Compounds for the treatment of neuromuscular disorders

Abstract

The present disclosure relates to compounds suitable for the treatment, amelioration and / or prevention of neuromuscular disorders, including overcoming drug-induced neuromuscular blockade. The compounds disclosed herein are capable of inhibiting the ClC-1 ion channel.

Description

[Technical field]

[0001] The present disclosure relates to compounds and their use for the treatment, amelioration and / or prevention of neuromuscular disorders, including overcoming drug-induced neuromuscular blockade.The compounds disclosed herein can inhibit ClC-1 ion channel.The present disclosure further relates to a method for the treatment, prevention and / or amelioration of neuromuscular disorders by administering the above composition to a person in need thereof. [Background technology]

[0002] Walking, breathing, and eye movement are examples of essential daily physiological actions that are driven by the contractile activity of skeletal muscles. Skeletal muscles are originally in a quiescent state, and contractile activity occurs only in response to commands from the central nervous system (CNS). Such neural commands take the form of action potentials that travel in several steps from the brain to the muscle fiber. The neuromuscular junction (NMJ) is a highly differentiated membrane region on muscle fibers where motor neurons come into close proximity with muscle fibers, and the NMJ is the site where neural action potentials are transmitted to muscular action potentials via synaptic transmission in a one-to-one manner.

[0003] Neuromuscular transmission refers to the series of cellular events at the NMJ by which an action potential in the lower motor neuron is transmitted to a corresponding action potential in the muscle fiber (Wood SJ, Slater CR. Safety factor at the neuromuscular junction. Prog. Neurobiol. 2001, 64, 393-429). When a nerve action potential reaches the presynaptic terminal, it is activated by voltage-gated P / Q-type Ca2+ receptors in the nerve terminal membrane. 2+ Ca channel 2+ This influx induces an influx of cytosolic Ca in the nerve terminal. 2+ This causes an increase in the level of acetylcholine (ACh), which induces the exocytosis of acetylcholine (ACh). The released ACh then diffuses across the synaptic cleft and activates nicotinic ACh receptors in the postsynaptic muscle fiber membrane. Upon activation, ACh receptors react with Na +The NMJ transmits an excitatory current flow into the muscle fiber, which results in a local depolarization of the muscle fiber at the NMJ, known as the end-plate potential (EPP). If the channel EPP is large enough, the voltage-gated Na + This action potential then propagates from the NMJ throughout the muscle fiber, releasing Ca from the sarcoplasmic reticulum. 2+ Ca release is induced. 2+ activates contractile proteins within the muscle fiber, thus causing the fiber to contract.

[0004] Failure of neuromuscular transmission is a cause of presynaptic dysfunction [Lambert-Eaton syndrome (Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011, 10, 1098-107)], amyotrophic lateral sclerosis (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)], and spinal muscular atrophy (Wadman RI, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3.Neurology,2012,79,2050-2055)] and postsynaptic dysfunction as occurs in myasthenia gravis (Le Panse R,Berrih-Aknin S.Autoimmune myasthenia gravis:autoantibody mechanisms and new developments on immune regulation.Curr Opin Neurol.,2013,26,569-576). Failure of excitation and / or propagation of action potentials in muscle may also result from reduced muscle excitability as in critical illness myopathy (CIM) (Latronico,N.,Bolton,CF Critical illness polyneuropathy and myopathy:a major cause of muscle weakness and paralysis.Lancet Neurol.2011,10,931-941). In Lambert-Eaton syndrome, presynaptic P / Q-type Ca 2+Autoimmune attack against the channel resulted in significantly reduced Ca delivery into nerve terminals during presynaptic action potentials. 2+ In myasthenia gravis, the most common finding is an autoimmune attack on nicotinic ACh receptors in the muscle fiber membrane or on the postsynaptic membrane. Congenital forms of myasthenia are also known. Common to diseases of failed neuromuscular transmission (Lambert-Eaton syndrome, amyotrophic lateral sclerosis, spinal muscular atrophy and myasthenia gravis) is a marked reduction in the current flow generated by ACh receptor activation, and thus an EPP becomes insufficient to trigger muscle fiber action potentials.

[0005] Neuromuscular blockers also reduce EPPs by antagonizing ACh receptors. In CIM with reduced muscle excitability, EPPs may be of normal amplitude, but they are still insufficient to elicit muscle fiber action potentials because the membrane potential threshold for action potential excitation is increased by the voltage-gated Na+ receptors in the muscle fibers. + This is because they become more depolarized due to the reduced function of the channels.

[0006] ACh release (Lambert-Eaton, amyotrophic lateral sclerosis, spinal muscular atrophy), ACh receptor function (myasthenia gravis, neuromuscular blockade) and voltage-gated Na + Although the function of ClC-1 channels (CIMs) is essential for synaptic transmission at the NMJ, the amplitude of the EPP is also influenced by inhibitory currents in the NMJ region of muscle fibers. These currents tend to exceed the excitatory currents mediated by ACh receptors, and, as predicted, they tend to reduce the EPP amplitude. The most important ion channel for passing such inhibitory membrane currents in muscle fibers is the muscle-specific ClC-1 Cl -(Kwiecinski H,Lehmann-Horn F,Rudel R.Membrane currents in human intercostal muscle at varied extracellular potassium.Muscle Nerve.1984,7,465-469;Kwiecinski H,Lehmann-Horn F,Rudel R.Drug-induced myotonia in human intercostal muscle.Muscle Nerve.1988,11,576-581;Pedersen,TH,F.de Paoli,and OBNielsen.Increased excitability of acidified skeletal muscle: role of chloride conductance.J.Gen.Physiol.,2005,125,237-246).

[0007] ACh esterase (AChE) inhibitors have traditionally been used to treat myasthenia gravis. This treatment results in improvement in most patients, but is accompanied by side effects, some of which are severe (Mehndiratta MM, Pandey S, Kuntzer T. Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev. 2014, Oct 13;10). As ACh is an import neurotransmitter in the autonomic nervous system, delayed breakdown of it can result in stomach discomfort, diarrhea, salivation, and muscle cramps. Overdosage is a serious concern as it can result in muscle paralysis and respiratory failure, a situation commonly referred to as cholinergic crisis. Despite the severe side effects of AChE inhibitors, these drugs are nowadays the treatment of choice for many disorders involving neuromuscular disorders. In patients in whom pyridostigmine (a parasympathomimetic drug and reversible AChE inhibitor) is inadequate, corticosteroids (prednisone) and immunosuppressants (azathioprine) are used. Plasma exchange can be used to obtain rapid but transient improvement.

[0008] Unfortunately, all currently employed drug regimens for the treatment of myasthenia gravis are associated with adverse long-term consequences (Howard, JF Jr. Adverse drug effects on neuromuscular transmission. Semin Neurol. 1990, 10, 89-102), despite research to identify novel therapeutic agents (Gilhus, NE New England Journal of Medicine, 2016, 375, 2570-2581).

[0009] The ClC-1 ion channel (Pedersen, TH, Riisager, A., Vincenzo de Paoli, F., Chen, TY, Nielsen, ObRole of physiological ClC-1 Cl- ion channel regulation for the excitability and function of working skeletal muscle. J. Gen. Physiol. 2016, 147, 291-308) has emerged as a promising drug target, but its potential is still largely unrealized.

[0010] There are publications of various ligands at the ClC-1 ion channel, see for example: Liantonio, A., Accardi, A., Carbonara, G., Fracchiolla, G., Loiodice, F., Tortorella P, Traverso S, Guida P, Pierno S, De Luca A, Camerino DC, Pusch M. Molecular requisites for drug binding to muscle ClC-1 and renal ClC-K channel revealed by the use of phenoxy- alkyl derivatives of 2-(p-chlorophenoxy)propionic acid. Mol. Pharmacol., 2002, 62, 265-271 and Liantonio, A. et al., Structural requisites of 2-(p-chlorophenoxy)propionic acid analogues for activity on native rat skeletal muscle chloride conductance and on heterologously expressed CLC-1. Br. J. Phamacol., 2003, 129, 1255-1264.

[0011] Liantonio, A., Pusch, M., Picollo, A., Guida, P., De Luca, A., Pierno, S., Fracchiolla, G., Loiodice, F., Tortorella, P., Conte-Camerino, D. Investigations of pharmacologic properties of the renal ClC-K1 chloride channel co-expressed with barttin by the use of 2-(p-chlorophenoxy)propionic acid derivatives and other structurally unrelated chloride hannels blockers. A paper in Journal of the American Society of Nephrology, 2004, 15, 13-20 disclosed ligands for the ClC-K1 chloride channel.

[0012] Pusch, M., Liantonio, A., Bertorello, L., Accardi, A., De Luca, A., Pierno, S., Tortorella, V., Conte-Camerino, D. Pharmacological characterization of chloride channels belonging to the ClC family by the use of chiral clofibric acid derivatives. In a paper published in Molecular Pharmacology, 2000, 58, 498-507, the authors disclosed the effect of the enantiomers of 2-(p-chlorophenoxy)propionic acid on ClC-1 and ClC-2 ion channels.

[0013] In the paper Ferorelli, S., Loiodice, F., Tortorella, V., Conte-Camerino, D., De Luca, A.M. Carboxylic acids and skeletal muscle chloride channel conductance: effects on the biological activity induced by the introduction of methyl groups on the aromatic ring of chiral α-(4-chloro-phenoxy)alkanoic acids, Farmaco, 2001, 56, 239-246, derivatives of (4-chlorophenoxy)alkanoic acids were tested on skeletal muscle chloride conductance.

[0014] Edoardo Aromataris investigated 4-chlorophenoxyisobutyric acid derivatives in his dissertation "Pharmacology of ClC-1 chloride channels"; see https: / / digital.library.adelaide.edu.au / dspace / bitstream / 2440 / 58973 / 8 / 02whole.pdf.

[0015] In WO 2016 / 202341, Pedersen et al. reported a series of phenoxypropionic acid and related compounds that appear to block the ClC-1 ion channel for use in the treatment, amelioration and / or prevention of neuromuscular disorders, but which have structural features distinct from those of the present disclosure. Summary of the Invention

[0016] The present disclosure includes a series of compounds that can reverse neuromuscular junction damage through inhibition of ClC-1 channels.

[0017] Compounds that inhibit the ClC-1 ion channel have been shown to be able to restore neuromuscular transmission, as evidenced by data generated by the study of the compounds placed in the biological models described herein, and therefore constitute a class of potential drugs that can be used to treat and / or ameliorate muscle weakness and / or muscle fatigue in neuromuscular junction disorders caused by disease or by neuromuscular blocking drugs.

[0018] The present disclosure relates to ClC-1 ion channel inhibitors that have application in the treatment of a variety of conditions, such as overcoming blockade, ALS, and myasthenic states, where muscle activation by the nervous system is impaired and symptoms of weakness and fatigue are prominent.

[0019] In one aspect, the present disclosure provides a compound of formula I: [ka] (In the formula, -R 1 is C 1-2 Selected from the group consisting of alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 6 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 6 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 6 C optionally substituted with 3-5 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 7 5-6 membered aromatic heterocycles optionally substituted with -R 3 is selected from the group consisting of deuterium, Cl and F; -R 4 is H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, and C 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 teeth, H、 one or more identical or different substituents R 8 Optionally replaced by C 1-5 alkyl, one or more identical or different substituents R 8 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 8 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 8 C optionally substituted with 3-6 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 9 benzyl optionally substituted with; -R 6 are independently deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl; 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 7 are independently deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -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 -O-, -S-, -CH2-, -CHR 6 - and -C(R 6 )2-; and -n is an integer 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0020] In another aspect, the disclosure relates to a compound as defined herein for use in the treatment, amelioration and / or prevention of a neuromuscular disorder and / or for use in overcoming and / or ameliorating neuromuscular blockade. In yet another aspect, the disclosure relates to a composition comprising a compound as defined herein. [Brief description of the drawings]

[0021] [Figure 1]Panel A shows a schematic of the positioning of three microelectrodes (V1, V2 and V3) when inserted into a single skeletal muscle fiber for Gm measurement. Note that the figure shows only the impaled fiber, but this is a portion of an intact muscle containing many such fibers. All electrodes recorded the membrane potential of the fiber, and the two terminal electrodes were used to inject current (-30 nA, 50 ms). The electrodes were inserted with known interelectrode distances (X1, X2 and X3). After insertion, current was passed first through the V1 electrode and then through the V3 electrode. The resulting membrane voltage deflection was measured by the other electrodes. Steady-state deflections of membrane potential were measured and divided by the magnitude of the injected current (-30 nA) to obtain the transduction resistance. These were then plotted against the interelectrode distance and fitted to an exponential function (Panel B) from which Gm could be calculated using linear cable theory. This procedure described in panels A and B was repeated for several muscle fibers in the muscle during exposure to increasing concentrations of compound A-3, with approximately 10 fibers at each concentration. The average Gm at each concentration was plotted as a function of compound concentration in panel C and fitted to a four-parameter sigmoidal function, from which the EC50 value for the compound was obtained (dotted line). [Diagram 2] Panel A shows representative muscle force traces before and after exposure to Compound A-3. Traces of muscle force from a representative muscle stimulated to contract in 1) control conditions before the addition of neuromuscular blockers, 2) muscle force response to stimulation after 90 min incubation with tubocurarine (in this case the muscle shows severe neuromuscular transmission disorder), and 3) muscle force response after the addition of 50 μM Compound A-3 are shown. Panel B shows the mean muscle force (AUC) from the three muscles relative to their initial force. Traces shown in Panel A (1, 2, 3) respectively correspond to the dotted lines in Panel B. Thus, muscle force is lost by 90 min incubation in tubocurarine and is then restored when Compound A-3 is added.

[0022] definition The term “C 1-2 Alkyl, C 1-3 Alkyl" and "C 1-5"Alkyl" refers to a branched or unbranched alkyl group having 1 to 2, 1 to 3, or 1 to 5 carbon atoms, respectively, including, but not limited to, methyl, ethyl, prop-1-yl, prop-2-yl, 2-methylprop-1-yl, 2-methylprop-2-yl, 2,2-dimethylprop-1-yl, but-1-yl, but-2-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, pent-1-yl, pent-2-yl, and pent-3-yl.

[0023] The terms "C2 alkenyl" and "C 2-5 "Alkenyl" refers to a branched or unbranched alkenyl group having, respectively, 2 or 2 to 5 carbon atoms, two of which are joined by a double bond, including, but not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and isopentenyl.

[0024] The terms "C2 alkynyl" and "C 2-5 "Alkynyl" refers to a branched or unbranched alkynyl group having, respectively, 2 or 2 to 5 carbon atoms, two of which are joined 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, but-1,3-diynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, penta-2,4-diynyl and penta-1,3-diynyl.

[0025] The term “C 3-5 Cycloalkyl" and "C 3-6 "Cycloalkyl" refers to a group having 3 to 5 or 3 to 6 carbon atoms, respectively, containing a monocyclic or bicyclic carbocyclic ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-5 Examples of cycloalkyl are oxiran-3-yl, oxetan-2-yl, oxetan-3-yl.

[0026] The term "5-6 membered aromatic heterocycle" refers to a group having 5-6 carbon atoms in which 1-3 carbon atoms are replaced with heteroatoms selected from the group including nitrogen, sulfur and oxygen. Attachment to the heterocycle may be at the position of a heteroatom of the heterocycle or through a carbon atom.

[0027] Five-membered aromatic heterocycles include, but are not limited to, 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.

[0028] Six-membered aromatic heterocycles include, but are not limited to, pyridine, pyrazine, pyrimidine, and pyridazine.

[0029] As used herein, the term "half-life" is the time it takes for a compound to lose half of its pharmacological activity. The term "plasma half-life" is the time it takes for a compound to lose half of its pharmacological activity in plasma.

[0030] The term "treatment" refers to combating a disease or disorder. "Treatment" or "treating", as used herein, includes any desired effect on the symptoms or pathology of a disease or condition, and may further include minimal change or improvement in one or more measurable markers of the disease or condition being treated. "Treatment" or "treating" does not necessarily indicate a complete eradication or cure of the disease or condition, or its associated symptoms. In some embodiments, the term "treatment" encompasses amelioration and prevention.

[0031] The term "amelioration" refers to a reduction in the severity of the symptoms of a disease or condition. Efforts that improve the patient's condition, or that endeavor to remedy a condition that is difficult for the patient to tolerate, or at least make it more tolerable, are considered "ameliorative" treatments.

[0032] The terms "prevent" or "preventing" refer to eliminating, avoiding, forestalling, stopping, or hindering something from happening, especially by pre-treatment.

[0033] The term "overcome" or "overcoming" refers to the ability of a compound to restore neuronal excitability of skeletal muscle exposed ex vivo or in vivo to a non-depolarizing neuromuscular blocking agent or another pharmaceutical agent capable of inhibiting neuromuscular transmission.

[0034] The term "nonpolarizing blockers" refers to pharmaceutical agents that antagonize activation of acetylcholine receptors at the postsynaptic muscle fiber membrane by blocking the acetylcholine binding site on the receptor. These agents are used to block neuromuscular transmission and induce muscle paralysis in conjunction with surgery.

[0035] The term "ester hydrolyzing agent" refers to a chemical reagent capable of converting an ester functional group to a carboxylic acid by elimination of the alcohol moiety of the original ester, including, but not limited to, acids, bases, fluoride sources, PBr3, PCl3 and lipase enzymes.

[0036] The term "restoration of muscle force in muscle with neuromuscular dysfunction" refers to the ability of a compound to restore muscle contractile force in nerve-stimulated healthy rats after 90 minutes exposure to submaximal concentration (115 nM) tubocurarine.Muscle force restoration is quantified as the percentage of muscle force restored by the compound relative to the muscle force before tubocurarine.

[0037] The term "total membrane conductance (G m) is an electrophysiological measure of the ability of ions to cross the muscle fiber surface membrane. It reflects the function of ion channels active in resting muscle fibers, of which ClC-1 is found to contribute approximately 80% in most animal species. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] compound It is within the scope of the present disclosure to provide compounds for use in the treatment, amelioration and / or prevention of neuromuscular disorders that reduce neuromuscular function. As disclosed herein, inhibition of ClC-1 improves or restores neuromuscular function. Compounds of the present disclosure include compounds that can inhibit ClC-1 channels, thereby improving or restoring neuromuscular function. In one embodiment, the EC 50 is <50 μM, for example <40 μM, for example <30 μM, for example <20 μM, for example <15 μM, for example <10 μM, and for example <5 μM. In one embodiment, the force recovery in a muscle with neuromuscular dysfunction is >5%, for example >10%, for example >15%, for example >20%, for example >25%, for example >30%, for example >35%. Force recovery in a muscle can be measured as the amount of force recovered in the muscle as a percentage of the initial muscle force after the muscle is exposed to a compound of the present disclosure, for example a compound as described in Example 23. In one aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, -R 1 is C 1-2 Selected from the group consisting of alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 6 C optionally substituted with 2-5alkenyl, one or more, the same or different R 6 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 6 C optionally substituted with 3-5 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 7 5-6 membered aromatic heterocycles optionally substituted with -R 3 is selected from the group consisting of deuterium, Cl and F; -R 4 is H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, and C 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 teeth, H、 one or more identical or different substituents R 8 Optionally replaced by C 1-5 alkyl, one or more identical or different substituents R 8 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 8 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 8 C optionally substituted with 3-6 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 9 benzyl optionally substituted with; -R 6 are independently deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5Alkyl, and -SC 3-5 cycloalkyl; 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 7 are independently deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -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 -O-, -S-, -CH2-, -CHR 6 - and -C(R 6 )2-; and -n is an integer 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0039] In one aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, -R 1is selected from the group consisting of F, Cl, Br and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 6 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 6 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 6 C optionally substituted with 3-5 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 7 5-6 membered aromatic heterocycles optionally substituted with -R 3 is selected from the group consisting of deuterium and F; -R 4 is H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, and C 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 teeth, H、 one or more identical or different substituents R 8 Optionally replaced by C 1-5 alkyl, one or more identical or different substituents R 8 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 8 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 8 C optionally substituted with 3-6 Cycloalkyl, one or more identical or different substituents R 9phenyl optionally substituted with, and one or more identical or different substituents R 9 benzyl optionally substituted with; -R 6 are independent, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more identical or different substituents R 8 , optionally substituted with deuterium, F, -CN; -R 7 is independent, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more identical or different substituents R 8 , optionally substituted with deuterium, F, -CN; -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 -O-, -S-, -CH2-, -CHR 6 - and -C(R 6 )2-; and -n is an integer 0, 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0040] In one embodiment, R 1 is C 1-2 In one embodiment, R 1 is C alkenyl. In one embodiment, R 1 is C alkynyl. In one embodiment, R1 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.

[0041] In one embodiment, R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 In one embodiment, R 2 is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl. 2 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, and the methyl, ethyl, n-propyl or isopropyl groups are each independently selected from one or more identical or different substituents R 6 In one embodiment, R 2 represents one or more identical or different substituents R 6 C optionally substituted with 2-5 In one embodiment, R is an alkenyl. 2 represents one or more identical or different substituents R 6 C optionally substituted with 2-5 In one embodiment, R 2 represents one or more identical or different substituents R 6 C optionally substituted with 3-5 In one embodiment, R 2 represents one or more identical or different substituents R 9 In one embodiment, R 2 represents one or more identical or different substituents R 7 is a 5- to 6-membered aromatic heterocycle optionally substituted with

[0042] In one embodiment, R 3 is deuterium. In one embodiment, R3 is Cl. In one embodiment, R 3 is F.

[0043] In one embodiment, R 4 represents one or more identical or different substituents R 7 C optionally substituted with 1-5 In one embodiment, R 4 is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl. 4 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, and the methyl, ethyl, n-propyl or isopropyl groups are each independently selected from one or more identical or different substituents R 7 In one embodiment, R 4 is Me. In one embodiment, R 4 is -CHF. In one embodiment, R 4 represents one or more identical or different substituents R 7 Optionally substituted with -CH2-OC 1-5 In one embodiment, R 4 represents one or more identical or different substituents R 7 Optionally substituted with -CH2-SC 1-5 It is an alkyl.

[0044] In one embodiment, R 4 represents one or more identical or different substituents R 7 C optionally substituted with 2-5 In one embodiment, R is an alkenyl. 4 represents one or more identical or different substituents R 7 C optionally substituted with 2-5 In one embodiment, R 4 represents one or more identical or different substituents R 7 Optionally substituted with -CH2-C 2-4 In one embodiment, R 4 represents one or more identical or different substituents R 7 C optionally substituted with3-5 In one embodiment, R 4 is H. 4 If H, then R 4 The carbon to which is attached is not an asymmetric center.

[0045] In one embodiment, R 5 is H. In one embodiment, R 5 represents one or more identical or different substituents R 8 C optionally substituted with 1-5 In one embodiment, R 5 represents one or more identical or different substituents R 8 C optionally substituted with 3-6 In one embodiment, R 5 represents one or more identical or different substituents R 9 In one embodiment, R 5 represents one or more identical or different substituents R 9 is benzyl optionally substituted with

[0046] In one embodiment, R 6 is deuterium. In one embodiment, R 6 is F. In one embodiment, R 6 is CN. In one embodiment, R 6 represents one or more identical or different substituents R 8 Optionally substituted with -OC 1-5 In one embodiment, R 6 represents one or more identical or different substituents R 8 Optionally substituted with -OC 3-5 In one embodiment, R 6 represents one or more identical or different substituents R 8 -SC optionally substituted with 1-5 In one embodiment, R 6 represents one or more identical or different substituents R 8 -SC optionally substituted with 3-5It is cycloalkyl.

[0047] In one embodiment, 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 represents one or more identical or different substituents R 8 Optionally substituted with -OC 1-5 In one embodiment, R 7 represents one or more identical or different substituents R 8 Optionally substituted with -OC 3-5 In one embodiment, R 7 represents one or more identical or different substituents R 8 -SC optionally substituted with 1-5 In one embodiment, R 7 represents one or more identical or different substituents R 8 -SC optionally substituted with 3-5 In one embodiment, R 7 represents one or more identical or different substituents R 8 C optionally substituted with 3-5 It is cycloalkyl.

[0048] In one embodiment, R 8 is deuterium. In one embodiment, R 8 is F.

[0049] In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3.

[0050] In one embodiment, X is a bond. In one embodiment, X is -O-. In one embodiment, X is -S-. In one embodiment, X is -CH2-. In one embodiment, X is -CHR 6 In one embodiment, X is -C(R6 )2-.

[0051] In one embodiment, R 1 is Cl or Br, and R 2 represents one or more identical or different substituents R 7 R is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl, optionally substituted with 5 is H.

