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WO2024261020A1 - Inhibiteurs de clc-1 destinés à être utilisés dans le traitement de la sclérose en plaques et de maladies neuromusculaires - Google Patents

Inhibiteurs de clc-1 destinés à être utilisés dans le traitement de la sclérose en plaques et de maladies neuromusculaires Download PDF

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Publication number
WO2024261020A1
WO2024261020A1 PCT/EP2024/067027 EP2024067027W WO2024261020A1 WO 2024261020 A1 WO2024261020 A1 WO 2024261020A1 EP 2024067027 W EP2024067027 W EP 2024067027W WO 2024261020 A1 WO2024261020 A1 WO 2024261020A1
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substituents
bromo
different
optionally substituted
phenoxy
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Inventor
Thomas Kongstad Petersen
Nicholas Michael Kelly
Thomas Holm PEDERSEN
Claire Margaret SAMPSON
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NMD Pharma AS
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NMD Pharma AS
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Priority to AU2024311729A priority Critical patent/AU2024311729A1/en
Publication of WO2024261020A1 publication Critical patent/WO2024261020A1/fr
Priority to IL324311A priority patent/IL324311A/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis

Definitions

  • the present disclosure relates to compounds capable of inhibiting the CIC-1 ion channel for use in treating, ameliorating and/or preventing multiple sclerosis and other neuromuscular diseases.
  • MS Multiple sclerosis
  • MS is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, visual loss, muscle weakness, and trouble with sensation or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). In the relapsing forms of MS, between attacks, symptoms may disappear completely, although some permanent neurological problems often remain, especially as the disease advances.
  • Multiple sclerosis is the most common immune-mediated disorder affecting the central nervous system. Nearly one million people have MS in the United States in 2022, and in 2020, about 2.8 million people were affected globally, with rates varying widely in different regions and among different populations. The disease usually begins between the ages of 20 and 50 and is twice as common in women as in men.
  • Phenotypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis, but also for treatment decisions.
  • RRMS is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave problems, the latter in about 40% of attacks and being more common the longer a person has had the disease. This describes the initial course of 80% of individuals with MS.
  • the relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS).
  • CIS clinically isolated syndrome
  • a person has an attack suggestive of demyelination, but does not fulfil the criteria for multiple sclerosis. 30 to 70% of persons who experience CIS, later develop MS.
  • PPMS occurs in roughly 10-20% of individuals with the disease, with no remission after the initial symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.
  • the usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in RRMS, around 40 years of age.
  • SPMS occurs in around 65% of those with initial RRMS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The most common length of time between disease onset and conversion from RRMS to SPMS is 19 years.
  • Medications approved by the FDA include interferons beta-1 a and beta-1 b, monoclonal antibodies (e.g. natalizumab, alemtuzumab and ocrelizumab), and immunomodulators (e.g. glatiramer acetate, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, diroximel fumarate. Siponimod, Cladribine, Ozanimod).
  • Jitter is the variability in the arrival time of muscle fibre action potentials to the recording electrode between consecutive electrical discharges when measuring neuromuscular function using single fiber electromyography (sfEMG).
  • Blocking is complete NMJ transmission failure of muscle fibre action potentials to the recording electrode between consecutive electrical discharges when measuring neuromuscular function using sfEMG.
  • Normalisation of jitter and/or reduction of block could improve neuromuscular function by ensuring that an increased number of muscle fibres in a muscle respond together at the same time thereby improving muscle force and control.
  • the present invention relates to CIC-1 inhibitors for use in the treatment, prevention and/or amelioration of multiple sclerosis and other neuromuscular diseases.
  • NMD712 ((S)-2-(p-bromophenoxy)butyric acid) restores muscle function and NMJ transmission in a pharmacological rat model of neuromuscular dysfunction.
  • the figure displays stimulated muscle force (A), compound muscle action potentials (CMAP) (B), jitter (C) and block (D) from rats before (white, pre- neuromuscular blocking agent (NMBA)) and during a constant infusion of NMBA to reach a stable level of decreased neuromuscular function (Grey, Control) relative to pre-NMBA.
  • NMD712 was administered orally (50 mg/kg) and the four parameters were measured 60 minutes post-dose (checked).
  • NMD712 resulted in a restoration of all four measured parameters: muscle force (A), CMAP (B), jitter (C) and block (D).
  • A muscle force
  • B CMAP
  • C jitter
  • D block
  • N 4 animals, values are MEAN ⁇ SEM. *statistical significance based on 2-way ANOVA with multiple comparisons (** p ⁇ 0.01 , *** p ⁇ 0.001 , **** p ⁇ 0.0001).
  • Figure 2 depicts the study design of a clinical observational study that enrolled patients with CMT types 1 and 2 and healthy age-matched controls at two study sites. Clinical tests are listed in the order of testing.
  • CMTES2 CMT Examination Score2.
  • RNS Repetitive Nerve Stimulation.
  • SFEMG Single Fibre EMG. *CMTES2 only performed at visit 1.
  • Figure 3 depicts jitter and blocking from visit 1 of a clinical observational study of healthy subjects and Charcot-Marie-Tooth (CMT) patients displayed as individual data with medians for healthy controls and CMT patients (A and B) and for CMT 1 and CMT2 patients (C and D). Mean Consecutive Difference (MCD).
