WO2020254559A1 - Compounds for the treatment of neuromuscular disorders - Google Patents

Compounds for the treatment of neuromuscular disorders Download PDF

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Publication number
WO2020254559A1
WO2020254559A1 PCT/EP2020/067072 EP2020067072W WO2020254559A1 WO 2020254559 A1 WO2020254559 A1 WO 2020254559A1 EP 2020067072 W EP2020067072 W EP 2020067072W WO 2020254559 A1 WO2020254559 A1 WO 2020254559A1
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Prior art keywords
substituents
bromo
difluoropropyl
different
phenoxy
Prior art date
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PCT/EP2020/067072
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English (en)
French (fr)
Inventor
Lars J.S. Knutsen
Nicholas Kelly
Martin Brandhøj SKOV
Anders Riisager
Neerja Saraswat
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NMD Pharma AS
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NMD Pharma AS
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Priority to JP2021575325A priority Critical patent/JP7662196B2/ja
Priority to AU2020298088A priority patent/AU2020298088B2/en
Priority to CA3138332A priority patent/CA3138332A1/en
Priority to PE2021001997A priority patent/PE20220391A1/es
Priority to CN202080044543.7A priority patent/CN114008012B/zh
Priority to US17/620,294 priority patent/US12415771B2/en
Priority to MX2021013508A priority patent/MX2021013508A/es
Priority to KR1020217038226A priority patent/KR102822753B1/ko
Priority to IL288234A priority patent/IL288234B2/en
Priority to SG11202112250QA priority patent/SG11202112250QA/en
Priority to PH1/2021/552771A priority patent/PH12021552771A1/en
Priority to BR112021025637A priority patent/BR112021025637A2/pt
Application filed by NMD Pharma AS filed Critical NMD Pharma AS
Priority to EP20732951.7A priority patent/EP3986852B1/en
Publication of WO2020254559A1 publication Critical patent/WO2020254559A1/en
Priority to ZA2021/08083A priority patent/ZA202108083B/en
Priority to SA521431094A priority patent/SA521431094B1/ar
Priority to CONC2021/0016931A priority patent/CO2021016931A2/es
Anticipated expiration legal-status Critical
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Definitions

  • the present disclosure relates to compounds and their use in treating, ameliorating and/or preventing neuromuscular disorders, including the reversal of drug-induced neuromuscular blockade.
  • the compounds as defined herein can inhibit the CIC-1 ion channel.
  • the disclosure further relates to methods of treating, preventing and/or ameliorating neuromuscular disorders, by administering said composition to a person in need thereof.
  • NMJ neuromuscular junction
  • Neuromuscular transmission refers to the sequence of cellular events at the NMJ whereby an action potential in the lower motor neuron is transmitted to a corresponding action potential in a muscle fibre (Wood SJ, Slater CR. Safety factor at the
  • ACh receptors Upon activation, ACh receptors convey an excitatory current flow of Na + into the muscle fibre, which results in a local depolarization of the muscle fibre at the NMJ that is known as the endplate potential (EPP). If the EPP is sufficiently large, voltage gated Na + channels in the muscle fibre will activate and an action potential in the muscle fibre will ensue. This action potential then propagates from the NMJ throughout the muscle fibre and triggers release of Ca 2+ release from the sarcoplasmic reticulum. The released Ca 2+ activates the contractile proteins within the muscle fibres, thus resulting in contraction of the fibre.
  • EPP endplate potential
  • myasthenia gravis the most common finding is an autoimmune attack on the post-synaptic membrane either against the nicotinic ACh receptors or the musk- receptor in the muscle fibre membrane. Congenital forms of myasthenia are also known.
  • Common to disorders with neuromuscular transmission failure (Lambert Eaton syndrome, amyotrophic lateral sclerosis, spinal muscular atrophy and myasthenia gravis) is that the current flow generated by ACh receptor activation is markedly reduced, and EPPs therefore become insufficient to trigger muscle fibre action potentials.
  • Neuromuscular blocking agents also reduce EPP by antagonizing ACh receptors.
  • the EPP may be of normal amplitude but they are still insufficient to trigger muscle fibre action potentials because the membrane potential threshold for action potential excitation has become more depolarized because of loss of function of voltage gated Na + channels in the muscle fibres.
  • ACh release (Lambert Eaton, amyotrophic lateral sclerosis, spinal muscular atrophy), ACh receptor function (myasthenia gravis, neuromuscular blockade) and function of voltage gated Na + channels (CIM) are essential components in the synaptic transmission at NMJ
  • the magnitude of the EPP is also affected by inhibitory currents flowing in the NMJ region of muscle fibres. These currents tend to outbalance excitatory current through ACh receptors and, expectedly, they thereby tend to reduce EPP amplitude.
  • the most important ion channel for carrying such inhibitory membrane currents in muscle fibres is the muscle-specific CIC-1 Cl ion channel (Kwiecihski H, Lehmann-Horn F, Rudel R.
  • ACh esterase (AChE) inhibitors are traditionally used in the treatment of myasthenia gravis. This treatment leads to improvement in most patients but it is associated with side effects, some of which are serious (Mehndiratta MM, Pandey S, Kuntzer T.
  • Acetylcholinesterase inhibitor treatment for myasthenia gravis Cochrane Database Syst Rev. 2014, Oct 13; 10). Because ACh is an import neurotransmitter in the autonomic nervous system, delaying its breakdown can lead to gastric discomfort, diarrhoea, salivation and muscle cramping. Overdosing is a serious concern as it can lead to muscle paralysis and respiratory failure, a situation commonly referred to as cholinergic crisis. Despite the serious side effects of AChE inhibitors, these drugs are today the treatment of choice for a number of disorders involving neuromuscular impairment. In patients where pyridostigmine (a parasympathomimetic and a reversible AChE inhibitor) is insufficient, corticosteroid treatment (prednisone) and
  • the CIC-1 ion channel (Pedersen, T.H., Riisager, A., Vincenzo de Paoli, F., Chen, T-Y, Nielsen, O.B. Role of physiological CIC-1 Cl ion channel regulation for the excitability and function of working skeletal muscle. J. Gen. Physiol. 2016, 147, 291 - 308) is emerging as a target for potential drugs, although its potential has been largely unrealised.
  • the present disclosure comprises a series of compounds that can alleviate disorders of the neuromuscular junction through inhibition of CIC-1 channels.
  • the present disclosure is directed to CIC-1 ion channel inhibitors with application in the treatment of a range of conditions, such as reversal of block, ALS, and myasthenic conditions, in which muscle activation by the nervous system is compromised and symptoms of weakness and fatigue are prominent.
  • the disclosure concerns a compound of Formula (I): 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 C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , 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 , phenyl optionally substituted with one or more, identical or different, substituents R 9 , and 5-6 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, 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 7 ;
  • - R 7 is independently selected from the group consisting deuterium, F, Cl, -CN,
  • C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, -S-C1-5 alkyl, and -S-C3-5 cycloalkyl wherein the C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, - S-C1-5 alkyl, and -S-C3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - R 9 is independently selected from the group consisting of deuterium
  • - X is a bond or selected from the group consisting of -0-, -S-, -CH2-, -CHR 6 -, and -C(R 6 )2-;
  • - n is an integer 0, 1 , 2, or 3;
  • the disclosure concerns a compound as defined herein for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.
  • the disclosure concerns a composition comprising a compound as defined herein.
