Compounds for the treatment of neuromuscular disorders

Abstract

The present disclosure relates to compounds suitable for treating, improving and / or preventing neuromuscular disorders (including reversing drug-induced neuromuscular blockade). Compounds as defined herein can inhibit ClC-1 ion channels.

Description

Technical Field

[0001] The present disclosure relates to compounds for treating, improving and / or preventing neuromuscular disorders, including reversing drug-induced neuromuscular blockade, and their use in treating, improving and / or preventing neuromuscular disorders, including reversing drug-induced neuromuscular blockade. Compounds as defined herein can inhibit ClC-1 ion channels. The present disclosure further relates to methods for treating, preventing and / or improving neuromuscular disorders by administering the composition to a person in need thereof. Background of the Invention

[0003] Walking, breathing and eye movement are examples of basic daily physiological activities driven by the contractile activity of skeletal muscle. Skeletal muscle itself is static, and contractile activity occurs only in response to commands from the central nervous system (CNS). This neuronal command takes the form of an action potential, which is transmitted from the brain to the muscle fiber in several steps. Neuromuscular junction (NMJ) is a highly specialized membrane area on the muscle fiber where motor neurons are in close contact with muscle fibers, and at the NMJ, the neuronal action potential is transmitted to the muscle action potential in a one-to-one manner through synaptic transmission.

[0004] Neuromuscular transmission refers to the sequence of cellular events at the NMJ whereby an action potential in the lower motor neuron is transmitted to a corresponding action potential in the muscle fiber (Wood SJ, Slater CR. Safety factor at the neuromuscular junction. Prog. Neurobiol. 2001, 64, 393-429). When a neuronal action potential reaches the presynaptic terminal, it triggers Ca 2+ Voltage-gated P / Q-type Ca 2+ This influx leads to the influx of cytoplasmic Ca 2+ The increase in Na triggers the exocytosis of acetylcholine (ACh). The released ACh then diffuses across the synaptic cleft to activate the nicotinic ACh receptors in the postsynaptic muscle fiber membrane. Once activated, the ACh receptors transmit Na + This causes a local depolarization of the muscle fiber at the NMJ, called the end plate potential (EPP). If the EPP is large enough, the voltage-gated Na + The channel will be activated and an action potential will ensue in the muscle fiber. This action potential then propagates from the NMJ to the entire muscle fiber and triggers the Ca 2+ Release from the sarcoplasmic endoplasmic reticulum. Released Ca 2+ Activates contractile proteins within muscle fibers, causing the fibers to contract.

[0005] Failure of neuromuscular transmission may result from presynaptic dysfunction [Lambert Eaton syndrome (LambertEaton 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 (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), spinal muscular atrophy (spinal muscular atrophy) (Wadman RI, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the neuromuscular junction in spinalmuscular atrophy types 2 and 3. Neurology, 2012, 79, 2050-2055) and caused by postsynaptic dysfunction, such 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)].The inability to excite and / or propagate action potentials in muscles may also be due to reduced muscle excitability, such as in critical illness myopathy (CIM) (Latronico, N., Bolton, CFMritical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011, 10, 931-941). In Lambert Eaton syndrome, for presynaptic P / Q-type Ca. 2+ Autoimmune attack on the channels results in a decrease in Ca influx into the nerve terminal during the presynaptic action potential. 2+ Significantly reduce, and therefore cause the reduction of ACh being released into the synaptic cleft. In myasthenia gravis, the most common discovery is the autoimmune attack on the postsynaptic membrane for the nicotinic ACh receptor or musk receptor in the sarcolemma. Congenital forms of myasthenia are also known. Common for the illness (Lambert Eaton syndrome, amyotrophic lateral sclerosis, spinal muscular atrophy and myasthenia gravis) with neuromuscular transmission failure is that the current produced by ACh receptor activation is significantly reduced, so EPP is not enough to trigger the muscle fiber action potential.

[0006] Neuromuscular blocking agents also reduce EPPs by antagonizing ACh receptors. In CIM with reduced muscle excitability, EPPs may have normal amplitudes, but they are still insufficient to trigger a muscle fiber action potential because the membrane potential threshold for action potential firing is due to the voltage-gated Na in the muscle fiber. + The channel loses function and becomes more depolarized.

[0007] Although ACh release (Lambert Eaton, amyotrophic lateral sclerosis, spinal muscular atrophy), ACh receptor function (myasthenia gravis, neuromuscular blockade), and voltage-gated Na + The function of the channel (CIM) is an essential component in synaptic transmission at the NMJ, but the amplitude of the EPP is also affected by inhibitory currents flowing in the NMJ region of the muscle fiber. These currents tend to dominate over excitatory currents through ACh receptors, and it is expected that they tend to reduce the EPP amplitude. The most important ion channel carrying this inhibitory membrane current in muscle fibers is the muscle-specific ClC-1Cl -Ion channels (Kwieciński H, Lehmann-Horn F, Rüdel R. Membrane currents in human intercostalmuscle at varied extracellular potassium. Muscle Nerve. 1984, 7, 465-469; Kwieciński H, Lehmann-Horn F, Rüdel R. Drug-induced myotonia in human intercostalmuscle. 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).

[0008] ACh esterase (AChE) inhibitors are traditionally used to treat myasthenia gravis. This treatment leads to improvement in most patients, but it is associated with side effects, some of which are serious (Mehndiratta MM, Pandey S, Kuntzer T. Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev. 2014, Oct 13; 10). Since ACh is an input neurotransmitter in the autonomic nervous system, delaying its decomposition can lead to stomach discomfort, diarrhea, salivation, and muscle cramps. Overdose is a serious problem because it can lead to muscle paralysis and respiratory failure, a condition commonly referred to as cholinergic crisis. Despite the serious side effects of AChE inhibitors, these drugs are still the treatment of choice for many conditions involving neuromuscular damage today. In patients who are inadequate to pyridostigmine (a parasympathomimetic and reversible AChE inhibitor), corticosteroid therapy (prednisone) and immunosuppressive therapy (azathioprine) are used. Plasma exchange may be used to achieve rapid but transient improvement.

[0009] Unfortunately, all currently used 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), although research is identifying new therapies (Gilhus, NE New England Journal of Medicine, 2016, 375, 2570-2581).

[0010] ClC-1 ion channel (Pedersen, TH, Riisager, A., Vincenzo de Paoli, F., Chen, TY, Nielsen, OBRole of physiological ClC-1Cl - ion channel regulation for the excitability and function of working skeletal muscle.J.Gen.Physiol.2016,147,291–308) is emerging as a potential drug target, although its potential has largely remained unrecognized.

[0011] There are publications on various ligands for 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-alkylderivatives of 2-(p-chlorophenoxy)propionic acid. Mol. Pharmacol., 2002, 62, 265–271; and Liantonio, A. et al., Structural requisites of 2-(p-chlorophenoxy)propionicacid analogues for activity on native rat skeletal muscle chloride conductance and on heterologously expressed CLC-1. Br. J. Phamacol., 2003, 129, 1255–1264.

[0012] In the article 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. Journal of the American Society of Nephrology, 2004, 15, 13-20, ligands for the ClC-K1 chloride channel are disclosed.

[0013] In the publication 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. Molecular Pharmacology, 2000, 58, 498–507, the authors disclose the effects of 2-(p-chlorophenoxy)propionic acid enantiomers on ClC-1 and ClC-2 ion channels.

[0014] In the article Ferorelli, S., Loiodice, F., Tortorella, V., Conte-Camerino, D., DeLuca, AMCarboxylic acids and skeletal muscle chloride channel conductance: effects on the biological activity induced by the introduction of methylgroups on the aromatic ring of chiral α-(4-chloro-phenoxy)alkanoic acids, Farmaco, 2001, 56, 239–246, the skeletal muscle chloride conductance of derivatives of (4-chloro-phenoxy)alkanoic acid was tested.

[0015] Edoardo Aromataris studied 4-chlorophenoxyisobutyric acid derivatives in his PhD thesis “Pharmacology of the ClC-1ChlorideChannel”, see https: / / digital.library.adelaide.edu.au / dspace / bitstream / 2440 / 58973 / 8 / 02whole.pdf

[0016] 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 the treatment, improvement and / or prevention of neuromuscular disorders. However, they have structural features that are different from those in the present disclosure. SUMMARY OF THE INVENTION

[0018] The present disclosure includes a series of compounds that can alleviate neuromuscular junction disorders by inhibiting ClC-1 channels.

[0019] It has been found that compounds that inhibit the ClC-1 ion channel are able to restore neuromuscular transmission, as demonstrated by the data generated by studying this group of compounds in the biological model described herein. Therefore, these compounds constitute a group of potential drugs that can be used to treat and / or improve muscle weakness and / or muscle fatigue in neuromuscular junction disorders caused by diseases or neuromuscular blocking agents.

[0020] Thus, the present disclosure relates to inhibitors of the ClC-1 ion channel for use in treating a range of conditions, such as reversal blockade, ALS, and myasthenic conditions, in which activation of the muscles by the nervous system is impaired and symptoms of weakness and fatigue are evident.

[0021] In one aspect, the present disclosure relates to compounds of formula (I):

[0022]

[0023] in:

[0024] -R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br and I;

[0025] -R 2 is selected from optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle;

[0026] -R 3 is selected from the group consisting of deuterium, Cl and F;

[0027] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0028] -R 5 is selected from H, optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 9 substituted benzyl;

[0029] -R 6 Independently selected from deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, where -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0030] -R 7 independently selected from 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, wherein C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0031] -R 8 are independently selected from deuterium and F;

[0032] -R 9 independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F;

[0033] -X is a bond or is selected from -O-, -S-, -CH2-, -CHR 6 -and-C(R 6 )2-; and

[0034] -n is an integer 0, 1, 2, or 3;

[0035] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0036] In another aspect, the disclosure relates to a compound as defined herein for use in treating, ameliorating and / or preventing neuromuscular disorders, and / or for reversing 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

[0037] Figure 1 Figure A shows that when inserted into a single skeletal muscle fiber for G m Figure 1. Schematic diagram of the positioning of the three microelectrodes (V1, V2, and V3) during the measurement. Note that only the impaled fibers are shown in the figure, although it is part of an intact muscle containing many such fibers. All electrodes record the membrane potential of the fiber, and the two peripheral electrodes are used to inject current (-30nA, 50ms). The electrodes are inserted with known inter-electrode distances (X1, X2, and X3). After insertion, the current first passes through the V1 electrode and then through the V3 electrode. The final deflection of the membrane voltage is measured by the other electrodes. The steady-state deflection of the membrane potential is measured and divided by the magnitude of the injected current (-30nA) to obtain the transfer resistance. These are then plotted against the inter-electrode distance and fit to an exponential function (Figure B), from which G can be calculated using linear cable theory. m The method described in Figures A and B was repeated for several fibers from a muscle during exposure to increasing concentrations of Compound A-3, approximately 10 fibers per concentration. In Figure C, the average G at each concentration was plotted. m The EC values ​​of the compounds were obtained by fitting them to a 4-parameter sigmoid function. 50 Value (dashed line).

[0038] Figure 2 : Panel A shows representative force traces before and after exposure to compound A-3. Force traces of representative muscles stimulated to contract under 1) control conditions before the addition of neuromuscular blockers, 2) force response to stimulation after 90 minutes of incubation with tubocurarine, where the muscle shows severe neuromuscular transmission disorders, and 3) muscle force response after the addition of 50 μM compound A-3. Panel B shows the average force (AUC) of the three muscles relative to their initial force. The traces shown in panel A (1, 2, 3) correspond to the dotted lines in panel B, respectively. Therefore, the force was lost due to incubation in tubocurarine for 90 minutes, and then the force was restored when compound A-3 was added.

[0039] definition

[0040] The term "C 1-2 -alkyl", "C 1-3 -alkyl" and "C 1-5"-alkyl" refers to a branched or unbranched alkyl group having 1-2, 1-3 or 1-5 carbon atoms, including but not limited to methyl, ethyl, propan-1-yl, propan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, 2,2-dimethyl-propan-1-yl, butan-1-yl, butan-2-yl, 3-methyl-butan-1-yl, 3-methyl-butan-2-yl, pentan-1-yl, pentan-2-yl and pentan-3-yl.

[0041] The terms "C2-alkenyl" and "C 2-5 "-Alkenyl" refers to a branched or unbranched alkenyl group having 2 or 2-5 carbon atoms, respectively, wherein two carbon atoms are connected by a double bond, including but not limited to ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and isopentenyl.

[0042] The terms "C2-alkynyl" and "C 2-5 The term "-alkynyl" refers to a branched or unbranched alkynyl group having 2 or 2 to 5 carbon atoms, respectively, wherein two carbon atoms are connected by a triple bond, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, but-1,3-diynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, pent-2,4-diynyl and pent-1,3-diynyl.

[0043] 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, including monocyclic or bicyclic carbocyclic rings, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A C in which one -CH2- is replaced by -O- 3-5 Examples of cycloalkyl are oxiran-2-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl and tetrahydrofuran-3-yl.

[0044] The term "5-6 membered aromatic heterocycle" refers to a group having 5 to 6 carbon atoms, wherein 1 to 3 carbon atoms in the ring have been replaced by heteroatoms selected from nitrogen, sulfur and oxygen. The binding to the heterocycle can be at the position of the heteroatom or through a carbon atom of the heterocycle.

[0045] The 5-membered aromatic heterocycle includes, but is 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.

[0046] 6-membered aromatic heterocycles include, but are not limited to, pyridine, pyrazine, pyrimidine, and pyridazine.

[0047] 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" refers to the time it takes for a compound to lose half of its pharmacological activity in plasma.

[0048] The term "treat" refers to combating a disease or condition. As used herein, "treat" includes any desired effect on the symptoms or pathology of a disease or condition as described herein, and may include even the smallest change or improvement in one or more measurable markers of the disease or condition being treated. "Treatment" does not necessarily mean that the disease or condition or its associated symptoms have been completely eradicated or cured. In some embodiments, the term "treat" encompasses both amelioration and prevention.

[0049] The term "amelioration" refers to a lessening in severity of the symptoms of a disease or condition. Improvement of a patient's condition, or activities that endeavor to correct or at least make intolerable conditions associated with a patient's condition more tolerable, is considered "ameliorative" treatment.

[0050] The term "prevent" means to stop, avoid, exclude, restrain, stop or hinder something from happening, especially by anticipatory action.

[0051] The term "reversal" refers to the ability of a compound to restore neural excitability of skeletal muscle exposed in vitro or in vivo to a non-depolarizing neuromuscular blocking agent or another agent capable of inhibiting neuromuscular transmission.

[0052] The term "nondepolarizing blocker" refers to an agent that antagonizes the activation of acetylcholine receptors on the postsynaptic muscle fiber membrane by blocking the acetylcholine binding site on the receptor. These agents are used to block neuromuscular transmission and cause muscle paralysis associated with surgery.

[0053] The term "ester hydrolyzing agent" refers to a chemical agent capable of converting an ester functional group to a carboxylic acid by eliminating the alcohol portion of the original ester, including but not limited to acids, bases, fluoride sources, PBr3, PCl3 and lipases.

[0054] The term "restoration of force in muscles with neuromuscular dysfunction" refers to the ability of a compound to restore contractile force in nerve-stimulated healthy rat muscle after 90 minutes of exposure to a submaximal concentration of tubocurarine (115 nM). Restoration of force is quantified as the percentage of pre-tubocurarine force restored by the compound.

[0055] The term "total membrane conductance (Gm)" is an electrophysiological measure of the ability of ions to cross the surface membrane of a muscle fiber. It reflects the function of ion channels active in resting muscle fibers, of which ClC-1 is known to contribute approximately 80% in most animal species. DETAILED DESCRIPTION OF THE INVENTION

[0057] Compound

[0058] Compounds for treating, ameliorating and / or preventing neuromuscular disorders that reduce neuromuscular function are provided within the scope of the present disclosure. As disclosed herein, inhibition of ClC-1 improves or restores neuromuscular function. The compounds disclosed herein include compounds that are capable of inhibiting the ClC-1 channel, thereby improving or restoring neuromuscular function. In one embodiment, the EC of the compound is 50 The amount of force restored in a muscle as a percentage of the initial force is <50 μM, such as <40 μM, such as <30 μM, such as <20 μM, such as <15 μM, such as <10 μM, such as <5 μM. In one embodiment, the force restored in a muscle with neuromuscular dysfunction is >5%, such as >10%, such as >15%, such as >20%, such as >25%, such as >30%, such as >35%. The force restored in a muscle can be determined as the amount of force restored in a muscle as a percentage of the initial force after the muscle has been exposed to a compound of the present disclosure (), such as described in Example 23.

[0059] In one aspect, the present disclosure relates to compounds of formula (I):

[0060]

[0061] in:

[0062] -R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br and I;

[0063] -R 2 is selected from optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle;

[0064] -R 3 is selected from the group consisting of deuterium, Cl and F;

[0065] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0066] -R 5 is selected from H, optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 9 substituted benzyl;

[0067] -R 6 Independently selected from deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, where -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0068] -R 7 independently selected from 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, wherein C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0069] -R 8 are independently selected from deuterium and F;

[0070] -R 9 independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F;

[0071] -X is a bond or is selected from -O-, -S-, -CH2-, -CHR 6 -and-C(R 6 )2-; and

[0072] -n is an integer 0, 1, 2, or 3;

[0073] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0074] In one aspect, the present disclosure relates to compounds of formula (I):

[0075]

[0076] in:

[0077] -R 1 is selected from the group consisting of F, Cl, Br and I;

[0078] -R 2 is selected from optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle;

[0079] -R 3 Selected from deuterium and F;

[0080] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-5cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0081] -R 5 is selected from H, optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 9 substituted benzyl;

[0082] -R 6 Independently selected from -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 8 Substitution: deuterium, F and -CN;

[0083] -R 7 Independently selected from C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, which may be optionally substituted by one or more identical or different substituents R 8 , deuterium, F and -CN substitution;

[0084] -R 8 are independently selected from deuterium and F;

[0085] -R 9 independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F;

[0086] -X is a bond or is selected from -O-, -S-, -CH2-, -CHR 6 -and-C(R 6 )2-; and

[0087] -n is an integer 0, 1, 2, or 3;

[0088] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0089] In one embodiment, R 1 It is C 1-2 In one embodiment, R 1 is C2 alkenyl. In one embodiment, R 1 is C2 alkynyl. In one embodiment, R 1 is CN. In one embodiment, R 1 is CF3. In one embodiment, R 1 is NO2. In one embodiment, R 1 is Cl or Br. In one embodiment, R 1 In one embodiment, R 1 It's Br.

[0090] In one embodiment, R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 In one embodiment, R 2 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl. 2 is selected from methyl, ethyl, n-propyl and isopropyl, wherein methyl, ethyl, n-propyl or isopropyl is replaced by one or more identical or different substituents R 6 In one embodiment, R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 In one embodiment, R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 In one embodiment, R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 In one embodiment, R 2 is optionally substituted by one or more identical or different substituents R 9 In one embodiment, R 2 is optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle.

[0091] In one embodiment, R 3 In one embodiment, R 3In one embodiment, R 3 It's F.

[0092] In one embodiment, R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 1-5 In one embodiment, R 4 is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl. 4 is selected from methyl, ethyl, n-propyl and isopropyl, wherein methyl, ethyl, n-propyl or isopropyl is replaced by one or more identical or different substituents R 7 In one embodiment, R 4 is Me. In one embodiment, R 4 is -CH2F. In one embodiment, R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted -CH2-OC 1-5 In one embodiment, R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted -CH2-SC 1-5 alkyl.

[0093] In one embodiment, R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 2-5 In one embodiment, R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 2-5 In one embodiment, R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted -CH2-C 2-4 In one embodiment, R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 3-5 In one embodiment, R 4 is H. When R 4 When H is 4 The bound carbon is not a stereogenic center.

[0094] In one embodiment, R 5 is H. In one embodiment, R 5 is optionally substituted by one or more identical or different substituents R 8 Substituted C1-5 In one embodiment, R 5 is optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 In one embodiment, R 5 is optionally substituted by one or more identical or different substituents R 9 In one embodiment, R 5 is optionally substituted by one or more identical or different substituents R 9 Substituted benzyl.

[0095] In one embodiment, R 6 In one embodiment, R 6 is F. In one embodiment, R 6 is CN. In one embodiment, R 6 is optionally substituted by one or more identical or different substituents R 8 Replaced-OC 1-5 In one embodiment, R 6 is optionally substituted by one or more identical or different substituents R 8 Replaced-OC 3-5 In one embodiment, R 6 is optionally substituted by one or more identical or different substituents R 8 Substituted-SC 1-5 In one embodiment, R 6 is optionally substituted by one or more identical or different substituents R 8 Substituted-SC 3-5 Cycloalkyl.

[0096] In one embodiment, R 7 In one embodiment, R 7 is F. In one embodiment, R 7 In one embodiment, R 7 is CN. In one embodiment, R 7 is optionally substituted by one or more identical or different substituents R 8 Replaced-OC 1-5 In one embodiment, R 7 is optionally substituted by one or more identical or different substituents R 8 Replaced-OC 3-5 In one embodiment, R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted-SC1-5 In one embodiment, R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted-SC 3-5 In one embodiment, R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted C 3-5 Cycloalkyl.

