unknown onset seizure).

[0154] Focal onset seizures may be further characterised by the level of awareness. In some embodiments, the focal onset seizure is focal onset seizure with awareness. In some embodiments, the focal onset seizure is a focal onset seizure with impaired awareness (with impairment).

[0155] Focal onset seizures may be further characterised by motor onset or non-motor onset features. In some embodiments, the focal onset seizure is a focal onset seizure with a motor onset feature, such as a motor onset feature selected from automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic and tonic. In some embodiments, the focal onset seizure is a focal onset seizure with a non-motor onset feature, such as a nonmotor onset feature selected from autonomic, behaviour arrest, cognitive, emotional and sensory.

[0156] Focal onset seizures may also present with focal to bilateral tonic-clonic propagation. In some embodiments, the focal onset seizure is a focal to bilateral tonic-clonic seizure.

[0157] Generalised onset seizures may be characterised by motor or non-motor (absence) features. In some embodiments, the generalised onset seizure is a generalised onset seizure with a motor feature, such as a motor feature selected from tonic-clonic,clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic and epileptic spasms. In some embodiments, the generalised onset seizure is a generalised onset seizure with a non-motor (absence) feature, such as a non-motor (absence) feature selected from typical, atypical, myoclonic and eyelid myoclonia.

[0158] Seizures with unknown onset may be characterised by motor or non-motor features. In some embodiments, the unknown onset seizure is an unknown onset seizure with a motor feature, such as a motor feature selected from tonic-clonic and epileptic spasms. In some embodiments, the unknown onset seizure is an unknown onset seizure with a non-motor (absence) feature, such as behavioural arrest.

[0159] In some embodiments, the condition associated with seizure is a seizure type that may be present in one or more of focal onset, generalised onset or unknown onset seizures, such as a seizure type selected from typical absence seizure, atypical absence seizure, atonic seizure, clonic seizure, tonic seizure, tonic-clonic seizure, febrile seizure, focal to bilateral tonic clonic seizure, gelastic and dacrystic seizure, myoclonic seizure, myoclonic- tonic-clonic seizure, myoclonic-atonic seizure, and epileptic (or infantile) spasms.

[0160] In some embodiments, the condition associated with seizure is an epilepsy, such as an epilepsy selected from focal epilepsy, generalised epilepsy, and combined generalised & focal epilepsy.

[0161] In some embodiments, the condition associated with seizure is an epilepsy syndrome, such as an epilepsy syndrome selected from syndromes with onset in neonates and infancy; syndromes with onset in childhood; syndromes with onset at a variable age; syndromes with onset in adulthood; and idiopathic generalised epilepsy syndromes (IGEs).

[0162] In some embodiments, the condition associated with seizure is an epilepsy syndrome with onset in neonates and infancy, such as an epilepsy syndrome with onset in neonates and infancy selected from self-limited epilepsies (such as self-limited neonatal epilepsy, self-limited infantile epilepsy, or myoclonic eplilepsy in infancy), developmental and epileptic encephalopathies - DEEs (such as epilepsy in infancy with migrating focal seizures, infantile epileptic spasms syndrome, or Dravet syndrome), and etiology-specific syndromes (such as KCNQ2-DEE, glucose transporter 1 deficiency syndrome, or Sturge Weber syndrome).

[0163] In some embodiments, the condition associated with seizure is an epilepsy syndrome with onset in childhood, such as an epilepsy syndrome with onset in childhood selected from self-limited focal epilepsies (such as childhood occipital visual epilepsy (COVE), or idiopathic photosensitive occipital lobe epilepsy (POLE)), DEEs (such asepilepsy with myoclonic atonic seizures, Lennox Gastaut syndrome, or epileptic encephalopathy with spike-and-wave activation in sleep), and genetic generalised epilepsies (such as epilepsy with eyelid myoclonia, or epilepsy with myoclonic absence).

[0164] In some embodiments, the condition associated with seizure is an epilepsy syndrome with onset at a variable age, such as an epilepsy syndrome with onset at variable age selected from sleep-related hypermotor / hyperkinetic epilepsy (SHE), progressive myoclonus epilepsies (PME), febrile-infection related epilepsy syndrome (FIRES) and Rasmussen syndrome.

[0165] In some embodiments, the condition associated with seizure is an idiopathic generalised epilepsy syndrome (IGE), such as an IGE selected from childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalised tonic-clonic seizures alone (GTCA).Absence Seizures

[0166] Absence seizures are one of the most common seizure types in patients with idiopathic generalised epilepsy (IGE) (Berg et al., Epilepsia 2000). Absence seizures persisting into adult life are particularly difficult to treat, with patients often being treated with multiple drugs resulting in significant side-effects without attaining seizure control.

[0167] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof are useful in methods of treating absence seizures.

[0168] In some embodiments, the present invention is directed towards a method for treating absence seizures, wherein the method comprises administering to a patient, wherein said patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0169] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) absence seizures.

[0170] In some embodiments, the present invention is directed towards compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof for use in methods for treating absence seizures.

[0171] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof for treating absence seizures. In some embodiments, the present invention is directed towardsthe use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof in a method of manufacturing a medicament for treating absence seizures.

[0172] In some embodiments, the absence seizures are refractory absence seizures. In some embodiments, the absence seizures are refractory to one or more anti-epileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0173] In some embodiments, the patient has epilepsy. In some embodiments, the patient has an idiopathic generalized epilepsy (IGE) syndrome. In some embodiments, the patient has childhood absence epilepsy (CAE). In some embodiments, the patient has CAE and is aged between 2 and 12 years, such as 4 and 10 years, for example, 5-7 years. In some embodiments, the patient has juvenile absence epilepsy (JAE). In some embodiments, the patient has JAE and is aged between 10 and 17 years.

[0174] In some embodiments, the absence seizures are atypical absence seizures. In some embodiments, the absence seizures may be adult absence seizures, juvenile absence seizures, or childhood absence seizures. In some embodiments, the absence seizures are adult absence seizures. In some embodiments, the absence seizures are juvenile absence seizures. In some embodiments, the absence seizures are childhood absence seizures.

[0175] In some embodiments, the methods described herein further comprise identifying a patient that has absence seizures, followed by the administration of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, to the patient that has been identified as having absence seizures.Psychiatric Disorders

[0176] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful in methods of treating psychiatric disorders.

[0177] In some embodiments, the present invention is directed towards a method for treating psychiatric disorders, wherein the method comprises administering to a patient, wherein said patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0178] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) psychiatric disorders.

[0179] In some embodiments, the present invention is directed towards compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, for use in methods for treating psychiatric disorders.

[0180] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof for treating psychiatric disorders. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof in a method of manufacturing a medicament for treating psychiatric disorders.

[0181] Psychiatric disorders may, for example, include mood disorders such as depression, major depressive disorder, and dysthymic disorder (e.g., mild depression); bipolar disorder (e.g., I and / or II); anxiety disorders (e.g., generalized anxiety disorder (GAD) and social anxiety disorder); stress; post-traumatic stress disorder (PTSD); schizophrenia; compulsive disorders (e.g., obsessive compulsive disorder (OCD)); autism spectrum disorder; and attention-deficit / hyperactivity disorder (ADHD).

[0182] Psychiatric disorders may be a mood disorder, for example clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, schizophrenia, suicidality, suicidal ideation, or suicidal behavior. Psychiatric disorders may also be agitation or psychosis. For example, the agitation or psychosis may be in a patient with a neurodegenerative disease such as Alzheimer’s. In some embodiments, the method described herein provides therapeutic effect to a patient suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease, disorder or condition described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e.g., Parkinson’s Disease), women’s health disorders or conditions).

[0183] A psychiatric disorder may be schizophrenia, addiction, autism spectrum disorder, or ADHD. In some embodiments, the addiction is opioid addiction, nicotine addiction, alcohol use disorder, or general substance use disorder.

[0184] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful in methods of treating schizophrenia, addiction, autism spectrum disorder, or ADHD.

[0185] In some embodiments, the present invention is directed towards a method for treating schizophrenia, addiction, autism spectrum disorder, or ADHD wherein the method comprises administering to a patient, wherein said patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0186] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) schizophrenia, addiction, autism spectrum disorder, or ADHD.

[0187] In some embodiments, the present invention is directed towards compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, for use in methods for treating schizophrenia, addiction, autism spectrum disorder, or ADHD.

[0188] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating schizophrenia, addiction, autism spectrum disorder, or ADHD. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating schizophrenia, addiction, autism spectrum disorder, or ADHD.Epilepsy

[0189] Epilepsy is a central nervous system disorder in which nerve cell activity in the brain becomes disrupted, causing recurrent seizures that can manifest as abnormal movements, periods of unusual behaviour, sensations, and sometimes loss of consciousness. Seizure symptoms will vary widely, from a simple blank stare for a few seconds to repeated twitching of the arms or legs during a seizure.

[0190] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful in methods of treating epilepsy and / or epilepsy syndromes.

[0191] In some embodiments, the present invention is directed towards a method for treating epilepsy and / or epilepsy syndromes, wherein the method comprises administering to a patient, wherein said patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0192] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) epilepsy and / or epilepsy syndromes.

[0193] In some embodiments, the present invention is directed towards compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, for use in methods for treating epilepsy and / or epilepsy syndromes.

[0194] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating epilepsy and / or epilepsy syndromes. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating epilepsy and / or epilepsy syndromes.

[0195] Epilepsy may involve a generalized seizure, involving multiple areas of the brain, or a focal seizure. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may cry out or make some sound, stiffen for several seconds to a minute and then have rhythmic movements of the arms and legs. The eyes may be open, and / or the person may appear not to be breathing and turn blue. The return to consciousness may be gradual, and the person may be confused from minutes to hours. The following are the main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, and absence (typical, atypical, myoclonic, eyelid myoclonia) seizures, and epileptic spasms. In a focal seizure, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain having abnormal electrical activity, symptoms may vary.

[0196] Epilepsy, as described herein, includes a generalized, focal, complex focal (e.g., seizures involving only part of the brain, but where consciousness is compromised), tonic- clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0197] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, may be particularly useful in the treatment of epilepsy, wherein the patient with epilepsy experiences absence seizures.

[0198] In some embodiments, the present invention is directed towards a method for treating epilepsy in a patient that experiences absence seizures, wherein the method comprises administering to the patient, wherein the patient is in need of such treatment, atherapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0199] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) epilepsy in a patient, wherein the patient with epilepsy experiences absence seizures.

[0200] In some embodiments, the present invention is directed towards a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method for treating epilepsy in a patient, wherein the patient with epilepsy experiences absence seizures.

[0201] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating epilepsy in a patient, wherein the patient with epilepsy experiences absence seizures. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating epilepsy in a patient, wherein the patient with epilepsy experiences absence seizures.

[0202] The compounds, or pharmaceutically acceptable salts thereof, and / or compositions described herein may also be useful in the treatment of epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance West syndrome.

[0203] In some embodiments, the epilepsy syndrome comprises epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West’s syndrome, Juvenile Myoclonic Epilepsy, Landau- Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glutl deficiency. In some embodiments, the epilepsy syndrome is childhood absence epilepsy (CAE). In some embodiments, the epilepsy syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy syndrome is Lennox- Gastaut syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy.