  • CMT Charcot-Marie-Tooth
  • C1-2 alkyl refers to a branched or unbranched alkyl group having from one to two, one to three or one to five carbon atoms respectively, including but not limited to methyl, ethyl, prop-1 -yl, prop-2-yl, 2-methyl- prop-1-yl, 2-methyl-prop-2-yl, 2,2-dimethyl-prop-1-yl, but-1-yl, but-2-yl, 3-methyl-but-1- yl, 3-methyl-but-2-yl, pent-1-yl, pent-2-yl and pent-3-yl.
  • C2 alkenyl and C2-5 alkenyl refers to a branched or unbranched alkenyl group having two or from two to five carbon atoms respectively, two of which are connected by a double bond, including but not limited to ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and isopentenyl.
  • C3-5 cycloalkyl and “C3-6 cycloalkyl” refers to a group having three to five or three to six carbon atoms respectively including a monocyclic or bicyclic carbocycle, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Examples of C3-5 cycloalkyl wherein one -CH2- is replaced by -O- are oxiran-2-yl, oxetan-2-yl, oxetan-3-yl, oxolan-2-yl and oxolan-3-yl.
  • C1-2 alkylthio refers to an alkyl group having from one to two carbon atoms attached to a sulfur atom, and binding is to the sulfur atom.
  • Examples of C1-2 alkthio are methylthio and ethylthio.
  • 4-6 membered heterocycle refers to a group having four, five or six carbon atoms respectively wherein between 1 and 3 carbon atoms in the ring have been replaced with a heteroatom selected from the group comprising nitrogen, sulphur and oxygen. Binding to the heterocycle may be at the position of the heteroatom or via a carbon atom of the heterocycle.
  • 4-membered heterocycles include but are not limited to oxetane, azetidine and thietane.
  • 6-membered heterocycles include but are not limited to pyridine, pyrazine, pyrimidine, pyridazine, tetrahydropyran, thiane, piperidine, 1 , 4-dioxane, morpholine, 1,4- oxathiane, 1,4-diathiane and piperazine.
  • 5 membered aromatic heterocycle refers to an aromatic group having five carbon atoms wherein between 1 and 3 carbon atoms in the ring have been replaced with a heteroatom selected from the group comprising nitrogen, sulphur and oxygen. Binding to the heterocycle may be at the position of the heteroatom or via a carbon atom of the heterocycle.
  • 5-membered aromatic heterocycles include but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3- oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1 ,2-thiazol-3-yl, 1 ,2-thiazol-4-yl, 1,2- thiazol-5-yl, 1 ,3-thiazol-2-yl, 1 ,3-thiazol-4-yl, 1 ,3-thiazol-5-yl, 1 ,2,3-thiadiazol-4-yl, 1,2,3- thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,3,4-thiadiazol-2-yl, 1,2,5
  • half-life is the time it takes for the compound to lose one-half of its pharmacologic activity.
  • plasma half-life is the time that it takes the compound to lose one-half of its pharmacologic activity in the blood plasma.
  • treatment refers to the combating of a disease or disorder.
  • Treatment includes any desirable effect on the symptoms or pathology of a disease or condition as described herein, and may include even minimal changes or improvements in one or more measurable markers of the disease or condition being treated. “Treatment” or “treating” does not necessarily indicate complete eradication or cure of the disease or condition, or associated symptoms thereof.
  • the term “treatment” encompasses amelioration and prevention.
  • amelioration refers to moderation in the severity of the symptoms of a disease or condition. Improvement in a patient's condition, or the activity of making an effort to correct, or at least make more acceptable, conditions that are difficult to endure related to patient's conditions is considered “ameliorative” treatment.
  • prevent refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action.
  • jitter refers to the variability in the arrival time of action potentials to the recording electrode between consecutive electrical discharges when measuring neuromuscular function using single fiber electromyography (sfEMG). For example, jitter can be measured by calculating, with a recording electrode, the variation in the time interval between two action potentials of a same motor unit.
  • sfEMG single fiber electromyography
  • blocking refers to complete NMJ transmission failure of action potentials to the recording electrode between consecutive electrical discharges when measuring neuromuscular function using sfEMG.
  • Blocking of neuromuscular transmission can be detected by determining the percentage of paired successful action potentials, from different muscle fibers of a same motor unit in a neuromuscular tissue, to the total number voluntary activations of said motor unit. For example, blocking can be detected by (i) first counting the number of paired successful action potentials from different muscle fibers of a same motor unit in a neuromuscular tissue, (ii) dividing the number of paired successful action potentials by the total number of action potentials occurring in at least one of the motor unit's muscle fibers and (iii) multiplying the result of the division by 100. If, for example, different pairs of muscle fibers of the same motor unit undergo 100 voluntary activations and 90 of the activations result in a detectable action potential in one but not the other muscle fiber, then the degree of blocking that motor unit suffers from is 10%.
  • Skeletal muscle specific CIC-1 chloride ion channels carry the inhibitory currents that counteract neuromuscular transmission. Inhibition of CIC-1 reduces the inhibitory current and thereby increases muscle membrane excitability and enhances neuromuscular transmission (Pedersen et al 2021). Administration of a CIC-1 inhibitor will both normalise jitter and increase the probability of an action potential firing (i.e. reducing block) by making the muscle membrane more excitable. Reduction of block and normalisation of jitter will reduce the incidence of NMJ transmission failure and enhance muscle function thereby resulting in increased muscle strength and control.
  • the present invention relates to CIC-1 inhibitors for use in the treatment, prevention and/or amelioration of multiple sclerosis and other neuromuscular diseases.