[0097] In one embodiment, R 8 In one embodiment, R 8 It's F.

[0098] In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3.

[0099] 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(R 6 )2-.

[0100] In one embodiment, R 1 is Cl or Br, R 2 is selected from methyl, ethyl, n-propyl and isopropyl, which are optionally substituted by one or more identical or different substituents R 7 Replace, and R 5 It's H.

[0101] In one embodiment the compound has an enantiomeric excess of >90% ee, such as >90% ee, such as >95% ee, such as >98% ee.

[0102] In one embodiment, the present disclosure relates to compounds of formula (II):

[0103]

[0104] in:

[0105] -R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br and I;

[0106] -R 2 is selected from optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5alkyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle;

[0107] -R 3 is selected from the group consisting of deuterium, Cl and F;

[0108] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0109] -R 5 is selected from H, optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 9 substituted benzyl;

[0110] -R 6 Independently selected from deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, where -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5The cycloalkyl group is optionally substituted by one or more identical or different substituents R 8 replace;

[0111] -R 7 independently selected from 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, wherein C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0112] -R 8 are independently selected from deuterium and F;

[0113] -R 9 are independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

[0114] -n is an integer 0, 1, 2, or 3;

[0115] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0116] In one embodiment, the present disclosure relates to compounds of formula (II):

[0117]

[0118] in:

[0119] -R 1 is selected from the group consisting of F, Cl, Br and I;

[0120] -R 2 is selected from optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9substituted phenyl and optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle;

[0121] -R 3 Selected from deuterium and F;

[0122] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0123] -R 5 is selected from H, optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 9 substituted benzyl;

[0124] -R 6 Independently selected from -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 8 Substitution: deuterium, F and -CN;

[0125] -R 7 Independently selected from 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 optionally substituted by one or more identical or different substituents R 8 Substitution: deuterium, F and -CN;

[0126] -R 8 are independently selected from deuterium and F;

[0127] -R 9 are independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

[0128] -n is an integer 0, 1, 2, or 3;

[0129] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0130] In one embodiment, the present disclosure relates to compounds of formula (II):

[0131]

[0132] in:

[0133] -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br and I;

[0134] -R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl;

[0135] -R 3 is selected from the group consisting of deuterium, Cl and F;

[0136] -R 4 Selected from H, deuterium, C 1-5 Alkyl and C 2-5 alkynyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0137] -R 5 It is H;

[0138] -R 6 Independently selected from deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, where -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0139] -R 7 independently selected from deuterium, F, Cl, -CN, C 3-5 Cycloalkyl, -OC1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, wherein C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0140] -R 8 are independently selected from deuterium and F; and

[0141] -n is an integer 0, 1, 2, or 3;

[0142] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0143] In one embodiment, the present disclosure relates to compounds of formula (III):

[0144]

[0145] in:

[0146] -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br and I;

[0147] -R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl;

[0148] -R 3 is selected from H, deuterium, Cl and F;

[0149] -R 4 Selected from H, deuterium, C 1-5 Alkyl and C 2-5 alkynyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0150] -R 6 Independently selected from deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, where -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0151] -R 7 independently selected from 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, wherein C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace; and

[0152] -R 8 are independently selected from deuterium and F;

[0153] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0154] In one embodiment, the present disclosure relates to compounds of formula (III):

[0155]

[0156] in:

[0157] -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br and I;

[0158] -R 2 is optionally substituted by one or more identical or different substituents R 8 Substituted C 1-3 alkyl;

[0159] -R 3 is selected from H, deuterium, Cl and F;

[0160] -R 4 Selected from H, deuterium, C 1-3 Alkyl and C 2-3 alkynyl, each of which may be optionally substituted by one or more identical or different substituents R 8 replace; and

[0161] -R 8 are independently selected from deuterium and F;

[0162] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0163] In one embodiment, the compound is selected from:

[0164] (2S)-2-[4-Bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropanoic acid;

[0165] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butanoic acid;

[0166] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0167] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoic acid;

[0168] (2S)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0169] 2-[4-Bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid;

[0170] (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propanoic acid;

[0171] (2S)-2-{4-bromo-2-[difluoro(phenyl)methyl]phenoxy}propanoic acid;

[0172] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-2-cyclopropylacetic acid;

[0173] (2S)-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propanoic acid;

[0174] (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0175] (2S)-2-[4-Bromo-2-(cyclopropyldifluoromethyl)phenoxy]propanoic acid;

[0176] (2S)-2-{4-bromo-2-[difluoro(1,3-thiazol-2-yl)methyl]phenoxy}propanoic acid;

[0177] (2S)-2-[4-Bromo-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid;

[0178] (2S)-2-[4-Bromo-2-(cyclobutyldifluoromethyl)phenoxy]propanoic acid;

[0179] (2R)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;

[0180] (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-chloropropionic acid;

[0181] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]pent-4-ynoic acid;

[0182] (2S)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid;

[0183] (2S)-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propanoic acid;

[0184] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2-2H)propanoic acid;

[0185] (2R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0186] (2S)-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propanoic acid;

[0187] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid;

[0188] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy]propanoic acid;

[0189] (2S)-2-[4-Cyano-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0190] (2R)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;

[0191] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propanoic acid;

[0192] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)(3,5,6- 2 H3) phenoxy]propionic acid;

[0193] 2-[4-Bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid;

[0194] (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid;

[0195] (2S)-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propanoic acid;

[0196] (2R)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0197] (2S)-2-[2-(1,1-difluoropropyl)-4-vinylphenoxy]propanoic acid;

[0198] 2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid;

[0199] (2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoic acid;

[0200] 2-[4-Bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid;

[0201] 2-[4-Chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid;

[0202] (2S)-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propanoic acid;

[0203] (2R)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0204] (2S)-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0205] (2R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanoic acid;

[0206] (2R)-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;

[0207] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutyric acid;

[0208] (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butanoic acid;

[0209] (2S)-2-[2-(1,1-difluoropropyl)-4-vinyl-5-fluorophenoxy]propanoic acid;

[0210] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid;

[0211] (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid;

[0212] (2R)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropionic acid;

[0213] (2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propanoic acid;

[0214] (2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoic acid;

[0215] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutanoic acid;

[0216] (2R)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropionic acid;

[0217] (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid; and

[0218] (2S)-2-[4-Bromo-2-(1,1-difluoro-3-methoxypropyl)phenoxy]propanoic acid.

[0219] Treatment

[0220] In one aspect, the present disclosure relates to the use of compounds of formula (I) and / or formula (II) and / or formula (III) in treating, ameliorating and / or preventing neuromuscular disorders. In one aspect, the present disclosure relates to the use of compounds of formula (I) and / or formula (II) and / or formula (III) in reversing and / or ameliorating neuromuscular blockade. Thus, in one aspect, the present invention relates to compounds of formula (I):

[0221]

[0222] Where R 1 To R 9 , n and X are as defined in the present disclosure,

[0223] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, for use in treating, improving and / or preventing neuromuscular disorders, and / or for reversing and / or improving neuromuscular blockade.

[0224] In one embodiment, the present disclosure relates to compounds of formula (II):

[0225]

[0226] Where R 1 To R9 and n is as defined in this disclosure,

[0227] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, for use in treating, improving and / or preventing neuromuscular disorders, and / or for reversing and / or improving neuromuscular blockade.

[0228] In one embodiment, the present disclosure relates to compounds of formula (III):

[0229]

[0230] Where R 1 To R 8 and n is as defined in this disclosure,

[0231] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof, for use in treating, improving and / or preventing neuromuscular disorders, and / or for reversing and / or improving neuromuscular blockade.

[0232] In one embodiment, the compound for treating, ameliorating and / or preventing neuromuscular disorders, and / or for reversing and / or ameliorating neuromuscular blockade is selected from:

[0233] (2S)-2-[4-Bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropanoic acid;

[0234] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butanoic acid;

[0235] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0236] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoic acid;

[0237] (2S)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0238] 2-[4-Bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid;

[0239] (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propanoic acid;

[0240] (2S)-2-{4-bromo-2-[difluoro(phenyl)methyl]phenoxy}propanoic acid;

[0241] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-2-cyclopropylacetic acid;

[0242] (2S)-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propanoic acid;

[0243] (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0244] (2S)-2-[4-Bromo-2-(cyclopropyldifluoromethyl)phenoxy]propanoic acid;

[0245] (2S)-2-{4-bromo-2-[difluoro(1,3-thiazol-2-yl)methyl]phenoxy}propanoic acid;

[0246] (2S)-2-[4-Bromo-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid;

[0247] (2S)-2-[4-Bromo-2-(cyclobutyldifluoromethyl)phenoxy]propanoic acid;

[0248] (2R)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;

[0249] (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-chloropropionic acid;

[0250] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]pent-4-ynoic acid;

[0251] (2S)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid;

[0252] (2S)-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propanoic acid;

[0253] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2-2H)propanoic acid;

[0254] (2R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0255] (2S)-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propanoic acid;

[0256] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid;

[0257] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy]propanoic acid;

[0258] (2S)-2-[4-Cyano-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0259] (2R)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;

[0260] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propanoic acid;

[0261] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)(3,5,6- 2 H3) phenoxy]propionic acid;

[0262] 2-[4-Bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid;

[0263] (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid;

[0264] (2S)-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propanoic acid;

[0265] (2R)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0266] (2S)-2-[2-(1,1-difluoropropyl)-4-vinylphenoxy]propanoic acid;

[0267] 2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid;

[0268] (2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoic acid;

[0269] 2-[4-Bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid;

[0270] 2-[4-Chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid;

[0271] (2S)-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propanoic acid;

[0272] (2R)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0273] (2S)-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0274] (2R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanoic acid;

[0275] (2R)-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;

[0276] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutyric acid;

[0277] (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butanoic acid;

[0278] (2S)-2-[2-(1,1-difluoropropyl)-4-vinyl-5-fluorophenoxy]propanoic acid;

[0279] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid;

[0280] (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid;

[0281] (2R)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropionic acid;

[0282] (2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propanoic acid;

[0283] (2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoic acid;

[0284] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutanoic acid;

[0285] (2R)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropionic acid;

[0286] (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid; and

[0287] (2S)-2-[4-Bromo-2-(1,1-difluoro-3-methoxypropyl)phenoxy]propanoic acid.

[0288] In one embodiment, the compound according to the present disclosure or the compound for use according to the present disclosure is modified in order to increase its half-life, in particular its plasma half-life, when administered to a patient.

[0289] In one embodiment, the compound according to the present disclosure or the compound for use according to the present disclosure further comprises a moiety conjugated to the compound, thereby generating a partially-conjugated compound. In one embodiment, the plasma and / or serum half-life of the partially-conjugated compound is longer than the plasma and / or serum half-life of the non-partially conjugated compound.

[0290] In one embodiment, the moiety conjugated to the compound according to or for use according to the present disclosure is one or more types of moieties selected from albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies and antibody fragments.

[0291] Neuromuscular disorders

[0292] The compounds of the present disclosure or the compounds used in the present disclosure are used to treat, improve and / or prevent neuromuscular disorders, or to reverse neuromuscular blockade caused by non-depolarizing neuromuscular blocking agents or antibiotics.

[0293] The inventors of the present disclosure have shown that inhibition of ClC-1 channels enhances neuromuscular transmission. Therefore, ClC-1 function may contribute to muscle weakness in conditions where neuromuscular transmission is impaired.

[0294] Thus, in one embodiment of the present disclosure, the compounds described herein or used herein inhibit the ClC-1 channel. Thus, it is understood that the compounds of formula (I) and / or the compounds of formula (I) used inhibit the ClC-1 channel.

[0295] Neuromuscular disorders may also include neuromuscular dysfunction.

[0296] Neuromuscular disorders include, for example, disorders with symptoms of muscle weakness and fatigue. Such disorders may include conditions in which the safety factor of neuromuscular transmission is reduced. In one embodiment, the neuromuscular disorder is a motor neuron disorder. A motor neuron disorder is a disorder in which the safety factor of neuromuscular transmission is reduced. In one embodiment, the motor neuron disorder is selected from 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 spinalmuscular 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, Lochmüller 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, T X-linked spinal and bulbar muscular atrophy with myasthenic symptoms.Journal of the Neurological Sciences, 1997, 146, 183-185), Kennedy's disorder (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-Barré syndrome (Ansar, V., Valadi, N. Guillain-Barré Syndrome Prim. Care, 2015, 42, 189-193), poliomyelitis (Trojan, DA, Gendron, D., Cashman, NR Electrophysiology and electrodiagnosis of the post-polio motor unit. Orthopedics, 1991, 14, 1353-1361, and Birk TJ Poliomyelitis and the post-polio syndrome: exercise capacity 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 junctiondysfunction in type 1diabetic 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 3stages of sarcopenia.2017,55(5),676-684). .

[0297] 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 syndrome. In yet another embodiment, the neuromuscular disorder is critical illness myopathy (CIM).

[0298] As described 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).

[0299] In one embodiment, the compounds of the present disclosure or the compounds used in the present disclosure are used to prevent neuromuscular disorders. The compounds or the compounds of the use can be used, for example, to prevent nerve gases known to cause muscle weakness and fatigue symptoms, or as a treatment thereof (Kawamura, Y., Kihara, M., Nishimoto, K., Taki, M. Efficacy of a halfdose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Pathophysiology, 2003, 9, 189-194). In one disclosure, the compounds of the present disclosure or the compounds used in the present disclosure are used to treat botulism poisoning (Sellin, LC, The action of botulinum toxin at the neuromuscular junction, Med Biol., 1981, 59, 11-20). In one disclosure, the compounds of the present disclosure or the compounds used in the present disclosure are used to treat snake bites (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).

[0300] 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, CJPersistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness. Crit. Care Med. 2003, 31, 1012–1016) is a common name for a medical condition characterized by debilitating symptoms, including fatigue that persists for at least six months in adults. CFS may also be referred to as systemic exercise intolerance disorder (SEID), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS) or several other terms. Symptoms of CFS include malaise after exertion; non-restorative sleep, widespread muscle and joint pain, fatigue, and weakness.

[0301] In another embodiment, the neuromuscular disorder is myotubular myopathy (Dowling, JJ et al, Myotubular myopathy and the neuromuscular junction: anovel 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).

[0302] In yet another embodiment, 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 that develop in critically ill patients.

[0303] Neuromuscular disorders can also include metabolic myopathy (Milone, M., Wong, LJ Diagnosis of mitochondrial myopathies. Mol. Genet. Metab., 2013, 110, 35-41) and mitochondrial myopathy (Srivastava, A., Hunter, JM Reversal of neuromuscular block. Br. J. Anaesth. 2009, 103, 115-129). Metabolic myopathy is caused by defects in biochemical metabolism that mainly affect muscles. These may include glycogen storage disease, lipid storage disease and 3-phosphocreatine storage disease. Mitochondrial myopathy is a myopathy associated with mitochondrial disorders. Symptoms of mitochondrial myopathy include problems with the muscles and nervous system, such as muscle weakness, exercise intolerance, hearing loss, and difficulty in balance and coordination.

[0304] In another embodiment, the neuromuscular disorder is periodic paralysis, in particular hypokalemic periodic paralysis, which is a skeletal muscle excitability disorder characterized by recurring episodes of weakness often triggered by exercise, stress or carbohydrate-rich meals (Wu, F., Mi, W., Cannon, SC, Neurology, 2013, 80, 1110-1116; and Suetterlin, K. et at, Current Opinion Neurology, 2014, 27, 583-590) or hyperkalemic periodic paralysis, which is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood (Ammat, T. et at, Journal of General Physiology, 2015, 146, 509-525).

[0305] In one embodiment, the neuromuscular disorder is a myasthenic condition. Myasthenic conditions are characterized by muscle weakness and neuromuscular transmission disorders. Congenital myasthenia gravis (Finlayson, S., Beeson, D., Palace, J. Congenital myasthenic syndromes: an update. Pract. Neurol., 2013, 13, 80–91) is an inherited neuromuscular disorder caused by several types of defects at the neuromuscular junction.

[0306] 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 also examples of myasthenia conditions. Myasthenia gravis is an autoimmune or congenital neuromuscular disorder, causing fluctuating muscle weakness and fatigue. In the most common case, myasthenia is caused by circulating antibodies that block ACh receptors at the postsynaptic neuromuscular junction, which inhibits the excitatory effects of 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 (also known as LEMS, Lambert–Eaton syndrome, or Eaton–Lambert syndrome) is a rare autoimmune disorder characterized by muscle weakness of the limbs. It is the result of an autoimmune reaction in which antibodies are formed against presynaptic voltage-gated calcium channels in the neuromuscular junction and possibly other nerve terminal proteins.

[0307] Thus, in one embodiment of the present disclosure, the neuromuscular disorder is myasthenia gravis. In another embodiment, the neuromuscular disorder is Lambert-Eaton syndrome.

[0308] Neuromuscular blockade is used in cases related to surgery under general anesthesia. Reversal agents are used to restore muscle function more quickly and safely after such blockade. Complications of excessive muscle weakness after intraoperative blockade may lead to delayed disconnection of mechanical ventilation and respiratory complications after surgery. These complications can have a significant impact on surgical outcomes and the patient's future quality of life, so improved reversal 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). Therefore, in one embodiment, neuromuscular disorders are induced via neuromuscular blockers. In a specific embodiment, neuromuscular disorders are muscle weakness caused by neuromuscular blockade after surgery. In another embodiment of the present disclosure, the compound or the compound used is used to reverse and / or improve neuromuscular blockade after surgery. In one embodiment, neuromuscular blockade is drug-induced. In one embodiment, neuromuscular blockade is induced by antibiotics. In one embodiment, neuromuscular blockade is induced by a non-depolarizing neuromuscular blocking agent.

[0309] Pharmaceutical preparations

[0310] In one embodiment, a composition comprising a compound according to the present disclosure or a compound used according to the present disclosure is provided. Compositions according to the present disclosure are used to treat, improve and / or prevent neuromuscular disorders, and / or to reverse and / or improve neuromuscular blockade. Therefore, the compositions and compounds described herein can be pharmaceutically acceptable. In one embodiment, the compositions described herein are in the form of a pharmaceutical preparation. In one embodiment, the compositions described herein also include a pharmaceutically acceptable carrier. Examples of possible preparations and products are included in, for example, Handbook of Pharmaceutical Excipients and Remington's Pharmaceutical Sciences.

[0311] Combination therapy

[0312] The compositions of the present disclosure may include other active ingredients / agents or other components to increase the effectiveness of the compositions. Therefore, in one embodiment, the compositions further include at least one other active agent. It is understood that the active agent may be suitable for treating, preventing or improving the neuromuscular disorder.

[0313] In certain embodiments, the active agent is an acetylcholinesterase inhibitor. The acetylcholinesterase inhibitor can be, for example, selected from: delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine, edrophonium, huperzine, ladostinigil, ungeremine, and lactucopicrin.

[0314] In certain embodiments, the acetylcholinesterase inhibitor is selected from neostigmine, physostigmine, and pyridostigmine. In certain embodiments, the acetylcholinesterase inhibitor is neostigmine or pyridostigmine.

[0315] The active agent can also be an immunosuppressive drug. Immunosuppressive drugs are drugs that suppress or reduce the strength of the body's immune system. They are also called anti-rejection drugs. Immunosuppressive drugs include but are not limited to glucocorticoids, corticosteroids, cytostatics, antibodies, and drugs that act on immunophilins. In one embodiment, the active agent is prednisone.

[0316] The active agent may also be an agent used for anti-myotonic therapy. Such agents include, for example, voltage-gated Na + Channel blockers and aminoglycosides.

[0317] The active agent may also be an agent used to reverse postoperative neuromuscular blockade. Such agents include, for example, neostigmine or suggammadex (Org 25969, trade name Bridion). The active agent may also be a drug used to increase the Ca2+ of the contractile filaments in the muscle. 2+Such agents include tirasemtiv 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).

[0318] The active agent can also block the voltage-gated K + Such agents include 3,4-aminopyridine.

[0319] method

[0320] In one aspect, the disclosure relates to a method of treating, preventing and / or ameliorating a neuromuscular disorder, the method comprising administering to a person in need thereof a therapeutically effective amount of a compound as defined herein or a compound for use as defined herein. In one embodiment, the person is a human.

[0321] In one aspect, the disclosure relates to a method of reversing and / or ameliorating neuromuscular blockade, the method comprising administering to a human in need thereof a therapeutically effective amount of a compound as defined herein or a compound for use as defined herein.

[0322] In one aspect, the disclosure relates to a method of restoring neuromuscular transmission, the method comprising administering to a human in need thereof a therapeutically effective amount of a compound as defined herein or a compound for use as defined herein.

[0323] A person in need may be a person with a neuromuscular disorder or a person at risk of developing a neuromuscular disorder or a person with symptoms of muscle weakness and / or fatigue. In another embodiment, a person in need is a person with reduced safety of neuromuscular transmission and prolonged recovery after neuromuscular blockade. The types of neuromuscular disorders are defined above. In one embodiment, the person has amyotrophic lateral sclerosis, spinal muscular atrophy, myasthenia gravis, or Lambert-Eaton syndrome.