[0052] In one embodiment, the enantiomeric excess of the compound is >90% ee, such as >90% ee, for example >95% ee, and for example >98% ee. In one embodiment, the present disclosure provides a compound of formula (II): [ka] (In the formula, -R 1 is C 1-2 Selected from the group consisting of alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 6 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 6 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 6 C optionally substituted with 3-5 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 7 5-6 membered aromatic heterocycles optionally substituted with -R 3 is selected from the group consisting of deuterium, Cl and F; -R 4is H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, and C 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 teeth, H、 one or more identical or different substituents R 8 Optionally replaced by C 1-5 alkyl, one or more identical or different substituents R 8 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 8 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 8 C optionally substituted with 3-6 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 9 benzyl optionally substituted with; -R 6 are independently deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl; 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 7 are independently deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5Alkyl, and -SC 3-5 cycloalkyl, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -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; and -n is an integer 0, 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0053] In one embodiment, the present disclosure provides a compound of formula (II): [ka] (In the formula, -R 1 is selected from the group consisting of F, Cl, Br and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 6 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 6 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 6 C optionally substituted with 3-5 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 75-6 membered aromatic heterocycles optionally substituted with -R 3 is selected from the group consisting of deuterium and F; -R 4 is H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, and C 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 teeth, H、 one or more identical or different substituents R 8 Optionally replaced by C 1-5 alkyl, one or more identical or different substituents R 8 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 8 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 8 C optionally substituted with 3-6 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 9 benzyl optionally substituted with; -R 6 are independent, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more identical or different substituents R 8 , optionally substituted with deuterium, F, -CN; -R 7 is independent, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC1-5 Alkyl, and -SC 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more identical or different substituents R 8 , optionally substituted with deuterium, F, -CN; -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; and -n is an integer 0, 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0054] In one embodiment, the present disclosure provides a compound of formula (II): [ka] (In the formula, -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 is alkyl; -R 3 is selected from the group consisting of deuterium, Cl and F; -R 4 is H, deuterium, C 1-5 Alkyl and C 2-5 alkynyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 is H; -R 6 are independently deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC1-5 Alkyl, and -SC 3-5 cycloalkyl; 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 7 are independently deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 8 is independently selected from the group consisting of deuterium and F; and -n is an integer 0, 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0055] In one embodiment, the present disclosure provides a compound of formula (III): [ka] (In the formula, -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 is alkyl; -R 3 is selected from the group consisting of H, deuterium, Cl and F; -R 4 is H, deuterium, C 1-5 Alkyl and C 2-5 alkynyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 6 are independently deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl; 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 7 are independently deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 and -R 8 are independently selected from the group consisting of deuterium and F; or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0056] In one embodiment, the present disclosure provides a compound of formula (III): [ka] (In the formula, -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 8 C optionally substituted with 1-3 is alkyl; -R 3 is selected from the group consisting of H, deuterium, Cl and F; -R 4 is H, deuterium, C 1-3 Alkyl and C 2-3 alkynyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 8 may be optionally substituted with; -R 8 are independently selected from the group consisting of deuterium and F; or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0057] In one embodiment, the compound is selected from the list consisting of: (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid; (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propanoic acid; (2S)-2-{4-bromo-2-[difluoro(phenyl)methyl]phenoxy}propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-2-cyclopropylacetic acid; (2S)-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(cyclopropyldifluoromethyl)phenoxy]propanoic acid; (2S)-2-{4-bromo-2-[difluoro(1,3-thiazol-2-yl)methyl]phenoxy}propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid; (2S)-2-[4-bromo-2-(cyclobutyldifluoromethyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-chloropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]pent-4-ynoic acid; (2S)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2- 2 H) Propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy]propanoic acid; (2S)-2-[4-cyano-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)(3,5,6- 2 H3) phenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethenylphenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid; 2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; (2S)-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2R)-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethenyl-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid; (2R)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propanoic acid; (2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutanoic acid; (2R)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid; and (2S)-2-[4-bromo-2-(1,1-difluoro-3-methoxypropyl)phenoxy]propanoic acid.

[0058] Treatment method In one aspect, the disclosure relates to the use of compounds of formula (I) and / or formula (II) and / or formula (III) in the treatment, amelioration and / or prevention of neuromuscular disorders. In one aspect, the disclosure relates to the use of compounds of formula (I) and / or formula (II) and / or formula (III) in overcoming and / or ameliorating neuromuscular blockade. Thus, in one aspect, the disclosure relates to compounds of formula (I): [ka] (In the formula, R 1 ~R 9 , n, and X are as defined herein), or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0059] In one embodiment, the present disclosure provides a compound of formula (II): [ka] (In the formula, R 1 ~R 9 and n is as defined herein; or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0060] In one embodiment, the present disclosure provides a compound of formula (III): [ka] (In the formula, R1 ~R 8 and n is as defined herein; or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0061] In one embodiment, the compound for use in the treatment, amelioration and / or prevention of neuromuscular disorders and / or for use in overcoming and / or ameliorating neuromuscular blockade is selected from the list consisting of: (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid; (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propanoic acid; (2S)-2-{4-bromo-2-[difluoro(phenyl)methyl]phenoxy}propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-2-cyclopropylacetic acid; (2S)-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(cyclopropyldifluoromethyl)phenoxy]propanoic acid; (2S)-2-{4-bromo-2-[difluoro(1,3-thiazol-2-yl)methyl]phenoxy}propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid; (2S)-2-[4-bromo-2-(cyclobutyldifluoromethyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-chloropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]pent-4-ynoic acid; (2S)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2- 2 H) Propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy]propanoic acid; (2S)-2-[4-cyano-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)(3,5,6- 2 H3) phenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethenylphenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid; 2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; (2S)-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2R)-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethenyl-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid; (2R)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propanoic acid; (2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutanoic acid; (2R)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid; and (2S)-2-[4-bromo-2-(1,1-difluoro-3-methoxypropyl)phenoxy]propanoic acid.

[0062] In one embodiment, the compound or compound for use according to the present disclosure has been modified to increase its half-life, particularly its plasma half-life, upon administration to a patient.

[0063] In one embodiment, the compound or compound for use according to the present disclosure further comprises a moiety attached to said compound, thereby producing a partially bound compound, in one embodiment, said partially bound compound has a plasma and / or serum half-life longer than the plasma and / or serum half-life of the non-partially bound compound.

[0064] In one embodiment, the moiety attached to the compound or to a compound for use according to the present disclosure is one or more types of moieties selected from the group consisting of albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies, and antibody fragments.

[0065] Neuromuscular disorders The compounds or compounds for use in the present disclosure are used for the treatment, amelioration and / or prevention of neuromuscular disorders, or to overcome neuromuscular blockade caused by non-depolarizing neuromuscular blocking agents or antibiotics.

[0066] The inventors of the present disclosure have shown that inhibition of ClC-1 channels enhances neuromuscular transmission. ClC-1 function may therefore contribute to muscle weakness in conditions of impaired neuromuscular transmission.

[0067] Therefore, in one embodiment of the present disclosure, the compound or the compound for use described herein inhibits the ClC-1 channel. Therefore, it is understood that the compound and / or the compound for use of formula (I) inhibits the ClC-1 channel.

[0068] Neuromuscular disorders may also include neuromuscular dysfunction.

[0069] 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 disorder is a motor neuron disorder. A motor neuron disorder is a disorder with reduced safety of neuromuscular transmission. In one embodiment, the motor neuron disorder is 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 RI, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3. Neurology, 2012, 79, 2050-2055), Charcot-Marie-Tooth disease (Bansagi B, Griffin H, Whittaker RG, Antoniadi T, Evangelista T, Miller J, Greenslade M, Forester N, Duff J, Bradshaw A,Kleinle S,Boczonadi V,Steele H,Ramesh V,Franko E,Pyle A,Lochmuller H,Chinnery PF,Horvath R.Genetic heterogeneity of motor neuropathies.Neurology,2017,28;88(13):1226-1234),X-linked spinal and bulbar muscular atrophy(Yamada,M.,Inaba,A.,Shiojiri,TX-linked spinal and bulbar muscular atrophy with myasthenic symptoms.Journal of the Neurological Sciences,1997,146,183-185), Kennedy's disease (Stevic,Z.,Peric,S.,Pavlovic,S.,Basta,I.,Lavrnic,D.,Myasthenic symptoms in a patient with Kennedy's disorder.Acta Neurologica Belgica,2014,114,71-73), multifocal motor neuropathy (Roberts,M.,Willison,HJ,Vincent,A.,Newsom-Davis,J.Multifocal motor neuropathy human sera block distal motor nerve conduction in mice.Ann Neurol.1995,38,111-118), Guillain-Barre syndrome (Ansar,V.,Valadi,N.Guillain-Barre Syndrome Prim.Care,2015,42,189-193), polioparesis (Trojan,DA,Gendron,D.,Cashman,NRElectrophysiology and electrodiagnosis of the post-polio motor unit.Orthopedics,1991,14,1353-1361,and Birk TJPoliomyelitis and the post-polio syndrome:exercise capacities and adaptation-current research,future directions,and widespread applicability.Med.Sci.Sports Exerc.,1993,25,466-472), post-polio syndrome (Garcia, CC, Potian, JG, Hognason, K., Thyagarajan, B., Sultatos, LG, Souayah, N., Routh, VH, McArdle, JJAcetylcholinesterase deficiency contributes to neuromuscular junction dysfunction in type 1 diabetic neuropathy. Am. J. Physiol. Endocrinol. Metab., 2012, 15, E551-561) and sarcopenia (Gilmore KJ, Morat T., Doherty TJ, Rice CL, Motor unit number estimation and neuromuscular fidelity in 3 stages of sarcopenia. 2017, 55(5), 676-684).

[0070] Thus, in one embodiment of the present disclosure, the neuromuscular disorder is amyotrophic lateral sclerosis (ALS). In another embodiment, the neuromuscular disorder is spinal muscular atrophy (SMA). In another embodiment, the neuromuscular disorder is Charcot-Marie-Tooth disease (CMT). In another embodiment, the neuromuscular disorder is sarcopenia. In yet another embodiment, the neuromuscular disorder is critical illness myopathy (CIM).

[0071] As mentioned above, neuromuscular disorders include, for example, disorders with symptoms of muscle weakness and fatigue. Such disorders may include, for example, diabetes (Burton, A. Take your pyridostigmine: that's an (ethical?) order! Lancet Neurol., 2003, 2, 268).

[0072] In one embodiment, the compound or the compound for use in the present disclosure is used for the prevention of neuromuscular disorders.The compound or the compound for use can be used, for example, prophylactically or as a treatment against nerve gases 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).In one disclosure, the compound or the compound for use in the present disclosure is used for the treatment of botulism (Sellin, LC, The action of botulinum toxin at the neuromuscular junction, Med Biol., 1981, 59, 11-20). In one disclosure, the compound or a compound for use in the present disclosure is used to treat snakebite (Silva A., Maduwage K., Buckley NA, Lalloo DG, de Silva HJ, Isbister GK, Antitivenom for snake venom-induced neuromuscular paralysis, Cochrane Database of Systematic Reviews, 2017, 3, Art. No.: CD012604).

[0073] In another embodiment, the neuromuscular disorder is chronic fatigue syndrome.Chronic fatigue syndrome (CFS) (Fletcher, SN, Kennedy, DD, Ghosh, IR, Misra, VP, Kiff, K., Coakley, JH, Hinds, CJ Persistent neuromuscular and 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 at least 6 months in adults.CFS may also be referred to as systemic exertion intolerance disorder (SEID), myalgic encephalomyelitis (ME), postviral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), or by some other terminology. Symptoms of CFS include post-exertional fatigue; unrefreshing sleep, widespread muscle and joint pain, physical fatigue, and muscle weakness. In another embodiment, the neuromuscular disorder is myotubular myopathy (Dowling, JJ et al, Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models, Disease Models & Mechanisms, 2012, 5, 852-859). In another embodiment, the neuromuscular disorder is Duchenne muscular dystrophy (van der Pijl, MM et al, Characterization of neuromuscular synapse function abnormalities in multiple Duchenne muscular dystrophy mouse models, European Journal of Neuroscience, 2016, 43, 1623-1635).

[0074] In further embodiments, the neuromuscular disorder is critical illness polyneuropathy (Angelini C. Spectrum of metabolic myopathies. Biochim. Biophys. Acta., 2015, 1852, 615-621) or CIM (Latronico, N., Bolton, CF 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 in critically ill patients.

[0075] Neuromuscular disorders may also include metabolic myopathies (Milone, M., Wong, L. J. Diagnosis of mitochondrial myopathies. Mol. Genet. Metab., 2013, 110, 35-41) and mitochondrial myopathies (Srivastava, A., Hunter, J. M. Eversal of neuromuscular block. Br. J. Anaesth. 2009, 103, 115-129). Metabolic myopathies result from abnormalities in biochemical metabolism that primarily affect muscle. These may include glycogen storage disease, lipid storage disorders, and 3-phosphocreatine storage disorders. Mitochondrial myopathies are a type of muscle disease associated with mitochondrial disorders. Symptoms of mitochondrial myopathies include muscular and neurological disorders such as muscle weakness, exercise intolerance, hearing loss, and balance and coordination disorders.

[0076] In another embodiment, the neuromuscular disorder is periodic paralysis, in particular hypokalemic periodic paralysis, which is a disorder of skeletal muscle excitability with recurrent episodes of weakness often precipitated by exercise, stress, or a carbohydrate-rich diet (Wu, F., Mi, W., Cannon, S.C., Neurology, 2013, 80, 1110-1116 and Suetterlin, K. et at, Current Opinion Neurology, 2014, 27, 583-590) or hyperkalemic periodic paralysis, which is a genetic autosomal dominant disorder affecting sodium channels in muscle cells and their ability to regulate potassium levels in the blood (Ammat, T. et at, Journal of General Physiology, 2015, 146, 509-525).

[0077] In some embodiments, the neuromuscular disorder is a myasthenic condition. The myasthenic condition is 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 a genetic neuromuscular disorder caused by several types of defects at the neuromuscular junction.

[0078] Myasthenia gravis and Lambert-Eaton syndrome (Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011, 10, 1098-107) are examples of myasthenic conditions. Myasthenia gravis is an autoimmune or congenital neuromuscular disorder that fluctuates between 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 effect of the neurotransmitter ACh on nicotinic ACh receptors at the neuromuscular junction (Gilhus, NE, Owe, JF, Hoff, JM, Romi, F., Skeie, GO, Aarli, JA Myasthenia Gravis: A Review of Available Treatment Approaches, Autoimmune Diseases, 2011, Article ID 84739). Lambert-Eaton myasthenic syndrome (LEMS, also known as Lambert-Eaton syndrome or Eaton-Lambert syndrome) is a rare autoimmune disease characterized by muscle weakness in the limbs. It is the result of an autoimmune reaction in which antibodies are formed against presynaptic voltage-gated calcium channels and possibly other nerve ending proteins in the neuromuscular junction.

[0079] Thus, in one embodiment of the present disclosure, the neuromuscular disorder is myasthenia gravis, hi another embodiment, the neuromuscular disorder is Lambert-Eaton syndrome.

[0080] Neuromuscular blockade is used in conjunction with surgery under total paralysis. Reversing agents are used for rapid and safe recovery of muscle function after such blockade. Complications associated with excessive muscle weakness during surgery after blockade may result in delayed weaning from mechanical ventilation and postoperative respiratory complications. These complications may have a significant effect on the outcome of surgery and future quality of life of the patient, and improved reversing agents are needed (Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. 2010 111(1):120-8). Thus, in one embodiment, the neuromuscular disorder is neuromuscular blocking drug-induced. In one particular embodiment, the neuromuscular disorder is muscle weakness caused by neuromuscular blockade after surgery. In another embodiment of the present disclosure, the compound or compound for use is used to overcome and / or improve neuromuscular blockade after surgery. In one embodiment, the neuromuscular blockade is drug-induced. In one embodiment, the neuromuscular blockade is induced by an antibiotic.In one embodiment, the neuromuscular blockade is induced by a non-depolarizing neuromuscular blocking agent.

[0081] Pharmaceutical preparations In one embodiment, a composition comprising the compound or a compound for use according to the present disclosure is provided. The composition according to the present disclosure is used for treating, improving and / or preventing neuromuscular disorders, and / or for use in overcoming and / or improving neuromuscular blockade. Thus, the composition and the compound described herein may be pharmaceutically acceptable. In one embodiment, the composition described herein is in the form of a pharmaceutical formulation. In one embodiment, the composition described herein further comprises a pharmaceutically acceptable carrier. Examples of possible formulations and preparations are found, for example, in Handbook of Pharmaceutical Excipients and Remington's Pharmaceutical Sciences.

[0082] Combination therapy The composition of the present disclosure may contain additional active ingredients / medicines or other ingredients to enhance the efficiency of the composition.Thus, in one embodiment, the composition further comprises at least one additional active agent.It can be understood that the active agent can be suitable for treating, preventing or improving the above-mentioned neuromuscular disorder.

[0083] In certain embodiments, the active agent may be an acetylcholinesterase inhibitor.The acetylcholinesterase inhibitor may be selected from the group consisting of, for example, delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidine, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungelemine and lactucopicrin.

[0084] In certain embodiments, the acetylcholinesterase inhibitor is selected from the group consisting of neostigmine, physostigmine and pyridostigmine. In certain embodiments, the acetylcholinesterase inhibitor is neostigmine or pyridostigmine.

[0085] The active agent may be an immunosuppressant. Immunosuppressants are drugs that suppress or reduce the strength of the body's immune system. They are also known as anti-rejection drugs. Immunosuppressants include, but are not limited to, glucocorticoids, corticosteroids, cytostatic drugs, antibodies and drugs that act on immunophilins. In one embodiment, the active agent is prednisone.

[0086] The active agent may be an agent used in antimyotonic therapy. Such agents include, for example, voltage-gated Na + channel blockers, and aminoglycosides.

[0087] The active agent may be an agent to overcome neuromuscular blockade following surgery. Such agents include, for example, neostigmine or sugammadex (Org25969, trade name Bridion). The active agent inhibits the Ca2+ binding of contractile filaments in muscle. 2+ It may be a drug for enhancing sensitivity. Such drugs include tirasemtib and CK-2127107 (Hwee, DT, Kennedy, AR, Hartman, JJ, Ryans, J., Durham, N., Malik, FI, Jasper, JR 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).

[0088] The active agent activates voltage-gated K + It may also be a drug for increasing ACh release by blocking the channel, such as 3,4-aminopyridine.

[0089] method In one aspect, the disclosure relates to a method of treating, preventing and / or ameliorating a neuromuscular disorder, said method comprising administering to a person in need thereof a therapeutically effective amount of the compound or a compound for use as defined herein. In one embodiment, the person is a human.

[0090] In one aspect, the present disclosure relates to a method of overcoming and / or ameliorating neuromuscular blockade, said method comprising administering to a person in need thereof a therapeutically effective amount of the compound or compounds for the uses defined herein.

[0091] In one aspect, the present disclosure relates to a method for the restoration of neuromuscular transmission, said method comprising administering to a person in need thereof a therapeutically effective amount of the compound or compounds for use as defined herein.

[0092] The person in need thereof may be a person with a neuromuscular disorder or at risk of developing a neuromuscular disorder or a person with symptoms of muscle weakness and / or fatigue. In another embodiment, the person in need thereof is a person with reduced neuromuscular transmission safety associated with long-term recovery after neuromuscular blockade. The type of neuromuscular disorder is defined herein above. In one embodiment, the person is a person with amyotrophic lateral sclerosis, spinal muscular atrophy, myasthenia gravis, or Lambert-Eaton syndrome.

[0093] A therapeutically effective amount is that amount that produces a therapeutic response or desired effect in the person taking it. Routes of administration, formulations and dosages can be determined by those skilled in the art.

[0094] The method of treatment may be combined with other methods known to treat, prevent and / or ameliorate neuromuscular disorders.The method of treatment may be combined with, for example, the administration of any of the drugs mentioned herein above.In one embodiment, the treatment is combined with, for example, the administration of an acetylcholinesterase inhibitor, such as neostigmine or pyridostigmine.

[0095] In one embodiment, the present invention relates to a method for restoring force in muscle with neuromuscular dysfunction, said method comprising administering to a subject in need thereof a compound or composition as defined herein.In one embodiment, said force restoration is >5%, for example >10%, for example >15%, for example >20%, for example >25%, for example >30%, for example >35%.The force restoration in muscle can be measured as the amount of force restored in muscle as a percentage of initial force after the muscle is exposed to a compound of the present disclosure, for example a compound as described in Example 23.

[0096] Another aspect of the disclosure relates to the use of a compound defined herein for the manufacture of a medicament for the treatment, prevention and / or amelioration of a neuromuscular disorder.

[0097] Another aspect relates to the use of a compound as defined herein for the manufacture of a medicament or antagonist for overcoming and / or ameliorating post-surgical neuromuscular blockade.

[0098] Method of production In one aspect, the disclosure relates to a method of making a compound or a compound for use according to formula (I). One method for the preparation of the present compounds or compounds for use according to the present disclosure comprises the steps of: a.Formula (GM.III) [ka] , (In the formula, R 4 and R 5 is defined herein) under Mitsunobu or similar reaction conditions to give a compound having the formula (GM.II): [ka] , (In the formula, R 1 , R 2 , R 3 , n and X are as defined herein) to produce a compound having the formula (GM.IV): [ka] producing a compound having the formula: ba) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound as defined herein.

[0099] One method for the preparation of the present compounds or compounds for use according to the present disclosure comprises the steps of: a.Formula (GM.VI) [ka] , (In the formula, R 4 and R 5 is defined herein and Y is a leaving group (e.g., methanesulfonate or tosylate) under conditions that include a suitable base, such as a sterically hindered amine or an alkali metal carbonate, to give a compound of formula (GM.II): [ka] , (In the formula, R 1 , R 2 , R 3 , n and X are as defined herein) to produce a compound having the formula (GM.IV): [ka] producing a compound having the formula: ba) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound as defined herein.

[0100] One method for the preparation of the present compounds or compounds for use according to the present disclosure comprises the steps of: a. Formula (GM.VIII) [ka] , (In the formula, R 4 and R 5 is defined herein), by reacting a compound having the formula (GM.VII) [ka] , (In the formula, 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 give a compound having the formula (GM.IV): [ka] producing a compound having the formula: ba) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound as defined herein.

[0101] One method for the preparation of the present compounds or compounds for use according to the present disclosure comprises the steps of: a.Formula (GM.IX) [ka] , (In the formula, R 4 is defined herein, and R 10 is a suitable protecting group, such as a silyl-containing moiety, to form a compound of formula (GM.II) under Mitsunobu or similar reaction conditions. [ka] , (In the formula, R 1 , R 2 , R 3 , n and X are as defined herein) to produce a compound having the formula (GM.X): [ka] producing a compound having the formula: The protecting group R of the resulting compound of ba) 10 removing the cb) reacting the resulting compound with an oxidizing agent, thus producing a compound as defined herein.

[0102] One method for the preparation of the present compounds or compounds for use according to the present disclosure comprises the steps of: a.Formula (GM.III) [ka] , (In the formula, R 4 and R5 is defined herein), by reacting a compound having the formula (GM.XI): [ka] , (In the formula, R 1 , R 2 , R 3 , n and X are as defined herein) to produce a compound having the formula (GM.XII): [ka] producing a compound having the formula: b) converting the keto group of the resulting compound to an alkyl difluoro group; and cb) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound as defined herein.

[0103] One method for the preparation of the present compounds or compounds for use according to the present disclosure comprises the steps of: a. Formula (GM.XIII) [ka] , (In the formula, R 1 , R 3 , R 4 , R 5 and n is as defined herein) under acylation conditions to obtain a compound having the formula (GM.XII): [ka] producing a compound having the formula: b) converting the keto group of the resulting compound to an alkyldifluoro group, wherein X is a bond and R 2 is defined herein; and cb) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound as defined herein.

[0104] One method for the preparation of the present compounds or compounds for use according to the present disclosure comprises the steps of: a.Formula (GM.IX) [ka] , (In the formula, R 4 and R 9 is defined herein), by reacting a compound having the formula (GM.XV): [ka] , (In the formula, R 1 , R 2 , R 3 and n is as defined herein) to produce a compound having the formula (GM.XIV): [ka] producing a compound having the formula: b) converting the keto group of the resulting compound to an alkyl difluoro group; The protecting group R of the resulting compound of cb) 10 removing the Reacting the product of dc) with an oxidizing agent, thus producing a compound as defined herein.