  • the compounds for use of the present disclosure comprise compounds capable of inhibiting the CIC-1 channel thereby improving or restoring neuromuscular function, i.e. the compounds are CIC-1 inhibitors.
  • the ECso of the compound is ⁇ 50 pM, such as ⁇ 40 pM, such as ⁇ 30 pM, such as ⁇ 20 pM, such as ⁇ 15 pM, such as ⁇ 10 pM, and such as ⁇ 5 pM.
  • the ECso of the compound may for example be determined as described in Example 1.
  • the recovery of force in muscles with neuromuscular dysfunction is >5%, for example >10%, for example >15%, for example >20%, for example >25%, for example >30% and for example >35%.
  • the recovery of force in muscles with neuromuscular dysfunction may for example be determined as described in Example 2.
  • the compound may result in a positive shift in the half activation voltage of CIC-1 channels, AV1/2.
  • the half activation voltage of CIC-1 channels may for example be determined as described in Example 3.
  • the compound may increase the tetanic force in an in situ muscle contractile experiment.
  • the increase the tetanic force may for example be determined as described in Example 4.
  • CIC-1 inhibitors are for example described in WO 2016/202341 , WO 2019/115777, WO 2019/115780, WO 2019/115781 , EP19181263, WO 2020/254553, WO 2020/254558 and WO 2020/254559.
  • the present disclosure relates to a method of treating, preventing and/or ameliorating multiple sclerosis, said method comprising administering a CIC-1 inhibitor to a subject in need thereof. In one aspect, the present disclosure relates to a method of treating, preventing and/or ameliorating multiple sclerosis, said method comprising administering a therapeutically effective amount of the compound for use as defined herein to a subject in need thereof. In one embodiment, the subject is a human being.
  • the present disclosure relates to use of a CIC-1 inhibitor for the manufacture of a medicament for the treatment, prevention and/or amelioration of multiple sclerosis. In one aspect, the present disclosure relates to use of a compound as defined herein, for the manufacture of a medicament for the treatment, prevention and/or amelioration of multiple sclerosis.
  • the CIC-1 inhibitor restores contractile force in the muscles of the subject.
  • Contractile force ex vivo may for example be measured as described in Example 2 herein whilst contractile force in a clinical setting may for example be measured as described in Scott et al, 2011.
  • the present disclosure relates to a CIC-1 inhibitor for use in a method of restoring contractile force in the muscles of a subject suffering from multiple sclerosis.
  • the present disclosure relates to a method of restoring contractile force in the muscles of a subject suffering from multiple sclerosis, said method comprising administering a CIC-1 inhibitor to the subject in need thereof.
  • the present disclosure relates to use of a CIC-1 inhibitor for the manufacture of a medicament for restoring contractile force in the muscles of a subject suffering from multiple sclerosis.
  • Contractile force ex vivo may for example be measured as described in Example 2 herein whilst contractile force in a clinical setting may for example be measured as described in Scott et al, 2011.
  • the CIC-1 inhibitor reduces the incidence of NMJ transmission failure in the muscles of the subject.
  • NMJ transmission failure may for example be measured as described in Example 5 herein whilst contractile force in a clinical setting may for example be measured as described in Scott et al, 2011.
  • the present disclosure relates to a CIC-1 inhibitor for use in a method of reducing the incidence of NMJ transmission failure in the muscles of a subject suffering from multiple sclerosis.
  • the present disclosure relates to a method of reducing the incidence of NMJ transmission failure in the muscles of a subject suffering from multiple sclerosis, said method comprising administering a CIC-1 inhibitor to the subject in need thereof.
  • the present disclosure relates to use of a CIC-1 inhibitor for the manufacture of a medicament for reducing the incidence of NMJ transmission failure in the muscles of a subject suffering from multiple sclerosis.
  • the CIC-1 inhibitor increases the probability of an action potential firing in the muscles of the subject.
  • An increase in the probability of an action potential firing may be determined in a subject as described in Example 6 or as described by Weir et al, 1979.
  • the present disclosure relates to a CIC-1 inhibitor for use in a method of increasing the probability of an action potential firing in the muscles of a subject suffering from multiple sclerosis. In one aspect, the present disclosure relates to a method of increasing the probability of an action potential firing in the muscles of a subject suffering from multiple sclerosis, said method comprising administering a CIC-1 inhibitor to the subject in need thereof. In one aspect, the present disclosure relates to use of a CIC-1 inhibitor for the manufacture of a medicament for increasing the probability of an action potential firing in the muscles of a subject suffering from multiple sclerosis.
  • the CIC-1 inhibitor normalises jitter in the muscles of the subject. Normalisation of jitter in the muscles of the subject may be determined as described in Example 6.
  • the present disclosure relates to a CIC-1 inhibitor for use in a method of normalising jitter in the muscles of a subject suffering from multiple sclerosis.
  • the present disclosure relates to a method of normalising jitter in the muscles of a subject suffering from multiple sclerosis, said method comprising administering a CIC-1 inhibitor to the subject in need thereof.
  • the present disclosure relates to use of a CIC-1 inhibitor for the manufacture of a medicament for normalising jitter in the muscles of a subject suffering from multiple sclerosis.