[0324] The therapeutically effective amount is an amount that produces a therapeutic response or desired effect in a subject. The route of administration, formulation and dosage can be determined by those skilled in the art.

[0325] The treatment method can be combined with other methods known to treat, prevent and / or improve neuromuscular disorders. The treatment method can be combined, for example, with the administration of any of the agents mentioned above. In one embodiment, the treatment is combined with the administration of an acetylcholinesterase inhibitor such as neostigmine or pyridostigmine.

[0326] In one embodiment, the present invention relates to a method for restoring force in a muscle with neuromuscular dysfunction, the method comprising administering to a subject in need thereof a compound or composition as defined herein. In one embodiment, the force recovery is>5%, such as>10%, such as>15%, such as>20%, such as>25%, such as>30%, such as>35%. The recovery of force in a muscle can be determined as the amount of force recovered in the muscle as a percentage of the initial force after the muscle has been exposed to a compound of the present disclosure, for example as described in Example 23.

[0327] Another aspect of the invention relates to the use of a compound as defined herein for the manufacture of a medicament for the treatment, prevention and / or amelioration of a neuromuscular disorder.

[0328] Another aspect relates to the use of a compound as defined herein for the manufacture of a medicament or reversal agent for reversing and / or improving post-operative neuromuscular blockade.

[0329] Preparation method

[0330] In one aspect, the present disclosure relates to methods of preparing a compound according to formula (I) or using a compound according to formula (I).

[0331] A method for preparing a compound according to the present disclosure or a compound used according to the present disclosure comprises the following steps:

[0332] a. Making a compound having formula (GM.III)

[0333]

[0334] Where R 4 and R 5 As defined herein,

[0335] with a compound having the formula (GM.II) under Mitsunobu or similar reaction conditions,

[0336]

[0337] Where R 1 , R 2 , R 3 , n and X are as defined herein, to produce a compound having formula (GM.IV)

[0338]

[0339] b. reacting the product compound of a) with an ester hydrolyzing agent to produce a compound as defined herein.

[0340] A method for preparing a compound according to the present disclosure or a compound used according to the present disclosure comprises the following steps:

[0341] a. Making a compound having formula (GM.VI)

[0342]

[0343] Where R 4 and R 5 as defined herein, and Y is a leaving group (eg, mesylate or tosylate),

[0344] with a compound of formula (GM.II) under conditions involving a suitable base such as a sterically hindered amine or an alkali metal carbonate

[0345]

[0346] Where R 1 , R 2 , R 3 , n and X are as defined herein, to produce a compound having formula (GM.IV)

[0347]

[0348] b. reacting the product compound of a) with an ester hydrolyzing agent to produce a compound as defined herein.

[0349] A method for preparing a compound according to the present disclosure or a compound used according to the present disclosure comprises the following steps:

[0350] a. Making a compound having formula (GM.VIII)

[0351]

[0352] Where R 4 and R 5 As defined herein,

[0353] Reaction with a compound having formula (GM.VII)

[0354]

[0355] Where 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 produce a compound having formula (GM.IV)

[0356]

[0357] b. reacting the product compound of a) with an ester hydrolyzing agent to produce a compound as defined herein.

[0358] A method for preparing a compound according to the present disclosure or a compound used according to the present disclosure comprises the following steps:

[0359] a. Making a compound having formula (GM.IX)

[0360]

[0361] Where R 4 As defined herein, and R 10 is a suitable protecting group, such as a silyl-containing moiety,

[0362] Reaction with a compound having the formula (GM.II) under Mitsunobu or similar reaction conditions

[0363]

[0364] Where R 1 , R 2 , R 3 , n and X are as defined herein, to produce a compound having the formula (GM.X)

[0365]

[0366] b. Removal of the protective group R of the product compound of a) 10 ;and

[0367] c. reacting the product compound of b) with an oxidizing agent to produce a compound as defined herein.

[0368] A method for preparing a compound according to the present disclosure or a compound used according to the present disclosure comprises the following steps:

[0369] a. Making a compound having formula (GM.III)

[0370]

[0371] Where R 4 and R 5 As defined herein,

[0372] reacting with a compound having the formula (GM.XI),

[0373]

[0374] Where R 1 , R 2 , R 3 , n and X are as defined herein, to produce a compound having formula (GM.XII)

[0375]

[0376] b. converting the keto group of the product compound of a) into an alkyl-difluoro group; and

[0377] c. reacting the product compound of b) with an ester hydrolyzing agent to produce a compound as defined herein.

[0378] A method for preparing a compound according to the present disclosure or a compound used according to the present disclosure comprises the following steps:

[0379] a. Making a compound having formula (GM.XIII)

[0380]

[0381] Where R 1 , R 3 , R 4 , R 5 and n is as defined herein,

[0382] Reaction under acylation conditions to produce a compound having formula (GM.XII)

[0383]

[0384] b. converting the keto group of the product compound of a) into an alkyl-difluoro group, wherein X is a bond and R 2 As defined herein; and

[0385] c. reacting the product compound of b) with an ester hydrolyzing agent to produce a compound as defined herein.

[0386] A method for preparing a compound according to the present disclosure or a compound used according to the present disclosure comprises the following steps:

[0387] a. Making a compound having formula (GM.IX)

[0388]

[0389] Where R 4 and R 9 As defined herein,

[0390] reacting with a compound having formula (GM.XV),

[0391]

[0392] Where R 1 , R 2 , R 3 and n are as defined herein, to produce a compound having formula (GM.XIV)

[0393]

[0394] b. converting the keto group of the product compound of a) into an alkyl-difluoro group;

[0395] c. Removal of the protective group R of the product compound of b) 10 ;and

[0396] d. reacting the product of c) with an oxidizing agent to produce a compound as defined herein.

[0397] project

[0398] 1. Compounds of formula (I):

[0399]

[0400] in:

[0401] -R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br and I;

[0402] -R 2 is selected from optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle;

[0403] -R 3 is selected from the group consisting of deuterium, Cl and F;

[0404] -R4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0405] -R 5 is selected from H, optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 9 substituted benzyl;

[0406] -R 6 Independently selected from deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, where -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0407] -R 7 independently selected from 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, wherein C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8replace;

[0408] -R 8 are independently selected from deuterium and F;

[0409] -R 9 independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F;

[0410] -X is a bond or is selected from -O-, -S-, -CH2-, -CHR 6 -and-C(R 6 )2-; and

[0411] -n is an integer 0, 1, 2, or 3;

[0412] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0413] 2. A compound according to any one of the preceding items, wherein the compound has formula (I):

[0414]

[0415] in:

[0416] -R 1 is selected from the group consisting of F, Cl, Br and I;

[0417] -R 2 is selected from optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle;

[0418] -R 3 Selected from deuterium and F;

[0419] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-5cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0420] -R 5 is selected from H, optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 9 substituted benzyl;

[0421] -R 6 Independently selected from -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 8 Substitution: deuterium, F and -CN;

[0422] -R 7 Independently selected from 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 optionally substituted by one or more identical or different substituents R 8 Substitution: deuterium, F and -CN;

[0423] -R 8 are independently selected from deuterium and F;

[0424] -R 9 independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F;

[0425] -X is a bond or is selected from -O-, -S-, -CH2-, -CHR 6 -and-C(R 6 )2-; and

[0426] -n is an integer 0, 1, 2, or 3;

[0427] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0428] 3. A compound according to any one of the preceding items, wherein the compound has formula (II):

[0429]

[0430] in:

[0431] -R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br and I;

[0432] -R 2 is selected from optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle;

[0433] -R 3 is selected from the group consisting of deuterium, Cl and F;

[0434] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0435] -R 5 is selected from H, optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5Alkynyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 9 substituted benzyl;

[0436] -R 6 Independently selected from deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, where -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0437] -R 7 independently selected from 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, wherein C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0438] -R 8 are independently selected from deuterium and F;

[0439] -R 9 are independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

[0440] -n is an integer 0, 1, 2, or 3;

[0441] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0442] 4. A compound according to any one of the preceding items, wherein the compound has formula (II):

[0443]

[0444] in:

[0445] -R 1 is selected from the group consisting of F, Cl, Br and I;

[0446] -R 2 is selected from optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle;

[0447] -R 3 Selected from deuterium and F;

[0448] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0449] -R 5 is selected from H, optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 2-5 Alkynyl, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 Cycloalkyl, optionally substituted by one or more identical or different substituents R 9 substituted phenyl and optionally substituted by one or more identical or different substituents R 9 substituted benzyl;

[0450] -R 6 Independently selected from -OC1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 cycloalkyl, each of which may be optionally substituted by one or more identical or different substituents R 8 Substitution: deuterium, F and -CN;

[0451] -R 7 Independently selected from 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 optionally substituted by one or more identical or different substituents R 8 Substitution: deuterium, F and -CN;

[0452] -R 8 are independently selected from deuterium and F;

[0453] -R 9 are independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

[0454] -n is an integer 0, 1, 2, or 3;

[0455] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0456] 5. The compound according to any one of the preceding items, wherein the compound has formula (II):

[0457]

[0458] in:

[0459] -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br and I;

[0460] -R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl;

[0461] -R 3 is selected from the group consisting of deuterium, Cl and F;

[0462] -R 4 Selected from H, deuterium, C 1-5 Alkyl and C 2-5 alkynyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0463] -R 5 It is H;

[0464] -R 6 Independently selected from deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, wherein -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0465] -R 7 independently selected from 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, wherein C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0466] -R 8 are independently selected from deuterium and F; and

[0467] -n is an integer 0, 1, 2, or 3;

[0468] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0469] 6. A compound according to any one of the preceding items, wherein the compound has formula (III):

[0470]

[0471] in:

[0472] -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br and I;

[0473] -R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C1-5 alkyl;

[0474] -R 3 is selected from H, deuterium, Cl and F;

[0475] -R 4 Selected from H, deuterium, C 1-5 Alkyl and C 2-5 Alkynyl, C 1-5 Alkyl and C 2-5 Each alkynyl group may be optionally substituted by one or more identical or different substituents R 7 replace;

[0476] -R 6 Independently selected from deuterium, F, -CN, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 Cycloalkyl, where -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0477] -R 7 independently selected from 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, wherein C 3-5 Cycloalkyl, -OC 1-5 Alkyl, -OC 3-5 Cycloalkyl, -SC 1-5 Alkyl and -SC 3-5 The cycloalkyl group may be optionally substituted by one or more identical or different substituents R 8 replace;

[0478] -R 8 are independently selected from deuterium and F;

[0479] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0480] 7. A compound according to any one of the preceding items, wherein the compound has formula (III):

[0481]

[0482] in:

[0483] -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br and I;

[0484] -R 2 is optionally substituted by one or more identical or different substituents R 8 Substituted C 1-3 alkyl;

[0485] -R 3 is selected from H, deuterium, Cl and F;

[0486] -R 4 Selected from H, deuterium, C 1-3 Alkyl and C 2-3 Alkynyl, C 1-3 Alkyl and C 2-3 Each alkynyl group may be optionally substituted by one or more identical or different substituents R 8 replace; and

[0487] -R 8 are independently selected from deuterium and F;

[0488] or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0489] 8. A compound according to any one of the preceding items, wherein R 1 It is C 1-2 alkyl.

[0490] 9. A compound according to any one of the preceding items, wherein R 1 It is a C2 alkenyl group.

[0491] 10. A compound according to any one of the preceding items, wherein R 1 It is a C2 alkynyl group.

[0492] 11. A compound according to any one of the preceding items, wherein R 1 It is CN.

[0493] 12. A compound according to any one of the preceding items, wherein R 1 It's CF3.

[0494] 13. A compound according to any one of the preceding items, wherein R 1 It's NO2.

[0495] 14. A compound according to any one of the preceding items, wherein R 1 It is Cl or Br.

[0496] 15. A compound according to any one of the preceding items, wherein R 1 It is Cl.

[0497] 16. A compound according to any one of the preceding items, wherein R 1 It's Br.

[0498] 17. A compound according to any one of the preceding items, wherein R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 1-5 alkyl.

[0499] 18. A compound according to any one of the preceding items, wherein R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 1-3 alkyl.

[0500] 19. A compound according to any one of the preceding items, wherein R 2 Selected from methyl, ethyl, n-propyl and isopropyl.

[0501] 20. A compound according to any one of the preceding items, wherein R 2 is selected from methyl, ethyl, n-propyl and isopropyl, wherein methyl, ethyl, n-propyl or isopropyl is replaced by one or more identical or different substituents R 6 replace.

[0502] 21. A compound according to any one of the preceding items, wherein R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkenyl.

[0503] 22. A compound according to any one of the preceding items, wherein R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 2-5 Alkynyl.

[0504] 23. A compound according to any one of the preceding items, wherein R 2 is optionally substituted by one or more identical or different substituents R 6 Substituted C 3-5 Cycloalkyl.

[0505] 24. A compound according to any one of the preceding items, wherein R 2 is optionally substituted by one or more identical or different substituents R 9 Substituted phenyl.

[0506] 25. A compound according to any one of the preceding items, wherein R 2 is optionally substituted by one or more identical or different substituents R 7 Substituted 5-6 membered aromatic heterocycle.

[0507] 26. A compound according to any one of the preceding items, wherein R 3 It's deuterium.

[0508] 27. A compound according to any one of the preceding items, wherein R 3 It's F.

[0509] 28. A compound according to any one of the preceding items, wherein R 3 It is Cl.

[0510] 29. A compound according to any one of the preceding items, wherein R 4 It's H.

[0511] 30. A compound according to any one of the preceding items, wherein R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 1-5 alkyl.

[0512] 31. A compound according to any one of the preceding items, wherein R 4 Selected from methyl, ethyl, n-propyl and isopropyl.

[0513] 32. A compound according to any one of the preceding items, wherein R 4 It's me.

[0514] 33. A compound according to any one of the preceding items, wherein R 4 It is -CH2F.

[0515] 34. A compound according to any one of the preceding items, wherein R 4 is selected from methyl, ethyl, n-propyl and isopropyl, wherein methyl, ethyl, n-propyl or isopropyl is replaced by one or more identical or different substituents R 7 replace.

[0516] 35. A compound according to any one of the preceding items, wherein R 4 is - optionally substituted by one or more identical or different substituents R 7 Substituted -CH2-OC 1-5 alkyl.

[0517] 36. A compound according to any one of the preceding items, wherein R 4is optionally substituted by one or more identical or different substituents R 7 Substituted -CH2-SC 1-5 alkyl.

[0518] 37. A compound according to any one of the preceding items, wherein R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 2-5 Alkenyl.

[0519] 38. A compound according to any one of the preceding items, wherein R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 2-5 Alkynyl.

[0520] 39. A compound according to any one of the preceding items, wherein R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted -CH2-C 2-4 Alkynyl.

[0521] 40. A compound according to any one of the preceding items, wherein R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 3-5 Cycloalkyl.

[0522] 41. A compound according to any one of the preceding items, wherein R 5 It's H.

[0523] 42. A compound according to any one of the preceding items, wherein R 5 is optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl.

[0524] 43. A compound according to any one of the preceding items, wherein R 5 is optionally substituted by one or more identical or different substituents R 8 Substituted C 3-6 Cycloalkyl.

[0525] 44. A compound according to any one of the preceding items, wherein R 5 is optionally substituted by one or more identical or different substituents R 9 Substituted phenyl.

[0526] 45. A compound according to any one of the preceding items, wherein R 5is optionally substituted by one or more identical or different substituents R 9 Substituted benzyl.

[0527] 46. ​​A compound according to any one of the preceding items, wherein R 6 It's deuterium.

[0528] 47. A compound according to any one of the preceding items, wherein R 6 It's F.

[0529] 48. A compound according to any one of the preceding items, wherein R 6 It is CN.

[0530] 49. A compound according to any one of the preceding items, wherein R 6 is optionally substituted by one or more identical or different substituents R 8 Replaced-OC 1-5 alkyl.

[0531] 50. A compound according to any one of the preceding items, wherein R 6 is optionally substituted by one or more identical or different substituents R 8 Replaced-OC 3-5 Cycloalkyl.

[0532] 51. A compound according to any one of the preceding items, wherein R 6 is optionally substituted by one or more identical or different substituents R 8 Substituted-SC 1-5 alkyl.

[0533] 52. A compound according to any one of the preceding items, wherein R 6 is optionally substituted by one or more identical or different substituents R 8 Substituted-SC 3-5 Cycloalkyl.

[0534] 53. A compound according to any one of the preceding items, wherein R 7 It's deuterium.

[0535] 54. A compound according to any one of the preceding items, wherein R 7 It's F.

[0536] 55. A compound according to any one of the preceding items, wherein R 7 It is CN.

[0537] 56. A compound according to any one of the preceding items, wherein R 7 is optionally substituted by one or more identical or different substituents R 8Replaced-OC 1-5 alkyl.

[0538] 57. A compound according to any one of the preceding items, wherein R 7 is optionally substituted by one or more identical or different substituents R 8 Replaced-OC 3-5 Cycloalkyl.

[0539] 58. A compound according to any one of the preceding items, wherein R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted-SC 1-5 alkyl.

[0540] 59. A compound according to any one of the preceding items, wherein R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted-SC 3-5 Cycloalkyl.

[0541] 60. A compound according to any one of the preceding items, wherein R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted C 3-5 Cycloalkyl.

[0542] 61. A compound according to any one of the preceding items, wherein R 8 It's deuterium.

[0543] 62. A compound according to any one of the preceding items, wherein R 8 It's F.

[0544] 63. The compound according to any of the preceding items, wherein n is 0.

[0545] 64. The compound according to any of the preceding items, wherein n is 1.

[0546] 65. The compound according to any of the preceding items, wherein n is 2.

[0547] 66. The compound according to any of the preceding items, wherein n is 3.

[0548] 67. The compound according to any of the preceding items, wherein X is a bond.

[0549] 68. The compound according to any of the preceding items, wherein X is -O-.

[0550] 69. The compound according to any of the preceding items, wherein X is -S-.

[0551] 70. The compound according to any of the preceding items, wherein X is -CH2-.

[0552] 71. A compound according to any one of the preceding items, wherein X is -CHR 6 -.

[0553] 72. A compound according to any one of the preceding items, wherein X is -C(R 6 )2-.

[0554] 73. A compound according to any one of the preceding items, wherein R 1 is Cl or Br, R 2 is selected from methyl, ethyl, n-propyl and isopropyl, which are optionally substituted by one or more identical or different substituents R 7 Replace, and R 5 It's H.

[0555] 74. The compound according to any one of the preceding items, wherein the compound is selected from:

[0556] (2S)-2-[4-Bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropanoic acid;

[0557] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butanoic acid;

[0558] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0559] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoic acid;

[0560] (2S)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0561] 2-[4-Bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid;

[0562] (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propanoic acid;

[0563] (2S)-2-{4-bromo-2-[difluoro(phenyl)methyl]phenoxy}propanoic acid;

[0564] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-2-cyclopropylacetic acid;

[0565] (2S)-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propanoic acid;

[0566] (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0567] (2S)-2-[4-Bromo-2-(cyclopropyldifluoromethyl)phenoxy]propanoic acid;

[0568] (2S)-2-{4-bromo-2-[difluoro(1,3-thiazol-2-yl)methyl]phenoxy}propanoic acid;

[0569] (2S)-2-[4-Bromo-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid;

[0570] (2S)-2-[4-Bromo-2-(cyclobutyldifluoromethyl)phenoxy]propanoic acid;

[0571] (2R)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;

[0572] (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-chloropropionic acid;

[0573] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]pent-4-ynoic acid;

[0574] (2S)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]pent-4-ynoic acid;

[0575] (2S)-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propanoic acid;

[0576] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2- 2 H) propionic acid;

[0577] (2R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;

[0578] (2S)-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propanoic acid;

[0579] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid;

[0580] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy]propanoic acid;

[0581] (2S)-2-[4-Cyano-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0582] (2R)-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;

[0583] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propanoic acid;

[0584] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)(3,5,6- 2 H3) phenoxy]propionic acid;

[0585] 2-[4-Bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid;

[0586] (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid;

[0587] (2S)-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propanoic acid;

[0588] (2R)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0589] (2S)-2-[2-(1,1-difluoropropyl)-4-vinylphenoxy]propanoic acid;

[0590] 2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid;

[0591] (2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoic acid;

[0592] 2-[4-Bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid;

[0593] 2-[4-Chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid;

[0594] (2S)-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propanoic acid;

[0595] (2R)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid;

[0596] (2S)-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propanoic acid;

[0597] (2R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanoic acid;

[0598] (2R)-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;

[0599] (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutyric acid;

[0600] (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butanoic acid;

[0601] (2S)-2-[2-(1,1-difluoropropyl)-4-vinyl-5-fluorophenoxy]propanoic acid;

[0602] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid;

[0603] (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid;

[0604] (2R)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropionic acid;

[0605] (2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propanoic acid;

[0606] (2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoic acid;

[0607] (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutanoic acid;

[0608] (2R)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropionic acid;

[0609] (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid; and

[0610] (2S)-2-[4-Bromo-2-(1,1-difluoro-3-methoxypropyl)phenoxy]propanoic acid.