[0105] item 1. Formula (I): [ka] (In the formula, -R 1 is C 1-2 Selected from the group consisting of alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5alkyl, one or more identical or different substituents R 6 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 6 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 6 C optionally substituted with 3-5 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 7 5-6 membered aromatic heterocycles optionally substituted with -R 3 is selected from the group consisting of deuterium, Cl and F; -R 4 is H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, and C 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 represents one or more identical or different substituents R 8 H, C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 8 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 8 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 8 C optionally substituted with 3-6 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 9 benzyl optionally substituted with; -R 6 are independently deuterium, F, -CN, -OC 1-5Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl; 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 7 are independently deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -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 -O-, -S-, -CH2-, -CHR 6 - and -C(R 6 )2-; and -n is an integer 0, 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 2. The compound according to item 1, wherein the compound has the formula (I): [ka] (In the formula, -R 1 is selected from the group consisting of F, Cl, Br and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 6 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 6 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 6 C optionally substituted with 3-5 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 7 5-6 membered aromatic heterocycles optionally substituted with -R 3 is selected from the group consisting of deuterium and F; -R 4 is H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, and C 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 represents one or more identical or different substituents R 8 H, C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 8 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 8 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 8 C optionally substituted with 3-6 Cycloalkyl, one or more identical or different substituents R 9phenyl optionally substituted with, and one or more identical or different substituents R 9 benzyl optionally substituted with; -R 6 are independent, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more identical or different substituents R 8 , optionally substituted with deuterium, F, -CN; -R 7 is independent, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more identical or different substituents R 8 , optionally substituted with deuterium, F, -CN; -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 -O-, -S-, -CH2-, -CHR 6 - and -C(R 6 )2-; and -n is an integer 0, 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 3. The compound according to item 1 or 2, wherein the compound has the formula (II): [ka] (In the formula, -R 1 is C 1-2Selected from the group consisting of alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 6 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 6 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 6 C optionally substituted with 3-5 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 7 5-6 membered aromatic heterocycles optionally substituted with -R 3 is selected from the group consisting of deuterium, Cl and F; -R 4 is H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, and C 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 represents one or more identical or different substituents R 8 H, C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 8 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 8 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 8 C optionally substituted with 3-6 Cycloalkyl, one or more identical or different substituents R 9phenyl optionally substituted with, and one or more identical or different substituents R 9 benzyl optionally substituted with; -R 6 are independently deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl; 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 7 are independently deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -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; and -n is an integer 0, 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 4. The compound according to any one of items 1 to 3, wherein the compound has the formula (II): [ka] (In the formula, -R 1 is selected from the group consisting of F, Cl, Br and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 6 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 6 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 6 C optionally substituted with 3-5 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 7 5-6 membered aromatic heterocycles optionally substituted with -R 3 is selected from the group consisting of deuterium and F; -R 4 is H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, and C 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 represents one or more identical or different substituents R 8 H, C optionally substituted with 1-5 alkyl, one or more identical or different substituents R 8 C optionally substituted with 2-5 alkenyl, one or more, the same or different R 8 C optionally substituted with 2-5 Alkynyl, one or more, the same or different R 8C optionally substituted with 3-6 Cycloalkyl, one or more identical or different substituents R 9 phenyl optionally substituted with, and one or more identical or different substituents R 9 benzyl optionally substituted with; -R 6 are independent, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more identical or different substituents R 8 , optionally substituted with deuterium, F, -CN; -R 7 is independent, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, each of which may be selected from the group consisting of one or more identical or different substituents R 8 , optionally substituted with deuterium, F, -CN; -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; and -n is an integer 0, 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 5. The compound according to any one of items 1 to 4, wherein the compound has the formula (II): [ka] (In the formula, -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 is alkyl; -R 3 is selected from the group consisting of deuterium, Cl and F; -R 4 is H, deuterium, C 1-5 Alkyl and C 2-5 alkynyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 5 is H; -R 6 are independently deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl; 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 7 are independently deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 8is independently selected from the group consisting of deuterium and F; and -n is an integer 0, 1, 2, or 3) or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 6. The compound according to any one of items 1 to 5, wherein the compound has the formula (III): [ka] (In the formula, -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 is alkyl; -R 3 is selected from the group consisting of H, deuterium, Cl and F; -R 4 is H, deuterium, C 1-5 Alkyl and C 2-5 alkynyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 7 may be optionally substituted with; -R 6 are independently deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl; 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 7 are independently deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 cycloalkyl, C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl, and -SC 3-5 Cycloalkyl may be substituted with one or more identical or different substituents R 8 may be optionally substituted with; -R 8 are independently selected from the group consisting of deuterium and F. or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 7. The compound according to any one of items 1 to 6, wherein the compound has the formula (III): [ka] (In the formula, -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br, and I; -R 2 represents one or more identical or different substituents R 8 C optionally substituted with 1-3 is alkyl; -R 3 is selected from the group consisting of H, deuterium, Cl and F; -R 4 is H, deuterium, C 1-3 Alkyl and C 2-3 alkynyl, each of which may be selected from the group consisting of one or more of the same or different substituents R 8 may be optionally substituted with; -R 8 are independently selected from the group consisting of deuterium and F. or a pharma- ceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 8. The compound according to any one of items 1 to 7, wherein R1 is C 1-2 A compound which is an alkyl. 9. The compound according to any one of items 1 to 8, wherein R 1 is a C2 alkenyl, 10. The compound according to any one of items 1 to 9, wherein R 1 is a C2 alkynyl compound. 11. The compound according to any one of items 1 to 10, wherein R 1 is CN, the compound. 12. The compound according to any one of items 1 to 11, wherein R 1 is CF3, the compound. 13. The compound according to any one of items 1 to 12, wherein R 1 is NO2, a compound. 14. The compound according to any one of items 1 to 13, wherein R 1 is Cl or Br. 15. The compound according to any one of items 1 to 14, wherein R 1 is Cl, the compound. 16. The compound according to any one of items 1 to 15, wherein R 1 is Br, the compound. 17. The compound according to any one of items 1 to 16, wherein R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-5 A compound which is an alkyl. 18. The compound according to any one of items 1 to 17, wherein R 2 represents one or more identical or different substituents R 6 C optionally substituted with 1-3 A compound which is an alkyl. 19. The compound according to any one of claims 1 to 18, wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl. 20. The compound according to any one of claims 1 to 19, wherein R 2is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, and the methyl, ethyl, n-propyl or isopropyl groups are each independently selected from one or more identical or different substituents R 6 The compound is substituted with 21. The compound according to any one of items 1 to 20, wherein R 2 represents one or more identical or different substituents R 6 C optionally substituted with 2-5 A compound which is an alkenyl. 22. The compound according to any one of items 1 to 21, wherein R 2 represents one or more identical or different substituents R 6 C optionally substituted with 2-5 A compound which is an alkynyl. 23. The compound according to any one of items 1 to 22, wherein R 2 represents one or more identical or different substituents R 6 C optionally substituted with 3-5 A compound which is a cycloalkyl. 24. The compound according to any one of items 1 to 23, wherein R 2 represents one or more identical or different substituents R 9 The compound wherein R is phenyl optionally substituted with R. 25. The compound according to any one of items 1 to 24, wherein R 2 represents one or more identical or different substituents R 7 A compound, wherein the ring is a 5- to 6-membered aromatic heterocycle optionally substituted with 26. The compound according to any one of items 1 to 25, wherein R 3 is deuterium, the compound. 27. The compound according to any one of items 1 to 26, wherein R 3 is F, the compound. 28. The compound according to any one of items 1 to 27, wherein R 3 is Cl, the compound. 29. The compound according to any one of items 1 to 28, wherein R 4 is H, the compound. 30. The compound according to any one of items 1 to 29, wherein R 4 represents one or more identical or different substituents R 7 C optionally substituted with 1-5 A compound which is an alkyl. 31. The compound according to any one of claims 1 to 30, wherein R 4 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl. 32. The compound according to any one of items 1 to 31, wherein R 4 is Me, the compound. 33. The compound according to any one of items 1 to 32, wherein R 4 is -CH2F, the compound. 34. The compound according to any one of claims 1 to 33, wherein R 4 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, and the methyl, ethyl, n-propyl or isopropyl groups are each independently selected from one or more identical or different substituents R 7 The compound is substituted with 35. The compound according to any one of items 1 to 34, wherein R 4 represents one or more identical or different substituents R 7 Optionally substituted with -CH2-OC 1-5 A compound which is an alkyl. 36. The compound according to any one of items 1 to 35, wherein R 4 represents one or more identical or different substituents R 7 Optionally substituted with -CH2-SC 1-5 A compound which is an alkyl. 37. The compound according to any one of items 1 to 36, wherein R 4 represents one or more identical or different substituents R 7 C optionally substituted with 2-5 A compound which is an alkenyl. 38. The compound according to any one of items 1 to 37, wherein R 4 represents one or more identical or different substituents R 7C optionally substituted with 2-5 A compound which is an alkynyl. 39. The compound according to any one of items 1 to 38, wherein R 4 represents one or more identical or different substituents R 7 Optionally substituted with -CH2-C 2-4 A compound which is an alkynyl. 40. The compound according to any one of items 1 to 39, wherein R 4 represents one or more identical or different substituents R 7 C optionally substituted with 3-5 A compound which is a cycloalkyl. 41. The compound according to any one of items 1 to 40, wherein R 5 is H, the compound. 42. The compound according to any one of items 1 to 41, wherein R 5 represents one or more identical or different substituents R 8 C optionally substituted with 1-5 A compound which is an alkyl. 43. The compound according to any one of items 1 to 42, wherein R 5 represents one or more identical or different substituents R 8 C optionally substituted with 3-6 A compound which is a cycloalkyl. 44. The compound according to any one of items 1 to 43, wherein R 5 represents one or more identical or different substituents R 9 The compound wherein R is phenyl optionally substituted with R. 45. The compound according to any one of items 1 to 44, wherein R 5 represents one or more identical or different substituents R 9 The compound wherein R is benzyl optionally substituted with R. 46. ​​The compound according to any one of items 1 to 45, wherein R 6 is deuterium, the compound. 47. The compound according to any one of items 1 to 46, wherein R 6 is F, the compound. 48. The compound according to any one of items 1 to 47, wherein R 6 is CN, the compound. 49. The compound according to any one of items 1 to 48, wherein R 6 represents one or more identical or different substituents R 8 Optionally substituted with -OC 1-5 A compound which is an alkyl. 50. The compound according to any one of items 1 to 49, wherein R 6 represents one or more identical or different substituents R 8 Optionally substituted with -OC 3-5 A compound which is a cycloalkyl. 51. The compound according to any one of items 1 to 50, wherein R 6 represents one or more identical or different substituents R 8 -SC optionally substituted with 1-5 A compound which is an alkyl. 52. The compound according to any one of items 1 to 51, wherein R 6 represents one or more identical or different substituents R 8 -SC optionally substituted with 3-5 A compound which is a cycloalkyl. 53. The compound according to any one of items 1 to 52, wherein R 7 is deuterium, the compound. 54. The compound according to any one of items 1 to 53, wherein R 7 is F, the compound. 55. The compound according to any one of items 1 to 54, wherein R 7 is CN, the compound. 56. The compound according to any one of items 1 to 55, wherein R 7 represents one or more identical or different substituents R 8 Optionally substituted with -OC 1-5 A compound which is an alkyl. 57. The compound according to any one of items 1 to 56, wherein R 7 represents one or more identical or different substituents R 8Optionally substituted with -OC 3-5 A compound which is a cycloalkyl. 58. The compound according to any one of items 1 to 57, wherein R 7 represents one or more identical or different substituents R 8 -SC optionally substituted with 1-5 A compound which is an alkyl. 59. The compound according to any one of items 1 to 58, wherein R 7 represents one or more identical or different substituents R 8 -SC optionally substituted with 3-5 A compound which is a cycloalkyl. 60. The compound according to any one of items 1 to 59, wherein R 7 represents one or more identical or different substituents R 8 C optionally substituted with 3-5 A compound which is a cycloalkyl. 61. The compound according to any one of items 1 to 60, wherein R 8 is deuterium, the compound. 62. The compound according to any one of items 1 to 61, wherein R 8 is F, the compound. 63. The compound according to any one of items 1 to 62, wherein n is 0. 64. The compound according to any one of items 1 to 63, wherein n is 1. 65. The compound according to any one of items 1 to 64, wherein n is 2. 66. The compound according to any one of items 1 to 65, wherein n is 3. 67. The compound according to any one of items 1 to 66, wherein X is a bond. 68. The compound according to any one of items 1 to 67, wherein X is -O-. 69. The compound according to any one of items 1 to 68, wherein X is -S-. 70. The compound according to any one of items 1 to 69, wherein X is -CH2-. 71. The compound according to any one of items 1 to 70, wherein X is -CHR 6 -A compound. 72. The compound according to any one of items 1 to 71, wherein X is -C(R 6 )2-, a compound. 73. The compound according to any one of items 1 to 72, wherein R 1 is Cl or Br, and R 2 represents one or more identical or different substituents R 7 R is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl, optionally substituted with 5 is H, the compound. 74. The compound according to any one of items 1 to 73, which is selected from the following list: (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid; (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propanoic acid; (2S)-2-{4-bromo-2-[difluoro(phenyl)methyl]phenoxy}propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-2-cyclopropylacetic acid; (2S)-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(cyclopropyldifluoromethyl)phenoxy]propanoic acid; (2S)-2-{4-bromo-2-[difluoro(1,3-thiazol-2-yl)methyl]phenoxy}propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid; (2S)-2-[4-bromo-2-(cyclobutyldifluoromethyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-chloropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]pent-4-ynoic acid; (2S)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2- 2 H) Propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy]propanoic acid; (2S)-2-[4-cyano-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)(3,5,6- 2 H3) phenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethenylphenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid; 2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; (2S)-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2R)-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethenyl-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid; (2R)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propanoic acid; (2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutanoic acid; (2R)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid; and (2S)-2-[4-bromo-2-(1,1-difluoro-3-methoxypropyl)phenoxy]propanoic acid. 75. A compound according to any one of items 1 to 74, which has activity at the ClC-1 receptor. 76. A compound according to any one of items 1 to 75, which is an inhibitor of the ClC-1 ion channel. 77. The compound according to item 80, which is 50is <50 μM, such as <40 μM, for example <30 μM, such as <20 μM, for example <15 μM, such as <10 μM, for example <5 μM. 78. The compound according to any one of items 1 to 77, wherein the force recovery in muscles with neuromuscular dysfunction is >5%, such as >10%, for example >15%, for example >20%, for example >25%, for example >30%, for example >35%. 79. A compound according to any one of items 1 to 78, which improves the force recovered in isolated rat soleus muscle following exposure to tubocurarine. 80. A composition comprising a compound according to any one of items 1 to 79. 81. The composition according to any one of items 1 to 80, which is a pharmaceutical composition. 82. A compound or composition according to any one of items 1 to 81 for use as a medicament. 83. The composition according to any one of items 1 to 82, further comprising a pharma- ceutically acceptable carrier. 84. The composition according to any one of items 1 to 83, further comprising at least one additional active agent. 85. The composition according to any one of items 1 to 84, wherein the additional active agent is suitable for the treatment, prevention or amelioration of said neuromuscular disorder. 86. The composition according to any one of items 1 to 85, wherein the additional active agent is an acetylcholinesterase inhibitor. 87. The compound according to any one of items 1 to 86, wherein the acetylcholinesterase inhibitor is selected from the group consisting of delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidine, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungelemine and lactucopicrin. 88. The composition according to any one of items 1 to 87, wherein the acetylcholinesterase inhibitor is neostigmine or pyridostigmine. 89. The composition according to any one of items 1 to 88, wherein the additional active agent is sugammadex. 90. The composition according to any one of items 1 to 89, wherein the additional active agent is tirasemtib or CK-2127107. 91. The composition according to any one of items 1 to 90, wherein the additional active agent is 3,4-aminopyridine. 92. A method for producing a compound according to any one of items 1 to 91, comprising the steps of: a.Formula (GM.III) [ka] , (In the formula, R 4 and R 5 is defined in any one of items 1 to 91) by reacting a compound having the formula (GM.II) under Mitsunobu or similar reaction conditions [ka] , (In the formula, R 1 , R 2 , R 3 , n and X are as defined in any one of items 1 to 91), to obtain a compound having the formula (GM.IV) [ka] producing a compound having the formula: ba) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound according to any one of items 1 to 91. 93. A method for producing a compound according to any one of items 1 to 92, comprising the steps of: a.Formula (GM.VI) [ka] , (In the formula, R 4 and R 5 is defined herein and Y is a leaving group (e.g., methanesulfonate or tosylate) under conditions that include a suitable base, such as a sterically hindered amine or an alkali metal carbonate, to give a compound of formula (GM.II): [ka] , (In the formula, R 1 , R 2 , R 3 , n and X are as defined in any one of items 1 to 92), to obtain a compound having the formula (GM.IV) [ka] producing a compound having the formula: ba) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound according to any one of items 1 to 92. 94. A method for producing a compound according to any one of items 1 to 93, comprising the steps of: a. Formula (GM.VIII) [ka] , (In the formula, R 4 and R 5 is defined in any one of items 1 to 93) with a compound having the formula (GM.VII) [ka] , (In the formula, R 1 , R 2 , R 3, n and X are as defined in any one of items 1 to 93, and Q is a suitable leaving group, such as a halogen, such as fluorine or iodine, to obtain a compound having the formula (GM.IV): [ka] producing a compound having the formula: ba) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound according to any one of items 1 to 93. 95. A method for producing a compound according to any one of items 1 to 94, comprising the steps of: a.Formula (GM.IX) [ka] , (In the formula, R 4 is defined in any one of items 1 to 94, and R 10 is a suitable protecting group, such as a silyl-containing moiety, to form a compound of formula (GM.II) under Mitsunobu or similar reaction conditions. [ka] , (In the formula, R 1 , R 2 , R 3 , n and X are as defined in any one of items 1 to 94), to obtain a compound having the formula (GM.X) [ka] producing a compound having the formula: The protecting group R of the resulting compound of ba) 10 removing the cb) reacting the resulting compound with an oxidizing agent, thus producing a compound according to any one of items 1 to 94. 96. A method for producing a compound according to any one of items 1 to 95, comprising the steps of: a.Formula (GM.III) [ka] , (In the formula, R 4 and R 5 is defined in any one of items 1 to 95) with a compound having the formula (GM.XI) [ka] , (In the formula, R 1 , R 2 , R 3 , n and X are as defined in any one of items 1 to 95), to obtain a compound having the formula (GM.XII) [ka] producing a compound having the formula: b) converting the keto group of the resulting compound to an alkyl difluoro group; and cb) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound according to any one of items 1 to 95. 97. A method for producing a compound according to any one of items 1 to 96, comprising the steps of: a. Formula (GM.XIII) [ka] , (In the formula, R 1 , R 3 , R 4 , R 5 and n is defined in any one of items 1 to 96) under acylation conditions to obtain a compound having the formula (GM.XII) [ka] producing a compound having the formula: b) converting the keto group of the resulting compound to an alkyldifluoro group, wherein X is a bond and R2 is defined in any one of items 1 to 96; and cb) reacting the resulting compound with an ester hydrolysis reagent, thus producing a compound according to any one of items 1 to 96. 98. A method for producing a compound according to any one of items 1 to 97, comprising the steps of: a.Formula (GM.IX) [ka] , (In the formula, R 4 and R 9 is defined herein), by reacting a compound having the formula (GM.XV): [ka] , (In the formula, R 1 , R 2 , R 3 and n is as defined herein) to produce a compound having the formula (GM.XIV): [ka] producing a compound having the formula: b) converting the keto group of the resulting compound to an alkyl difluoro group; The protecting group R of the resulting compound of cb) 10 removing the Reacting the product of dc) with an oxidizing agent, thus producing a compound as defined herein. 99. A compound according to any one of items 1 to 98 for use in the treatment, amelioration and / or prevention of neuromuscular disorders and / or for use in overcoming and / or ameliorating neuromuscular blockade. 100. A compound for use according to any one of claims 1 to 99, wherein the neuromuscular disorder is myasthenia gravis. 101. A compound for use according to any one of claims 1 to 100, wherein the neuromuscular disorder is autoimmune myasthenia gravis. 102. A compound for use according to any one of claims 1 to 101, wherein the neuromuscular disorder is congenital myasthenia gravis. 103. A compound for use according to any one of claims 1 to 102, wherein the neuromuscular disorder is Lambert-Eaton syndrome. 104. A compound for use according to any one of claims 1 to 103, wherein the neuromuscular disorder is critical illness myopathy. 105. A compound for use according to any one of claims 1 to 104, wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS). 106. A compound for use according to any one of claims 1 to 105, wherein the neuromuscular disorder is spinal muscular atrophy (SMA). 107. A compound for use according to any one of claims 1 to 106, wherein the neuromuscular disorder is critical illness myopathy (CIM). 108. A compound for use according to any one of claims 1 to 107, wherein the neuromuscular disorder is Charcot-Marie-Tooth disease (CMT). 109. A compound for use according to any one of claims 1 to 108, wherein the neuromuscular disorder is sarcopenia. 110. A compound for use according to any one of claims 1 to 109, wherein the neuromuscular disorder results from diabetic polyneuropathy. 111. A compound for use according to any one of claims 1 to 110, wherein the neuromuscular disorder is periodic paralysis. 112. A compound for use according to any one of claims 1 to 111, wherein the neuromuscular disorder is hypokalemic periodic paralysis or hyperkalemic periodic paralysis. 113. A compound for use according to any one of claims 1 to 112, wherein the neuromuscular disorder is a myotubular myopathy. 114. A compound for use according to any one of claims 1 to 113, wherein the neuromuscular disorder is Duchenne muscular dystrophy. 115. A compound according to any one of claims 1 to 114 for use in the treatment of botulism. 116. A compound according to any one of claims 1 to 115 for use in the treatment of snakebites. 117. A compound according to any one of claims 1 to 116 for use in the treatment of nerve gas poisoning or in prophylactic treatment against nerve gas poisoning. 118. A compound for use according to any one of claims 1 to 117, wherein the neuromuscular disorder is selected from the group consisting of Guillain-Barre syndrome, polio, post-polio syndrome, chronic fatigue syndrome, and critical illness polyneuropathy. 119. A compound for use according to any one of claims 1 to 118, wherein the compound is for use in treating symptoms of an indication selected from the group consisting of myasthenia gravis (e.g. autoimmune and congenital myasthenia gravis), Lambert-Eaton syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), reversed diabetic polyneuropathy, Guillain-Barré syndrome, polio, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, periodic paralysis, sarcopenia, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy and Duchenne muscular dystrophy. 120. A compound for use according to any one of claims 1 to 119, wherein the neuromuscular disorder is induced by a neuromuscular blocking agent. 121. A compound for use according to any one of claims 1 to 120, wherein the neuromuscular blockade is post-operative neuromuscular blockade. 122. A compound for use according to any one of claims 1 to 121, wherein the neuromuscular blockade is drug-induced. 123. A compound for use according to any one of claims 1 to 122, wherein the drug is an antibiotic. 124. A compound for use according to any one of claims 1 to 123, wherein the drug is a non-depolarizing neuromuscular blocking agent. 125. A compound for use according to any one of claims 1 to 124, which has been further modified to increase its half-life, in particular its plasma half-life, when administered to a patient. 126. A compound for use according to any one of claims 1 to 125, further comprising a moiety attached to said compound, thereby producing a partially attached compound. 127. A compound for use according to any one of claims 1 to 126, wherein the partially bound compound has a plasma and / or serum half-life longer than the plasma and / or serum half-life of the non-partially bound compound. 128. A compound for use according to any one of claims 1 to 127, wherein the moiety attached to the compound is one or more types of moieties selected from the group consisting of albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies and antibody fragments. 129. A compound for use according to any one of claims 1 to 128, the compound being contained in a composition. 130. A compound for use according to any one of claims 1 to 129, wherein the composition is a pharmaceutical composition. 131. A compound for use according to any one of claims 1 to 130, wherein the composition further comprises a pharma- ceutically acceptable carrier. 132. A compound for use according to any one of claims 1 to 131, further comprising at least one additional active agent. 133. A compound for use according to any one of claims 1 to 132, wherein said additional active agent is suitable for treating, preventing or ameliorating said neuromuscular disorder. 134. A compound for use according to any one of claims 1 to 133, wherein the additional active agent is an acetylcholinesterase inhibitor. 135. A compound for use according to any one of claims 1 to 134, wherein the acetylcholinesterase inhibitor is selected from the group consisting of delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidine, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine and lactucopicrin. 136. A compound for use according to any one of claims 1 to 135, wherein the acetylcholinesterase inhibitor is neostigmine or pyridostigmine. 137. A compound for use according to any one of claims 1 to 136, wherein the additional active agent is sugammadex. 138. A compound for use according to any one of claims 1 to 137, wherein the additional active agent is tirasemtib. 139. A compound for use according to any one of claims 1 to 138, wherein the additional active agent is a 3,4-aminopyridine. 140. A method for treating, preventing and / or ameliorating a neuromuscular disorder, comprising administering to a person in need thereof a therapeutically effective amount of a compound defined in any one of claims 1-139. 141. Use of a compound as defined in any one of claims 1 to 140 for the manufacture of a drug for the treatment, prevention and / or amelioration of neuromuscular disorders and / or for overcoming and / or ameliorating neuromuscular blockade. 142. A method for overcoming and / or ameliorating neuromuscular blockade, comprising administering to a person in need thereof a therapeutically effective amount of a compound defined in any one of claims 1 to 141. 143. A method for restoration of neuromuscular transmission, comprising administering to a person in need thereof a therapeutically effective amount of a compound defined in any one of claims 1 to 142. 144. A method for restoration of neuromuscular transmission, comprising administering to an individual in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 143.

[0106] Working Example material and method

[0107] Chemicals Compounds for testing were obtained from a variety of suppliers including Enamine, Vitas, and CanAm Bioresearch. For syntheses of specific compounds, see below.

[0108] NMR spectra 1 H-NMR and 19 F-NMR was recorded on a Bruker AM-300 spectrometer and calibrated with residual non-deuterated solvent as an internal standard. Spectra were processed using Spinworks version 4.0 (developed by Dr. Kirk Marat, Department of Chemistry, University of Manitoba) or on a Bruker 400MHZ Ultrashield plus equipped with a BBO 400MHz S1 5mm probe or a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbe®, calibrated with residual non-deuterated solvent as an internal standard, and processed using topspin version 3.2.7.

[0109] LC / MS Systems Samples were analyzed by direct injection on a Waters Acquity QDa Mass Detector equipped with a Waters 2695 HPLC and a WATERS Micromass equipped with a WATERS 2795 HPLC. Mass spectra were processed using WATERS Masslynx software. Mass spectra were recorded in ESI scan mode (negative / positive).

[0110] HPLC method Products were analyzed by Waters 2695 HPLC consisting of a Waters 996 photodiode array detector, Kromasil Eternity C18, 5 μm, 4.6×150 mm column. Flow rate: 1 mL / min, run time 20 min. Chromatograms were processed using Waters Empower software. Method 1A: Solvent A: methanol; Solvent B: 0.1% formic acid in water. Gradient 0-100% solvent B in 15 min, monitored at 280 nm. Method 1A: Solvent C: acetonitrile; Solvent D: 0.1% formic acid in water. Gradient 10 to 100% solvent C vs. D in 15 min, monitored at 280 nm.

