Method for preparing ClC-1 chloride channel inhibitor

Abstract

The present disclosure relates to an improved chemical process for preparing a compound of formula I as a ClC-1 chloride channel inhibitor using a compound of formula II as a starting material. (Formula I, Formula II)

Description

Technical Field

[0001] The present disclosure relates to novel chemical methods for the synthesis of ClC-1 chloride channel inhibitors.

[0002] background

[0003] The present disclosure relates to chemical methods for preparing compounds that are ClC-1 chloride channel inhibitors. As described in WO2016 / 202341, ClC-1 chloride channel inhibitors can be used to treat neuromuscular disorders, such as myasthenia gravis and ALS, or to reverse and / or improve neuromuscular blockade. Summary of the invention

[0004] In order to develop a method for treating neuromuscular diseases, ClC-1 chloride channel inhibitors are needed. The present disclosure provides a new method for preparing a compound of formula I that can be industrially applied. As demonstrated by the data generated by studying the compound set in the biological model described herein, the compound of formula I inhibits the ClC-1 ion channel and can restore neuromuscular transmission. Therefore, these compounds can be used to treat or improve muscle weakness and muscle fatigue in neuromuscular junction disorders caused by diseases or neuromuscular blockers.

[0005] In one aspect, the present disclosure provides a method for preparing a compound of formula I

[0006]

[0007] comprising step a), wherein

[0008] i) reacting the compound of formula II with an acid or a base

[0009]

[0010] as well as

[0011] ii) isolating the compound of formula I from the reaction mixture,

[0012] Where R 1 To R 9 and n are as defined herein.

[0013] The present disclosure also relates to novel compounds of formula II as defined herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1: Picture A illustrates the voltage scheme for inducing current in the whole cell membrane patch of CHO cells expressing human ClC-1 channels. Picture B shows the representative whole cell current traces from the patched (patched) CHO cells expressing human ClC-1 channels. Current is induced by applying the voltage scheme shown in picture A.

[0015] Figure 2 : Picture A shows a representative I / V graph of constant current density in CHO cells expressing ClC-1 before (circles) and after (squares) application of 100 μM of the ClC-1 inhibitor 9-anthracenecarboxylic acid (9-AC, Sigma A89405). Picture B shows an I / V graph of transient tail current density obtained from the same CHO cells expressing ClC-1 as shown in Picture A before (circles) and after (squares) application of 100 μM 9-AC.

[0016] Figure 3 : Figure 3 Representative graphs of normalized transient tail currents obtained from CHO cell membrane patches expressing ClC-1 before (circles) and after (squares) application of 100 μM 9-AC are shown. The transient tail current at each voltage step was normalized to the maximum tail current obtained after a (+) 120 mV voltage step and fitted with a Boltzmann function to determine the half-activation potential V 1 / 2 .

[0017] definition

[0018] The term "C 1-3 Alkyl" and "C 1-5 “Alkyl” refers to a branched or unbranched alkyl group having one to three or one to five carbon atoms, respectively, 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.

[0019] The term "C 2-5 The term "alkenyl" refers to a branched or unbranched alkenyl group having two to five carbon atoms in which two carbon atoms are connected by a double bond, including but not limited to ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and isopentenyl.

[0020] The term "C 2-5The term “alkynyl” refers to a branched or unbranched alkynyl group having two to five carbon atoms in which two carbon atoms are linked 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.

[0021] The term "C 3-5 Cycloalkyl" and "C 3-6 "Cycloalkyl" refers to groups having three to five or three to six carbon atoms, respectively, including monocyclic or bicyclic carbocyclic rings, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0022] Detailed description

[0023] The present disclosure provides novel industrially applicable processes for preparing compounds of formula I that are ClC-1 chloride channel inhibitors. The processes of the present invention allow for better control of impurities, reduce or eliminate the need for chromatography steps and have higher yields, thereby providing better cost of goods.