  • Panel A shows a schematic representation of the positioning of the three microelectrodes (Vi, V2 and V3) when inserted in a single skeletal muscle fibre for G m determination. Please note that the drawing illustrates only the impaled fibre although it is part of an intact muscle that contains many such fibres. All electrodes recorded the membrane potential of the fibre and the two peripheral electrodes were used to inject current (-30 nA, 50 ms). The electrodes were inserted with known inter-electrode distances (Xi, X2 and X3). After insertion, current was passed first via the Vi electrode and then via the V3 electrode. The resulting deflections in the membrane voltage were measured by the other electrodes.
  • Panel A shows representative force traces before and after exposure to compound A-3. Force traces from a representative muscle stimulated to contract in 1) control condition before addition of neuromuscular blocking agent, 2) the force response to stimulation after 90 minutes incubation with Tubocurarine. Here the muscle displays severe neuromuscular transmission impediment, and 3) The muscle force response after addition of 50 mM compound A-3. Panel B shows average force (AUC) from 3 muscles relative to their initial force. The traces presented in panel A (1 , 2, 3), correspond to the dotted lines in panel B, respectively. Thus, force is lost due to 90 min incubation in tubocurarine and is subsequently recovered when compound A-3 is added.
  • AUC average force
  • 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
  • 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.
  • C2 alkynyl and “C2-5 alkynyl” refers to a branched or unbranched alkynyl group having two or from two to five carbon atoms respectively, two of which are connected by a triple bond, including but not limited to ethynyl, prop-1 -ynyl, prop-2- ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, buta-1 ,3-diynyl, pent-1-ynyl, pent-2-ynyl, pent-3- ynyl, pent-4-ynyl, penta-2,4-diynyl and penta-1 ,3-diynyl.
  • 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.
  • 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.
  • 5-6 membered aromatic heterocycle refers to a group having five to six 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, oxazole, thiazole, isoxazole, isothiazole, 1 ,2,3-triazole,
  • 6-membered aromatic heterocycles include but are not limited to pyridine, pyrazine, pyrimidine and pyridazine.
  • 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” or “treating,” as used herein, 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. In some
  • the term“treatment” encompasses amelioration and prevention.
  • the term“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.
  • the term“prevent” or“preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action.
  • reversal refers to the ability of a compound to restore nerve- stimulated force in skeletal muscle exposed either ex vivo or in vivo to a non depolarizing neuromuscular blocking agent or another pharmaceutical that is able to depress neuromuscular transmission
  • non-depolarizing blockers refers to pharmaceutical agents that antagonize the activation of acetylcholine receptors at the post-synaptic muscle fibre membrane by blocking the acetylcholine binding site on the receptor. These agents are used to block neuromuscular transmission and induce muscle paralysis in connection with surgery.
  • ester hydrolysing reagent refers to a chemical reagent which is capable of converting an ester functional group to a carboxylic acid with elimination of the alcohol moiety of the original ester, including but not limited to acid, base, a fluoride source, PBr3, PC and lipase enzymes.
  • the term“recovery of force in muscle with neuromuscular dysfunction” refers to the ability of a compound to recover contractile force in nerve-stimulated healthy rat muscle after exposure to submaximal concentration of (115 nM) tubocurarine for 90 mins. Recovery of force is quantified as the percentage of the force prior to tubocurarine that is recovered by the compound.
  • total membrane conductance (Gm) is the electrophysiological measure of the ability of ions to cross the muscle fibre surface membrane. It reflects the function of ion channels that are active in resting muscle fibres of which CIC-1 is known to contribute around 80 % in most animal species.
  • the EC50 of the compound is ⁇ 50 mM, 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 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 muscle can be determined as the amount of force restored in muscle as a percentage of the initial force after a muscle has been exposure to a compound of the present disclosure, for example as described in Example 23.
  • the disclosure concerns a compound of Formula (I):
  • R 1 is selected from the group consisting of C 1-2 alkyl, C 2 alkenyl, C 2 alkynyl,
  • R 2 is selected from the group consisting of C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , 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 , phenyl optionally substituted with one or more, identical or different, substituents R 9 , and 5-6 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, 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 7 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C2-5 alkenyl optionally substituted with one or more, identical or different,
  • - R 6 is independently selected from the group consisting of deuterium, F, -CN,
  • - R 7 is independently selected from the group consisting deuterium, F, Cl, -CN,
  • C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, -S-C1-5 alkyl, and -S-C3-5 cycloalkyl wherein the C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, - S-C1-5 alkyl, and -S-C3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - R 9 is independently selected from the group consisting of deuterium
  • - X is a bond or selected from the group consisting of -0-, -S-, -CH2-, -CHR 6 -, and -C(R 6 )2-;
  • - n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the disclosure concerns a compound of Formula (I):
  • R 1 is selected from the group consisting of F, Cl, Br, and I;
  • R 2 is selected from the group consisting of C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , C 2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C 2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C 3-5 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 9 , and 5-6 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 and F;
  • R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C2-5 alkenyl, C 2-5 alkynyl, and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 8 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 8 , C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 , phenyl optionally substituted with one or more, identical or different, substituents R 9 , and benzyl optionally substituted with one or more, identical or different, substituents R 9 ;
  • - R 6 is independently selected from the group consisting of -O-C1-5 alkyl, -O-C3-
  • R 7 is independently selected from the group consisting C3-5 cycloalkyl, -O-C1-
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - R 9 is independently selected from the group consisting of deuterium
  • - X is a bond or selected from the group consisting of -0-, -S-, -CH2-, -CHR 6 -, and -C(R 6 )2-;
  • - n is an integer 0, 1 , 2, or 3;
  • 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 Cl. In one embodiment, R 1 is Br.
  • R 2 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.
  • R 2 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 2 is C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 2 is C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 2 is C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 2 is phenyl optionally substituted with one or more, identical or different, substituents R 9 .
  • R 2 is 5-6 membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 .
  • 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 7 .
  • 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 7 .
  • R 4 is Me.
  • R 4 is -CH2F.
  • R 4 is -CH2-O-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 7 . In one embodiment, R 4 is -CH2-S-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 7 .
  • R 4 is C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 7 .
  • R 4 is C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 7 .
  • R 4 is -CH2-C2-4 alkynyl optionally substituted with one or more, identical or different, substituents R 7 .
  • R 4 is C3-5 cycloalkyl optionally
  • 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 9 . In one embodiment, R 5 is benzyl optionally substituted with one or more, identical or different, substituents R 9 .
  • R 6 is deuterium. In one embodiment, R 6 is F. In one embodiment, R 6 is CN. In one embodiment, R 6 is -O-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 6 is -O-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 6 is -S-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 6 is -S-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 .
  • R 7 is deuterium. In one embodiment, R 7 is F. In one embodiment, R 7 is Cl. In one embodiment, R 7 is CN. In one embodiment, R 7 is -O-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 7 is -O-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 7 is -S-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 7 is -S-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 . In one embodiment, R 7 is C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 .
  • R 8 is deuterium. In one embodiment, R 8 is F.
  • n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3.
  • X is a bond. In one embodiment, X is -0-. In one embodiment, X is -S-. In one embodiment, X is -CH2-. In one embodiment, X is -CHR 6 -. In one
  • X is -C(R 6 )2-.
  • R 1 is Cl or Br
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl optionally substituted with one or more, identical or different, substituents R 7 , and R 5 is H.
  • the enantiomeric excess of the compounds are >90% e.e, for example >90% e.e, for example >95% .e.e, and for example >98% e.e.