[0111] Acid Dichotomy LCMS was performed on a Waters Acquity UPLC system consisting of an Acquity I Class Sample Manager-FL, an Acquity I Class Binary Solvent Manager and an Acquity UPLC Column Manager. Ultraviolet detection was performed with an Acquity UPLC PDA detector (scanning from 210 nm to 400 nm) and mass detection was performed with an Acquity QDa detector (mass scan from 100 to 1250 Da; positive and negative modes simultaneously). Separation of the analytes was achieved using a Waters Acquity UPLC BEH C18 column (2.1x50 mm 1.7 mm). Samples were prepared by dissolving in 1 mL of 50% v / v MeCN in water (with or without sonication). These solutions were filtered through a 0.45 mm syringe filter prior to analysis. All solvents used (including formic acid) 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 0.8 mL / min; injection volume 2 mL and equilibration time between samples 1.5 min. [Table 1]

[0112] Basic dichotomy Samples were prepared by dissolving in 1 mL of 50% v / v MeCN in water (with or without sonication). These solutions were filtered through a 0.45 mm syringe filter prior to analysis. All solvents (and ammonium bicarbonate) used (including 35% ammonia solution) were HPLC grade. Conditions: 10 mM ammonium bicarbonate + 0.1% v / v ammonia solution [eluent A]; 0.1% v / v 35% ammonia solution in MeCN [eluent B]; flow rate 0.8 mL / min; injection volume 2 mL and equilibration time between samples 1.5 min. [Table 2]

[0113] Acid quaternity Samples were prepared by dissolving in 1 mL of 50% v / v MeCN in water (with or without sonication). These solutions were filtered through a 0.45 mm syringe filter prior to analysis. All solvents used (including formic acid) 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 0.8 mL / min; injection volume 2 mL and equilibration time between samples 1.5 min. [Table 3]

[0114] Basic Quartering Samples were prepared by dissolving in 1 mL of 50% v / v MeCN in water (with or without sonication). These solutions were filtered through a 0.45 mm syringe filter prior to analysis. All solvents used (including 36% ammonia solution) were HPLC grade. Conditions: 0.1% ammonia in water [eluent A]; 0.1% ammonia in MeCN [eluent B]; flow rate 0.8 mL / min; injection volume 2 mL and equilibration time between samples 1.5 min. [Table 4]

[0115] Chiral SCF method 1 Compounds were analyzed using a Waters ACQUITY ultra-performance convergence chromatography (UPC2) system equipped with a binary solvent delivery pump, an autosampler, a column oven (CM-30S), a backpressure regulator, and a diode array detector. Column: Lux A1 (4.6mm x 250mm, 5μm). Conditions: 40°C, 4mL / min, isocratic 10:90 EtOH:CO2 (0.1% v / v TFA), 125 BarG.

[0116] Chiral HPLC HPLC instrument equipped with an Agilent 1200 binary pump, an Agilent 1200 variable wavelength detector (visible and UV detector) and a Shodex 150x4.5mm, 3μm chiral column. Flow rate: 0.5mL / min. Solvent A: 0.05% CH3COOH and 0.2M NaCl in water. Solvent B: Acetonitrile. Chiral HPLC analysis was carried out at 280nm wavelength under isocratic conditions (75% solvent A and 25% solvent B). Chromatograms were processed using Agilent ChemStation software.

[0117] General synthesis strategy Compounds of formula (I) may be synthesised by the following general method. General law A [ka] Method A involves the synthesis of compounds (GM.V) which are aryloxy-substituted acetic acid derivatives, where R 1 ~R 9 , n and X are as defined above in formula (I). Compound (GM.II) is available commercially or synthetically and can be converted to the ether (GM.IV) by a method involving modifications to the Mitsunobu reaction conditions. The ether can be prepared by reacting the ester functional group -COR 5which can be hydrolyzed under a range of standard conditions, including acid or base, to give the carboxylic acid structure (GM.V). These standard conditions can also include enzymatic hydrolysis, for example, with esterases or lipases. The ester molecule (GM.IV) can be, for example, hydrolyzed by converting the (CH3)3SiCH2CH2O- group to -OR 5 When GM.IV is present as GM.III, a fluoride ion source such as tetra-n-butylammonium fluoride can be used to convert (GM.IV) to the corresponding carboxylic acid (GM.V).

[0118] Substituted phenols of general formula (GM.II) can be prepared by a variety of standard methods, e.g., by ester rearrangement in the Fries rearrangement, by rearrangement of N-phenylhydroxylamine in the Bamberger rearrangement, by hydrolysis of phenolic esters or ethers, by reduction of quinones, by displacement of aromatic amines, or by the Bucherer reaction with a hydroxyl group, water and sodium bisulfite. Other methods include hydrolysis of diazonium salts, rearrangement of dienones in the dienone-phenol rearrangement, oxidation of arylsilanes, and the Hock process.

[0119] Phenols of formula (GM.II), where X is a bond, can be synthesized by Grignard reaction on 2-hydroxybenzonitrile derivatives with a suitable Grignard reagent.

[0120] General law B [ka] Method B involves the synthesis of compounds (GM.V) which are aryloxy-substituted acetic acid derivatives, where R 1 ~R 9 , n and X are as defined above in formula (I) and this method is related to method A. Compounds (GM.II) are commercially available or available synthetically and can be converted to ethers (GM.IV) by displacement of an appropriate leaving group Y, e.g., methanesulfonate or tosylate, under conditions involving a suitable base such as a sterically hindered amine or an alkali metal carbonate.

[0121] General law C [ka] Carboxylic acids of general formula (GM.V) may further be prepared by the procedures set out in general method C. Phenolic ethers of formula (GM.IV) may be prepared by displacement of the leaving group Q of (GM.VII). Q may be, for example, a halogen such as fluorine or iodine, and the ether product of formula (GM.IV) may be converted to the carboxylic acid derivative (GM.V) by one of the series of methods outlined in method A, including hydrolysis of the ester functionality.

[0122] General law D [ka] Carboxylic acids of general formula (GM.V) can be prepared by the procedure shown in general method D. Phenolic ethers of formula (GM.II) can be prepared, for example, by utilizing Mitsunobu conditions on the phenolic structure (GM:II), where (GM.IX) is a suitable secondary alcohol, where R 1 ~R 9 , n and X are as defined above in formula (I), -R 10 is a suitable protecting group, such as a silyl-containing moiety. The protecting group -R 10 Upon removal of the carboxylate, the primary alcohol (GM.X) can be oxidized to the carboxylic acid under standard conditions including potassium permanganate, Jones oxidation conditions, Haynes oxidation, ruthenium tetroxide or TEMPO.

[0123] General Law E [ka] R 1 ~R 9Carboxylic acids of general formula (GM.V), where n and X are as defined above in formula (I), can be prepared by the procedure set forth in general method E. Phenols (GM.XI) are available commercially or synthetically and can be converted to ethers (GM.XII) by methods involving modifications to the Mitsunobu reaction conditions. The acyl group in ethers (GM.XII) can be converted to alkyl difluoro derivatives by a range of fluorination conditions including the use of deoxofluor as a reagent to afford compounds (GM.V) after ester hydrolysis.

[0124] General law F [ka] R 1 ~R 9 Carboxylic acids of general formula (V), where n and n are as defined above in formula (I) and X is a bond, can be prepared by the procedure shown in general method E. Phenyl ethers (GM.XIII), prepared by methods similar to those shown above, can be converted to ethers (GM.XII) by a method involving the classical Friedel-Crafts aromatic acylation reaction, one well-known variant of which proceeds via an alkanoic acid chloride in the presence of a Lewis acid. The acyl group in the resulting ether (GM.XII) can be converted to an alkyl difluoro derivative by a series of fluorination conditions involving the use of deoxofluor as a reagent to give compounds (GM.V) after ester hydrolysis. An alternative method is to carry out the acylation on a protected primary alcohol derivative and oxidize the deprotected alcohol as described above in general method D.

[0125] General Law G [ka] R 1 ~R 9Carboxylic acids of general formula (XVIII), where n and n are as defined above in formula (I), formula (II) and formula (III), may be prepared by the procedures set out in general method G. Phenols (GM.XV) are commercially available or may be prepared from phenols (GM.XIV) via rearrangement using, for example, AlCl3, followed by reaction with, for example, an acyl halide. Phenols (GM.XV) are then converted to ethers (GM.XVI) by methods involving modifications to the Mitsunobu reaction conditions. Optionally, the protecting group -R is removed before the acyl group in ethers (GM.XVI) is converted to the alkyl difluoro derivatives (GM.XVII) by a set of fluorination conditions involving the use of deoxofluor as a reagent. 10 It may be necessary to change the protecting group -R 10 Upon removal of , the primary alcohol can be oxidized to the carboxylic acid (GM.XVIII) under standard conditions including potassium permanganate, Jones oxidation conditions, Haynes oxidation, ruthenium tetroxide, or TEMPO.

[0126] General law H [ka] R 1 ~R 9 Carboxylic acids of general formula (GM.V), where n and X are as defined in formula (I) above, can be prepared by the procedures set forth in general method G. Phenols (GM.XI), which are commercially available or can be prepared as described in general method G, can be converted to alkyl difluoro derivatives (GM.II) by a series of fluorination conditions, including the use of deoxofluor as a reagent. The alkyl difluoro derivatives (GM.II) are then coupled with esters (GM.III) using methods involving modifications to the Mitsunobu reaction conditions to give esters (GM.IV). The esters (GM.IV) can undergo further functional group modifications, for example on the aromatic ring, before being hydrolyzed to the carboxylic acids (GM.V).

[0127] Compound example Table 1 below shows examples of compounds defined by general formula (I) that have been prepared with a purity of >95%. [Table 5] TIFF0007662196000072.tif238161TIFF0007662196000073.tif239161TIFF000 7662196000074.tif239161TIFF0007662196000075.tif238162TIFF0007662196 000076.tif239160TIFF0007662196000077.tif238160TIFF0007662196000078. tif238161TIFF0007662196000079.tif238161TIFF0007662196000080.tif30160

[0128] Example 1: Synthesis of (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoic acid [ka] Step 1: Synthesis of (S)-methyl 2-(2-acetyl-4-bromophenoxy)propanoate 2 To a 150 mL solution of (R)-methyl 2-hydroxypropanoate 1 (3.07 g, 29.44 mmol), 1-(5-bromo-2-hydroxyphenyl)ethanone (6.33 g, 29.44 mmol) and TPP (9.28 g, 35.38 mmol) in DCM pre-cooled to 0° C., DIAD (6.96 mL) was added slowly with stirring. The ice bath was then removed and the mixture was stirred at room temperature overnight before being concentrated under reduced pressure. After removal of the solvent, the residue was passed through a short silica gel column (hexane-EtOAc, 25:1, 10:1) to give the desired product 2 (7.9 g, 89%) as a pale yellow oil. 1H NMR(300MHz,CDCl3)δ7.83(d,1H);7.48(dd,1H);6.67(d,1H);4.87(q,1H);3.75(s,3H);2.67(s,3H);1.68(d,3H). Step 2: Synthesis of (S)-methyl 2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)propanoate 3 To a solution of (S)-methyl 2-(2-acetyl-4-bromophenoxy)propanoate 2 (3.99 g, 13.3 mmol) in anhydrous CHCl (40 mL) in a sealed tube, add deoxofluor (24.5 ml, 133 mmol, 10 equiv), flush with argon, and seal the cap. The resulting mixture was stirred at 40 °C for 7-8 days until the starting material was completely consumed. After completion of the reaction, the reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution and mixed for 20-30 min. The aqueous layer was extracted with ethyl acetate (2x100 mL). The combined organic extracts were washed with brine and dried (NaSO). After removal of the solvent, the residue was passed through a short silica gel column (hexane-EtOAc, 25:1, 5:1) to give the desired product 3 (3.55 g, 83%) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ7.65(d,1H);7.42(dd,1H);6.66(d,1H);4.79(q,1H);3.75(s,3H);2.04(d,3H);1.64(d,3H);F 19 NMR(300MHz,CDCl3)δ-85.67,-89.11. Step 3: Synthesis of sodium (S)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)propanoate 4 To a solution of (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) was added and the resulting mixture was stirred at room temperature for 1-2 h (reaction was monitored by TLC). After completion of the reaction, volatiles were removed and the reaction mixture was diluted with water (30 mL). The aqueous layer was washed with DCM (2x20 mL) to remove impurities and unreacted ester. The aqueous layer was separated, water was removed under reduced pressure and the product 4 was dried under reduced pressure to give the desired product 4 as a pale yellow solid (1.54 g, 99%). 1 H NMR(300MHz,CDCl3)δ7.56(d,1H);7.46(dd,1H);6.87(d,1H);4.51(q,1H);2.09(d,3H);1.60(d,3H).F 19 NMR(300MHz,CDCl3)δ-86.77,-89.58. MS(ES-): m / z 307.0(MH) - .HPLC retention time: 11.16 minutes Chiral SCF method 1: 1.17 min (>99% ee). (R) enantiomer, 1.43 min.

[0129] Example 2: Synthesis of (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid The compounds were prepared as described in Example 1. (S)-Methyl 2-(4-bromo-2-propionylphenoxy)propanoate 1 H NMR (300MHz, CDCl3) δ7.84(d,1H),7.52(dd,1H),6.72(d,1H),4.91(q,1H),3.82(s,3H),3.16-3.07(m,2H),1.73(d,3H),1.23(t,3H). (S)-Methyl 2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)propanoate 1H NMR(300MHz,CDCl3)δ7.48(dd,1H),7.27(dd,1H),6.50(d,1H),4.63(q,1H),3.59(s,3H),3.34-3.14(m,2H),1.48(d,3H),0.79(t,3H). 19 F NMR (300 MHz, CDCl3) δ-93.5 and -99 ppm. (S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid 1 H NMR(300MHz,CDCl3)δ9.69(br s,1H),7.45(dd,1H),7.27(dd,1H),6.52(d,1H),4.63(q,1H),2.9-2.05(m,2H),1.50(d,3H),0.74(t,3H). 19 F NMR (300 MHz, CDCl3) δ-94 and -98 ppm. MS(ES-): m / z 321.2(MH) - .HPLC retention time: 13.56 minutes Chiral SCF Method 1: 1.09 min (>97.2% ee). (R) enantiomer, 1.25 min.

[0130] Example 3: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropanoic acid [ka] Synthesis of (S)-1-(benzyloxy)-3-fluoropropan-2-ol (R) benzyl glycidyl ether (200 g, 1.22 mol, 1.0 eq), CsF (191 g, 1.26 mol, 1.0 eq), and KHF2 (99 g, 1.27 mol, 1.0 eq) were added to a flask at room temperature under N2. 1M TBAF in THF (3.91 L, 3.2 eq) was added [no exotherm] and the reaction was stirred at room temperature under N2. The reaction was heated to 65° C. over 1 hour 30 minutes and stirred at 65° C. for 21 hours, at which point LC showed 76% product. The reaction was cooled to 25° C. and KHF2 (99 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. for 18 hours, at which point LC showed 77% product. The reaction was cooled to room temperature and H2O (3.90 L) was added over 5 min [mild exotherm]. The aqueous component was extracted with toluene (3x1.00 L). The combined organic extracts were washed with 20% K2CO3(aq) (1.90 L) and H2O (2x1.90 L) before being reduced in vacuo to give 315 g of crude product with 87% purity by LC. The material was purified by column chromatography (2.0 Kg, 10 eq. SiO2, 5→15% EtOAc in heptane) and the product eluted in two portions reduced in vacuo. The first portion gave 19 g (8% yield) of product at 91% by LC, the second portion was 97% by LC, and 1 To give 163 g (73% yield), >95% by 1 H NMR. Step 1: Synthesis of (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromophenyl)propan-1-one 2 To a 60 mL stirred solution of 1-(5-bromo-2-hydroxyphenyl)propan-1-one (4.0 g, 17.5 mmol), (S)-1-(benzyloxy)-3-fluoropropan-2-ol (3.85 g, 21.0 mmol), and triphenylphosphine (5.5 g, 21.0 mmol) in dichloromethane pre-cooled to 0 °C, DIAD (4.25 g, 21.0 mmol) was added slowly. The ice bath was then removed and the reaction mixture was stirred at room temperature overnight before being 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 2 (5.0 g, 72.5%) as a pale yellow oil. 1 H NMR (300MHz, CDCl3) δ7.82(d,1H),7.53(dd,1H),7.45-7.32(m,5H),6.95(d,1H),4.83-4.56(m,5H),3.78(dd,2H),3.02(q,2H),1.19(t,3H). 19 F NMR(300MHz,CDCl3)δ-230.69ppm. Step 2: Synthesis of (R)-1-(5-bromo-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)propan-1-one 3 To (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromophenyl)propan-1-one (5.0 g, 12.7 mmol) in a 250 mL round bottom flask was added pyridine·HCl (36.65 g, 31.7 mmol). The reaction mixture was heated at 180 °C for 90 min. After cooling, the reaction mixture was quenched with HO (50 mL) and the product was extracted with ethyl acetate (2x100 mL), washed with HO (2x30 mL), brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was passed through a silica gel column (EtOAc / Hexane, 0-50%) to give the desired product 3 (2.84 g, 73.5%) as a white solid. 1H NMR(300MHz,CDCl3)δ7.74(d,1H),7.59(dd,1H),7.07(d,1H),4.80(d,1H),4.7 1-4.59(m,2H),3.96-3.81(m,2H),3.50(t,1H),3.12-2.85(m,2H),1.24(t,3H). 19 F NMR(300MHz,CDCl3)δ-229.52ppm. Step 3: Synthesis of (R)-2-(4-bromo-2-propionylphenoxy)-3-fluoropropyl acetate 4 To a stirred solution of (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. The product was extracted with DCM (2×25 mL), washed with HO (3×20 mL), brine (20 mL), dried over sodium sulfate and concentrated to give the crude product 4 (2.21 g, quantitative), which was used in the next step without further purification. 1 H NMR(300MHz,CDCl3)δ7.81(d,1H),7.58(dd,1H),7.01(d,1H),4.88-4.75(m, 2H),4.64(m,1H),4.50-4.34(m,2H),3.01(q,2H),2.13(s,3H),1.21(t,3H). Step 4: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropyl acetate 5 To a solution of (R)-2-(4-bromo-2-propionylphenoxy)-3-fluoropropyl acetate (2.21 g, 6.4 mmol) in anhydrous CHCl (1 mL) in a sealed tube was added deoxofluor (14.15 ml, 64.0 mmol), flushed with argon, and the cap was sealed. The resulting mixture was stirred at 40° C. for 5-7 days. The reaction mixture was poured into ice-cold water (20 mL), saturated aqueous sodium carbonate solution was carefully added, and the mixture was stirred for 20-30 min. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (25 mL) and dried (NaSO). 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 5 (1.3 g, 55.2%) as a pale yellow oil. 1 H NMR(300MHz,CDCl3)δ7.62(d,1H),7.48(dd,1H),6.95(d,1H),4.74-4.64(m,2H ),4.56(m,1H),4.40-4.28(m,2H),2.38-2.19(m,2H),2.07(s,3H),0.92(t,3H). 19 F NMR(300MHz,CDCl3)δ-96.31,-96.58,-230.69ppm. Step 5: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropan-1-ol 6 To a solution of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropyl acetate (1.3 g, 3.5 mmol) in MeOH / HO (20 / 10 mL) was added KCO (0.975 g, 7.0 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated and passed through a short silica gel column (EtOAc / Hexane, 1-40%) to give the desired product 6 (1.0 g, 87.6%) as a white solid. 1H NMR(300MHz,CDCl3)δ7.67(m,1H),7.55(dd,1H),7.02(d,1H),4.81(m,1H),4.7 3-4.61(m,2H),4.01-3.84(m,2H),2.47-2.27(m,2H),2.05(m,1H),1.00(t,3H). 19 F NMR(300MHz,CDCl3)δ-94.10,-98.99,-230.30ppm. Step 6: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropanoic acid 7 To a stirred solution of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropan-1-ol (1.0 g, 3.06 mmol), sodium chlorite (0.7 g, 7.66 mmol) in acetonitrile (26 mL) and 1 M sodium phosphate buffer (pH 6, 26 mL) was added sodium hypochlorite (10 drops, 4-4.99 M solution), followed by TEMPO (0.024 g, 0.153 mmol). The reaction mixture was stirred at room temperature for 2 h. Additional sodium hypochlorite (4 drops, 4-4.99 M 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. After completion of the reaction, the mixture was cooled to 0° C., 1M NaOH solution was added to adjust the pH to about 13, and the product was washed with DCM (40 mL). The aqueous layer was separated, cooled to 0° C. again, and acidified to pH about 1 using 1M HCl. The product was extracted with ethyl acetate (2×50 mL), washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give 7 as a white solid (1.0 g, 96.1%). 1 H NMR(300MHz,CDCl3)δ9.62-8.91(br s,1H),7.72(d,1H),7.54(dd,1H),6.80(d,1H),5.06-4.87(m,3H),2.52-2.32(m,2H),2.05(m,1H),1.00(t,3H). 19F NMR(300MHz,CDCl3)δ-94.61,-97.86,-228.93ppm. Step 7: Synthesis of sodium (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropanoate 8 To a stirred solution of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropanoic acid (1.0 g, 2.94 mmol) in acetonitrile (15 mL) was added NaHCO3 (0.247 g, 2.94 mmol) in 5 mL of water at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The acetonitrile was removed in situ and the aqueous solution was lyophilized to give 8 as a white solid (1.0 g, 94%). 1 H NMR(300MHz,CD3OD)δ7.55(d,1H),7.49(dd,1H),6.87(d,1H),4.89-4.84(m,1H),4.76-4.63(m,2H),2.57-2.37(m,2H),0.94(t,3H). 19 F NMR(300MHz,CDCl3)δ-96.91,-97.92,-226.21ppm. MS(ES-): m / z 339.4(MH), HPLC retention time: 11.68 minutes

[0131] Example 4: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropanoic acid [ka] Step 1: Synthesis of (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromophenyl)ethanone 2 To a stirred solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (1.18 g, 4.98 mmol), (S)-1-(benzyloxy)-3-fluoropropan-2-ol (0.92 g, 4.99 mmol), and triphenylphosphine (1.57 g, 5.98 mmol) in 60 mL of dichloromethane pre-cooled to 0 °C, DIAD (1.21 g, 5.98 mmol) was added slowly. The ice bath was then removed and the reaction mixture was stirred at room temperature overnight before being 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 2 (1.1 g, 57.7%) as a pale yellow oil. 1 H NMR (300MHz, CDCl3) δ7.89(d,1H),7.56(dd,1H),7.46-7.30(m,5H),6.96(d,1H),4.87-4.64(m,3H),4.60(d,2H),3.80(dd,2H),2.66(s,3H). 19 F NMR(300MHz,CDCl3)δ-230.48ppm. Step 2: Synthesis of (R)-1-(5-bromo-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)ethanone 3 To (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromophenyl)ethanone (1.1 g, 2.88 mmol) in a 100 mL round bottom flask was added pyridine·HCl (8.33 g, 72.1 mmol). The reaction mixture was heated at 180 °C for 90 min and then cooled. The reaction mixture was quenched with HO (30 mL) and the product was extracted with ethyl acetate (2x50 mL), washed with HO (2x30 mL), brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was passed through a silica gel column (EtOAc / Hexane, 0-50%) to give the desired product 3 (0.8 g, 95.2%) as a colorless liquid. 1H NMR (300MHz, CDCl3) δ7.81(d,1H),7.59(dd,1H),7.05(d,1H),4.81(d,1H),4.76-4.49(m,2H),4.02-3.72(m,2H),3.38(t,1H),2.65(s,3H). 19 F NMR(300MHz,CDCl3)δ-229.93ppm. Step 3: Synthesis of (R)-2-(2-acetyl-4-bromophenoxy)-3-fluoropropyl acetate 4 To a stirred solution of (R)-1-(5-bromo-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)ethanone (0.8 g, 2.75 mmol) in 25 mL of dichloromethane at 0° C. was added triethylamine (0.333 g, 3.29 mmol) followed by dropwise addition of acetyl chloride (0.259 g, 3.29 mmol). The reaction mixture was stirred at room temperature for 1 h. The product was extracted with DCM (2×50 mL), washed with HO (3×30 mL), brine (30 mL), dried over sodium sulfate and concentrated to give the crude product 4 (0.92 g, quantitative), which was used in the next step without further purification. 1 H NMR(300MHz,CDCl3)δ7.88(d,1H),7.60(dd,1H),7.03(d,1H),4.92-4.74(m,2H),4.73-4.58(m,1H),4.54-4.32(m,2H),2.66(s,3H),2.13(s,3H). 19 F NMR(300MHz,CDCl3)δ-231.06ppm. Step 4: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropyl acetate 5 To a solution of (R)-2-(2-acetyl-4-bromophenoxy)-3-fluoropropyl acetate (0.92 g, 2.76 mmol) in anhydrous CHCl (1 mL) in a sealed tube was added deoxofluor (5.09 ml, 27.6 mmol), flushed with argon, and the cap was sealed. The resulting mixture was stirred at 40° C. for 5-7 days. The reaction mixture was poured into ice-cold water (20 mL), saturated aqueous sodium carbonate was carefully added, and the mixture was stirred for 20-30 min. The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (25 mL) and dried (NaSO). 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 5 (0.69 g, 70.3%) as a pale yellow oil. 1 H NMR(300MHz,CDCl3)δ7.71(d,1H),7.54(dd,1H),7.02(d,1H),4.86-4.69(m,2H),4.68-4.56(m,1H),4.50-4.32(m,2H),2.13(s,3H),2.03(t,3H). 19 F NMR(300MHz,CDCl3)δ-86.97,-87.97,-230.69ppm. Step 5: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropan-1-ol 6 To a solution of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropyl acetate (0.69 g, 1.94 mmol) in MeOH / HO (40 / 4 mL) was added KCO (0.536 g, 3.88 mmol). The reaction was stirred at room temperature for 2 h, then concentrated and passed through a short silica gel column (EtOAc / Hexanes, 1-40%) to give the desired product 6 (0.55 g, 90.4%) as a white solid. 1H NMR(300MHz,CDCl3)δ7.70(d,1H),7.55(dd,1H),7.02(d,1H),4.82(dd,1H),4.76-4.61(m,2H),4.02-3.85(m,2H),2.06(t,3H). 19 F NMR(300MHz,CDCl3)δ-86.08,-88.97,-230.49ppm. Step 6: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropanoic acid 7 To a stirred solution of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropan-1-ol (0.55 g, 1.76 mmol), sodium chlorite (0.397 g, 4.39 mmol) in acetonitrile (15 mL) and 1 M sodium phosphate buffer (pH approx. 6, 15 mL) was added sodium hypochlorite (5 drops, 4-4.99 M solution), followed by TEMPO (13.7 mg, 0.088 mmol). The reaction mixture was stirred at room temperature for 2 h, additional sodium hypochlorite (5 drops, 4-4.99 M 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. After completion of the reaction, the mixture was cooled to 0° C., 1M NaOH solution was added to adjust the pH to about 13, and the product was washed with DCM (40 mL). The aqueous layer was separated, cooled to 0° C. again, and acidified to pH about 1 using 1M HCl. The product was extracted with ethyl acetate (2×50 mL), washed with water (2×20 mL), brine (20 mL), dried over sodium sulfate, filtered, and concentrated to give 7 as a white solid (0.53 g, 92.2%). 1 H NMR(300MHz,CDCl3)δ10.46-9.91(br,1H);7.72(d,1H);7.49(dd,1H);6.78(d,1H);5.04-4.88(m,2H);4.84(d,1H);2.09(t,3H). 19 F NMR(300MHz,CDCl3)δ-228.15,-88.33,-86.24;ES-MS:326[M-1]. HPLC retention time: 10.852 min, 99.45% purity at 280 nm.