[0204] In some embodiments the epileptic syndrome is a developmental epileptic encephalopathy in a patient harboring a variant in a Cav3 gene. In some embodiments, the epilepsy syndrome is associated with mutations in CACNA1G, CACNA1 H and / or CACNA1I.

[0205] In some embodiments, the epilepsy syndrome is Doose syndrome or myoclonic astatic epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spike and wave during sleep (CSWS). In some embodiments, the epilepsy syndrome is Landau Kleffner Syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0206] In some embodiments, the epilepsy is selected from the group consisting of epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS). In some embodiments, the epilepsy is selected from the group consisting of epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).

[0207] In some embodiments, the epilepsy is epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); and / or Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), and juvenile absence epilepsy (JAE).

[0208] In some embodiments, the epilepsy is epilepsy with absence seizures, such as idiopathic generalized epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE). In some embodiments, the epilepsy with absence seizures is childhood absence epilepsy (CAE). In some embodiments, the epilepsy with absence seizures with absence seizures is juvenile absence epilepsy (JAE).

[0209] In some embodiments, the epilepsy is idiopathic generalized epilepsy, such as idiopathic generalized epilepsy with absence seizures. In some embodiments, the idiopathic generalized epilepsy with absence seizures is childhood absence epilepsy (CAE). In some embodiments, the idiopathic generalized epilepsy with absence seizures is juvenile absence epilepsy (JAE).

[0210] In some embodiments, the epilepsy is childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE). In some embodiments, the epilepsy is childhood absence epilepsy (CAE). In some embodiments, the epilepsy is juvenile absence epilepsy (JAE).Genetic Epilepsies

[0211] In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is genetic generalized epilepsy. In some embodiments, epilepsy or an epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric focal epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating focal seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy, and developmental epileptic encephalopathy in a patient harboring a variant in a Cav3 gene (such as a mutation in CACNA1G, CACNA1 H and / or CACNA1I).

[0212] In some embodiments, the present invention is directed towards a method of treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric focal epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating focal seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy) comprising administering to a patient, wherein said patient is in need of such treatment, a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the present invention is directed towards a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method for treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalizedEpilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric focal epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating focal seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy).

[0214] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric focal epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating focal seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy).

[0215] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric focal epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating focal seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy).Movement disorder

[0216] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof are useful in methods of treating movement disorders.

[0217] In some embodiments, the present invention is directed towards a method for treating movement disorders wherein the method comprises administering to a patient,wherein said patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0218] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) movement disorders.

[0219] In some embodiments, the present invention is directed towards a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method for treating movement disorders.

[0220] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating movement disorders. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating movement disorders.

[0221] In some embodiments, treatment is effective to prevent a movement disorder. For example, treatment may include preventing a movement disorder in an individual who may be predisposed to the movement disorder but does not yet experience or display the pathology or symptomatology of the movement disorder. In some embodiments, treatment is effective to inhibit a movement disorder. For example, treatment may include inhibiting a movement disorder in an individual who is experiencing or displaying the pathology or symptomatology of the movement disorder ( / .e., arresting further development of the pathology and / or symptomatology). In some embodiment, treatment is effective to ameliorate a movement disorder. For example, treatment may include ameliorating a movement disorder in an individual who is experiencing or displaying the pathology or symptomatology of the movement disorder ( / .e., reversing the pathology and / or symptomatology) such as decreasing the severity of movement disorder or reducing or alleviating one or more symptoms of the movement disorder.

[0222] In some embodiments, treatment is effective to reduce or eliminate one or more symptoms of the movement disorder in the individual. Examples of symptoms of movement disorders include, without limitation, tremors (e.g., rhythmic tremors), unsteady gait (e.g., ataxia), dystonic movements, freezing (bradykinesia), tics, spasms, other dyskinetic movements, chorea, seizures, pain, sensory problems, psychiatric symptoms, cognitive impairment, hearing impairment, and mood changes. In some embodiments, treatment is effective to reduce or eliminate tremors in the individual. The tremor may include but notlimited to essential tremor, Parkinsonian tremor, dystonic tremor, cerebellar tremor, psychogenic tremor, orthostatic tremor, and physiologic tremor. The tremor may be any appropriate type of tremor (e.g., a familial tremor, an action tremor, a postural tremor, a kinetic tremor, and / or a resting tremor). The tremor may affect any appropriate part of a mammal (e.g., hands, head, voice, arms, fingers, legs, chin, and other parts of an individual’s body). In some embodiments, treatment is effective to reduce or eliminate tremors in the individual’s upper limb.

[0223] In some embodiments, treatment is effective to reduce the severity of the movement disorder (e.g., essential tremor) and / or a symptom of a movement disorder in the individual by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. Any appropriate method may be used to evaluate the severity of a movement disorder and / or a symptom of a movement disorder. In some embodiments, the severity of a movement disorder and / or a symptom of a movement disorder can include evaluating one or more global functional measures. In some embodiments, the severity of a movement disorder and / or a symptom of a movement disorder can include evaluating one or more specific functional measures. Examples of methods that can be used to evaluate the severity of a movement disorder and / or a symptom of a movement disorder include, without limitation, measurements of activities of daily living (e.g., as measured using TETRAS), clinician global impression of improvement (e.g., as measured using CGI-I), patient global impression of change (e.g., as measured using PGIC), tremor specific goal attainment (e.g., as measured using GAS), quality of life (e.g., as measured using QUEST tremor medication satisfaction sub-item), and archimedes spiral (e.g., as measured using pen and paper as in the TETRAS-PS sub-item and / or measured digitally using a tablet and stylus such as in iMotor).

[0224] Methods to evaluate the severity of a movement disorder and / or a symptom of a movement disorder are described in, for example, Elble et al, 2013 Movement Disorders, 28 1793; Fahn et al. “Clinical rating Scale for Tremor,” p. 225-34 In: Jankovik J and Tolosa E. Parkinson’s Disease and Movement Disorders. 1988 Baltimore-Milnich: Urban & Schwarzenberg; and Haubenberger et al, 2016 Movement Disorders, 31, No. 9; Fahn et al. Recent Developments in Parkinson’s Disease, Vol 2. Florham Park, NJ. Macmillan Health Care Information 1987, pp 153-163 and 293-304; Treatment guidelines for essential tremor by the American academy of neurology such as those available at the website aan.com / Guidelines / home / GuidelineDetail / 492; and Treatment guidelines for Parkinson’s disease by the American academy of neurology such as those available at the website movementdisorders.org / MDS-Files1 / Resources / PDFs / TreatmentsforMotorSymptomsofPD- 2018.pdf.

[0225] In some embodiments, the movement disorder may be essential tremor, Parkinson’s tremor, dystonia(s), spinocerebellar ataxia, or amyotrophic lateral sclerosis.

[0226] In some embodiments, the movement disorder is essential tremor or Parkinson’s tremor. In some embodiments, the movement disorder is essential tremor. In some embodiments, the movement disorder is Parkinson’s tremor.

[0227] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful in methods of treating essential tremor or Parkinson’s tremor.

[0228] In some embodiments, the present invention is directed towards a method for treating essential tremor or Parkinson’s tremor, wherein the method comprises administering to a patient, wherein the patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0229] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) essential tremor or Parkinson’s tremor.

[0230] In some embodiments, the present invention is directed towards a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method for treating essential tremor or Parkinson’s tremor.

[0231] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating essential tremor or Parkinson’s tremor. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating essential tremor or Parkinson’s tremor.Pain

[0232] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful in methods of treating pain.

[0233] In some embodiments, the present invention is directed towards a method for treating pain, wherein the method comprises administering to a patient, wherein the patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0234] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) pain.

[0235] In some embodiments, the present invention is directed towards a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method for treating pain.

[0236] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating pain. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating pain.

[0237] In some embodiments, the pain comprises acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine. In some embodiments, the pain comprises acute pain or chronic pain. In some embodiments, the pain comprises neuropathic pain, inflammatory pain, or nociceptive pain. In some embodiments, the pain comprises central pain (e.g., thalamic pain). In some embodiments, the pain comprises migraine.

[0238] In some embodiments, the pain is neuropathic pain, such as chemotherapy- induced peripheral neuropathy or diabetic peripheral neuropathy; or inflammatory pain such IBS inflammatory pain or rheumatoid arthritis joint pain.

[0239] In some embodiments, the methods described herein further comprise identifying a patient having pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine) prior to administration of a compound or a pharmaceutically acceptable salt as disclosed herein.

[0240] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful in methods of treating neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy; or inflammatory pain, such as IBS inflammatory pain.

[0241] In some embodiments, the present invention is directed towards a method for treating neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy; or inflammatory pain (such as IBS inflammatory pain), wherein the method comprises administering to a patient, wherein the patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0242] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating (and in the manufacture of medicaments for treating) neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy; or inflammatory pain, such as IBS inflammatory pain.

[0243] In some embodiments, the present invention is directed towards a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method for treating neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy; or inflammatory pain such as IBS inflammatory pain.

[0244] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy, or inflammatory pain such as IBS inflammatory pain. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy; or inflammatory pain such as IBS inflammatory pain.Sleep Disorder

[0245] The compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful in methods of treating or preventing a sleep disorder.

[0246] In some embodiments, the present invention is directed towards a method for treating or preventing a sleep disorder, wherein the method comprises administering to a patient, wherein the patient is in need of such treatment, a therapeutically effective amount of a compound of Formula I A or Formula IB, or a pharmaceutically acceptable salt thereof.

[0247] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating or preventing (and in the manufacture of medicaments for treating or preventing) a sleep disorder.

[0248] In some embodiments, the present invention is directed towards a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing a sleep disorder.

[0249] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating or preventing a sleep disorder. In some embodiments, the present invention isdirected towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating or preventing a sleep disorder.

[0250] In some embodiments, the sleep disorder is selected from the group consisting of a central disorder of hypersomnolence, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, hypersomnia associated with a psychiatric disorder, insufficient sleep syndrome, circadian rhythm sleep-wake disorders, delayed sleep-wake phase disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm, non-24- hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, and circadian rhythm sleep-wake disorder not otherwise specified (NOS).Cancer

[0251] Cav3 channels T-type channels are known to be involved in cell growth and differentiation and to be over-expressed in various stages of tumours. Expression of Cav3 channel genes, such as CACNA1G, CACNA1 H, and CACNA1 I, is altered in several classes of cancer (Wang et al., 2015).

[0252] In some embodiments, the present invention is directed towards a method for treating or preventing cancer, wherein the method comprises administering to a patient, wherein the patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0253] Similarly, the compounds of Formula IA or Formula IB, or pharmaceutically acceptable salts thereof, are useful for treating or preventing (and in the manufacture of medicaments for treating or preventing) cancer.

[0254] In some embodiments, the present invention is directed towards a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing cancer.

[0255] In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer. In some embodiments, the present invention is directed towards the use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in a method of manufacturing a medicament for treating or preventing cancer.

[0256] In some embodiments, the cancer is selected from breast cancer, colorectal cancer, oesophageal cancer, gastric cancer, lung cancer, prostate cancer, renal cancer, sarcoma, and uterine cancer.