  • the compound for use is a compound of Formula (I):
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - R 12 is selected from the group consisting of
  • R 14 is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 and phenyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 15 is selected from the group consisting of -OH, -OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 and -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 18 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 19 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 19 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R 20 ;
  • - R 19 is independently selected from the group consisting of F, Cl, Br, I, -CN,
  • - R 20 is independently selected from the group consisting of F, Cl, Br, I, -CN,
  • R 22 is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 and phenyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • - X is selected from the group consisting of N and CR 23 ;
  • - Y is selected from the group consisting of NH, O and S;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (II):
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 2 is a 5-membered aromatic heterocycle which may be optionally substituted with one or more, identical or different, substituents R 7 ;
  • - R 3 is selected from the group consisting of deuterium, F and Cl;
  • - R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (IX): wherein:
  • R 1 is selected from the group consisting of H, deuterium, F, Cl, Br and I, preferably Cl or Br;
  • - R 3 is selected from the group consisting of deuterium, F, and Cl;
  • - R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - m is an integer 0, 1 or 2;
  • - n is an integer 0, 1 , 2 or 3, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • m is 0. In one embodiment, m is 1. In one embodiment, m is 2.
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 3 is selected from the group consisting of deuterium, F, and Cl;
  • R 4 is selected from the group consisting of C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl, C2-5 alkenyl and C2-5 alkynyl;
  • R 6 is independently selected from deuterium and F; and
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl, and cyclopropyl.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is -CF2-C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6
  • R 3 is selected from the group consisting of deuterium, Cl and F
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • the compound for use is a compound of Formula (X):
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • R 9 is selected from the group consisting of C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 ;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is of Formula (X) and:
  • - R 1 is selected from the group consisting of F, Cl, Br, and I;
  • - R 3 is selected from the group consisting of deuterium and F;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R B8 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is of Formula (X) and:
  • R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl,
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl and C2-5 alkynyl each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from deuterium and F;
  • R 9 is C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 ;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl,
  • R 3 is selected from the group consisting of H, deuterium, Cl and F;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R B8 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • R 9 is C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 ; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (XI): wherein:
  • R 1 is selected from the group consisting of C2 alkynyl, NO2, Cl, Br, and I;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-3 alkyl and C2-3 alkynyl each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 9 is C1-3 alkyl optionally be substituted with one or more, identical or different, substituents R 6 ; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 9 is methyl. In one embodiment, R 9 is ethyl. In one embodiment, R 9 is n-propyl. In one embodiment, R 9 is isopropyl. In one embodiment, R 9 is cyclopropyl.
  • the compound for use is a compound is of Formula (II):
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br and I;
  • R 3 is selected from the group consisting of deuterium, Cl and F
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (II):
  • R 1 is selected from the group consisting of F, Cl, Br, and I;
  • R 2 is selected from the group consisting of hydrogen, deuterium, F, Cl and
  • R 4 is selected from the group consisting of C1-5 alkyl, C2-5 alkenyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which is substituted with one or more, identical or different, substituents R 6 , and C2-5 alkynyl, which may be optionally substituted with one or more, identical or different, substituents R 6 ; and
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • -R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - n is 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (II):
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 2 is selected from the group consisting of hydrogen, deuterium, F, Cl, and
  • R 4 is selected from the group consisting of C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, and C5 cycloalkenyl, each of which is substituted with one or more, identical or different, substituents R 6 ; and
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - n is 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (II):
  • R 1 is selected from the group consisting of H, Br, Cl, F and I;
  • R 4 is selected from the group consisting of -CH3, -CH2-CH3, -CH(CH3)2, -
  • - n is 0, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.
  • the compound for use is a compound of Formula (II):
  • - R 1 is selected from the group consisting of F, Cl, Br, I, -CN, and -CF3;
  • R 2 is selected from the group consisting of C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • - R 3 is selected from the group consisting of deuterium, F, and Cl;
  • - R 4 is selected from the group consisting of C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (XII):
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 2 is C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 10 is C1-2 alkanediyl which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-6 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ; phenyl optionally substituted with one or more, identical or different, substituents R 8 ; and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 11 is C1-2 alkyl optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - n is an integer 0, 1 , 2 or 3;
  • - X a is O or S; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (XIII):
  • R 1 is selected from the group consisting of Cl and Br;
  • R 2 is C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 3 is selected from the group consisting of deuterium and F;
  • R 11 is C1-2 alkyl optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • - n is an integer 0, 1 , 2 or 3;
  • - X a is O or S; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (XIV):
  • R 1 is selected from the group consisting of Cl and Br;
  • R 3 is selected from the group consisting of deuterium and F;
  • R 11 is C1-2 alkyl optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • - p is an integer 1 or 2;
  • - n is an integer 0, 1 , 2 or 3;
  • - X a is O or S; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • X a is O. In one embodiment, X a is S. In one embodiment, p is 1. In one embodiment, p is 2.
  • R 1 is C1-2 alkyl. In one embodiment, R 1 is C2 alkenyl. In one embodiment, R 1 is C2 alkynyl. In one embodiment, R 1 is CN. In one embodiment, R 1 is CF3. In one embodiment, R 1 is NO2. In one embodiment, R 1 is Cl or Br. In one embodiment, R 1 is F. In one embodiment, R 1 is Cl. In one embodiment, R 1 is Br. In one embodiment, R 1 is I. In one embodiment, R 2 is H. In one embodiment, R 2 is deuterium. In one embodiment, R 2 is F. In one embodiment, R 2 is Cl. In one embodiment, R 2 is Br. In one embodiment, R 2 is I.
  • R 2 is C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 2 is vinyl.
  • R 2 is C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 2 is ethynyl.
