Maxi-k potassium channel openers and therapeutic applications thereof

Abstract

The present invention relates to the 3-phenyl-indolin-2-one compounds (1) to (4) and pharmaceutically acceptable salts and solvates thereof, as defined herein, as well as pharmaceutical compositions containing these compounds. The compounds according to the invention are maxi-K potassium channel openers and have been found to be particularly well suited for use in therapy, including in the treatment or prevention of fragile X associated disorders, such as fragile X syndrome (I).

Description

[0001] Maxi-K potassium channel openers and therapeutic applications thereof

[0002] The present application claims the benefit of priority of European patent application EP24175310.2 filed on May 10, 2024, which is incorporated herein by reference in its entirety.

[0003] The present invention relates to the 3-phenyl-indolin-2-one compounds (1) to (5) and pharmaceutically acceptable salts and solvates thereof, as defined herein below, as well as pharmaceutical compositions containing these compounds. The compounds according to the invention are maxi-K potassium channel openers and have been found to be particularly well suited for use in therapy, including in the treatment or prevention of fragile X associated disorders, such as fragile X syndrome.

[0004] Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the most common monogenic cause of autism globally (Riley C et al., Pediatrics, 2017, 139: S147-S52; Thurman AJ et al., Res Dev Disabil, 2014, 35: 1072-86). FXS is caused by a trinucleotide (CGG) repeat expansion in the 5' untranslated promoter region of the FMR1 gene, which encodes the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates a wide range of mRNAs in neurons. The normal range of CGG triplet repeats in typically-developing (non-FXS) individuals is 5 to 44 (Grigsby J, Clin Neuropsychol, 2016, 30: 815-33), compared with >200 CGG repeats in individuals with FXS. A "full mutation” of >200 CGG repeats results in increased epigenetic modification (methylation) of the promoter, transcriptional silencing of FMR1 and the commensurate loss or deficiency of FMRP. Although less common (<1 %), FXS also can be caused by loss of function mutations and deletions in FMR1.

[0005] Maxi-K potassium channels are large-conductance, calcium (Ca2+)-activated potassium channels, which can conduct large amounts of potassium ions (K+) across the cell membrane and are therefore also known as big potassium (“BK”) channels or calcium-activated big potassium ("BKCa”) channels (Latorre R et al., Biol Res, 2006, 39(3): 385-401). Maxi-K potassium channels (BKCa channels) are widely distributed in the brain. They function as neuronal calcium sensors and contribute to repolarization of neurons and control of neuronal signaling via regulation of cellular excitability and neurotransmitter release. In the brain, the pharmacological opening of BKCa channels can protect neurons by enhancing an endogenous neuroprotective mechanism (Gribkoff VK et al., Nat Med, 2001 , 7: 471-7).

[0006] The gene encoding BKCa (KCNMA1) was identified within a de novo balanced 9q23 / 10q22 translocation of a patient exhibiting both autism and intellectual deficiency (Laumonnier F et al., Am J Psychiatry, 2006, 163: 1622-9). Demonstration of KCNMA1 haploinsufficiency and reduced BKCa channel function in this patient suggested an underlying BKCa channelopathy behind the clinical phenotypes of autism and intellectual disability.

[0007] BKCa is a known molecular target of FMRP (Deng PY et al., Neuron, 2013, 77: 696-711). Functionally, presynaptic BKCa channels have been shown to play an important role in FMRP regulation of action potential duration, neurotransmitter release, and short-term plasticity in hippocampal pyramidal neurons. Single channel recordings in CA3 pyramidal neurons showed that BKCa potassium channel open probability was reduced by loss of FMRP and that FMRP acts on BKCa potassium channels by modulating the channel's gating kinetics; genetic upregulation of BKCa was shown to normalize synaptic and circuit deficits in a mouse model of FXS (Deng PY et al., J Physiol, 2016, 594: 83-97). Positive modulation of BKCa function may thus represent a novel way to address deficits created by loss of FMRP in the nervous system, and may provide a novel approach to the treatment of FXS.

[0008] Preclinical validation for this hypothesis is found in studies with BK channel openers. The Fmr1 knockout (KO) mouse model recapitulates many of the clinical abnormalities observed in FXS patients and is considered an appropriate model for preclinical assessment of potential therapies against FXS. In this model, a single intraperitoneal (IP) injection of 2 mg / kg BMS-204352 (corresponding to a Cmax of about 130 ng / mL) reversed dendritic spine abnormalities, rescued hippocampal glutamate homeostasis, and reversed a range of behavioral phenotypes (Hebert B et al., Orphanet J Rare Dis, 2014, 9: 124).

[0009] Moreover, BK channel openers have also been proposed for the therapeutic intervention in other diseases, including Williams-Beuren syndrome (Piquemal M et al., bioRxiv, 2020, doi: 10.1101 / 2020.12.22.423977).

[0010] The compound BMS-204352 (MaxiPost™), i.e. (3S)-(+)-(5-chloro-2-methoxyphenyl)-1 ,3-dihydro-3-fluoro-6- (trifl uoromethy l)-2H-indol-2-one, is a highly potent maxi-K potassium channel opener, which was originally developed by Bristol-Myers Squibb for the treatment of acute ischemic stroke (Jensen BS, CNS Drug Rev, 2002, 8(4): 353-60). However, it has been found that this compound gives rise to a metabolic degradation product that covalently binds to plasma proteins, which poses a major risk of undesirable side effects and thus limits the therapeutic potential of this compound, particularly for long-term administration (Dalvie D et al., "Influence of aromatic rings on ADME properties of drugs”, in: Smith DA (ed.), "Metabolism, Pharmacokinetics and Toxicity of Functional Groups”, Royal Society of Chemistry, Cambridge (UK), 2010, p. 275-327; Evans DC et al., Chem Res Toxicol, 2004, 17(1): 3-16).

[0011] Other oxindoles besides BMS-204352, particularly other 3-fluorooxindoles, have also been proposed as potassium channel modulators but suffer from similar drawbacks (Hewawasam P et al., Bioorg Med Chem Lett, 2002, 12(7): 1023-6; Malysz J et al., Naunyn Schmiedebergs Arch Pharmacol, 2004, 369(5): 481-9; US 5,565,483; US 5,602,169; EP 0 747 354; WO 02 / 00217; WO 02 / 32419; WO 02 / 066426; WO 03 / 080047; WO 2013 / 001412).

[0012] Moreover, certain indole derivatives have been described as synthetic intermediates or for different therapeutic applications unrelated to potassium channel modulation (Kiindig EP et al., Angew Chem Int Ed Engl, 2007, 46(44): 8484-7; Wurtz S et al., J Am Chem Soc, 2009, 131 (24): 8344-5; Liu L et al., Org Lett, 2011 , 13(7): 1666-9; Dey C et al., Chem Commun (Camb), 2012, 48(25): 3064-6; Kinthada LK et al., Org Biomol Chem, 2014, 12(41): 8152-73; US 2007 / 0203184; WO 01 / 74775; WO 2014 / 154760).

[0013] A range of maxi-K potassium channel openers having a potent stimulating activity and a favorable side effect profile as well as their therapeutic use, including their use in the treatment of fragile X syndrome, have been described in WO 2021 / 234084. To date, however, none of the maxi-K potassium channel openers disclosed in the state of the art have successfully undergone clinical development and obtained marketing approval for the treatment of fragile X syndrome or related disorders.

[0014] Therefore, there is still an unmet need for improved maxi-K potassium channel openers which can be used in the therapy of patients suffering from fragile X syndrome or other diseases / disorders in which maxi-K potassium channels are implicated.

[0015] The present invention addresses this need and solves the problem of providing improved maxi-K potassium channel openers having advantageous properties. Thus, the compounds provided herein (particularly the compounds (1), (2), (3), (4) and (5) described herein below) have surprisingly been found to exhibit an outstandingly potent stimulating activity on maxi-K potassium channels, an improved selectivity for maxi-K channels over other potassium channels, an improved half-life (both in vitro and in vivo), an improved CYP inhibition profile, an improved intrinsic solubility, and a consistent beneficial pharmacokinetic (PK) profile across different mammalian species showing high oral bioavailability (e.g., as solution or suspension formulation), high volume of distribution and low clearance. Moreover, the compounds of the invention do not give rise to metabolic degradation products that form covalent adducts with proteins (as in the case of BMS-204352) and, thus, exhibit an improved side effect profile and allow chronic administration. Taken together, all these properties render the compounds of the present invention highly advantageous for use in therapy, particularly as a chronic medication for the treatment or prevention of fragile X syndrome and other diseases / disorders in which maxi-K potassium channels are implicated.

[0016] Furthermore, the compounds according to the present invention have surprisingly been found to exhibit a considerably improved stimulating activity on maxi-K potassium channels (BK channels) as compared to the activity of the compounds taught in WO 2021 / 234084. In particular, as described in detail in Example 7 below, the maxi-K potassium channel opener efficacy of the tested compounds according to the invention was found to be superior to that of the structurally closest compounds described in WO 2021 / 234084.

[0017] The present invention thus provides a compound selected from: or a pharmaceutically acceptable salt or solvate thereof.

[0018] The above-depicted compounds (1), (2), (3), (4) and (5) as well as the pharmaceutically acceptable salts and solvates of each of these compounds are also referred to herein as the "compounds of the invention”.

[0019] The present invention further provides a pharmaceutical composition comprising a compound of the invention, i.e. any of the compounds (1) to (5) or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable excipient. In line with this, the invention also relates to the compounds provided herein or the aforementioned pharmaceutical composition for use as a medicament (or for use in therapy).

[0020] Moreover, the present invention relates to any one of the compounds of the invention or the aforementioned pharmaceutical composition for use in the treatment or prevention of a fragile X associated disorder (particularly fragile X syndrome). The invention also relates to any one of the compounds of the invention or the aforementioned pharmaceutical composition for use in the treatment or prevention of other diseases / disorders in which maxi-K potassium channels are implicated, particularly diseases / disorders mediated by (or involving) a malfunction, impairment or downregulation of maxi-K potassium channels.

[0021] The invention likewise relates to the use of any one of the compounds of the invention, particularly the use of compound (1), (2), (3), (4) or (5) or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament (or a pharmaceutical composition) for the treatment or prevention of a disease / disorder, particularly a fragile X associated disorder (such as fragile X syndrome) or any other disease / disorder in which maxi-K potassium channels are implicated (particularly a disease / disorder mediated by, or involving, a malfunction, impairment or downregulation of maxi-K potassium channels).

[0022] The present invention furthermore relates to a method of treating or preventing a disease / disorder, particularly a fragile X associated disorder (such as fragile X syndrome) or any other disease / disorder in which maxi-K potassium channels are implicated (particularly a disease / disorder mediated by, or involving, a malfunction, impairment or downregulation of maxi-K potassium channels), the method comprising administering a therapeutically effective amount of a compound of the invention (particularly compound (1 ), (2), (3), (4) or (5) or a pharmaceutically acceptable salt or solvate thereof) to a subject (preferably a human) in need thereof.

[0023] The fragile X associated disorder to be treated or prevented in accordance with the present invention may be, in particular, a genetic disease / disorder caused by (or associated with) a change or mutation in the fragile X mental retardation 1 (FMR1) gene and / or in the fragile X mental retardation 2 (FMR2) gene, such as a pathologically enhanced number of CGG repeats (e.g., the presence of about 45 or more CGG repeats, particularly about 55 or more CGG repeats, especially more than about 200 CGG repeats, or even more than about 230 CGG repeats in the FMR1 gene), or a disease / disorder caused by (or associated with) a deficiency, absence, functional impairment, or dysfunction of the protein encoded by the FMR1 gene, i.e. fragile X mental retardation protein (FMRP), and / or of the protein encoded by the FMR2 gene, particularly a disease / disorder caused by (or associated with) a change or mutation in the FMR1 gene. The term "fragile X associated disorder” is used herein synonymously and interchangeably with "fragile X spectrum disorder”. Corresponding fragile X associated disorders have been described in the literature, e.g., in: Maddalena A et al., Genet Med, 2001 , 3(3): 200-5; Monaghan KG et al., Genet Med, 2013, 15(7): 575-86; Mulley JC et al., J Med Genet, 1995, 32(3): 162-9; Geez J, Ann Hum Genet, 2000, 64(Pt 2): 95-106; Myrick LK et al., Proc Natl Acad Sci USA, 2015, 112(4): 949-56; Hagerman PJ et al., Ann N Y Acad Sci, 2015, 1338(1): 58-70; Jacquemont S et al., Eur J Hum Genet, 2011 , 19(9); Hall DA et al., Handb Clin Neurol, 2018, 147: 377-91 ; Hunter JE et al., "FMR1 Disorders", in: Adam MP et al. (eds), GeneReviews, University of Washington, Seattle (WA), USA, 1998 (updated in November 2019); Lozano R et al., Intractable Rare Dis Res, 2014, 3(4): 134- 46; and the references cited in the aforementioned publications. Each of the aforementioned documents is incorporated herein by reference in its entirety.

[0024] Preferably, the fragile X associated disorder to be treated or prevented in accordance with the present invention is selected from fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), fragile X-associated polycystic ovarian syndrome, fragile XE-associated mental retardation (FRAXE), a clinical syndrome associated with pathogenic mutations in the FMR1 gene (particularly such mutations that result in altered BK channel function; see, e.g., Myrick LK et al., Proc Natl Acad Sci USA, 2015, 112(4): 949-56), and a clinical syndrome associated with pathogenic variation in the KCNMA1 gene (such as, e.g., paroxysmal nonkinesigenic dyskinesia (PNKD), particularly PNKD3, with or without generalized epilepsy; see, e.g., Liang L et al., Hum Mol Genet, 2019, 28(17): 2937-51). More preferably, the fragile X associated disorder is selected from fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), fragile X-associated polycystic ovarian syndrome, and fragile XE-associated mental retardation (FRAXE). Even more preferably, the fragile X associated disorder is selected from fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Yet even more preferably, the fragile X associated disorder is fragile X syndrome.

[0025] Accordingly, the present invention relates, in particular, to a compound of the invention (or a pharmaceutical composition comprising said compound and optionally a pharmaceutically acceptable excipient) for use in the treatment or prevention of fragile X syndrome (FXS), fragile X-associated tremor / ataxia syndrome (FXTAS), or fragile X-associated primary ovarian insufficiency (FXPOI), preferably for use in the treatment or prevention of fragile X syndrome.