[0024] Therefore, in one aspect, the present disclosure provides a method for preparing a compound of formula I,

[0025]

[0026] It comprises step a), wherein

[0027] i) reacting a compound of formula II with an acid or a base,

[0028]

[0029] as well as

[0030] ii) isolating the compound of formula I from the reaction mixture,

[0031] in

[0032] -R 1 is selected from the group consisting of H, F, Cl, Br and I;

[0033] -R 2 Selected from C 1-5 Alkyl and C 3-5 Cycloalkyl;

[0034] -R 3 is selected from the group consisting of deuterium, F, Cl, Br and I;

[0035] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5Alkynyl, C 3-5 Cycloalkyl and C 5 Cycloalkenyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0036] -R 5 is selected from optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 Alkyl, C 2-5 Alkenyl, 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;

[0037] -R 6 Selected from H, deuterium, C 1-5 Alkyl and C 3-5 Cycloalkyl;

[0038] -R 7 independently selected from deuterium, tritium, F, Cl, Br, I, CN, isocyanide, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 8 Replaced OC 1-3 alkyl, optionally substituted by one or more identical or different substituents R 8 Replaced SC 1-3 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted CH 2 -OC 1-3 alkyl and optionally substituted by one or more identical or different substituents R 8 Substituted CH 2 -SC 1-3 alkyl;

[0039] -R 8 are independently selected from deuterium and F;

[0040] -R 9 are independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

[0041] -n is an integer 0, 1, 2, or 3.

[0042] In one embodiment, R1 is Cl or Br. In one embodiment, R 1 In one embodiment, R 1 It's Br.

[0043] In one embodiment, R 2 It is C 1-5 In one embodiment, R 2 is selected from the group consisting of 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. In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 In one embodiment, R 2 It is 2-methyl-propan-2-yl.

[0044] In one embodiment, R 3 In one embodiment, R 3 It's F.

[0045] In one embodiment, R 4 is H. 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 C 3-5 Cycloalkyl substituted C 1-5 Alkyl, the C 3-5 The cycloalkyl group is optionally substituted by one or more identical or different substituents R 8 In one embodiment, R 4 is Me. In one embodiment, R 4 is Et. In one embodiment, R 4 Yes-CH 2 F. In one embodiment, R 5 It is cyclopropyl.

[0046] In one embodiment, R 5 is optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 In one embodiment, R 5is Me. In one embodiment, R 5 is Et. In one embodiment, R 5 It is 2-methyl-propan-2-yl.

[0047] In one embodiment, R 6 is H. In one embodiment, R 6 In one embodiment, R 6 It is C 1-5 In one embodiment, R 6 Selected from 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.

[0048] In one embodiment, R 7 In one embodiment, R 7 is F. In one embodiment, R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted C 3-5 In one embodiment, R 4 Is R 7 Substituted C 1-5 Alkyl, where R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted C 3-5 Cycloalkyl.

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

[0050] In one embodiment, the compound of formula II is reacted with an acid. In one embodiment, the compound of formula II is reacted with a concentrated acid. In one embodiment, the compound of formula II is reacted with an acid selected from formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, hydrochloric acid and sulfuric acid or a mixture thereof (e.g., a mixture of formic acid and acetic acid). In one embodiment, the acid is acetic acid. In one embodiment, the acid is formic acid. In one embodiment, the acid is concentrated acetic acid. In one embodiment, the acid is concentrated formic acid. In one embodiment, the acid is concentrated acetic acid. In one embodiment, the acid is a mixture of concentrated formic acid and concentrated acetic acid.

[0051] In one embodiment, step a)i) is carried out at a temperature of 70 to 140°C, such as 80 to 130°C, such as 90 to 120°C.

[0052] In one embodiment, the reaction time of step a)i) is from 12 hours to 96 hours, such as from 24 hours to 72 hours, such as from 36 hours to 60 hours.

[0053] In one embodiment, the amount of acid used in step a) i) is from 3 mL per gram of starting material to 15 mL per gram of starting material.

[0054] In one embodiment, the compound of formula I is isolated from the reaction mixture by adding water and extracting the product into an organic solvent. In one embodiment, the organic solvent used for extraction is selected from toluene, ethyl acetate, isopropyl acetate and methyl tert-butyl ether. In one embodiment, the organic solvent used for extraction is methyl tert-butyl ether.

[0055] In one embodiment, the compound of formula I is purified by crystallization from an organic solvent selected from toluene, ethyl acetate, isopropyl acetate, and methyl tert-butyl ether. In one embodiment, the compound of formula I is purified by crystallization from toluene.

[0056] In one embodiment, the method further comprises step b), wherein

[0057] i) making a compound of formula III

[0058]

[0059] Reaction with N-chlorosuccinimide in an organic solvent;

[0060] ii) the compound of formula IV

[0061]

[0062] adding a base to the reaction mixture; and

[0063] iii) isolating the compound of formula II from the reaction mixture,

[0064] Where R 1 To R 9 and n are as defined herein.