  • the disclosure concerns a compound of Formula (II): 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 C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , 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 , phenyl optionally substituted with one or more, identical or different, substituents R 9 , and 5-6 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, 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 7 ;
  • - R 7 is independently selected from the group consisting deuterium, F, Cl, -CN,
  • C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, -S-C1-5 alkyl, and -S-C3-5 cycloalkyl wherein the C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, - S-C1-5 alkyl, and -S-C3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - R 9 is independently selected from the group consisting of deuterium
  • - n is an integer 0, 1 , 2, or 3;
  • the disclosure concerns 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 C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C 2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C 3-5 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 9 , and 5-6 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 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 7 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 8 , C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 8 , C3-6 cycloalkyl optionally
  • - R 6 is independently selected from the group consisting of -O-C1-5 alkyl, -O-C3-
  • R 7 is independently selected from the group consisting C3-5 cycloalkyl, -O-C1-
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - R 9 is independently selected from the group consisting of deuterium
  • - n is an integer 0, 1 , 2, or 3;
  • the disclosure concerns a compound of Formula (II): Formula (II)
  • R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl,
  • R 2 is C 1-5 alkyl optionally be substituted with one or more, identical or
  • 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 7 ;
  • - R 6 is independently selected from the group consisting of deuterium, F, -CN,
  • - R 7 is independently selected from the group consisting deuterium, F, Cl, -CN,
  • C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, -S-C1-5 alkyl, and -S-C3-5 cycloalkyl wherein the C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, - S-C1-5 alkyl, and -S-C3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - n is an integer 0, 1 , 2, or 3;
  • the disclosure concerns a compound of Formula (III):
  • R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl,
  • R 2 is C 1-5 alkyl optionally be substituted with one or more, identical or
  • R 3 is selected from the group consisting of H, 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 7 ;
  • - R 6 is independently selected from the group consisting of deuterium, F, -CN,
  • - R 7 is independently selected from the group consisting deuterium, F, Cl, -CN,
  • S-C1-5 alkyl, and -S-C3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the disclosure concerns a compound of Formula (III): Formula (III)
  • R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br, and I;
  • R 2 is C 1-3 alkyl optionally be substituted with one or more, identical or
  • R 3 is selected from the group consisting of H, 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 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • the compound is selected from the list consisting of
  • the disclosure relates to the use of compounds of Formula (I) and/or Formula (II) and/or Formula (III) in treating, ameliorating and/or preventing a neuromuscular disorder.
  • the disclosure relates to the use of compounds of Formula (I) and/or Formula (II) and/or Formula (III) in reversing and/or ameliorating a neuromuscular blockade.
  • the disclosure relates to a compound of Formula (I):
  • R 1 to R 9 , n and X are defined as disclosed herein,
  • the disclosure concerns a compound of Formula (II):
  • R 1 to R 9 and n are defined as disclosed herein,
  • a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.
  • the disclosure concerns a compound of Formula (III):
  • R 1 to R 8 and n are defined as disclosed herein,
  • the compound for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade is a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.
  • neuromuscular blockade is selected from the list consisting of
  • the compound or the compound for use according to the present disclosure has been modified in order to increase its half-life when administered to a patient, in particular its plasma half-life.
  • the compound or the compound for use according to the present disclosure further comprises a moiety conjugated to said compound, thus generating a moiety-conjugated compound.
  • said moiety-conjugated compound has a plasma and/or serum half-life being longer than the plasma and/or serum half-life of the non-moiety conjugated compound.
  • the moiety conjugated to the compound or compound for use according to the present disclosure is one or more type(s) of moieties selected from the group consisting of albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies and antibody fragments.
  • the compound or compound for use of the present disclosure is used for treating, ameliorating and/or preventing a neuromuscular disorder, or reversing neuromuscular blockade caused by non-depolarizing neuromuscular blocker or antibiotic agent.
  • CIC-1 function may therefore contribute to muscle weakness in conditions of compromised neuromuscular transmission.
  • the compound or the compound for use as described herein inhibits CIC-1 channels.
  • compounds and/or compounds for use of Formula (I) inhibit CIC-1 channels.
  • the neuromuscular disorder may also include neuromuscular dysfunctions.
  • Neuromuscular disorders include for example disorders with symptoms of muscle weakness and fatigue. Such disorders may include conditions with reduced
  • neuromuscular transmission safety factor In one embodiment the neuromuscular disorders are motor neuron disorders. Motor neuron disorders are disorders with reduced safety in the neuromuscular transmission. In one embodiment motor neuron disorders are selected from the group consisting of amyotrophic lateral sclerosis (ALS) (Killian JM, Wilfong AA, Burnett L, Appel SH, Boland D. Decremental motor responses to repetitive nerve stimulation in ALS. Muscle Nerve, 1994, 17, 747-754), spinal muscular atrophy (SMA) (Wadman Rl, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3.
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • Acetylcholinesterase deficiency contributes to neuromuscular junction dysfunction in type 1 diabetic neuropathy.
  • Am. J. Physiol. Endocrinol. Metab., 2012, 15, E551 - 561) and sarcopenia (Gilmore K.J., Morat T., Doherty T.J., Rice C.L., Motor unit number estimation and neuromuscular fidelity in 3 stages of sarcopenia. 2017, 55 (5), 676-684).
  • the neuromuscular disorder is amyotrophic lateral sclerosis (ALS).
  • the neuromuscular disorder is spinal muscular atrophy (SMA).
  • the neuromuscular disorder is Charcot-Marie tooth disease (CMT).
  • CMT Charcot-Marie tooth disease
  • neuromuscular disorder is sarcopenia.
  • the neuromuscular disorder is critical illness myopathy (CIM).
  • the neuromuscular disorders include for example disorders with symptoms of muscle weakness and fatigue.
  • Such disorder may for example include diabetes (Burton, A. Take your pyridostigmine: that's an (ethical?) order! Lancet Neurol., 2003, 2, 268).
  • the compound or the compound for use of the present disclosure is used to prevent neuromuscular disorder.
  • the compound or the compound for use may for example be used prophylactically or as a treatment against nerve gas that is known to cause symptoms of muscle weakness and fatigue (Kawamura, Y., Kihara, M., Nishimoto, K., Taki, M. Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Pathophysiology, 2003, 9, 189-194).
  • the compound or the compound for use of the present disclosure is used in the treatment of botulism poisoning (Sellin, L.C., The action of botulinum toxin at the neuromuscular junction, Med Biol., 1981, 59, 11-20.
  • botulism poisoning Sesen, L.C., The action of botulinum toxin at the neuromuscular junction, Med Biol., 1981, 59, 11-20.
  • the compound or the compound for use of the present disclosure is used in the treatment of snake bites (Silva A., Maduwage K., Buckley N.A., Lalloo D.G., de Silva H.J., Isbister G.K., Antivenom for snake venom-induced neuromuscular paralysis, Cochrane
  • the neuromuscular disorders is chronic fatigue syndrome.
  • Chronic fatigue syndrome Fletcher, S.N., Kennedy, D.D., Ghosh, I.R., Misra, V.P., Kiff, K., Coakley, J.H., Hinds, C.J. Persistent neuromuscular and
  • CFS neurophysiologic abnormalities in long-term survivors of prolonged critical illness.
  • Crit. Care Med. 2003, 31, 1012 - 1016) is the common name for a medical condition characterized by debilitating symptoms, including fatigue that lasts for a minimum of six months in adults.
  • CFS may also be referred to as systemic exertion intolerance disorder (SEID), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), or by several other terms.