  • R 2 is C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 2 is cyclopropyl. In one embodiment, R 2 is cyclobutyl.
  • R 2 is -CF2-C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 .
  • R 2 is Me-CF2-.
  • R 2 is Et-CF2-.
  • R 2 is n Pr-CF2-.
  • R 2 is 'Pr-CF2-.
  • R 2 is cyclopropyl-CF2-.
  • R 2 is 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 .
  • R 2 is selected from the group consisting of furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, 1 ,2,5-oxadiazole, 1 ,2,3- oxadiazole, 1 ,2,4-oxadiazole, 1 ,3,4-oxadiazole, 1 ,2,5-thiadiazole, 1 ,2,3-thiadiazole,
  • R 2 is selected from the group consisting of thiophene, pyrrole, isoxazole, 1 ,2,4-oxadiazole and 1 ,3,4- oxadiazole. In one embodiment, R 2 is selected from the group consisting of 1 ,2-oxazol- 3-yl, 1 ,2-oxazol-4-yl, 1 ,2-oxazol-5-yl, 1 ,3-oxazol-2-yl, 1 ,3-oxazol-4-yl, 1 ,3-oxazol-5-yl,
  • R 2 is selected from the group consisting of 1 ,2,3-thiadiazol-4-yl, 1 ,3,4-thiadiazol-2-yl, 1 ,2-thiazol-3-yl, 1 ,2-oxazol-3-yl,
  • R 2 is selected from isoxazol-5-yl and isoxazol-3-yl. In one embodiment, R 2 is 1 ,2-oxazol-3-yl. In one embodiment, R 2 is 1 ,2-oxazol-4-yl. In one embodiment, R 2 is 1 ,2-oxazol-5-yl. In one embodiment, R 2 is 1 ,3-oxazol-2-yl. In one embodiment, R 2 is 1 ,3-oxazol-4-yl.
  • R 2 is 1 ,3-oxazol-5-yl. In one embodiment, R 2 is 1 ,2-thiazol-3-yl. In one embodiment, R 2 is 1 ,2-thiazol-4-yl. In one embodiment, R 2 is 1 ,2-thiazol-5-yl. In one embodiment, R 2 is 1 ,3-thiazol-2-yl. In one embodiment, R 2 is 1 ,3-thiazol-4-yl. In one embodiment, R 2 is 1 ,3-thiazol-5-yl. In one embodiment, R 2 is 1 ,2,3-thiadiazol-4-yl. In one embodiment, R 2 is 1 ,2,3-thiadiazol-5-yl.
  • R 2 is 1 ,2,4-thiadiazol- 3-yl. In one embodiment, R 2 is 1 ,2,4-thiadiazol-5-yl. In one embodiment, R 2 is 1 ,3,4- thiadiazol-2-yl. In one embodiment, R 2 is 1 ,2,5-thiadiazol-3-yl. In one embodiment, R 2 is 1 ,2,3-oxadiazol-4-yl. In one embodiment, R 2 is 1 ,2,3-oxadiazol-5-yl. In one embodiment, R 2 is 1 ,2,4-oxadiazol-3-yl. In one embodiment, R 2 is 1 ,2,4-oxadiazol-5-yl. In one embodiment, R 2 is 1 ,3,4-oxadiazol-2-yl. In one embodiment, R 2 is 1 ,2,5- oxadiazol-3-yl.
  • R 3 is deuterium. In one embodiment, R 3 is Cl. In one embodiment, R 3 is F.
  • R 4 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 4 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.
  • R 4 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl wherein the methyl, ethyl, n- propyl or isopropyl group is substituted with one or more, identical or different, substituents R 6 .
  • R 4 is Me.
  • R 4 is Et.
  • R 4 is -CH2F.
  • R 4 is -CH2-CH2F. In one embodiment, R 4 is C1-2 alkoxy-Ci-2 alkyl optionally substituted with one or more, identical or different, substituents R 6 . In one embodiment, R 4 is C1-2 alkylthio-Ci-2 alkyl optionally substituted with one or more, identical or different, substituents R 6 . In one embodiment, R 4 is selected from the group consisting of MeOCFk-, EtOCFk-, MeSCFk- and EtSCFk-. In one embodiment, R 4 is C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 .
  • R 4 is C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 .
  • R 4 is prop-2-ynyl.
  • R 4 is -CH2-C2-4 alkynyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 4 is C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 4 is selected from the group consisting of cyclopropyl and cyclobutyl.
  • R 4 is H.
  • R 4 is deuterium. When R 4 is H, the carbon to which R 4 is bound is not a stereogenic centre.
  • R 5 is H. In one embodiment, R 5 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 5 is C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 5 is phenyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 5 is benzyl optionally substituted with one or more, identical or different, substituents R 8 .
  • R 6 is deuterium. In one embodiment, R 6 is F.
  • R 7 is deuterium. In one embodiment, R 7 is F. In one embodiment, R 7 is selected from the group consisting of methyl, ethyl or cyclopropyl.
  • R 8 is deuterium. In one embodiment, R 8 is methoxy. In one embodiment, R 8 is nitro. In one embodiment, R 8 is cyano. In one embodiment, R 8 is Cl. In one embodiment, R 8 is Br. In one embodiment, R 8 is I. In one embodiment, R 8 is F.
  • R 14 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 . In one embodiment, R 14 is C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 . In one embodiment, R 14 is phenyl optionally substituted with one or more, identical or different, substituents R 8 .