[0065] In one embodiment, the solvent in step b)i) is dimethylformamide (DMF). In one embodiment, the compound of formula IV is selected from ethyl vinyl ether, n-butyl vinyl ether and tert-butyl vinyl ether. In one embodiment, the compound of formula IV is n-butyl vinyl ether. In one embodiment, the base in step b)ii) is a trialkylamine. In one embodiment, the base in step b)ii) is selected from trimethylamine, triethylamine, triisopropylamine and N,N-diisopropylethylamine. In one embodiment, the base in step b)ii) is triethylamine.

[0066] In one embodiment, the method further comprises step c), wherein

[0067] i) making a compound of formula V

[0068]

[0069] Reaction with hydroxylamine in an organic solvent;

[0070] ii) adding a base to the reaction mixture; and

[0071] iii) isolating the compound of formula III from the reaction mixture,

[0072] Where R 1 To R 9 and n are as defined herein.

[0073] In one embodiment, the method further comprises step d), wherein

[0074] i) the compound of formula VI

[0075]

[0076] Adding to a compound of formula VII in an organic solvent;

[0077]

[0078] ii) adding a base to the reaction mixture; and

[0079] iii) isolating the compound of formula V from the reaction mixture,

[0080] Where R 1 To R 9 and n are as defined herein and LG is a leaving group.

[0081] In one embodiment, the leaving group is selected from tosylate, mesylate, triflate, nosylate, brosylate, bromide, iodide and chloride.

[0082] In one embodiment, the method comprises step a) as outlined in Scheme 1). In one embodiment, the method comprises steps a) and b) as outlined in Scheme 1). In one embodiment, the method comprises steps a), b) and c) as outlined in Scheme 1). In one embodiment, the method comprises steps a), b), c) and d) as outlined in Scheme 1.

[0083]

[0084] Scheme 1: Synthesis of compounds of formula I

[0085] In one embodiment, the compound of formula I is an inhibitor of the ClC-1 chloride channel.

[0086] In one embodiment, the compound of formula I is at least 80% pure, such as at least 90% pure, such as at least 95% pure, such as at least 96% pure, such as at least 97% pure, such as at least 98% pure.

[0087] In certain embodiments, compounds according to or used in accordance with the present disclosure may have an enantiomeric excess of >90%. In certain embodiments, compounds according to or used in accordance with the present disclosure may have an enantiomeric excess of >95%.

[0088] In one embodiment, the compound of formula I is selected from:

[0089] (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]-2-cyclopropylacetic acid;

[0090] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid;

[0091] 2-[4-Bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]acetic acid;

[0092] 2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]acetic acid;

[0093] (2S)-2-[4,5-dichloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0094] (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0095] (2S)-2-[4-Chloro-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0096] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid;

[0097] (2S)-2-[4-Fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0098] (2S)-2-[4-chloro-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0099] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid;

[0100] (2S)-2-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid;

[0101] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0102] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid;

[0103] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid;

[0104] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid;

[0105] (2S)-2-[4-Bromo-2-(5-methyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0106] (2S)-2-[4-bromo-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; and

[0107] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0108] In one aspect, the present disclosure relates to a method for preparing a pharmaceutical composition, comprising the following steps:

[0109] i) preparing a compound according to the invention selected from the group consisting of:

[0110] (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]-2-cyclopropylacetic acid;

[0111] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid;

[0112] 2-[4-Bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]acetic acid;

[0113] 2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]acetic acid;

[0114] (2S)-2-[4,5-dichloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0115] (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0116] (2S)-2-[4-Chloro-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0117] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid;

[0118] (2S)-2-[4-Fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0119] (2S)-2-[4-chloro-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0120] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid;

[0121] (2S)-2-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid;

[0122] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0123] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid;

[0124] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid;

[0125] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid;

[0126] (2S)-2-[4-Bromo-2-(5-methyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0127] (2S)-2-[4-bromo-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; and

[0128] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, and

[0129] ii) formulating the compound into a pharmaceutical composition.

[0130] In one aspect, the present disclosure relates to compounds of formula II as defined herein.