[0257] In some embodiments, the cancer is breast cancer, such as invasive lobular breast carcinoma, invasive breast carcinoma stroma, or ductal breast carcinoma in situ epithelia. In some embodiments, the cancer is colorectal cancer, such as rectosigmoid adenocarcinoma. In some embodiments, the cancer is oesophageal cancer, such as oesophageal adenocarcinoma. In some embodiments, the cancer is gastric cancer, such as gastrointestinal stromal tumour. In some embodiments, the cancer is lung cancer, such as non-small cell lung cancer, such as lung adenocarcinoma. In some embodiments, the cancer is prostate cancer, such as carcinoma of the prostate. In some embodiments, the cancer is renal cancer, such as clear cell sarcoma of the kidney or renal Wilms tumour. In some embodiments, the cancer is sarcoma, such as synovial sarcoma, dedifferentiated liposarcoma, or myxoid / round cell liposarcoma. In some embodiments, the cancer is uterine cancer, such as uterine corpus leiomyoma.Formulation, Dosage Forms and Administration

[0258] When employed as pharmaceuticals, the compounds and salts thereof provided herein can be administered in the form of pharmaceutical compositions. Pharmaceutical compositions according to the invention can be used in all embodiments wherein compounds and salts according to the invention are used. For example, pharmaceutical compositions comprising a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, can be used in the methods of treating a disease, disorder or condition disclosed herein. In addition, methods of treating a disease, disorder or condition disclosed herein may comprise the administration a pharmaceutical composition comprising a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof. Uses of pharmaceutical compositions comprising a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease, disorder or condition are also provided herein. Uses of pharmaceutical compositions comprising a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, for treating a disease, disorder or condition disclosed herein are also provided.

[0259] These compositions can be prepared as using standard methods such as described in, for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins, and Handbook of Pharmaceutical Excipients, 9thedition, 2020, pub. Pharmaceutical Press, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, (e.g., intrathecal or intraventricular, administration). Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. In some embodiments, the compounds, salts, and pharmaceutical compositions provided herein are suitable for parenteral administration. In some embodiments, the compounds, salts, and pharmaceutical compositions provided herein are suitable for intravenous administration.

[0260] Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0261] Also provided are pharmaceutical compositions which contain, as the active ingredient, a compound provided herein, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (e.g., excipients). In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0262] Some examples of suitable excipients include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include, without limitation, lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; flavoring agents, or combinations thereof.

[0263] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like. A subject or patient may be an adult or a child, and the formulation may be adjusted accordingly.Embodiments of the invention

[0264] Embodiments of the invention, which can be combined with each other as shown, are described below. Wherein a method of treating a condition or disease, or a particular condition / disease or type of condition / disease, is disclosed, so too is a compound according to Formula I A or IB, or a pharmaceutically acceptable salt thereof, for use in such a method, as well as a pharmaceutically composition, comprising a compound according to Formula IA or IB, or a pharmaceutically acceptable salt thereof, for use in such a method.

[0265] It should be understood that references herein to compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in methods of treatment should also be interpreted as references to:• the use of compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the manufacture of medicaments;• the use of compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in methods of treatment; and / or• methods of treatment using compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0266] These embodiments are exemplified embodiments only and are not intended to be limiting on the subject-matter of the invention.1. A compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof:Formula IA Formula IB2. The compound, or the pharmaceutically acceptable salt thereof, according to embodiment 1, wherein the compound is of Formula IA, or is a pharmaceutically acceptable salt thereof.3. The compound, or the pharmaceutically acceptable salt thereof, according to embodiment 1, wherein the compound is of Formula IB, or is a pharmaceutically acceptable salt thereof.4. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1 to 3.5. The pharmaceutical composition according to embodiment 4, wherein the composition comprises at least one pharmaceutically acceptable carrier.6. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or a pharmaceutical composition according to embodiment 4 or embodiment 5 for use as a medicament.7. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or the pharmaceutical composition according to embodiment 4 or embodiment 5 for use in a method of treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels.8. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 7, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of a psychiatric disorder, a movement disorder, a sleep disorder, pain, seizures, and epilepsy.9. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 7, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of a psychiatric disorder, a movement disorder, a sleep disorder, pain, seizures, epilepsy, and cancer.10. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 7, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of essential tremor; Parkinson’s tremor; dystonia(s); spinocerebellar ataxia; epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenileabsence epilepsy (JAE), or juvenile myoclonic epilepsy (JME); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE); photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); febrile seizures (FS); autism spectrum disorder; ADHD; primary aldosteronism; amyotrophic lateral sclerosis; chronic pain syndrome; schizophrenia; addiction; neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy; and inflammatory pain, such as IBS inflammatory pain.11. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 7, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of essential tremor; Parkinson’s tremor; dystonia(s); spinocerebellar ataxia; epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE); photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); febrile seizures (FS); autism spectrum disorder; ADHD; primary aldosteronism; amyotrophic lateral sclerosis; chronic pain syndrome; schizophrenia; addiction; neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy; and inflammatory pain, such as IBS inflammatory pain.12. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 10 or embodiment 11, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is seizures.13. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 12, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is absence seizures.14. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 10 or embodiment 11, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME);myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).15. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 10 or embodiment 11, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from the group consisting of epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).16. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 14 or embodiment 15, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is epilepsy with absence seizures and / or idiopathic generalized epilepsy.17. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 16, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is epilepsy with absence seizures.18. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 16, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is idiopathic generalized epilepsy.19. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 16 to 18, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is idiopathic generalized epilepsy with absence seizures.20. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 16 to 19, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is childhood absence epilepsy (CAE).21. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 16 to 19, wherein the disease,disorder or condition associated with abnormal function or activity of Cav3 channels is juvenile absence epilepsy (JAE).22. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or the pharmaceutical composition according to embodiment 4 or embodiment 5 for use in a method of treating seizures in a patient in need thereof.23. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 22, wherein the seizures comprise absence seizures.24. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 22 or embodiment 23, wherein the patient has epilepsy, for example, epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).25. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 22 or embodiment 23, wherein the patient has epilepsy, for example, epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).26. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 24 or embodiment 25, wherein the patient has epilepsy with absence seizures and / or idiopathic generalized epilepsy.27. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 26, wherein the patient has epilepsy with absence seizures.28. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 26, wherein the patient has idiopathic generalized epilepsy.29. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 26 to 28, wherein the patient has idiopathic generalized epilepsy with absence seizures.30. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 26 to 29, wherein the patient has childhood absence epilepsy (CAE).31. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 26 to 29, wherein the patient has juvenile absence epilepsy (JAE).32. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3, or the pharmaceutical composition according to embodiment 4 or embodiment 5, for use in a method of treating absence seizures in a patient in need thereof.33. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 32, wherein the patient has epilepsy; epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).34. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 32, wherein the patient has epilepsy; epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).35. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 33 or embodiment 34, wherein the patient has epilepsy with absence seizures and / or idiopathic generalized epilepsy.36. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 35, wherein the patient has epilepsy with absence seizures.37. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 35, wherein the patient has idiopathic generalized epilepsy.38. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 35 to 37, wherein the patient has idiopathic generalized epilepsy with absence seizures.39. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 35 to 38, wherein the patient has childhood absence epilepsy (CAE).40. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 35 to 38, wherein the patient has juvenile absence epilepsy (JAE).41. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or the pharmaceutical composition according to embodiment 4 or embodiment 5 for use in a method of treating epilepsy.42. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to according to embodiment 41 wherein the epilepsy is selected from the group consisting of epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).43. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to according to embodiment 41 wherein the epilepsy is selected from the group consisting of epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).44. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 42 or embodiment 43, wherein the patient has epilepsy with absence seizures and / or idiopathic generalized epilepsy.45. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 44, wherein the patient has epilepsy with absence seizures.46. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 44, wherein the patient has idiopathic generalized epilepsy.47. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 44 to 46, wherein the patient has idiopathic generalized epilepsy with absence seizures.48. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 44 to 47, wherein the patient has childhood absence epilepsy (CAE).49. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to any one of embodiments 44 to 47, wherein the patient has juvenile absence epilepsy (JAE).50. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or the pharmaceutical composition according to embodiment 4 or embodiment 5 for use in a method of treating a movement disorder.51. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to according to embodiment 50 wherein the movement disorder is selected from the group consisting of essential tremor, Parkinson’s tremor, dystonia(s), spinocerebellar ataxia, and amyotrophic lateral sclerosis.52. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to according to embodiment 50 wherein the movement disorder is essential tremor or Parkinson’s tremor.53. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or the pharmaceutical composition according to embodiment 4 or embodiment 5 for use in a method of treating a psychiatric disorder.54. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 53 wherein the psychiatric disorder is schizophrenia, addiction, autism spectrum disorder or ADHD.55. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or the pharmaceutical composition according to embodiment 4 or embodiment 5 for use in a method of treating or preventing pain.56. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 55 wherein the pain is selected from the group consisting of chronic pain syndrome, neuropathic pain, such as chemotherapy- induced peripheral neuropathy or diabetic peripheral neuropathy, and inflammatory pain such as IBS inflammatory pain.57. A process of preparing a compound, or a pharmaceutically acceptable salt thereof, according to Formula IA or Formula IB:Formula IA Formula IB58. The process according to embodiment 57, wherein the process comprises reacting 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid or 2-(3-(pentafluoro- A6-sulfanyl)phenyl)acetic acid with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine.59. The process according to embodiment 57, wherein the compound, or the pharmaceutically acceptable salt thereof, is of Formula IA.60. The process according to embodiment 59, wherein the process comprises reacting 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine.61 . The process according to embodiment 59 or 60, wherein the process comprises cooling a solution of 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid and (R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethan-1 -amine.62. The process according to embodiment 61 , wherein the process comprises adding a base to the cooled solution.63. The process according to embodiment 62, wherein the base is triethylamine.64. The process according to embodiment 62 or embodiment 63 wherein the process comprises the slow addition of a peptide coupling agent.65. The process according to embodiment 64, wherein the peptide coupling agent is T3P.66. The process according to embodiment 57, wherein the compound, or the pharmaceutically acceptable salt thereof, is of Formula IB.67. The process according to embodiment 66, wherein the process comprises reacting 2-(3-(pentafluoro-A6-sulfanyl)phenyl)acetic acid with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethan-1-amine.68. The process according to embodiment 66 or 67, wherein the process comprises cooling a solution of 2-(3-(pentafluoro-A6-sulfanyl)phenyl)acetic acid and (R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethan-1 -amine.69. The process according to embodiment 68, wherein the process comprises adding a base to the cooled solution.70. The process according to embodiment 69, wherein the base is triethylamine.71 . The process according to embodiment 69 or embodiment 70 wherein the process comprises the slow addition of a peptide coupling agent.72. The process according to embodiment 71 , wherein the peptide coupling agent is T3P.73. A compound, or pharmaceutically acceptable salt thereof, obtained by or obtainable by the process of any one of embodiments 57 to 72.74. A compound, or pharmaceutically acceptable salt thereof, obtained by or obtainable by a process which comprises reacting 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid or 2-(3-(pentafluoro- A6-sulfanyl)phenyl)acetic acid with (R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethan-1-amine.75. A compound, or pharmaceutically acceptable salt thereof, obtained by or obtainable by a process which comprises reacting 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine.76. A compound, or pharmaceutically acceptable salt thereof, obtained by or obtainable by a process which comprises reacting 2-(3-(pentafluoro- A6- sulfanyl)phenyl)acetic acid with (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine.77. A compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3 or the pharmaceutical composition according to embodiment 4 or embodiment 5 for use in a method of treating or preventing a sleep disorder.78. The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment 77, wherein the sleep disorder is selected from the group consisting of a central disorder of hypersomnolence; narcolepsy type I; narcolepsy type II; idiopathic hypersomnia; Kleine-Levin syndrome; hypersomnia due to a medical disorder; hypersomnia due to a medication or substance; hypersomnia associated with a psychiatric disorder; insufficient sleep syndrome; circadian rhythm sleep-wake disorders; delayed sleep-wake phase disorder; advanced sleep-wake phase disorder; irregular sleep-wake rhythm; non-24-hour sleep-wake rhythm disorder; shift work disorder; jet lag disorder; and circadian rhythm sleep-wake disorder not otherwise specified (NOS).79. A compound, or a pharmaceutically acceptable salt, of any one of embodiments 1 to 3 for use in a method of treating or preventing seizures.