[0026] As explained above, the invention also encompasses the treatment or prevention of other diseases / disorders in which maxi-K potassium channels are implicated, particularly diseases / disorders mediated by (or involving) a malfunction, impairment or downregulation of maxi-K potassium channels, using a compound of the invention. In particular, the diseases / disorders to be treated or prevented in accordance with the present invention include, for example, stroke (e.g., ischemic stroke), ischemia reperfusion injury, ischemic heart disease, hypertension (e.g., partial hypertension or arterial hypertension), myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), multiple sclerosis, spasticity (e.g., muscle spasticity, or spasticity in a subject / patient suffering from multiple sclerosis), tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder (OAB), urinary incontinence, irritable bowel syndrome (IBS), faecal incontinence, constipation, gastro-oesophageal reflux disorder (GERD), impaired gastrointenstinal passage, detrusor underactivity, erectile dysfunction, opioid- induced respiratory depression, anxiety, an anxiety disorder (e.g., generalized anxiety disorder (GAD) or social anxiety disorder (SAD)), sensory processing disorder (SPD), autism, an autism spectrum disorder, a social (pragmatic) communication disorder, attention deficit hyperactivity disorder (ADHD), social phobia, intellectual disability, pain (e.g., neuropathic pain), epilepsy, an epilepsy and / or seizure disorder (e.g., Dravet syndrome), generalized epilepsy-paroxysmal dyskinesia syndrome (GEPD), temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt-Hopkins syndrome, 16p11.2 deletion syndrome, Williams-Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis (or prevention of preterm labor), migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome, Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia (SCA; e.g., SCA1 , SCA2, or SCA7), DNMf-related disorder, DNMf-related epilepsy, DNM1- encephalopathy, CDKL5 deficiency disorder (ODD), / / MAMinked channelopathy (see, e.g., Bailey CS et al., J Gen Physiol, 2019, 151 (10): 1173-89, doi: 10.1085 / jgp.201912457), a / / Mfi1-linked disorder, a KCNMB2-\m ed disorder, a KCNMB3-linked disorder, a KCNMB4-\ inked disorder, an LRRC26-linked disorder, an LRRC52-\ inked disorder, an LRRC55-\ inked disorder, or an LRRC38-\ inked disorder.

[0027] The present invention thus also relates to a compound of the invention (particularly compound (1), (2), (3), (4) or (5) or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition comprising said compound and optionally a pharmaceutically acceptable excipient, for use in the treatment or prevention of a disease / disorder selected from stroke (e.g., ischemic stroke), ischemia reperfusion injury, ischemic heart disease, hypertension (e.g., partial hypertension or arterial hypertension), myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), multiple sclerosis, spasticity (e.g., muscle spasticity, or spasticity in a subject / patient suffering from multiple sclerosis), tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder (OAB), urinary incontinence, irritable bowel syndrome (IBS), faecal incontinence, constipation, gastro-oesophageal reflux disorder (GERD), impaired gastrointenstinal passage, detrusor underactivity, erectile dysfunction, opioid- induced respiratory depression, anxiety, an anxiety disorder (e.g., generalized anxiety disorder (GAD) or social anxiety disorder (SAD)), sensory processing disorder (SPD), autism, an autism spectrum disorder, a social (pragmatic) communication disorder, attention deficit hyperactivity disorder (ADHD), social phobia, intellectual disability, pain (e.g., neuropathic pain), epilepsy, an epilepsy and / or seizure disorder (e.g., Dravet syndrome), generalized epilepsy-paroxysmal dyskinesia syndrome (GEPD), temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt-Hopkins syndrome, 16p11.2 deletion syndrome, Williams-Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis (or prevention of preterm labor), migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome, Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia (SCA; e.g., SCA1 , SCA2, or SCA7), DMVH-related disorder, DMVH-related epilepsy, DNM1- encephalopathy, CDKL5 deficiency disorder (CDD), KCNMAf -I inked channelopathy, a / O / MBMinked disorder, a KCNMB2-\ inked disorder, a KCNMB3-linked disorder, a KCNMB4-\ inked disorder, an _RRC26-linked disorder, an / _RRC52-linked disorder, an _RRC55-linked disorder, and an LRRC38-\ inked disorder.

[0028] Moreover, the invention likewise relates to the use of a compound of the invention (particularly compound (1), (2), (3), (4) or (5) or a pharmaceutically acceptable salt or solvate thereof) in the preparation of a medicament (or a pharmaceutical composition) for the treatment or prevention of a disease / disorder selected from stroke (e.g., ischemic stroke), ischemia reperfusion injury, ischemic heart disease, hypertension (e.g., partial hypertension or arterial hypertension), myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), multiple sclerosis, spasticity (e.g., muscle spasticity, or spasticity in a subject / patient suffering from multiple sclerosis), tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder (OAB), urinary incontinence, irritable bowel syndrome (IBS), faecal incontinence, constipation, gastro-oesophageal reflux disorder (GERD), impaired gastrointenstinal passage, detrusor underactivity, erectile dysfunction, opioid-induced respiratory depression, anxiety, an anxiety disorder (e.g., generalized anxiety disorder (GAD) or social anxiety disorder (SAD)), sensory processing disorder (SPD), autism, an autism spectrum disorder, a social (pragmatic) communication disorder, attention deficit hyperactivity disorder (ADHD), social phobia, intellectual disability, pain (e.g., neuropathic pain), epilepsy, an epilepsy and / or seizure disorder (e.g., Dravet syndrome), generalized epilepsy-paroxysmal dyskinesia syndrome (GEPD), temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt-Hopkins syndrome, 16p11.2 deletion syndrome, Williams-Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis (or prevention of preterm labor), migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome, Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia (SCA; e.g., SCA1 , SCA2, or SCA7), DNM1- related disorder, DNMf-related epilepsy, DNMf-encephalopathy, CDKL5 deficiency disorder (CDD), KCMWAMinked channelopathy, a / O / MBMinked disorder, a KCNMB2-linked disorder, a KCNMB3-\ inked disorder, a KCNMB4- linked disorder, an LRRC26-linked disorder, an LRRC52-\ inked disorder, an LRRC55-\ inked disorder, and an LRRC38-linked disorder.

[0029] In accordance with the above, the invention further relates to a method of treating or preventing a disease / disorder selected from stroke (e.g., ischemic stroke), ischemia reperfusion injury, ischemic heart disease, hypertension (e.g., partial hypertension or arterial hypertension), myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), multiple sclerosis, spasticity (e.g., muscle spasticity, or spasticity in a subject / patient suffering from multiple sclerosis), tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder (OAB), urinary incontinence, irritable bowel syndrome (IBS), faecal incontinence, constipation, gastro-oesophageal reflux disorder (GERD), impaired gastrointenstinal passage, detrusor underactivity, erectile dysfunction, opioid- induced respiratory depression, anxiety, an anxiety disorder (e.g., generalized anxiety disorder (GAD) or social anxiety disorder (SAD)), sensory processing disorder (SPD), autism, an autism spectrum disorder, a social (pragmatic) communication disorder, attention deficit hyperactivity disorder (ADHD), social phobia, intellectual disability, pain (e.g., neuropathic pain), epilepsy, an epilepsy and / or seizure disorder (e.g., Dravet syndrome), generalized epilepsy-paroxysmal dyskinesia syndrome (GEPD), temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt-Hopkins syndrome, 16p11.2 deletion syndrome, Williams-Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis (or prevention of preterm labor), migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome, Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia (SCA; e.g., SCA1 , SCA2, or SCA7), DNMf-related disorder, DNMf-related epilepsy, DNM1- encephalopathy, CDKL5 deficiency disorder (ODD), KCNMA1 -I inked channelopathy, a / / MBMinked disorder, a KCNMB2-\ inked disorder, a KCNMB3-linked disorder, a KCNMB4-\ inked disorder, an _RRC26-linked disorder, an / _RRC52-linked disorder, an _RRC55-linked disorder, and an / _RRC38-linked disorder, the method comprising administering a therapeutically effective amount of a compound of the invention (particularly compound (1), (2), (3), (4) or (5), or a pharmaceutically acceptable salt or solvate thereof) to a subject (preferably a human) in need thereof.

[0030] The present invention furthermore relates to the use of a compound of the invention (particularly compound (1), (2),

[0031] (3), (4) or (5) or a pharmaceutically acceptable salt or solvate thereof) as a maxi-K potassium channel opener in research, particularly as a research tool compound for stimulating maxi-K potassium channels. Accordingly, the invention refers to the in vitro use of a compound of the invention, particularly compound (1), (2), (3), (4) or (5) or a pharmaceutically acceptable salt or solvate thereof, as a maxi-K potassium channel opener and, in particular, to the in vitro use of a compound of the invention as a research tool compound acting as a maxi-K potassium channel opener. The invention likewise relates to a method, particularly an in vitro method, of stimulating maxi-K potassium channels, the method comprising the application of a compound of the invention, particularly compound (1), (2), (3),

[0032] (4) or (5) or a pharmaceutically acceptable salt or solvate thereof. The invention further relates to a method of stimulating maxi-K potassium channels, the method comprising applying a compound of the invention to a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal). The invention also refers to a method, particularly a non-therapeutic in vitro method, of stimulating maxi-K potassium channels in a sample (e.g., a biological sample), the method comprising applying a compound of the invention to said sample. The present invention further provides a method of stimulating maxi-K potassium channels, the method comprising contacting a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal) with a compound of the invention. The terms "sample”, "test sample” and "biological sample” include, without being limited thereto: a cell, a cell culture, or a cellular or subcellular extract; biopsied material obtained from an animal (e.g., a human), or an extract thereof; or blood, serum, plasma, saliva, urine, or any other body fluid, or an extract thereof. It is to be understood that the term “in vitro" is used in this specific context in the sense of "outside a living human or animal body”, which includes, in particular, experiments performed with cells, cellular or subcellular extracts, and / or biological molecules in an artificial environment such as an aqueous solution or a culture medium which may be provided, e.g., in a flask, a test tube, a Petri dish, a microtiter plate, etc.

[0033] As explained above, the present invention provides the following compounds (1), (2), (3), (4) and (5):

[0034] Thus, in one embodiment, the compound of the invention is compound (1) or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, the compound of the invention is compound (2) or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, the compound of the invention is compound (3) or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, the compound of the invention is compound (4) or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, the compound of the invention is compound (5) or a pharmaceutically acceptable salt or solvate thereof.

[0035] The compounds provided herein have an asymmetrically substituted carbon atom at position 3 of the indolin-2-one ring comprised in said compounds (i.e., the carbon ring atom carrying the chloro- and hydroxy-substituted phenyl ring). Accordingly, each one of these compounds may have the (R)-configuration or the (S)-configuration at the carbon atom in 3-position of the indolin-2-one ring comprised in the respective compound. The present invention specifically relates to an optically active isomer, particularly the (3R)-isomer or the (3S)-isomer, of any one of the compounds (1), (2), (3), (4) or (5), or a pharmaceutically acceptable salt or solvate thereof. Such individual isomers can be obtained from the corresponding racemate, e.g., by chiral column chromatography, or via salt formation with a chiral resolving agent followed by crystallization. The invention also relates to any mixtures, including a racemic mixture (or racemate), of the (3R)-isomer and the (3S)-isomer of any one of the compounds (1), (2), (3), (4) or (5), or a pharmaceutically acceptable salt or solvate thereof.

[0036] Accordingly, the compound of the invention may be, e.g., any one of the following compounds (1 a), (1 b), (2a), (2b), (3a), (3b), (4a), (4b), (5a) or (5b), or a pharmaceutically acceptable salt or solvate of any one of these compounds:

[0037]

[0038] Among the compounds (1) to (5), the compounds (1) and (2) are preferred, and compound (1) is particularly preferred. Accordingly, it is preferred that the compound of the invention is compound (1) or (2), or a pharmaceutically acceptable salt or solvate thereof, more preferably the compound of the invention is compound (1) or a pharmaceutically acceptable salt or solvate thereof.

[0039] With respect to compound (1), the stereoisomer (1 a) is particularly preferred. Likewise, with respect to compound (2), the stereoisomer (2a) is particularly preferred. Thus, it is particularly preferred that the compound of the invention is compound (1 a) or (2a), or a pharmaceutically acceptable salt or solvate thereof, and even more preferably the compound of the invention is compound (1 a) or a pharmaceutically acceptable salt or solvate thereof.

[0040] In accordance with the above, the compound of the invention may be any one of the specific compounds described herein below in the examples section of this specification, either in non-salt form or as a pharmaceutically acceptable salt or solvate of the respective compound.

[0041] Thus, the compound of the invention may be selected from:

[0042] 3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one;

[0043] 4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one;

[0044] 2-[3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile;

[0045] 3-(4-chloro-2-hydroxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one; 3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6-(trifluoromethyl)indolin-2-one; or a pharmaceutically acceptable salt or solvate of any one of the above-mentioned compounds.

[0046] Moreover, as explaind above, the invention specifically and individually relates to each stereoisomer of the above- mentioned compounds, including in particular to each one of these compounds having the (R)-configuration at the carbon atom in 3-position of the indolin-2-one ring comprised in the respective compound, or to each one of these compounds having the (S)-configuration at the carbon atom in 3-position of the indolin-2-one ring comprised in the respective compound. Thus, the compound of the invention may be selected from: (3S)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one; (3R)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one;

[0047] (3S)-4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one;

[0048] (3R)-4, 6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one;

[0049] 2-[(3S)-3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile; 2-[(3R)-3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile; (3S)-3-(4-chloro-2-hydroxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one; (3R)-3-(4-chloro-2-hydroxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one; (3S)-3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6-(trifluoromethyl)indolin-2-one; (3R)-3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6-(trifluoromethyl)indolin-2-one; or a pharmaceutically acceptable salt or solvate of any one of the above-mentioned compounds.

[0050] Particularly preferred compounds of the invention are 3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin- 2-one (or a pharmaceutically acceptable salt or solvate thereof) or 4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3- methyl-indolin-2-one (or a pharmaceutically acceptable salt or solvate thereof). For each of these compounds, the (3R)-isomer, the (3S)-isomer, or any mixture (including a racemic mixture) of the (3R)-isomer and the (3S)-isomer can be used. In the case of 3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one, the (3S)-isomer is especially preferred, i.e., the compound is preferably (3S)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6- (trifl uoromethy l)indol in-2-one (or a pharmaceutically acceptable salt or solvate thereof). In the case of 4,6-dichloro-3- (5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one, the (3R)-isomer is especially preferred, i.e., the compound is preferably (3R)-4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one (or a pharmaceutically acceptable salt or solvate thereof).

[0051] The compounds of the invention can be prepared in accordance with, or in analogy to, the synthetic routes described herein below in the examples section. Furthermore, a general description of synthetic approaches that can be adapted and applied for the preparation of the compounds of the invention is provided in WO 2021 / 234084 which is incorporated herein by reference in its entirety.

[0052] As used herein, the terms "optional”, "optionally” and "may” denote that the indicated feature may be present but can also be absent. Whenever the term "optional”, "optionally” or "may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, if a component of a composition is indicated to be "optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0053] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms "a”, "an” and "the” are used interchangeably with "one or more” and "at least one”. Thus, for example, a composition comprising "a” pharmaceutically acceptable excipient can be interpreted as referring to a composition comprising "one or more” pharmaceutically acceptable excipients.

[0054] As used herein, the term "about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term "about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint. If the term "about” is used in connection with the endpoint of an open-ended range, it preferably refers to the corresponding range starting from the lower endpoint -10% or from the upper endpoint +10%, more preferably to the range starting from the lower endpoint -5% or from the upper endpoint +5%, and even more preferably to the open-ended range defined by the exact numerical value of the corresponding endpoint. If the term "about” is used in connection with a parameter that is quantified in integers, such as the number of CGG repeats in the FMR1 gene or the FMR2 gene, then the numbers corresponding to ±10% or ±5% of the indicated numerical value are to be rounded to the nearest integer (using the tie-breaking rule "round half up”).