[0131] In one embodiment, the compound of formula II is selected from:

[0132] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0133] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0134] (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0135] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0136] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0137] (2S)-tert-butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0138] (2S)-2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0139] (2S)-2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0140] (2S)-2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0141] (2S)-2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0142] (2S)-2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0143] (2S)-2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0144] (2S)-tert-butyl 2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0145] (2S)-tert-butyl 2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0146] (2S)-tert-butyl 2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0147] (2S)-2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0148] (2S)-2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0149] (2S)-2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0150] (2S)-2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0151] (2S)-2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0152] (2S)-2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0153] (2S)-tert-butyl 2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0154] (2S)-tert-butyl 2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0155] (2S)-tert-butyl 2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0156] (2S)-methyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate;

[0157] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid methyl ester;

[0158] Methyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0159] Methyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0160] (2S)-2-[4,5-dichloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0161] (2S)-methyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0162] (2S)-methyl 2-[4-chloro-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0163] (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid methyl ester;

[0164] (2S)-2-[4-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0165] (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid methyl ester;

[0166] (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid methyl ester;

[0167] (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0168] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid methyl ester;

[0169] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid methyl ester;

[0170] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid methyl ester;

[0171] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0172] Ethyl (2S)-2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate;

[0173] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropionic acid ethyl ester;

[0174] Ethyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0175] Ethyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0176] (2S)-2-[4,5-dichloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0177] (2S)-2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0178] (2S)-2-[4-chloro-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0179] (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropionic acid ethyl ester;

[0180] (2S)-2-[4-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0181] (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid ethyl ester;

[0182] (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid ethyl ester;

[0183] (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0184] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropionic acid ethyl ester;

[0185] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid ethyl ester;

[0186] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid ethyl ester;

[0187] (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0188] tert-Butyl (2S)-2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate;

[0189] (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropanoate;

[0190] tert-Butyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0191] tert-Butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0192] tert-Butyl (2S)-2-[4,5-dichloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0193] (2S)-tert-butyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0194] (2S)-tert-butyl 2-[4-chloro-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0195] (2S)-tert-butyl 2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoate;

[0196] (2S)-tert-butyl 2-[4-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0197] tert-Butyl (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoate;

[0198] (2S)-tert-butyl 2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoate;

[0199] (2S)-tert-butyl 2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0200] (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoate;

[0201] (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoate;

[0202] (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoate;

[0203] (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0204] (2S)-methyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate;

[0205] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid methyl ester;

[0206] Methyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0207] Methyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0208] (2S)-2-[4,5-dichloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0209] (2S)-methyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0210] (2S)-methyl 2-[4-chloro-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0211] (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid methyl ester;

[0212] (2S)-2-[4-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0213] (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid methyl ester;

[0214] (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid methyl ester;

[0215] (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0216] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid methyl ester;

[0217] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid methyl ester;

[0218] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid methyl ester;

[0219] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester;

[0220] Ethyl (2S)-2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate;

[0221] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropionic acid ethyl ester;

[0222] Ethyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0223] Ethyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0224] (2S)-2-[4,5-dichloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0225] (2S)-2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0226] (2S)-2-[4-chloro-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0227] (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropionic acid ethyl ester;

[0228] (2S)-2-[4-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0229] (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid ethyl ester;

[0230] (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid ethyl ester;

[0231] (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0232] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropionic acid ethyl ester;

[0233] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid ethyl ester;

[0234] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid ethyl ester;

[0235] (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester;

[0236] tert-Butyl (2S)-2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate;

[0237] (2S)-tert-butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropanoate;

[0238] tert-Butyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0239] tert-Butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate;

[0240] (2S)-tert-butyl 2-[4,5-dichloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0241] Tert-butyl (2S)-2-[4-chloro-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0242] (2S)-tert-butyl 2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoate;

[0243] Tert-butyl (2S)-2-[4-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0244] tert-Butyl (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoate;

[0245] (2S)-tert-butyl 2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoate;

[0246] (2S)-tert-butyl 2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate;

[0247] (2S)-tert-butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoate;

[0248] (2S)-tert-butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoate;

[0249] tert-Butyl (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoate; and

[0250] Tert-butyl (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate.

[0251] The present disclosure also relates in part to pharmaceutical compositions comprising compounds of formula I prepared by the disclosed methods. In one embodiment, the compounds of formula I prepared by the above methods can be included in pharmaceutical compositions. These compositions can also include one or more conventional pharmaceutically acceptable carriers. The compositions can include additional active ingredients / agents or other components to increase the efficacy of the compositions.

[0252] Therefore, another aspect of the present disclosure is a process for the preparation of a pharmaceutical composition comprising a compound of formula I, characterized in that the compound of formula I is prepared by a process according to the present invention.

[0253] Pharmaceutical compositions comprising a compound of formula I of the present disclosure and a pharmaceutically acceptable carrier constitute another aspect of the present invention.