[0132] Example 5: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)propanoic acid [ka] Step 1: Synthesis of (S)-methyl 2-(4-bromo-5-fluoro-2-propionylphenoxy)propanoate 2 To a stirred solution of 1-(5-bromo-4-fluoro-2-hydroxyphenyl)propan-1-one (0.613 g, 2.49 mmol), (R)-methyl 2-hydroxypropanoate (0.311 g, 2.99 mmol), and triphenylphosphine (0.784 g, 2.99 mmol) in 20 mL of dichloromethane pre-cooled to 0 °C, DIAD (0.605 g, 2.99 mmol) was added slowly. The ice bath was then removed and the reaction mixture was stirred at room temperature overnight before being 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 pale yellow oil. 1 H NMR(300MHz,CDCl3)δ8.02(d,1H),6.62(d,1H),4.89(q,1H),3.85(s,3H),3.20-3.00(m,2H),1.76(d,3H),1.24(t,3H). 19 F NMR(300MHz,CDCl3)δ-98.44ppm. Step 2: Synthesis of (S)-methyl 2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)propanoate 3 To a solution of (S)-methyl 2-(4-bromo-5-fluoro-2-propionylphenoxy)propanoate (0.52 g, 1.57 mmol) in anhydrous CHCl (0.5 mL) in a sealed tube, deoxofluor (2.9 mL, 15.7 mmol) was added, flushed with argon, and the cap was sealed. The resulting mixture was stirred at 40° C. for 5-7 days. The reaction mixture was poured into ice-cold water (10 mL), saturated aqueous sodium carbonate was carefully added, and the mixture was stirred for 20-30 min. The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL) and dried (NaSO). 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 3 (0.45 g, 81.0%) as a pale yellow oil. 1 H NMR (300MHz, CDCl3) δ7.68(dd,1H),6.57(d,1H),4.74(q,1H),3.77(s,3H),2.47-2.27(m,2H),1.64(d,3H),0.93(t,3H). 19 F NMR(300MHz,CDCl3)δ-92.58,-98.20,-102.00ppm. Step 3: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)propanoic acid 4 To a stirred solution of (S)-methyl 2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)propanoate (0.45 g, 1.27 mmol) in MeOH / H2O (20 / 5 mL) at 0 °C was added NaOH (0.061 g, 1.53 mmol). The reaction mixture was stirred at room temperature for 1-2 h. The reaction mixture was concentrated and 10 mL of H2O was added. The mixture was cooled to 0 °C and acidified to pH 2 with 1 M HCl. The product was extracted with EtOAc (2x10 mL), washed with H2O (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated to give compound 4 (0.4 g, 92.6%) as a white solid. 1H NMR(300MHz,CDCl3)δ9.57-8.08(br s,1H),7.69(dd,1H),6.62(d,1H),4.78(q,1H),2.43-2.23(m,2H),1.70(d,3H),0.92(t,3H). 19 F NMR(300MHz,CDCl3)δ-93.27,-97.65,-101.65ppm. MS(ES-): m / z 339.3(MH), HPLC retention time: 12.04 minutes

[0133] Example 6: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropanoic acid [ka] Step 1: Synthesis of 1-(5-bromo-4-fluoro-2-hydroxyphenyl)propan-1-one 2 To a stirred solution of 4-bromo-3-fluorophenol 1 (13.7 g, 71.7 mmol) in 175 mL of dichloromethane at 0° C. was added triethylamine (7.91 g, 78.18 mmol) followed by dropwise addition of propionyl chloride (7.29 g, 78.9 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The product was extracted with DCM (2×90 mL), washed with HO (3×75 mL), brine (60 mL), dried over sodium sulfate and concentrated. The crude material was taken up in a 100 mL round bottom flask and AlCl3 (6.4 g, 48.0 mmol) was added. The reaction mixture was heated at 110 °C for 90 min and then cooled. The reaction mixture was quenched with 1M HCl (90 mL), extracted with ethyl acetate (2x150 mL), washed with H2O (2x60 mL), brine (40 mL), dried over sodium sulfate 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 (16.6 g, 93.6%) as a light brown solid. 1H NMR (300MHz, CDCl3) δ12.55(d,1H),7.95(d,1H),6.76(d,1H),2.99(q,2H),1.24(t,3H). 19 F NMR(300MHz,CDCl3)δ-94.156ppm. Step 2: Synthesis of (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromo-4-fluorophenyl)propan-1-one 3 To a stirred solution of 1-(5-bromo-4-fluoro-2-hydroxyphenyl)propan-1-one (2.05 g, 8.31 mmol), (S)-1-(benzyloxy)-3-fluoropropan-2-ol (1.53 g, 8.31 mmol), and triphenylphosphine (2.62 g, 9.98 mmol) in 25 mL of dichloromethane pre-cooled to 0 °C, DIAD (1.89 g, 9.37 mmol) was added slowly. The ice bath was then removed and the reaction mixture was stirred at room temperature for 4 days before being 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 pale yellow oil. 1 H NMR (300MHz, CDCl3) δ7.86(d,1H),7.33-7.15(m,5H),6.75(d,1H),4.70(d,1H),4.67-4.44(m,4H),3.66(d,2H),2.87(q,2H),1.06(t,3H). 19 F NMR(300MHz,CDCl3)δ-95.85,-230.30ppm. Step 3: Synthesis of (R)-1-(5-bromo-4-fluoro-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)propan-1-one 4 To (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromo-4-fluorophenyl)propan-1-one (1.5 g, 3.62 mmol) in a 250 mL round bottom flask was added pyridine·HCl (10.5 g, 90.7 mmol). The reaction mixture was heated at 180 °C for 90 min. The reaction mixture was cooled, quenched with HO (30 mL), and the product was extracted with ethyl acetate (2x50 mL), washed with HO (2x20 mL), brine (15 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was passed through a short silica gel column (EtOAc / Hexane, 0-50%) to give the desired product 4 (1.08 g, 92.1%) as a white solid. 1 H NMR(300MHz,CDCl3)δ7.83(d,1H),6.92(d,1H),4.75(d,1H),4.66-4.50(m,2H),3.92-3.77(m,2H),3.38(t,1H),3.07-2.79(m,2H),1.16(t,3H). 19 F NMR(300MHz,CDCl3)δ-97.68,-229.52ppm. Step 4: Synthesis of (R)-2-(4-bromo-5-fluoro-2-propionylphenoxy)-3-fluoropropyl acetate 5 To a stirred solution of (R)-1-(5-bromo-4-fluoro-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)propan-1-one (1.08 g, 3.34 mmol) in 20 mL of dichloromethane at 0° C. was added triethylamine (0.40 g, 4.0 mmol), followed by dropwise addition of acetyl chloride (0.31 g, 4.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The product was extracted with DCM (2×30 mL), washed with HO (2×30 mL), brine (20 mL), dried over sodium sulfate and concentrated to give the crude product 5 (1.21 g, quantitative), which was used in the next step without further purification. 1H NMR (300MHz, CDCl3) δ7.93(d,1H),6.89(d,1H),4.84-4.53(m,3H),4.46-4.27(m,2H),2.94(q,2H),2.08(s,3H),1.15(t,3H). 19 F NMR(300MHz,CDCl3)δ-98.26,-230.88ppm. Step 5: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropyl acetate 6 To a solution of (R)-2-(4-bromo-5-fluoro-2-propionylphenoxy)-3-fluoropropyl acetate (1.21 g, 3.31 mmol) in anhydrous CHCl (10.8 mL) in a sealed tube was added deoxofluor (5.1 ml, 33.1 mmol), flushed with argon, and the cap was sealed. The resulting mixture was stirred at 40° C. for 5-7 days. The reaction mixture was poured into ice-cold water (20 mL), saturated aqueous sodium carbonate solution was carefully added, and the mixture was stirred for 20-30 min. The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with brine (20 mL) and dried (NaSO). 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 6 (0.68 g, 53.0%) as an oil. 1 H NMR (300MHz, CDCl3) δ7.67(d,1H),6.89(d,1H),4.78-4.49(m,3H),4.41-4.26(m,2H),2.38-2.15(m,2H),2.07(s,3H),0.91(t,3H). 19 F NMR (300 MHz, CDCl3) δ -94.91, -96.02, -101.74, -230.49 ppm. Step 6: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropan-1-ol 7 To a stirred solution of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropyl acetate (0.68 g, 1.75 mmol) in MeOH / HO (40 / 4 mL) was added KCO (0.485 g, 3.51 mmol). The mixture was stirred at room temperature for 2 h, concentrated, and passed through a short silica gel column (EtOAc / Hexane, 1-40%) to give the desired product 7 (0.59 g, 97.3%) as a white solid. 1 H NMR(300MHz,CDCl3)δ7.67(d,1H),6.89(d,1H),4.81-4.68(m,1H),4.66-4. 49(m,2H),3.94-3.78(m,2H),2.40-2.17(m,2H),2.04(m,1H),0.94(t,3H). 19 F NMR(300MHz,CDCl3)δ-93.29,-97.91,-101.56,-230.10ppm. Step 7: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropanoic acid 8 To a stirred solution of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropan-1-ol (0.59 g, 1.70 mmol) and sodium chlorite (386 mg, 4.27 mmol) in acetonitrile (15.5 mL) and 1 M sodium phosphate buffer (pH approx. 6, 15.5 mL) was added sodium hypochlorite (5 drops, 4-4.99 M solution), followed by TEMPO (13.3 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 2 h. Additional sodium hypochlorite (4 drops, 4-4.99 M solution) and TEMPO (6.24 mg, 0.04 mmol) were added and the addition of sodium hypochlorite and TEMPO was repeated three more times at 8 h intervals. After completion of the reaction, the mixture was cooled to 0° C., 1M NaOH solution was added to adjust the pH to about 13, and washed with DCM (30 mL). The aqueous layer was separated, cooled to 0° C. again, and acidified to pH about 1 using 1M HCl. The product was extracted with ethyl acetate (2×30 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered, and concentrated to give the product 8 as a white solid (0.56 g, 91.2%). 1 H NMR(300MHz,CDCl3)δ8.74-7.98(br s,1H),7.73(d,1H),6.68(d,1H),5.03-4.79(m,3H),2.47-2.21(m,2H),0.94(t,3H). 19 F NMR(300MHz, CDCl3)δ-93.66,-97.02,-101.25,-228.55ppm. MS(ES-): m / z 358(MH) HPLC retention time: 11.816 min, purity 98.19% at 280 nm.

[0134] Example 7: Synthesis of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropanoic acid [ka] Step 1: Synthesis of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)propan-1-one 2 To a stirred solution of 4-chloro-3-fluorophenol (4.75 g, 32.0 mmol) in 60 mL of dichloromethane at 0° C. was added triethylamine (4.20 g, 41.6 mmol), followed by dropwise addition of propionyl chloride (3.14 g, 34.0 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The product was extracted with DCM (2×30 mL), washed with HO (3×25 mL), brine (20 mL), dried over sodium sulfate and concentrated. The crude material was taken up in a 250 mL round bottom flask and AlCl3 (6.4 g, 48.0 mmol) was added. The reaction mixture was heated at 110 °C for 90 min and then cooled. The reaction mixture was cooled and quenched with 1M HCl (30 mL) and the product was extracted with ethyl acetate (2x50 mL), washed with H2O (2x20 mL), brine (10 mL), dried over sodium sulfate 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 brown solid. 1 H NMR (300MHz, CDCl3) δ12.57(d,1H),7.85(d,1H),6.81(d,1H),3.03(q,2H),1.29(t,3H). 19 F NMR(300MHz,CDCl3)δ-102.14ppm. Step 2: Synthesis of (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-chloro-4-fluorophenyl)propan-1-one 3 To a stirred solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)propan-1-one (1.25 g, 6.2 mmol), (S)-1-(benzyloxy)-3-fluoropropan-2-ol (1.4 g, 7.4 mmol), and triphenylphosphine (1.95 g, 7.4 mmol) in 25 mL of dichloromethane pre-cooled to 0 °C, DIAD (1.5 g, 7.4 mmol) was added slowly. The ice bath was then removed and the reaction mixture was stirred at room temperature for 4 days before being 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 (1.6 g, 70.1%) as a pale yellow oil. 1 H NMR (300MHz, CDCl3) δ7.86(d,1H),7.45-7.32(m,5H),6.91(d,1H),4.84(d,1H),4.80-4.56(m,4H),3.79(d,2H),3.01(q,2H),1.19(t,3H). 19 F NMR(300MHz,CDCl3)δ-106.42,-230.61ppm. Step 3: Synthesis of (R)-1-(5-chloro-4-fluoro-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)propan-1-one 4 To (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-chloro-4-fluorophenyl)propan-1-one (1.6 g, 4.35 mmol) in a 250 mL round bottom flask was added pyridine·HCl (12.5 g, 108.7 mmol). The reaction mixture was heated at 180 °C for 90 min and then cooled. The reaction mixture was quenched with HO (30 mL) and the product was extracted with ethyl acetate (2x50 mL), washed with HO (2x20 mL), brine (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was passed through a short silica gel column (EtOAc / Hexane, 0-50%) to give the desired product 4 (0.78 g, 64.4%) as a white solid. 1H NMR(300MHz,CDCl3)δ7.76(d,1H),7.01(d,1H),4.82(d,1H),4.70-4.58(m,2H),3.95-3.87(m,2H),3.36(t,1H),3.11-2.86(m,2H),1.24(t,3H). 19 F NMR(300MHz,CDCl3)δ-105.66,-229.13ppm. Step 4: Synthesis of (R)-2-(4-chloro-5-fluoro-2-propionylphenoxy)-3-fluoropropyl acetate 5 To a stirred solution of (R)-1-(5-chloro-4-fluoro-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)propan-1-one (0.77 g, 2.77 mmol) in 20 mL of dichloromethane at 0° C. was added triethylamine (0.42 g, 4.16 mmol) followed by dropwise addition of acetyl chloride (0.261 g, 3.32 mmol). The reaction mixture was stirred at room temperature for 1 h. The product was extracted with DCM (2×20 mL), washed with HO (2×20 mL), brine (10 mL), dried over sodium sulfate and concentrated to give the crude product 5 (0.887 g, quantitative), which was used in the next step without further purification. 1 H NMR (300MHz, CDCl3) δ7.86(d,1H),6.97(d,1H),4.83-4.65(m,3H),4.51-4.36(m,2H),3.01(q,2H),2.14(s,3H),1.22(t,3H). 19 F NMR(300MHz,CDCl3)δ-106.05,-230.88ppm. Step 5: Synthesis of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropyl acetate 6 To a solution of (R)-2-(4-chloro-5-fluoro-2-propionylphenoxy)-3-fluoropropyl acetate (0.887 g, 2.77 mmol) in anhydrous CHCl (1 mL) in a sealed tube was added deoxofluor (5.1 ml, 27.7 mmol), flushed with argon, and the cap was sealed. The resulting mixture was stirred at 40° C. for 5-7 days. The reaction mixture was poured into ice-cold water (20 mL), saturated aqueous sodium carbonate solution was carefully added, and the mixture was stirred for 20-30 min. The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL) and dried (NaSO). 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 6 (0.59 g, 62.2%) as a pale yellow oil. 1 H NMR (300MHz, CDCl3) δ7.60(d,1H),6.98(d,1H),4.81-4.59(m,3H),4.45-4.34(m,2H),2.43-2.23(m,2H),2.14(s,3H),0.98(t,3H). 19 F NMR (300 MHz, CDCl3) δ -95.31, -95.71, -109.63, -230.30 ppm. Step 6: Synthesis of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropan-1-ol 7 To a stirred solution of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropyl acetate (0.44 g, 1.29 mmol) in MeOH / HO (10 / 2 mL) was added KCO (0.391 g, 2.83 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated and passed through a short silica gel column (EtOAc / Hexane, 1-40%) to give the desired product 7 (0.37 g, 95.6%) as a white solid. 1H NMR(300MHz,CDCl3)δ7.59(d,1H),6.98(d,1H),4.85-4.79(m,1H),4.69-4. 57(m,2H),4.01-3.87(m,2H),2.47-2.25(m,2H),2.00(m,1H),1.00(t,3H). 19 F NMR(300MHz,CDCl3)δ-93.30,-98.05,-109.44,-230.10ppm. Step 7: Synthesis of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropanoic acid 8 To a stirred solution of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropan-1-ol (0.24 g, 0.799 mmol) and sodium chlorite (181 mg, 2.0 mmol) in acetonitrile (7 mL) and 1 M sodium phosphate buffer (pH 6, 7 mL) was added sodium hypochlorite (4 drops, 4-4.99 M solution), followed by TEMPO (6.24 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 2 h. Additional sodium hypochlorite (4 drops, 4-4.99 M solution) and TEMPO (6.24 mg, 0.04 mmol) were added and the addition of sodium hypochlorite and TEMPO was repeated three more times at 8 h intervals. After completion of the reaction, the mixture was cooled to 0° C., 1M NaOH solution was added to adjust the pH to about 13, and washed with DCM (15 mL). The aqueous layer was separated and cooled to 0° C. again. The aqueous layer was acidified to pH about 1 with 1M HCl, and the product was extracted with ethyl acetate (2×15 mL), washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give the product 8 as a white solid (0.23 g, 91.6%). 1 H NMR(300MHz,CDCl3)δ8.30-7.67(br s,1H),7.58(d,1H),6.70(d,1H),5.01-4.82(m,3H),2.46-2.23(m,2H),0.93(t,3H). 19F NMR(300MHz, CDCl3)δ-93.75,-97.08,-109.14,-228.60ppm. MS(ES-): m / z 313(MH) - , HPLC retention time: 11.76 minutes Chiral HPLC: 7.62 min, 99.4% ee

[0135] Example 8: Synthesis of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid [ka] Step 1: Synthesis of 1-{2-[(R)-2-(benzyloxy)-1-(fluoromethyl)ethoxy]-5-bromo-4-fluorophenyl}-1-ethanone 3 To a stirred solution of 1-(5-bromo-4-fluoro-2-hydroxyphenyl)-1-ethanone (1.0 g, 4.29 mmol), (S)-1-(benzyloxy)-3-fluoropropan-2-ol (0.79 g, 4.29 mmol), and triphenylphosphine (1.35 g, 5.15 mmol) in 25 mL of dichloromethane pre-cooled to 0 °C, DIAD (1.04 g, 5.15 mmol) was added slowly. The ice bath was then removed and the reaction mixture was stirred at room temperature for 5 days before being 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 (0.94 g, 54.8%) as a pale yellow oil. 1 H NMR (300MHz, CDCl3) δ7.91(d,1H),7.32-7.16(m,5H),6.77(d,1H),4.72(d,1H),4.69-4.42(m,4H),3.68(d,2H),2.51(s,3H). 19 F NMR(300MHz,CDCl3)δ-97.82,-230.10ppm. Step 2: Synthesis of 1-{2-[(R)-1-(fluoromethyl)-2-hydroxyethoxy]-5-bromo-4-fluorophenyl}-1-ethanone 4 To 1-{2-[(R)-2-(benzyloxy)-1-(fluoromethyl)ethoxy]-5-bromo-4-fluorophenyl}-1-ethanone (0.94 g, 2.35 mmol) in a 250 mL round bottom flask was added pyridine·HCl (6.8 g, 58.86 mmol). The reaction mixture was heated at 180 °C for 40 min. The reaction mixture was cooled, quenched with HO (30 mL), and the product was extracted with ethyl acetate (2x50 mL), washed with HO (2x20 mL), brine (15 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was passed through a short silica gel column (EtOAc / Hexane, 0-50%) to give the desired product 4 (0.41 g, 56.3%) as a white solid. 1 H NMR (300MHz, CDCl3) δ7.84(d,1H),6.88(d,1H),4.75(d,1H),4.68-4.50(m,2H),3.93-3.78(br,2H),3.60(t,1H),2.55(s,3H). 19 F NMR(300MHz,CDCl3)δ-97.01,-230.07ppm. Step 3: Synthesis of (R)-2-(2-acetyl-4-bromo-5-fluorophenoxy)-3-fluoropropyl acetate 5 To a stirred solution of 1-{2-[(R)-1-(fluoromethyl)-2-hydroxyethoxy]-5-bromo-4-fluorophenyl}-1-ethanone (0.41 g, 1.32 mmol) in 10 mL of dichloromethane at 0° C., triethylamine (0.20 g, 1.98 mmol) was added, followed by dropwise addition of acetyl chloride (0.125 g, 1.59 mmol). The reaction mixture was stirred at room temperature for 1 h. The product was extracted with DCM (2×20 mL), washed with HO (2×20 mL), brine (10 mL), dried over sodium sulfate, and concentrated to give the crude product 5 (0.46 g, quantitative), which was used in the next step without further purification. 1H NMR (300MHz, CDCl3) δ7.93(d,1H),6.89(d,1H),4.85-4.53(m,3H),4.46-4.23(m,2H),2.55(s,3H),2.05(s,3H). 19 F NMR(300MHz,CDCl3)δ-97.53,-230.98ppm. Step 4: Synthesis of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropyl acetate 6 To a solution of R)-2-(2-acetyl-4-bromo-5-fluorophenoxy)-3-fluoropropyl acetate (0.46 g, 1.31 mmol) in anhydrous CHCl (1 mL) in a sealed tube, deoxofluor (2.41 ml, 13.1 mmol) was added, flushed with argon, and the cap was sealed. The resulting mixture was stirred at 40° C. for 5 days. The reaction mixture was poured into ice-cold water (20 mL) and saturated aqueous sodium carbonate was carefully added. The mixture was stirred for 20-30 min. The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL) and dried (NaSO). 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 6 (0.286 g, 58.5%) as a pale yellow oil. 1 H NMR (300MHz, CDCl3) δ7.69(d,1H),6.90(d,1H),4.79-4.50(m,3H),4.42-4.26(m,2H),2.07(s,3H),1.94(t,3H). 19 F NMR (300 MHz, CDCl3) δ -86.01, -87.05, -101.67, -230.38 ppm. Step 5: Synthesis of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanol 7 To a stirred solution of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropyl acetate (0.20 g, 0.54 mmol) in MeOH / H2O (10 / 2 mL) was added K2CO3 (0.15 g, 1.07 mmol) and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated and passed through a short silica gel column (EtOAc / Hexane, 1-40%) to give the desired product 7 (0.16 g, 90.15%) as a white solid. 1 H NMR(300MHz,CDCl3)δ7.75(dd,1H),6.95(d,1H),4.88-4.76(m,1H),4.72-4.55(m,2H),4.03-3.84(m,2H),2.24-2.13(br,H),2.04(t,3H). 19 F NMR(300MHz,CDCl3)δ-85.22,-88.01,-101.49,-230.16ppm. Step 6: Synthesis of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid 8 To a stirred solution of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanol (0.15 g, 0.453 mmol), sodium chlorite (102.4 mg, 1.13 mmol) in acetonitrile (3.9 mL) and 1 M sodium phosphate buffer (pH 6, 3.9 mL) was added sodium hypochlorite (9 drops, 4-4.99 M solution), followed by TEMPO (3.54 mg, 0.023 mmol). The reaction mixture was stirred at room temperature for 2 hours. Additional sodium hypochlorite (9 drops, 4-4.99 M solution) and TEMPO (3.54 mg, 0.023 mmol) were added and the addition of sodium hypochlorite and TEMPO was repeated three more times at 8 hour intervals. After completion of the reaction, the reaction was cooled to 0°C. 1M NaOH solution was added to adjust the pH to about 13 and the mixture was washed with DCM (15 mL). The aqueous layer was separated and cooled to 0° C. again before being acidified to pH about 1 with 1M HCl. The product was extracted with ethyl acetate (2×15 mL), washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to give the product 8 as a white solid (0.151 g, 96.9%). 1 H NMR (300MHz, CDCl3) δ7.75(d,1H),6.67(d,1H),6.60-6.01(br,1H),5.07-4.88(m,2H),4.85(d,1H),2.02(t,3H). 19 F NMR(300MHz, CDCl3)δ-85.37,-87.48,-101.10,-228.46ppm. MS(ES-): m / z 343(MH). HPLC retention time: 11.37 minutes. Chiral HPLC: 14.12 min, 99.5% ee