[0055] It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.

[0056] As used herein, the term "comprising” (or "comprise”, "comprises”, "contain”, "contains”, or "containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of "containing, inter alia”, i.e., "containing, among further optional elements, In addition, this term also includes the narrower meanings of "consisting essentially of' and "consisting of”. For example, the term "A comprising B and C” has the meaning of "A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., "A containing B, C and D” would also be encompassed), but this term also specifically and invidiually includes the meaning of "A consisting essentially of B and C” and the meaning of "A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0057] The scope of the present invention embraces all pharmaceutically acceptable salt forms of the compounds of the invention (particularly the compound (1), (2), (3), (4) or (5), including also any of the compounds (1 a), (1 b), (2a), (2b), (3a), (3b), (4a), (4b), (5a) or (5b)) such as, e.g., any salt formed from a group susceptible to deprotonation (particularly the phenolic hydroxy group comprised in the compounds of the invention) with a physiologically acceptable cation. Exemplary base addition salts include, for instance: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts.

[0058] The present invention also specifically relates to each one of the compounds provided herein, particularly any one of the compounds (1), (2), (3), (4) or (5) (including also any of the compounds (1 a), (1 b), (2a), (2b), (3a), (3b), (4a), (4b), (5a) or (5b)), in non-salt form. In accordance with the invention, it is particularly preferred that the respective compound is employed in non-salt form.

[0059] Moreover, the scope of the invention embraces the compounds provided herein, particularly any one of the compounds (1), (2), (3), (4) or (5) (including also any of the compounds (1 a), (1 b), (2a), (2b), (3a), (3b), (4a), (4b), (5a) or (5b)), in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of the invention are also encompassed. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of any one of the compounds (1), (2), (3), (4) or (5) (including also any of the compounds (1 a), (1 b), (2a), (2b), (3a), (3b), (4a), (4b), (5a) or (5b)) are likewise embraced by the present invention.

[0060] Furthermore, the compounds of the invention may exist in the form of different isomers, in particular stereoisomers (e.g., enantiomers) or tautomers. All such isomers of the compounds of the invention are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds described herein as well as any mixtures thereof (including, in particular, racemic mixtures / racemates). The racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of the compounds provided herein. For compounds exhibiting tautomerism, the chemical formulae / drawings provided herein depict only one of the possible tautomeric forms. It will be understood that the chemical formulae and chemical names provided herein encompass any tautomeric form of the corresponding compound and are not limited to the specific tautomeric form depicted by the respective drawing or identified by the respective chemical name of the compound.

[0061] In particular, the present invention specifically relates to an optical isomer (or optically active isomer) of any one of the compounds (1), (2), (3), (4) or (5), or a pharmaceutically acceptable salt or solvate thereof, wherein the carbon atom in 3-position of the indolin-2-one ring comprised in the respective compound is in (R)-configuration, and further specifically relates to an optical isomer (or optically active isomer) of any one of the compounds (1), (2), (3), (4) or (5), or a pharmaceutically acceptable salt or solvate thereof, wherein the carbon atom in 3-position of the indolin-2- one ring comprised in the respective compound is in (S)-configuration. The invention also relates to any mixtures of such isomers, including a corresponding racemic mixture.

[0062] The scope of the invention further embraces any of the compounds (1), (2), (3), (4) or (5), or a pharmaceutically acceptable salt or solvate thereof, wherein one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e.,2H; also referred to as “D”). Accordingly, the invention also embraces compounds (including any of the specific compounds described herein) which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds of the invention can be increased using deuteration techniques known in the art. For example, a compound of the invention, or a reactant or precursor to be used in the synthesis of the corresponding compound of the invention, can be subjected to an H / D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 2012, 20(18): 5658-67; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 2010, 53(11-12): 635-44; Modvig A et al., J Org Chem, 2014, 79: 5861-8 (each of which is incorporated herein by reference in its entirety). The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compounds of the invention are not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or1H hydrogen atoms in the compounds of the invention is preferred.

[0063] The present invention also embraces compounds in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g.,18F,11C,13N and / or15O. Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET). The invention thus includes (i) compounds of the invention, in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by18F atoms, (ii) compounds of the invention, in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by11C atoms, (iii) compounds of the invention, in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by13N atoms, and (iv) compounds of the invention, in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by15O atoms. In general, it is preferred that none of the atoms in the compounds of the invention are replaced by specific isotopes.

[0064] The compounds of the present invention may be administered as compounds per se or may be formulated as medicaments / pharmaceutical compositions. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0065] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., polyethylene glycol), including poly (ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS 1000, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142- 34-6), poloxamer 188 (e.g., Kolliphor® P188), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, o-cyclodextrin, p-cyclodextrin, y-cyclodextrin, hydroxyethyl-p-cyclodextrin, hydroxypropyl-p-cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y- cyclodextrin, dihydroxypropyl-p-cyclodextrin, sulfobutylether-p-cyclodextrin, sulfobutylether-y-cyclodextrin, glucosyl- o-cyclodextrin, glucosyl-p-cyclodextrin, diglucosyl-p-cyclodextrin, maltosyl-o-cyclodextrin, maltosyl-p-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-p-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-p- cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0066] Preferably, the pharmaceutical compositions comprise any one or more of polysorbate 80 (e.g., an aqueous composition comprising 5% polysorbate 80), vitamin E-TPGS 1000 (also referred to as VitE-TPGS1000, or D-a- tocopherol polyethylene glycol 1000 succinate, or tocofersolan; e.g., an aqueous composition comprising 5% vitamin E-TPGS 1000), sodium lauryl sulfate (e.g., an aqueous composition comprising 5% sodium lauryl sulfate), poloxamer 188 (e.g., Kolliphor® P188; also referred to as polyethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), CAS no. 9003-11-6; e.g., an aqueous composition comprising 10% poloxamer 188), hydroxypropyl-p- cyclodextrin (also referred to as HP-p-CD; e.g., an aqueous composition comprising 20 to 40% HP-p-CD), sulfobutylether-p-cyclodextrin (also referred to as SBE-p-CD; e.g., an aqueous composition comprising 20 to 40% SBE-p-CD), or any one or more of Transcutol HP (or di(ethylene glycol) ethyl ether, CAS 111-90-0), Labrasol ALF (or caprylocaproyl polyoxyl-8 glycerides), Lauroglycol 90 (or propylene glycol monolaurate type II), Capryol 90 (or propylene glycol monocaprylate type II), or Miglyol 812 (or triglycerides of capric / caprylic acids, CAS 52622-27-2).

[0067] The pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methy l-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0068] The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22ndedition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems. The compounds of the invention, or the above described pharmaceutical compositions comprising a compound of the invention, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration. It is preferred that said compounds or pharmaceutical compositions are administered orally.

[0069] If said compounds or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and / or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0070] Preferably, said compounds or pharmaceutical compositions are administered orally, e.g., in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications, or said compounds or pharmaceutical compositions are administered oromucosally, particularly via the buccal route or the sublingual route, e.g., in the form of a buccal film, a buccal tablet, a sublingual film or a sublingual tablet.

[0071] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. For oral administration, the compounds or pharmaceutical compositions are preferably administered by oral ingestion, particularly by swallowing. The compounds or pharmaceutical compositions can thus be administered to pass through the mouth into the gastrointestinal tract, which can also be referred to as "oral-gastrointestinal” administration.

[0072] Alternatively, said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.

[0073] Said compounds or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(— )-3- hydroxybutyric acid. Sustained-release pharmaceutical compositions also include I iposomally entrapped compounds. The present invention thus also relates to liposomes or lipid particles containing a compound of the invention.

[0074] Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, the rectal route, or the ocular route. For ophthalmic use, they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0075] It is also envisaged to prepare dry powder formulations of the compounds of the invention for pulmonary administration, particularly inhalation. Such dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to an emulsification / spray drying process.

[0076] For topical application to the skin, said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.

[0077] The present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route. A preferred route of administration is oral administration. Thus, for each one of the compounds of the invention or the corresponding pharmaceutical compositions provided herein, it is particularly preferred that the respective compound or pharmaceutical composition is to be administered orally (particularly by oral ingestion).

[0078] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0079] For example, any of the compounds of the invention may be orally administered in a daily amount of about 0.5 mg to about 400 mg, particularly in a daily amount of about 1 mg to about 200 mg (e.g., about 1 mg, about 5 mg, about 20 mg, about 50 mg, about 100 mg, about 150 mg, or about 200 mg, or any amount or subrange between any of the aforementioned exemplary amounts), which may be administered, e.g., in the form of a single dose per day or in the form of two doses per day. Accordingly, the compound may be orally administered, e.g., at a dose of about 13 mg to about 100 mg (e.g., about 13 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg, or any dose or subrange between any of the aforementioned exemplary doses) twice a day (BID).

[0080] The compounds of the invention, or a pharmaceutical composition comprising a compound of the invention, can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated or prevented with the compound of the invention). Thus, the present invention relates to any one of the compounds (1), (2), (3), (4) or (5), or a pharmaceutically acceptable salt or solvate thereof, or a corresponding pharmaceutical composition, for use in the monotherapeutic treatment or prevention of a fragile X associated disorder (such as fragile X syndrome) or for use in the monotherapeutic treatment or prevention of any disease / disorder in which maxi-K potassium channels are implicated. In particular, the invention relates to the monotherapeutic administration of a compound of the invention, or a corresponding pharmaceutical composition, without concomitantly administering any further therapeutic agents against a fragile X associated disorder (or any further therapeutic agents against fragile X syndrome).

[0081] However, the compounds of the invention, or a pharmaceutical composition comprising a compound of the invention, can also be administered in combination with one or more further therapeutic agents. If a compound of the invention is used in combination with a second therapeutic agent active against the same disease or condition, the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used. The combination of a compound of the invention with one or more further therapeutic agents may comprise the simultaneous / concomitant administration of the compound of the invention and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential / separate administration of the compound of the invention and the further therapeutic agent(s). If administration is sequential, either the compound of the invention or the one or more further therapeutic agents may be administered first. If administration is simultaneous, the one or more further therapeutic agents may be included in the same pharmaceutical formulation as the compound of the invention, or they may be administered in two or more different (separate) pharmaceutical formulations. Such different pharmaceutical formulations may be administered via the same route or via different routes of administration.

[0082] The subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male human or a female human) or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig). Most preferably, the subject / patient to be treated in accordance with the invention is a human.

[0083] The term "treatment” of a disease or disorder, as used herein, is well known in the art. "Treatment” of a disease or disorder implies that the corresponding disease or disorder is suspected or has been diagnosed in a patient / subject. A patient / subject suspected of suffering from a disease or disorder typically shows specific clinical and / or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disease or disorder). The "treatment” of a disease or disorder may, for example, lead to a halt in the progression of the disease or disorder (e.g., no deterioration of symptoms) or a delay in the progression of the disease or disorder (in case the halt in progression is of a transient nature only). The "treatment” of a disease or disorder may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject / patient suffering from the disease or disorder. Accordingly, the "treatment” of a disease or disorder may also refer to an amelioration of the disease or disorder, which may, e.g., lead to a halt in the progression of the disease or disorder or a delay in the progression of the disease or disorder. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject / patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disease or disorder may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disease or disorder) or palliative treatment (including symptomatic relief).

[0084] The term "prevention” of a disease or disorder, as used herein, is also well known in the art. For example, a patient / subject suspected of being prone to suffer from a disease or disorder may particularly benefit from a prevention of the disease or disorder. The subject / patient may have a susceptibility or predisposition for a disease or disorder, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disease or disorder to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (for example, the patient / subject does not show any clinical or pathological symptoms). Thus, the term "prevention” comprises the use of a compound of the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician. It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments.

[0085] In this specification, a number of documents including patent applications and scientific literature are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0086] The reference in this specification to any prior publication (or information derived therefrom) is not and should not be taken as an acknowledgment or admission or any form of suggestion that the corresponding prior publication (or the information derived therefrom) forms part of the common general knowledge in the technical field to which the present specification relates.

[0087] The present invention particularly relates to the following items:

[0088] A compound selected from: or a pharmaceutically acceptable salt or solvate thereof.

[0089] 2. The compound of item 1 , wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0090] 3. The compound of item 1 , wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0091] 4. The compound of item 1 , wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0092] 5. The compound of item 1 , wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0093] 6. The compound of item 1 , wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0094] 7. The compound of any one of items 1 to 6, wherein the compound has the (S)-configuration at the carbon atom in 3-position of the indolin-2-one ring comprised in said compound.

[0095] 8. The compound of any one of items 1 to 6, wherein the compound has the (R)-configuration at the carbon atom in 3-position of the indolin-2-one ring comprised in said compound. 9. The compound of item 1 or 2, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0096] 10. The compound of item 1 or 2, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0097] 11. The compound of item 1 or 3, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0098] 12. The compound of item 1 or 3, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0099] 13. The compound of item 1 or 4, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof. 14. The compound of item 1 or 4, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0100] 15. The compound of item 1 or 5, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0101] 16. The compound of item 1 or 5, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0102] The compound of item 1 or 6, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof.

[0103] 18. The compound of item 1 or 6, wherein said compound is or a pharmaceutically acceptable salt or solvate thereof. 19. A compound selected from:

[0104] 3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one;

[0105] 4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one;

[0106] 2-[3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile;

[0107] 3-(4-chloro-2-hydroxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one;

[0108] 3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6-(trifluoromethyl)indolin-2-one; or a pharmaceutically acceptable salt or solvate thereof.

[0109] 20. The compound of item 19, wherein said compound is selected from:

[0110] (3S)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one;

[0111] (3R)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one;

[0112] (3S)-4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one;

[0113] (3R)-4, 6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one;

[0114] 2-[(3S)-3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl] acetonitrile;

[0115] 2-[(3R)-3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl] acetonitrile;

[0116] (3S)-3-(4-chloro-2-hydroxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one;

[0117] (3R)-3-(4-chloro-2-hydroxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one;

[0118] (3S)-3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6-(trifluoromethyl)indolin-2-one;

[0119] (3R)-3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6-(trifluoromethyl)indolin-2-one; or a pharmaceutically acceptable salt or solvate thereof.

[0120] 21. The compound of item 19, wherein said compound is 3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6- (trifluoromethyl)indolin-2-one or a pharmaceutically acceptable salt or solvate thereof.

[0121] 22. The compound of item 21, wherein said compound is (3S)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6- (trifluoromethyl)indolin-2-one or a pharmaceutically acceptable salt or solvate thereof.

[0122] 23. The compound of item 19, wherein said compound is 4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl- indolin-2-one or a pharmaceutically acceptable salt or solvate thereof

[0123] 24. The compound of item 23, wherein said compound is (3R)-4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3- methyl-indolin-2-one or a pharmaceutically acceptable salt or solvate thereof.

[0124] 25. A pharmaceutical composition comprising the compound of any one of items 1 to 24 and optionally a pharmaceutically acceptable excipient.