[0611] 75. The compound according to any of the preceding clauses, wherein the compound is active at the ClC-1 receptor.

[0612] 76. The compound according to any one of the preceding clauses, wherein the compound is a ClC-1 ion channel inhibitor.

[0613] 77. The compound according to item 80, wherein EC 50<50 μM, such as <40 μM, such as <30 μM, such as <20 μM, such as <15 μM, such as <10 μM, such as <5 μM.

[0614] 78. The compound according to any of the preceding items, wherein the restoration of force in muscles with neuromuscular dysfunction is >5%, such as >10%, such as >15%, such as >20%, such as >25%, such as >30%, such as >35%.

[0615] 79. The compound according to any of the preceding items, wherein the compound improves recovered force in isolated rat soleus muscle after exposure to tubocurarine.

[0616] 80. A composition comprising a compound according to any one of the preceding items.

[0617] 81. The composition according to any of the preceding items, wherein the composition is a pharmaceutical composition.

[0618] 82. A compound or composition according to any of the preceding items for use as a medicament.

[0619] 83. The composition according to any one of the preceding items, wherein the composition further comprises a pharmaceutically acceptable carrier.

[0620] 84. The composition according to any of the preceding items, wherein the composition further comprises at least one other active agent.

[0621] 85. A composition according to any one of the preceding items, wherein the other active agent is suitable for treating, preventing or ameliorating the neuromuscular disorder.

[0622] 86. A composition according to any one of the preceding items, wherein the other active agent is an acetylcholinesterase inhibitor.

[0623] 87. A composition according to any of the preceding items, wherein the acetylcholinesterase inhibitor is selected from delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium chloride, demecarium bromide, rivastigmine, phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine, edrophonium, huperzine, radostigmine, enzimine and oleuropein.

[0624] 88. The composition according to any one of the preceding items, wherein the acetylcholinesterase inhibitor is neostigmine or pyridostigmine.

[0625] 89. The composition according to any of the preceding items, wherein the other active agent is sugammadex.

[0626] 90. The composition according to any of the preceding items, wherein the other active agent is tirasemtiv or CK-2127107.

[0627] 91. The composition according to any of the preceding items, wherein the other active agent is 3,4-aminopyridine.

[0628] 92. A method for preparing a compound according to any one of the preceding items, the method comprising the following steps:

[0629] a. Making a compound having formula (GM.III)

[0630]

[0631] Where R 4 and R 5 As defined in any of the preceding items,

[0632] with a compound having the formula (GM.II) under Mitsunobu or similar reaction conditions,

[0633]

[0634] Where R 1 , R 2 , R 3 , n and X are defined as in any of the preceding items to produce a compound having formula (GM.IV)

[0635]

[0636] b. reacting the product compound of a) with an ester hydrolyzing agent to produce a compound as defined in any one of the preceding items.

[0637] 93. A method for preparing a compound according to any one of the preceding items, the method comprising the following steps:

[0638] a. Making a compound having formula (GM.VI)

[0639]

[0640] Where R 4 and R 5 as defined herein, and Y is a leaving group (eg, mesylate or tosylate),

[0641] with a compound of formula (GM.II) under conditions involving a suitable base such as a sterically hindered amine or an alkali metal carbonate

[0642]

[0643] Where R 1 , R 2 , R 3 , n and X are defined as in any of the preceding items to produce a compound having formula (GM.IV)

[0644]

[0645] b. reacting the product compound of a) with an ester hydrolysis agent to produce a compound according to any one of the preceding items.

[0646] 94. A method for preparing a compound according to any one of the preceding items, the method comprising the following steps:

[0647] a. Making a compound having formula (GM.VIII)

[0648]

[0649] Where R 4 and R 5 As defined in any of the preceding items,

[0650] Reaction with a compound having formula (GM.VII)

[0651]

[0652] Where R 1 , R 2 , R 3 , n and X are as defined in any of the preceding items, and Q is a suitable leaving group, such as a halogen, such as fluorine or iodine, to produce a compound having formula (GM.IV)

[0653]

[0654] b. reacting the product compound of a) with an ester hydrolysis agent to produce a compound according to any one of the preceding items.

[0655] 95. A method for preparing a compound according to any one of the preceding items, the method comprising the following steps:

[0656] a. Making a compound having formula (GM.IX)

[0657]

[0658] Where R 4 As defined in any of the preceding items, and R 10 is a suitable protecting group, such as a silyl-containing moiety,

[0659] Reaction with a compound having the formula (GM.II) under Mitsunobu or similar reaction conditions

[0660]

[0661] Where R 1 , R 2 , R 3 , n and X are defined as in any of the preceding items to produce a compound having the formula (GM.X)

[0662]

[0663] b. Removal of the protective group R of the product compound of a) 10 ;and

[0664] c. reacting the product compound of b) with an oxidizing agent to produce a compound according to any one of the preceding items.

[0665] 96. A method for preparing a compound according to any one of the preceding items, the method comprising the following steps:

[0666] a. Making a compound having formula (GM.III)

[0667]

[0668] Where R 4 and R 5 As defined in any of the preceding items,

[0669] reacting with a compound having the formula (GM.XI),

[0670]

[0671] Where R 1 , R 2 , R 3 , n and X are defined as in any of the preceding items to produce a compound having formula (GM.XII)

[0672]

[0673] b. converting the keto group of the product compound of a) into an alkyl-difluoro group; and

[0674] c. reacting the product compound of b) with an ester hydrolyzing agent to produce a compound according to any one of the preceding items.

[0675] 97. A method for preparing a compound according to any one of the preceding items, the method comprising the following steps:

[0676] a. Making a compound having formula (GM.XIII)

[0677]

[0678] Where R 1 , R 3 , R 4 , R 5 and n is as defined in any of the preceding items,

[0679] Reaction under acylation conditions to produce a compound having formula (GM.XII)

[0680]

[0681] b. converting the keto group of the product compound of a) into an alkyl-difluoro group, wherein X is a bond and R 2 as defined in any of the preceding items; and

[0682] c. reacting the product compound of b) with an ester hydrolyzing agent to produce a compound according to any one of the preceding items.

[0683] 98. A method for preparing a compound according to any one of the preceding items, the method comprising the following steps:

[0684] a. Making a compound having formula (GM.IX)

[0685]

[0686] Where R 4 and R 9 As defined herein,

[0687] reacting with a compound having formula (GM.XV),

[0688]

[0689] Where R 1 , R 2 , R 3 and n are as defined herein, to produce a compound having formula (GM.XIV)

[0690]

[0691] b. converting the keto group of the product compound of a) into an alkyl-difluoro group;

[0692] c. Removal of the protective group R of the product compound of b) 10 ;and

[0693] d. reacting the product of c) with an oxidizing agent to produce a compound as defined herein.

[0694] 99. A compound according to any one of the preceding items for use in the treatment, amelioration and / or prevention of neuromuscular disorders, and / or for reversing and / or improving neuromuscular blockade.

[0695] 100. Compound for use according to any of the preceding items, wherein the neuromuscular disorder is myasthenia gravis.

[0696] 101. Compound for use according to any of the preceding items, wherein the neuromuscular disorder is autoimmune myasthenia gravis.

[0697] 102. Compound for use according to any of the preceding items, wherein the neuromuscular disorder is congenital myasthenia gravis.

[0698] 103. Compound for use according to any of the preceding items, wherein the neuromuscular disorder is Lambert-Eaton syndrome.

[0699] 104. The compound for use according to any of the preceding items, wherein the neuromuscular disorder is critical illness myopathy.

[0700] 105. The compound for use according to any of the preceding items, wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS).

[0701] 106. The compound for use according to any of the preceding items, wherein the neuromuscular disorder is spinal muscular atrophy (SMA).

[0702] 107. The compound for use according to any of the preceding items, wherein the neuromuscular disorder is critical illness myopathy (CIM).

[0703] 108. Compound for use according to any of the preceding items, wherein the neuromuscular disorder is Charcot-Marie-Tooth disease (CMT).

[0704] 109. The compound for use according to any of the preceding items, wherein the neuromuscular disorder is sarcopenia.

[0705] 110. Compound for use according to any of the preceding items, wherein the neuromuscular disorder is caused by diabetic polyneuropathy.

[0706] 111. Compound for use according to any of the preceding items, wherein the neuromuscular disorder is periodic paralysis.

[0707] 112. Compound for use according to any of the preceding items, wherein the neuromuscular disorder is hypokalemic periodic paralysis or hyperkalemic periodic paralysis.

[0708] 113. Compound for use according to any of the preceding items, wherein the neuromuscular disease is myotubular myopathy.

[0709] 114. The compound for use according to any of the preceding items, wherein the neuromuscular disease is Duchenne muscular dystrophy.

[0710] 115. A compound for use according to any of the preceding items for the treatment of botulism.

[0711] 116. A compound for use according to any of the preceding items for the treatment of snake bites.

[0712] 117. A compound for use according to any of the preceding items for the treatment or prevention of nerve gas poisoning.

[0713] 118. Compound for use according to any of the preceding items, wherein the neuromuscular disorder is selected from Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome and critical illness polyneuropathy.

[0714] 119. A compound for use according to any of the preceding items, wherein the compound is used to treat the 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), critical illness myopathy (CIM), reversal diabetic polyneuropathy, Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, periodic paralysis, sarcopenia syndrome, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy and Duchenne muscular dystrophy.

[0715] 120. The compound for use according to any of the preceding items, wherein the neuromuscular disorder is induced via a neuromuscular blocking agent.

[0716] 121. The compound for use according to any of the preceding items, wherein the neuromuscular blockade is post-operative neuromuscular blockade.

[0717] 122. Compound for use according to any of the preceding items, wherein the neuromuscular blockade is drug-induced.

[0718] 123. A compound for use according to any of the preceding items, wherein the drug is an antibiotic.

[0719] 124. A compound for use according to any of the preceding items, wherein the drug is a non-depolarizing neuromuscular blocking agent.

[0720] 125. A compound for use according to any of the preceding items, wherein the compound has been further modified so as to increase its half-life, in particular its plasma half-life, when administered to a patient.

[0721] 126. The compound for use according to any of the preceding items, wherein the compound further comprises a moiety conjugated to the compound, thereby generating a moiety-conjugated compound.

[0722] 127. A compound for use according to any of the preceding items, wherein the partially-conjugated compound has a plasma and / or serum half-life that is longer than the plasma and / or serum half-life of the non-partially conjugated compound.

[0723] 128. The compound for use according to any of the preceding items, wherein the moiety conjugated to the compound is one or more types of moieties selected from albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies and antibody fragments.

[0724] 129. A compound for use according to any one of the preceding items, wherein the compound is comprised in a composition.

[0725] 130. A compound for use according to any of the preceding items, wherein the composition is a pharmaceutical composition.

[0726] 131. A compound for use according to any of the preceding items, wherein the composition further comprises a pharmaceutically acceptable carrier.

[0727] 132. A compound for use according to any of the preceding items, wherein the composition further comprises at least one other active agent.

[0728] 133. A compound for use according to any of the preceding items, wherein the other active agent is suitable for treating, preventing or ameliorating the neuromuscular disorder.

[0729] 134. The compound for use according to any of the preceding items, wherein the other active agent is an acetylcholinesterase inhibitor.

[0730] 135. A compound for use according to any of the preceding items, wherein the acetylcholinesterase inhibitor is selected from delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium chloride, demecarium bromide, rivastigmine, phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine, tensilon, huperzine, radostigmine, enzimine and oleuropein.

[0731] 136. The compound for use according to any of the preceding items, wherein the acetylcholinesterase inhibitor is neostigmine or pyridostigmine.

[0732] 137. The compound for use according to any of the preceding items, wherein the other active agent is sugammadex.

[0733] 138. The compound for use according to any of the preceding items, wherein the other active agent is tirasemtiv.

[0734] 139. The compound for use according to any of the preceding items, wherein the other active agent is 3,4-aminopyridine.

[0735] 140. A method for treating, preventing and / or ameliorating a neuromuscular disorder, said method comprising administering to a person in need thereof a therapeutically effective amount of a compound as defined in any one of the preceding items.

[0736] 141. Use of a compound as defined in any of the preceding items for the preparation of a medicament for the treatment, amelioration and / or prevention of neuromuscular disorders, and / or for reversing and / or improving neuromuscular blockade.

[0737] 142. A method for reversing and / or ameliorating neuromuscular blockade, said method comprising administering to a human in need thereof a therapeutically effective amount of a compound as defined in any of the preceding items.

[0738] 143. A method for restoring neuromuscular transmission, the method comprising administering to a human in need thereof a therapeutically effective amount of a compound as defined in any one of the preceding clauses.

[0739] 144. A method for restoring neuromuscular transmission, the method comprising administering to a subject in need thereof a compound as defined in any one of the preceding clauses. Example

[0740] Materials and methods

[0741] Chemicals

[0742] Compounds used for testing were obtained from various suppliers including Enamine, Vitas, and CanAmBioresearch. See below for the synthesis of specific compounds.

[0743] NMR spectroscopy

[0744] 1 H-NMR and 19 F-NMR spectra were recorded on a Bruker AM-300 spectrometer and calibrated using residual non-deuterated solvent as 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 Ultrashieldplus equipped with a BBO 400MHz S1 5mm probe and a Z-gradient probe, or on a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbeTM, using residual non-deuterated solvent as internal standard for calibration and processed using topspin version 3.2.7.

[0745] LC / MS Systems

[0746] The samples were analyzed by direct injection into a Waters Acquity QDa mass spectrometer equipped with a Waters 2695HPLC and a WATERS Micromass equipped with a WATERS 2795HPLC. Mass spectra were processed using WATERS Masslynx software. Mass spectra were recorded in ESI scan mode (negative / positive).

[0747] HPLC method

[0748] The product was analyzed using a Waters 2695 HPLC, which consisted of a Waters 996 photodiode array detector, a Kromasil Eternity C18, 5 μm, 4.6×150 mm column. Flow rate: 1 mL / min, run time 20 minutes. The chromatograms were processed using WATERS Empower software.

[0749] Method 1A: Solvent A: methanol; Solvent B: 0.1% formic acid in water. Gradient of solvent B 0-100% in 15 minutes and monitored at 280 nm.

[0750] Method 1A: Solvent C: acetonitrile; Solvent D: 0.1% formic acid in water. Gradient of solvent C vs D 10-100% over 15 minutes and monitored at 280 nm.

[0751] Acid 2-minute method

[0752] LCMS analysis was performed using a Waters Acquity UPLC system consisting of an Acquity Class I Sample Manager-FL, an Acquity Class I Binary Solvent Manager, and an Acquity UPLC Column Manager. UV detection was provided by an Acquity UPLC PDA detector (scanning range from 210 nm to 400 nm), and mass detection was provided by an Acquity QDa detector (mass scan range 100-1250 Da; both positive and negative modes). Separation of the analytes was achieved using a Waters Acquity UPLC BEH C18 column (2.1x50 mm 1.7 mm).

[0753] Samples were prepared by dissolving (with or without sonication) into 1 mL of 50% v / v MeCN in water. These solutions were filtered with a 0.45 mm syringe filter before submission for 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, equilibration time between samples 1.5 min.

[0754] gradient:

[0755] Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.25 95 5 1.25 5 95 1.55 5 95 1.65 95 5 2.00 95 5

[0756] Alkaline 2-minute method

[0757] Samples were prepared by dissolving (with or without sonication) into 1 mL of 50% v / v MeCN in water. These solutions were filtered with a 0.45 mm syringe filter before submission for analysis. All solvents (and ammonium bicarbonate) used (including 35% ammonia solution) were HPLC grade.

[0758] Conditions: 10 mM ammonium bicarbonate + 0.1% v / v 35% ammonia solution [eluent A]; 0.1% v / v 35% ammonia in MeCN [eluent B]; flow rate 0.8 mL / min; injection volume 2 mL, equilibration time between samples 1.5 min.

[0759] gradient:

[0760] Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.25 95 5 1.25 5 95 1.55 5 95 1.65 95 5 2.00 95 5

[0761] Acid 4-minute method

[0762] Samples were prepared by dissolution (with or without sonication) into 1 mL of 50% v / v MeCN in water. These solutions were filtered using a 0.45 mm syringe filter before submission for analysis. All solvents used (including formic acid) were of HPLC grade.

[0763] 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, equilibration time between samples 1.5 min.

[0764] gradient:

[0765] Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.25 95 5 2.75 5 95 3.25 5 95 3.35 95 5 4.00 95 5

[0766] Alkaline 4-minute method

[0767] Samples were prepared by dissolution (with or without sonication) into 1 mL of 50% v / v MeCN in water. These solutions were filtered with a 0.45 mm syringe filter before submission for analysis. All solvents used (including 36% ammonia solution) were HPLC grade.

[0768] 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, equilibration time between samples 1.5 min.

[0769] gradient:

[0770] Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.25 95 5 2.75 5 95 3.25 5 95 3.35 95 5 4.00 95 5

[0771] Chiral SCF Method 1

[0772] Compounds were analyzed using a Waters ACQUITY Ultra Performance Convergence Chromatography (UPC2) system equipped with a binary solvent delivery pump, autosampler, column oven (CM-30S), backpressure regulator, and diode array detector.

[0773] Column: Lux A1 (4.6 mm x 250 mm, 5 μm).

[0774] Conditions: 40°C, 4 mL / min, isocratic 10:90 EtOH:CO2 (0.1% v / v TFA), 125 BarG.

[0775] Chiral HPLC

[0776] The HPLC instrument was equipped with an Agilent 1200 binary pump, an Agilent 1200 variable wavelength detector (UV-vis detector) and a Shodex 150×4.5 mm, 3 μm chiral column. Flow rate 0.5 mL / min. Solvent A: 0.05% CH3COOH and 0.2 M NaCl in water. Solvent B: acetonitrile. Chiral HPLC analysis was performed under isocratic conditions (75% solvent A and 25% solvent B) at a wavelength of 280 nm. The chromatograms were processed using Agilent ChemStation software.

[0777] General synthetic strategy

[0778] The compounds of formula (I) can be synthesized by the following general method:

[0779] General Method A

[0780]

[0781] Method A involves the synthesis of compound (GM.V), which is an aryloxy-substituted acetic acid derivative, wherein R 1 To R 9 , n and X are as defined above in formula (I). Compound (GM.II) is commercially available or synthesized and can be converted to ether (GM.IV) by a method that includes a modification of the Mitsunobu reaction conditions. This ether contains an ester functional group -CO2R 5 , which can be hydrolyzed under a range of standard conditions (including acid or base) to provide the carboxylic acid structure (GM.V). These standard conditions may also, for example, involve enzymatic hydrolysis, using, for example, esterases or lipases. If the ester molecule (GM.IV) includes, for example, a (CH3)3SiCH2CH2O- group as the -OR 5 , then a fluoride ion source (such as tetra-n-butylammonium fluoride) can be used to convert (GM.IV) into the corresponding carboxylic acid (GM.V).

[0782] Substituted phenols of general formula (GM.II) can be prepared by a variety of standard methods, for example by ester rearrangement in Fries rearrangement, N-phenylhydroxylamine rearrangement in Bamberger rearrangement, hydrolysis of phenolic esters or ethers, by quinone reduction, or by replacement of aromatic amines or hydroxyls with water and sodium hydrosulfide in Bucherer reaction. Other methods include hydrolysis of diazonium salts, by rearrangement of diene ketones in diene ketone phenol rearrangement, by oxidation of aryl silanes, by Hock method.

[0783] Phenols of formula (GM.II) wherein X is a bond can be prepared by a Grignard reaction of a suitable Grignard reagent for a 2-hydroxybenzonitrile derivative.

[0784] General Method B

[0785]

[0786] Method B involves the synthesis of compound (GM.V), an aryloxy-substituted acetic acid derivative, wherein R 1 To R 9 , n and X are as defined above in formula (I) and in connection with method A. Compound (GM.II) is commercially available or synthetically obtained and can be converted to the ether (GM.IV) by displacement of a suitable leaving group Y (e.g. mesylate or tosylate) under conditions involving a suitable base such as a sterically hindered amine or an alkali metal carbonate.

[0787] General Method C

[0788]

[0789] Carboxylic acids of general formula (GM.V) can alternatively be prepared by the procedures described in general method C. Phenol ethers of formula (GM.IV) can be prepared by displacing a suitable leaving group Q in (GM.VII). Q may for example be a halogen, such as fluorine or iodine, and the ether product of formula (GM.IV) can be converted to the carboxylic acid derivative (GM.V) by one of a range of methods outlined in method A, including hydrolysis of the ester function.

[0790] General Method D

[0791]

[0792] Carboxylic acids of general formula (GM.V) can be prepared by the procedure outlined in General Method D. Phenol ethers of formula (GM.II) can be prepared by using, for example, Mitsunobu conditions on the phenol structure (GM.II), and (GM.IX) is a suitable secondary alcohol, wherein R 1 To R 9 , n and X are as defined above in formula (I), and -R 10 is a suitable protecting group, such as a silyl-containing moiety. 10 That is, after the deprotection step, the primary alcohol (GM.X) can be oxidized to the carboxylic acid under standard conditions including potassium permanganate, Jones oxidation conditions, Heyns oxidation, ruthenium tetroxide or TEMPO.