[0254] project

[0255] 1. A method for preparing a compound of formula I

[0256]

[0257] It comprises step a), wherein

[0258] i) reacting the compound of formula II with an acid or a base

[0259]

[0260] as well as

[0261] ii) isolating the compound of formula I from the reaction mixture,

[0262] in

[0263] -R 1 is selected from the group consisting of H, F, Cl, Br and I;

[0264] -R 2 Selected from C 1-5 Alkyl and C 3-5 Cycloalkyl;

[0265] -R 3 is selected from the group consisting of deuterium, F, Cl, Br and I;

[0266] -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl and C 5 Cycloalkenyl, each of which may be optionally substituted by one or more identical or different substituents R 7 replace;

[0267] -R5 is selected from optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 Alkyl, C 2-5 Alkenyl, 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;

[0268] -R 6 Selected from H, deuterium, C 1-5 Alkyl and C 3-5 Cycloalkyl;

[0269] -R 7 independently selected from deuterium, tritium, F, Cl, Br, I, CN, isocyano, R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 8 Replaced OC 1-3 alkyl, optionally substituted by one or more identical or different substituents R 8 Replaced SC 1-3 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted CH 2 -OC 1-3 alkyl and optionally substituted by one or more identical or different substituents R 8 Substituted CH 2 -SC 1-3 alkyl;

[0270] -R 8 are independently selected from deuterium and F;

[0271] -R 9 are independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

[0272] -n is an integer 0, 1, 2, or 3.

[0273] 2. The method of any of the preceding items, wherein R 1 It is Cl or Br.

[0274] 3. The method of any of the preceding items, wherein R 1 It is Cl.

[0275] 4. The method of any of the preceding items, wherein R 1 It's Br.

[0276] 5. The method of any of the preceding items, wherein R 2 It is C 1-5 alkyl.

[0277] 6. The method of any of the preceding items, wherein R 2 Selected from 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.

[0278] 7. The method of any of the preceding items, wherein R 2 It is ethyl.

[0279] 8. The method of any of the preceding items, wherein R 2 It is propan-1-yl.

[0280] 9. The method of any of the preceding items, wherein R 2 It is propan-2-yl.

[0281] 10. The method of any of the preceding items, wherein R 2 It is butan-1-yl.

[0282] 11. The method of any of the preceding items, wherein R 2 It is 2-methyl-propan-2-yl.

[0283] 12. The method of any of the preceding items, wherein R 3 It's F.

[0284] 13. The method of any of the preceding items, wherein R 3 It's deuterium.

[0285] 14. The method of any of the preceding items, wherein R 4 It's H.

[0286] 15. The method of any 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.

[0287] 16. The method of any of the preceding items, wherein R 4 It's me.

[0288] 17. The method of any of the preceding items, wherein R 4It's Et.

[0289] 18. The method of any of the preceding items, wherein R 4 Yes-CH 2 F.

[0290] 19. The method of any of the preceding items, wherein R 4 It is cyclopropyl.

[0291] 20. The method of any 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.

[0292] 21. The method of any of the preceding items, wherein R 5 It's me.

[0293] 22. The method of any of the preceding items, wherein R 5 It's Et.

[0294] 23. The method of any of the preceding items, wherein R 5 It is 2-methyl-propan-2-yl.

[0295] 24. The method of any of the preceding items, wherein R 6 It's H.

[0296] 25. The method of any of the preceding items, wherein R 6 It is D.

[0297] 26. The method of any of the preceding items, wherein R 6 It is C 1-5 alkyl.

[0298] 27. The method of any of the preceding items, wherein R 6 Selected from 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.

[0299] 28. The method of any of the preceding items, wherein R 7 It's deuterium.

[0300] 29. The method of any of the preceding items, wherein R 7 It's F.

[0301] 30. The method of any of the preceding items, wherein R 7 is optionally substituted by one or more identical or different substituents R8 Substituted C 3-5 Cycloalkyl.

[0302] 31. The method of any of the preceding items, wherein R 4 Is R 7 Substituted C 1-5 Alkyl, where R 7 is optionally substituted by one or more identical or different substituents R 8 Substituted C 3-5 Cycloalkyl.

[0303] 32. The method of any of the preceding items, wherein n=0.

[0304] 33. The method of any of the preceding items, wherein n=1.

[0305] 34. The method of any of the preceding items, wherein n=2.

[0306] 35. The method of any of the preceding items, wherein n=3.

[0307] 36. The process according to any of the preceding items, wherein the compound of formula II is reacted with a base.

[0308] 37. The process of any of the preceding items, wherein the compound of formula II is reacted with an acid.

[0309] 38. The process of any of the preceding items, wherein the compound of formula II is reacted with a concentrated acid.