[0125] 26. The compound of any one of items 1 to 24 or the pharmaceutical composition of item 25 for use as a medicament. The compound of any one of items 1 to 24 or the pharmaceutical composition of item 25 for use in the treatment or prevention of a disease / disorder selected from a fragile X associated disorder, stroke, ischemia reperfusion injury, ischemic heart disease, hypertension, myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease, multiple sclerosis, spasticity, tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder, urinary incontinence, irritable bowel syndrome, faecal incontinence, constipation, gastro-oesophageal reflux disorder, impaired gastrointenstinal passage, detrusor underactivity, erectile dysfunction, opioid-induced respiratory depression, anxiety, an anxiety disorder, sensory processing disorder, autism, an autism spectrum disorder, a social or pragmatic communication disorder, attention deficit hyperactivity disorder, social phobia, intellectual disability, pain, epilepsy, an epilepsy and / or seizure disorder, Dravet syndrome, generalized epilepsy-paroxysmal dyskinesia syndrome, temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt-Hopkins syndrome, 16p11.2 deletion syndrome, Williams-Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis, migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome, Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia, DNMf-related disorder, DNMf-related epilepsy, DNM1 -encephalopathy, CDKL5 deficiency disorder, / / MAMinked channelopathy, a KCNMB1- linked disorder, a KCNMB2-\ inked disorder, a KCNMB3-\ inked disorder, a KCNMB4-\ inked disorder, an / _RRC26-linked disorder, an LRRC52-\ inked disorder, an / _RRC55-linked disorder, and an LRRC38-\ inked disorder. The compound of any one of items 1 to 24 or the pharmaceutical composition of item 25 for use in the treatment or prevention of a fragile X associated disorder. The compound for use according to item 28 or the pharmaceutical composition for use according to item 28, wherein the fragile X associated disorder is selected from fragile X syndrome, fragile X-associated tremor / ataxia syndrome, fragile X-associated primary ovarian insufficiency, fragile X-associated polycystic ovarian syndrome, and fragile XE-associated mental retardation. The compound for use according to item 28 or the pharmaceutical composition for use according to item 28, wherein the fragile X associated disorder is fragile X syndrome. Use of the compound of any one of items 1 to 24 in the preparation of a medicament for the treatment or prevention of a disease / disorder selected from a fragile X associated disorder, stroke, ischemia reperfusion injury, ischemic heart disease, hypertension, myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease, multiple sclerosis, spasticity, tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder, urinary incontinence, irritable bowel syndrome, faecal incontinence, constipation, gastro-oesophageal reflux disorder, impaired gastrointenstinal passage, detrusor underactivity, erectile dysfunction, opioid-induced respiratory depression, anxiety, an anxiety disorder, sensory processing disorder, autism, an autism spectrum disorder, a social or pragmatic communication disorder, attention deficit hyperactivity disorder, social phobia, intellectual disability, pain, epilepsy, an epilepsy and / or seizure disorder, Dravet syndrome, generalized epilepsy-paroxysmal dyskinesia syndrome, temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt-Hopkins syndrome, 16p11.2 deletion syndrome, Williams-Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis, migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome, Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia, DNMf-related disorder, DNMf-related epilepsy, DNM1 -encephalopathy, CDKL5 deficiency disorder, KCNMA1 -I inked channelopathy, a KCNMB1- linked disorder, a KCNMB2-\ inked disorder, a KCNMB3-\ inked disorder, a KCNMB4-\ inked disorder, an LRRC26-linked disorder, an LRRC52-\ inked disorder, an LRRC55-linked disorder, and an LRRC38-\ inked disorder.

[0126] 32. Use of the compound of any one of items 1 to 24 in the preparation of a medicament for the treatment or prevention of a fragile X associated disorder.

[0127] 33. The use of item 32, wherein the fragile X associated disorder is selected from fragile X syndrome, fragile X- associated tremor / ataxia syndrome, fragile X-associated primary ovarian insufficiency, fragile X-associated polycystic ovarian syndrome, and fragile XE-associated mental retardation.

[0128] 34. The use of item 32, wherein the fragile X associated disorder is fragile X syndrome.

[0129] 35. A method of treating or preventing a disease / disorder selected from a fragile X associated disorder, stroke, ischemia reperfusion injury, ischemic heart disease, hypertension, myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease, multiple sclerosis, spasticity, tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder, urinary incontinence, irritable bowel syndrome, faecal incontinence, constipation, gastro-oesophageal reflux disorder, impaired gastrointenstinal passage, detrusor underactivity, erectile dysfunction, opioid-induced respiratory depression, anxiety, an anxiety disorder, sensory processing disorder, autism, an autism spectrum disorder, a social or pragmatic communication disorder, attention deficit hyperactivity disorder, social phobia, intellectual disability, pain, epilepsy, an epilepsy and / or seizure disorder, Dravet syndrome, generalized epilepsy- paroxysmal dyskinesia syndrome, temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt- Hopkins syndrome, 16p11.2 deletion syndrome, Williams-Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis, migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome, Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia, DNMf-related disorder, DNMf-related epilepsy, DNMf-encephalopathy, CDKL5 deficiency disorder, KCNMA1 -I inked channelopathy, a KCNMB / -linked disorder, a KCNMB2-linked disorder, a KCNMB3-\ inked disorder, a KCNMB4-linked disorder, an LRRC26-linked disorder, an LRRC52-linked disorder, an LRRC55- linked disorder, and an LRRC38-linked disorder, the method comprising administering a therapeutically effective amount of the compound of any one of items 1 to 24 or the pharmaceutical composition of item 25 to a subject in need thereof. 36. A method of treating or preventing a fragile X associated disorder, the method comprising administering a therapeutically effective amount of the compound of any one of items 1 to 24 or the pharmaceutical composition of item 25 to a subject in need thereof.

[0130] 37. The method of item 36, wherein the fragile X associated disorder is selected from fragile X syndrome, fragile X-associated tremor / ataxia syndrome, fragile X-associated primary ovarian insufficiency, fragile X- associated polycystic ovarian syndrome, and fragile XE-associated mental retardation.

[0131] 38. The method of item 36, wherein the fragile X associated disorder is fragile X syndrome.

[0132] 39. The compound for use according to any one of items 26 to 30 or the pharmaceutical composition for use according to any one of items 26 to 30, the use of any one of items 31 to 34, or the method of any one of items 35 to 38, wherein the subject to be treated is a human.

[0133] 40. In vitro use of a compound as defined in any one of items 1 to 24 as a maxi-K potassium channel opener.

[0134] The present invention is also illustrated by the following figures:

[0135] Figure 1 : Effect of compound (1 a) (administered at a dose of 10, 20, 30 or 60 mg / kg) on AGS-induced WRJ (A), TCS (B) and death (C) in Fmr1 KO mice challenged with loud sounds (audiogenic seizure, AGS); see Example 9.

[0136] Figure 2: Phase 1 clinical study with compound (1 a), multiple dose crossover cohort with electroencephalography (EEG) measurements; see Example 10. Statistical probability maps (topography) of changes in specific power spectra of compound (1 a) versus placebo.

[0137] The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

[0138] EXAMPLES

[0139] The compounds described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly relates to the compound defined by the chemical formula.

[0140] Example 1 : Synthesis of compound (1a) ((3S)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6- (trifluoromethyl)indolin-2-one) and compound (1b) ((3R)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6- (trifluoromethyl)indolin-2-one)

[0141] Step 1 :

[0142] To a solution of 2-(2-methoxyphenyl)acetic acid (35 g, 210.62 mmol, 1 eq) in THF (400 mL) was added dropwise SO2CI2 (42.64 g, 315.93 mmol, 31 .59 mL, 1 .5 eq) at 0 °C. After addition, the mixture was stirred at 0 °C for 30 min. Then the mixture was warmed to 25 °C and stirred at 25 °C for 1.5 hours (hrs). LCMS showed the reaction was completed and one peak with desired m / z was detected. The reaction mixture was quenched by addition H2O (800 mL) at 0 °C, and then extracted with EtOAc 2400 mL (600 mL*4). The combined organic layers were washed with saturated brines 1600 mL (800 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The compound 2-(5-chloro-2-methoxyphenyl)acetic acid (58 g, crude) was obtained as a white solid and used into next step without further purification.

[0143] LCMS: ET17005-7-P1A (M+H+): 201.0@ 1.082 min

[0144] Step 2:

[0145] To a solution of 2-(5-chloro-2-methoxyphenyl)acetic acid (58 g, 289.11 mmol, 1 eq) in EtOH (600 mL) was added H2SO4 (12 M, 3.61 mL, 0.15 eq) and then the mixture was stirred at 80°C for 12 hrs. Thin-layer chromatography (TLC) indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=1 / 0 to 1 :0). The compound ethyl 2-(5-chloro-2-methoxyphenyl)acetate (24.3 g, 79.05 mmol, 27.34% yield, 74.39% purity) was obtained as a yellow oil.

[0146] LCMS: ET17005-17-P1 A (M+H+): 229.0 @ 1.236 min

[0147] 1H NMR (400 MHz, methanol-^) 3 ppm 7.25 - 7.20 (m, 1 H), 7.20 - 7.15 (m, 1 H), 6.91 (d, J = 12.0 Hz, 1 H), 4.20 - 4.10 (m, 2 H), 3.79 (s, 3 H), 3.33 (s, 2 H), 1.24 (t, J = 4.0 Hz, 3 H).

[0148] Step 3:

[0149] To a solution of ethyl 2-(5-chloro-2-methoxyphenyl)acetate (4 g, 17.49 mmol, 1 eq) and 1-fluoro-2-nitro-4- (trifluoromethyl)benzene (4.39 g, 20.99 mmol, 2.95 mL, 1.2 eq) in THF (40 mL) was added LIHMDS (1 M, 22.74 mL, 1 .3 eq) at -40°C. Then the mixture was warmed to 25 °C and stirred at 25 °C for 12 hrs. LCMS showed 14% of ethyl 2-(5-chloro-2-methoxyphenyl)acetate was remained. The reaction mixture was quenched by addition of saturated NH4C1 100 mL at 0°C, and then extracted with EtOAc 450 mL (150 mL*3). The combined organic layers were washed with saturated brines 300 mL (150 mL*2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=1 / 0 to 10:1). The compound ethyl 2-(5-chloro-2-methoxyphenyl)-2-(2-nitro-4-(trifluoromethyl)phenyl)acetate (3.2 g, 7.66 mmol, 43.79% yield) was obtained as a yellow solid.

[0150] LCMS: ET17005-18-P1 A (M+H+): 418.0 @ 1.366 min

[0151] 1H NMR (400 MHz, methanol-^) 3 ppm 8.23 (s, 1 H), 7.81 (d, J = 4.0 Hz, 1 H), 7.35 - 7.25 (m, 2 H), 7.10 (d, J = 4.0 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 5.79 (s, 1 H), 4.20 - 4.10 (m, 2 H), 3.64 (s, 3 H), 1.15 (t, J = 8.0 Hz, 3 H).

[0152] Step 4:

[0153] To a solution of ethyl 2-(5-chloro-2-methoxyphenyl)-2-(2-nitro-4-(trifluoromethyl)phenyl)acetate (400 mg, 957.48 pimol, 1 eq) in DMF (5 mL) was added NaH (57.45 mg, 1.44 mmol, 60% purity, 1.5 eq) slowly at 0 °C and stirred at 0 °C for 0.5 hr. Then to the mixture was added iodoethane (597.33 mg, 3.83 mmol, 306.32 piL, 4 eq). The mixture was stirred at 45°C for 1 hr under N2 atmosphere. TLC indicated the reaction was completed. The reaction mixture was quenched by addition H2O 100 mL at 25°C, and then extracted with EtOAc 100 mL (50 mL * 2). The combined organic layers were washed with saturated brines 80 mL (40 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=1 / 0 to 10 / 1). The compound ethyl 2-(5-chloro-2-methoxyphenyl)-2-(2-nitro-4- (trifluoromethyl)phenyl)butanoate (217 mg, 486.75 pimol, 50.84% yield) was obtained as a yellow oil.

[0154] 1H NMR (400 MHz, DMSO-d6) 6 ppm 7.86 (s, 1 H), 7.74 (d, J = 4.0 Hz, 1 H), 7.70 - 7.60 (m, 2 H), 7.30 - 7.20 (m, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 4.20 - 4.10 (m, 2 H), 3.33 (s, 3 H), 2.75 - 2.55 (m, 2 H), 1.14 (t, J = 8.0 Hz, 3 H), 0.82 (t, J = 8.0 Hz, 3 H).

[0155] Step 5:

[0156] To a solution of ethyl 2-(5-chloro-2-methoxyphenyl)-2-(2-nitro-4-(trifluoromethyl)phenyl)butanoate (197 mg, 441.89 pimol, 1 eq) in EtOH (3 mL) and H2O (1 mL) was added Na2S2C>4 (769.36 mg, 4.42 mmol, 961.69 piL, 10 eq) and stirred at 80 °C for 12 hrs. TLC indicated ethyl 2-(5-chloro-2-methoxyphenyl)-2-(2-nitro-4- (trifluoromethyl)phenyl)butanoate was consumed completely and two new spots formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=10 / 1 to 3: 1). The compound 3-(5-chloro-2-methoxyphenyl)-3- ethy l-6-(trifl uoromethy l)indoli n-2-one (65 mg, 169.11 pimol, 38.27% yield, 96.2% purity) was obtained as a white solid. LCMS: LCMS (M+H+): 370.0 @ 2.635 min

[0157] 1H NMR (400 MHz, DMSO-d6) 6 ppm 10.76 (s, 1 H), 7.58 (d, J = 4.0 Hz, 1 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.21 (d, J = 4.0 Hz, 1 H), 7.06 (s, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 1 H), 3.41 (s, 3 H), 2.30 - 2.20 (m, 1 H), 0.58 (t, J = 8.0 Hz, 3 H).

[0158] Step 6:

[0159] The compound 3-(5-chloro-2-methoxyphenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one (20 g) was purified by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALPAK AD (250mm*50mm, 10 pirn); mobile phase: [0.1 %NH3H2C IPA]; B%: 40%-40%, 7min). Then the crude product was triturated with Petroleum ether 50 mL at 20 °C for 2 hr. The mixture was filtered and the filter cake was concentrated under reduced pressure to give a residue. The compound (3R)-3-(5-chloro-2-methoxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one (8.5 g, 42.5% yield, 98.4% purity) was obtained as a white solid.

[0160] LCMS: LCMS of (3R)-3-(5-chloro-2-methoxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one (M+H+): 370.0 @ 2.909 min

[0161] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.75 (s, 1 H), 7.58 (d, J = 4.0 Hz, 1 H), 7.35 (d, J = 4.0 Hz, 1 H), 7.21 (d, J = 4.0 Hz, 1 H), 7.06 (s, 1 H),7.02 (d, J = 8.0 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 1 H), 3.41 (s, 3 H), 2.30 - 2.20 (m, 1 H), 2.15 - 2.00 (m, 1 H), 0.58 (t, J = 8.0 Hz, 3 H).

[0162] The crude product was triturated with Petroleum ether 200 mL at 20°C for 2 hr. The mixture was filtered and the filter cake was concentrated under reduced pressure to give a residue. The compound (3S)-3-(5-chloro-2-methoxy- pheny l)-3-ethy l-6-(trifl uoromethy l)indol in-2-one (8 g, 40% yield, 98.3% purity) was obtained as a white solid.