[0793] General Method E

[0794]

[0795] General formula (GM.V) (where R 1 To R9 Carboxylic acids (wherein GM.XII is defined as above for formula (I)) can be prepared by the procedure shown in General Method E. Phenols (GM.XI) are commercially available or synthetically obtained and can be converted to ethers (GM.XII) by methods including modifications to the Mitsunobu reaction conditions. The acyl group in the ether (GM.XII) can be converted to an alkyl-difluoro derivative by a series of fluorination conditions (including the use of deoxofluor as a reagent) to provide compounds (GM.V) after ester hydrolysis.

[0796] General Method F

[0797]

[0798] The carboxylic acid of formula (V) (wherein R 1 To R 9 and n is as defined in formula (I) above and X is a bond) can be prepared by the procedure as 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 methods including the classic Friedel Crafts aromatic acylation reaction, a well-known variation of which is carried out by alkanoyl 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, including the use of deoxofluor as a reagent, to provide the compound (GM.V) after ester hydrolysis. Another procedure is to acylate the protected primary alcohol derivative and oxidize the deprotected alcohol as described in General Method D above.

[0799] General Method G

[0800]

[0801] The carboxylic acid of the general formula (XVIII) (wherein R 1 To R 9 and n as defined above in formula (I), formula (II) and formula (III)) can be prepared by the procedure as shown in general method G. Phenol (GM.XV) is commercially available or can be prepared from phenol (GM.XIV) by reaction with, for example, an acyl halide followed by rearrangement using, for example, AlCl3. Phenol (GM.XV) is then converted to ether (GM.XVI) by methods including variations of Mitsunobu reaction conditions. In some cases, it may be necessary to change the protecting group -R 10 , the acyl group in the ether (GM.XVI) is then converted to the alkyl-difluoro derivative (GM.XVII) via a series of fluorination conditions including the use of deoxofluor as a reagent. 10The primary alcohol can then be oxidized to the carboxylic acid (GM.XVIII) under standard conditions including potassium permanganate, Jones oxidation conditions, Heyns oxidation, ruthenium tetroxide, or TEMPO.

[0802] General Method H

[0803]

[0804] Carboxylic acid of general formula (GM.V) (wherein R 1 To R 9 , n and X are as defined in formula (I) above) can be prepared by the procedure as shown in General Method G. Phenol (GM.XI) is commercially available or can be prepared as described in General Method G, which can be converted to alkyl-difluoro derivatives (GM.II) through a series of fluorination conditions (including the use of deoxofluor as a reagent). Alkyl-difluoro derivatives (GM.II) are then coupled with esters (GM.III) using methods including variations of Mitsunobu reaction conditions to obtain esters (GM.IV). Esters (GM.IV) can be further functionally modified, for example on the aromatic ring, and then hydrolyzed to carboxylic acids (GM.V).

[0805] Exemplary compounds

[0806] Table 1 below illustrates the preparation of example compounds defined by general formula (I) in >95% purity.

[0807] Table 1: Exemplary embodiments of the present disclosure

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824] Example 1: Synthesis of (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propionic acid

[0825]

[0826] Step 1: Synthesis of (S)-methyl 2-(2-acetyl-4-bromophenoxy)propionate 2

[0827] Under stirring, DIAD (6.96 mL) was slowly added to a solution of (R)-2-hydroxypropionic acid methyl ester 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 150 mL DCM previously cooled to 0 ° C. The ice bath was then removed, and the mixture was stirred at room temperature overnight and then concentrated under reduced pressure. After removing 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 light yellow oil.

[0828] 1 H 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).

[0829] Step 2: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)propanoate 3

[0830] To a solution of (S)-methyl 2-(2-acetyl-4-bromophenoxy)propanoate 2 (3.99 g, 13.3 mmol) in dry CH2Cl2 (40 mL) in a sealed tube was added de-oxofluor (24.5 ml, 133 mmol, 10 eq), purged with argon and sealed with a cap. The resulting mixture was stirred at 40 °C for 7-8 days until the starting material was completely consumed. After the reaction was complete, the reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution and stirred for 20 to 30 minutes. The aqueous layer was extracted with ethyl acetate (2x100 mL). The combined organic extracts were washed with brine and dried (Na2SO4). 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.

[0831] 1 F 19 NMR (300MHz, CDCl3) δ-85.67,-89.11.

[0832] Step 3: Synthesis of sodium (S)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)propionate 4

[0833] Solid NaOH (200 mg, 5.01 mmol) was added to a solution of (S)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)propanoic acid methyl ester 3 (1.62 g, 5.01 mmol) in MeOH (32 mL) and water (8 mL) at <10 °C, and the resulting mixture was stirred at room temperature for 1-2 h (the reaction was monitored by TLC). After the reaction was complete, the volatiles were removed and the reaction mixture was diluted with water (30 mL). The water layer was washed with DCM (2x20 mL) to remove impurities and unreacted ester. The water layer was separated, water was removed under reduced pressure, and the product 4 was dried in vacuo to obtain the desired product 4 as a light yellow solid (1.54 g, 99%).

[0834] 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.

[0835] MS (ES-): m / z 307.0 (MH) -. HPLC retention time: 11.16min

[0836] Chiral SCF Method 1: 1.17 min (>99% ee). (R)-enantiomer at 1.43 min.

[0837] Example 2: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)propionic acid

[0838] This compound was prepared as described in Example 1.

[0839] (S)-2-(4-bromo-2-propionylphenoxy)propionic acid methyl ester

[0840] 1H 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).

[0841] (S)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)propionic acid methyl ester

[0842] 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 (300MHz, CDCl3) delta -93.5 and -99ppm.

[0843] (S)-2-(4-Bromo-2-(1,1-difluoropropyl)phenoxy)propanoic acid

[0844] 1H 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 (300MHz, CDCl3) delta -94 and -98ppm.

[0845] MS (ES-): m / z 321.2 (MH) - . HPLC retention time: 13.56min

[0846] Chiral SCF Method 1: 1.09 min (>97.2% ee). (R)-enantiomer at 1.25 min.

[0847] Example 3: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropionic acid

[0848]

[0849] Synthesis of (S)-1-(Benzyloxy)-3-fluoropropan-2-ol

[0850] (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 RT under N2. 1M TBAF in THF (3.91 L, 3.2 eq.) was added [no exotherm] and the reaction was stirred at RT under N2. The reaction was heated to 65°C in 1 h 30 min and stirred at 65°C for 21 h, at which time LC showed 76% of product. The reaction was cooled to 25°C and KHF2 (9.9 g, 0.13 mol, 0.1 eq) and CsF (19.1 g, 0.13 mol, 0.1 eq) were added. The reaction was heated to 65°C and maintained for 18 h, at which time LC showed 77% of product. The reaction was cooled to room temperature and H2O (3.90 L) was added over 5 min [mild exotherm]. The aqueous phase was extracted with toluene (3 x 1.00 L). The combined organic extracts were washed with 20% K2CO3 (aq) (1.90 L) and H2O (2 x 1.90 L) and then concentrated in vacuo to give 315 g of crude product with 87% purity by LC. The material was passed through column chromatography (2.0 Kg, 10 eq. SiO2, 5→15% EtOAc in heptane), the product was eluted, and two portions were obtained, which were concentrated in vacuo. The first portion gave 19 g (8% yield) of product with 91% by LC, and the second portion gave 163 g (73% yield) with 97% by LC, 1 H NMR showed >95%.

[0851] Step 1: Synthesis of (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromophenyl)propan-1-one 2

[0852] To a 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 60 mL of dichloromethane previously cooled to 0°C was slowly added DIAD (4.25 g, 21.0 mmol). The ice bath was then removed and the reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate / hexanes to give the desired product 2 (5.0 g, 72.5%) as a light yellow oil.

[0853] 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).

[0854] 19 F NMR (300MHz, CDCl3) δ-230.69ppm.

[0855] Step 2: Synthesis of (R)-1-(5-bromo-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)propan-1-one 3

[0856] Pyridine·HCl (36.65 g, 31.7 mmol) was added 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. The reaction mixture was heated at 180 °C for 90 min. The reaction mixture was cooled and then quenched with H2O (50 mL), and the product was extracted with ethyl acetate (2x100 mL), washed with H2O (2x30 mL), brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was passed through a silica gel column (EtOAc / hexanes, 0-50%) to give the desired product 3 (2.84 g, 73.5%) as a white solid.

[0857] 1 H 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).

[0858] 19 F NMR (300MHz, CDCl3) δ-229.52ppm.

[0859] Step 3: Synthesis of (R)-2-(4-bromo-2-propionylphenoxy)-3-fluoropropyl acetate 4

[0860] 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 (2x50 mL), washed with H2O (3x20 mL), brine (20 mL), dried over sodium sulfate and concentrated to give crude product 4 (2.21 g, quantitative) which was used in the next step without further purification.

[0861] 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).

[0862] Step 4: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropyl acetate 5

[0863] In a sealed tube, deoxo-fluor (14.15 ml, 64.0 mmol) was added to a solution of (R)-2-(4-bromo-2-propionylphenoxy)-3-fluoropropyl acetate (2.21 g, 6.4 mmol) in dry CH2Cl2 (1 mL), purged with argon, and sealed with a cap. The resulting mixture was stirred at 40 °C for 5-7 days. The reaction mixture was poured into ice-cold water (20 mL), and saturated aqueous sodium carbonate solution was carefully added and the mixture was stirred for 20 to 30 min. The aqueous layer was extracted with ethyl acetate (2x50 mL). The combined organic extracts were washed with brine (25 mL) and dried (Na2SO4). 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 light yellow oil.

[0864] 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).

[0865] 19 F NMR (300MHz, CDCl3) δ-96.31, -96.58, -230.69ppm.

[0866] Step 5: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropan-1-ol 6

[0867] To a solution of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropyl acetate (1.3 g, 3.5 mmol) in MeOH / H2O (20 / 10 mL) was added K2CO3 (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.

[0868] 1 H 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).

[0869] 19 F NMR (300MHz, CDCl3) δ-94.10, -98.99, -230.30ppm.

[0870] Step 6: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropionic acid 7

[0871] 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 hours. 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 the reaction was complete, the mixture was cooled to 0 °C and 1 M NaOH solution was added to adjust the pH to 13 and the product was washed with DCM (40 mL). The aqueous layer was separated, cooled to 0 °C again, and acidified with 1M HCl to pH ∼ 1. The product was extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to give 7 as a white solid (1.0 g, 96.1%).

[0872] 1H 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).

[0873] 19 F NMR (300MHz, CDCl3) δ-94.61,-97.86,-228.93ppm.

[0874] Step 7: Synthesis of sodium (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropionate 8

[0875] 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) at 0°C was added 5 mL of aqueous solution of NaHCO3 (0.247 g, 2.94 mmol). The reaction mixture was stirred at room temperature for 30 min. The acetonitrile was removed in situ and the aqueous solution was lyophilized to afford 8 as a white solid (1.0 g, 94%).

[0876] 1H 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).

[0877] 19 F NMR (300MHz, CDCl3) δ-96.91,-97.92,-226.21ppm.

[0878] MS (ES-): m / z 339.4 (MH), HPLC retention time: 11.68 min

[0879] Example 4: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropionic acid

[0880]

[0881] Step 1: Synthesis of (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromophenyl)ethanone 2

[0882] 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 previously cooled to 0°C was slowly added DIAD (1.21 g, 5.98 mmol). The ice bath was then removed and the reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate / hexanes to give the desired product 2 (1.1 g, 57.7%) as a light yellow oil.

[0883] 1H 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).

[0884] 19 F NMR (300MHz, CDCl3) δ-230.48ppm.

[0885] Step 2: Synthesis of (R)-1-(5-bromo-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)ethanone 3

[0886] In a 100 mL round bottom flask, pyridine·HCl (8.33 g, 72.1 mmol) was added to (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromophenyl)ethanone (1.1 g, 2.88 mmol). The reaction mixture was heated at 180°C for 90 min and then cooled. The reaction mixture was quenched with H2O (30 mL), and the product was extracted with ethyl acetate (2x50 mL), washed with H2O (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.

[0887] 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).

[0888] 19 F NMR (300MHz, CDCl3) δ-229.93ppm.

[0889] Step 3: Synthesis of (R)-2-(2-acetyl-4-bromophenoxy)-3-fluoropropyl acetate 4

[0890] 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 (2x50 mL), washed with H2O (3x30 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.

[0891] 1H 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).

[0892] 19 F NMR (300MHz, CDCl3) δ-231.06ppm.

[0893] Step 4: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropyl acetate 5

[0894] In a sealed tube, deoxo-fluor (5.09 ml, 27.6 mmol) was added to a solution of (R)-2-(2-acetyl-4-bromophenoxy)-3-fluoropropyl acetate (0.92 g, 2.76 mmol) in dry CH2Cl2 (1 mL), purged with argon, and sealed with a cap. 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 to 30 min. The aqueous layer was extracted with ethyl acetate (2x30 mL). The combined organic extracts were washed with brine (25 mL) and dried (Na2SO4). After removing 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 light yellow oil.

[0895] 1H 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).

[0896] 19 F NMR (300MHz, CDCl3) δ-86.97,-87.97,-230.69ppm.

[0897] Step 5: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropan-1-ol 6

[0898] To a solution of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropyl acetate (0.69 g, 1.94 mmol) in MeOH / H2O (40 / 4 mL) was added K2CO3 (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.

[0899] 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).

[0900] 19 F NMR (300MHz, CDCl3) δ-86.08, -88.97, -230.49ppm.

[0901] Step 6: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)-3-fluoropropionic acid 7

[0902] 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 ~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 hours, 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 the reaction was complete, the mixture was cooled to 0 °C and 1 M NaOH solution was added to adjust the pH to 13, and the product was washed with DCM (40 mL). The aqueous layer was separated, cooled to 0°C again, and acidified with 1M HCl to pH 1. The product was extracted with ethyl acetate (2x50 mL), washed with water (2x20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to give the product 7 as a white solid (0.53 g, 92.2%).

[0903] 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);

[0904] 19 F NMR (300MHz, CDCl3) δ-228.15, -88.33, -86.24; ES-MS: 326[M-1].

[0905] HPLC retention time: 10.852 min, 99.45% purity @ 280 nm.

[0906] Example 5: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)propionic acid

[0907]

[0908] Step 1: Synthesis of (S)-methyl 2-(4-bromo-5-fluoro-2-propionylphenoxy)propionate 2

[0909] 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 previously cooled to 0°C was slowly added DIAD (0.605 g, 2.99 mmol). The ice bath was then removed and the reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-20% ethyl acetate / hexanes to give the desired product 2 (0.52 g, 62.9%) as a light yellow oil.

[0910] 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).

[0911] 19 F NMR (300MHz, CDCl3) δ-98.44ppm.

[0912] Step 2: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)propanoate 3

[0913] In a sealed tube, deoxo-fluor (2.9 ml, 15.7 mmol) was added to a solution of (S)-2-(4-bromo-5-fluoro-2-propionylphenoxy)propionic acid methyl ester (0.52 g, 1.57 mmol) in dry CH2Cl2 (0.5 mL), purged with argon, and sealed with a cap. The resulting mixture was stirred at 40 ° C for 5-7 days. The reaction mixture was poured into ice-cold water (10 mL), and saturated aqueous sodium carbonate solution was carefully added and the mixture was stirred for 20 to 30 min. The aqueous layer was extracted with ethyl acetate (2x30 mL). The combined organic extracts were washed with brine (15 mL) and dried (Na2SO4). After removing the solvent, the residue was purified by silica gel column chromatography using 0-20% ethyl acetate / hexane to obtain the desired product 3 (0.45 g, 81.0%) as a light yellow oil.

[0914] 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).

[0915] 19 F NMR (300MHz, CDCl3) δ-92.58,-98.20,-102.00ppm.

[0916] Step 3: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)propanoic acid 4

[0917] 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.

[0918] 1 H 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).

[0919] 19 F NMR (300MHz, CDCl3) δ-93.27,-97.65,-101.65ppm.

[0920] MS (ES-): m / z 339.3 (MH), HPLC retention time: 12.04 min

[0921] Example 6: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropionic acid

[0922]

[0923] Step 1: Synthesis of 1-(5-bromo-4-fluoro-2-hydroxyphenyl)propan-1-one 2

[0924] 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 x 90 mL), washed with H2O (3 x 75 mL), brine (60 mL), dried over sodium sulfate, and concentrated.

[0925] The crude material was placed 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 obtain the desired product 2 (16.6 g, 93.6%) as a light brown solid.

[0926] 1 H NMR (300MHz, CDCl3) δ12.55(d,1H),7.95(d,1H),6.76(d,1H),2.99(q,2H),1.24(t,3H).

[0927] 19 F NMR (300MHz, CDCl3) δ-94.156ppm.

[0928] Step 2: Preparation of (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromo-4-fluorophenyl)propan-1-one 3 synthesis

[0929] 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 previously cooled to 0°C was slowly added DIAD (1.89 g, 9.37 mmol). The ice bath was then removed and the reaction mixture was stirred at room temperature for 4 days and then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate / hexanes to give the desired product 3 (1.5 g, 43.6%) as a light yellow oil.

[0930] 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).

[0931] 19 F NMR (300MHz, CDCl3) δ-95.85,-230.30ppm.

[0932] Step 3: Synthesis of (R)-1-(5-bromo-4-fluoro-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)propan-1-one 4

[0933] In a 250 mL round bottom flask, pyridine HCl (10.5 g, 90.7 mmol) was added to (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-bromo-4-fluorophenyl)propan-1-one (1.5 g, 3.62 mmol). The reaction mixture was heated at 180 °C for 90 min. The reaction mixture was cooled, quenched with H2O (30 mL), and the product was extracted with ethyl acetate (2x50 mL), washed with H2O (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 / hexanes, 0-50%) to give the desired product 4 (1.08 g, 92.1%) as a white solid.

[0934] 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).

[0935] 19F NMR (300MHz, CDCl3) δ-97.68,-229.52ppm.

[0936] Step 4: Synthesis of (R)-2-(4-bromo-5-fluoro-2-propionylphenoxy)-3-fluoropropyl acetate 5

[0937] 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 (2x30 mL), washed with H2O (2x30 mL), brine (20 mL), dried over sodium sulfate and concentrated to give crude product 5 (1.21 g, quantitative), which was used in the next step without further purification.

[0938] 1 H 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).

[0939] 19 F NMR (300MHz, CDCl3) δ-98.26,-230.88ppm.

[0940] Step 5: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropyl acetate 6

[0941] In a sealed tube, deoxo-fluor (5.1 ml, 33.1 mmol) was added to a solution of (R)-2-(4-bromo-5-fluoro-2-propionylphenoxy)-3-fluoropropyl acetate (1.21 g, 3.31 mmol) in dry CH2Cl2 (10.8 mL), purged with argon, and sealed with a cap. The resulting mixture was stirred at 40 °C for 5-7 days. The reaction mixture was poured into ice-cold water (20 mL), and saturated aqueous sodium carbonate solution was carefully added and the mixture was stirred for 20 to 30 min. The aqueous layer was extracted with ethyl acetate (2x40 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). 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.

[0942] 1H 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).

[0943] 19 F NMR (300MHz, CDCl3) δ -94.91, -96.02, -101.74, -230.49ppm.

[0944] Step 6: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropan-1-ol 7

[0945] 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 / H2O (40 / 4 mL) was added K2CO3 (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 / hexanes, 1-40%) to give the desired product 7 (0.59 g, 97.3%) as a white solid.

[0946] 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).

[0947] 19 F NMR (300MHz, CDCl3) δ-93.29, -97.91, -101.56, -230.10ppm.

[0948] Step 7: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropanoic acid 8

[0949] 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 ~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 hours. 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 the reaction was complete, the mixture was cooled to 0 °C and 1 M NaOH solution was added to adjust pH ~13 and washed with DCM (30 mL). The aqueous layer was separated, cooled to 0°C again, and then acidified with 1M HCl to pH ∼ 1. The product was extracted with ethyl acetate (2x30 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%).

[0950] 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).

[0951] 19 F NMR (300MHz, CDCl3) δ-93.66, -97.02, -101.25, -228.55ppm.

[0952] MS (ES-): m / z 358 (MH)

[0953] HPLC retention time: 11.816 min, 98.19% purity @ 280 nm.

[0954] Example 7: Synthesis of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropionic acid

[0955]

[0956] Step 1: Synthesis of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)propan-1-one 2

[0957] 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 x 30 mL), washed with H2O (3 x 25 mL), brine (20 mL), dried over sodium sulfate and concentrated.

[0958] The crude material was placed 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 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 obtain the desired product 2 (3.5 g, 54%) as a light yellow solid.

[0959] 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).

[0960] 19 F NMR (300MHz, CDCl3) δ-102.14ppm.