  • R 15 is -OH. In one embodiment, R 15 is -OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 . In one embodiment, R 15 is -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 18 is H. In one embodiment, when R 18 is H then R 17 is not H. In one embodiment, R 18 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 19 . In one embodiment, R 18 is C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 19 . In one embodiment, R 18 is phenyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 18 is 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R 20 .
  • R 19 is -S-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 19 is -SO-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 19 is -SO-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 19 is -SO2-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 19 is - SO2-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 19 is phenyl optionally substituted with one or more, identical or different, substituents R 8 .
  • R 19 is pyrrolidin-1-yl optionally substituted with one or more, identical or different, substituents R 20 .
  • R 19 is 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R 20 .
  • R 22 C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 22 is C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 22 is phenyl optionally substituted with one or more, identical or different, substituents R 8 .
  • X is N. In one embodiment, X is CR 23 wherein R 23 is H. In one embodiment, X is CR 23 wherein R 23 is NH2. In one embodiment, X is CR 23 wherein R 23 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 . In one embodiment, X is CR 23 wherein R 23 is C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 . In one embodiment, X is CR 23 wherein R 23 is -OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • Y is NH. In one embodiment, Y is O. In one embodiment, Y is S.
  • n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3.
  • R 12 is '' vw .
  • the compound for use is a compound of Formula (II):
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (II):
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br and I;
  • R 3 is selected from the group consisting of deuterium, Cl and F
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of Cl and Br
  • R 2 is selected from the group consisting of H, deuterium or F
  • R 4 is selected from the group consisting of Me, Et and -CH2F.
  • the compound for use is a compound of Formula (II):
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 2 is a 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • - R 3 is selected from the group consisting of deuterium, F, and Cl;
  • - R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl and cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is F, Cl or Br
  • R 2 is 1 ,2-oxazol-5-yl
  • R 4 is H
  • R 5 is H
  • R 6 is H
  • n is 1 , 2 or 3.
  • the compound for use is of Formula (II) and
  • R 1 is selected from the group consisting of F, Cl, Br and I, preferably Cl or Br;
  • R 2 is selected from the group consisting of 1 ,2,3-thiadiazol-4-yl, 1 ,3,4- thiadiazol-2-yl, 1 ,2-thiazol-3-yl, 1 ,2-oxazol-3-yl, 1 ,2-oxazol-5-yl and 1 ,3- oxazol-4-yl each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, F, and Cl;
  • R 4 is selected from the group consisting of C1-5 alkyl and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 7 is independently selected from the group consisting of H, deuterium, F, Cl,
  • R 6 is independently selected from deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (II):
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 2 is a 5-membered aromatic heterocycle which may be optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, F and Cl;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of Cl and Br
  • R 2 is selected from the group consisting of 1 ,2-oxazol-3-yl, 1 ,2-oxazol-5-yl, 1 ,3-oxazol-4-yl and 1 ,2,3-thiadiazol-4-yl
  • R 4 is selected from the group consisting of Me, Et and - CH 2 F.
  • the compound for use is a compound of Formula (II):
  • R 1 is selected from the group consisting of C1-2 alkyl, C 2 alkenyl, C 2 alkynyl,
  • R 2 is -CF 2 -CI-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 - R 3 is selected from the group consisting of deuterium, Cl and F
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of Cl and Br
  • R 2 is selected from the group consisting of -CF2Me and -CF2Et
  • R 4 is selected from the group consisting of Me, Et and -CH2F.
  • the compound for use is a compound of Formula (III):
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • - X is selected from the group consisting of N and CR 23 ;
  • - Y is selected from the group consisting of NH, O and S;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is of Formula (IVa) or Formula (IVb)
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • - R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • - R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (V):
  • - R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl, CN, CF 3 , NO 2 , F, Cl, Br, and I;
  • - R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • R 14 is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 and phenyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • - R 15 is selected from the group consisting of -OH, -OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 and -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 ; - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (VI):
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is a compound of Formula (VII)
  • - R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl, CN, CF 3 , NO 2 , F, Cl, Br, and I;
  • - R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • R 18 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 19 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 19 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R 20 ;
  • - R 19 is independently selected from the group consisting of F, Cl, Br, I, -CN,
  • R 12 is .
  • the compounds for use is a compound of Formula (VIII)
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- Ci-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • R 22 is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 and phenyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound for use is selected from the group consisting of: (S)-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)-3-methoxypropionic acid; (S)-2-[2-(1 ,1-difluoropropyl)-4,5-difluorophenoxy]propionic acid;
  • the present disclosure relates to a method for treating a neuromuscular disorder comprising at least one or more of: subjecting different muscle fibers of the same motor unit in a neuromuscular tissue of a patient being examined for the neuromuscular disorder to a number of activations; detecting, with a medical device and a recording electrode, the number of paired successful action potentials from the number of activations; determining whether the patient is suffering from or at risk of blocking by dividing the number of paired successful action potentials over a total number of activations; and, when the number of paired successful action potentials over the total number of activations is below a threshold of 95%, administering a CIC-1 inhibitor to the patient, wherein the administering of the CIC-1 inhibitor increases the number of paired successful action potentials over the total
  • a ‘paired successful action potential’ is when voluntary activation of the muscle elicits an action potential in two muscle fibers of the same motor unit with a recording electrode. It can be measured as time (jitter) and/or the success in eliciting an action potential in both muscle fibers (block).
  • a motor unit can be defined as ‘one motor neuron and all of its associated muscle fibers’.