[0163] LCMS: LCMS of (3S)-3-(5-chloro-2-methoxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one (M+H+): 370.0 @ 2.909 min

[0164] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.75 (s, 1 H), 7.58 (d, J = 4.0 Hz, 1 H), 7.40 - 7.30 (m, 1 H), 7.21 (d, J = 4.0 Hz, 1 H), 7.06 (s, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 1 H), 3.41 (s, 3 H),2.30 - 2.20 (m, 1 H), 2.15 - 2.00 (m, 1 H), 0.58 (t, J = 8.0 Hz, 3 H). temporarily assigened

[0165] Step 7:

[0166] To a solution of (3R)-3-(5-chloro-2-methoxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one (500.00 mg, 1.35 mmol, 1 eq) in DCE (10 mL) was added B Bra (1 .69 g, 6.76 mmol, 651 .46 piL, 5 eq) at 0 °C under N2. The mixture was stirred at 50 °C for 2 hrs. LCMS showed the reaction was completed and one main peak with desired mass was detected. The reaction mixture was quenched by addition of saturated (sat.) NaHCOa 50 mL at 20°C, and then extracted with EtOAc 90 mL (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Combined with another batch (0.5 g scale) for purification. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*50mm*10um; mobile phase: [water (NH4HCO3) - ACN]; B%: 50% - 70%, 10 min). The compound (3R)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin- 2-one (99.44% purity) (0.4513 g, 47% yield) was obtained as a white solid.

[0167] LCMS: LCMS of (3R)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one (compound (1 b)) (M+H+): 356.0 @ 2.768 min

[0168] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.72 (s, 1 H), 9.74 (s, 1 H), 7.48 (d, J = 4.0 Hz, 1 H), 7.25 - 7.15 (m, 2 H), 7.04 (d, J = 8.0 Hz, 2 H), 6.63 (d, J = 8.0 Hz, 1 H), 2.30 - 2.20 (m, 1 H), 2.15 - 2.00 (m, 1 H), 0.58 (t, >8.0 Hz, 3 H). Synthesis of compound (1a) ((3S)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one) temporarily assigened

[0169] Step 8:

[0170] To a solution of (3S)-3-(5-chloro-2-methoxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one (1 g, 2.70 mmol, 1 eq) in DCE (20 mL) was added BBra (3.39 g, 13.52 mmol, 1.30 mL, 5 eq) at O °C under N2. The mixture was stirred at 50 °C for 2 hrs. LCMS showed the reaction was completed and one main peak with desired mass was detected. The reaction mixture was quenched by addition of sat. NaHCOa 100 mL at 20°C, and then extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*50mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 50%-70%, 10min). The compound (3S)-3-(5-chloro- 2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one (521.80 mg, 1.47 mmol, 54.24% yield, 100% purity) was obtained as a white solid.

[0171] LCMS: LCMS of (3S)-3-(5-chloro-2-hydroxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one (compound (1 a)) (M+H+): 356.0 @ 2.769 min

[0172] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.72 (s, 1 H), 9.74 (s, 1 H), 7.48 (d, J = 4.0 Hz, 1 H), 7.25 - 7.10 (m, 2 H), 7.04 (d, J = 8.0 Hz, 2 H), 6.63 (d, J = 8.0 Hz, 1 H), 2.30 - 2.20 (m, 1 H), 2.15 - 2.00 (m, 1 H), 0.58 (t, J = 8.0 Hz, 3 H).

[0173] Example 2: Synthesis of compound (2) (4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one) Step 1 :

[0174] To a mixture of Mg (1.69 g, 69.44 mmol, 5 eq) and I2 (352.48 mg, 1.39 mmol, 279.74 pL, 0.1 eq) in THF (20 mL) was added dropwise 2-bromo-4-chloro-1 -methoxy-benzene (9.23 g, 41.66 mmol, 3 eq) in THF (10 mL) at O °C. After addition, the reaction mixture was stirred at 40 °C for 0.5 hr (stage 1). To a solution of 4, 6-dichloroindolin-2, 3-dione (3 g, 13.89 mmol, 1 eq) in THF (10 mL) was addded NaH (833.17 mg, 20.83 mmol, 60% purity, 1.5 eq) at 0 °C, the mixture was stirred at 15 °C for 0.5 hr. The solution of stage 1 was added to the mixture at 0 °C and the reaction mixture was stirred at 15 °C for 15 hrs. TLC indicated starting material was consumed completely and one new spot formed. The residue was diluted with H2O (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with H2O (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 1). The compound 4,6-dichloro-3-(5-chloro-2-methoxy-phenyl)-3-hydroxy-indolin-2-one (3.5 g, 9.76 mmol, 70.28% yield) was obtained as a yellow solid.

[0175] Step 2:

[0176] To a solution of 4,6-dichloro-3-(5-chloro-2-methoxy-phenyl)-3-hydroxy-indolin-2-one (2 g, 5.58 mmol, 1 eq) in DCM (20 mL) was added SOCI2 (3.32 g, 27.89 mmol, 2.02 mL, 5 eq) at 15 °C. The mixture was stirred at 50 °C for 12 hrs under N2. TLC indicated the starting material was consumed completely. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=8 / 1 to 1 / 1). The compound 3,4, 6-trichloro-3-(5-chloro-2-methoxy-phenyl)indolin-2-one (1.7 g, 4.51 mmol, 80.84% yield) was obtained as a yellow solid.

[0177] Step 3:

[0178] To a solution of 3,4,6-trichloro-3-(5-chloro-2-methoxy-phenyl)indolin-2-one (1.5 g, 3.98 mmol, 1 eq) in THF (30 mL) was added AIMea (2 M, 15.91 mL, 8 eq) at 0 °C. The mixture was stirred at 50 °C for 12 hrs. LCMS indicated starting material was consumed. The reaction mixture was quenched with H2O (50 mL), diluted with EtOAc (50 mL) and filtered. The organic phase was separated, and the aqueous phase was extracted with EtOAc (30 mL * 2). The combined organic layers were washed with H2O (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C 18250*50 mm*15 pm; mobile phase: [water (0.05% HCI)-ACN]; B%: 45%-70%, 20 min). The compound 4,6-dichloro-3-(5- chloro-2-methoxy-phenyl)-3-methyl-indolin-2-one (716 mg, 2.01 mmol, 50.47% yield) was obtained as a white solid. LCMS: (M+H)+: 356.0&358.0 @ 2.528 min

[0179] Step 4:

[0180] To a solution of 4,6-dichloro-3-(5-chloro-2-methoxy-phenyl)-3-methyl-indolin-2-one (100 mg, 280.40 pmol, 1 eq) in DCM (5 mL) was added BBra (140.49 mg, 560.80 pmol, 54.04 pL, 2 eq) at 0 °C. The mixture was stirred at 15 °C for 5 hrs. TLC indicated starting material was consumed completely. The reaction mixture was quenched by addition of H2O (5 mL) at 15 °C, extracted with DCM (5 mL * 2). The combined organic layers were washed with H2O (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C 18 100*25 mm*5 pm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 40%-57%, 10 min). The compound 4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl- indolin-2-one (11.6 mg, 33.78 pimol, 12.05% yield, 99.76% purity) was obtained as a white solid.

[0181] LCMS: (M+H)+: 342.0&344.0 @ 2.334 min

[0182] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.82 (s, 1 H), 9.74 (s, 1 H),7.46 (d, J = 4.0 Hz, 1 H), 7.20 - 7.10 (m, 1 H), 6.97 (d, J = 4.0 Hz, 1 H), 6.86 (d, J = 4.0 Hz, 1 H), 6.65 (d, J = 8.0 Hz, 1 H), 1.65 (s, 3 H).

[0183] Example 3: Synthesis of compound (2a) ((3R)-4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2- one) and compound (2b) ((3S)-4, 6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one) compound (2b) compound (2a) temporarily assigened temporarily assigened

[0184] Step 1 :

[0185] To a solution of 4, 6-dichloroindoline-2, 3-dione (100 g, 462.92 mmol, 1 eq) in THF (1000 mL) was added dropwise MeMgBr (3 M, 462.92 mL, 3 eq) at -60 °C over 30 min in 2 L three-neck bottle under N2. After addition, the mixture was stirred at -60 °C for 1 h, and then the resulting mixture was stirred at 20 °C for 2 hrs. TLC (Petroleum Ether: EtOAc = 2: 1) indicated starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition of aqueous (aq.) NH4C1 1600 mL at 20 °C, and then diluted with H2O 1000 mL and extracted with EtOAc 6000 mL (2000 mL * 3). The combined organic layers were washed with brine 2000 mL (1000 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with Petroleum ether : Ethyl acetate=10:1 (200 mL) at 20 °C for 30 min. The compound 4,6-dichloro- 3-hydroxy-3-methyl-indolin-2-one (88 g, 712.63 mmol, 76.97% yield, 94.5% purity) was obtained as light yellow solid. LCMS: (M+1): 230.1 232.1 @ 0.635 min

[0186] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.62 (s, 1 H),7.09 (d, J = 2.0 Hz, 1 H), 6.81 (d, J = 1.6 Hz, 1 H), 6.05 (s, 1 H), 1.47 (s, 3 H).

[0187] Step 2:

[0188] To a solution of 4,6-dichloro-3-hydroxy-3-methyl-indolin-2-one (50 g, 215.46 mmol, 1 eq) in DCE (1500 mL) was added Cui (20.52 g, 107.73 mmol, 0.5 eq) and 4-chlorophenol (41.55 g, 323.19 mmol, 31.72 mL, 1.5 eq) at -35 °C. The mixture was degassed and purged with N2 for 3 times. The mixture was added TfOH (64.67 g, 430.92 mmol, 38.04 mL, 2 eq) at -35 °C under N2. The mixture was stirred at -35 °C for 1 h under N2, and then the resulting mixture was stirred at 20 °C for 9 hrs. TLC (Petroleum Ether: EtOAc = 2:1) indicated starting material was consumed completely and one new spot formed. The reaction mixture was quenched by aq. NaHCOa 800 mL at 20 °C, and extracted with EtOAc (800 mL * 3). The combined organic layers were washed with brine 2000 mL (1000 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with the mixture solution (Petroleum Ether: EtOAc = 8:1 , 100 mL) at 20 °C for 60 min. The compound 4,6- dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one (65 g, 183.66 mmol, 85.24% yield, 97.4% purity) was obtained as slight yellow solid.

[0189] LCMS: (M-1): 340.1 342.1 @ 0.822 min

[0190] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.83 (s, 1 H),9.75 (s, 1 H),7.45 (d, J = 2.4Hz, 1 H), 7.18 (t, J=4.0Hz, 1 H), 6.96 (d, J = 2.0Hz, 1 H), 6.85 (d, J = 4.0Hz, 1 H), 6.64 (d, J = 8.0Hz, 1 H), 1 .64 (s, 3H).

[0191] Step 3:

[0192] The racemate product 4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one (215 g, 627.28 mmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: [0.1 %NH3H2O IPA];B%: 40%-40%,7.5min) to get the two crude products.

[0193] Peak 1 (compound (2b)): The product was concentrated under reduced pressure and triturated with Petroleum ether 500mL at 20 °C for 12 h. The mixture was filtered and the filter cake was concentrated under reduced pressure to give a residue. The compound (3S)-4, 6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one (102.08 g, 47.5% yield, 99.81% purity) was obtained as yellow solid.

[0194] LCMS: (M-1): 340.0 342.0@ 3.100 min.

[0195] 1H NMR (400 MHz, methanol-^) 3 ppm 7.50 (d, J = 2.4 Hz, 1 H), 7.15 - 7.10 (m, 1 H), 6.89 (t, J = 2.0 Hz, 2 H), 6.64 (d, J = 8.0 Hz, 1 H), 1.75 (s, 3 H).

[0196] Peak 2 (compound (2a)): The product was concentrated under reduced pressure and triturated with Petroleum ether 300 mL at 20 °C for 60 min. The mixture was filtered and the filter cake was concentrated under reduced pressure to give a residue. The compound (3R)-4,6-dichloro-3-(5-chloro-2-hydroxy-phenyl)-3-methyl-indolin-2-one (101.26 g, 294.55 mmol, 47.10 yield, 99.66% purity) was obtained as yellow solid.

[0197] LCMS: (M-1): 340.0 341.9 @ 3.063 min.

[0198] 1H NMR (400 MHz, methanol-^) 3 ppm 7.50 (d, J = 2.4 Hz, 1 H), 7.15 - 7.10 (m, 1 H), 6.90 - 6.85 (m, 2 H), 6.64 (d, J = 8.0 Hz, 1 H), 1.76 (s, 3 H).

[0199] Example 4: Synthesis of compound (3a) (2-[(3S)-3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6-

[0200] (trifluoromethyl)indolin-3-yl]acetonitrile) and compound (3b) (2-[(3R)-3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6-

[0201] (trifluoromethyl)indolin-3-yl]acetonitrile)

[0202]

[0203] Step 1 :

[0204] To a solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (100 g, 498.46 mmol, 1 eq) in EtOH (1000 mL) was added H2SO4 (7.33 g, 74.77 mmol, 3.99 mL, 0.15 eq). The mixture was stirred at 80 °C for 12 hr. TLC indicated 2-(5-chloro- 2-methoxy-phenyl)acetic acid was consumed completely and two new spots formed. The reaction mixture was concentrated under reduced pressure to give a residue. 6 batches were done in parallel and combined for the purification. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=40 / 1 to 5 / 1). The compound ethyl 2-(5-chloro-2-methoxy-phenyl)acetate (480 g, 2.10 mol, 70.19% yield) was obtained as a yellow oil. Step 2:

[0205] To a solution of ethyl 2-(5-chloro-2-methoxy-phenyl)acetate (128 g, 559.75 mmol, 1 eq) and 1-fluoro-2-nitro-4- (trifluoromethyl)benzene (140.45 g, 671.71 mmol, 94.26 mL, 1.2 eq) in THF (1000 mL) was dropwise added LiHMDS (1 M, 1.50 L, 2.68 eq) at -40 °C under N2. The mixture was stirred at 25 °C for 12 hr. TLC indicated ethyl 2-(5-chloro-

[0206] 2-methoxy-phenyl)acetate was consumed completely and many new spots formed. The reaction mixture was cooled to 0 °C, poured into sat. NH4CI aq. 2000 mL at 0 °C and stirred at 25 °C for 0.5 h, then extracted with EtOAc 1500 mL (500 mL * 3). The combined organic layers were washed with brine 1200 mL (400 mL * 3), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=1 / 0 to 50 / 1). The compound ethyl 2-(5-chloro-2- methoxy-phenyl)-2-[2-nitro-4-(trifluoromethyl)phenyl]acetate (150 g, 359.06 mmol, 64.15% yield) was obtained as white solid.

[0207] 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.41 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.50 - 7.40 (m, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 4.0 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 5.79 (s, 1 H), 4.20 - 4.10 (m, 2 H), 3.70 (s, 3 H), 1.20 - 1.10 (m, 3 H).