[0961] Step 2: Preparation of (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-chloro-4-fluorophenyl)propan-1-one 3 synthesis

[0962] 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 previously cooled to 0°C was slowly added DIAD (1.5 g, 7.4 mmol). The ice bath was then removed and the reaction mixture was stirred at room temperature for 4 days and then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate / hexanes to give the desired product 3 (1.6 g, 70.1%) as a light yellow oil.

[0963] 1H 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).

[0964] 19 F NMR (300MHz, CDCl3) δ-106.42,-230.61ppm.

[0965] Step 3: Synthesis of (R)-1-(5-chloro-4-fluoro-2-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)propan-1-one 4

[0966] In a 250 mL round bottom flask, pyridine HCl (12.5 g, 108.7 mmol) was added to (R)-1-(2-(1-(benzyloxy)-3-fluoropropan-2-yloxy)-5-chloro-4-fluorophenyl)propan-1-one (1.6 g, 4.35 mmol). The reaction mixture was heated at 180 °C for 90 min and then cooled. The reaction mixture was quenched with H2O (30 mL) and the product was extracted with ethyl acetate (2x50 mL), washed with H2O (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 / hexanes, 0-50%) to give the desired product 4 (0.78 g, 64.4%) as a white solid.

[0967] 1 H 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).

[0968] 19 F NMR (300MHz, CDCl3) δ-105.66,-229.13ppm.

[0969] Step 4: Synthesis of (R)-2-(4-chloro-5-fluoro-2-propionylphenoxy)-3-fluoropropyl acetate 5

[0970] 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 (2x20 mL), washed with H2O (2x20 mL), brine (10 mL), dried over sodium sulfate and concentrated to give crude product 5 (0.887 g, quantitative) which was used in the next step without further purification.

[0971] 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).

[0972] 19 F NMR (300MHz, CDCl3) δ-106.05,-230.88ppm.

[0973] Step 5: Synthesis of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropyl acetate 6

[0974] In a sealed tube, deoxo-fluor (5.1 ml, 27.7 mmol) was added to a solution of (R)-2-(4-chloro-5-fluoro-2-propionylphenoxy)-3-fluoropropyl acetate (0.887 g, 2.77 mmol) in dry CH2Cl2 (1 mL), purged with argon, and sealed with a cap. 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 to 30 min. The aqueous layer was extracted with ethyl acetate (2x30 mL). The combined organic extracts were washed with brine (15 mL) and dried (Na2SO4). 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 light yellow oil.

[0975] 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).

[0976] 19F NMR (300 MHz, CDCl3) δ -95.31 and, -95.71, -109.63, -230.30 ppm.

[0977] Step 6: Synthesis of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropan-1-ol 7

[0978] 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 / H2O (10 / 2 mL) was added K2CO3 (0.391 g, 2.83 mmol), and the mixture 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 (0.37 g, 95.6%) as a white solid.

[0979] 1 H 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).

[0980] 19 F NMR (300MHz, CDCl3) δ-93.30, -98.05, -109.44, -230.10ppm.

[0981] Step 7: Synthesis of (R)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)-3-fluoropropanoic acid 8

[0982] 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 hours. 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 the reaction was complete, the mixture was cooled to 0 °C, 1 M NaOH solution was added to adjust the pH to 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 ~1 with 1 M HCl and the product was extracted with ethyl acetate (2 x 15 mL), washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to give product 8 as a white solid (0.23 g, 91.6%).

[0983] 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).

[0984] 19 F NMR (300MHz, CDCl3) δ-93.75, -97.08, -109.14, -228.60ppm.

[0985] MS (ES-): m / z 313 (MH), HPLC retention time: 11.76 min

[0986] Chiral HPLC: 7.62min, 99.4%ee

[0987] Example 8: Synthesis of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid

[0988]

[0989] Step 1: Preparation of 1-{2-[(R)-2-(benzyloxy)-1-(fluoromethyl)ethoxy]-5-bromo-4-fluorophenyl}-1-ethanone 3 synthesis

[0990] 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 previously cooled to 0°C was slowly added DIAD (1.04 g, 5.15 mmol). The ice bath was then removed and the reaction mixture was stirred at room temperature for 5 days and then concentrated under reduced pressure. After removal of the solvent, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate / hexanes to give the desired product 3 (0.94 g, 54.8%) as a light yellow oil.

[0991] 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).

[0992] 19 F NMR (300MHz, CDCl3) δ-97.82,-230.10ppm.

[0993] Step 2: Synthesis of 1-{2-[(R)-1-(fluoromethyl)-2-hydroxyethoxy]-5-bromo-4-fluorophenyl}-1-ethanone 4

[0994] In a 250 mL round bottom flask, pyridine HCl (6.8 g, 58.86 mmol) was added to 1-{2-[(R)-2-(benzyloxy)-1-(fluoromethyl)ethoxy]-5-bromo-4-fluorophenyl}-1-ethanone (0.94 g, 2.35 mmol). The reaction mixture was heated at 180 ° C for 40 minutes. The reaction mixture was cooled, quenched with H2O (30 mL), and the product was extracted with ethyl acetate (2x50 mL), washed with H2O (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.

[0995] 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).

[0996] 19 F NMR (300MHz, CDCl3) δ-97.01,-230.07ppm.

[0997] Step 3: Synthesis of (R)-2-(2-acetyl-4-bromo-5-fluorophenoxy)-3-fluoropropyl acetate 5

[0998] 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 was added triethylamine (0.20 g, 1.98 mmol), 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 (2x20 mL), washed with H2O (2x20 mL), brine (10 mL), dried over sodium sulfate and concentrated to give crude product 5 (0.46 g, quantitative), which was used in the next step without further purification.

[0999] 1 H 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).

[1000] 19 F NMR (300MHz, CDCl3) δ-97.53,-230.98ppm.

[1001] Step 4: Synthesis of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropyl acetate 6

[1002] In a sealed tube, deoxo-fluor (2.41 ml, 13.1 mmol) was added to a solution of (R)-2-(2-acetyl-4-bromo-5-fluorophenoxy)-3-fluoropropyl acetate (0.46 g, 1.31 mmol) in dry CH2Cl2 (1 mL), purged with argon, and sealed with a cap. 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 solution was carefully added. The mixture was stirred for 20 to 30 min. The aqueous layer was extracted with ethyl acetate (2x30 mL). The combined organic extracts were washed with brine (15 mL) and dried (Na2SO4). After removing 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 light yellow oil.

[1003] 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).

[1004] 19 F NMR (300MHz, CDCl3) δ-86.01and,-87.05,-101.67,-230.38ppm.

[1005] Step 5: Synthesis of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanol 7

[1006] 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 / hexanes, 1-40%) to give the desired product 7 (0.16 g, 90.15%) as a white solid.

[1007] 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).

[1008] 19 F NMR (300MHz, CDCl3) δ-85.22, -88.01, -101.49, -230.16ppm.

[1009] Step 6: Synthesis of (R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanoic acid 8

[1010] 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 h intervals. Upon completion, the reaction was cooled to 0 °C. 1 M NaOH solution was added to adjust the pH to 13 and the mixture was washed with DCM (15 mL). The aqueous layer was separated and cooled to 0°C again, then acidified with 1M HCl to pH ˜1. 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%).

[1011] 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).

[1012] 19 F NMR (300MHz, CDCl3) δ-85.37, -87.48, -101.10, -228.46ppm.

[1013] MS (ES-): m / z 343 (MH).

[1014] HPLC retention time: 11.37 min.

[1015] Chiral HPLC: 14.12min, 99.5%ee

[1016] Example 9: Synthesis of Sodium (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propionate

[1017]

[1018] Step 1: Synthesis of 4-bromo-2-(hydroxy(thiazol-2-yl)methyl)phenol

[1019] To a cooled (-78°C) solution of 1,3-thiazole (2.8 mL, 40 mmol, 2.0 eq.) in THF (22.6 mL) was added n-butyl lithium (2.7 M in heptane, 14.7 mL, 40 mmol, 2.0 eq.), followed by slow warming of the reaction mixture to room temperature over 1 h. The reaction mixture was cooled to -78°C again, and a solution of 5-bromo-2-hydroxybenzaldehyde (4.0 g, 20 mmol, 1.0 eq.) in THF (12 mL) was added, followed by slow warming to room temperature and stirring for 18 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), 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.

[1020] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 284.0 / 286.0 (MH) - ; Retention time: 0.95min; 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).

[1021] Step 2: Synthesis of (5-bromo-2-hydroxyphenyl)(thiazol-2-yl)methanone

[1022] To a solution of 4-bromo-2-(hydroxy(thiazol-2-yl)methyl)phenol (540mg, 1.9mmol, 1.0eq.) in DCM (9.4mL) was added manganese (IV) oxide (820mg, 9.4mmol, 5.0eq.), and the reaction was stirred at room temperature overnight. The reaction mixture was filtered through a pad of celite, and the pad was washed with DCM (2x5mL). The filtrate was concentrated under reduced pressure to give the title compound (488mg, 1.7mmol, 91%) as a dark yellow solid, which was used in subsequent reactions without additional purification.

[1023] UPLC-MS: acidic 2-minute run MS (ES+): no m / z; retention time: 1.26 min; purity: 86%. 1H 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).

[1024] Step 3: Synthesis of methyl (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoate

[1025] DAST (2.3 mL, 17 mmol, 10.0 eq.) was added to a cooled (0 ° C) solution of (5-bromo-2-hydroxyphenyl) (thiazol-2-yl) ketone (488 mg, 1.7 mmol, 1.0 eq.) in DCM (8.6 mL), the reaction bottle was sealed, and the mixture was slowly warmed to room temperature overnight. The reaction mixture was poured into ice water (50 mL) and extracted with DCM (2x50 mL). The combined organic extracts were washed with saturated sodium bicarbonate aqueous solution (50 mL) and brine (50 mL), dried over sodium sulfate, and the solvent was concentrated under reduced pressure to about 10 mL. The resulting solution was immediately cooled to 0°C again, diluted with THF (8.6 mL), and treated with (R)-methyl lactate (0.17 mL, 1.8 mmol, 1.05 eq.), triphenylphosphine (496 mg, 1.9 mmol, 1.1 eq.), and DIAD (0.37 mL, 1.9 mmol, 1.1 eq.) in sequence. The reaction mixture was allowed to slowly warm 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 give the title compound (142 mg, 0.36 mmol, 21%) as a colorless oil.

[1026] UPLC-MS: Acidic 2-minute run MS (ES+): m / z 392 / 394 (M+H) + ; Retention time: 1.23min; 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).

[1027] Step 4: Synthesis of (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoic acid

[1028] A solution of (S)-methyl 2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoate (142 mg, 0.36 mmol, 1.0 eq.) in THF (2.2 mL) was treated with 1 M aqueous sodium hydroxide solution (2.2 mL, 2.2 mmol, 6.0 eq.). 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 solution and extracted with EtOAc (2 x 10 mL). The combined secondary 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.

[1029] UPLC-MS: Acidic 4 minutes run MS (ES-): m / z 376.0 / 378.0 (MH) - ; Retention time: 1.72min; 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.

[1030] Step 5: Synthesis of sodium (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propionate

[1031] To a solution of (S)-2-(4-bromo-2-(difluoro(thiazol-2-yl)methyl)phenoxy)propanoic acid (101 mg, 0.27 mmol, 1.0 eq.) in water (11.4 mL) and MeCN (22.9 mL) was added 1 M aqueous sodium bicarbonate solution (0.28 mL, 0.28 mmol, 1.05 eq.), and the reaction was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and dried in a vacuum oven at 40 °C overnight to give the title compound (105 mg, 0.26 mmol, 98%) as an off-white powder.

[1032] UPLC-MS: Acidic 2-minute run MS (ES+): m / z 378.0 / 380.0 (M+H) + ; Retention time: 0.85min; Purity: 100%. 1H 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).

[1033] Example 10: Synthesis of Sodium (S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propionate

[1034]

[1035] Step 1: Synthesis of 4-bromo-2-(cyclobutyl(hydroxy)methyl)phenol

[1036] Freshly prepared cyclobutylmagnesium bromide (14.9 mL, 14.9 mmol, 3.0 eq.) was added dropwise to a cooled (0 °C) solution of 5-bromosalicylaldehyde (1.0 g, 5.0 mmol, 1.0 eq.) in THF (40 mL), and the reaction was slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (150 mL) and extracted with EtOAc (3 x 80 mL). The combined organic extracts were dried over sodium sulfate, concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (Si, 0-100% DCM in hexane) to give the title compound (1.01 g, 79%) as a yellow crystalline solid.

[1037] UPLC-MS: basic 2-minute run MS (ES-): m / z 255.0 / 257.0 (MH) - ; Retention time: 1.09min; Purity: 100%. 1 H NMR(chloroform-d)δ8.09(s,1H),7.41–7.29(m,1H),7.13(d,J=2.5Hz,1H),6.82(d,J=8.6Hz,1H),4 .75(d,J=8.5Hz,1H),2.93–2.82(m,1H),2.78(s,1H),2.31–2.12(m,1H),2.09–1.82(m,5H).

[1038] Step 2: Synthesis of (5-bromo-2-hydroxyphenyl)(cyclobutyl)methanone

[1039] To DCM (22mL) solution of bromo-2-(cyclobutyl(hydroxy)methyl)phenol (1.14g, 4.98mmol, 1.0eq.), manganese oxide (IV) (2.16g, 24.9mmol, 5.0eq.) was added, and the mixture was stirred at room temperature overnight. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain a viscous brown oil, which was stored in a refrigerator overnight. The oil was then dissolved in DCM (25mL) again, and fresh manganese oxide (IV) (8.81g, 101mmol, 20.0eq.) was added. The resulting mixture was stirred at room temperature for 24h. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain a crude title compound (3.52g), which was used in the next step without further purification.

[1040] UPLC-MS: basic 2-minute run MS (ES-): m / z 253.0 / 255.0 (MH) - ; Retention time: 1.31min; Purity: 77%.

[1041] Step 3: Synthesis of (S)-methyl 2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoate

[1042] DAST (3.9 mL, 29.0 mmol, 10.0 eq.) was added to a cooled (0 °C) solution of (5-bromo-2-hydroxyphenyl)(cyclobutyl)methanone (750 mg, 2.9 mmol, 1.0 eq.) in DCM (14.7 mL), the reaction flask was sealed, and the mixture was slowly warmed to room temperature within 1 h. The reaction mixture was poured into ice water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over sodium sulfate, and the solvent was concentrated under reduced pressure to about 10 mL. The resulting solution was immediately cooled to 0°C again, diluted with THF (14.7 mL), and treated with (R)-methyl lactate (0.30 mL, 3.1 mol, 1.05 eq.), triphenylphosphine (848 mg, 3.2 mol, 1.1 eq.), and DIAD (0.64 mL, 3.2 mol, 1.1 eq.) in sequence. The reaction mixture was allowed to slowly warm 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.

[1043] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 361.0 / 363.0 (MH) - ; Retention time: 1.37min; Purity: 100%. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.55 (dd, J = 2.5, 1.1 Hz, 1H), 7.33 (ddd, J = 8.8, 2.5, 0.9 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 4.68 (q, J = 6.8 Hz, 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 = 6.8 Hz, 3H).

[1044] Step 4: Synthesis of (S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoic acid

[1045] A solution of (S)-methyl 2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoate (158 mg, 0.44 mmol, 1.0 eq.) in water (5.2 mL), THF (7.8 mL) and MeOH (2.6 mL) was treated with 1 M aqueous sodium hydroxide solution (2.6 mL, 2.6 mmol, 6.0 eq.). After 1 h, the reaction mixture was partitioned between water (25 mL) and EtOAc (25 mL), the aqueous layer was acidified with 1 M aqueous hydrochloric acid solution and re-extracted with EtOAc (2 x 25 mL). The combined secondary organic extracts were 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 which solidified on standing.

[1046] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 347.0 / 349.0 (MH) - ; Retention time: 1.20min; 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=6.8H z,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).

[1047] Step 5: Synthesis of sodium (S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propionate

[1048] A solution of (S)-2-(4-bromo-2-(cyclobutyldifluoromethyl)phenoxy)propanoic acid (142 mg, 0.41 mmol, 1.0 eq.) in MeCN (10 mL) and water (5 mL) was treated with 1 M aqueous sodium bicarbonate (0.43 mL, 0.43 mmol, 1.05 eq.). 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.

[1049] UPLC-MS: Acidic 4-minute run MS (ES-): m / z 347.0 / 349.0 (MH) - ; Retention time: 2.06min; 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).

[1050] Example 11: Synthesis of Sodium (S)-2-(4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy)propionate

[1051]

[1052] Step 1: Synthesis of 4-bromo-2-fluoro-6-(1-hydroxypropyl)phenol

[1053] To a cooled (0°C) solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (3.0 g, 13.7 mmol, 1.0 eq.) in THF (150 mL) was added ethylmagnesium bromide (14 mL, 3.0 M in diethyl ether, 41.1 mmol, 3.0 eq.) dropwise, and the reaction was stirred for 1 h. The reaction mixture was then poured into saturated aqueous ammonium chloride (200 mL) and extracted with EtOAc (3 x 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.

[1054] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 247.0 / 249.0 (MH) - ; Retention time: 1.02min; Purity: 86%.1 H NMR (chloroform-d) δ: 7.71 (s, 1H), 7.12 (dd, J = 9.9, 2.3Hz, 1H), 6.99–6.93 (m, 1H), 4.77 (dd,J=7.4,5.9Hz,1H),3.22(s,1H),1.93–1.70(m,2H),0.95(t,J=7.4Hz,3H).

[1055] Step 2: Synthesis of 1-(5-bromo-3-fluoro-2-hydroxyphenyl)propan-1-one

[1056] To a solution of 4-bromo-2-fluoro-6-(1-hydroxypropyl)phenol (3.84 g, 13.7 mmol, 1.0 eq.) in DCM (70 mL) was added manganese (IV) oxide (6.70 g, 77.1 mmol, 5.6 eq.), and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through diatomaceous earth, 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 eq.), and the mixture was stirred at room temperature for 5 h. The reaction mixture was filtered through diatomaceous earth, 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.

[1057] UPLC-MS: basic 2-minute run MS (ES-): m / z 245.0 / 247.0 (MH) - ; Retention time: 1.06min; 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).

[1058] Step 3: Synthesis of (S)-methyl 2-(4-bromo-2-fluoro-6-propionylphenoxy)propionate

[1059] To a cooled (0°C) solution of 1-(5-bromo-3-fluoro-2-hydroxyphenyl)propan-1-one) (501 mg, 2.03 mmol, 1.0 eq.) in THF (7.5 mL) were added (2R)-methyl 2-hydroxypropanoate (211 mg, 2.03 mmol, 1.0 eq.), triphenylphosphine (585 mg, 2.23 mmol, 1.1 eq.) and diisopropyl azodicarboxylate (0.44 mL, 2.23 mmol, 1.1 eq.) in sequence. The reaction was slowly warmed 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 give the title compound (480 mg, 1.44 mmol, 67%) as a colorless oil.

[1060] UPLC-MS: Acidic 4-minute run MS (ES-): m / z 333.0 / 335.0 (MH) - ; Retention time: 2.06min; 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).

[1061] Step 4: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy)propanoate

[1062] A mixture of (S)-2-(4-bromo-2-fluoro-6-propionylphenoxy)propionic acid methyl ester (470 mg, 1.41 mmol, 1.0 eq.) and Deoxo-Fluor solution (50% in THF, 6 mL, 14.1 mmol, 10 eq.) 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 a cooled (0 ° C) saturated aqueous sodium bicarbonate solution (50 mL). The aqueous mixture was extracted with DCM (3x25 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 hexane) to give the title compound (135 mg, 0.36 mmol, 26%) as a yellow / brown semi-solid.

[1063] UPLC-MS: acidic 2-minute run MS (ES-): no m / z; retention time: 1.34 min; purity: 95%. 1 H NMR (CHLOROFORM-d) δ7.43 (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 FNMR (376MHz, chloroform-d) δ -93.67 (d, J = 246.9Hz), -97.26 (dd, J = 2.9, 247.0Hz), -125.43 (d, J = 2.7Hz).

[1064] Step 5: Synthesis of sodium (S)-2-(4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy)propionate

[1065] To a solution of (S)-2-[4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy]propanoic acid methyl ester (106 mg, 0.29 mmol, 1.0 eq.) in MeOH (2.1 mL) was added 1 M aqueous sodium hydroxide solution (0.31 mL, 0.31 mmol, 1.06 eq.), and the mixture was stirred at room temperature for 4 h. The mixture was then concentrated under reduced pressure, and the resulting solid was dried in a vacuum oven at 45 ° C overnight to give the title compound (96 mg, 0.26 mmol, 89%) as a peach solid.

[1066] UPLC-MS: Acidic 4 minutes run MS (ES-): m / z 339.0 / 341.0 (MH) - ; Retention time: 1.93min; 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).