  • Examples of a medical device and a recording electrode are a clinical electrodiagnostic system are the Cadwell Sierra Wave (Kennewick, WA, USA), a concentric needle recording electrode (25 mm X 30 gauge, Dantec) and 1-10 kHz for high- and low-pass filter settings.
  • neuromuscular tissue of a patient being examined examples include the abductor pollicis brevis muscle, the trapezius muscle, the frontalis muscle and the extensor digitorum muscle.
  • the method comprises administering the CIC-1 inhibitor to the patient when the number of paired successful action potentials over the total number of activations is below a threshold of 90%, below a threshold of 85%, below a threshold of 80%, below a threshold of 75%, below a threshold of 70%, below a threshold of 65%, below a threshold of 60%, below a threshold of 55% or below a threshold of 50%.
  • the administering of the CIC-1 inhibitor increases the number of paired successful action potentials over the total number of activations by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 75%, any percentage or range of percentages between 5% and 75%, any percentage or range of percentages between 10% and 50%, or any percentage or range of percentages between 10% and 30%.
  • the administering of the CIC-1 inhibitor to the patient restores contractile force of the patient’s muscles by at least 5%, by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 75%, at least 100%, at least 150%, at least 200%, any percentage or range of percentages between 10% and 400%, any percentage or range of percentages between 15% and 200%, or any percentage or range of percentages between 20% and 100%.
  • the administering of the CIC-1 inhibitor to the patient reduces incidence of neuromuscular junction transmission failure in the patient’s muscles by at least 5%, by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 75%, any percentage or range of percentages between 5% and 75%, any percentage or range of percentages between 10% and 50%, or any percentage or range of percentages between 10% and 30%.
  • the present disclosure relates to a method for treating a neuromuscular disorder comprising at least one or more of: acquiring, with a medical device and a recording electrode, a variation in a time interval between two action potentials of the same motor unit in a neuromuscular tissue of a patient being examined for the neuromuscular disorder; determining whether the variation in the time interval between the two action potentials of the same motor unit exceeds or meets a threshold of 40 ps; and administering a CIC-1 inhibitor to the patient when the variation in the time interval between the two action potentials exceeds or meets the threshold, wherein the administering of the CIC-1 inhibitor reduces the variation in the time interval between the two action potentials between consecutive electrical discharges by at least 10%.
  • the method comprises determining whether the variation in the time interval between the two action potentials of the same motor unit exceeds or meets a threshold of at least 40 ps, of at least 45 ps, of at least 50 ps, of at least 55 ps, of at least 60 ps, of at least 65 ps, of at least 70 ps, of at least 75 ps, of at least 80 ps, of at least 85 ps, of at least 90 ps, of at least 95 ps, of at least 100 ps, of at least 150 ps, of at least 200 ps or of at least 250 ps.
  • the administering of the CIC-1 inhibitor reduces the variation in the time interval between the two action potentials between consecutive electrical discharges by at 5 ps, at least 10 ps, at least 15 ps, at least 20 ps, at least 25 ps, at least 30 ps, at least 40 ps, at least 50 ps, at least 75 ps, at least 100 ps, any point or range between 5 ps and 200 ps, any point or range between 5 ps and 100 ps or any point or range between 10 ps and 50 ps.
  • the variation in the time interval between two action potentials is measured using single fiber electromyography (SFEMG).
  • SFEMG single fiber electromyography
  • the administering of the CIC-1 inhibitor to the patient reduces the variation in the time interval between the two action potentials between consecutive electrical discharges by at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 75%, at least 100%, at least 150%, at least 200%, any percentage or range of percentages between 10% and 400%, any percentage or range of percentages between 15% and 200%, or any percentage or range of percentages between 20% and 100%.
  • the methods for treating a neuromuscular disorder can also be used to prevent and/or ameliorate the neuromuscular disorder.
  • the neuromuscular disorder is at least one of the following: sarcopenia, myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle specific kinase myasthenia gravis (MuSK-MG), Lambert-Eaton Syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie Tooth disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy, Duchenne muscular dystrophy, Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disorder, multiple sclerosis and multifocal motor neuropathy.
  • the neuromuscular disorder is multiple sclerosis.
  • a compound for use in the treatment, prevention and/or amelioration of multiple sclerosis wherein the compound is a CIC-1 inhibitor.
  • a compound for use in a method of restoring contractile force in the muscles of a subject suffering from multiple sclerosis wherein the compound is a CIC-1 inhibitor.
  • a compound for use in a method of reducing the incidence of NMJ transmission failure in the muscles of a subject suffering from multiple sclerosis wherein the compound is a CIC-1 inhibitor.
  • a compound for use in a method of increasing the probability of an action potential firing in the muscles of a subject suffering from multiple sclerosis wherein the compound is a CIC-1 inhibitor.