[0136] Example 9: Synthesis of sodium (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoate [ka] Step 1: Synthesis of 4-bromo-2-(hydroxy(thiazol-2-yl)methyl)phenol To a cooled (-78°C) solution of 1,3-thiazole (2.8mL, 40mmol, 2.0eq) in THF (22.6mL) was added n-butyllithium (2.7M in heptane, 14.7mL, 40mmol, 2.0eq) dropwise, then the reaction mixture was allowed to warm slowly to room temperature over 1h. The reaction mixture was re-cooled to -78°C for the dropwise addition of a solution of 5-bromo-2-hydroxybenzaldehyde (4.0g, 20mmol, 1.0eq) in THF (12mL), then allowed to warm slowly to room temperature and stirred for 18h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (20mL) and extracted with EtOAc (3x50mL). The combined organic layers were washed with brine (50mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Si, 0-30% EtOAc in hexanes) to afford the title compound (2.64 g, 9.2 mmol, 46%) as a beige solid. UPLC-MS: Acidic bisection method MS(ES-): m / z 284.0 / 286.0(MH) - ;Holding time: 0.95 minutes;Purity: 67%. 1 H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 3.3 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.36-7.27 (m, 2H), 6.85 (d, J = 8.6 Hz, 1H), 6.26 (s, 1H). Step 2: Synthesis of (5-bromo-2-hydroxyphenyl)(thiazol-2-yl)methanone To a solution of 4-bromo-2-(hydroxy(thiazol-2-yl)methyl)phenol (540 mg, 1.9 mmol, 1.0 equiv) in DCM (9.4 mL) was added manganese(IV) oxide (820 mg, 9.4 mmol, 5.0 equiv) and the reaction was stirred at room temperature. The reaction mixture was filtered through a pad of Celite and the pad was washed with DCM (2x5 mL). The filtrate was concentrated under reduced pressure to give the title compound (488 mg, 1.7 mmol, 91%) as a dark yellow solid which was used in the subsequent reaction without further purification. UPLC-MS: Acidic bisection MS (ES+): m / z not available; retention time: 1.26 min; purity: 86%. 1 H NMR (400 MHz, chloroform-d) δ 12.15 (s, 1H), 9.31 (d, J = 2.5 Hz, 1H), 8.08 (d, J = 3.0 Hz, 1H), 7.72 (d, J = 3.0 Hz, 1H), 7.55 (dd, J = 9.0, 2.5 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H). Step 3: Synthesis of methyl (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoate To a cooled (0° C.) solution of (5-bromo-2-hydroxyphenyl)(thiazol-2-yl)methanone (488 mg, 1.7 mmol, 1.0 equiv.) in DCM (8.6 mL) was added DAST (2.3 mL, 17 mmol, 10.0 equiv.), the reaction vial was sealed, and the mixture was allowed to warm slowly to room temperature overnight. The reaction mixture was poured into ice water (50 mL) and extracted with DCM (2×50 mL). The combined organic extracts were washed successively with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, and the solvent was concentrated under reduced pressure to approximately 10 mL. The resulting solution was immediately recooled to 0° C., diluted with THF (8.6 mL) and treated sequentially with (R)-methyl lactate (0.17 mL, 1.8 mmol, 1.05 equiv), triphenylphosphine (496 mg, 1.9 mmol, 1.1 equiv) and DIAD (0.37 mL, 1.9 mmol, 1.1 equiv). The reaction mixture was allowed to warm slowly to room temperature overnight. The reaction was concentrated under reduced pressure and the crude product was purified twice by flash column chromatography (Si, 5-30% EtOAc in hexanes followed by 10-50% DCM in hexanes) to afford the title compound (142 mg, 0.36 mmol, 21%) as a colorless oil. UPLC-MS: Acidic bisection method MS(ES+): m / z 392 / 394(M+H) + ;Retention time: 1.23 minutes;Purity: 93%. 1 H NMR (400 MHz, chloroform-d) δ 7.96 (d, J = 2.5 Hz, 1H), 7.82 (dt, J = 3.3, 1.7 Hz, 1H), 7.57-7.48 (m, 2H), 6.64 (d, J = 8.8 Hz, 1H), 4.60 (q, J = 6.8 Hz, 1H), 3.67 (s, 3H), 1.27 (d, J = 6.7 Hz, 3H). Step 4: Synthesis of (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoic acid A solution of methyl (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoate (142 mg, 0.36 mmol, 1.0 equiv) in THF (2.2 mL) was treated with 1 M aqueous sodium hydroxide (2.2 mL, 2.2 mmol, 6.0 equiv). The reaction mixture was allowed to stand at room temperature for 30 min. The reaction mixture was washed with EtOAc (3 mL). The aqueous layer was acidified to pH ∼3 with 1 M aqueous hydrochloric acid and extracted with EtOAc (2x10 mL). The combined organic extracts were washed with brine (15 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (101 mg, 0.27 mmol, 73%) as a colorless oil. UPLC-MS: Acidic 4-division method MS(ES-): m / z 376.0 / 378.0(MH) - ;Retention time: 1.72 minutes;Purity: 100%. 1 H NMR(400MHz,DMSO-d6)δ13.16(s,1H),8.00(d,J=3.1Hz,1H),7.94-7.84(m,1H),7.81(d,J=2.5Hz,1 H),7.71(dd,J=8.9,2.5Hz,1H),6.90(d,J=9.0Hz,1H),4.71(q,J=6.6Hz,1H),1.09(d,J=6.8Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-85.27. Step 5: Synthesis of sodium (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoate To a solution of (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoic acid (101 mg, 0.27 mmol, 1.0 equiv) in water (11.4 mL) and MeCN (22.9 mL) was added 1 M aqueous sodium bicarbonate (0.28 mL, 0.28 mmol, 1.05 equiv) and the reaction was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and dried overnight at 40° C. in a vacuum oven to give the title compound (105 mg, 0.26 mmol, 98%) as an off-white powder. UPLC-MS: Acidic bisection method MS(ES+): m / z 378.0 / 380.0(M+H)+ ;Holding time: 0.85 minutes;Purity: 100%. 1 H NMR(DMSO-d6)δ:7.97(d,J=3.2Hz,1H),7.86(dt,J=3.2,1.6Hz,1H),7.71(d,J=2.5Hz,1H),7. 60(dd,J=8.9,2.6Hz,1H),6.80(d,J=8.9Hz,1H),3.89(q,J=6.7Hz,1H),0.91(d,J=6.7Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-85.01(d,J=2.0Hz).

[0137] Example 10: Synthesis of sodium (S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoate [ka] Step 1: Synthesis of 4-bromo-2-(cyclobutyl(hydroxy)methyl)phenol To a cooled (0° C.) solution of 5-bromosalicylaldehyde (1.0 g, 5.0 mmol, 1.0 equiv) in THF (40 mL) was added freshly prepared cyclobutylmagnesium bromide (14.9 mL, 14.9 mmol, 3.0 equiv) and the reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was poured into saturated aqueous ammonium chloride (150 mL) and extracted with EtOAc (3×80 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (Si, 0-100% DCM in hexanes) to afford the title compound (1.01 g, 79%) as a yellow crystalline solid. UPLC-MS: Basic dichotomy MS(ES-):m / z 255.0 / 257.0(MH) - ;Retention time: 1.09 minutes;Purity: 100%. 1H NMR (chloroform-d) δ 8.09 (s, 1H), 7.41-7.29 (m, 1H), 7.13 (d, J = 2.5 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 4.75 (d, J = 8.5 Hz, 1H), 2.93-2.82 (m, 1H), 2.78 (s, 1H), 2.31-2.12 (m, 1H), 2.09-1.82 (m, 5H). Step 2: Synthesis of (5-bromo-2-hydroxyphenyl)(cyclobutyl)methanone To a solution of 4-bromo-2-(cyclobutyl(hydroxy)methyl)phenol (1.14 g, 4.98 mmol, 1.0 equiv) in DCM (22 mL) was added manganese(IV) oxide (2.16 g, 24.9 mmol, 5.0 equiv) and the mixture was stirred at room temperature overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give a viscous brown oil that was stored in the freezer over the weekend. This oil was then redissolved in DCM (25 mL) and fresh manganese(IV) oxide (8.81 g, 101 mmol, 20.0 equiv) was added. The resulting mixture was stirred at room temperature for 24 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give the crude title compound (3.52 g), which was used in the next step without further purification. UPLC-MS: Basic dichotomy MS(ES-):m / z 253.0 / 255.0(MH) - ;Retention time: 1.31 minutes;Purity: 77%. Step 3: Synthesis of methyl (S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoate To a cooled (0° C.) solution of (5-bromo-2-hydroxyphenyl)(cyclobutyl)methanone (750 mg, 2.9 mmol, 1.0 equiv.) in DCM (14.7 mL) was added DAST (3.9 mL, 29.0 mmol, 10.0 equiv.), the reaction vial was sealed, and the mixture was allowed to warm slowly to room temperature over 1 h. The reaction mixture was poured into ice water (50 mL) and extracted with DCM (2×50 mL). The combined organic extracts were washed successively with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, and the solvent was concentrated under reduced pressure to approximately 10 mL. The resulting solution was immediately recooled to 0° C., diluted with THF (14.7 mL) and treated sequentially with (R)-methyl lactate (0.30 mL, 3.1 mol, 1.05 equiv), triphenylphosphine (848 mg, 3.2 mol, 1.1 equiv) and DIAD (0.64 mL, 3.2 mol, 1.1 equiv). The reaction mixture was allowed to warm slowly to room temperature overnight. The reaction was concentrated under reduced pressure and the crude product was purified twice by flash column chromatography (Si, 0-50% DCM in hexanes followed by 5-20% DCM in hexanes) to give the title compound (158 mg, 0.44 mmol, 15%) as a colorless oil. UPLC-MS: Acidic bisection method MS(ES-): m / z 361.0 / 363.0(MH) - ;Retention time: 1.37 minutes;Purity: 100%. 1 H NMR (400MHz, chloroform-d) δ7.55(dd,J=2.5,1.1Hz,1H),7.33(ddd,J=8.8,2.5,0.9Hz,1H),6.57(d,J=8.8Hz,1H),4.68(q,J=6 .8Hz,1H),3.68(s,3H),3.50-3.33(m,1H),2.25-2.11(m,1H),2.03-1.87(m,2H),1.87-1.69(m,3H),1.57(d,J=6.8Hz,3H). Step 4: Synthesis of (S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoic acid A solution of methyl (S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoate (158 mg, 0.44 mmol, 1.0 equiv) in water (5.2 mL), THF (7.8 mL) and MeOH (2.6 mL) was treated with 1 M aqueous sodium hydroxide (2.6 mL, 2.6 mmol, 6.0 equiv). After 1 h, the reaction mixture was partitioned between water (25 mL) and EtOAc (25 mL) and the aqueous layer was acidified with 1 M aqueous hydrochloric acid and re-extracted with EtOAc (2x25 mL). The combined second extract was washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (142 mg, 0.41 mmol, 93%) as a colorless oil that solidified on standing. UPLC-MS: Acidic bisection method MS(ES-): m / z 347.0 / 349.0(MH) - ;Holding time: 1.20 minutes;Purity: 90%. 1 H NMR (400MHz, chloroform-d) δ7.55(d,J=2.5Hz,1H),7.37(dd,J=8.8,2.5Hz,1H),6.64(d,J=8.8Hz,1H),4.73(q,J=6. 8Hz,1H),3.45-3.24(m,1H),2.15(dq,J=11.4,8.8Hz,1H),2.01(s,1H),1.93-1.70(m,4H),1.62(d,J=6.8Hz,3H). 19 F NMR (376 MHz, chloroform-d) δ-101.99 (d, J = 248.2 Hz), -106.98 (d, J = 248.2 Hz). Step 5: Synthesis of sodium (S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoate A solution of ((S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoic acid (142 mg, 0.41 mmol, 1.0 equiv) in MeCN (10 mL) and water (5 mL) was treated with 1 M aqueous sodium bicarbonate (0.43 mL, 0.43 mmol, 1.05 equiv). After 30 min, the reaction was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 40° C. overnight to afford the title compound (146 mg, 0.39 mmol, 97%) as an off-white solid. UPLC-MS: Acidic 4-division method MS(ES-): m / z 347.0 / 349.0(MH) - ;Retention time: 2.06 minutes;Purity: 86%. 1 H NMR(DMSO-d6)δ:7.50-7.40(m,2H),6.83(d,J=8.9Hz,1H),4.36(q,J=6.7H z,1H),3.72(m,1H),2.10(m,1H),2.01-1.70(m,5H),1.40(d,J=6.6Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ:-99.92(d,J=242.7Hz),-105.96(d,J=242.6Hz).

[0138] Example 11: Synthesis of sodium (S)-2-(4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy)propanoate [ka] Step 1: Synthesis of 4-bromo-2-fluoro-6-(1-hydroxypropyl)phenol To a cooled (0° C.) solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (3.0 g, 13.7 mmol, 1.0 equiv) in THF (150 mL) was added ethylmagnesium bromide (14 mL, 3.0 M in diethyl ether, 41.1 mmol, 3.0 equiv) dropwise and the reaction was stirred for 1 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (200 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3.84 g, 13.7 mmol, 97%) as a viscous yellow oil, which was used in the next step without further purification. UPLC-MS: Acidic bisection method MS(ES-): m / z 247.0 / 249.0(MH) - ;Retention time: 1.02 minutes;Purity: 86%. 1H NMR (chloroform-d) δ: 7.71 (s, 1H), 7.12 (dd, J = 9.9, 2.3 Hz, 1H), 6.99-6.93 (m, 1H), 4.77 (dd, J = 7.4, 5.9 Hz, 1H), 3.22 (s, 1H), 1.93-1.70 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). Step 2: Synthesis of 1-(5-bromo-3-fluoro-2-hydroxyphenyl)propan-1-one To a solution of 4-bromo-2-fluoro-6-(1-hydroxypropyl)phenol (3.84 g, 13.7 mmol, 1.0 equiv) in DCM (70 mL) was added manganese(IV) oxide (6.70 g, 77.1 mmol, 5.6 equiv) and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through Celite and the filter cake was washed with DCM (20 mL). The filtrate was treated with manganese(IV) oxide (6.70 g, 77.1 mmol, 5.6 equiv) and the mixture was stirred at room temperature for 5 h. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure and the crude material was purified by flash column chromatography (Si, 0-100% DCM in hexanes) to give the title compound (511 mg, 2.0 mmol, 13%) as a bright yellow crystalline solid. UPLC-MS: Basic dichotomy MS(ES-):m / z 245.0 / 247.0(MH) - ;Retention time: 1.06 minutes;Purity: 97%. 1 H NMR (400 MHz, chloroform-d) δ 1.25 (t, J = 7.2 Hz, 3H), 3.03 (q, J = 7.2 Hz, 2H), 7.42 (ddd, J = 9.8, 2.3, 0.6 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 12.30 (d, J = 0.6 Hz, 1H). Step 3: Synthesis of methyl (S)-2-(4-bromo-2-fluoro-6-propionylphenoxy)propanoate To a cooled (0° C.) solution of 1-(5-bromo-3-fluoro-2-hydroxyphenyl)propan-1-one (501 mg, 2.03 mmol, 1.0 equiv) in THF (7.5 mL) was added sequentially methyl (2R)-hydroxypropanoate (211 mL, 2.03 mmol, 1.0 equiv), triphenylphosphine (585 mL, 2.23 mmol, 1.1 equiv) and diisopropyl azodicarboxylate (0.44 mL, 2.23 mmol, 1.1 equiv). The reaction was allowed to warm slowly to room temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography (Si, 0-40% EtOAc in hexanes) to afford the title compound (480 mg, 1.44 mmol, 67%) as a colorless oil. UPLC-MS: Acidic 4-division method MS(ES-): m / z 333.0 / 335.0(MH) - ;Retention time: 2.06 minutes;Purity: 97%. 1 H NMR (400 MHz, chloroform-d) δ 7.45 (dd, J = 2.5, 1.6 Hz, 1H), 7.33 (dd, J = 11.0, 2.4 Hz, 1H), 4.89 (qd, J = 6.8, 0.7 Hz, 1H), 3.69 (s, 3H), 3.16 (dq, J = 18.2, 7.3 Hz, 1H), 2.93 (dq, J = 18.2, 7.2 Hz, 1H), 1.63 (dd, J = 6.9, 0.8 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H). Step 4: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy)propanoate A mixture of methyl (S)-2-(4-bromo-2-fluoro-6-propionylphenoxy)propanoate (470 mg, 1.41 mmol, 1.0 equiv) and deoxofluor solution (50% in THF, 6 mL, 14.1 mmol, 10 equiv) was stirred at room temperature for 72 h and then heated to 40° C. for 7 days. The reaction mixture was cooled to room temperature and then poured into chilled (0° C.) saturated aqueous sodium bicarbonate (50 mL). The aqueous mixture was extracted with DCM (3×25 mL) and the combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude dark oil was purified by flash column chromatography (Si, 0-60% EtOAc in hexanes) to give the title compound (135 mg, 0.36 mmol, 26%) as a yellow / brown semi-solid. UPLC-MS: Acidic bisection MS (ES-): m / z not available; retention time: 1.34 min; purity: 95%. 1 H NMR (chloroform-d) δ 7.43 (qd, J = 1.0, 1.5 Hz, 1H), 7.31 (ddd, J = 0.8, 2.5, 11.1 Hz, 1H), 4.84 (qd, J = 1.6, 6.8 Hz, 1H), 3.77 (s, 3H), 2.44-2.25 (m, 2H), 1.59-1.53 ​​(m, 3H), 0.94 (t, J = 7.5 Hz, 3H). 19 F NMR(376MHz,chloroform-d)δ-93.67(d,J=246.9Hz),-97.26(dd,J=2.9,247.0Hz),-125.43(d,J=2.7Hz). Step 5: Synthesis of sodium (S)-2-(4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy)propanoate To a solution of methyl (S)-2-(4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy)propanoate (106 mg, 0.29 mmol, 1.0 equiv) in MeOH (2.1 mL) was added 1 M aqueous sodium hydroxide (0.31 mL, 0.31 mmol, 1.06 equiv) and the reaction was stirred at room temperature for 4 h. The mixture was then concentrated under reduced pressure and the resulting solid was dried overnight at 45° C. in a vacuum oven to give the title compound (96 mg, 0.26 mmol, 89%) as a pink solid. UPLC-MS: Acidic 4-division method MS(ES-): m / z 339.0 / 341.0(MH) - ;Retention time: 1.93 minutes;Purity: 100%. 1 H NMR(DMSO-d6)δ:7.50(ddd,J=12.6,2.5,0.9Hz,1H),7.24(dt,J=2.6,1.3Hz,1H),4.80( qd,J=6.8,4.5Hz,1H),2.50(m,2H),1.34(dd,J=6.8,1.0Hz,3H),0.87(t,J=7.5Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-124.78(d,J=3.9Hz),-96.92(dd,J=240.6,3.9Hz),-89.00(d,J=240.7Hz).

[0139] Example 12: Synthesis of (S)-2-(4-cyano-2-(1,1-difluoropropyl)phenoxy)propanoic acid [ka] Step 1: Synthesis of methyl (S)-2-(4-cyano-2-(1,1-difluoropropyl)phenoxy)propanoate A degassed solution of methyl (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoate (100 mg, 0.24 mmol, 1.0 equiv), zinc dicarbonitrile (24 mg, 0.20 mmol, 0.85 equiv) and tetrakis(triphenylphosphine)palladium (27 mg, 0.02 mmol, 0.10 equiv) in NMP (0.8 mL) was heated at 150° C. for 15 min under microwave irradiation. The reaction was filtered, diluted with EtOAc (20 mL) and washed sequentially with saturated aqueous sodium bicarbonate (2×20 mL), water (20 mL) and brine (20 mL). The organic phase was concentrated under reduced pressure and purified by flash chromatography (Si, 0-40% EtOAc in hexanes) to give the title compound (35 mg, 0.10 mmol, 42%) as a colorless oil. UPLC-MS: Acidic bisection method MS(ES-): m / z 282.1(MH) -;Retention time: 1.16 minutes;Purity: 72%. 1 H NMR (400MHz, chloroform-d) δ7.86-7.79(m,1H),7.64(dd,J=8.7,2.0Hz,1H),6.81(d,J=8.7Hz,1H),4. 90(q,J=6.8Hz,1H),3.76(s,3H),2.54-2.27(m,2H),1.68(d,J=6.8Hz,3H),0.94(t,J=7.5Hz,3H). 19 F NMR (376 MHz, chloroform-d) δ-93.51--100.37 (m). Step 2: Synthesis of (S)-2-(4-cyano-2-(1,1-difluoropropyl)phenoxy)propanoic acid To a stirred solution of methyl (2S)-2-[4-cyano-2-(1,1-difluoropropyl)phenoxy]propanoate (35 mg, 0.10 mmol, 1.0 equiv) in MeOH (0.9 mL) was added 1 M aqueous sodium hydroxide (0.12 mL, 0.12 mmol, 1.2 equiv) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, 5-95% MeCN in water + 0.1% formic acid) to give the title compound (14 mg, 0.05 mmol, 53%) as a colorless oil. UPLC-MS: Acidic 4-division method MS(ES-): m / z 268.0(MH) - ;Retention time: 1.54 minutes;Purity: 100%. 1 H NMR(400MHz,MeOH-d4)δ7.80-7.71(m,2H),7.07(d,J=8.5Hz,1H),4.96(q,J= 6.8Hz,1H),2.63-2.28(m,2H),1.63(d,J=6.8Hz,3H),0.92(t,J=7.5Hz,3H). 19 F NMR(376MHz,MeOH-d4)δ-89.28--109.92(m).

[0140] Example 13: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-4,5-difluorophenoxy)propanoic acid [ka] Step 1: Synthesis of 4,5-difluoro-2-(1-hydroxypropyl)phenol To a cooled (0° C.) solution of 4,5-difluoro-2-hydroxybenzaldehyde (2.5 g, 15.8 mmol, 1.0 equiv.) in THF (110 mL) was added ethylmagnesium bromide (11.1 mL, 3.0 M in diethyl ether, 33.3 mmol, 2.1 equiv.) dropwise and the reaction was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was then poured into saturated aqueous ammonium chloride solution (200 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3.27 g, 16.3 mmol, quantitative yield) as an amber oil, which was used in the next step without further purification. UPLC-MS: Acidic bisection method MS(ES-): m / z 187.1(MH) - ;Holding time: 0.95 minutes;Purity: 94%. 1 H NMR(400MHz,chloroform-d)δ8.02(s,1H),6.74(dd,J=10.6,8.7Hz,1H),6.67(dd,J=11.6,6.9Hz,1H ),4.70(td,J=6.8,2.8Hz,1H),2.55(d,J=3.4Hz,1H),1.98-1.73(m,2H),0.97(t,J=7.4Hz,3H). 19 F NMR (376 MHz, chloroform-d) δ -137.56 (ddd, J = 8.7, 11.6, 22.3 Hz), -149.62 (ddd, J = 7.4, 10.9, 22.4 Hz). Step 2: Synthesis of 1-(4,5-difluoro-2-hydroxyphenyl)propan-1-one To a solution of 4,5-difluoro-2-(1-hydroxypropyl)phenol (3.27 g, 16.3 mmol, 1.0 equiv) in 1,4-dioxane (22 mL) was added manganese(IV) oxide (6.67 g, 76.7 mmol, 4.4 equiv) and the reaction was stirred at reflux for 4.5 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and the filter cake was washed with 4:1 EtOAc:MeOH (2x100 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (Si, 0-20% EtOAc in hexanes) to give the title compound (1.37 g, 7.4 mmol, 35%) as a yellow solid, which was used in the subsequent reaction without further purification. UPLC-MS: Acidic bisection method MS(ES-): m / z 185.1(MH) - ;Holding time: 1.15 minutes;Purity: 83%. 1 H NMR (400 MHz, chloroform-d) δ 12.41 (s, 1H), 7.55 (dd, J = 8.8, 10.6 Hz, 1H), 6.77 (dd, J = 6.7, 11.5 Hz, 1H), 2.95 (q, J = 7.3 Hz, 2H), 1.24 (td, J = 0.8, 7.2 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-123.00--124.00 (m), -147.67 (ddd, J = 22.4, 10.6, 6.8 Hz). Step 3+4: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-4,5-difluorophenoxy)propanoate To a solution of triethylamine trihydrofluoride (0.88 mL, 5.4 mmol, 2.0 equiv) in DCM (7.7 mL) was added Crystal Fluor-E (2.46 g, 10.7 mmol, 4.0 equiv) and 1-(4,5-difluoro-2-hydroxyphenyl)propan-1-one (500 mg, 2.7 mmol, 1.0 equiv) successively and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice and the resulting mixture was extracted with DCM (2x20 mL). The combined organic phases were washed with water (3x25 mL), dried over magnesium sulfate and concentrated to 1 / 4 volume under reduced pressure. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent) and the appropriate fractions were collected and concentrated to approximately 10 mL under reduced pressure. The solution was cooled to 0° C. and then treated sequentially with methyl (2R)-2-hydroxypropanoate (280 mg, 2.7 mol, 1.0 equiv), triphenylphosphine (775 mg, 3.0 mol, 1.1 equiv), and DIAD (0.58 mL, 3.0 mol, 1.1 equiv) and stirred at room temperature for 72 h. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-20% EtOAc in hexanes) to give the title compound (654 mg, 1.8 mmol, 68%) as a yellow oil. UPLC-MS: Acidic bisection method MS(ES-): m / z 293.0(MH) - ;Retention time: 1.26 minutes;Purity: 82%. 1 H NMR (400 MHz, chloroform-d) δ 7.42-7.31 (m, 1H), 6.64 (dd, J = 6.3, 11.6 Hz, 1H), 4.70 (q, J = 6.8 Hz, 1H), 3.77 (s, 3H), 2.51-2.24 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-92.61 (dddd, J = 245.8, 15.5, 12.3, 3.2 Hz), -98.04 (dt, J = 245.9, 20.6 Hz), -131.77--133.21 (m), -146.19 (ddd, J = 22.1, 10.9, 6.4 Hz). Step 5: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-4,5-difluorophenoxy)propanoic acid A solution of methyl (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoate (100 mg, 0.34 mmol, 1.0 equiv) in MeOH (2 mL) was treated with 1 M aqueous sodium hydroxide (0.36 mL, 0.36 mmol, 1.05 equiv) and the reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC chromatography (5-95% MeCN in water + 0.1% ammonium hydroxide) to afford the title compound (69 mg, 0.25 mmol, 73%) as a colorless gum. UPLC-MS: Acidic 4-division method MS(ES-): m / z 279.1(MH) - ;Retention time: 1.79 minutes;Purity: 100%. 1 H NMR(400MHz,DMSO-d6)δ7.42(dd,J=11.2,9.1Hz,1H),7.07(dd,J=12.9,6.7Hz,1H),4 .78(q,J=6.7Hz,1H),2.49-2.25(m,2H),1.43(d,J=6.7Hz,3H),0.85(t,J=7.4Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-90.73(dddd,J=242.5,16.1,12.5,3.1Hz),-95.87(dt,J=242.3,19.9Hz),-133.94(dt,J=22.9,10.4Hz),-148.62--149.79(m).