  • SEID systemic exertion intolerance disorder
  • ME myalgic encephalomyelitis
  • PVFS post-viral fatigue syndrome
  • CIDS chronic fatigue immune dysfunction syndrome
  • Symptoms of CFS include malaise after exertion; unrefreshing sleep, widespread muscle and joint pain, physical exhaustion, and muscle weakness.
  • the neuromuscular disorder is myotubular myopathy (Dowling, J.J. et al, Myotubular myopathy and the neuromuscular junction:
  • the neuromuscular disorder is Duchenne muscular dystrophy (van der Pijl, M.M. et al, Characterization of neuromuscular synapse function abnormalities in multiple Duchenne muscular dystrophy mouse models, European Journal of Neuroscience, 2016, 43, 1623-1635.
  • the neuromuscular disorder is a critical illness polyneuropathy (Angelini C. Spectrum of metabolic myopathies. Biochim. Biophys. Acta., 2015, 1852, 615 - 621) or CIM (Latronico, N., Bolton, C.F. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011 , 10, 931-941).
  • Critical illness polyneuropathy and CIM are overlapping syndromes of widespread muscle weakness and neurological dysfunction developing in critically ill patients.
  • the neuromuscular disorder may also include metabolic myopathy (Milone, M., Wong, L.J. Diagnosis of mitochondrial myopathies. Mol. Genet. Metab., 2013, 110, 35 - 41) and mitochondrial myopathy (Srivastava, A., Hunter, J.M. Reversal of neuromuscular block. Br. J. Anaesth. 2009, 103, 115 - 129).
  • Metabolic myopathies result from defects in biochemical metabolism that primarily affects muscle. These may include glycogen storage disorders, lipid storage disorder and 3-phosphocreatine storage disorder.
  • Mitochondrial myopathy is a type of myopathy associated with mitochondrial disorder. Symptoms of mitochondrial myopathies include muscular and neurological problems such as muscle weakness, exercise intolerance, hearing loss and trouble with balance and coordination.
  • the neuromuscular disorder is periodic paralysis, in particular hypokalemic periodic paralysis which is a disorder of skeletal muscle excitability that presents with recurrent episodes of weakness, often triggered by exercise, stress, or carbohydrate-rich meals (Wu, F., Mi, W., Cannon, S.C., Neurology, 2013, 80, 11 IQ- 1116 and Suetterlin, K. et at, Current Opinion Neurology, 2014, 27, 583-590) or hyperkalemic periodic paralysis which is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood (Ammat, T. et at, Journal of General Physiology, 2015, 146, 509-525).
  • hypokalemic periodic paralysis which is a disorder of skeletal muscle excitability that presents with recurrent episodes of weakness, often triggered by exercise, stress, or carbohydrate-rich meals (Wu, F., Mi, W., Cannon, S.C., Neurology, 2013, 80, 11 IQ
  • the neuromuscular disorder is a myasthenic condition.
  • Myasthenic conditions are characterized by muscle weakness and neuromuscular transmission failure.
  • Congenital myasthenia gravis (Finlayson, S., Beeson, D., Palace, J. Congenital myasthenic syndromes: an update. Pract. Neurol., 2013, 13, 80 - 91) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction.
  • Myasthenia gravis and Lambert-Eaton syndrome are examples of myasthenic conditions.
  • Myasthenia gravis is either an autoimmune or congenital neuromuscular disorder that leads to fluctuating muscle weakness and fatigue. In the most common cases, muscle weakness is caused by circulating antibodies that block ACh receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of the
  • Lambert-Eaton myasthenic syndrome also known as LEMS, Lambert-Eaton syndrome, or Eaton-Lambert syndrome
  • Lambert-Eaton myasthenic syndrome is a rare autoimmune disorder that is characterized by muscle weakness of the limbs. It is the result of an autoimmune reaction in which antibodies are formed against presynaptic voltage-gated calcium channels, and likely other nerve terminal proteins, in the neuromuscular junction.
  • the neuromuscular disorder is myasthenia gravis.
  • the neuromuscular disorder is Lambert- Eaton syndrome.
  • Neuromuscular blockade is used in connection with surgery under general
  • the neuromuscular disorder has been induced by a neuromuscular blocking agent.
  • the neuromuscular disorder is muscle weakness caused by neuromuscular blockade after surgery.
  • the compound or the compound for use is used for reversing and/or ameliorating neuromuscular blockade after surgery.
  • the neuromuscular blockade is drug induced.
  • the neuromuscular blockade is induced by an antibiotic.
  • the neuromuscular blockade is induced by a non-depolarizing neuromuscular blocker.
  • compositions comprising the compound or the compound for use, according to the present disclosure.
  • the composition according to the present disclosure is used for treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.
  • the compositions and compounds described herein can be pharmaceutically acceptable.
  • the composition as described herein is in the form of a pharmaceutical formulation.
  • the composition as described herein further comprises a pharmaceutically acceptable carrier. Examples of potential formulations and preparations are contained, for example, in the Handbook of
  • composition of the present disclosure may comprise further active
  • composition further comprises at least one further active agent.
  • the active agent can be suitable for treating, preventing or ameliorating said neuromuscular disorder.
  • the active agent in certain embodiments can be an acetylcholine esterase inhibitor.
  • Said acetylcholine esterase inhibitor may for example be selected from the group consisting of delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine and lactucopicrin.
  • the acetylcholine esterase inhibitor is selected from the group consisting of neostigmine, physostigmine and pyridostigmine. In certain embodiments, the acetylcholine esterase inhibitor is neostigmine or pyridostigmine.
  • the active agent may also be an immunosuppressive drug.
  • Immunosuppressive drugs are drugs that suppress or reduce the strength of the body’s immune system. They are also known as anti-rejection drugs. Immunosuppressive drugs include but are not limited to glucocorticoids, corticosteroids, cytostatics, antibodies and drugs acting on immunophilins. In one embodiment the active agent is prednisone.
  • the active agent may also be an agent that is used in anti-myotonic treatment.
  • agents include for example blockers of voltage gated Na + channels, and
  • the active agent may also be an agent for reversing a neuromuscular blockade after surgery.
  • agents include for example neostigmine or sugammadex (Org 25969, tradename Bridion).
  • the active agent may also be an agent for increasing the Ca 2+ sensitivity of the contractile filaments in muscle.
  • agents include tirasemtiv and CK-2127107 (Hwee, D.T., Kennedy, A.R., Hartman, J.J., Ryans, J., Durham, N., Malik, F.I., Jasper, J.R.
  • the small-molecule fast skeletal troponin activator, CK-2127107 improves exercise tolerance in a rat model of heart failure. Journal of Pharmacology and Experimental Therapeutics, 2015, 353, 159 - 168).
  • the active agent may also be an agent for increasing ACh release by blocking voltage gated K + channels in the pre-synaptic terminal.
  • agent includes 3,4-aminopyridine.
  • the present disclosure relates to a method of treating, preventing and/or ameliorating a neuromuscular disorder, said method comprising administering a therapeutically effective amount of the compound or the compound for use as defined herein to a person in need thereof.
  • the person is a human being.
  • the present disclosure relates to a method of reversing and/or ameliorating a neuromuscular blockade, said method comprising administering a therapeutically effective amount of the compound or the compound for use as defined herein to a person in need thereof.
  • the present disclosure relates to a method for recovery of
  • neuromuscular transmission said method comprising administering a therapeutically effective amount of the compound or the compound for use as defined herein to a person in need thereof.