[1067] Example 12: Synthesis of (S)-2-(4-cyano-2-(1,1-difluoropropyl)phenoxy)propionic acid

[1068]

[1069] Step 1: Synthesis of methyl (S)-2-(4-cyano-2-(1,1-difluoropropyl)phenoxy)propionate

[1070] A degassed solution of (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid methyl ester (100 mg, 0.24 mmol, 1.0 eq.), zinc dicarbonitrile (24 mg, 0.20 mmol, 0.85 eq.) and tetrakis(triphenylphosphine)palladium (27 mg, 0.02 mmol, 0.10 eq.) in NMP (0.8 mL) was heated at 150 ° C under microwave irradiation for 15 min. The reaction was filtered, diluted with EtOAc (20 mL), and washed with saturated sodium bicarbonate aqueous solution (2x20 mL), water (20 mL) and brine (20 mL) in sequence. The organic phase was concentrated under reduced pressure and purified by flash chromatography (Si, 0-40% EtOAc in hexane) to give the title compound (35 mg, 0.10 mmol, 42%) as a colorless oil.

[1071] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 282.1 (MH) - ; Retention time: 1.16min; Purity: 72%. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.86–7.79 (m, 1H), 7.64 (dd, J = 8.7, 2.0 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 4.90 (q, J = 6.8 Hz, 1H), 3.76 (s, 3H), 2.54–2.27 (m, 2H), 1.68 (d, J = 6.8 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ -93.51–-100.37 (m).

[1072] Step 2: Synthesis of (S)-2-(4-cyano-2-(1,1-difluoropropyl)phenoxy)propionic acid

[1073] To a stirred solution of (2S)-2-[4-cyano-2-(1,1-difluoropropyl)phenoxy]propanoic acid methyl ester (35 mg, 0.10 mmol, 1.0 eq.) in MeOH (0.9 mL) was added 1 M aqueous sodium hydroxide solution (0.12 mL, 0.12 mmol, 1.2 eq.), 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.

[1074] UPLC-MS: Acidic 4 minutes run MS (ES-): m / z 268.0 (MH) - ; Retention time: 1.54min; 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).

[1075] Example 13: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-4,5-difluorophenoxy)propionic acid

[1076]

[1077] Step 1: Synthesis of 4,5-difluoro-2-(1-hydroxypropyl)phenol

[1078] To a cooled (0°C) solution of 4,5-difluoro-2-hydroxybenzaldehyde (2.5 g, 15.8 mmol, 1.0 eq.) in THF (110 mL) was added ethylmagnesium bromide (11.1 mL, 3.0 M in ether, 33.3 mmol, 2.1 eq.), and the reaction was slowly warmed to room temperature and stirred overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution (200 mL) and extracted with EtOAc (3 x 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) as an amber oil, which was used in the next step without further purification.

[1079] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 187.1 (MH) - ; Retention time: 0.95min; Purity: 94%. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (s, 1H), 6.74 (dd, J = 10.6, 8.7 Hz, 1H), 6.67 (dd, J = 11.6, 6.9 Hz, 1H), 4.70 (td, J = 6.8, 2.8 Hz, 1H), 2.55 (d, J = 3.4 Hz, 1H), 1.98–1.73 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 19F 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).

[1080] Step 2: Synthesis of 1-(4,5-difluoro-2-hydroxyphenyl)propan-1-one

[1081] To a solution of 4,5-difluoro-2-(1-hydroxypropyl)phenol (3.27 g, 16.3 mmol, 1.0 eq.) in 1,4-dioxane (22 mL) was added manganese (IV) oxide (6.67 g, 76.7 mmol, 4.4 eq.) 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 (2 x 100 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 next reaction without further purification.

[1082] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 185.1 (MH) - ; Retention time: 1.15min; 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).

[1083] Step 3+4: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-4,5-difluorophenoxy)propionate

[1084] XtalFluor-E (2.46g, 10.7mmol, 4.0eq.) and 1-(4,5-difluoro-2-hydroxyphenyl) propan-1-one (500mg, 2.7mmol, 1.0eq.) are added successively to DCM (7.7mL) solution of triethylamine trihydrofluoride (0.88mL, 5.4mmol, 2.0eq.), and the reaction is stirred at room temperature overnight. The reaction mixture is poured on ice, and the resulting mixture is extracted with DCM (2x20mL). The combined organic phase is washed with water (3x25mL), dried over magnesium sulfate, and concentrated under reduced pressure to 1 / 4 volume. The remaining solution is directly purified by flash column chromatography (Si, DCM eluent), and suitable fractions are collected and concentrated under reduced pressure to about 10mL. The solution was cooled to 0°C and then treated with (2R)-methyl 2-hydroxypropanoate (280 mg, 2.7 mmol, 1.0 eq.), triphenylphosphine (775 mg, 3.0 mol, 1.1 eq.) and DIAD (0.58 mL, 3.0 mol, 1.1 eq.) in sequence 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.

[1085] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 293.0 (MH) - ; Retention time: 1.26min; 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).

[1086] Step 5: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-4,5-difluorophenoxy)propanoic acid

[1087] A solution of (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid methyl ester (100 mg, 0.34 mmol, 1.0 eq.) in MeOH (2 mL) was treated with 1 M aqueous sodium hydroxide solution (0.36 mL, 0.36 mmol, 1.05 eq.) 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 give the title compound (69 mg, 0.25 mmol, 73%) as a colorless gum.

[1088] UPLC-MS: Acidic 4 minutes run MS (ES-): m / z 279.1 (MH) - ; Retention time: 1.79min; 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).

[1089] Example 14: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-4-vinylphenoxy)propionic acid

[1090]

[1091] Step 1: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)propanoate

[1092] XtalFluor-E (6.0g, 26.2mmol, 4.0eq.) and 1-(5-bromo-2-hydroxyphenyl) propan-1-one (1.5g, 6.5mmol, 1.0eq.) are added successively to DCM (19mL) solution of triethylamine trihydrofluoride (2.1mL, 13.1mmol, 2.0eq.), and the reaction is stirred at room temperature overnight. The reaction mixture is poured on ice, and the resulting mixture is extracted with DCM (2x20mL). The combined organic phase is washed with water (3x25mL), dried over magnesium sulfate and concentrated under reduced pressure to 1 / 4 volume. The remaining solution is directly purified by flash column chromatography (Si, DCM eluent), and suitable fractions are collected and concentrated under reduced pressure to about 20mL. The solution was cooled to 0°C and then treated with (2R)-methyl 2-hydroxypropanoate (0.69 mL, 7.2 mmol, 1.1 eq.), triphenylphosphine (1.89 g, 7.2 mol, 1.1 eq.) and DIAD (1.4 mL, 7.2 mol, 1.1 eq.) in sequence 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.

[1093] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 335.0 / 337.0 (MH) - ; Retention time: 1.31min; Purity: 85%. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.65 (dd, J = 2.5, 1.1 Hz, 1H), 7.48–7.41 (m, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.80 (q, J = 6.8 Hz, 1H), 3.77 (s, 3H), 2.53–2.30 (m, 2H), 1.65 (d, J = 6.8 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ -85.67–-106.78 (m).

[1094] Step 2: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-4-vinylphenoxy)propionate

[1095] To a degassed solution of (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propanoic acid methyl ester (239 mg, 0.71 mmol, 1.0 eq.) and tributyl(vinyl)tin (0.41 mL, 1.42 mmol, 2.0 eq.) in 1,4-dioxane (2.8 mL) was added tetrakis(triphenylphosphine)palladium (41.0 mg, 0.035 mmol, 0.05 eq.) 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 give the title compound (144 mg, 0.25 mmol, 36%) as a colorless oil which was used in the next step without further purification.

[1096] UPLC-MS: basic 2-minute run MS (ES-): m / z 283.2 (MH) - ; Retention time: 1.29min; Purity: 57%. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.62–7.55 (m, 1H), 7.38 (dd, J = 8.6, 1.8 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.68 (m, 1H), 5.68 (dd, J = 17.6, 0.7 Hz, 1H), 5.21 (d, J = 11.5 Hz, 1H), 4.84 (m, 1H), 3.77 (s, 3H), 2.64–2.22 (m, 2H), 1.66 (d, J = 6.8 Hz, 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).

[1097] Step 3: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-4-vinylphenoxy)propionic acid

[1098] To a stirred solution of (2S)-2-[2-(1,1-difluoropropyl)-4-vinylphenoxy]propanoic acid methyl ester (137 mg, 0.48 mmol, 1.0 eq.) in MeOH (2.6 mL) was added 1 M aqueous sodium hydroxide solution (0.51 mL, 0.51 mmol, 1.05 eq.), 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 give the title compound (23 mg, 0.085 mmol, 18%) as a white solid.

[1099] UPLC-MS: Acidic 4 minutes run MS (ES-): m / z 269.1 (MH)- ; Retention time: 1.85min; 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).

[1100] Example 15: Synthesis of Sodium (S)-2-(2-(1,1-difluoropropyl)-4-methylphenoxy)propionate

[1101]

[1102] Step 1: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-4-methylphenoxy)propionate

[1103] XtalFluor-E (2.79 g, 12.2 mmol, 4.0 eq.) and 1-(2-hydroxy-5-methylphenyl)propan-1-one (0.47 mL, 3.05 mmol, 1.0 eq.) were added to triethylamine trihydrofluoride (0.99 mL, 6.09 mmol, 2.0 eq.) DCM (8.7 mL) solution 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 phase was washed with water (3x25 mL), dried over magnesium sulfate and concentrated under reduced pressure to 1 / 4 volume. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent), and suitable fractions were collected and concentrated under reduced pressure to about 12 mL. The solution was cooled to 0°C and then treated with (2R)-methyl 2-hydroxypropanoate (0.32 mL, 3.3 mmol, 1.1 eq.), triphenylphosphine (879 mg, 3.3 mol, 1.1 eq.) and DIAD (0.66 mL, 3.3 mol, 1.1 eq.) in sequence 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.

[1104] UPLC-MS: acidic 2-minute run MS (ES+): m / z; 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).

[1105] Step 2: Synthesis of sodium (S)-2-(2-(1,1-difluoropropyl)-4-methylphenoxy)propionate

[1106] To a solution of methyl (2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoate (213 mg, 0.78 mmol, 1.0 eq.) in MeOH (4.2 mL) was added 1 M aqueous sodium hydroxide solution (0.82 mL, 0.82 mmol, 1.05 eq.), 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) as a white solid.

[1107] UPLC-MS: Acidic 4 minutes run MS (ES+): m / z 257.0 (M+H) + ; Retention time: 1.81min; 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).

[1108] Example 16: Synthesis of (S)-2-(2-(1,1-difluoroethyl)-4-ethynylphenoxy)propionic acid

[1109]

[1110] Step 1: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)propionate

[1111] XtalFluor-E (2.13g, 9.3mmol, 4.0eq.) and 1-(5-bromo-2-hydroxyphenyl) second-1-ketone (500mg, 2.3mmol, 1.0eq.) are added to triethylamine trihydrofluoride (0.76mL, 4.7mmol, 2.0eq.) DCM (6.7mL) solution successively, and the reaction is stirred at room temperature overnight. The reaction mixture is poured on ice, and the resulting mixture is extracted with DCM (2x20mL). The combined organic phase is washed with water (3x25mL), dried over magnesium sulfate, and concentrated under reduced pressure to 1 / 4 volume. The remaining solution is directly purified by flash column chromatography (Si, DCM eluent), and suitable fractions are collected and concentrated under reduced pressure to about 12mL. The solution was cooled to 0°C and then treated with (2R)-methyl 2-hydroxypropionate (0.22 mL, 2.3 mmol, 1.0 eq.), triphenylphosphine (671 mg, 2.6 mol, 1.1 eq.) and DIAD (0.50 mL, 2.6 mol, 1.1 eq.) in sequence 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.

[1112] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 321.0 / 323.0 (MH) - ; Retention time: 1.26min; Purity: 89%. 1 H NMR (400 MHz, chloroform-d) δ 7.66 (dd, J = 2.5, 1.0 Hz, 1H), 7.42 (dd, J = 8.8, 2.5 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 4.80 (q, J = 6.8 Hz, 1H), 3.75 (s, 3H), 2.04 (dd, J = 19.3, 18.3 Hz, 3H), 1.64 (d, J = 6.8 Hz, 3H). 95% purity. 19 F NMR (376 MHz, chloroform-d) δ -84.43–-91.12 (m).

[1113] Step 2: (S)-2-(2-(1,1-difluoroethyl)-4-((trimethylsilyl)ethynyl)phenoxy)propanoic acid methyl Synthesis of esters

[1114] To a degassed mixture of (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propanoic acid methyl ester (200 mg, 0.62 mmol, 1.0 eq.), ethynyltrimethylsilane (0.18 mL, 1.2 mmol, 2.0 eq.), copper(I) iodide (12 mg, 0.06 mmol, 0.1 eq.) and triethylamine (0.13 mL, 0.93 mmol, 1.5 eq.) in toluene (1.8 mL) was added bis(triphenylphosphine)palladium dichloride (43 mg, 0.06 mmol, 0.1 eq.), and the mixture was stirred 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) as a dark crude oil, which was used in the next step without further purification.

[1115] UPLC-MS: acidic 2-minute run MS (ES+): no m / z; 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 FNMR (376 MHz, chloroform-d) δ -81.29–-92.61 (m).

[1116] Step 3: Synthesis of methyl (S)-2-(2-(1,1-difluoroethyl)-4-ethynylphenoxy)propanoate

[1117] To a solution of (S)-methyl 2-(2-(1,1-difluoroethyl)-4-((trimethylsilyl)ethynyl)phenoxy)propanoate (215 mg, 0.62 mmol, 1.0 eq.) in THF (2 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 1.9 mL, 1.9 mmol, 3.0 eq.), and the mixture was stirred at room temperature for 3 h. 1 M aqueous hydrochloric acid solution (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.

[1118] UPLC-MS: Acidic 2-minute run MS (ES+): m / z 269.2 (M+H) + ; Retention time: 1.20min; Purity: 75%. 1H 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).

[1119] Step 4: Synthesis of (S)-2-(2-(1,1-difluoroethyl)-4-ethynylphenoxy)propanoic acid

[1120] To a solution of methyl (2S)-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propanoate (84 mg, 0.31 mmol, 1.0 eq) in MeOH (1.7 mL) was added 1 M aqueous sodium hydroxide solution (0.33 mL, 0.33 mmol, 1.05 eq.), 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.

[1121] UPLC-MS: Acidic 4 minutes run MS (ES+): m / z 255.1 (M+H) + ; Retention time: 1.54min; 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).

[1122] Example 17: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-5-fluoro-4-vinylphenoxy)ammonium propionate

[1123]

[1124] Step 1: Synthesis of 4-bromo-5-fluoro-2-(1-hydroxypropyl)phenol

[1125] To a cooled (0°C) solution of 5-bromo-4-fluoro-2-hydroxybenzaldehyde (5.0 g, 22.8 mmol, 1.0 eq.) in THF (228 mL) was added ethylmagnesium bromide (22.8 mL, 3.0 M in diethyl ether, 68.5 mmol, 3.0 eq.) dropwise, 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 x 100 mL). The combined organic extracts were washed with brine (2 x 100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (6.14 g, 24.7 mmol, quantitative) as a colorless oil, which was used in the next step without further purification.

[1126] UPLC-MS: basic 2-minute run MS (ES-): m / z 247.0 / 249.0 (MH) - ; Retention time: 1.03min; 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 FNMR (376 MHz, chloroform-d) δ-107.57 (dd, J=9.7, 7.8 Hz).

[1127] Step 2: Synthesis of 1-(5-bromo-4-fluoro-2-hydroxyphenyl)propan-1-one

[1128] To a solution of 4-bromo-5-fluoro-2-(1-hydroxypropyl)phenol (6.14 g, 24.7 mmol, 1.0 eq.) in 1,4-dioxane (25 mL) was added manganese (IV) oxide (8.57 g, 98.6 mmol, 4.0 eq.) and the reaction was heated to reflux for 2.5 h. The reaction mixture was cooled, filtered through a pad of celite, and the pad was washed with EtOAc (100 mL) and then with 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.

[1129] UPLC-MS: basic 2-minute run MS (ES-): m / z 245.0 / 247.0 (MH) - ; Retention time: 1.24min; Purity: 100%. 1H 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).

[1130] Step 3: Synthesis of methyl (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)propanoate

[1131] XtalFluor-E (1.85 g, 8.10 mmol, 4.0 eq.) and 1-(5-bromo-4-fluoro-2-hydroxyphenyl)propan-1-one) (500 mg, 2.02 mmol, 1.0 eq.) were added to a DCM (6 mL) solution of triethylamine trihydrofluoride (0.66 mL, 4.04 mmol, 2.0 eq.) 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 phase was washed with water (3x25 mL), dried over magnesium sulfate and concentrated under reduced pressure to 1 / 4 volume. The remaining solution was directly purified by flash column chromatography (Si, DCM eluent), and suitable fractions were collected and concentrated under reduced pressure to about 12 mL. The solution was cooled to 0°C and then treated with (2R)-methyl 2-hydroxypropionate (0.21 mL, 2.22 mmol, 1.1 eq.), triphenylphosphine (584 mg, 2.22 mol, 1.1 eq.) and DIAD (0.44 mL, 2.22 mol, 1.1 eq.) in sequence 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.

[1132] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 353.0 / 355.0 (MH) - ; Retention time: 1.32min; Purity: 90%. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.68 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 9.9 Hz, 1H), 4.75 (q, J = 6.8 Hz, 1H), 3.77 (s, 3H), 2.48–2.27 (m, 2H), 1.65 (d, J = 6.8 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H). 19F NMR (376 MHz, chloroform-d) δ -89.65–-99.10 (m), -101.34–-103.92 (m).

[1133] Step 4: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-5-fluoro-4-vinylphenoxy)propionate

[1134] To a degassed solution of (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid methyl ester (200 mg, 0.56 mmol, 1.0 eq.) and tributyl(vinyl)tin (0.33 mL, 1.13 mmol, 1.1 eq.) in 1,4-dioxane (2.3 mL) was added Pd(PPh3)4 (33 mg, 0.03 mmol, 0.05 eq.), and the mixture was heated at 100 ° C in a sealed tube for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (25 mL) and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-10% EtOAc in hexane) to give the title compound (69 mg, 0.23 mmol, 41%) as a colorless oil.

[1135] UPLC-MS: basic 2-minute run MS (ES-): m / z 301.1 (MH) - ; Retention time: 1.32min; 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).

[1136] Step 5: Synthesis of (S)-2-(2-(1,1-difluoropropyl)-5-fluoro-4-vinylphenoxy)ammonium propionate

[1137] A solution of (2S)-2-[2-(1,1-difluoropropyl)-4-vinyl-5-fluorophenoxy]propanoic acid methyl ester (47 mg, 0.16 mmol, 1.0 eq.) in MeOH (1.1 mL) was treated with 1 M aqueous sodium hydroxide solution (0.16 mL, 0.16 mmol, 1.0 eq.) 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 give the title compound (18 mg, 0.06 mmol, 38%) as an off-white powder.

[1138] UPLC-MS: Acidic 4 minutes run MS (ES-): m / z 287.1 (MH) - ; Retention time: 1.91min; 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).

[1139] Example 18: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)butyric acid

[1140]

[1141] Step 1+2: Synthesis of (S)-methyl 2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)butyrate

[1142] XtalFluor-E (1.85g, 8.10mmol, 4.0eq.) and 1-(5-bromo-4-fluoro-2-hydroxyphenyl) propan-1-one (500mg, 2.02mmol, 1.0eq.) are added successively to DCM (6mL) solution of triethylamine trihydrofluoride (0.66mL, 4.05mmol, 2.0eq.), and the reaction is stirred at room temperature for 2 days. The reaction mixture is poured on ice, and the resulting mixture is extracted with DCM (2x20mL). The combined organic phase is washed with water (3x25mL), dried over sodium sulfate, and concentrated under reduced pressure to 1 / 4 volume. The remaining solution is directly purified by flash column chromatography (Si, DCM eluent), and suitable fractions are collected and concentrated under reduced pressure to about 10mL. The solution was cooled to 0°C and then treated with (2R)-methyl 2-hydroxypropionate (239 mg, 2.02 mmol, 1.0 eq.), triphenylphosphine (583 mg, 2.22 mol, 1.1 eq.) and DIAD (0.44 mL, 2.22 mol, 1.1 eq.) in sequence 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.

[1143] UPLC-MS: acidic 2-minute run MS (ES+): no m / z; 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).

[1144] Step 3: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy)butyric acid

[1145] A solution of methyl (2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoate (150 mg, 0.26 mmol, 1.0 eq.) in MeOH (1.4 mL) was treated with 1 M aqueous sodium hydroxide (0.28 mL, 0.28 mmol, 1.05 eq.) 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 light yellow gum.

[1146] UPLC-MS: basic 4-minute run MS (ES-): m / z 353.0 / 355.0 (MH) - ; Retention time: 1.41min; 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).

[1147] Example 19: Synthesis of (S)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)butyric acid

[1148]

[1149] Step 1: Synthesis of 5-fluoro-2-(1-hydroxypropyl)phenol

[1150] To a cooled (-40°C) solution of 4-fluoro-2-hydroxybenzaldehyde (5.0 g, 35.7 mmol, 1.0 eq.) in THF (250 mL) was added ethylmagnesium bromide (25 mL, 3.0 M in diethyl ether, 75.0 mmol, 3.1 eq.), and the reaction was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was poured into saturated aqueous ammonium chloride (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (6.70 g, 39.4 mmol, quantitative) as a bright amber oil, which was used in the next step without further purification.