[0141] Example 14: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-4-vinylphenoxy)propanoic acid [ka] Step 1: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)propanoate To a solution of triethylamine trihydrofluoride (2.1 mL, 13.1 mmol, 2.0 equiv.) in DCM (19 mL), Crystal Fluor-E (6.0 g, 26.2 mmol, 4.0 equiv.) and 1-(5-bromo-2-hydroxyphenyl)propan-1-one (1.5 g, 6.5 mmol, 1.0 equiv.) were added successively and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice and the resulting mixture was extracted with DCM (2x20 mL). The combined organic phases were washed with water (3x25 mL), dried over magnesium sulfate and concentrated to 1 / 4 volume under reduced pressure. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent) and the appropriate fractions were collected and concentrated to approximately 20 mL under reduced pressure. The solution was cooled to 0° C. and then treated sequentially with methyl (2R)-2-hydroxypropanoate (0.69 mL, 7.2 mol, 1.1 equiv), triphenylphosphine (1.89 g, 7.2 mol, 1.1 equiv), and DIAD (1.4 mL, 7.2 mol, 1.1 equiv) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and purified twice by flash column chromatography (Si, 0-10% EtOAc in hexanes followed by 5-60% EtOAc in hexanes) to give the title compound (1.52 g, 4.5 mmol, 69%) as a yellow oil. UPLC-MS: Acidic bisection method MS(ES-): m / z 335.0 / 337.0(MH) - ;Retention time: 1.31 minutes;Purity: 85%. 1 H NMR(400MHz,chloroform-d)δ7.65(dd,J=2.5,1.1Hz,1H),7.48-7.41(m,1H),6.68(d,J=8.8Hz,1H),4. 80(q,J=6.8Hz,1H),3.77(s,3H),2.53-2.30(m,2H),1.65(d,J=6.8Hz,3H),0.96(t,J=7.5Hz,3H). 19 F NMR (376 MHz, chloroform-d) δ-85.67--106.78 (m). Step 2: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-4-vinylphenoxy)propanoate To a degassed solution of methyl (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoate (239 mg, 0.71 mmol, 1.0 equiv) and tributyl(ethenyl)stannane (0.41 mL, 1.42 mmol, 2.0 equiv) in 1,4-dioxane (2.8 mL), tetrakis(triphenylphosphine)palladium (41.0 mg, 0.035 mmol, 0.05 equiv) was added and the reaction was heated at 100° C. for 4 h. The mixture was filtered through Celite and purified by flash column chromatography (Si, 0-10% EtOAc in hexanes) to afford the title compound (144 mg, 0.25 mmol, 36%) as a colorless oil, which was used in the next step without further purification. UPLC-MS: Acidic bisection method MS(ES-): m / z 283.2(MH) - ;Retention time: 1.29 minutes;Purity: 57%. 1 H NMR (400MHz, chloroform-d) δ7.62-7.55(m,1H),7.38(dd,J=8.6,1.8Hz,1H),6.75(d,J=8.5Hz,1H),6.68(m,1H),5.68(dd,J=17. 6,0.7Hz,1H),5.21(d,J=11.5Hz,1H),4.84(m,1H),3.77(s,3H),2.64-2.22(m,2H),1.66(d,J=6.8Hz,3H),1.03-0.91(m,3H). 19 F NMR (376 MHz, chloroform-d) δ-92.76--93.37 (m), -99.10 (dtd, J = 245.7, 19.8, 4.1 Hz). Step 3: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-4-vinylphenoxy)propanoic acid To a stirred solution of methyl (2S)-2-[2-(1,1-difluoropropyl)-4-ethenylphenoxy]propanoate (137 mg, 0.48 mmol, 1.0 equiv) in MeOH (2.6 mL) was added 1 M aqueous sodium hydroxide (0.51 mL, 0.51 mmol, 1.05 equiv) and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC chromatography (5-95% MeCN in water + 0.1% ammonium hydroxide) to afford the title compound (23 mg, 0.085 mmol, 18%) as a white solid. UPLC-MS: Acidic 4-division method MS(ES-): m / z 269.1(MH) - ;Holding time: 1.85 minutes;Purity: 99%. 1 H NMR(400MHz,DMSO-d6)δ13.23(s,1H),7.58-7.52(m,1H),7.50(s,1H),6.94(d,J=8.6Hz,1H),6.72(dd,J=17.7,11.0Hz,1H),5.72 (d,J=17.0Hz,1H),5.19(d,J=11.6Hz,1H),4.97(q,J=6.8Hz,1H),2.48-2.20(m,2H),1.51(d,J=6.7Hz,3H),0.86(t,J=7.5Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-83.76--106.49(m).

[0142] Example 15: Synthesis of sodium (S)-2-(2-(1,1-difluoropropyl)-4-methylphenoxy)propanoate [ka] Step 1: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-4-methylphenoxy)propanoate To a solution of triethylamine trihydrofluoride (0.99 mL, 6.09 mmol, 2.0 equiv) in DCM (8.7 mL) was added Crystal Fluor-E (2.79 g, 12.2 mmol, 4.0 equiv) and 1-(2-hydroxy-5-methylphenyl)propan-1-one (0.47 mL, 3.05 mmol, 1.0 equiv) successively and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice and the resulting mixture was extracted with DCM (2x20 mL). The combined organic phases were washed with water (3x25 mL), dried over magnesium sulfate and concentrated to 1 / 4 volume under reduced pressure. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent) and the appropriate fractions were collected and concentrated to approximately 12 mL under reduced pressure. The solution was cooled to 0° C. and then treated sequentially with methyl (2R)-2-hydroxypropanoate (0.32 mL, 3.3 mol, 1.1 equiv), triphenylphosphine (879 mg, 3.3 mol, 1.1 equiv), and DIAD (0.66 mL, 3.3 mol, 1.1 equiv) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-10% EtOAc in hexanes) to give the title compound (286 mg, 0.85 mmol, 35%) as a colorless oil. UPLC-MS: Acidic bisection MS (ES+): m / z not available; retention time: 1.27 min; purity: 91%. 1 H NMR (400 MHz, chloroform-d) δ 7.34 (s, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 4.79 (q, J = 6.8 Hz, 1H), 3.77 (s, 3H), 2.55-2.34 (m, 2H), 2.32 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-86.24--107.45 (m). Step 2: Synthesis of sodium (S)-2-(2-(1,1-difluoropropyl)-4-methylphenoxy)propanoate To a solution of methyl (2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoate (213 mg, 0.78 mmol, 1.0 equiv) in MeOH (4.2 mL) was added 1 M aqueous sodium hydroxide (0.82 mL, 0.82 mmol, 1.05 equiv) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure, dissolved in water (2 mL) and lyophilized to give the title compound (219 mg, 0.78 mmol, quantitative yield) as a white solid. UPLC-MS: Acidic 4-section method MS(ES+): m / z 257.0(M+H) + ;Retention time: 1.81 minutes;Purity: 100%. 1 H NMR(400MHz,DMSO-d6)δ7.14(s,1H),7.09(d,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),4.22(q, J=6.6Hz,1H),2.50-2.32(m,2H),2.23(s,3H),1.33(d,J=6.7Hz,3H),0.85(t,J=7.5Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-86.62--107.16(m).

[0143] Example 16: Synthesis of (S)-2-(2-(1,1-difluoroethyl)-4-ethynylphenoxy)propanoic acid [ka] Step 1: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)propanoate To a solution of triethylamine trihydrofluoride (0.76 mL, 4.7 mmol, 2.0 equiv) in DCM (6.7 mL) was added Crystal Fluor-E (2.13 g, 9.3 mmol, 4.0 equiv) and 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (500 mg, 2.3 mmol, 1.0 equiv) successively and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice and the resulting mixture was extracted with DCM (2x20 mL). The combined organic phases were washed with water (3x25 mL), dried over magnesium sulfate and concentrated to 1 / 4 volume under reduced pressure. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent) and the appropriate fractions were collected and concentrated to approximately 12 mL under reduced pressure. The solution was cooled to 0° C. and then treated sequentially with methyl (2R)-2-hydroxypropanoate (0.22 mL, 2.3 mol, 1.0 equiv), triphenylphosphine (671 mg, 2.6 mol, 1.1 equiv), and DIAD (0.50 mL, 2.6 mol, 1.1 equiv) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-10% EtOAc in hexanes) to give the title compound (425 mg, 1.3 mmol, 50%) as a colorless oil. UPLC-MS: Acidic bisection method MS(ES-): m / z 321.0 / 323.0(MH) - ;Retention time: 1.26 minutes;Purity: 89%. 1 H NMR (400MHz, chloroform-d) δ 7.66 (dd, J = 2.5, 1.0Hz, 1H), 7.42 (dd, J = 8.8, 2.5Hz, 1H), 6.66 (d, J = 8.8Hz, 1H), 4.80 (q, J = 6.8Hz, 1H), 3.75 (s, 3H), 2.04 (dd, J = 19.3, 18.3Hz, 3H), 1.64 (d, J = 6.8Hz, 3H). 95% purity. 19 F NMR (376 MHz, chloroform-d) δ-84.43--91.12 (m). Step 2: Synthesis of methyl (S)-2-(2-(1,1-difluoroethyl)-4-((trimethylsilyl)ethynyl)phenoxy)propanoate To a degassed solution of methyl (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoate (200 mg, 0.62 mmol, 1.0 equiv.) and ethynyltrimethylsilane (0.18 mL, 1.2 mmol, 2.0 equiv.), copper(I) iodide (12 mg, 0.06 mmol, 0.1 equiv.) and triethylamine (0.13 mL, 0.93 mmol, 1.5 equiv.) in toluene (1.8 mL), bis(triphenylphosphine)dichloropalladium (43 mg, 0.06 mmol, 0.1 equiv.) was added and the mixture was heated at 100° C. for 1 h. The reaction was filtered through Celite and the filtrate was concentrated under reduced pressure to give the title compound (325 mg, 0.62 mmol, quantitative yield) as a crude dark oil, which was used in the next step without further purification. UPLC-MS: Acidic bisection MS (ES+): m / z not available; retention time: 1.42 min; purity: 68%. 1 H NMR (400 MHz, chloroform-d) δ 7.47 (s, 1H), 7.31-7.17 (m, 1H), 6.50 (d, J = 8.6 Hz, 1H), 4.65 (q, J = 6.8 Hz, 1H), 3.55 (s, 3H), 1.84 (t, J = 18.9 Hz, 3H), 1.46 (d, J = 6.8 Hz, 3H), 0.05 (s, 9H). 19 F NMR (376 MHz, chloroform-d) δ-81.29--92.61 (m). Step 3: Synthesis of methyl (S)-2-(2-(1,1-difluoroethyl)-4-ethynylphenoxy)propanoate To a solution of methyl (S)-2-(2-(1,1-difluoroethyl)-4-((trimethylsilyl)ethynyl)phenoxy)propanoate (215 mg, 0.62 mmol, 1.0 equiv) in THF (2 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 1.9 mL, 1.9 mmol, 3.0 equiv) and the mixture was stirred at room temperature for 3 h. 1 M aqueous hydrochloric acid (1 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (Si, 0-20% EtOAc in hexanes) to give the title compound (84 mg, 0.31 mmol, 37%) as a brown oil. UPLC-MS: Acidic bisection method MS(ES+): m / z 269.2(M+H) + ;Holding time: 1.20 minutes;Purity: 75%. 1 H NMR (400 MHz, chloroform-d) δ 7.68 (s, 1H), 7.45 (d, J = 6.8 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 4.85 (q, J = 6.7 Hz, 1H), 3.75 (s, 3H), 3.01 (s, 1H), 2.04 (dd, J = 19.4, 18.2 Hz, 3H), 1.66 (d, J = 6.8 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-87.80--89.94 (m). Step 4: Synthesis of (S)-2-(2-(1,1-difluoroethyl)-4-ethynylphenoxy)propanoic acid To a solution of methyl (2S)-2-[2-(1,1-difluoroethyl)-4-ethenylphenoxy]propanoate (84 mg, 0.31 mmol, 1.0 equiv) in MeOH (1.7 mL) was added 1 M aqueous sodium hydroxide (0.33 mL, 0.33 mmol, 1.05 equiv) and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC chromatography (5-95% MeCN in water + 0.1% formic acid) to give the title compound (22 mg, 0.09 mmol, 28%) as an off-white solid. UPLC-MS: Acidic 4-division method MS(ES+): m / z 255.1(M+H) + ;Retention time: 1.54 minutes;Purity: 100%. 1 H NMR(400MHz,DMSO-d6)δ7.48(dd,J=8.3,2.2Hz,1H),7.44(d,J=2.2Hz,1H),6.91(d,J=8.5Hz,1H ),4.63(q,J=6.6,6.1Hz,1H),4.05(s,1H),2.05(dd,J=19.9,18.6Hz,3H),1.44(d,J=6.7Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-83.53(dq,J=242.5,18.8Hz),-87.25(dq,J=241.8,19.7Hz).

[0144] Example 17: Synthesis of ammonium (S)-2-(2-(1,1-difluoropropyl)-5-fluoro-4-vinylphenoxy)propanoate [ka] Step 1: Synthesis of 4-bromo-5-fluoro-2-(1-hydroxypropyl)phenol To a cooled (0° C.) solution of 5-bromo-4-fluoro-2-hydroxybenzaldehyde (5.0 g, 22.8 mmol, 1.0 equiv.) in THF (228 mL) was added dropwise ethylmagnesium bromide (22.8 mL, 3.0 M in diethyl ether, 68.5 mmol, 3.0 equiv.) and the reaction was stirred for 1 h. The reaction mixture was then poured into saturated aqueous ammonium chloride solution (200 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over sodium sulfate and then concentrated under reduced pressure to give the title compound (6.14 g, 24.7 mmol, quantitative yield) as a colorless oil, which was used in the next step without further purification. UPLC-MS: Basic dichotomy MS(ES-):m / z 247.0 / 249.0(MH) - ;Retention time: 1.03 minutes;Purity: 97%. 1 H NMR (400 MHz, chloroform-d) δ 8.31 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 9.9 Hz, 1H), 4.73 (t, J = 6.6 Hz, 1H), 2.68 (s, 1H), 1.97-1.74 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-107.57 (dd, J = 9.7, 7.8 Hz). Step 2: Synthesis of 1-(5-bromo-4-fluoro-2-hydroxyphenyl)propan-1-one To a solution of 4-bromo-5-fluoro-2-(1-hydroxypropyl)phenol (6.14 g, 24.7 mmol, 1.0 equiv) in 1,4-dioxane (25 mL) was added manganese(IV) oxide (8.57 g, 98.6 mmol, 4.0 equiv) and the reaction was stirred at reflux for 2.5 h. The reaction mixture was cooled and filtered through a Celite pad, which was washed with EtOAc (100 mL) followed by MeOH (30 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (Si, 0-20% EtOAc in hexanes) to give the title compound (3.20 g, 13.0 mmol, 53%) as a yellow solid. UPLC-MS: Basic dichotomy MS(ES-):m / z 245.0 / 247.0(MH) - ;Retention time: 1.24 minutes;Purity: 100%. 1 H NMR (400 MHz, chloroform-d) δ 12.55 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 10.0 Hz, 1H), 2.99 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-91.85--98.32 (m). Step 3: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)propanoate To a solution of triethylamine trihydrofluoride (0.66 mL, 4.04 mmol, 2.0 equiv) in DCM (6 mL) was added Crystal Fluor-E (1.85 g, 8.10 mmol, 4.0 equiv) and 1-(5-bromo-4-fluoro-2-hydroxyphenyl)propan-1-one (500 mg, 2.02 mmol, 1.0 equiv) successively and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice and the resulting mixture was extracted with DCM (2x20 mL). The combined organic phases were washed with water (3x25 mL), dried over magnesium sulfate and concentrated to 1 / 4 volume under reduced pressure. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent) and the appropriate fractions were collected and concentrated to approximately 12 mL under reduced pressure. The solution was cooled to 0° C. and then sequentially treated with methyl (2R)-2-hydroxypropanoate (0.21 mL, 2.22 mmol, 1.1 equiv), triphenylphosphine (584 mg, 2.22 mol, 1.1 equiv), and DIAD (0.44 mL, 2.22 mol, 1.1 equiv) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 5-20% EtOAc in hexanes) to give the title compound (390 mg, 1.45 mmol, 54%) as a colorless oil. UPLC-MS: Acidic bisection method MS(ES-): m / z 353.0 / 355.0(MH) - ;Retention time: 1.32 minutes;Purity: 90%. 1 H NMR (400MHz, chloroform-d) δ7.68(d,J=7.8Hz,1H),6.58(d,J=9.9Hz,1H),4.75(q,J=6.8 Hz,1H),3.77(s,3H),2.48-2.27(m,2H),1.65(d,J=6.8Hz,3H),0.94(t,J=7.5Hz,3H). 19 F NMR (376 MHz, chloroform-d) δ-89.65--99.10 (m), -101.34--103.92 (m). Step 4: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-5-fluoro-4-vinylphenoxy)propanoate To a degassed solution of methyl (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoate (200 mg, 0.56 mmol, 1.0 equiv.) and tributylvinyltin (0.33 mL, 1.13 mmol, 1.1 equiv.) in 1,4-dioxane (2.3 mL), Pd(PPh3)4 (33 mg, 0.03 mmol, 0.05 equiv.) was added and the mixture was heated at 100° C. for 4 h in a sealed tube. The reaction mixture was cooled to room temperature, diluted with EtOAc (25 mL), and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-10% EtOAc in hexanes) to give the title compound (69 mg, 0.23 mmol, 41%) as a colorless oil. UPLC-MS: Basic dichotomy MS(ES-): m / z 301.1(MH) - ;Retention time: 1.32 minutes;Purity: 100%. 1 H NMR(DMSO-d6)δ7.63(d,J=8.6Hz,1H),6.99(d,J=12.7Hz,1H),6.75(dd,J=17.8,11.3Hz,1H),5.82(d,J=17.8Hz,1H),5.36(d,J=1 1.4Hz,1H),5.25(q,J=6.7Hz,1H),3.69(s,3H),2.36(tdd,J=17.0,14.1,7.4Hz,2H),1.52(d,J=6.7Hz,3H),0.87(q,J=7.2Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-90.86(dd,J=242.8,3.0Hz),-95.77(dd,J=242.8,2.2Hz),-113.48(t,J=2.6Hz). Step 5: Synthesis of ammonium (S)-2-(2-(1,1-difluoropropyl)-5-fluoro-4-vinylphenoxy)propanoate A solution of methyl (2S)-2-[2-(1,1-difluoropropyl)-4-ethenyl-5-fluorophenoxy]propanoate (47 mg, 0.16 mmol, 1.0 equiv) in MeOH (1.1 mL) was treated with 1 M aqueous sodium hydroxide (0.16 mL, 0.16 mmol, 1.0 equiv) and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC chromatography (5-95% MeCN in water + 0.1% ammonium hydroxide) to afford the title compound (18 mg, 0.06 mmol, 38%) as an off-white powder. UPLC-MS: Acidic 4-division method MS(ES-): m / z 287.1(MH) - ;Retention time: 1.91 minutes;Purity: 100%. 1 H NMR(DMSO-d6)δ7.53(d,J=8.8Hz,1H),6.79-6.60(m,2H),5.74(d,J=17.7Hz,1H),5.27(d,J=11.4Hz,1H), 4.34(q,J=6.8Hz,1H),2.40(ddq,J=7.7,15.4,22.7Hz,2H),1.38(d,J=6.6Hz,3H),0.86(t,J=6.9Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-90.64(dd,J=240.6,3.2Hz),-96.20(d,J=240.7Hz),-114.94(d,J=3.1Hz).

[0145] Example 18: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)butanoic acid [ka] Step 1+2: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)butanoate To a solution of triethylamine trihydrofluoride (0.66 mL, 4.05 mmol, 2.0 equiv) in DCM (6 mL) was added Crystal Fluor-E (1.85 g, 8.10 mmol, 4.0 equiv) and 1-(5-bromo-4-fluoro-2-hydroxyphenyl)propan-1-one (500 mg, 2.02 mmol, 1.0 equiv) successively and the reaction was stirred at room temperature for 2 days. The reaction mixture was poured onto ice and the resulting mixture was extracted with DCM (2x20 mL). The combined organic phases were washed with water (3x25 mL), dried over sodium sulfate and concentrated to 1 / 4 volume under reduced pressure. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent) and the appropriate fractions were collected and concentrated to approximately 10 mL under reduced pressure. The solution was cooled to 0° C. and then sequentially treated with methyl (2R)-2-hydroxypropanoate (239 mg, 2.02 mmol, 1.0 equiv), triphenylphosphine (583 mg, 2.22 mol, 1.1 equiv), and DIAD (0.44 mL, 2.22 mol, 1.1 equiv) and stirred at room temperature for 72 h. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-20% EtOAc in hexanes) to give the title compound (424 mg, 0.75 mmol, 37%) as a yellow oil. UPLC-MS: Acidic bisection MS (ES+): m / z not available; retention time: 1.37 min; purity: 76%. 1 H NMR (400 MHz, chloroform-d) δ 7.68 (dd, J = 7.8, 1.3 Hz, 1H), 6.53 (d, J = 10.0 Hz, 1H), 4.61 (t, J = 5.9 Hz, 1H), 3.76 (s, 3H), 2.48-2.21 (m, 2H), 2.12-1.95 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-92.46 (dtd, J = 245.7, 13.9, 3.2 Hz), -98.85 (dt, J = 245.8, 20.3 Hz), -102.12 (ddd, J = 10.2, 7.6, 2.9 Hz). Step 3: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)butanoic acid A solution of methyl (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoate (150 mg, 0.26 mmol, 1.0 equiv) in MeOH (1.4 mL) was treated with 1 M aqueous sodium hydroxide (0.28 mL, 0.28 mmol, 1.05 equiv) and the reaction was stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure to give the title compound (139 mg, 0.39 mmol, 99%) as a pale yellow gum. UPLC-MS: Basic quaternary method MS(ES-):m / z 353.0 / 355.0(MH) - ;Retention time: 1.41 minutes;Purity: 97%. 1 H NMR(400MHz,DMSO-d6)δ7.61(d,J=7.9Hz,1H),7.07(d,J=11.0Hz,1H),4.87(dd,J=6.4,4.6 Hz,1H),2.43-2.30(m,2H),2.01-1.78(m,2H),0.95(t,J=7.4Hz,3H),0.86(t,J=7.5Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-91.09(dt,J=242.4,14.3Hz),-97.00(dt,J=242.4,20.6Hz),-103.42(t,J=9.5Hz).