  • the person in need thereof may be a person having a neuromuscular disorder or a person at risk of developing a neuromuscular disorder or a person having symptoms of muscle weakness and/or fatigue.
  • the person in need thereof is a person with reduced neuromuscular transmission safety with prolonged recovery after neuromuscular blockade. Types of neuromuscular disorders are defined herein above.
  • the person has amyotrophic lateral sclerosis, spinal muscular atrophy, myasthenia gravis or Lambert-Eaton syndrome.
  • a therapeutically effective amount is an amount that produces a therapeutic response or desired effect in the person taking it.
  • Administration routes, formulations and dosages can be determined by persons of skill in the art.
  • the method of treatment may be combined with other methods that are known to treat, prevent and/or ameliorate neuromuscular disorders.
  • the treatment method may for example be combined with administration of any of the agents mentioned herein above.
  • the treatment is combined with administration of
  • acetylcholine esterase inhibitor such as for example neostigmine or pyridostigmine.
  • invention relates to a method for recovery of force in muscles with neuromuscular dysfunction, said method comprising administering a compound or a composition as defined herein to a subject in need thereof.
  • said recovery of force is >5%, such as >10%, such as >15%, such as >20%, such as >25%, such as >30%, such as >35%.
  • the recovery of force in muscle can be determined as the amount of force restored in muscle as a percentage of the initial force after a muscle has been exposure to a compound of the present disclosure, for example as described in Example 23.
  • Another aspect of the disclosure relates to use of a compound as defined herein, for the manufacture of a medicament for the treatment, prevention and/or amelioration of a neuromuscular disorder.
  • Another aspect relates to use of a compound as defined herein, for the manufacture of a medicament or a reversal agent for reversing and/or ameliorating a neuromuscular blockade after surgery.
  • the present disclosure relates to methods of manufacturing compounds or compounds for use according to formula (I).
  • One method for manufacturing the compounds or compounds for use according to the present disclosure comprises the steps of
  • R 4 and R 5 are defined herein with a compound having formula (GM.II) under Mitsunobu or similar reaction conditions
  • One method for manufacturing the compounds or compounds for use according to the present disclosure comprises the steps of
  • One method for manufacturing the compounds or compounds for use according to the present disclosure comprises the steps of
  • R 4 and R 5 are defined herein with a compound having formula (GM.VII) (GM.VII)
  • R 1 , R 2 , R 3 , n and X are as defined herein and Q is a suitable leaving group such as a halogen such as fluorine or iodine, to generate a compound having formula (GM.IV)
  • One method for manufacturing the compounds or compounds for use according to the present disclosure comprises the steps of
  • R 4 is defined herein and Rio is a suitable protecting group, such as a silyl-containing moiety, with a compound having formula (GM.II) under Mitsunobu or similar reaction conditions
  • R 1 , R 2 , R 3 , n and X are as defined herein to generate a compound having formula (GM.X) b. removing the protecting group Rio of product compound of a); and c. reacting the product compound of b) with an oxidising reagent thus generating a compound as defined herein.
  • One method for manufacturing the compounds or compounds for use according to the present disclosure comprises the steps of
  • One method for manufacturing the compounds or compounds for use according to the present disclosure comprises the steps of
  • R 1 , R 3 , R 4 , R 5 and n are defined herein under acylating conditions to generate a compound having formula (GM.XII)
  • One method for manufacturing the compounds or compounds for use according to the present disclosure comprises the steps of
  • R 4 and R 9 are defined herein with a compound having formula (GM.XV) (GM.XV)
  • 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 C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , 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 , phenyl optionally substituted with one or more, identical or different, substituents R 9 , and 5-6 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, 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 7 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C2-5 alkenyl optionally substituted with one or more, identical or different,
  • - R 6 is independently selected from the group consisting of deuterium, F, -CN,
  • - R 7 is independently selected from the group consisting deuterium, F, Cl, -CN,
  • C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, -S-C1-5 alkyl, and -S-C3-5 cycloalkyl wherein the C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, - S-C1-5 alkyl, and -S-C3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;
  • - R 8 is independently selected from the group consisting of deuterium and F
  • - R 9 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
  • - X is a bond or selected from the group consisting of -0-, -S-, -CH2-, -CHR 6 -, and -C(R 6 )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 2 is selected from the group consisting of C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , C 2-5 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 , phenyl optionally substituted with one or more, identical or different, substituents R 9 , and 5-6 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 and F;
  • - R 4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C2-5 alkenyl, C 2-5 alkynyl, and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
  • - R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C2-5 alkenyl optionally substituted with one or more, identical or different,
  • - R 6 is independently selected from the group consisting of -O-C1-5 alkyl, -O-C3-
  • R 7 is independently selected from the group consisting C3-5 cycloalkyl, -O-C1-
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - R 9 is independently selected from the group consisting of deuterium
  • - X is a bond or selected from the group consisting of -0-, -S-, -CH2-, -CHR 6 -, and -C(R 6 )2-;
  • - n is an integer 0, 1 , 2, or 3;
  • 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 C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , 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 , phenyl optionally substituted with one or more, identical or different, substituents R 9 , and 5-6 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, 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 7 ;
  • - R 7 is independently selected from the group consisting deuterium, F, Cl, -CN,
  • C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, -S-C1-5 alkyl, and -S-C3-5 cycloalkyl wherein the C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, - S-C1-5 alkyl, and -S-C3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - R 9 is independently selected from the group consisting of deuterium
  • - n is an integer 0, 1 , 2, or 3;
  • R 1 is selected from the group consisting of F, Cl, Br, and I;
  • R 2 is selected from the group consisting of C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , 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
  • R 3 is selected from the group consisting of deuterium 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 7 ;
  • R 5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C2-5 alkenyl optionally substituted with one or more, identical or different,
  • R 6 is independently selected from the group consisting of -O-C1-5 alkyl, -O-C3- 5 cycloalkyl, -S-C1-5 alkyl, and -S-C3-5 cycloalkyl, each of which may optionally be substituted with one or more, identical or different, substituents R 8 , deuterium, F and -CN;
  • R 7 is independently selected from the group consisting C3-5 cycloalkyl, -O-C1-
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - R 9 is independently selected from the group consisting of deuterium
  • - n is an integer 0, 1 , 2, or 3;
  • R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl,
  • R 2 is C 1-5 alkyl optionally be substituted with one or more, identical or
  • 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 7 ;
  • - R 6 is independently selected from the group consisting of deuterium, F, -CN,
  • - R 7 is independently selected from the group consisting deuterium, F, Cl, -CN,
  • C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, -S-C1-5 alkyl, and -S-C3-5 cycloalkyl wherein the C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, - S-C1-5 alkyl, and -S-C3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F;
  • - n is an integer 0, 1 , 2, or 3;
  • R 1 is selected from the group consisting of C 2 alkenyl, C 2 alkynyl, NO 2 , F, Cl,
  • R 2 is C 1-5 alkyl optionally be substituted with one or more, identical or
  • R 3 is selected from the group consisting of H, deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C 1-5 alkyl and C 2-5 alkynyl each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
  • - R 6 is independently selected from the group consisting of deuterium, F, -CN,
  • - R 7 is independently selected from the group consisting deuterium, F, Cl, -CN,
  • C3-5 cycloalkyl, -O-C1-5 alkyl, -O-C3-5 cycloalkyl, -S-C1-5 alkyl, and -S-C3-5 cycloalkyl wherein the C 3-5 cycloalkyl, -O-C 1-5 alkyl, -O-C 3-5 cycloalkyl, - S-C 1-5 alkyl, and -S-C 3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 1 is selected from the group consisting of C 2 alkenyl, C 2 alkynyl, NO 2 , F, Cl,
  • R 2 is C 1-3 alkyl optionally be substituted with one or more, identical or
  • R 3 is selected from the group consisting of H, deuterium, Cl and F;
  • R 4 is selected from the group consisting of H, deuterium, C 1-3 alkyl and C 2-3 alkynyl each of which may be optionally substituted with one or more, identical or different, substituents R 8 ;
  • R 8 is independently selected from the group consisting of deuterium and F; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
  • R 2 is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • R 2 is C1-3 alkyl optionally substituted with one or more, identical or different, substituents R 6 .