[0267] The invention is also defined with reference to the following clauses. These clauses are exemplified clauses only and are not intended to be limiting on the subject-matter of the invention.Clause A: A compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof:Formula IA Formula IB.Clause B: A compound, or a pharmaceutically acceptable salt thereof, as defined in Clause A, for use in a method of treating absence seizures.

[0268] The invention is also defined with reference to the following instances. These instances are exemplified instances only and are not intended to be limiting on the subjectmatter of the invention.

[0269] In a first instance of the invention, there is provided a compound of Formula I A or Formula IB, or a pharmaceutically acceptable salt thereof.

[0270] In a second instance of the invention, there is provided a pharmaceutical composition which comprises a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0271] In a third instance of the invention, there is provided a method of treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels, wherein the method comprises administering to a patient, wherein said patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second instance.

[0272] In a fourth instance of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second instance of the invention, for use in a method of treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels. In some embodiments, the method comprises administering to a patient, wherein the patient is in need of such treatment, a therapeutically effective amount of the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0273] In a fifth instance of the invention, there is provided a use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second instance of the invention, in the treatment or prevention of a disease, disorder or condition associated with abnormal function or activity of Cav3 channels.

[0274] In a sixth instance of the invention, there is provided a use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second instance of the invention, in the manufacture of a medicament for treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels.

[0275] In a seventh instance of the invention, there is provided a method of treating absence seizures, wherein the method comprises administering to a patient, wherein the patient is in need of such treatment, a therapeutically effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second instance.

[0276] In an eighth instance of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second instance of the invention, for use in a method oftreating absence seizures. In some embodiments, the method comprises administering to a patient, wherein the patient is in need of such treatment, a therapeutically effective amount of a compound of Formula I A or Formula IB, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0277] In a ninth instance of the invention, there is provided a use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second instance of the invention, in the treatment of absence seizures.

[0278] In a tenth instance of the invention, there is provided a use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second instance of the invention, in the manufacture of a medicament for treating absence seizures.

[0279] In an eleventh instance of the invention, there is provided a process of preparing a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[0280] In a twelfth instance of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, which is obtained by or obtainable by the process of the eleventh instance of the invention.

[0281] In a thirteenth instance of the invention, there is provided a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second instance of the invention, for use as a medicament.Worked Examples

[0282] Certain aspects and embodiments of the invention will now be illustrated by way of the following non-limiting examples and with reference to the figures described above.Formula IASynthesis of (R)-2-(4-(pentafluoro-A6-sulfanyl)phenyl)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)acetamide

[0283] A solution of 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid (1.53 g, 5.85 mmol, 1.05 equiv.) and (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1 -amine (1.22 g, 5.57 mmol, 1.00 equiv.) was prepared in ethyl acetate (20 mL). The starting materials were obtained commercially. The solution was cooled to 0 °C and triethylamine (2.33 mL, 16.71 mmol, 3 equiv.) was added followed by slow addition of T3P (50% weight sol. in EtOAc) (4.97 mL, 8.35 mmol, 1.50 equiv.). The reaction mixture was stirred for 1 hour at room temperature before being quenched with saturated sodium bicarbonate solution (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL). Combined organics were washed with water (2 x 5 mL) and brine (5 mL) before being dried (hydrophobic phase separator). Crude material was purified by silica gel flash chromatography (SiCL) using 0% to 60% ethyl acetate in heptane to yield the title compound 2.0 g (4.3 mmol, 77% yield).

[0284] 1H NMR and19F NMR spectra were recorded on a Bruker Avance Neo 500 (operating at 500 MHz and 471 MHz, respectively) or a Bruker Avance 500 (operating at 500 MHz and 471 MHz, respectively), and are reported relative to residual solvent peak for1H NMR (52.50 in DMSO; 5 7.26 in CDCI3) and against CFCI3for19F NMR (5 0.00 in DMSO).

[0285] 1H NMR (500 MHz, DMSO) 5 8.61 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 2.7 Hz, 1 H), 7.82 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 3H), 7.29 (d, J = 8.5 Hz, 1H), 4.93 (p, J = 7.0 Hz, 1 H), 4.85 (q, J = 8.9 Hz, 2H), 3.60 (s, 2H), 1.36 (d, J = 6.9 Hz, 3H).19F NMR (471 MHz, DMSO) 5 87.95 (p, J = 150.8 Hz, 1 F), 64.33 (d, J = 150.6 Hz, 4F), -72.62 (t, J = 8.8 Hz, 3F). UPLC-MS (method C): 98.7 %, RT = 4.89 min, ESI+ m / z 465 [M+H]+.Example 2Formula IBSynthesis of (R)-2-(3-(pentafluoro- A6-sulfanyl)phenyl)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)acetamide

[0286] A solution of 2-(3-(pentafluoro- A6-sulfanyl)phenyl)acetic acid (146 mg, 0.54 mmol, 1.00 equiv.) and (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1 -amine (120 mg, 0.54 mmol, 1.00 equiv.) was prepared in ethyl acetate (2 mL). The starting materials were obtained commercially. The solution was cooled to 0 °C and triethylamine (95 pL, 0.68 mmol, 1.25 equiv.) was added followed by slow addition of T3P (50% weight sol. in EtOAc) (356 pL, 0.59 mmol, 1.10 equiv.). The reaction mixture was stirred overnight at room temperature before being diluted with ethyl acetate (10 mL). Organics were washed with water (4 x 10 mL) and brine (3 x 10 mL) before being dried over sodium bicarbonate. Crude material was purified by silica gel flash chromatography (SiO2) using 5% to 50% ethyl acetate in heptane to yield the title compound 164 mg (0.35 mmol, 65% yield).

[0287] 1H NMR and19F NMR spectra were recorded on a Bruker Avance Neo 500 (operating at 500 MHz and 471 MHz, respectively) or a Bruker Avance 500 (operating at 500 MHz and 471 MHz, respectively), and are reported relative to residual solvent peak for1H NMR (52.50 in DMSO; 5 7.26 in CDCI3) and against CFCI3for19F NMR (5 0.00 in DMSO).1H NMR (500 MHz, CDCI3) 6 8.22 (d, J = 2.8 Hz, 1 H), 7.67 (dt, J = 6.4, 1.9 Hz, 2H), 7.49 - 7.40 (m, 2H), 7.24 (dd, J = 8.6, 2.9 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1 H), 6.84 (d, J = 7.4 Hz, 1H), 5.11 (p, J = 6.9 Hz, 1H), 4.39 (q, J = 8.0 Hz, 2H), 3.64 (s, 2H), 1.42 (d, J = 6.8 Hz, 3H).19F NMR (471 MHz, CDCI3) 6 85.29 - 83.43 (m, 1 F), 62.77 (d, J = 150.2 Hz, 4F), -73.91 (t, J = 7.9 Hz, 3F). UPLC-MS (method C): 99.9 %, RT = 5.09 min, ESI+ m / z 465 [M+H]+.Comparative Example

[0288] A further compound according to the disclosure of WO 2007 / 120729 was synthesized as a comparative example, according to the procedure detailed below.Formula 2

[0289] To a solution of 2-(4-trifluoromethylphenyl)acetic acid (1.00 g, 4.90 mmol) in MeCN (35 mL) was added (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1-amine (1.62 g, 7.35 mmol), NMI (2.01 g, 24.50 mmol) and TCFH (1.65 g, 5.88 mmol) at 25 °C gradually. The starting materials were obtained commercially. After addition, the mixture was stirred at 25 °C for 1 h and concentrated at reduced pressure. The residue was diluted with ethyl acetate (40 mL), washed with brine (3 x 30 mL), dried and concentrated. The residue was purified by prep-HPLC (FA) to afford to give the compound of Formula 2 (860 mg, 43.3% yield).

[0290] 1H NMR and19F NMR spectra were recorded on a Bruker Avance Neo 500 (operating at 500 MHz and 471 MHz, respectively) or a Bruker Avance 500 (operating at 500 MHz and 471 MHz, respectively), and are reported relative to residual solvent peak for1H NMR (52.50 in DMSO; 5 7.26 in CDCI3) and against CFCI3for19F NMR (5 0.00 in DMSO).1H NMR (400 MHz, DMSO) 5 8.61 (d, J = 7.8 Hz, 1 H), 8.34 (d, J = 2.8 Hz, 1 H), 7.65 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 7.8, 4.0 Hz, 3H), 7.30 (d, J = 8.7 Hz, 1 H), 4.94 (p, J = 7.0 Hz, 1H), 4.85 (q, J = 8.8 Hz, 2H), 3.60 (s, 2H), 1.37 (d, J = 7.0 Hz, 3H).19F NMR (376 MHz, DMSO) - 72.64, -60.83. LCMS (ESI) m / z: calcd. for C18H16F6N2O2 406.11 ; found 407.3 [M+H]+Example 3 - Cav3 channel inhibition

[0291] The patch clamp method is an electrophysiological technique that can directly measure the membrane potential and / or the amount of current passing across the cell membrane, and can be used to study the effects of a compound on membrane channels such as Cav3 channels (Dallas et al., 2021 ; Francois et al., 2013). The compounds of examples 1 and 2 and the comparative example were analysed to assess their ability to inhibit Cav3 channels according to the following protocol.

[0292] The objective of the study was to examine the in vitro effects of the different compounds on the Cav3 channels Cav3.1 (human CACNA1G gene), Cav3.2 (human CACNA1H gene), or Cav3.3 (human CACNA1I gene), stably over-expressed in HEK293 cells, respectively. The experiment was carried out on the automated patch clamp system, SyncroPatch 384PE (Nanion Technologies). Recordings were gathered in Nanion 384-well Patch Clamp chips with 8 recording holes per well.

[0293] The plate configuration for the testing process is described below. Each test article was evaluated at 8 concentrations (0.01, 0.03, 0.1, 0.3, 1 , 3, 10 and 30 pM). One Cav3 subtype was evaluated per experiment (plate). The positive control article used was TTA-A2. Four (4) well repeats were used to average the values for each concentration of test article or positive control article per experiment (plate). Thirty-two (32) well repeats were used to average the values for the vehicle control per experiment (plate).