[0208] Step 3:

[0209] To a solution of ethyl 2-(5-chloro-2-methoxy-phenyl)-2-[2-nitro-4-(trifluoromethyl)phenyl]acetate (50 g, 119.69 mmol, 1 eq) in DMA (200 mL) was added NaH (7.18 g, 179.53 mmol, 60% purity, 1.5 eq) at 0 °C under N2, after 0.5 h,

[0210] 3-iodoprop-1-ene (40.21 g, 239.37 mmol, 21.85 mL, 2 eq) was added to the mixture and then the mixture was stirred at 20 °C for 4.5 h under N2. TLC indicated ethyl 2-(5-chloro-2-methoxy-phenyl)-2-[2-nitro-4- (trifluoromethyl)phenyl]acetate was consumed completely and many new spots formed. 7 batches were done in parallel and combined for the purification. The reaction mixture was cooled to 0 °C and then quenched by adding NH4CI 2000 mL dropwise at 0 °C under N2, after that the resulting mixture was stirred at 0 °C for 30 min, extracted with EtOAc 2400 mL (800 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=1 / 0 to 50 / 1). The compound ethyl 2-(5-chloro-2-methoxy-phenyl)-2-[2-nitro-4- (trifl uoromethy l)pheny I] pent-4-enoate (270 g, 589.74 mmol, 51 .92% yield) was obtained as white solid.

[0211] 1H NMR (400 MHz, CHLOROFORM-d) 7.90 (s, 1 H), 7.70 - 7.60 (m, 2 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.30 - 7.25 (m, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.70 - 5.60 (m, 1 H), 5.00 - 4.90 (m, 2 H), 4.25 - 4.10 (m, 2 H), 3.45 - 3.30 (m, 5 H), 1.18 (t, J = 4.0 Hz, 3 H).

[0212] Step 4:

[0213] To a solution of ethyl 2-(5-chloro-2-methoxy-phenyl)-2-[2-nitro-4-(trifluoromethyl)phenyl]pent-4-enoate (50 g, 109.21 mmol, 1 eq) in AcOH (500 mL) was added Fe (18.30 g, 327.63 mmol, 3 eq) at 60 °C. The mixture was stirred at 60 °C for 12 hr. LC-MS showed no ethyl 2-(5-chloro-2-methoxy-phenyl)-2-[2-nitro-4-(trifluoromethyl)phenyl]pent-4- enoate remained. Several new peaks were shown on LC-MS and -80% of desired compound was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=10 / 1 to 3 / 1). The compound 3-allyl-3- (5-chloro-2-methoxy-phenyl)-6-(trifluoromethyl)indolin-2-one (160 g, 389.76 mmol, 71.38% yield) was obtained as white solid. LCMS(M+H+): 382.2 @ 0.985 min

[0214] 1H NMR (400 MHz, CHLOROFORM-d) 9.32 (s, 1 H), 7.50 (d, J = 4.0 Hz, 1 H), 7.25 - 7.15 (m, 1 H), 7.15 - 7.10 (m, 1 H), 7.05 (s, 1 H), 6.89 (d, J = 8.0 Hz, 1 H), 6.67 (d, J = 8.0 Hz, 1 H), 5.40 - 5.30 (m, 1 H), 4.99 (d, J = 16.0 Hz, 1 H), 4.91 (d, J = 12.0 Hz, 1 H), 3.39 (s, 3 H), 3.00 - 2.90 (m, 2 H).

[0215] Step 5:

[0216] Ozone (6.29 g, 130.97 mmol, 1 eq) was bubbled into a solution of 3-allyl-3-(5-chloro-2-methoxy-phenyl)-6- (trifluoromethyl)indolin-2-one (50 g, 130.97 mmol, 1 eq) in DOM (1000 mL) at -78 °C for 120 minutes. After excess O3 was purged by O2, Me2S (81.37 g, 1.31 mol, 96.19 mL, 10 eq) was added at -78 °C. The resulting mixture was stirred at 25 °C for 3 hr. TLC indicated 3-allyl-3-(5-chloro-2-methoxy-phenyl)-6-(trifluoromethyl)indolin-2-one was consumed completely and two new spots formed. The reaction mixture was diluted by NaHCOa (500 mL) at 25 °C under N2 atmosphere, extracted with DCM (200 mL * 3), dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product 2-[3-(5-chloro-2-methoxy-phenyl)-2-oxo-6- (trifluoromethyl)indolin-3-yl]acetaldehyde (50 g, crude) as yellow oil was used into the next step without further purification.

[0217] Step 6:

[0218] To a solution of hydroxylamine hydrochloride (13.58 g, 195.44 mmol, 1.5 eq) in H2O (500 mL) was added Na2COa (6.90 g, 65.15 mmol, 0.5 eq) and 2-[3-(5-chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetaldehyde (50 g, 130.29 mmol, 1 eq) in EtOH (500 mL) at 25 °C. The mixture was stirred at 25 °C for 4 hr. LC-MS showed no 2-[3-(5-chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetaldehyde remained. Several new peaks were shown on LC-MS and -82% of desired compound was detected. The reaction mixture was diluted with H2O 500 mL and extracted with EtOAc 900 mL (300 mL * 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product (1 E)-2-[3-(5-chloro-2- methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetaldehyde oxime (50 g, crude) as yellow solid was used into the next step without further purification.

[0219] LCMS(M+H+): 399.2 @ 0.865 min

[0220] Step 7:

[0221] To a solution of (1 E)-2-[3-(5-chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetaldehyde oxime (50 g, 125.39 mmol, 1 eq) in DCM (500 mL) was added GDI (40.66 g, 250.78 mmol, 2 eq). The mixture was stirred at 25 °C for 2 hr. TLC indicated (1 E)-2-[3-(5-chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetaldehyde oxime was consumed completely and two new spots formed. The reaction mixture was diluted with H2O 1000 mL and extracted with DCM 900 mL (300 mL * 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=10 / 1 to 5 / 1). The compound 2-[3-(5-chloro-2-methoxy- phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile (30 g, 72.49 mmol, 57.81 % yield, 92% purity) was obtained as a white solid. Step 8:

[0222] 2-[3-(5-Chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile (250 g) was purified by SFC (Column ChiralPak IH, 250*50mm, 10um; Condition 0.1 %NH3H2C IPA Begin B 40% End B 40% Gradient Time(min) 7).

[0223] Peak 1 : The compound 2-[(3R)-3-(5-chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile (95.5 g, 37.36% yield, 97.8% purity) was obtained as white solid.

[0224] Peak 2: The compound 2-[(3S)-3-(5-chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile (92.2 g, 35.77% yield, 97% purity) was obtained as white solid.

[0225] Step 9:

[0226] To a solution of 2-[(3R)-3-(5-chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile (500 mg, 1.31 mmol, 1 eq) in DCE (10 mL) was added BBrs (1.64 g, 6.57 mmol, 569.40 piL, 5 eq) at 0 °C under N2. The mixture was stirred at 50 °C for 2 hr. LCMS showed 2-[(3R)-3-(5-chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-

[0227] 3-yl]acetoni trile was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition of aq. NaHCOa 50 mL at 20 °C, and then extracted with EtOAc 90 mL (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*50mm*10um; mobile phase: [water ( NH4HCO3)-ACN]; B%: 40%-60%, 10min). The compound 2-[(3R)-3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6- (trifluoromethyl)indolin-3-yl]acetonitrile (64 mg, 13.29% yield, 97.4% purity) was obtained as a white solid.

[0228] LCMS: (M+1): 367.0 369.0 @ 2.534 min

[0229] 1H NMR (400 MHz, DMSO-d6) 5 ppm 11.05 (s, 1 H), 10.10 - 10.00 (m, 1 H), 7.48 (d, J = 12.0 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.21 (t, J = 8.0 Hz, 2 H), 7.11 (s, 1 H),6.67 (t, J = 4.0 Hz, 1 H), 3.70 (d, J = 16.0 Hz, 1 H), 3.46 (d, J = 16.0 Hz, 1 H).

[0230] Step 10:

[0231] To a solution of 2-[(3S)-3-(5-chloro-2-methoxy-pheny l)-2-oxo-6-(trifl uoromethy l)indol in-3-y l]acetoni trile (450 mg, 1 .18 mmol, 1 eq) in DCE (15 mL) was added BBrs (1.48 g, 5.91 mmol, 569.40 piL, 5 eq) at O°C under N2. The mixture was stirred at 50°C for 2 hr. LCMS showed 2-[(3S)-3-(5-chloro-2-methoxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3- yl]acetonitrile was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition of NaHCOs 50 mL at 20°C, and then extracted with EtOAc 90 mL (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Combined with another batch (50 mg scale) for purification. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*50mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 40%-60%, 10min). The compound 2-[(3S)-3-(5-chloro-2-hydroxy-phenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile (93.87% purity) (127 mg, 26.37% yield) was obtained as a white solid.

[0232] LCMS: (M+1): 367.0 369.0 @ 2.536 min

[0233] 1H NMR (400 MHz, DMSO-d6) 5 ppm 11.02 (s, 1 H), 10.05 (d, J = 12.0 Hz, 1 H), 7.50 (s, 1 H), 7.30 - 7.15 (m, 3 H), 7.11 (s, 1 H),6.68 (d, J = 8.0 Hz, 1 H), 3.71 (d, J = 16.0 Hz, 1 H), 3.47 (d, J = 16.0 Hz, 1 H). Example 5: Synthesis of compound (4a) ((3S)-3-(4-chloro-2-hydroxy-phenyl)-3-methyl-6- (trifluoromethyl)indolin-2-one) and compound (4b) ((3R)-3-(4-chloro-2-hydroxy-phenyl)-3-methyl-6- (trifluoromethyl)indolin-2-one)

[0234] Step 1 :

[0235] To a solution of 2-(4-chloro-2-methoxy-phenyl)acetic acid (200 g, 996.92 mmol, 1 eq) in EtOH (1000 mL) was added H2SO4 (48.89 g, 498.46 mmol, 26.57 mL, 0.5 eq) at 20 °C under N2. The mixture was stirred at 80 °C for 12 hr. TLC indicated starting material was consumed completely, and one major new spot was detected. Combined with other 6 batches (200 g scales). The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O 500 mL and extracted with EtOAc 1500 mL (500 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with PE:EA = 8:1 at 20 °C for 60 min. The compound ethyl 2-(4-chloro-2-methoxy-phenyl)acetate (350 g, 22% yield, 98% purity) was obtained as a white solid.

[0236] LCMS: (M+1): 229.2 @ 0.493 min.

[0237] 1H NMR (400 MHz, chloroform-d) 5 ppm 7.12 (d, J = 8.0 Hz, 1 H), 6.93 (t, J = 1.6 Hz, 1 H), 6.88 (d, J = 4.0 Hz, 1 H), 4.25 - 4.10 (m, 2 H), 3.83 (s, 3 H), 3.59 (s, 2 H), 1.27 (t, J = 8.0 Hz, 3 H). Step 2:

[0238] To a solution of ethyl 2-(4-chloro-2-methoxy-phenyl)acetate (35 g, 153.06 mmol, 1 eq) in THF (350 mL) was added LiHMDS (1 M, 168.36 mL, 1.1 eq) at -60 °C under N2 for 1 hr. Then the mixture was added 1-fluoro-2-nitro-4- (trifluoromethyl)benzene (32.00 g, 153.06 mmol, 21.48 mL, 1 eq) at -60 °C under N2 for 0.5 hr. The mixture was stirred at -60 °C for 3.5 hr. TLC indicated starting material was consumed completely, and one major new spot was detected. Combined with other 4 batches (35 g scales). The reaction mixture was quenched by aq. NH4C1 1000 mL, and then extracted with EtOAc 3000 mL (1000 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with PE:EA = 5:1 at 20 °C for 60 min. The compound ethyl 2-(4-chloro-2-methoxy-phenyl)-2-[2-nitro-4-(trifluoromethyl)phenyl]acetate (180 g, 56% yield, 100% purity) was obtained as a white solid.

[0239] 1H NMR (400 MHz, chloroform-d) 5 ppm 8.24 (s, 1 H), 7.71 (d, J= 8.0 Hz, 1 H), 7.35 -7.25 (m, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 7.05 - 6.95 (m, 1 H), 6.89 (d, J = 1.6 Hz, 1 H), 5.90 (s, 1 H), 4.30 - 4.20 (m, 2 H), 3.71 (s, 3 H), 1.26 (t, J=8.0Hz, 3 H).

[0240] Step 3:

[0241] To a mixture of ethyl 2-(4-chloro-2-methoxy-phenyl)-2-[2-nitro-4-(trifluoromethyl)phenyl]acetate (30 g, 71.81 mmol, 1 eq) in DMF (300 mL) was added NaH (4.31 g, 107.72 mmol, 60% purity, 1.5 eq) in portions at 0 °C under N2. The mixture was added Mel (61.16 g, 430.87 mmol, 26.82 mL, 6 eq) at 0 °C under N2. The mixture was stirred at 20 °C for 3 hrs. TLC indicated starting material was consumed completely, and one major new spot formed. Combined with another batch (30 g scale). The reaction mixture was quenched by aq. NH4CI (1000 mL) at 25 °C, extracted with EtOAc (1000 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with PE:EA = 5: 1 at 20 °C for 30 min. The compound ethyl 2-(4-chloro-2-methoxy-phenyl)- 2-[2-nitro-4-(trifl uoromethy l)pheny I] propanoate (40 g, 64.5% yield) was obtained as a white solid.

[0242] Step 4:

[0243] A mixture of ethyl 2-(4-chloro-2-methoxy-phenyl)-2-[2-nitro-4-(trifluoromethyl)phenyl]propanoate (40 g, 92.64 mmol, 1 eq) in AcOH (70 mL) was degassed and purged with N2 for 3 times at 15 °C, and then the mixture was added Fe (25.87 g, 463.19 mmol, 5 eq) at 60 °C for 2 hrs under N2 atmosphere. TLC indicated starting material was consumed completely and one main new spot formed. Filter the reaction solution and concentrated under reduced pressure to give a residue. The compound 3-(4-chloro-2-methoxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one (30 g, crude) was obtained as a black oil. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate=10 / 1 to 3 / 1). Then the residue was further separated by SFC (condition: column: DAICEL CHIRALPAK AS (250mm*50mm, 10um); mobile phase: [Neu-IPA]; B%: 30%-30%, B4; 150min).

[0244] Peak 1 : The compound (3S)-3-(4-chloro-2-methoxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one (6 g, 16.87 mmol, 20.00% yield) was obtained as a white solid.

[0245] Peak 2: The compound (3R)-3-(4-chloro-2-methoxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one (6.1 g, 17.15 mmol, 20.33% yield) was obtained as a white solid. Step 5:

[0246] To a mixture of (3S)-3-(4-chloro-2-methoxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one (900 mg, 281.11 pmol, 1 eq) in DCE (18 mL) was added BBra (3.17 g, 12.65 mmol, 1.22 mL, 5 eq) at 0°C under N2, then heated to 50°C and stirred for 2 hrs. LCMS showed (3S)-3-(4-chloro-2-methoxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition of NaHCOa 50 mL at 20°C, and then extracted with EtOAc 90 mL (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Combined with another batch (100 mg scale) for purification. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*50 mm*10 pim; mobile phase: [water (NH4HCO3) -ACN]; B%: 40%-60%, 10min). The compound (3S)-3-(4-chloro- 2-hydroxy-pheny l)-3-methy l-6-(trifluoromethy l)indoli n-2-one (99.72% purity) (360.8 mg, 37.6% yield) was obtained as a white solid.