  • methyl, ethyl, n-propyl and isopropyl 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 .
  • O-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 7 .
  • R 1 is Cl or Br
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl optionally substituted with one or more, identical or different, substituents R 7 , and R 5 is H.
  • compound is an inhibitor of the CIC-1 ion channel.
  • 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%.
  • a composition comprising the compound according to any one of the preceding items.
  • composition is a pharmaceutical composition.
  • composition further comprises a pharmaceutically acceptable carrier.
  • composition further comprises at least one further active agent.
  • further active agent is suitable for treating, preventing or ameliorating said neuromuscular disorder.
  • further active agent is an acetylcholine esterase inhibitor.
  • acetylcholine esterase inhibitor is selected from the group consisting of delta-9- tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine and lactucopicrin.
  • acetylcholine esterase inhibitor is neostigmine or pyridostigmine.
  • further active agent is tirasemtiv or CK-2127107.
  • R 4 and R 5 are defined in any one of the preceding items with a compound having formula (GM.II) under Mitsunobu or similar reaction conditions
  • a method for manufacturing the compound according to any one of the preceding items comprising the steps of
  • R 4 and R 5 are defined in any one of the preceding items with a compound having formula (GM.VII) wherein R 1 , R 2 , R 3 , n and X are as defined in any one of the preceding items and Q is a suitable leaving group such as a halogen such as fluorine or iodine to generate a compound having formula (GM.IV)
  • R 4 is defined in any one of the preceding items and R10 is a suitable protecting group, such as a silyl-containing, with a compound having formula (GM.II) under Mitsunobu or similar reaction conditions
  • R 1 , R 2 , R 3 , n and X are as defined in any one of the preceding items to generate a compound having formula (GM.X) b. removing the protecting group Rio of product compound of a); and c. reacting the product compound of b) with an oxidising reagent thus generating a compound according to any one of the preceding items.
  • R 4 and R 5 are defined in any one of the preceding items with a compound having formula (GM.XI)
  • a method for manufacturing the compound according to any one of the preceding items comprising the steps of
  • R 1 , R 3 , R 4 , R 5 and n are defined in any one of the preceding items under acylating conditions to generate a compound having formula (GM.XII)
  • the compound for use according to any one of the preceding items wherein the neuromuscular disorder is Lambert-Eaton Syndrome.
  • the compound for use according to any one of the preceding items wherein the neuromuscular disorder is critical illness myopathy.
  • ALS amyotrophic lateral sclerosis
  • the compound for use according to any one of the preceding items wherein the neuromuscular disorder is spinal muscular atrophy (SMA).
  • SMA spinal muscular atrophy
  • CMT Charcot-Marie tooth disease
  • neuromuscular disorder is hypokalemic periodic paralysis or hyperkalemic periodic paralysis.
  • the compound for use according to any one of the preceding items wherein the neuromuscular disorder is Duchenne muscular dystrophy.
  • the compound for use according to any one of the preceding items wherein the neuromuscular disorder is selected from the group consisting of Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, and critical illness polyneuropathy.
  • neuromuscular blockade is neuromuscular blockade after surgery.
  • the moiety conjugated to the compound is one or more type(s) of moieties selected from the group consisting of albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies and antibody fragments.
  • composition is a pharmaceutical composition.
  • composition further comprises a pharmaceutically acceptable carrier.
  • composition further comprises at least one further active agent.
  • acetylcholine esterase inhibitor is selected from the group consisting of delta-9- tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine and lactucopicrin.
  • said acetylcholine esterase inhibitor is neostigmine or pyridostigmine.
  • a method of treating, preventing and/or ameliorating a neuromuscular disorder comprising administering a therapeutically effective amount of the compound as defined in any one of the preceding items to a person in need thereof.
  • a method of reversing and/or ameliorating a neuromuscular blockade said
  • a method for recovery of neuromuscular transmission comprising administering a therapeutically effective amount of the compound as defined in any one of the preceding items to a person in need thereof.
  • a method for recovering neuromuscular transmission comprising administering a compound as defined in any one of the preceding items to an individual in need thereof.
  • Method 1A Solvent A: methanol; solvent B: 0.1% formic acid in water. Gradient 0-100 % Solvent B over 15 minutes with monitoring at 280 nm.
  • Method 1A Solvent C: Acetonitrile; solvent D: 0.1 % formic acid in water. Gradient 10- 100 % Solvent C vs D over 15 minutes with monitoring at 280 nm.
  • LCMS analysis was carried out with a Waters Acquity UPLC system consist of a Acquity I Class Sample Manager-FL, an Acquity I Class Binary Solvent Manager and an Acquity UPLC Column Manager.
  • UV detection was afforded with an Acquity UPLC PDA detector (scanning from 210nm to 400nm) and mass detection was afforded with an Acquity QDa detector (mass scanning from 100-1250 Da; positive and negative modes simultaneously).
  • a Waters Acquity UPLC BEH C18 column (2.1x50mm 1.7mm) was used to achieve separation of analytes.
  • Samples were prepared by dissolving (with or without sonication) into 1 mL of 50%v/v MeCN in water. These solutions were filtered with 0.45mm syringe filter before submitting for analysis. All solvents (including formic acid) used were HPLC grade. Conditions: 0.1 % v/v Formic acid in water [Eluent A]; 0.1% v/v Formic acid in MeCN [Eluent B]; Flow rate 0.8mL/min; injection volume 2mL and 1.5 min equilibration time between samples.
  • Samples were prepared by dissolving (with or without sonication) into 1mL of 50%v/v MeCN in water. These solutions were filtered with 0.45mm syringe filter before submitting for analysis. All solvents (and ammonium bicarbonate) used (including 35% ammonia solution) were HPLC grade.
  • Samples were prepared by dissolving (with or without sonication) into 1ml_ of 50%v/v MeCN in water. These solutions were filtered with 0.45mm syringe filter before submitting for analysis. All solvents (including formic acid) used were HPLC grade. Conditions: 0.1 % v/v formic acid in water [Eluent A]; 0.1 % v/v formic acid in MeCN [Eluent B]; Flow rate 0.8ml_/min; injection volume 2ml_ and 1.5 min equilibration time between samples.
  • Samples were prepared by dissolving (with or without sonication) into 1ml_ of 50%v/v MeCN in water. These solutions were filtered with 0.45mm syringe filter before submitting for analysis. All solvents (including 36% ammonia solution) used were HPLC grade.
  • Method A involves the synthesis of compound (GM.V), which is an aryloxy substituted acetic acid derivative, wherein R 1 to R 9 , n and X are as defined in Formula (I) above.
  • Compound (GM.II) is available either commercially or synthetically, and can be converted into an ether (GM.IV) by methods which include variations on Mitsunobu reaction conditions.