[0146] Example 19: Synthesis of (S)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)butanoic acid [ka] Step 1: Synthesis of 5-fluoro-2-(1-hydroxypropyl)phenol To a cooled (-40°C) solution of 4-difluoro-2-hydroxybenzaldehyde (5.0g, 35.7mmol, 1.0eq) in THF (250mL) was added dropwise ethylmagnesium bromide (25mL, 3.0M in diethyl ether, 75.0mmol, 3.1eq) and the reaction was allowed to warm slowly to room temperature and stirred for 3h. The reaction mixture was poured into saturated aqueous ammonium chloride (200mL) and extracted with EtOAc (3x100mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (6.70g, 39.4mmol, quantitative yield) as a light amber oil which was used in the next step without further purification. UPLC-MS: Acidic bisection method MS(ES-): m / z 169.1(MH) - ;Retention time: 0.91 minutes;Purity: 87%. 1 H NMR (400 MHz, chloroform-d) δ 8.28 (bs, 1H), 6.86 (dd, J = 8.4, 6.4 Hz, 1H), 6.67-6.44 (m, 2H), 4.74 (t, J = 6.8 Hz, 1H), 2.69 (bs, 1H), 1.98-1.70 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) -113.64 (ddd, J = 10.4, 8.3, 6.3 Hz). Step 2: Synthesis of 1-(4-fluoro-2-hydroxyphenyl)propan-1-one To a solution of 5-fluoro-2-(1-hydroxypropyl)phenol (6.07 g, 35.7 mmol, 1.0 equiv) in 1,4-dioxane (50 mL) was added manganese(IV) oxide (13.7 g, 157 mmol, 4.4 equiv) and the reaction was stirred at reflux for 2.5 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and the filter cake was washed with 4:1 EtOAc:MeOH (2x250 mL). The filtrate was concentrated under reduced pressure and the crude material was purified by flash column chromatography (Si, 5-20% EtOAc in hexanes) to give the title compound (4.15 g, 24.7 mmol, 63%) as a yellow oil that crystallized on standing. UPLC-MS: Acidic bisection method MS(ES+): m / z 169.1(M+H) + ;Retention time: 1.13 minutes;Purity: 95%. 1 H NMR (400 MHz, chloroform-d) δ 12.68 (s, 1H), 7.77 (dd, J = 6.4, 8.9 Hz, 1H), 6.77-6.48 (m, 2H), 3.00 (q, J = 7.3 Hz, 2H), 1.24 (t, J = 7.3 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-99.76--99.87 (m). Step 3: Synthesis of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)propan-1-one To a solution of 1-(4-fluoro-2-hydroxyphenyl)propan-1-one (400 mg, 2.38 mmol, 1.0 equiv) in DCM (7.0 mL) was added benzyltrimethylazanium tetrachloro-λ 3 -Iodane (997 mg, 2.38 mmol, 1.0 equiv) was added and the mixture was stirred at room temperature in the dark for 4 days. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-15% EtOAc in hexanes) to give the title compound (454 mg, 2.24 mmol, 94%) as a yellow oil. UPLC-MS: Acidic bisection method MS(ES-): m / z 201.1 / 203.1(MH) - ;Retention time: 1.22 minutes;Purity: 75%. 1 H NMR (400 MHz, chloroform-d) δ 12.53 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 10.2 Hz, 1H), 2.99 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-102.04 (dd, J = 10.2, 8.3 Hz). Step 4+5: Synthesis of methyl (S)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)butanoate To a solution of triethylamine trihydrofluoride (0.72 mL, 4.44 mmol, 2.0 equiv) in DCM (6.4 mL) was added Crystal Fluor-E (2.03 g, 8.88 mmol, 4.0 equiv) and 1-(5-chloro-4-fluoro-2-hydroxyphenyl)propan-1-one (450 mg, 2.22 mmol, 1.0 equiv) successively and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice and the resulting mixture was extracted with DCM (2x20 mL). The combined organic phases were washed with water (3x25 mL), dried over magnesium sulfate and concentrated to 1 / 4 volume under reduced pressure. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent) and the appropriate fractions were collected and concentrated to approximately 10 mL under reduced pressure. The solution was cooled to 0° C. and then sequentially treated with methyl (2R)-2-hydroxypropanoate (262 mg, 2.22 mmol, 1.0 equiv), triphenylphosphine (641 mg, 2.44 mol, 1.1 equiv), and DIAD (0.48 mL, 2.44 mol, 1.1 equiv) and stirred at room temperature for 72 h. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-20% EtOAc in hexanes) to afford the title compound (208 mg, 0.49 mmol, 22%) as a yellow oil, which was used in the next step without further purification. UPLC-MS: Acidic bisection method MS(ES+): m / z 348.3 / 350.3(M+Na) + ;Retention time: 1.36 minutes;Purity: 76%. 1 H NMR (400 MHz, chloroform-d) δ 7.55 (dd, J = 8.4, 1.3 Hz, 1H), 6.55 (d, J = 10.5 Hz, 1H), 4.61 (t, J = 5.9 Hz, 1H), 3.76 (s, 3H), 2.49-2.22 (m, 2H), 2.12-1.94 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-91.91--93.10 (m), -98.84 (dt, J = 246.0, 20.6 Hz), -110.05 (td, J = 9.5, 8.2, 2.6 Hz). Step 6: Synthesis of (S)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)butanoic acid A solution of methyl (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoate (200 mg, 0.40 mmol, 1.0 equiv) in MeOH (2.1 mL) was treated with 1 M aqueous sodium hydroxide (0.42 mL, 0.42 mmol, 1.05 equiv) and the reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by preparative HPLC chromatography (5-95% MeCN in water + 0.1% formic acid) to afford the title compound (29 mg, 0.09 mmol, 23%) as an off-white solid. UPLC-MS: Acidic 4-division method MS(ES-): m / z 309.0 / 311.0(MH) - ;Holding time: 2.00 minutes;Purity: 100%. 1 H NMR(400MHz,DMSO-d6)δ13.58(bs,1H),7.53(d,J=8.4Hz,1H),7.14(d,J=11.5Hz,1H),4.97 (m,1H),2.49-2.23(m,2H),2.04-1.80(m,2H),0.96(t,J=7.4Hz,3H),0.86(t,J=7.4Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-90.89(t,J=14.2Hz),-91.46--91.62(m),-96.55(t,J=20.3Hz),-97.20(t,J=20.4Hz),-111.16(t,J=10.1Hz).

[0147] Example 20: Synthesis of sodium (S)-2-(2-(1,1-difluoropropyl)-4-nitrophenoxy)propanoate [ka] Step 1+2: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-4-nitrophenoxy)propanoate To a solution of triethylamine trihydrofluoride (0.84 mL, 5.12 mmol, 2.0 equiv) in DCM (7.3 mL) was added Crystal Fluor-E (2.35 g, 10.2 mmol, 4.0 equiv) and 1-(2-hydroxy-5-nitrophenyl)propan-1-one (500 mg, 2.56 mmol, 1.0 equiv) successively and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice and the resulting mixture was extracted with DCM (2x20 mL). The combined organic phases were washed with water (3x25 mL), dried over magnesium sulfate and concentrated to 1 / 4 volume under reduced pressure. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent) and the appropriate fractions were collected and concentrated to approximately 10 mL under reduced pressure. The solution was cooled to 0° C. and then treated sequentially with methyl (2R)-2-hydroxypropanoate (0.25 mL, 2.56 mmol, 1.0 equiv), triphenylphosphine (739 mg, 2.82 mmol, 1.1 equiv), and DIAD (0.55 mL, 2.82 mol, 1.1 equiv) and stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-20% EtOAc in hexanes) to give the title compound (616 mg, 2.03 mmol, 79%) as a pale yellow oil. UPLC-MS: Acidic bisection MS (ES+): m / z not available; retention time: 1.21 min; purity: 100%. 1 H NMR (400 MHz, chloroform-d) δ 8.45 (m, 1H), 8.26 (m, 1H), 6.84 (m, 1H), 4.96 (m, 1H), 3.87-3.64 (m, 3H), 2.41 (m, 2H), 1.83-1.62 (m, 3H), 0.97 (m, 3H). 19 F NMR (376 MHz, chloroform-d) δ-94.30 (d, J = 247.5 Hz), -99.15 (d, J = 247.7 Hz). Step 3: Synthesis of sodium (S)-2-(2-(1,1-difluoropropyl)-4-nitrophenoxy)propanoate A solution of methyl (2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]butanoate (32 mg, 0.11 mmol, 1.0 equiv) in MeOH (0.6 mL) was treated with 1 M aqueous sodium hydroxide (0.16 mL, 0.16 mmol, 1.5 equiv) and the reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to give the title compound (30 mg, 0.10 mmol, 91%) as a yellow solid. UPLC-MS: Acidic 4-division method MS(ES-): m / z 288.1(MH) - ;Retention time: 1.62 minutes;Purity: 100%. 1 H NMR(400MHz,DMSO-d6)δ8.26(dd,J=2.9,9.2Hz,1H),8.16(d,J=2.9Hz,1H),7.03(d,J=9.3 Hz,1H),4.55(q,J=6.7Hz,1H),2.44(m,2H),1.44(d,J=6.7Hz,3H),0.88(t,J=7.4Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-92.29(dt,J=242.3,14.4Hz),-97.91(dt,J=242.4,20.5Hz).

[0148] Example 21: Synthesis of sodium (S)-2-(5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy)propanoate [ka] Step 1: Synthesis of 5-chloro-4-fluoro-2-(1-hydroxypropyl)phenol To a cooled (-40°C) solution of 4-chloro-5-fluoro-2-hydroxybenzaldehyde (2.5g, 14.3mmol, 1.0eq) in THF (100mL) was added ethylmagnesium bromide (10mL, 3.0M in diethyl ether, 30.0mmol, 3.0eq) dropwise and the reaction was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was then poured into saturated aqueous ammonium chloride (200mL) and extracted with EtOAc (3x100mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3.20g, 12.8mmol, 90%) as an amber oil which was used in the next step without further purification. UPLC-MS: Acidic bisection method MS(ES-): m / z 203.1 / 205.1(MH) - ;Retention time: 1.01 minutes;Purity: 92%. 1 H NMR (400 MHz, chloroform-d) δ 7.92 (s, 1H), 7.02-6.81 (m, 1H), 6.74 (m, 1H), 4.79-4.61 (m, 1H), 1.97-1.71 (m, 2H), 0.98 (m, 3H). 19 F NMR (376 MHz, chloroform-d) δ-127.80--127.99 (m). Step 2: Synthesis of 1-(4-chloro-5-fluoro-2-hydroxyphenyl)propan-1-one To a solution of 5-chloro-4-fluoro-2-(1-hydroxypropyl)phenol (2.93 g, 14.3 mmol, 1.0 equiv) in 1,4-dioxane (18 mL) was added manganese(IV) oxide (5.50 g, 63.2 mmol, 4.4 equiv) and the reaction was stirred at reflux for 6 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and the filter cake was washed with 4:1 EtOAc:MeOH (2x250 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (Si, 0-20% EtOAc in hexanes) to give the title compound (1.02 g, 5.0 mmol, 35%) as a yellow solid. UPLC-MS: Acidic bisection method MS(ES-): m / z 201.1 / 203.1(MH) -;Retention time: 1.21 minutes;Purity: 92%. 1 H NMR (400 MHz, chloroform-d) δ 12.15 (s, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.05 (d, J = 6.3 Hz, 1H), 2.97 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ -126.77 (dd, J = 6.1, 8.9 Hz), -126.83 (dd, J = 3.4, 6.4 Hz). Step 3+4: Synthesis of methyl (S)-2-(5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy)propanoate To a solution of triethylamine trihydrofluoride (0.81 mL, 4.94 mmol, 2.0 equiv) in DCM (7.1 mL) was added Crystal Fluor-E (2.26 g, 9.87 mmol, 4.0 equiv) and 1-(4-chloro-5-fluoro-2-hydroxyphenyl)propan-1-one (500 mg, 2.47 mmol, 1.0 equiv) successively and the reaction was stirred at room temperature overnight. The reaction mixture was poured onto ice and the resulting mixture was extracted with DCM (2x20 mL). The combined organic phases were washed with water (3x25 mL), dried over magnesium sulfate and concentrated to 1 / 4 volume under reduced pressure. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent) and the appropriate fractions were collected and concentrated to approximately 20 mL under reduced pressure. The solution was cooled to 0° C. and then sequentially treated with methyl (2R)-2-hydroxypropanoate (257 mg, 2.47 mmol, 1.0 equiv), triphenylphosphine (712 mg, 2.71 mmol, 1.1 equiv), and DIAD (0.53 mL, 2.71 mol, 1.1 equiv) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-20% EtOAc in hexanes) to give the title compound (697 mg, 1.91 mmol, 77%) as a yellow solid. UPLC-MS: Acidic bisection method MS(ES-): m / z 309.0 / 311.0(MH) - ;Holding time: 1.30 minutes;Purity: 85%. 1H NMR(400MHz,chloroform-d)δ7.32(dd,J=9.3,1.1Hz,1H),6.82(d,J=5.8Hz,1H),4.73(q,J=6 .8Hz,1H),3.78(s,3H),2.50-2.26(m,2H),1.63(d,J=6.8Hz,3H),0.93(t,J=7.5Hz,3H). 19 F NMR(376MHz,chloroform-d)δ-93.38(ddd,J=246.3,15.4,13.0Hz),-98.67(dt,J=246.2,19.9Hz),-123.90(dd,J=9.3,5.7Hz). Step 5: Synthesis of sodium (S)-2-(5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy)propanoate A solution of methyl (2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoate (100 mg, 0.21 mmol, 1.0 equiv) in MeOH (1.1 mL) was treated with 1 M aqueous sodium hydroxide (0.22 mL, 0.22 mmol, 1.05 equiv) and the reaction was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure to give the title compound (100 mg, 0.31 mmol, 98%) as an off-white solid. UPLC-MS: Acidic 4-division method MS(ES-): m / z 295.0 / 297.0(MH) - ;Retention time: 1.86 minutes;Purity: 100%. 1 H NMR(400MHz,DMSO-d6)δ7.33(d,J=9.9Hz,1H),6.99(d,J=6.2Hz,1H),4.33(q, J=6.6Hz,1H),2.48-2.33(m,2H),1.37(d,J=6.6Hz,3H),0.86(t,J=7.5Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-91.66(dt,J=241.4,14.5Hz),-96.69(dt,J=241.6,20.3Hz),-128.48(dd,J=9.7,6.2Hz).

[0149] Example 22: Electrophysiological measurements of ClC-1 inhibition of compounds in rat muscle The research objective of these experiments was to evaluate whether compounds inhibited the ClC-1 channel in native tissue of rat skeletal muscle fibers. Apparent ClC-1 affinity is the concentration of compound at which 50% of complete inhibition of ClC-1 is observed (EC 50 ) reported. ClC-1Cl - Ion channels regulate the total membrane conductance (G) in resting skeletal muscle fibers of most animals, including rats and humans. m ) produces approximately 80% of the total amount of glycerol (Bretag, A H. Muscle chloride channels. Physiological Reviews, 1987, 67, 618-724). m Other ion channels contributing to G are therefore considered negligible, and the G m By comparing the measurements, it is possible to assess whether the compound inhibits ClC-1 in rat muscle. ClC-1 inhibition is observed in such recordings, as m This is reflected by a reduction in Experimentally, G mwas measured in individual fibers of whole rat soleus muscles using the three microelectrode technique described in this example. Full details are given elsewhere (Riisager et al., Determination of cable parameters in skeletal muscle fibres during repetitive firing of action potentials. Journal of Physiology, 2014, 592, 4417-4429). Briefly, intact rat soleus muscles were isolated separately from 12-14 week old Wistar rats and placed in an experimental chamber perfused with standard Krebs-Ringer solution containing 122 mM NaCl, 25 mM NaHCO3, 2.8 mM KCl, 1.2 mM KH2PO4, 1.2 mM MgSO4, 1.3 mM CaCl2, 5.0 mM D-glucose. During the experiment, the solution was kept at approximately 30°C and constantly equilibrated with a mixture of 95% O2 and 5% CO2, pH approximately 7.4. The experimental chamber was placed inside a Nikon upright microscope used to visualize individual muscle fibers and three electrodes (glass pipettes filled with 2 M potassium citrate). m For the measurements, electrodes were inserted into the same fiber with known interelectrode distances of 0.35–0.5 mm (V1–V2, X1) and 1.1–1.5 mm (V1–V3, X3) (Figure 1A). The membrane potential of the impaled muscle fiber was recorded by all electrodes. Two electrodes were additionally used to inject 50 ms current pulses of -30 nA. Taking into account the electrode positions, three different interelectrode distances could be identified (X1–X2, X1–X3, X2–X3), and thus the membrane potential response to current injection was obtained at three distances from the current injection point. The steady-state voltage deflection at each distance was divided by the magnitude of the injected current (-30 nA) and the resulting transduction resistance was plotted against the interelectrode distance and the data were fitted to a single exponential function from which G m could be calculated using linear cable theory (Fig. 1B). To establish the dose-response relationship, G mwas first determined in 10 muscle fibers in the absence of compound, and then at four increasing compound concentrations in 5–10 fibers at each concentration. m The average G at each concentration was determined. m The values ​​were plotted against compound concentration and the data was fitted to a sigmoidal function to obtain the EC 50 The EC values ​​were obtained (Figure 1C). Table 2 shows the EC 50 Values ​​are shown, with n-values ​​referring to the number of experiments in each case corresponding to recordings from approximately 50 fibres. [Table 6]

[0150] Example 23: Measurement of muscle strength in an in vitro model The present disclosure relates to compounds that inhibit ClC-1 ion channels, increase muscle excitability, and thereby improve muscle function in clinical conditions of muscle activation failure. Such conditions lead to reduced contractile function, weakness and fatigue of skeletal muscle.In this series of experiments, the compounds are tested for their ability to restore contractile function of isolated rat muscle when neuromuscular transmission is impaired, similar to neuromuscular disorders. Experimentally, soleus muscles from 4-5 week old rats were isolated with the motor nerves attached. The neuromuscular preparations were mounted in an experimental setup that allows electrical stimulation of the motor nerves. Stimulation of the motor nerves led to activation of muscle fibers, ensuring the recorded force generation. The neuromuscular preparations were also incubated in standard Krebs Ringer in these experiments (see Example 5), the solution being heated to 30°C and constantly equilibrated with a mixture of 95% O2 and 5% CO2, pH approx. 7.4. After mounting the neuromuscular preparation in the experimental apparatus, the contractile function of the muscle was first assessed under control conditions (Figure 2A). A submaximal concentration of the acetylcholine receptor blocker tubocurarine (115 nM) was then added to the experimental bath to impose a partial inhibition of the motor neuronal capacity to activate the muscle fibers. The experimental conditions mimic neuromuscular transmission failure in various neuromuscular disorders. After addition of tubocurarine, the contractile force declined to 10-50% of the control muscle force over the next 90 min. Then, 50 μM of the test compound was added and the contractile force was restored regardless of the continued presence of tubocurarine. To quantify the ability of the compounds to restore muscle force, the percentage of the initial muscle force recovered was measured 40 min after compound exposure (Figure 2B) and the point gains are reported in Table 3. [Table 7]

[0151] In conclusion, this example demonstrates that compounds of the present disclosure can increase muscle excitability, thereby improving muscle function in clinical conditions.

[0152] Example 24: Measurement of in situ muscle contractile properties Isometric hindlimb muscle strength was measured in 12 week old female Lewis rats in the presence and absence of compound. Rats were anesthetized with isoflurane (2-4%), intubated, and then connected to a microventilator (Microvent 1, Hallowell EMC, US). Two stimulating electrodes were inserted through the skin to stimulate the sciatic nerve. A small incision was made proximal to the ankle to expose the Achilles tendon, which was tied with a cotton thread and connected to a position-adjustable (vernier-controlled) force transducer (Fort250, World Precision Instruments). The Achilles tendon was then cut distal to the attached cotton thread. Rats were placed on a heating pad, and the feet were fixed with tape onto a foot plate to prevent movement artifacts from contraction of the ankle dorsiflexors. Muscle contractile properties were assessed by applying electrical current to the nerve (under supramaximal voltage conditions) and recording the force generated by the muscle. The muscle was stretched until maximal force was obtained, as assessed by 2 Hz stimulation. Isometric muscle force was measured at 12 Hz (twitch) for 10 pulses every 30 seconds and at 80 Hz (tetanus) for 1 second (80 pulses) every 5 minutes. This stimulation pattern was employed throughout the experiment, except in a few cases where 80 Hz stimulation was replaced by 12 Hz (10 pulses). Neuromuscular transmission was partially inhibited by a constant infusion of cisatracurium (Nimbex, GlaxoSmithKline) at a concentration of 0.1 mg / kg, with an adjustable infusion rate that was individually adjusted so that each animal obtained an inhibition level of approximately 50% of the muscle force generated by 12 Hz stimulation at the fourth pulse. When the level of neuromuscular inhibition was stable, the test article was injected intravenously at the selected concentration. The effect of the test article was evaluated by its ability to increase the muscle force generated from the applied stimulation pattern. The effect was evaluated based on its ability to increase muscle force by itself (tetanic, 80 Hz, stimulation) and the ratio between individual twitch peaks (12 Hz stimulation). The effect was monitored for at least 1 hour after the injection of the test article. In addition, the time of maximum effect on muscle force (both twitch and tetanic) from the injection of the test article was recorded, and, if possible, the time to disappearance of the effect (time to return to baseline) was recorded. When appropriate, the injection of the neuromuscular blocker was stopped while the stimulation pattern was continued, and the return of force to control levels was monitored. The animals were sacrificed by cervical dislocation while still fully sedated. Compound A-3 was administered intravenously at 17.5 mg / kg and produced a 64% increase in tetanic force. Compound A-4 was administered intravenously at 21.6 mg / kg and produced a 34% increase in tetanic force. Compound A-5 was administered intravenously at 10.5 mg / kg and produced a 47% increase in tetanic force. Compound A-7 was administered intravenously at 25.1 mg / kg and produced a 64% increase in tetanic force. Compound A-32 was administered intravenously at 11.2 mg / kg and produced a 75% increase in tetanic force. Compound A-31 was administered intravenously at 11.4 mg / kg and produced a 14% increase in tetanic force. Compound A-29 was administered intravenously at 22.0 mg / kg and produced a 76% increase in tetanic force. Compound A-23 was administered intravenously at 18.8 mg / kg and produced a 40% increase in tetanic force. Compound A-22 was administered intravenously at 10.4 mg / kg and produced a 57% increase in tetanic force. Compound A-16 was administered intravenously at 22.9 mg / kg and produced a 46% increase in tetanic force. Compound A-11 was administered intravenously at 17.6 mg / kg and produced a 44% increase in tetanic force. This demonstrates that compounds of the disclosure, such as compounds A-3, A-4, A-5, A-7, A-32, A-31, A-29, A-23, A-22, A-16 and A-11, can restore muscle force in vivo that is partially inhibited by neuromuscular blockers.

Claims

1. Formula (II): 【Chemistry 1】 (In the formula, -R １ is C １－２ Alkyl, C ２ Alkenyl, C ２ Alkynyl, CN, CF ３ , NO ２ , F, Cl, Br, and I; -R ２ represents one or more, the same or different, substituents R ６ C optionally substituted with １－５ alkyl, one or more, the same or different, substituents R ６ C optionally substituted with ２－５ alkenyl, one or more, the same or different, R ６ C optionally substituted with ２－５ alkynyl, one or more, the same or different, R ６ C optionally substituted with ３－５ cycloalkyl, one or more, the same or different, substituents R ９ and one or more, the same or different, substituents R ７ 5-6 membered aromatic heterocycles optionally substituted with -R ３ is selected from the group consisting of deuterium, Cl and F; -R ４ is H, deuterium, one or more, the same or different, substituents R ７ C optionally substituted with １－５ alkyl, one or more, the same or different, substituents R ７ C optionally substituted with ２－５ alkenyl, one or more, the same or different, substituents R ７ C optionally substituted with ２－５ Alkynyl and one or more, the same or different, substituents R ７ C optionally substituted with ３－５ cycloalkyl; -R ５ is H, one or more, the same or different, substituents R ８ C optionally substituted with １－５ alkyl, one or more, the same or different, substituents R ８ C optionally substituted with ２－５ alkenyl, one or more, the same or different, R ８ C optionally substituted with ２－５ alkynyl, one or more, the same or different, R ８ C optionally substituted with ３－６ cycloalkyl, one or more, the same or different, substituents R ９ and one or more, the same or different, substituents R ９ benzyl optionally substituted with; -R ６ are independently deuterium, F, —CN, —O—C １－５ Alkyl, —O—C ３－５ Cycloalkyl, -S-C １－５ Alkyl, and -S-C ３－５ cycloalkyl, wherein said -O-C １－５ Alkyl, —O—C ３－５ Cycloalkyl, -S-C １－５ Alkyl, and -S-C ３－５ Cycloalkyl may be substituted with one or more, the same or different, substituents R ８ may be optionally substituted with; -R ７ are independently deuterium, F, Cl, -CN, 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, 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 be substituted with one or more, the same or different, substituents R ８ may be optionally substituted with; -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; and - n is an integer 0, 1, 2, or 3. or a pharma- ceutically acceptable salt thereof.

2. Formula (III): 【Chemistry 2】 (In the formula, -R １ is C ２ Alkenyl, C ２ Alkynyl, NO ２ , F, Cl, Br, and I; -R ２ represents one or more, the same or different, substituents R ６ C optionally substituted with １－５ is alkyl; -R ３ is selected from the group consisting of H, deuterium, Cl and F; -R ４ is H, deuterium, one or more, the same or different, substituents R ７ C optionally substituted with １－５ alkyl and one or more, the same or different, substituents R ７ C optionally substituted with ２－５ alkynyl; -R ６ are independently deuterium, F, —CN, —O—C １－５ Alkyl, —O—C ３－５ Cycloalkyl, -S-C １－５ Alkyl, and -S-C ３－５ cycloalkyl, wherein said -O-C １－５ Alkyl, —O—C ３－５ Cycloalkyl, -S-C １－５ Alkyl, and -S-C ３－５ Cycloalkyl may be substituted with one or more, the same or different, substituents R ８ may be optionally substituted with; -R ７ are independently deuterium, F, Cl, -CN, 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, 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 be substituted with one or more, the same or different, substituents R ８ may be optionally substituted with; -R ８ are independently selected from the group consisting of deuterium and F.

2. The compound of claim 1, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

3. R １ The compound according to claim 1 or 2, wherein is Cl or Br.

4. R ２ represents one or more, the same or different, substituents R ６ C optionally substituted with １－３ The compound according to any one of claims 1 to 3, which is alkyl.

5. R ３ The compound according to any one of claims 1 to 4, wherein is F.

6. R ４ represents one or more, the same or different, substituents R ７ C optionally substituted with １－５ The compound according to any one of claims 1 to 5, which is alkyl.

7. R ４ is Me or CH ２ The compound according to any one of claims 1 to 6, wherein F is

8. R ４ represents one or more, the same or different, substituents R ７ C optionally substituted with ２－５ The compound of any one of claims 1 to 5, which is alkynyl.

9. R ５ The compound according to any one of claims 1 and 3 to 8, wherein

10. The compound according to any one of claims 1 to 9, selected from the group consisting of: (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid; (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propanoic acid; (2S)-2-{4-bromo-2-[difluoro(phenyl)methyl]phenoxy}propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-2-cyclopropylacetic acid; (2S)-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(cyclopropyldifluoromethyl)phenoxy]propanoic acid; (2S)-2-{4-bromo-2-[difluoro(1,3-thiazol-2-yl)methyl]phenoxy}propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid; (2S)-2-[4-bromo-2-(cyclobutyldifluoromethyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-chloropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]pent-4-ynoic acid; (2S)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2- ２ H) propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy]propanoic acid; (2S)-2-[4-cyano-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)(3,5,6- ２ H ３ ) phenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethenylphenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid; 2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; (2S)-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propanoic acid; (2R)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanoic acid; (2R)-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-ethenyl-5-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid; (2R)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propanoic acid; (2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoic acid; (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutanoic acid; (2R)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid; and (2S)-2-[4-bromo-2-(1,1-difluoro-3-methoxypropyl)phenoxy]propanoic acid.

11. The compound according to any one of claims 1 to 10 which is an inhibitor of the ClC-1 ion channel.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharma- ceutically acceptable carrier.

13. 11. A pharmaceutical composition for use in the treatment of symptoms of an indication selected from the group consisting of myasthenia gravis, Lambert-Eaton syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), reversed diabetic polyneuropathy, Guillain-Barre syndrome, polio, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, periodic paralysis, sarcopenia, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy and Duchenne muscular dystrophy, comprising a compound according to any one of claims 1 to 10.

14. A pharmaceutical composition for use in overcoming and / or ameliorating neuromuscular blockade, comprising a compound according to any one of claims 1 to 10.

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