[0294] Characteristics of the HEK293 cells used in the experiment are set out below.Organism Homo sapiensDesignation HEK293Tissue Kidney; Transformed with adenovirus 5 DNA; Stably transfected with human CACNA1G, CACNA1H or CACNA1I cDNA encoding human CaV3.1 , CaV3.2 and CaV3.3 channels, respectively.Morphology EpithelialAge / Stage EmbryoSource-Strain ATCC, Manassas, VASource-Sub Strain Charles River Labs., Cleveland, OH

[0295] The HEK293 cells were transfected with the appropriate ion channel cDNA(s) and stably transfected cell stocks were maintained in cryogenic storage until use. Stably transfected cells were cultured in Dulbecco’s Modified Eagle Medium / Nutrient Mixture F-12 (D-MEM / F-12) supplemented with 10% fetal bovine serum, 100 U / rnL penicillin G sodium, 100 pg / mL streptomycin sulfate and the appropriate selection antibiotics.

[0296] Before testing, cells in culture dishes were washed twice with Hank’s Balanced Salt Solution (HB-PS) and treated with Accutase for approximately 20 minutes. Immediately before use in the SyncroPatch, the cells were washed in HB-PS to remove the Accutase and re-suspended in HB-PS. All experiments were performed at ambient temperature (maintained by the SyncroPatch instrumentation at approximately 22°C).

[0297] The intracellular and extracellular solutions were prepared according to the following specifications.

[0298] Intracellular solution (mM): CsCI, 50; CsF, 90; MgCI2, 5; EGTA, 2.5; HEPES, 10; pH adjusted to 7.2 with CsOH. In preparation for a recording session, the intracellular solution was loaded into the intracellular compartment of N PC-384 chip.

[0299] Extracellular solution, HB-PS (composition in mM) NaCI, 137; KCI, 4.0; CaCI2, 6.8; MgCI2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH (refrigerated until use).

[0300] Extracellular solution was loaded into the wells of the Nanion 384-well Patch Clamp (NPC-384) chip (20 pL per well). Then, cell suspension was loaded into the wells (20 pL per well) of the NPC-384 chip. After obtaining the whole-cell configuration, membrane currents were recoded using the patch clamp amplifier in the SP384PE system. During an initial stabilization period, the currents were elicited with 200 ms voltage test pulses to -20 mV from the holding potential -110 mV; stimulation frequency was 0.1 Hz. Following three (3) minutes of the stimulation the vehicle control (DMSO) was added to the cells and the stimulation continued for three (3) additional minutes.

[0301] After the stabilization period, baseline currents were elicited with 200 ms test pulses to -20 mV from the holding potential -110 mV. After this pulse, the membrane potential was returned to -110 mV for 20s, followed by a 20 s conditioning potential at a more depolarizing potential (-60, -65 or -70 mV). The membrane potential was again stepped to -20 mV for 200 ms, following which the membrane potential was returned to - 110 mV for 5 minutes. Eight (8) concentrations of test articles were then applied to the cells (n = 4, where n = the number of replicate wells / concentration) via 384-channel pipettor. Each application consisted of the addition of 40 pL of 2X concentrated test article solution to the total 80 pL of final volume of the extracellular wells of NPC-384 chip. Duration of exposure to each test article concentration was at least five (5) minutes. Vehicle control was applied for a five-minute exposure interval (n = 32, where n = the number of replicates).

[0302] To verify the sensitivity of the assay to block, the positive control article (eight (8) concentrations) was applied for a five (5) minute exposure interval (n = 4, where n = the number of replicates per concentration).

[0303] In order to evaluate effects of the test articles on steady-state inactivation of the channels the voltage protocol set out in Figure 1 was used. Currents were elicited with 200 ms test pulses to -20 mV after 10 s conditioning periods at membrane potentials from -120 mV to -20 mV in 5 mV steps (as shown in Figure 1); the holding potential was -110 mV with a 500-ms pre-pulse to -120 mV; inter-pulse interval was 25 s.

[0304] Peak currents generated during the experiment were analysed using Matlab. After well exclusion criteria and rundown correction was applied, full steady-state inactivationcurves were produced for each treatment condition. V0.5, the midpoint of voltage dependent channel inactivation was derived from the normalized current availability curves fitted by a Boltzmann sigmoidal equation. Concentration response curves fitted with a Hill function were generated for each test article for Cav3.1 , Cav3.2, and Cav3.3 and IC50 values (concentration resulting in 50% inhibition of peak current) at each holding potential were derived. State-dependent inhibition is reflected as changes to the IC50 as the proportion of inactivated channels is increased as the holding potential is depolarized (becomes less negative). The IC50 values at V0.5 can then be used to compare across different studies, molecules and Cav3 subtypes.

[0305] Block (inhibition) was calculated as:% BlOCk = (1 - ITPX. TA / I TPx, Baseline) X 100%, where ITPI , Baseline and ITPX. TA are the inward peak Ca2+currents elicited by the TPx before a test article application (baseline current) and in the presence of a test article, respectively.

[0306] The data was corrected for run-down:%Block’ = 100%- ((%Block - %PC)*(100% I (%VC - %PC)), where %VC and %PC are the mean values of the current inhibition with the vehicle and high concentration of positive controls, respectively.

[0307] Concentration-response data was fit to an equation of the following form:% Block = [1 + ([Test] I IC5O)N], where [Test] is the concentration of test article, IC50 is the concentration of the test article producing half-maximal inhibition, N is the Hill coefficient and % Block is the percentage of ion channel current inhibited at each concentration of a test article. Nonlinear least squares fits were solved with the XLf / f add-in for Excel (Microsoft, Redmond, WA).

[0308] The results for the compounds of Formulae IA, IB and 2 across the different channels are presented in Table 1. Two batches of Formula IA were used.Table 1 : Mean Potency (IC50 nM) and State Dependency

[0309] The table above shows the IC50 for each of the three types of Cav3 channels for each tested compound, in partially inactivated state (at V0.5), and when resting (at -120 mV). It also shows the fold difference, which is the ratio between the two (IC50 at -120mV over IC50 at Vos).

[0310] As can be seen from the results above, the compounds according to the invention show good Cav3 inhibition across each of the different Cavchannels and, moreover, they show better Cav3 inhibition than the comparative compound of Formula 2. Moreover, the test compounds are more potent at inhibiting Cavchannels in the inactivated state compared to the resting state. This selectivity for the inactivated state means that the test compounds may preferentially target neurones that are pathologically firing, while sparing those that are undergoing normal signalling. Thus, the compounds of Formula IA and IB may be useful in methods of modulating or inhibiting the function or activity of Cav3 channels, such as in a cell sample, a tissue sample, or a subject. Similarly, the compounds of Formula I A and IB may be useful in the treatment of diseases associated with abnormal function of activity of Cav3 channels.Example 4 - CYP interactions

[0311] The induction potency of the compound of Formula IA towards human CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19 and 3A4 (mRNA level and enzyme activity) was studied in cryopreserved human hepatocytes from 3 donors at 6 concentrations.

[0312] Assays were carried out according to the SOLVO enzyme induction protocol (PR- ASY-CYP-General Protocol for CYP Induction Assays). The main steps of the assay were as follows:• Cryopreserved hepatocytes from three donors were plated and exposed to six concentrations (half-log dilution series, n=3, at soluble concentrations) of the test article for 48 hours.• Cells were incubated with reference inducers at one concentration to determine the maximum level of induction. Negative control compound (flumazenil) was be applied. Control compounds are listed below in Table A.• The medium was changed during the incubation to fresh after 24 hours.

[0313] After 48 hours, the medium was removed from the cells incubated with TA and induction controls, and the cells was rinsed with PBS. The medium containing probe substrate cocktail 1 (Table B) was added to the cells. After 45 minutes incubation, samples were taken from the incubation medium for bioanalysis. The rest of the medium was removed, the cells will be rinsed with PBS, and probe substrate cocktail 2 (Table B) was added to the cells. After 30 minutes incubation, samples were taken from the medium for bioanalysis. Equal volume of methanol was added to the samples, then stored at -20 °C until LC-MS / MS bioanalysis was performed to determine the level of metabolites.Table A - Control Compounds used in CYP induction assayTable B - Cocktail solutions for CYP activity assessment

[0314] Positive control inducers 50 pM omeprazole (CYP1A2), 1000 pM phenobarbital (CYP2B6, CYP2C8), 0.1 pM CITCO (CYP2B6) and 20 pM rifampicin (CYP3A4, CYP2C8, CYP2C9 and CYP2C19), and negative control 25 pM flumazenil, were each used at one concentration.

[0315] Analysis: Microsoft Excel 365 (Microsoft Corporation, Redmond, WA) was used for basic data processing and GraphPad Prism 10 (GraphPad Software Inc., San Diego, CA) was used for curve fitting and determination of reaction parameters.

[0316] Overall qPCR reaction curves were critically analyzed, and any clear outliers were excluded, without compromising true variability between samples.

[0317] Relative gene expression was determined with the delta-delta Ct method by the following calculations:^Ct — Ctiargei~Ctreference geneFold induction in mRN A = (2treated)~ct / (2Vehicle controlf^1

[0318] To compare the CYP induction by the test compounds to positive control inducers in the same donor, % of induction by the positive control was calculated as% of positive control for mRNA = ((Fold inductionsampie~F) / (F old indue tionpc-'\))* '\ 00 where the Fold inductionpcis the fold induction achieved in the same assay and same donor by the positive control inducers.

[0319] Relative enzyme activity (fold induction) is defined as a ratio between the metabolite concentration measured in samples treated with TA or controls and samples treated only with the solvent.Fold induction using enzyme activity = [Metabolite]sampie / [Metabolite]soivent

[0320] To compare the CYP enzyme activity induction by the test compounds to positive control inducers in the same donor, % of induction by the positive control was calculated as% of positive control for enzyme activity = (([Metabol ite]iA ~ [Metabolite]soivent) I ([Metabolite]pc- [Metabolitejsoivent))x100Results

[0321] The results of the CYP induction tests for the compound of Formula IA are shown below, and are compared to data prepared according to the same protocol for the compound of Formula 2.

[0322] From the table above, it is clear that the compound of Formula IA has less CYP induction at 1 pM than the compound of Formula 2, and less induction of both CYP2B6 and CYP3A4 at 10 pM, making it a better choice to reduce drug-drug interactions.2Example 5 - Brain distribution of compounds in rats

[0323] The compound of Formula IA was administered to male Sprague- Dawley rats, in order to assess the brain distribution of this compound in vivo.

[0324] Body weights were recorded prior to dose administration. The volume of each dose delivered (mL / kg) was based on each individual animal’s body weight. Doses (as assigned above) were administered in accordance with test facility standard operating procedures.

[0325] The test material was dissolved in water containing 0.5% HPMC and 10% Tween 80 in a glass vial. The formulation was stirred and / or sonicated to obtain a homogeneous suspension. A 5 mL aliquot was removed to have its pH measured and recorded.

[0326] Terminal blood samples were collected via aortic puncture following isoflurane anesthesia, or by an alternate approved collection site in accordance with test facility standard operating procedures. Blood samples were collected into tubes with an anticoagulant (K2 EDTA). Tubes were stored on wet ice until processed to plasma bycentrifugation (3000 x g at 5 °C for 10 minutes) within 30 minutes of collection. Samples were transferred into individual uniquely labeled matrix tubes and stored at nominal -70 °C until transferred to analytical chemistry for analysis.