  • This ether contains an ester functionality -CO2R 5 , which can be hydrolysed under a range of standard conditions, involving acid or base, to provide the carboxylic acid structure (GM.V).
  • These standard conditions can also for example involve an enzymic hydrolysis, employing for example an esterase or lipase.
  • an ester molecule includes for example a (CH3)3SiCH2CH20- group as -O-R 5 , then a fluoride ion source such as tetra-n-butylammonium fluoride can be employed to convert (GM.IV) into the corresponding carboxylic acid (GM.V).
  • a fluoride ion source such as tetra-n-butylammonium fluoride can be employed to convert (GM.IV) into the corresponding carboxylic acid (GM.V).
  • Substituted phenols of general formula (GM.II) can be prepared by a variety of standard methods, for example by an ester rearrangement in the Fries rearrangement, by a rearrangement of /V-phenylhydroxylamines in the Bamberger rearrangement, by hydrolysis of phenolic esters or ethers, by reduction of quinones, by replacement of an aromatic amine or by a hydroxyl group with water and sodium bisulfide in the Bucherer reaction.
  • Other methods include hydrolysis of diazonium salts, by rearrangement reaction of dienones in the dienone phenol rearrangement, by the oxidation of aryl silanes, by the Hock process.
  • Phenols of formula (GM.II), wherein X is a bond can be prepared by Grignard reaction of a suitable Grignard reagent to 2-hydroxybenzonitrile derivatives.
  • Method B involves the synthesis of compound (GM.V), an aryloxy substituted acetic acid derivative, wherein R 1 to R 9 , n and X are as defined in Formula (I) above, and is related to Method A.
  • Compound (GM.II) is available either commercially or
  • Carboxylic acids of general formula (GM.V) can additionally be prepared by the procedure illustrated in General Method C.
  • a phenolic ether of formula (GM.IV) can be prepared by displacement of a suitable leaving group Q in (GM.VII).
  • Q can for example be a halogen such as fluorine or iodine, and the ether product of formula (GM.IV) can be converted into the carboxylic acid derivative (GM.V) by one of a range of methods outlined in Method A, involving hydrolysis of the ester functionality.
  • General Method D
  • Carboxylic acids of general formula (GM.V) can be prepared by the procedure illustrated as General Method D.
  • a phenolic ether of formula (GM.II) can be prepared by utilising e.g. Mitsunobu conditions on the phenol structure (GM.II), and (GM.IX) is a suitable secondary alcohol wherein R 1 to R 9 , n and X are as defined in Formula (I) above and -Rio is a suitable protecting group, such as a silyl-containing moiety.
  • primary alcohol (GM.X) can be oxidised to a carboxylic acid under standard conditions involving potassium permanganate, Jones oxidation conditions, the Heyns oxidation, ruthenium tetroxide or TEMPO.
  • Carboxylic acids of general formula (GM.V) wherein R 1 to R 9 , n and X are as defined in Formula (I) above can be prepared by the procedure illustrated as General Method E.
  • the phenol (GM.XI) is available either commercially or synthetically, and can be converted into an ether (GM.XII) by methods which include variations on Mitsunobu reaction conditions.
  • the acyl group in the ether (GM.XII) can be converted into an alkyl-difluoro derivative by a range of fluorination conditions, including utilisation of deoxofluor as a reagent, to provide after ester hydrolysis compound (GM.V).
  • Carboxylic acids of general formula (V) wherein R 1 to R 9 and n are as defined in Formula (I) above and X is a bond can be prepared by the procedure illustrated as General Method E.
  • the phenyl ether (GM.XII I) prepared by methods analogous to those illustrated above, can be converted into an ether (GM.XII) by methods which include the classical Friedel Crafts aromatic acylation reaction, one well known variation of which proceeds via an alkanoic acid chloride in the presence of a Lewis Acid.
  • acyl group in the resultant ether can be converted into an alkyl- difluoro derivative by a range of fluorination conditions, including utilisation of deoxofluor as a reagent, to provide after ester hydrolysis compound (GM.V).
  • An alternative procedure is to perform the acylation on a protected primary alcohol derivative, and to oxidise the deprotected alcohol as described in General Method D above.
  • Carboxylic acids of general formula (XVIII) wherein R 1 to R 9 and n are as defined in Formula (I), Formula (II) and Formula (III) above can be prepared by the procedure illustrated as General Method G.
  • Phenol (GM.XV) is available commercially or can be prepared from phenol (GM.XIV) via reaction with for example an acyl halide followed by rearrangement using e.g. AIC .
  • Phenol (GM.XV) is then converted into ether (GM.XVI) by methods which include variations on Mitsunobu reaction conditions. In some cases, it may be necessary to change protecting group -R10 before the acyl group in ether
  • GM.XVI alkyl-difluoro derivative
  • GM.XVII alkyl-difluoro derivative
  • the primary alcohol can be oxidised to carboxylic acid (GM.XVIII) under standard conditions involving potassium permanganate, Jones oxidation conditions, the Heyns oxidation, ruthenium tetroxide or TEMPO.
  • Carboxylic acids of general formula (GM.V) wherein R 1 to R 9 , n and X are as defined in Formula (I) above can be prepared by the procedure illustrated as General Method G.
  • the phenol (GM.XI) which is available commercially or can be prepared as described in General Method G, can be converted into alkyl-difluoro derivative (GM.II) by a range of fluorination conditions, including utilisation of deoxofluor as a reagent.
  • the alkyl- difluoro derivative (GM.II) is then coupled with ester (GM.III) using methods which include variations on Mitsunobu reaction conditions to give ester (GM.IV).
  • Ester (GM.IV) can undergo further functional group modifications, for example on the aromatic ring, before being hydrolysed to carboxylic acids (GM.V).
  • Table 1 below illustrates Example compounds defined by the general Formula (I) which were prepared in >95% purity.
  • Table 1 Illustrative Examples of the Disclosure
  • Step 2 Synthesis of (S)-methyl 2-(4-bromo-2-(1 , 1-difluoroethyl)phenoxy) propanoate 3
  • (S)-methyl 2-(2-acetyl-4-bromophenoxy) propanoate 2 (3.99 g, 13.3 mmol) in dry CH2CI2 (40 ml_) in a seal tube was added de-oxofluor (24.5 ml, 133 mmol, 10 eq) and flush with argon and seal the cap.
  • de-oxofluor 24.5 ml, 133 mmol, 10 eq
  • reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate and stirred for 20 to 30 minutes.
  • the aqueous layer was extracted with ethyl acetate (2x100 ml_).
  • the combined organic extracts were washed with brine and dried (Na2SC>4).
  • the residue was passed through a short silica gel column (hexane-EtOAc, 25: 1 , 5: 1) to give desired product 3 (3.55 g, 83%) as a colourless oil.
  • Step 3 Synthesis of sodium (S)-2-(4-bromo-2-(1 , 1-difluoroethyl)phenoxy) propanoate 4
  • (S)-methyl 2-(4-bromo-2-(1 , 1-difluoroethyl)phenoxy) propanoate 3 (1.62 g, 5.01 mmol) in MeOH (32 ml_) and water (8 ml_) at ⁇ 10°C
  • solid NaOH 200 mg, 5.01 mmol
  • the compound was prepared as described in example 1.
  • the reaction was cooled to 25 °C and KHF2 (9.9 g, 0.13 mol, 0.1 eq) and CsF (19.1 g, 0.13 mol, 0.1 eq) were added.
  • the reaction was heated to 65 °C and for 18 h, at which point, LC indicated 77% product.