[0310] 39. The process of any of the preceding items, wherein the compound of formula II is reacted with an acid selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, hydrochloric acid and sulfuric acid, or mixtures thereof.

[0311] 40. The process of any of the preceding items, wherein the compound of formula II is reacted with concentrated formic acid.

[0312] 41. The process of any of the preceding items, wherein the compound of formula II is reacted with concentrated acetic acid.

[0313] 42. The process of any of the preceding items, wherein the compound of formula II is reacted with a mixture of concentrated formic acid and concentrated acetic acid.

[0314] 43. The process of any of the preceding items, wherein step a) is carried out at a temperature of 70 to 140°C, such as 80 to 130°C, such as 90 to 120°C.

[0315] 44. The method of any of the preceding items, wherein the reaction time of step a) is from 12 hours to 96 hours, such as from 24 hours to 72 hours, such as from 36 hours to 60 hours.

[0316] 45. The process of any of the preceding items, wherein the amount of acid used in step a) i) is from 3 mL per gram of starting material to 15 mL per gram of starting material.

[0317] 46. ​​The process of any of the preceding items, wherein in step b) the compound of formula I is isolated from the reaction mixture by adding water and extracting the product into an organic solvent.

[0318] 47. The process of any of the preceding items, wherein in step b) the compound of formula I is isolated from the reaction mixture by adding water and extracting the product into a compound selected from toluene, ethyl acetate, isopropyl acetate and methyl tert-butyl ether.

[0319] 48. The process of any of the preceding items, wherein the compound of formula I is purified by crystallization from an organic solvent.

[0320] 49. The process of any of the preceding items, wherein the compound of formula I is purified by crystallization from an organic solvent selected from toluene, ethyl acetate, isopropyl acetate and methyl tert-butyl ether.

[0321] 50. The method of any of the preceding items, wherein the method further comprises step b),

[0322] i) making a compound of formula III

[0323]

[0324] Reaction with N-chlorosuccinimide in an organic solvent;

[0325] ii) the compound of formula IV

[0326]

[0327] and a base are added to the reaction mixture; and

[0328] iii) isolating the compound of formula II from the reaction mixture,

[0329] Where R 1 To R 9 and n is as defined in item 1.

[0330] 51. The process of any of the preceding items, wherein the solvent in step b) i) is dimethylformamide (DMF).

[0331] 52. The process of any of the preceding items, wherein the mixture of formula IV is selected from ethyl vinyl ether, n-butyl vinyl ether and tert-butyl vinyl ether.

[0332] 53. The process of any of the preceding items, wherein the base in step b) ii) is selected from trimethylamine, triethylamine, triisopropylamine and N,N-diisopropylethylamine.

[0333] 54. The method of any of the preceding items, wherein the method further comprises step c), wherein

[0334] i) making a compound of formula V

[0335]

[0336] Reaction with hydroxylamine in an organic solvent;

[0337] ii) adding a base to the reaction mixture; and

[0338] iii) isolating the compound of formula III from the reaction mixture,

[0339] Where R 1 To R 9 and n is as defined in item 1.

[0340] 55. The process of any of the preceding items, wherein the organic solvent in step c) i) is an alcohol.

[0341] 56. The process of any of the preceding items, wherein the organic solvent in step c) i) is an alcohol selected from the group consisting of methanol, ethanol, propanol, n-butanol and tert-butanol.

[0342] 57. The process of any of the preceding items, wherein the base in step c) ii) is selected from pyridine, trimethylamine, triethylamine, triisopropylamine and N,N-diisopropylethylamine.

[0343] 58. The method of any of the preceding items, wherein the method further comprises step d), wherein

[0344] i) the compound of formula VI

[0345]

[0346] Adding to a compound of formula VII in an organic solvent;

[0347]

[0348] ii) adding a base to the reaction mixture; and

[0349] iii) isolating the compound of formula V from the reaction mixture,

[0350] Where R 1 To R 9 and n are as defined herein and LG is a leaving group.

[0351] 59. The process of any of the preceding items, wherein the leaving group (LG) of formula VI is selected from tosylate, mesylate, triflate, m-nitrobenzenesulfonate, p-brosylate, bromide, iodide and chloride.

[0352] 60. The process of any of the preceding items, wherein the leaving group (LG) of formula VI is tosylate.

[0353] 61. The process of any of the preceding items, wherein the organic solvent is selected from pentane, hexane, heptane, toluene, xylene, dichloromethane, tetrahydrofuran and acetonitrile.

[0354] 62. The process of any of the preceding items, wherein the base in step d) ii) is an inorganic base.