[0327] Immediately following terminal blood collection, animals were sacrificed via isoflurane inhalation, and CSF, liver, lung, heart, kidney and brain tissues were collected after exsanguination. For each animal, CSF was collected into a pre-weighed 0.2 mL lo-bind Eppendorf tube. The weight of the CSF and whether the CSF has been contaminated with blood was recorded. The CSF was stored on wet ice and transferred to -70 °C storage within 30 minutes, where CSF samples were stored until transferred for analysis.

[0328] Each tissue was placed in its own disposable container (to avoid sample contamination) and rinsed with saline to remove residual blood and gently blotted dry with sterile gauze. The tissue samples were placed in pre-weighed 15 mL Falcon conical tubes and individual sample weights were calculated and recorded. Tubes were flash frozen in liquid nitrogen placed on dry ice until stored at -70 °C until transferred to analytical chemistry for analysis.

[0329] Terminal blood collection and brain and CSF collection were performed. These samples were collected from 3 rats for each time point. The samples were collected pre dose, 0.25 hours post dose, 0.5 hours post dose, 1 hour post dose, 2 hours post dose, 4 hours post dose, 8 hours post dose, 24 hours post dose, 30 hours post dose, 48 hours post dose and 72 hours post dose. About 500 pL of blood was collected in each sample.

[0330] All samples were processed by protein precipitation method using a suitable internal standard and analyzed by LC-MS / MS employing a calibration curve with suitable range.Results

[0331] The unbound brain to unbound plasma partition ratio Kpuuof the compound of Formula IA was measured, and compared to values from the compound of Formula 2 by the same protocol.

[0332] The compound of Formula IA has a higher brain-penetration than the compound of Formula 2. This suggests that the compound of Formula IA may be a much more effective treatment than the compound of formula 2.Example 6 - Rat Pharmacokinetic Study

[0333] The compound of Formula IA was administered to male Sprague- Dawley rats to assess the pharmacokinetic parameters. The doses are set out in the table below.

[0334] Body weights were recorded prior to dose administration. The volume of each dose delivered (mL / kg) was based on each individual animal’s body weight. Doses (as assigned above) were administered in accordance with test facility standard operating procedures. Post-dose flushes were administered as applicable as outlined above.

[0335] IV administration: The test material was dissolved in DMSO in a glass vial and subsequently further dissolved in 30% HPpCD in water for injection in a glass vial to meet dose level requirements and obtain a clear solution. The formulations were sonicated and stirred to obtain a clear solution. The pH was measured and recorded. The formulation was filtered and the appearance of the formulation was noted.

[0336] PO administration: The test material was dissolved in water containing 0.5% HPMC and 10% Tween 80 in Purified Water (w / w / v) in an appropriate size glass container. The formulation was homogenized and stirred overnight to obtain a homogeneous-looking suspension. The pH was recorded and measured, the appearance of the formulation was noted and the dosing formulations were continuously stirred until and during dosing at ambient temperature.

[0337] Plasma samples were collected as per the schedule given below

[0338] Serial blood samples were collected via jugular vein cannula (JVC) in accordance with test facility standard operating procedures. An alternative approved collection site may have been used if the sample could not be collected from the primary collection site. All blood collection sites were documented.

[0339] Blood samples were collected into tubes with an appropriate anticoagulant as outlined above. Tubes were stored on wet ice until processed to plasma by centrifugation (3000 x g at 5°C for 10 minutes) within 30 minutes of collection. Samples were transferred into individual uniquely labeled matrix tubes and stored at nominal -70°C until transferred to analytical chemistry for analysis.Results

[0340] The parameters measured from the rats are set out below.

[0341] As a comparison, the half-life of the compound of Formula 2 was determined by the same protocol.

[0342] The half-life of the compound of Formula IA is much greater than compound of Formula 2. This suggests that the compound of Formula IA may show longer efficacy compared to compound of Formula 2.Example 7 - Genetic Absence Epilepsy Rat from Strasbourg (GAERS) Model

[0343] The genetic absence epilepsy rat from Strasbourg (GAERS) is a rodent model of absence epilepsy with strong translational validity. GAERS are a strain of Wistar rats that present with spontaneous behavioural and electrophysiological features of human absence seizures. The seizures observed in this model show electroencephalography (EEG) patterns of spike-and-wave discharges (SWDs) that closely mirror human absence seizures. Anti-seizure medications (ASMs) that supress SWD in human patients - such as valproate, ethosuximide and levetiracetam - also suppress SWDs in GAERS, and ASM that have no effect or even aggravate SWD in human - such as carbamazepine, phenytoin and pregabalin - also demonstrate the same effect in GAERS.Materials and Methods

[0344] All experiments were performed in accordance with the European Committee Council directive of September 22, 2010 on the protection of animals used for scientific purposes (2010 / 63 / EU).Sample Preparation

[0345] Polysorbate 80, methylcellulose (MC), and hydroxypropylmethylcellulose (HPMC) were obtained from Sigma Aldrich. Reverse Osmosis Deionized (RODI) Water was obtained from Cooper. Ethosuximide was obtained from Thermo Fisher Scientific. The compound of Formula 1A was prepared according to Example 1.

[0346] Vehicle 1: 10% Polysorbate 80 (w / v) and 0.5% MC (w / v) in RODI water. Vehicle 1 batches were stored at 2-8 °C and used within 14 days of preparation.

[0347] Vehicle 2: 10% Polysorbate 80 (w / v) and 0.5% HMPC (w / v) in RODI water. Vehicle 2 batches were stored at 2-8 °C and used within 14 days of preparation.

[0348] Positive Control: Ethosuximide was dissolved in RODI water at the dose concentration of 20 mg. / mL.

[0349] Test Compounds: The compound of Formula IA (0.06, 0.2, 0.6, 6.0 mg / mL) was dissolved in the indicated vehicle.Test System

[0350] Thirty-four adult male GAERS, split in two groups of 14 (Study 1) and 20 animals (Study 2), were obtained from INSERM, (Grenoble Institute of Neurosciences, Grenoble, France). These animals were aged 3 months at study start, with a weight of 190-245 g.

[0351] Animals were housed in groups in cages until surgery. After surgery, animals were housed in single cages. All cages were ventilated, and contained wood litter with free access to food and water. The animal house was maintained under artificial lighting on a 12 / 12 light-dark cycle (dark phase between 16:00 and 04:00) and at controlled ambient temperature (22 ± 2°C) and relative humidity.

[0352] All GAERS animals were implanted with an intraperitoneal telemetry transmitter (model TL11M2F20EET, Data Sciences International) for SWD recording.

[0353] Two hours prior to surgery, animals received an injection of buprenorphine (0.05 mg / kg, SC). Each animal was anesthetized with inhalational isoflurane (2 % in 0.5 L / min O2). The depth of anesthesia was controlled prior to surgery, and the breathing rate and cardiac rhythm were visually controlled during surgery. The body temperature was monitored and maintained constant during surgery. The abdominal wall was shaved, disinfected (using povidone) and incised to insert the transmitter. A dose of antibiotic (15 mg / kg ceftriaxone, Mylan, USA) was administered IP to prevent infection. The transmission connections were channelled under the skin, up to the skull of the animal.

[0354] Rats were placed in a stereotaxic frame. An ophthalmic gel was placed on the eyes to avoid the drying of the cornea. The scalp was shaved, disinfected with povidone, and incised. Burr holes (1 mm in diameter) were drilled through the skull to place 2 pairs of monopolar electrodes over the frontal (AP: +2 mm; ML: ±3 mm) and parietal cortices (AP: -7 mm; ML: ±3 mm), on both sides of the brain. Electrodes were sealed in place with dental acrylic cement and connected to the transmitter. All incisions (head and abdomen) were sterilized with povidone and closed with stitches.

[0355] After surgery, each animal was placed in its home cage and monitored until conscious. Animals received a second injection of buprenorphine (0.05 mg / kg, SC) 8 hours after the first administration. Animals were administered with the NSAID carpofen (5 mg / kg SC) once daily for 4 days following surgery. Animals were housed in their individual home cage for at least one week of recovery before any other intervention.

[0356] A 24h preliminary EEG was conducted for all animals to confirm acceptable signal- to-noise ratio for the recording and a sufficient number of SWD (>20 per hour during the monitored hour). Animals were left undisturbed for most of the recording. They were monitored for 1 hour, to prevent sleep during that period and ensure quiet wakefulness. Twelve animals (Study 1) and 16 animals (Study 2) were found valid according to these criteria.

[0357] Animals were euthanised at the end of the study and terminal samples collected.EEG Recoding and Sample Collection

[0358] EEG Recording-. GAERS were continuously recorded for 48 hours while able to move freely in their home cage environment. On the day of a recording session, the home cages of the selected animals were placed on the telemetry receivers. The recordings took place in the same room where the animals were normally housed, with the same light / dark cycle, temperature and humidity conditions. The EEG signal was continuously recorded using the DSI Dataquest A.R.T software, at a rate of 500 Hz, without any inline filter. During the whole duration of the recordings, animals were left undisturbed, apart from the period on day 2 when administrations were taking place. Animal health status, and stocks of food and water, were also checked during these administrations.

[0359] Tail Vein Microsamples: Blood was collected from awake (non-anesthetized) animals with a Minivette® via the lateral tail vein. Animals were restrained briefly using a piece of cloth. Once the desired blood volume was collected, a sterile gauze and gentle pressure were applied to the puncture site. The blood sample (target volume: > 0.05 ml) was collected in K2EDTA tubes, mixed gently, and placed on wet ice until centrifuged and separated to plasma as described below. Within 30 min of collection, blood samples were centrifuged at + 4°C at 1500 g for 10 minutes. The resultant plasma was immediately split into two aliquots (the Primary, containing 25 pL and the Backup, containing the remaining plasma) and transferred to two polypropylene tubes and frozen on dry ice. Any clotted and / or hemolyzed samples were noted in the study data.

[0360] Intracardiac Punctures: Animals were deeply anaesthetized with isoflurane. A terminal blood sample was collected via a cardiac puncture in the ventricle. The blood samples were collected in K2EDTA tubes, mixed gently, and placed on wet ice until centrifuged. Within 30 min of collection, blood samples were centrifuged at + 4°C at 1500 g for 10 minutes. The resultant plasma was immediately split into two aliquots (the Primary, containing -200 pL (Study 1) or -500 pL (Study 2); and the Backup, containing remaining plasma) and transferred to two polypropylene tubes and frozen on dry ice. Any clotted and / or hemolyzed samples were noted in the study record.

[0361] Brain Collections: Brains were harvested immediately after the terminal blood collection. The animal was decapitated. The brain, with the cerebellum, was immediately removed, rinsed with cold saline and split into two hemispheres. Each hemisphere was weighed, placed into a cryovial and frozen on dry ice.Data Analysis

[0362] EEG recordings were analyzed by a trained expert blinded to the treatment regime. SWD were detected using their characteristic features (a high amplitude signal exceeding background by a ratio of at least 2:1 , an oscillatory signal with spikes occurring at a frequency around 11 Hz, a synchronicity between the two pairs of electrodes, and a duration of at least 5 seconds). Recordings were verified by the analyst, to validate SWD, place their time boundaries, and eliminate artefacts. EEG data were analyzed for the following readouts:• Number of SWD• Average duration of SWD• Total time spent in SWD (i.e. the cumulative duration of SWD)

[0363] The software Prism v10 (GraphPad) was used for statistical analyses. The significant level is set at p < 0.05. All data are expressed as mean ± SEM.