  • the reaction was cooled to RT and H2O (3.90 L) was added over 5 mins [mild exotherm].
  • the aqueous was extracted with toluene (3 x 1.00 L).
  • Step 1 Synthesis of (f?)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5- bromophenyl)propan-1-one 2
  • Step 2 Synthesis of (f?)-1-(5-bromo-2-(1-fluoro-3-hvdroxypropan-2- yloxy)phenyl)propan-1-one 3
  • Step 3 Synthesis of (f?)-2-(4-bromo-2-propionylphenoxy)-3-fluoropropyl acetate 4
  • (R)-1-(5-bromo-2-(1-fluoro-3-hydroxypropan-2- yloxy)phenyl)propan-1-one (1.95 g, 6.4 mmol) in 25 mL of dichloromethane at 0°C was added triethylamine (0.97 g, 9.6 mmol), followed by dropwise addition of acetyl chloride (0.55 g, 7.05 mmol).
  • the reaction mixture was stirred at room temperature for 1 h.
  • Step 4 Synthesis of (f?)-2-(4-bromo-2-(1 , 1-difluoropropyl)phenoxy)-3-fluoropropyl acetate 5
  • Step 5 Synthesis of (f?)-2-(4-bromo-2-(1 , 1-difluoropropyl)phenoxy)-3-fluoropropan-1-ol 6
  • Extra sodium hypochlorite (4 drops, 4-4.99M solution) and TEMPO (0.024 g, 0.153 mmol) were added and the addition of sodium hypochlorite and TEMPO was repeated three more times at 8 h intervals.
  • the mixture was cooled to 0 °C and 1 M NaOH solution was added to adjust pH ⁇ 13 and the product washed with DCM (40 ml_).
  • the water layer was separated, cooled again to 0 °C, and acidified with 1 M HCI to pH ⁇ 1.
  • Step 7 Synthesis of sodium (f?)-2-(4-bromo-2-(1 , 1-difluoropropyl)phenoxy)-3- fluoropropanoate 8
  • Step 1 Synthesis of (f?)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5- bromophenvDethanone 2
  • Step 4 Synthesis of (f?)-2-(4-bromo-2-(1 ,1-difluoroethyl)phenoxy)-3-fluoropropyl acetate 5
  • Step 5 Synthesis of (f?)-2-(4-bromo-2-(1 , 1-difluoroethyl)phenoxy)-3-fluoropropan-1-ol 6
  • (R)-2-(4-bromo-2-(1 , 1-difluoroethyl)phenoxy)-3-fluoropropyl acetate (0.69 g, 1.94 mmol) in MeOH/H 2 0 (40/4 ml_) was added K 2 C0 3 (0.536 g, 3.88 mmol).
  • Step 6 Synthesis of (f?)-2-(4-bromo-2-(1 , 1-difluoroethyl)phenoxy)-3-fluoropropanoic acid 7
  • the reaction mixture was stirred at room temperature for 2 hours, Extra sodium hypochlorite (5 drops, 4- 4.99M solution) and TEMPO (0.024 g, 0.153 mmol) were added and the addition of sodium hypochlorite and TEMPO was repeated three more times at 8 h intervals.
  • the mixture was cooled to 0 °C and 1 M NaOH solution was added to adjust pH ⁇ 13 and the product washed with DCM (40 ml_). The water layer was separated, cooled again to 0 °C, and acidified with 1 M HCI to pH ⁇ 1.
  • Step 1 Synthesis of (S)-methyl 2-(4-bromo-5-fluoro-2-propionylphenoxy)propanoate 2
  • triphenylphosphine (0.784 g, 2.99 mmol) in 20 ml_ of dichloromethane previously cooled to 0°C was slowly added DIAD (0.605 g, 2.99 mmol). The ice bath was then removed and the reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-20% ethyl acetate/hexane to give the desired product 2 (0.52 g, 62.9%) as a light-yellow oil.
  • Step 2 Synthesis of (S)-methyl 2-(4-bromo-2-(1 ,1-difluoropropyl)-5- fluorophenoxy)propanoate 3
  • Step 1 Synthesis of 1-(5-bromo-4-fluoro-2-hvdroxyphenyl)propan-1-one 2
  • triphenylphosphine (2.62 g, 9.98 mmol) in 25 ml_ of dichloromethane previously cooled to 0°C was slowly added DIAD (1.89 g, 9.37 mmol). The ice bath was then removed, and the reaction mixture was stirred at room temperature for 4 days, then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate/hexane to give the desired product 3 (1.5 g, 43.6 %) as a light-yellow oil.
  • Step 3 Synthesis of (f?)-1-(5-bromo-4-fluoro-2-(1-fluoro-3-hvdroxypropan-2- yloxy)phenyl)propan-1-one 4
  • Step 5 Synthesis of (f?)-2-(4-bromo-2-(1 , 1-difluoropropyl)-5-fluorophenoxy)-3- fluoropropyl acetate 6
  • Step 6 Synthesis of (f?)-2-(4-bromo-2-(1 , 1-difluoropropyl)-5-fluorophenoxy)-3- fluoropropan-1-ol 7
  • Step 1 Synthesis of 1-(5-chloro-4-fluoro-2-hvdroxyphenyl)propan-1-one 2
  • the crude material was taken in 250 ml_ of round bottom flask and AlC (6.4 g, 48.0 mmol) was added.
  • the reaction mixture was heated at 110 °C for 90 min., then cooled.
  • the reaction mixture was quenched with 1M HCI (30 ml_), and the product extracted with ethyl acetate (2x 50 ml_), washed with H O (2x20 ml_), brine (10 ml_), dried over sodium sulphate and concentrated under reduced pressure.
  • the residue was passed through a short silica gel column (EtOAc/ hexane, 0-10%) to give the desired product 2 (3.5 g, 54%) as a light yellow solid.
  • Step 3 Synthesis of (f?)-1-(5-chloro-4-fluoro-2-(1-fluoro-3-hvdroxypropan-2- yloxy)phenyl)propan-1-one 4
  • reaction mixture was quenched with H O (30 ml_), and the product extracted with ethyl acetate (2x 50 ml_), washed with H O (2x20 ml_), brine (15 ml_), dried over sodium sulphate and concentrated under reduced pressure.
  • the residue was passed through a short silica gel column (EtOAc/ hexane, 0-50%) to give desired product 4 (0.78 g, 64.4%) as a white solid.
  • Step 5 Synthesis of (f?)-2-(4-chloro-2-(1 ,1-difluoropropyl)-5-fluorophenoxy)-3- fluoropropyl acetate 6
  • Step 6 Synthesis of (f?)-2-(4-chloro-2-(1 ,1-difluoropropyl)-5-fluorophenoxy)-3- fluoropropan-1-ol 7
  • Step 1 Synthesis of 1- ⁇ 2-r(f?)-2-(benzyloxy)-1-(fluoromethyl)ethoxy1-5-bromo-4- fluorophenylM-ethanone 3
  • triphenylphosphine (1.35 g, 5.15 mmol) in 25 ml_ of dichloromethane previously cooled to 0°C was slowly added DIAD (1.04 g, 5.15 mmol). The ice bath was then removed, and the reaction mixture was stirred at room temperature for 5 days, then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate/hexane to get desired product 3 (0.94 g, 54.8%) as a light-yellow oil.

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WO2024261020A1 (en) 2023-06-20 2024-12-26 Nmd Pharma A/S Clc-1 inhibitors for use in the treatment of multiple sclerosis and neuromuscular diseases

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