[1151] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 169.1 (MH) - ; Retention time: 0.91min; 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 FNMR (376 MHz, chloroform-d) -113.64 (ddd, J = 10.4, 8.3, 6.3 Hz).

[1152] Step 2: Synthesis of 1-(4-fluoro-2-hydroxyphenyl)propan-1-one

[1153] To a solution of 5-fluoro-2-(1-hydroxypropyl)phenol (6.07 g, 35.7 mmol, 1.0 eq.) in 1,4-dioxane (50 mL) was added manganese (IV) oxide (13.7 g, 157 mmol, 4.4 eq.) 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 (2 x 250 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 which crystallized upon standing.

[1154] UPLC-MS: Acidic 2-minute run MS (ES+): m / z 169.1 (M+H) + ; Retention time: 1.13min; 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).

[1155] Step 3: Synthesis of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)propan-1-one

[1156] To a solution of 1-(4-fluoro-2-hydroxyphenyl)propan-1-one (400 mg, 2.38 mmol, 1.0 eq.) in DCM (7.0 mL) was added benzyltrimethylazanium tetrachloro-λ3-iodanuide (997 mg, 2.38 mmol, 1.0 eq.), and the resulting mixture was stirred at room temperature for 4 days under light shielding. The mixture was concentrated under reduced pressure and purified by flash column chromatography (Si, 0-15% EtOAc in hexane) to give the title compound (454 mg, 2.24 mmol, 94%) as a yellow oil.

[1157] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 201.1 / 203.1 (MH) - ; Retention time: 1.22min; 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).

[1158] Step 4+5: Synthesis of (S)-methyl 2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)butyrate

[1159] XtalFluor-E (2.03g, 8.88mmol, 4.0eq.) and 1-(5-chloro-4-fluoro-2-hydroxyphenyl) propan-1-one (450mg, 2.22mmol, 1.0eq.) are added successively to DCM (6.4mL) solution of triethylamine trihydrofluoride (0.72mL, 4.44mmol, 2.0eq.), and the reaction is stirred at room temperature overnight. The reaction mixture is poured on ice, and the resulting mixture is extracted with DCM (2x20mL). The combined organic phase is washed with water (3x25mL), dried over magnesium sulfate, and concentrated under reduced pressure to 1 / 4 volume. The remaining solution is directly purified by flash column chromatography (Si, DCM eluent), and suitable fractions are collected and concentrated under reduced pressure to about 10mL. The solution was cooled to 0°C and then treated with (2R)-methyl 2-hydroxypropanoate (262 mg, 2.22 mmol, 1.0 eq.), triphenylphosphine (641 mg, 2.44 mol, 1.1 eq.) and DIAD (0.48 mL, 2.44 mol, 1.1 eq.) in sequence 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 (208 mg, 0.49 mmol, 22%) as a yellow oil which was used in the next step without further purification.

[1160] UPLC-MS: Acidic 2-minute run MS (ES+): m / z 348.3 / 350.3 (M+Na) + ; Retention time: 1.36min; 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).

[1161] Step 6: Synthesis of (S)-2-(4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy)butyric acid

[1162] A solution of methyl (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoate (200 mg, 0.40 mmol, 1.0 eq.) in MeOH (2.1 mL) was treated with 1 M aqueous sodium hydroxide solution (0.42 mL, 0.42 mmol, 1.05 eq.) 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 give the title compound (29 mg, 0.09 mmol, 23%) as an off-white solid.

[1163] UPLC-MS: Acidic 4 minutes run MS (ES-): m / z 309.0 / 311.0 (MH) - ; Retention time: 2.00min; 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).

[1164] Example 20: Synthesis of Sodium (S)-2-(2-(1,1-difluoropropyl)-4-nitrophenoxy)propionate

[1165]

[1166] Step 1+2: Synthesis of methyl (S)-2-(2-(1,1-difluoropropyl)-4-nitrophenoxy)propionate

[1167] XtalFluor-E (2.35g, 10.2mmol, 4.0eq.) and 1-(2-hydroxy-5-nitrophenyl) propan-1-one (500mg, 2.56mmol, 1.0eq.) are added successively to DCM (7.3mL) solution of triethylamine trihydrofluoride (0.84mL, 5.12mmol, 2.0eq.), and the reaction is stirred at room temperature overnight. The reaction mixture is poured on ice, and the resulting mixture is extracted with DCM (2x20mL). The combined organic phase is washed with water (3x25mL), dried over magnesium sulfate and concentrated under reduced pressure to 1 / 4 volume. The remaining solution is directly purified by flash column chromatography (Si, DCM eluent), suitable fractions are collected, and it is concentrated under reduced pressure to about 10mL. The solution was cooled to 0°C and then treated with (2R)-methyl 2-hydroxypropanoate (0.25 mL, 2.56 mmol, 1.0 eq.), triphenylphosphine (739 mg, 2.82 mmol, 1.1 eq.) and DIAD (0.55 mL, 2.82 mol, 1.1 eq.) in sequence 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 light yellow oil.

[1168] UPLC-MS: acidic 2-minute run MS (ES+): no m / z; retention time: 1.21 min; purity: 100%. 1 HNMR (400 MHz, CHLOROFORM-d) δ8.45 (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).

[1169] Step 3: Synthesis of sodium (S)-2-(2-(1,1-difluoropropyl)-4-nitrophenoxy)propionate

[1170] A solution of methyl (2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propanoate (32 mg, 0.11 mmol, 1.0 eq.) in MeOH (0.6 mL) was treated with 1 M aqueous sodium hydroxide solution (0.16 mL, 0.16 mmol, 1.5 eq.) 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.

[1171] UPLC-MS: Acidic 4 minutes run MS (ES-): m / z 288.1 (MH) - ; Retention time: 1.62min; 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).

[1172] Example 21: Synthesis of Sodium (S)-2-(5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy)propionate

[1173]

[1174] Step 1: Synthesis of 5-chloro-4-fluoro-2-(1-hydroxypropyl)phenol

[1175] To a cooled (-40°C) solution of 4-chloro-5-fluoro-2-hydroxybenzaldehyde (2.5 g, 14.3 mmol, 1.0 eq.) in THF (100 mL) was added ethylmagnesium bromide (10 mL, 3.0 M in ether, 30.0 mmol, 3.0 eq.), and the reaction was slowly warmed to room temperature and stirred overnight. Subsequently, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3.20 g, 12.8 mmol, 90%) as an amber oil, which was used in the next step without further purification.

[1176] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 203.1 / 205.1 (MH) - ; Retention time: 1.01min; 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).

[1177] Step 2: Synthesis of 1-(4-chloro-5-fluoro-2-hydroxyphenyl)propan-1-one

[1178] To a solution of 5-chloro-4-fluoro-2-(1-hydroxypropyl)phenol (2.93 g, 14.3 mmol, 1.0 eq.) in 1,4-dioxane (18 mL) was added manganese (IV) oxide (5.50 g, 63.2 mmol, 4.4 eq.), and the reaction was stirred at reflux for 6 h. The reaction mixture was cooled to room temperature, filtered through a celite pad, and the filter cake was washed with 4:1 EtOAc: MeOH (2 x 250 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (Si, 0-20% EtOAc in hexane) to give the title compound (1.02 g, 5.0 mmol, 35%) as a yellow solid.

[1179] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 201.1 / 203.1 (MH) - ; Retention time: 1.21min; 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).

[1180] Step 3+4: Synthesis of methyl (S)-2-(5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy)propanoate

[1181] XtalFluor-E (2.26g, 9.87mmol, 4.0eq.) and 1-(4-chloro-5-fluoro-2-hydroxyphenyl) propan-1-one (500mg, 2.47mmol, 1.0eq.) are added successively to DCM (7.1mL) solution of triethylamine trihydrofluoride (0.81mL, 4.94mmol, 2.0eq.), and the reaction is stirred at room temperature overnight. The reaction mixture is poured on ice, and the resulting mixture is extracted with DCM (2x20mL). The combined organic phase is washed with water (3x25mL), dried over magnesium sulfate and concentrated under reduced pressure to 1 / 4 volume. The remaining solution is directly purified by flash column chromatography (Si, DCM eluent), and suitable fractions are collected and concentrated under reduced pressure to about 20mL. The solution was cooled to 0°C and then treated with (2R)-methyl 2-hydroxypropanoate (257 mg, 2.47 mmol, 1.0 eq.), triphenylphosphine (712 mg, 2.71 mmol, 1.1 eq.) and DIAD (0.53 mL, 2.71 mol, 1.1 eq.) in sequence 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.

[1182] UPLC-MS: Acidic 2-minute run MS (ES-): m / z 309.0 / 311.0 (MH) - ; Retention time: 1.30min; Purity: 85%. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.32 (dd, J = 9.3, 1.1 Hz, 1H), 6.82 (d, J = 5.8 Hz, 1H), 4.73 (q, J = 6.8 Hz, 1H), 3.78 (s, 3H), 2.50–2.26 (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 -93.38 (ddd, J = 246.3, 15.4, 13.0 Hz), -98.67 (dt, J = 246.2, 19.9 Hz), -123.90 (dd, J = 9.3, 5.7 Hz).

[1183] Step 5: Synthesis of sodium (S)-2-(5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy)propionate

[1184] A solution of methyl (2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoate (100 mg, 0.21 mmol, 1.0 eq.) in MeOH (1.1 mL) was treated with 1 M aqueous sodium hydroxide solution (0.22 mL, 0.22 mmol, 1.05 eq.) 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.

[1185] UPLC-MS: Acidic 4-minute run MS (ES-): m / z 295.0 / 297.0 (MH) - ; Retention time: 1.86min; 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 FNMR (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).

[1186] Example 22: Electrophysiological measurements of compound inhibition of ClC-1 in rat muscle

[1187] The goal of these experiments was to evaluate whether compounds inhibit ClC-1 channels in native rat skeletal muscle fibers. Apparent ClC-1 affinity (EC 50 ).

[1188] ClC-1Cl - Ion channels generate approximately 80% of the total membrane conductance (G) in resting skeletal muscle fibers of most animals, including rats and humans. m )(Bretag, AH. Muscle chloride channels. Physiological Reviews, 1987, 67, 618-724). m Contributing ion channels are negligible and can be determined by comparing G before and after exposure to the compound. m The G values ​​were used to evaluate whether compounds inhibit ClC-1 in rat muscle. In such recordings, ClC-1 inhibition would be measured by Gm The decrease is reflected in the

[1189] Experimentally, G was measured in individual fibers throughout the rat soleus muscle using the three-microelectrode technique described in this example and in full detail elsewhere. m (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 cut from 12-14 week old Wistar rats and placed in an experimental chamber perfused with a standard Krebs Ringer solution containing 122 mM NaCl, 25 mM NaHCO3, 2.8 mM KCl, 1.2 mM KH2PO4, 1.2 mMMgSO4, 1.3 mM CaCl2, 5.0 mM D-glucose. During the experiment, the solution was maintained at approximately 30°C and continuously balanced with a mixture of 95% O2 and 5% CO2 (pH 7.4). The experimental chamber was placed in a Nikon upright microscope, which was used to visualize individual muscle fibers and three electrodes (glass pipettes filled with 2 M potassium citrate). For G m For measurement, electrodes were inserted into the same fiber with known inter-electrode distances of 0.35-0.5 mm (V1-V2, X1) and 1.1-1.5 mm (V1-V3, X3). Figure 1 A). The membrane potential of the impaled muscle fiber is recorded by all electrodes. In addition, two electrodes are used to inject a 50ms current pulse of -30nA. Given the position of the electrodes, three different inter-electrode distances can be identified (X1-X2, X1-X3, X2-X3), so the membrane potential response to current injection can be obtained at three distances from the current injection point. The steady-state voltage deflection at each distance is divided by the magnitude of the injected current (-30nA), and the resulting transfer resistance is then plotted against the inter-electrode distance, and the data are fitted to a single exponential function, from which G can be calculated using linear cable theory. m ( Figure 1 B).

[1190] To establish a dose-response relationship, G was first measured in 10 muscle fibers in the absence of compound. m , and then G was measured at four increasing compound concentrations. m 5-10 fibers were subjected to G at each concentration. m The average G at each concentrationm The values ​​were plotted against compound concentration and the data were fitted to a sigmoid function to obtain the EC 50 value( Figure 1 C) Table 2 shows the EC values ​​of a series of compounds. 50 Values, where n refers to the number of experiments, each of which reflects the recording of approximately 50 fibers.

[1191] Table 2: Inhibition of ClC-1 ion channels using compounds of the present disclosure

[1192]

[1193]

[1194] Example 23: Force Measurement in In Vitro Models

[1195] The present disclosure relates to compounds that inhibit ClC-1 ion channels and increase muscle excitability to improve muscle function in clinical conditions of muscle activation failure. This condition leads to loss of skeletal muscle contractile function, weakness and excessive fatigue. In this series of experiments, the ability of compounds to restore contractile function in isolated rat muscles was tested when neuromuscular transmission was impaired similar to neuromuscular disorders.

[1196] Experimentally, soleus muscles of 4-5 week old rats were isolated with their motor nerves remaining attached. The neuromuscular preparations were mounted in an experimental apparatus capable of electrically stimulating the motor nerves. Stimulation of the motor nerves resulted in activation of the muscle fibers and consequent force production, which was recorded. In these experiments, the neuromuscular preparations were also incubated in standard Krebs Ringer solution (see Example 5), and the solution was heated to 30°C and continuously equilibrated with a mixture of 95% O2 and 5% CO2 (pH ~ 7.4).

[1197] After mounting the neuromuscular preparation in the experimental apparatus, the contractile function of the muscle was initially assessed under control conditions ( Figure 2 A). A submaximal concentration of tubocurarine (115 nM), an acetylcholine receptor antagonist, is then added to the experimental bath to partially inhibit the ability of motor nerves to activate muscle fibers. The experimental conditions mimic failed neuromuscular transmission in a range of neuromuscular disorders. After the addition of tubocurarine, contractile force decreases to 10% to 50% of control force over the next 90 minutes. 50 μM of the test compound is then added, and contractile force is able to recover despite the continued presence of tubocurarine. To quantify the ability of the compound to restore force, the percentage of initial force recovered after 40 minutes of exposure to the compound is determined ( Figure 2 B), the percentage point increases are reported in Table 3.

[1198] Table 3: Percentage increase in initial force recovered

[1199]

[1200]

[1201] In summary, this example demonstrates that compounds of the present disclosure are able to increase muscle excitability, thereby improving muscle function in clinical conditions.

[1202] Example 24: Measurement of in situ muscle contraction properties

[1203] Isometric hindlimb strength was measured in 12-week-old female Lewis rats in the presence and absence of compound.

[1204] The rats were placed under isoflurane (2-4%) anesthesia, intubated, and then connected to a microventilator (Microvent 1, Hallowell EMC, USA). Two stimulating electrodes were inserted through the skin to stimulate the sciatic nerve. A small incision was made near the ankle to expose the Achilles tendon, which was tied with cotton rope and connected to a force sensor (Fort250, World PrecisionInstruments) with an adjustable position (vernier control). The Achilles tendon was then cut at a position relative to the distal end of the connected cotton thread. The rats were placed on a heated pad, and the feet were fixed to the pedals with tape to prevent motion artifacts due to contraction of the ankle dorsiflexor muscles.

[1205] The contractile properties of the muscle are assessed by applying current to the nerve (under supermaximal voltage conditions) and recording the force produced by the muscle. When assessed by 2Hz stimulation, the muscle is stretched until the maximum force is obtained. Isometric force is measured every 30 seconds at 12Hz (twitch), 10 pulses and every 5 minutes at 80Hz (tetanic) for 1 second (80 pulses). This stimulation mode has been used throughout the experiment, except in a few cases, when 80Hz stimulation is replaced by 12Hz (10 pulses). Cisatracurium (Nimbex, GlaxoSmithKline) with a constant infusion rate of 0.1mg / kg is used to partially inhibit neuromuscular transmission, wherein each animal is adjusted to obtain an inhibition level of about 50% of the 4th pulse forced to be produced under 12Hz stimulation. When the neuromuscular inhibition level is stable, the test substance is injected intravenously at a selected concentration. The effect of the test article was evaluated in terms of its ability to increase the force generated by the applied stimulation mode. The effect was evaluated by increasing the ability of the force itself (tonic, 80Hz, stimulation) and the ratio between each twitch peak (12Hz stimulation). The effect was monitored for at least 1 hour after the injection of the test article. In addition, if possible, the time from the injection of the test article to the maximum force effect (twitch and rigidity) was recorded, and the time when the effect disappeared (return to baseline) was recorded. When appropriate, the infusion of neuromuscular blocking agents was stopped, the stimulation mode was continued, and the force was monitored to recover to the control level. In the case of still complete sedation, the animals were killed by cervical dislocation.

[1206] The intravenous administration of compound A-3 was 17.5 mg / kg, resulting in a 64% increase in tetanic tension. The intravenous administration of compound A-4 was 21.6 mg / kg, resulting in a 34% increase in tetanic tension. The intravenous administration of compound A-5 was 10.5 mg / kg, resulting in a 47% increase in tetanic tension. The intravenous administration of compound A-7 was 25.1 mg / kg, resulting in a 64% increase in tetanic tension. The intravenous administration of compound A-32 was 11.2 mg / kg, resulting in a 75% increase in tetanic tension. The intravenous administration of compound A-31 was 11.4 mg / kg, resulting in a 14% increase in tetanic tension. The intravenous administration of compound A-29 was 22.9 mg / kg, resulting in a 76% increase in tetanic tension. The intravenous administration of compound A-23 was 18.8 mg / kg, resulting in a 40% increase in tetanic tension. The intravenous administration of compound A-22 was 10.4 mg / kg, resulting in a 57% increase in tetanic tension. The intravenous administration of compound A-16 at a dose of 22.9 mg / kg resulted in a 46% increase in tetanic tension, and the intravenous administration of compound A-11 at a dose of 17.6 mg / kg resulted in a 44% increase in tetanic tension.

[1207] This demonstrates that compounds of the present 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 force to muscles partially inhibited by neuromuscular blockers in vivo.

Claims

1. Compounds of formula (II): in: -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br and I; -R 2 Selected from C 1-5 Alkyl or C 3-5 Cycloalkyl; -R 3 is selected from the group consisting of deuterium, Cl and F; -R 4 Selected from H, C 1-5 Alkyl and C 2-5 Alkynyl, C 1-5 Alkyl and C 2-5 Each alkynyl group is optionally substituted by one or more identical or different substituents R 7 replace; -R 5 It is H; -R 7 are independently F or Cl; and -n is an integer 0, 1, 2, or 3; or a pharmaceutically acceptable salt or tautomer thereof.

2. The compound according to claim 1, wherein the compound has formula (III): in: -R 1 is selected from the group consisting of C2 alkenyl, C2 alkynyl, NO2, F, Cl, Br and I; -R 2 It is C 1-5 alkyl; -R 3 is selected from H, deuterium, Cl and F; -R 4 Selected from H, C 1-5 Alkyl and C 2-5 Alkynyl, C 1-5 Alkyl and C 2-5 Each alkynyl group is optionally substituted by one or more identical or different substituents R 7 replace; and -R 7 are independently F or Cl, or a pharmaceutically acceptable salt or tautomer thereof.

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

4. The compound according to claim 1 or 2, wherein R 2 It is C 1-3 alkyl.

5. The compound according to claim 1 or 2, wherein R 3 It's F.

6. The compound according to claim 1 or 2, wherein R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 1-3 alkyl.

7. The compound according to claim 1 or 2, wherein R 4 It is Me or CH2F.

8. The compound according to claim 1 or 2, wherein R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted -CH2-C 2-4 Alkynyl.

9. The compound according to claim 1, wherein the compound is selected from: (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-difluorobutyl)phenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid; (2S)-2-[4-Bromo-2-(cyclopropyldifluoromethyl)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-fluoropropionic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-chloropropionic 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; (2R)-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic 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-fluoropropionic 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]propionic acid; 2-[4-Bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; (2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid; (2R)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-vinylphenoxy]propanoic acid; 2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic 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-fluoropropionic 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-fluoropropionic acid; (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutyric acid; (2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butanoic acid; (2S)-2-[2-(1,1-difluoropropyl)-4-vinyl-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-fluoropropionic 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-fluoropropionic acid; and (2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid.

10. (2S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2-2H)propanoic acid or a pharmaceutically acceptable salt or tautomer thereof.

11. Use of a compound according to any one of claims 1 to 10 in the preparation of a ClC-1 ion channel inhibitor.

12. A composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 10 or a composition according to claim 12 for the preparation of a medicament for treating a symptom selected from the group consisting of myasthenia gravis, Lambert-Eaton syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), inverse diabetic polyneuropathy, Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, periodic paralysis, myasthenia syndrome, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy and Duchenne muscular dystrophy.

14. Use of a compound according to any one of claims 1 to 10 or a composition according to claim 12 in the preparation of a medicament for reversing and / or improving neuromuscular blockade.

Images