[0364] For the evaluations per bins of 1 hour or 4 hours, data were compared using a mixed model with repeated measures, with the factors recording time and compound condition. For the number of SWD and the total time of SWD, the Geisser-Greenhouse correction was applied. This correction was not applied for the average duration of SWD, due to the limited number of data (e.g. due to complete inhibition of SWD in some animals).

[0365] A first evaluation was made on the data obtained with the different vehicle administrations to detect any drift in responses. In both studies, the different comparisons showed no or negligible differences between the different vehicle administrations. Accordingly, all vehicle data from a study were pooled: data from an animal in the different vehicle administrations were first averaged, then a grand average was generated by averaging the mean response from each animal. Then data from control (ethosuximide) or from test compound, using the mean vehicle data for reference.

[0366] For the evaluations in a single bin of 3, 12 or 24 hours, data were compared using a mixed model with repeated measures (Study 1) or a student’s t-test (Study 2), with only the factor compound condition. The mean vehicle response was used for reference. In Study 1, when a dose of test compound or control (ethosuximide) was administered multiple times in different phases, a grand average was also generated by first averaging the different response of an animal, then averaging the mean response from all animals.Baseline

[0367] Baseline EEG was recorded for 24 hours prior to dosing (Study 1) or for 48 hours the week prior to the start of Study 2. GAERS were administered a single oral dose of vehicle, test compound, or the positive comparator, ethosuximide. Recordings continued for an additional 24 hours (Study 1) or 48 hours (Study 2) post-dose. The distribution of SWDs measured followed the expected circadian pattern in which the rats have more SWDs during the dark cycle, when the rats spend more time awake, versus the light cycle, when the rats spend more time asleep.Study 1: Evaluation of the dose response of compound of Formula IA in the GAERS telemetry model

[0368] The compound of Formula IA (0.3, 1 and 3 mg / kg in vehicle 1), and ethosuximide were evaluated for their ability to reduce SWDs in the GAERS telemetry model. Animals were administered a single oral dose of vehicle, test compound, or positive control via PO administration in a parallel group and cross-over manner.

[0369] Number of SWD’. Figure 2 shows the number of SWDs per hour over a 48 hr period (24 hr pre-dose and 24 hr post dose). Administration of the compound of Formula IA resulted in a significant reduction in the number of SWD at all dose levels. The significant differences were consistent, lasting from 17:00 to 19:00 and from 23:00 to 01:00 with the 0.3 mg / kg dose, from 16:00 to 03:00 with the 1 mg / kg dose, and from 16:00 to 04:00 with the 3 mg / kg dose. The reduction also extended to the light phase following administration with all 3 doses of test compound. Notably, with the 3 mg / kg dose, a significant reduction was observed at 06:00-07:00, 08:00-09:00, 10:00-11:00 and between 12:00 and 16:00.

[0370] In Figure 3, the number of seizures is quantified over the first 3 hours (A, left) and the first 12 hours (B, right) post dose. Over the 3 hr period, a significant and dosedependent inhibition of SWD by the test compound was observed. Compared to vehicle data, the test compound reduced SWD by 54.7 ± 10.3 % at 0.3 mg / kg, by 82.4 ±4.4% at 1 mg / kg and by 99.3 ±0.7% at 3 mg / kg. Over the 12 hr period, the effect of the test compound was still significant, and the inhibition reached 24.7 ±4.5% at 0.3 mg / kg, 66.3 ±4.6% at 1 mg / kg and 91.7 ±3.5% at 3 mg / kg. The effect of compound of Formula IA on SWDs at 0.3 mg / kg and 3 mg / kg was similar to the effect of ethosuximide at 30 mg and kg and 100 mg / kg, respectively.

[0371] Duration of SWD’. Figure 4 shows the average duration of SWD per hour over a 48 hr period (24 hr pre-dose and 24 hr post dose). Administration of the compound of Formula IA resulted in a significant reduction in the average duration of SWD measured perbins of 1 hour. With the 0.3 mg / kg dose, the average duration was significantly reduced for the first hour after administration (16:00-17:00), and a significant reduction was also observed during the light phase following administration (between 11:00-12:00 and 14:00- 15:00_. After administration of the 1 mg / kg dose, the average duration was significantly reduced almost continuously from 16:00 to 03:00 (except for the 18:00-19:00 period), and a significant reduction was also observed during the light period (between 09:00 and 10:00). Similarly to ethosuximide, the high dose of test compound (3 mg / kg) completely inhibited SWD for a long duration (as such, this dose was excluded from statistical analyses of the average duration of remaining SWD).

[0372] In Figure 5, the average duration of SWD is quantified over the first 3 hours (A, left) and the first 12 hours (B, right) post dose. Over the 3 hr period, the duration of remaining SWD was significantly reduced after administration of the test compound at 1 mg / kg. Compared to vehicle, the average duration was reduced by 21.8 ± 8.9% at 0.3 mg / kg and by 53.2 ± 3.9% at 1 mg / kg. Over the 12 hr period, the test compound still had a significant effect on the duration of remaining SWD at 1 mg / kg. The duration was reduced by 6.4 ± 4.3% at 0.3 mg / kg and 38.1 ± 3.7% at 1 mg / kg.

[0373] Time in SWD’. Figure 6 shows the total time in SWD in seconds per hour over a 48 hr period (24 hr pre-dose and 24 hr post dose). All doses of test compound induced a significant reduction in the total time in SWD. With the 0.3 mg / kg dose, the reduction was significant between 17:00 and 20:00, and again between 23:00 and 01:00. With the 1 mg / kg and 3 mg / kg doses, the significant reduction lasted for the whole dark phase following administration, from 16:00 to 04:00. In addition, both doses still showed significant effects at some timepoints of the following light phase.

[0374] In Figure 7, the total time in SWD is quantified over the first 3 hours (A, left) and the first 12 hours (B, right) post dose. Over the 3 hr period, the test compound produced a dose-dependent reduction of the total time spent in SWD. The total time was reduced by 60.4 ± 10.3% at 0.3 mg / kg, 91.5 ± 2.3% at 1 mg / kg, 99.6 ± 0.3% at 3 mg / kg. The effect was significant at all doses. Over the 12 hr period, the effect of the test compound was still significant at all doses. The total time overnight was reduced by 34.2 ± 2.1% at 0.3 mg / kg, 76.9 ± 3.3% at 1 mg / kg, and 95.6 ± 2.0% at 3 mg / kg.Study 2: Evaluation of the compound of Formula IA for 48 h post-dose in the GAERS telemetry model

[0375] In Study 1 , it was observed that SWDs were still reduced up to 24 hours after a single oral dose of the compound of Formula IA at 3 mg / kg. As such, an additional studywas conducted in which the EEG was recorded for 48 hours after dosing (Study 2). The study used the same GAERS rat model and study design as Study 1. Data was binned in bins of 4 hr to reduce bin-to-bin variability.

[0376] Number of SWD’. Figure 8 shows the number of SWDs per 4-hour bin over a 48 hr period post-dose. The number of SWD was significantly inhibited by the test compound at 3 mg / kg. Post-hoc analysis indicated that the difference versus the vehicle condition was continuously significant from 16:00 on day 1day 1 (immediately after administration) until 4:00 on day 2 (i.e. 36 hours after administration).

[0377] In Figure 9, the number of seizures is quantified over the first 12 hours (A, left) and the first 24 hours (B, right) post dose. Over these periods, the effect of the test compound was significant (12h period: p < 0.0001; 24h period: p < 0.0001). Compared to vehicle data, the inhibition reached 98.6 ± 0.8% over 12h and 94.0 ± 3.1% over 24h.

[0378] Duration of SWD’. Figure 10 shows the average duration of SWD over the first 12 hours (A, left) and the first 24 hours (B, right) post dose. Over the first 12 hours post-dose. The duration was reduced by 50.9 ± 6.5%. However, as only 3 animals presented SWD during that period, no statistical analysis was applied. When calculated over the first 24h after administration, the average was significantly reduced by 50.5 ± 5.2% (p < 0.0001).

[0379] Time in SWD’. Figure 11 shows the total time in SWD in seconds per 4-hour bin over a 48 hr period post-dose. The total time in SWD per bins of 4h was significantly reduced by administration of the test compound at 3 mg / kg in (p < 0.0001). The effect was significant over the first 28 hours after administration (from 16:00 on day 1 to 20:00 on day 2).

[0380] In Figure 12, the total time in SWD is quantified over the first 12 hours (A, left) and the first 24 hours (B, right) post dose. Over both periods, the effect of the test compound was significant (12h period: p < 0.0001; 24h period: p < 0.0001). The inhibition over 12h was by 99.3 ± 0.5%, and over 24h, it was by 96.8 ± 1.7%.Conclusions from GAERS Studies 1 and 2

[0381] Studies 1 and 2 demonstrate that the compound of Formula IA reduced the number of seizures, the average duration of seizures and the total time spent in seizures in a translationally-relevant disease model of absence seizure. Thus, the compound of Formula I A, and its isomer Formula IB, are likely to be useful in medical treatment, such as in the treatment of seizure.REFERENCES

[0382] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The contents of each of these references is incorporated herein.1. Park et al., “Ca(V)3. 1 is a tremor rhythm pacemaker in the inferior olive", Proc Natl Acad Sci USA., 2010, Vol. 107, pp. 10731-62. Park et al., “The potential role of T-type Ca2+ channels in motor coordination" , Front Neural Circuits, 2013, Vol. 7, pp. 1723. Miwa et al., “T. T-Type Calcium Channel as a New Therapeutic Target for Tremor”, Cerebellum, 2010, Vol. 10, pp. 563-5694. Cain et al., “Contributions of T-type calcium channel isoforms to neuronal firing", Channels (Austin), 2010, Vol. 4, pp. 475-4825. Hering et al., “Slow inactivation of the CaV3. 1 isotype of T-type calcium channels", J. Physiol., 2004, Vol. 555, pp. 331-3446. Cnaan et al., “Second monotherapy in childhood absence epilepsy”, Neurology, 2017, Vol. 88, pp. 1827. Glauser et al., “Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy”, N Engl J Med., 2010, Vol. 362, pp. 790-98. Ghaleb et al., “CACNA 11 gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders", Brain, 2021, Vol. 144, pp. 20929. Giordanetto et al, "T-type calcium channels inhibitors: a patent review", Expert Opin. The Pat., 2011, Vol. 21, pp 85-10110. Remington et al., “The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 2000, 20th edition11. Sheskey et al., “Handbook of Pharmaceutical Excipients", Pharmaceutical Press, 2020, 9th edition12. Blom, et al., “Preparative LC MS Purification: Improved Compound Specific Method Optimization" , J. Combi. Chem., 2004, Vol. 6(6), pp 874-88313. Still et al., “Rapid chromatographic technique for preparative separations with moderate resolution", J. Org. Chem., 1978, Vol. 43(14), pp 2923-2514. Advances in Heterocyclic Chemistry, Elsevier, 1963-2012, Vols. 1-10715. Journal of Heterocyclic Chemistry, Journal of Heterocyclic Chemistry, 1964-2012, Vols. 1-4916. Carreira, et al. (Ed.), Science of Synthesis, 2001-2010, Vols. 1-48 and Knowledge Updates KU2010 / 1-4, 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012)17. Katritzky, et al. (Ed.), “Comprehensive Organic Functional Group Transformations", Pergamon Press, 199618. Katritzky et al. (Ed.); “Comprehensive Organic Functional Group Transformations II", Elsevier, 2004, 2nd Edition19. Katritzky et al. (Ed.), “Comprehensive Heterocyclic Chemistry’, Pergamon Press, 198420. Katritzky et al., “Comprehensive Heterocyclic Chemistry II", Pergamon Press, 199621. Smith et al., “March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", Wiley, 2007, 6th Ed.22. Trost et al. (Ed.), “Comprehensive Organic Synthesis", Pergamon Press, 199123. Feng, YCA, et al., “Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals," Am. J. Human Gen., 2019, Vol. 105(2), pp. 267- 28224. Wang et al., “Meta-Analysis of Public Microarray Datasets Reveals Voltage-Gated Calcium Gene Signatures in Conical Cancer Patients”, PLoS ONE, 2015, Vol. 10(7) e0125766.25. Dallas et al. (Ed.), “Patch Clamp Electrophysiology’ , Humana Press, 202126. Francois et al., “State-dependent properties of a new T-type calcium channel blocker enhance Cav3.2 selectivity and support analgesic effects", PAIN, 2013, Vol. 154, pp. 283- 293