[0247] LCMS: (M+1): 342.0 344.0 @ 2.654 min

[0248] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.68 (s, 1 H), 9.93 (s, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.19 (d, J = 4.0 Hz, 1 H), 7.07 (s, 1 H), 7.00 - 6.90 (m, 2 H), 6.65 (s, 1 H), 1.57 (s, 3 H).

[0249] Step 6:

[0250] To a mixture of (R)-3-(4-chloro-2-methoxyphenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one (900 mg, 281.11 pmol, 1 eq) in DCE (18 mL) was added BBra (3.17 g, 12.65 mmol, 1.22 mL, 5 eq) at 0°C under N2, then heated to 50 °C and stirred for 2 hrs. LCMS showed (3R)-3-(4-chloro-2-methoxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one (900.00 mg, 2.53 mmol, 1 eq) was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition of NaHCOa 50 mL at 20°C, and then extracted with EtOAc 90 mL (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Combined with another batch (100 mg scale) for purification. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*50mm*10um; mobile phase: [water (NhhHCOsJ-ACN]; B%: 40%-60%, 10 min). The compound (3R)-3-(4-chloro-2-hydroxy-phenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one (99.52% purity) (418.3 mg, 43.6% yield) was obtained as a white solid.

[0251] LCMS: (M+1): 342.0 344.0 @ 2.654 min.

[0252] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.69 (s, 1 H), 9.98 (s, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.08 (s, 1 H), 6.95 (t, J = 8.0 Hz, 2 H), 6.66 (s, 1 H), 1.57 (s, 3 H).

[0253] Example 6: Synthesis of Compound (5) (3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6-(trifluoromethyl)indolin- 2-one)

[0254] EtMgBr, DCM, THF

[0255] 0 25 °C, 5 h

[0256] 1 2 compound (5) To a solution of 4-chlorophenol (358.55 mg, 2.79 mmol, 273.70 piL, 1.2 eq) in THF (10mL) was added EtMgBr (3 M, 0.85 mL, 1 .10 eq) at 25 °C. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was added to a solution of 6-(trifluoromethyl)indolin-2, 3-dione (500.00 mg, 2.32 mmol, 1 eq) in DCM (10 mL) at 0°C under N2 atmosphere. Then the mixture was stirred at 25°C for 5 hrs. The reaction mixture was partitioned between H2O (50 mL) and ethyl acetate (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (NH3-H2O condition). The compound 3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6- (trifl uoromethy l)i ndolin-2-one (290 mg, 835.36 pimol, 35.94% yield, 99% purity) was obtained as a red solid.

[0257] LCMS: NEG (M-H+) 341 .9 @ 2.611 min.

[0258] 1H NMR: (400 MHz, DMSO-d6) 5 ppm 10.60 (s, 1 H), 9.80 (s, 1 H), 7.71 (s, 1 H), 7.25 - 7.10 (m, 2 H), 7.06 (d, J = 8.0 Hz, 1 H), 7.03 (s, 1 H), 6.83 (s, 1 H), 6.61 (d, J = 8.0 Hz, 1 H).

[0259] Example 7: Primary pharmacology (BK channel opener efficacy)

[0260] The BK channel opener efficacy of the compounds (1 a), (1 b), (2a), (2b), (3a), (3b), (4a) and (4b) as well as the reference compounds 3-(5-chloro-2-hydroxyphenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one, (S)-3-(5-chloro-2- hydroxyphenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one, (R)-3-(5-chloro-2-hydroxyphenyl)-3-methyl-6-

[0261] (trifluoromethyl)indolin-2-one, 3-(5-chloro-2-methoxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one, (3S)-3-(5- chloro-2-methoxy-phenyl)-3-ethyl-6-(trifluoromethyl)indolin-2-one, (3R)-3-(5-chloro-2-methoxy-phenyl)-3-ethyl-6- (trifluoromethyl)indolin-2-one, 2-[(3S)-3-(5-chloro-2-methoxyphenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile,

[0262] 2-[(3R)-3-(5-chloro-2-methoxyphenyl)-2-oxo-6-(trifluoromethyl)indolin-3-yl]acetonitrile, (3S)-3-(4-chloro-2- methoxyphenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one and (3R)-3-(4-chloro-2-methoxyphenyl)-3-methyl-6- (trifluoromethyl)indolin-2-one at the human BK (KCa1.1) channel was assessed using an automated patch-clamp platform (SynchroPatch384i, Nanion). Specifically, the ability of test compounds to potentiate BK current activated by 600 nM intracellular calcium (i[Ca2+]) in HEK TRex FlplN / KCa1 .1 cells was determined. Efficacy of a test compound is defined as a % increase in the whole cell current (I) observed with 600 nM I [Ca2+] alone at a particular test compound concentration.

[0263] The table below summarizes the comparative efficacy of the tested compounds at human BK channels. Activation of BK channels is expressed as a % increase in opener activity of 600 nM i[Ca2+] alone. * Note: Activation of BK channels by (S)-3-(5-chloro-2-hydroxyphenyl)-3-methyl-6-(trifluoromethyl)indolin-2-one and (R)-3-(5-chloro-2-hydroxyphenyl)-

[0264] 3-methyl-6-(trifluoromethyl)indolin-2-one is expressed as a % of full activation of BK channels by the reference opener NS11021 (i.e., N'-[3,5-bis(trifluoromethyl)phenyl]-N-[4-bromo-2-(2H-tetrazol-5-yl-phenyl]thiourea, CAS no. 956014- 19-0; 30 piM) in presence of 600 nM i[Ca2+],

[0265]

[0266] These results show that all tested compounds potentiate the calcium-dependent activation of human BK channels and are thus effective as BK channel openers. Notably, however, the compounds according to the present invention were found to have an outstandingly potent BK channel opener activity. In particular, compounds (1 a), (1 b), (2a) and (2b) exhibited a remarkably superior activity in comparison to the structurally closest reference compounds, i.e. the corresponding stereoisomers of Examples 4 and 5 of WO 2021 / 234084.

[0267] Example 8: Behavioral pharmacology

[0268] The efficacy of compounds (1 a) and (2a) in reversing / rescuing syndrome-relevant phenotypes in a genetic mouse model of FXS (Fmr1 KO2) was investigated. Specifically, the in vivo pharmacology of both compounds (3, 10, and 30 mg / kg) was evaluated in a battery of seven separate behavioral paradigms described below following chronic (14- day) oral (po) administration of test compound.

[0269] Hyperactivity

[0270] Studies have estimated that 66% of boys and 30% of girls with FXS display abnormally elevated levels of hyperactivity (Bailey DB Jr et al., Am J Med Genet A, 2008, 146A(16):2060-9, doi: 10.1002 / ajmg.a.32439). Hyperactivity in mice can be reliably measured in an open field test, where elevation in total distance traveled is a surrogate measure to hyperactivity (Cogram P et al., Front Behav Neurosci, 2019, 13:141 , doi: 10.3389 / fnbeh.2019.00141). Elevated hyperactivity is a consistent and robust phenotype expressed in genetic mouse models of FXS. In the open field, chronic (14-day) oral administration of either compound (1 a) or compound (2a) significantly reduced total distance traveled by Fmr1 KO2 mice, with a minimum effective dose (MED) of 10 and 3 mg / kg respectively. Full rescue of the hyperactivity phenotype, defined as normalization of hyperactivity to levels of wild-type (normal control) mice was also observed with both compounds, and no evidence of tolerance to effects with repeat dosing.

[0271] Aggression

[0272] Aggressive behavior is common in both males and females with FXS (Wheeler AC et al., J Intellect Disabi I Res, 2016, 60(2):113-25, doi: 10.1111 / jir.12238). Mounting behavior is an aggressive expression of social dominance, and common endpoint for quantifying aggressive behaviors in mice. Fmr1 KO2 mice exhibit significant increases in mounting behavior when compared to wild-type mice (Cogram P et al., Front Behav Neurosci, 2019, 13: 141 , doi: 10.3389 / fnbeh.2019.00141). Chronic (14-day) oral administration of either compound (1 a) or compound (2a) significantly reduced aggressive behavior, as measured by a decrease in the number of mounts by Fmr1 KO2 mice, with a MED of 10 mg / kg observed for both compounds. Full reversal of aggression phenotypes in Fmr1 KO2 mice, defined as reversal of mounting to levels of wild-type controls, was also observed with both compounds and no evidence of tolerance to effects with repeat dosing.

[0273] Anxiety

[0274] Anxiety is among the most prevalent symptoms reported in children and adults with FXS (Ezell J et al., J Autism Dev Disord, 2019, 49(3): 1131-41 , doi: 10.1007 / s10803-018-3804-6). Anxiety behaviors can be reliably measured in mice using the novelty suppressed feeding (hyponeophagia) paradigm (Deacon RM, J Vis Exp, 2011 , 51 :2613, doi: 10.3791 / 2613). Similar to patients, Fmr1 KO2 mice exhibit significantly elevated levels of anxiety behaviors when compared to wild-type mice (Spencer CM et al., Genes Brain Behav, 2005, 4(7):420-30, doi: 10.1111 / j.1601- 183X.2005.00123.x). Chronic (14-day) oral administration of either compound (1 a) or compound (2a) produced significant anxiolytic-like efficacy in Fmr1 KO2 mice, as measured by a reduction in the latency to eat novel food vs wild-type controls, with a MED of 10 mg / kg observed for both compounds. Full rescue of anxiety phenotype in Fmr1 KO2 mice, defined as reduction in latency to levels of wildtype, was also observed with both compounds, and no evidence of tolerance to effects with repeat dosing.

[0275] Daily Living

[0276] In mice, nest building is a spontaneous home cage behavior that offers a sensitive tool to quantify the effects of genotype or drug on activities of daily living and animal well-being (Jirkof P, J Neurosci Methods, 2014, 234: 139-46, doi: 10.1016 / j.jneumeth.2014.02.001). Nest building is observed across the animal kingdom, and is important for shelter, sleep and thermoregulation (Deacon RM, NatProtoc, 2006, 1 (3): 1117-9, doi: 10.1038 / nprot.2006.170). Fmr1 KO2 mice exhibit significant impairments in nest building when compared to wild-type controls, mirroring impairments in activities of daily living observed in individuals with FXS (Carreno-Munoz Ml et al., Neuropsychopharmacology, 2018, 43(3):492-502, doi: 10.1038 / npp.2017.149). Chronic (14-day) oral administration of either compound (1 a) or compound (2a) significantly improved nest-building scores in Fmr1 KO2 mice, reversing impairments with a MED of 10 mg / kg observed for both compounds. Full rescue of the nest-building behavior in Fmr1 KO2 mice, defined as an increase of nest-building score to levels of wild-type controls, was also observed with both compounds, and no evidence of tolerance to effects with repeat dosing.

[0277] Cognition

[0278] Deficits in cognitive functioning and intellectual disability are a cardinal feature of FXS (Huddleston LB et al., Wiley Interdiscip Rev Cogn Sci, 2014, 5(4):501-8, doi: 10.1002 / wcs.1296). Consistent with observations from FXS patients, Fmr1 KO2 mice exhibit impairments in tests of cognitive function such as the novel object recognition (NOR) paradigm (Ventura R et al., Behav Pharmacol, 2004, 15(5-6):433-42, doi: 10.1097 / 00008877-200409000-00018). Chronic (14- day) oral administration of either compound (1 a) or compound (2a) significantly improved cognitive impairments in Fmr1 KO2 mice, restoring preference for exploring a novel object vs familiar, with a MED of 3 and 30 mg / kg respectively. Full rescue of cognitive impairments in the Fmr1 KO2 mice was also observed for both compounds, with no evidence of tolerance to effects with repeat dosing.

[0279] Repetitive behaviors

[0280] Restricted repetitive behaviors are most often associated with ASD in humans, but these behaviors are also present in FXS. Repetitive self-grooming (auto-grooming) is a stereotyped behavior in rodents important for maintaining hygiene and is also physiologically important for thermoregulation, social communication and de-arousal (Kalueff AV et al., Nat Rev Neurosci, 2016, 17(1):45-59, doi: 10.1038 / nrn.2015.8). Fmr1 KO2 mice exhibit significantly elevated levels of auto-grooming when compared to wild-type mice, mirroring the increased repetitive behaviors observed as a core area of impairment in FXS (Reisinger DL et al., Brain Sci, 2020, 10(4):239, doi: 10.3390 / brainsci10040239; Kazdoba TM et al., Intractable Rare Dis Res, 2014, 3(4):118-33, doi: 10.5582 / irdr.2014.01024). Chronic (14-day) oral administration of either compound (1 a) or compound (2a) significantly reduced repetitive self-grooming score in Fmr1 KO2 mice, with a minimum effective dose (MED) of 10 and 3 mg / kg respectively. Full rescue of the repetitive behavior phenotype in Fmr1 KO2 mice, defined as reduction of auto-grooming to levels of wild-type mice, was also observed with both compounds, and no evidence of tolerance to effects with repeat dosing. Social memory

[0281] Social behavior abnormalities involving impaired cognitive processes (delayed socialization) are common in FXS, often contributing to the development of ASD comorbidity (Budimirovic DB et al., Am J Med Genet A, 2006, 140A(17):1814-26, doi: 10.1002 / ajmg.a.31405). In mice, abnormalities in social behavior can be simply evaluated using the standardized three-chamber sociability test, which characterizes rodents' innate preference for social novelty by measuring the ratio of time spent investigating an unfamiliar stranger mouse versus a familiar conspecific (Nadler JJ et al., Genes Brain Behav, 2004, 3(5):303-14, doi: 10.1111 / j.1601 -183X.2004.00071 .x). In contrast to wild type controls, Fmr1 KO2 mice fail to exhibit a preference for investigating a novel mouse when presented a choice, spending equal time investigating novel and familiar mice (Mines MA et al., PLoS One, 2010, 5(3):e9706, doi: 10.1371 / journal. pone.0009706). Chronic (14-day) oral administration of either compound (1a) or compound (2a) significantly improved impairments in social cognition in Fmr1 KO2 mice, as defined by a restoration of social preference for the unfamiliar mouse, with a MED of 3 and 30 mg / kg respectively. Full reversal of social impairments (phenotype rescue) in Fmr1 KO2 mice was also observed for both compounds, defined as restoration of time spent investigating unfamiliar / familiar to levels of wild-type controls, and no evidence of tolerance to effects with repeat dosing.

[0282] Summary

[0283] The tables below summarize the efficacy profile of compound (1 a) and compound (2a) across a battery of syndromerelevant phenotypes in the genetic Fmr1 KO2 model of FXS. Both compounds were active in reversing FXS-relevant phenotypes in all paradigms tested, with MED noted for each paradigm.