[0355] 63. The process of any of the preceding items, wherein the base in step d) ii) is an inorganic base selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide.

[0356] 64. The method of any of the preceding items, wherein the compound of formula I is selected from:

[0357] (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]-2-cyclopropylacetic acid;

[0358] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid;

[0359] 2-[4-Bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]acetic acid;

[0360] 2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]acetic acid;

[0361] (2S)-2-[4,5-dichloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0362] (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0363] (2S)-2-[4-Chloro-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0364] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid;

[0365] (2S)-2-[4-Fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0366] (2S)-2-[4-chloro-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0367] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid;

[0368] (2S)-2-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid;

[0369] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0370] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid;

[0371] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid;

[0372] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid;

[0373] (2S)-2-[4-Bromo-2-(5-methyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0374] (2S)-2-[4-bromo-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; and

[0375] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

[0376] 65. The method of any of the preceding items, wherein the compound of formula I is an inhibitor of the ClC-1 chloride channel.

[0377] 66. The method of any of the preceding items, wherein the compound of formula I has a purity of at least 80%, such as a purity of at least 90%, such as a purity of at least 95%, such as a purity of at least 96%, such as a purity of at least 97%, such as a purity of at least 98%.

[0378] 67. A method for preparing a pharmaceutical composition comprising the following steps

[0379] i) preparing a compound selected from the following according to any one of the preceding items:

[0380] (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]-2-cyclopropylacetic acid;

[0381] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid;

[0382] 2-[4-Bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]acetic acid;

[0383] 2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]acetic acid;

[0384] (2S)-2-[4,5-dichloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0385] (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0386] (2S)-2-[4-Chloro-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0387] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid;

[0388] (2S)-2-[4-Fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0389] (2S)-2-[4-chloro-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0390] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid;

[0391] (2S)-2-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid;

[0392] (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0393] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid;

[0394] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid;

[0395] (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid;

[0396] (2S)-2-[4-Bromo-2-(5-methyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;

[0397] (2S)-2-[4-bromo-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; and

[0398] (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; and

[0399] ii) formulating the compound into a pharmaceutical composition. Example

[0400] Materials and methods

[0401] NMR spectroscopy

[0402] Recorded on a Jeol LA400 (400 MHz) spectrometer 1 H-NMR spectra, and using the residual non-deuterated solvent as an internal reference (for CHCl 3 It was calibrated with a value of 7.24 ppm.

[0403] LCMS method

[0404] Instrument: Agilent 1260 Infinity series LC (high pressure degasser, binary pump, autosampler and column oven) equipped with Agilent 1100 DAD detector, scanning range from 210 nm to 315 nm. Mass detection was provided by API 2000 mass spectrometer (electrospray).

[0405] Column: Agilent Poroshell 120EC-C18 (2.7 μm, 3.0 x 50 mm).

[0406] Conditions: 0.1% v / v formic acid in water [eluent A]; MeCN [eluent B]; flow rate 0.8 mL / min, and equilibration time between samples 1.5 minutes.

[0407] gradient:

[0408] Time (min) Eluent A (%) Eluent B (%) 0.01 95 5 0.20 95 5 2.00 5 95 3.00 5 95 3.25 95 5 3.50 95 5

[0409] Chiral SCF method

[0410] 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), back pressure regulator, and diode array detector.

[0411] Column: Lux A1 (4.6 mm x 250 mm, 5 μm).

[0412] Conditions: 40°C, 4 mL / min, isocratic 15:85 EtOH:CO 2 (0.1% v / v TFA), 125 BarG.

[0413] Example 1: Synthesis of (2S)-2-(4-bromo-2-(isoxazol-3-yl)phenoxy)propionic acid

[0414] (S)-2-(4-bromo-2-(isoxazol-3-yl)phenoxy)propanoic acid B.6 was prepared using the route shown below.

[0415]

[0416] Synthesis of methyl (S)-2-(4-bromo-2-formylphenoxy)propionate B.3

[0417] 5-Bromo-2-hydroxybenzaldehyde B.1 (9.26 g, 46.10 mmol) was added to a stirred solution of (R)-methyl 2-(tosyloxy)propanoate B.2 (11.90 g, 46.10 mmol) in hexane (180 mL) and the resulting mixture was heated to 80° C. until dissolved. Potassium carbonate (12.74 g, 92.20 mmol) was added to the reaction mixture and stirred at 80° C. for 36 h and at room temperature for 60 h.