Claims

CLAIMS1. A compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof:Formula IA Formula IB.A compound of Formula 1A, or a pharmaceutically acceptable salt thereof:Formula IA3. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt, of claim 1 or 2, optionally wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier.

4. A compound, or a pharmaceutically acceptable salt, of claim 1 or claim 2, for use as a medicament.

5. A compound, or a pharmaceutically acceptable salt, of claim 1 or claim 2, for use in a method of treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels.

6. The compound, or pharmaceutically acceptable salt, for use of claim 5, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from seizure, epilepsy, a movement disorder, a psychiatric disorder, a sleep disorder, pain, and cancer.

7. A compound, or a pharmaceutically acceptable salt, of claim 1 or 2 for use in a method of treating or preventing seizures.

8. The compound, or pharmaceutically acceptable salt, for use of claim 7, wherein the seizures are a seizure type selected from focal onset seizure (focal seizure), generalised onset seizure (generalised seizure), and seizure with unknown onset (unknown onset seizure).

9. The compound, or pharmaceutically acceptable salt, for use of claim 7, wherein the seizures are a seizure type selected from typical absence seizure, atypical absence seizure, atonic seizure, clonic seizure, tonic seizure, tonic-clonic seizure, febrile seizure, focal to bilateral tonic clonic seizure, gelastic and dacrystic seizure, myoclonic seizure, myoclonic- tonic-clonic seizure, myoclonic-atonic seizure, and epileptic (or infantile) spasms.

10. The compound, or pharmaceutically acceptable salt, for use of claim 7, wherein the seizures are absence seizures.

11. The compound, or pharmaceutically acceptable salt, for use of claims 7 to 10, wherein the patient has epilepsy, for example, epilepsy with absence seizures, such as an epilepsy selected from childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).

12. The compound, or pharmaceutically acceptable salt, for use of claim 11, wherein the patient has childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE).

13. A compound, or a pharmaceutically acceptable salt, of claim 1 or 2 for use in a method of treating epilepsy.

14. The compound, or pharmaceutically acceptable salt, for use of claim 13, wherein the epilepsy is selected from focal epilepsy, generalised epilepsy, and combined generalised & focal epilepsy.

15. The compound, or pharmaceutically acceptable salt, for use of claim 13, wherein the epilepsy is an epilepsy syndrome selected from syndromes with onset in neonates and infancy, syndromes with onset in childhood, syndromes with onset at a variable age, syndromes with onset in adulthood; and idiopathic generalised epilepsy syndromes (IGEs).

16. The compound, or pharmaceutically acceptable salt, for use of claim 13, wherein the epilepsy is selected from epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE); Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).

17. The compound, or pharmaceutically acceptable salt, for use of claim 16, wherein the epilepsy is selected from childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE).

18. A compound, or a pharmaceutically acceptable salt, of claim 1 or 2 for use in a method of treating a movement disorder.

19. The compound, or pharmaceutically acceptable salt, for use of claim 18, wherein the movement disorder is selected from essential tremor, Parkinson’s tremor, dystonia(s), spinocerebellar ataxia, and amyotrophic lateral sclerosis.

20. A compound, or a pharmaceutically acceptable salt, of claim 1 or 2 for use in a method of treating a psychiatric disorder.

21. The compound, or pharmaceutically acceptable salt, for use of claim 20, wherein the psychiatric disorder is selected from schizophrenia, addiction, autism spectrum disorder and ADHD.

22. A compound, or a pharmaceutically acceptable salt, of claim 1 or 2 for use in a method of treating or preventing a sleep disorder.

23. The compound, or pharmaceutically acceptable salt, for use of claim 22, wherein the sleep disorder is selected from a central disorder of hypersomnolence; narcolepsy type I; narcolepsy type II; idiopathic hypersomnia; Kleine-Levin syndrome; hypersomnia due to a medical disorder; hypersomnia due to a medication or substance; hypersomnia associated with a psychiatric disorder; insufficient sleep syndrome; circadian rhythm sleep-wake disorders; delayed sleep-wake phase disorder; advanced sleep-wake phase disorder; irregular sleep-wake rhythm; non-24-hour sleep-wake rhythm disorder; shift work disorder; jet lag disorder; and circadian rhythm sleep-wake disorder not otherwise specified (NOS).

24. A compound, or a pharmaceutically acceptable salt, of claim 1 or 2 for use in a method of treating or preventing pain.

25. The compound, or pharmaceutically acceptable salt, for use of claim 24, wherein the pain is selected from chronic pain syndrome, neuropathic pain, such as chemotherapy- induced peripheral neuropathy or diabetic peripheral neuropathy, and inflammatory pain such as IBS inflammatory pain.

26. A compound, or a pharmaceutically acceptable salt, of claim 1 or 2 for use in a method of treating cancer.

27. The compound, or pharmaceutically acceptable salt, for use of claim 26, wherein the cancer is selected from breast cancer, colorectal cancer, oesophageal cancer, gastric cancer, lung cancer, prostate cancer, renal cancer, sarcoma, and uterine cancer.

28. A method of treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels, wherein the method comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2.

29. The method of claim 28, wherein the wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from seizure, epilepsy, a movement disorder, a psychiatric disorder, a sleep disorder, pain, and cancer.

30. A method of treating or preventing seizures, wherein the method comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2.

31. The method of claim 30, wherein the seizures are absence seizures.

32. The method of claim 30 or 31, wherein the patient has childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE).

33. A method of treating epilepsy, wherein the method comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2.

34. The method of claim 33, wherein the epilepsy is selected from epilepsy with absence seizures, such as childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE);Idiopathic Generalized Epilepsy (IGE), such as idiopathic generalized epilepsy with absence seizures, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) or perioral myoclonus with absences (POMA); myoclonic astatic epilepsy (MAE); temporal lobe epilepsy (TLE), photosensitive epilepsy; generalized epilepsy with febrile seizures plus (GEFS+); and febrile seizures (FS).

35. A method of treating a movement disorder, wherein the method comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2.

36. The method of claim 35, wherein the movement disorder is selected from essential tremor, Parkinson’s tremor, dystonia(s), spinocerebellar ataxia, and amyotrophic lateral sclerosis.

37. A method of treating a psychiatric disorder, wherein the method comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2.

38. The method of claim 37, wherein the psychiatric disorder is selected from schizophrenia, addiction, autism spectrum disorder and ADHD.

39. A method of treating or preventing a sleep disorder, wherein the method comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2.

40. The method of claim 39, wherein the sleep disorder is selected from a central disorder of hypersomnolence; narcolepsy type I; narcolepsy type II; idiopathic hypersomnia; Kleine-Levin syndrome; hypersomnia due to a medical disorder; hypersomnia due to a medication or substance; hypersomnia associated with a psychiatric disorder; insufficient sleep syndrome; circadian rhythm sleep-wake disorders; delayed sleep-wake phase disorder; advanced sleep-wake phase disorder; irregular sleep-wake rhythm; non-24-hour sleep-wake rhythm disorder; shift work disorder; jet lag disorder; and circadian rhythm sleepwake disorder not otherwise specified (NOS).

41. A method of treating or preventing pain, wherein the method comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2.

42. The method of claim 41, wherein the pain is selected from chronic pain syndrome, neuropathic pain, such as chemotherapy-induced peripheral neuropathy or diabetic peripheral neuropathy, and inflammatory pain such as IBS inflammatory pain.

43. A method of treating cancer, wherein the method comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2.

44. The method of claim 43, wherein the cancer is selected from breast cancer, colorectal cancer, oesophageal cancer, gastric cancer, lung cancer, prostate cancer, renal cancer, sarcoma, and uterine cancer.

45. Use of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2 for treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels.

46. The use of claim 45, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from seizure, epilepsy, a movement disorder, a psychiatric disorder, a sleep disorder, pain, and cancer.

47. Use of a compound, or a pharmaceutically acceptable salt, of claim 1 or 2 for the manufacture of a medicament for treating or preventing a disease, disorder or condition associated with abnormal function or activity of Cav3 channels.

48. The use of claim 47, wherein the disease, disorder or condition associated with abnormal function or activity of Cav3 channels is selected from seizure, epilepsy, a movement disorder, a psychiatric disorder, a sleep disorder, pain, and cancer.

49. A method of modulating or inhibiting the function or activity of Cav3 channels in a cell sample or tissue sample, wherein the method comprises contacting the cell sample or tissue sample with a compound, or a pharmaceutically acceptable salt, of claim 1 or 2.

50. The method of claim 49, where in the method comprises modulating or inhibiting the function or activity of one of more isoforms of Cav3 channels.51 . The method of claim 50, wherein the isoform is selected from Cav3.1 , Cav3.2, and Cav3.3.

52. A process of preparing a compound of claim 1 or 2, or a pharmaceutically acceptable salt, wherein the process comprises reacting 2-(4-(pentafluoro-A6-sulfanyl)phenyl)acetic acid, or 2-(3-(pentafluoro- A6-sulfanyl)phenyl)acetic acid, with (R)-1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethan-1 -amine.

53. The process of claim 52, wherein the process comprises cooling a solution of 2-(4- (pentafluoro-A6-sulfanyl)phenyl)acetic acid, or 2-(3-(pentafluoro- A6-sulfanyl)phenyl)acetic acid, and (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethan-1 -amine54. The process of claim 53, wherein the process comprises adding a base to the cooled solution, optionally wherein the base is triethylamine.

55. The process of claim 53 or 54, wherein the process comprises slow addition of a peptide coupling agent, optionally wherein the peptide coupling agent is T3P.

56. A compound, or pharmaceutically acceptable salt thereof, obtained by or obtainable by the process of claims 52 to 55.

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