[0284] These in vivo results demonstrate that compounds (1 a) and (2a) of the present invention exhibit a broad and remarkably potent efficacy profile in reversing / rescuing fragile X syndrome (FXS)-relevant phenotypes in the genetic Fmr1 KO2 mouse model of FXS, indicating an advantageous therapeutic activity of these compounds in the treatment of fragile X syndrome.

[0285] Example 9: Efficacy of compound (1a) in reducing audiogenic seizure in a genetic mouse model of fragile X syndrome (Fmr1 KO)

[0286] Abnormalities in sensory processing are a common clinical feature of FXS, frequently manifesting as sensory hypersensitivity. Auditory hypersensitivity can be a debilitating feature of FXS, often giving rise to social anxiety, stereotyped repetitive behaviors, and delays in language development (Razak KA et al., Front Psychiatry, 2021, 12:720752, doi: 10.3389 / fpsyt.2021.720752). Fmr1 KO mice exhibit abnormal sensitivity to sensory stimuli, particularly hypersensitivity to auditory stimuli (Chen L et al., Neuroscience, 2001 , 103(4): 1043-50, doi: 10.1016 / s0306-4522(01 )00036-7). Audiogenic seizure (AGS) is a type of generalized convulsive seizure evoked by loud sound, and is expressed as an extreme manifestation of auditory hypersensitivity in Fmr1 KO mice, providing a translation-relevant basic sensory phenotype to evaluate experimental therapeutics (Tao X et al., Neuroscience, 2023, 509:113-24, doi: 10.1016 / j.neuroscience.2022.11 .014).

[0287] Methods

[0288] Young (P21) Fmr1 KO mice exhibit extreme sensory sensitivity to auditory stimuli and succumb to seizures and death when challenged with loud sounds (AGS) whereas WT mice exhibit no AGS. The test is performed by placing a test mouse (P21) to a clean, empty cage with a lid (identical in size to their home cage), which is then placed into a sound attenuation chamber with speaker affixed to top of cage. Following a 5 min habituation period (no sound), test mouse is exposed to a loud acoustic stimulus (105-110 dB SPL) presented at a 2-8 kHz frequency for 15 min.

[0289] The typical AGS responses of Fmr1 KO mice include wild running and jumping (WRJ), tonic-clonic seizures (TCS), and respiratory arrest (resulting in death). AGS score was assigned based on each mouse's motor responses as follows: 0 - no seizing at all; 1 - only one bout of WRJ; 2 - more than one bout of WRJ separated by gaps of normal movement; 3 - only one bout of TCS; 4 - more than one bout of TCS; 5 - death (respiratory arrest) (AGS score modified from: Gonzales D et al., J Neurosci, 2019, 39 (49): 9852-9863, doi: 10.1523 / jneurosci.0886-19.2019). WRJ behavior was identified as continuous and rapid running accompanied by "popcorn-like” jumps. TCS behavior was identified when an animal lay on the cage bottom with hindlimb extension. The time of death was noted when an animal showed respiratory arrest which was indicated by the appearance of a deep respiratory gasp and relaxation of pinna. The latency of each motor response or death from the sound onset was recorded, as well as the duration and bouts of each behavior. AGS seizure phenotypes were scored on experimenter observation for entire 20-minute test, using the scoring method described above.

[0290] Testing was performed 1 hour after by intraperitoneal (IP) administration of either vehicle (1.25% DMSO, 1.25% Tween80, 97.5% saline) or compound (1 a) (10, 20, 30 or 60 mg / kg), with each treatment cohort including n=12 animals.

[0291] Results

[0292] Acute peripheral administration (IP) of compound (1 a) resulted in dose-dependent reductions in all AGS-induced WRJ (see Figure 1A) and TCS (see Figure 1 B), with a minimum effective dose (MED) of 20 mg / kg. A complete (100%) amelioration of AGS-evoked WRJ and TCS was observed at the highest dose tested (60 mg / kg). Within a 15-minute test session following auditory stimulus, a majority of Fmr1 KO mice succumb to respiratory death. Acute peripheral administration of compound (1 a) promotes dose-dependent increases in the latency to death in Fmr1 KO mice subjected to AGS and resulted in 100% survival rate for animals administered the highest dose of 60 mg / kg, IP (see Figure 1C).

[0293] These results demonstrate that compound (1 a) is highly effective in reducing audiogenic seizure in a mouse model of fragile X syndrome, which further confirms that this compound is well suited for the therapy of FXS.

[0294] Example 10: Phase 1 clinical study

[0295] Compound (1 a) was dosed in a phase 1 study in healthy volunteers. This first in-human study was designed to evaluate the safety and tolerability of single (Part 1 , SAD) and multiple (Part 2, MAD) ascending oral doses of compound (1 a) administered to healthy participants, as well as to assess plasma levels of compound (1 a) to better understand the pharmacokinetic (PK) profile of this compound in humans. This study also explored the potential effects of compound (1 a) of repeated dosing (10 days) on electroencephalography (EEG) variables recorded from participants in Part 3.

[0296] This study consisted of 3 parts, a single ascending doses (SAD) part with alternating cohorts (Part 1 , dose range between 1 mg and 200 mg), a multiple ascending doses (MAD) part with sequential cohorts (Part 2, dose range between 13 mg BID and 100 mg BID, 10 days of dosing), and a multiple dose crossover cohort with EEG measurements (Part 3, 100 mg BID). In total 56 male and female healthy volunteers were dosed with either placebo (n=8) or at least one dose of compound (1 a) (n=48).

[0297] Compound (1 a) was safe and well tolerated in this study. It was found that compound (1 a) demonstrates linear and dose proportional pharmacokinetics after both single and repeated doses across the dose range evaluated in this study.

[0298] The EEG part of the study used a crossover design in 8 male healthy volunteers. The following EEG parameters were measured at baseline (pre-dosing) and at day 10: habituation task (9-min auditory stimulation with trains of four white noise bursts with eyes open); chirp task (11-min auditory stimulation with chirp stimuli (amplitude-modulated 1 kHz waves) with eyes open); ECV (3-min vigilance-controlled EEG with eyes closed); and EOR (3-min resting EEG with eyes open). Compared to placebo, compound (1 a) showed significant changes on EEG variables in the eyes closed condition on day 10 of dosing indicating central target engagement. As shown in Figure 2, the drug profile is characterized by an increase in absolute and relative frontal theta power and a decrease of absolute and relative occipital alpha power. The relative power in the combined delta and theta band is increased, while the relative power in the combined alpha band is decreased, resulting in a significant decrease of the alpha slow-wave index (ASI). Moreover, the dominant alpha frequency is slowed and the variability of the frequency of the alpha waves are increased, as indicated by an increase of the frequency deviation in the alpha band.

[0299] The topography of these effects of compound (1 a) on brain excitability observed in the EEG part of the study specifically maps to cortical regions that are commonly reported as abnormal by EEG in patients with fragile X syndrome. This pattern of regional effects on brain excitability replicates observations from EEG profiling of compound (1 a) in preclinical animal studies and, as such, provides a proof of mechanism in human subjects.

Claims

CLAIMSA compound selected from:or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein said compound isor a pharmaceutically acceptable salt or solvate thereof.The compound of claim 1, wherein said compound isor a pharmaceutically acceptable salt or solvate thereof.

4. The compound of any one of claims 1 to 3, wherein the compound has the (S)-configuration at the carbon atom in 3-position of the indolin-2-one ring comprised in said compound.

5. The compound of any one of claims 1 to 3, wherein the compound has the (R)-configuration at the carbon atom in 3-position of the indolin-2-one ring comprised in said compound.

6. The compound of claim 1 , wherein said compound is selected from:or a pharmaceutically acceptable salt or solvate thereof.

7. The compound of any one of claims 1 , 2 or 6, wherein said compound isor a pharmaceutically acceptable salt or solvate thereof.

8. The compound of any one of claims 1 , 3 or 6, wherein said compound isor a pharmaceutically acceptable salt or solvate thereof.

9. A pharmaceutical composition comprising the compound of any one of claims 1 to 8 and optionally a pharmaceutically acceptable excipient.

10. The compound of any one of claims 1 to 8 or the pharmaceutical composition of claim 9 for use as a medicament.

11. The compound of any one of claims 1 to 8 or the pharmaceutical composition of claim 9 for use in the treatment or prevention of a disease / disorder selected from a fragile X associated disorder, stroke, ischemia reperfusion injury, ischemic heart disease, hypertension, myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease, multiple sclerosis, spasticity, tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder, urinary incontinence, irritable bowel syndrome, faecal incontinence, constipation, gastro-oesophageal reflux disorder, impaired gastrointenstinal passage, detrusorunderactivity, erectile dysfunction, opioid-induced respiratory depression, anxiety, an anxiety disorder, sensory processing disorder, autism, an autism spectrum disorder, a social or pragmatic communication disorder, attention deficit hyperactivity disorder, social phobia, intellectual disability, pain, epilepsy, an epilepsy and / or seizure disorder, Dravet syndrome, generalized epilepsy-paroxysmal dyskinesia syndrome, temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt-Hopkins syndrome, 16p11.2 deletion syndrome, Williams-Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis, migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome, Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia, DNMf-related disorder, DNMf-related epilepsy, DNM1 -encephalopathy, CDKL5 deficiency disorder, KCNMA1 -I inked channelopathy, a KCNMB1- linked disorder, a KCNMB2-\ inked disorder, a KCNMB3-\ inked disorder, a KCNMB4-\ inked disorder, an / _RRC26-linked disorder, an LRRC52-\ inked disorder, an _RRC55-linked disorder, and an LRRC38-\ inked disorder.

12. The compound of any one of claims 1 to 8 or the pharmaceutical composition of claim 9 for use in the treatment or prevention of a fragile X associated disorder.

13. The compound for use according to claim 12 or the pharmaceutical composition for use according to claim 12, wherein the fragile X associated disorder is selected from fragile X syndrome, fragile X-associated tremor / ataxia syndrome, fragile X-associated primary ovarian insufficiency, fragile X-associated polycystic ovarian syndrome, and fragile XE-associated mental retardation.

14. The compound for use according to claim 12 or the pharmaceutical composition for use according to claim 12, wherein the fragile X associated disorder is fragile X syndrome.

15. The compound for use according to any one of claims 10 to 14 or the pharmaceutical composition for use according to any one of claims 10 to 14, wherein the compound or the pharmaceutical composition is to be administered orally.

16. The compound for use according to any one of claims 10 to 15 or the pharmaceutical composition for use according to any one of claims 10 to 15, wherein the compound or the pharmaceutical composition is to be administered to a human subject.

17. In vitro use of a compound as defined in any one of claims 1 to 8 as a maxi-K potassium channel opener.

18. Use of the compound of any one of claims 1 to 8 in the preparation of a medicament for the treatment or prevention of a disease / disorder selected from a fragile X associated disorder, stroke, ischemia reperfusion injury, ischemic heart disease, hypertension, myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease, multiple sclerosis, spasticity, tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder, urinary incontinence, irritable bowel syndrome, faecal incontinence,constipation, gastro-oesophageal reflux disorder, impaired gastrointenstinal passage, detrusor underactivity, erectile dysfunction, opioid-induced respiratory depression, anxiety, an anxiety disorder, sensory processing disorder, autism, an autism spectrum disorder, a social or pragmatic communication disorder, attention deficit hyperactivity disorder, social phobia, intellectual disability, pain, epilepsy, an epilepsy and / or seizure disorder, Dravet syndrome, generalized epilepsy-paroxysmal dyskinesia syndrome, temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt-Hopkins syndrome, 16p11.2 deletion syndrome, Williams- Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis, migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome, Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia, DNMf-related disorder, DNMf-related epilepsy, DNM1- encephalopathy, CDKL5 deficiency disorder, KCNMA1 -I inked channelopathy, a / / MBMinked disorder, a KCNMB2-\ inked disorder, a KCNMB3-\ inked disorder, a KCNMB4-\ inked disorder, an / _RRC26-linked disorder, an LRRC52-\ inked disorder, an LRRC55-\ inked disorder, and an LRRC38-linked disorder.

19. Use of the compound of any one of claims 1 to 8 in the preparation of a medicament for the treatment or prevention of a fragile X associated disorder.

20. The use of claim 19, wherein the fragile X associated disorder is selected from fragile X syndrome, fragile X-associated tremor / ataxia syndrome, fragile X-associated primary ovarian insufficiency, fragile X- associated polycystic ovarian syndrome, and fragile XE-associated mental retardation.

21. The use of claim 19, wherein the fragile X associated disorder is fragile X syndrome.

22. The use of any one of claims 18 to 21 , wherein the medicament is for oral administration.

23. The use of any one of claims 18 to 22, wherein the medicament is for administration to a human subject.

24. A method of treating or preventing a disease / disorder selected from a fragile X associated disorder, stroke, ischemia reperfusion injury, ischemic heart disease, hypertension, myocardial infarction, allergic rhinitis, asthma, chronic obstructive pulmonary disease, multiple sclerosis, spasticity, tremor, a muscular disorder, dyskinesia, bladder dysfunction, overactive bladder, urinary incontinence, irritable bowel syndrome, faecal incontinence, constipation, gastro-oesophageal reflux disorder, impaired gastrointenstinal passage, detrusor underactivity, erectile dysfunction, opioid-induced respiratory depression, anxiety, an anxiety disorder, sensory processing disorder, autism, an autism spectrum disorder, a social or pragmatic communication disorder, attention deficit hyperactivity disorder, social phobia, intellectual disability, pain, epilepsy, an epilepsy and / or seizure disorder, Dravet syndrome, generalized epilepsy-paroxysmal dyskinesia syndrome, temporal lobe epilepsy, psychosis, schizophrenia, negative symptoms of schizophrenia, cognitive impairment in schizophrenia, Phelan-McDermid syndrome, Rett syndrome, Pitt-Hopkins syndrome, 16p11.2 deletion syndrome, Williams-Beuren syndrome, open-angle ocular hypertension, glaucoma, tinnitus, diabetic retinopathy, tocolysis, migraine, Liang-Wang syndrome, Smith-Lemli-Opitz syndrome, Angelman syndrome,Hutchinson-Gilford progeria syndrome, spinocerebellar ataxia, DNMf-related disorder, DNMf-related epilepsy, DNM1 -encephalopathy, CDKL5 deficiency disorder, KCNMAf -I inked channelopathy, a KCNMB1- linked disorder, a KCNMB2-\ inked disorder, a KCNMB3-\ inked disorder, a KCNMB4-\ inked disorder, an _RRC26-linked disorder, an LRRC52-\ inked disorder, an _RRC55-linked disorder, and an LRRC38-\ inked disorder, the method comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 8 to a subject in need thereof.

25. A method of treating or preventing a fragile X associated disorder, the method comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 8 to a subject in need thereof.

26. The method of claim 25, wherein the fragile X associated disorder is selected from fragile X syndrome, fragile X-associated tremor / ataxia syndrome, fragile X-associated primary ovarian insufficiency, fragile X- associated polycystic ovarian syndrome, and fragile XE-associated mental retardation.

27. The method of claim 25, wherein the fragile X associated disorder is fragile X syndrome.

28. The method of any one of claims 24 to 27, wherein the compound is orally administered to the subject.

29. The method of any one of claims 24 to 28, wherein the subject is a human.

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