  • a compound for use in a method of normalising jitter in the muscles of a subject suffering from multiple sclerosis wherein the compound is a CIC-1 inhibitor.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - R 12 is selected from the group consisting of:
  • R 14 is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 and phenyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 15 is selected from the group consisting of -OH, -OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 and -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 18 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 19 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 19 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R 20 ;
  • - R 19 is independently selected from the group consisting of F, Cl, Br, I, -CN,
  • - R 20 is independently selected from the group consisting of F, Cl, Br, I, -CN,
  • R 22 is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 and phenyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • - X is selected from the group consisting of N and CR 23 ;
  • - Y is selected from the group consisting of NH, O and S;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl and cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • - X is selected from the group consisting of N and CR 23 ;
  • - Y is selected from the group consisting of NH, O and S;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- Ci-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • R 14 is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 and phenyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • - R 15 is selected from the group consisting of -OH, -OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 and -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 ;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • R 18 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 19 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 19 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R 20 ;
  • - R 19 is independently selected from the group consisting of F, Cl, Br, I, -CN,
  • - R 20 is independently selected from the group consisting of F, Cl, Br, I, -CN,
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • - R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • R 22 is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 and phenyl optionally substituted with one or more, identical or different, substituents R 8 ; and
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 2 is a 5-membered aromatic heterocycle which may be optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, F and Cl;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 2 is 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 .
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 2 is a 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, F, and Cl;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl and cyclopropyl;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of F, Cl, Br and I, preferably Cl or Br;
  • R 2 is selected from the group consisting of 1 ,2,3-thiadiazol-4-yl, 1 ,3,4- thiadiazol-2-yl, 1 ,2-thiazol-3-yl, 1 ,2-oxazol-3-yl, 1 ,2-oxazol-5-yl and 1 ,3- oxazol-4-yl each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 3 is selected from the group consisting of deuterium, F, and Cl;
  • R 4 is selected from the group consisting of C1-5 alkyl and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 7 is independently selected from the group consisting of H, deuterium, F, Cl,
  • - R 6 is independently selected from deuterium and F;
  • - R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of Cl and Br
  • R 2 is selected from the group consisting of 1 ,2-oxazol-3-yl, 1 ,2-oxazol-5-yl, 1 ,3-oxazol-4-yl and
  • R 4 is selected from the group consisting of Me, Et and -CH 2 F.
  • R 2 is selected from the group consisting of furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, 1 ,2,3-triazole, 1 ,2,4- triazole, 1 ,2,5-oxadiazole, 1 ,2,3-oxadiazole, 1 ,2,4-oxadiazole, 1 ,3,4- oxadiazole, 1 ,2,5-thiadiazole, 1 ,2,3-thiadiazole, 1 ,2,4-thiadiazole and 1 ,3,4- thiadiazole.
  • R 2 is selected from the group consisting of thiophene, pyrrole, isoxazole, 1 ,2,4- oxadiazole and 1 ,3,4-oxadiazole.
  • R 2 is selected from the group consisting of 1 ,2-oxazol-3-yl, 1 ,2-oxazol-4-yl, 1 ,2- oxazol-5-yl, 1 ,3-oxazol-2-yl, 1 ,3-oxazol-4-yl, 1 ,3-oxazol-5-yl, 1 ,2-thiazol-3-yl, 1 ,2-thiazol-4-yl, 1 ,2-thiazol-5-yl, 1 ,3-thiazol-2-yl, 1 ,3-thiazol-4-yl, 1 ,3-thiazol- 5-yl, 1 ,2,3-thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4- thiadiazol-5-yl, 1 ,3,4-thiadiazol-2-yl,
  • R 2 is selected from the group consisting of 1 ,2,3-thiadiazol-4-yl, 1 ,3,4-thiadiazol- 2-yl, 1 ,2-thiazol-3-yl, 1 ,2-oxazol-3-yl, 1 ,2-oxazol-5-yl and 1 ,3-oxazol-4-yl each of which may be optionally substituted with one or more, identical or different, substituents R 7 .
  • R 1 is selected from the group consisting of H, deuterium, F, Cl, Br and I, preferably Cl or Br;
  • R 3 is selected from the group consisting of deuterium, F, and Cl;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl and cyclopropyl;
  • R 6 is independently selected from deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;
  • - m is an integer 0, 1 or 2;
  • - n is an integer 0, 1 , 2 or 3.
  • R 1 is selected from the group consisting of F, Cl, Br and I;
  • R 3 is selected from the group consisting of deuterium, F, and Cl;
  • R 4 is selected from the group consisting of C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl, C2-5 alkenyl and C2-5 alkynyl;
  • R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl, and cyclopropyl;
  • R 6 is independently selected from deuterium and F.
  • R 1 is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,
  • R 2 is -CF2-C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 ;
  • - R 3 is selected from the group consisting of deuterium, Cl and F;
  • - R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3- 5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 , C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 8 , and benzyl optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 6 is independently selected from the group consisting of deuterium and F;
  • R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - n is an integer 0, 1 , 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of Cl and Br
  • R 2 is selected from the group consisting of -CF2Me and -CF2Et
  • R 4 is selected from the group consisting of Me, Et and -CH2F.

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Abstract

La présente invention concerne des composés capables d'inhiber le canal ionique ClC-1 pour une utilisation dans le traitement, le soulagement et/ou la prévention de la sclérose en plaques et d'autres maladies neuromusculaires.
PCT/EP2024/067027 2023-06-20 2024-06-19 Inhibiteurs de clc-1 destinés à être utilisés dans le traitement de la sclérose en plaques et de maladies neuromusculaires Pending WO2024261020A1 (fr)

Priority Applications (2)

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AU2024311729A AU2024311729A1 (en) 2023-06-20 2024-06-19 Clc-1 inhibitors for use in the treatment of multiple sclerosis and neuromuscular diseases
IL324311A IL324311A (en) 2023-06-20 2025-10-29 CLC-1 inhibitors for use in the treatment of multiple sclerosis and neuromuscular diseases

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EP23180395 2023-06-20
EP23180395.8 2023-06-20
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