[0418] Under vacuum, remove solvent and distribute resistates between water (400mL) and ethyl acetate (400mL).Water layer is extracted with more ethyl acetate.Organic layer is merged together and water (2x 300mL) and salt water washing, through dried over sodium sulfate, filter and under reduced pressure concentrate to provide light yellow oil.Use heptane: ethyl acetate 10-20% as solvent system, carry out this thick material of purification to provide the product of expectation by silica gel flash column chromatography: (S)-2-(4-bromo-2-formylphenoxy) methyl propionate B.3, is colorless oil, and its solidification spends the night (8.08g, 62% yield).

[0419] 1H NMR (400MHz, CDCl 3 )δ10.54(s,1H),7.94(d,J=2.7Hz,1H),7.56(dd,J=8.9,2.7Hz,1H),6.71( d, J=8.9Hz, 1H), 4.84 (q, J=6.8Hz, 1H), 3.74 (s, 3H), 1.68 (d, J=6.8Hz, 3H). LC / MS(Agilent)m / z 286.8(M+H) + , at 2.54min.

[0420] Synthesis of methyl (S,E)-2-(4-bromo-2-((hydroxyimino)-methyl)phenoxy)propionate B.4

[0421] Hydroxylamine hydrochloride (1.87 g, 26.90 mmol) was added to a stirred solution of (S)-methyl 2-(4-bromo-2-formylphenoxy)propanoate B.3 (7.25 g, 26.90 mmol) in methanol (150 mL) pre-cooled to -40°C under nitrogen. Pyridine (2.6 mL, 29.60 mmol) was then added dropwise to the mixture and stirred at this temperature for 1 h. The reaction mixture was stored at 4°C overnight.

[0422] Reactant mixture is warmed up to room temperature and poured in water (400mL).This solution is extracted with ethyl acetate (2x 400mL).Organic layer is merged together and washed with water (2x 300mL) and salt water, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide desired product (S, E)-2-(4-bromo-2-((hydroxyimino)-methyl)phenoxy)methyl propionate B.4, is white solid (8.20g, quantitative yield).

[0423] 1H NMR (400MHz, CDCl 3 )δ8.49(s,1H),7.87(d,J=2.6Hz,1H),7.35(dd,J=8.8,2.6Hz,1H),6.61(d,J=8.8Hz,1H),4.74(q,J=6.8Hz,1H),3.72(s,3H),1.63(d,J=6.8Hz,3H). LC / MS(Agilent)m / z 301.9(M+H) + , at 2.42min.

[0424] Synthesis of methyl (2S)-2-(4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy)propanoate B.5

[0425] N-Chlorosuccinimide (3.90 g, 28.95 mmol) was added to a solution of (S,E)-2-(4-bromo-2-((hydroxyimino)-methyl)phenoxy)propanoic acid methyl ester B.4 (7.95 g, 26.40 mmol) in dimethylformamide (200 mL) at room temperature, followed by 1 M hydrochloric acid solution (1 mL aqueous solution). The resulting reaction mixture was stirred at room temperature for 75 min. Thereafter, the mixture was cooled to 0 ° C and triethylamine (4.42 mL, 31.70 mmol) was added thereto, followed by butyl vinyl ether (4.1 mL, 31.70 mmol). The reaction mixture was stirred at room temperature for 3.5 h.

[0426] The reaction mixture was poured into water (350 mL), acidified to pH 5 with 1 M hydrochloric acid solution, and extracted with methyl tert-butyl ether (2 x 350 mL). The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired product (2S)-methyl 2-(4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy)propanoate B.5 (about 1:1 mixture of diastereomers) as a yellow oil (10.30 g, 98% yield).

[0427] 1H NMR (400MHz, CDCl 3 )δ7.99 and 7.97 (two d, J=2.5 Hz, 1H), 7.37 (dd, J=8.9, 2.5 Hz, 1H), 6.63 and 6.61 (two d, J=8.9 Hz, 1H), 5.62 (m, 1H), 4.78 (m, 1H), 3.81 (m, 1H), 3.73 and 3.71 (two s, 3H), 3.59 (m, 1H), 3.48 (m, 1H), 3.35 and 3.31 (two dd, J=13.4, 1.5 Hz, 1H), 1.61 (d, J=6.8 Hz, 3H), 1.56 (m, 2H), 1.35 (m, 2H), 0.90 and 0.89 (two t, J=7.4 Hz, 3H). LC / MS (Agilent) m / z 399.9 (M+H) + , at 2.91min.

[0428] Synthesis of (2S)-2-(4-bromo-2-(isoxazol-3-yl)phenoxy)propionic acid B.6

[0429] A solution of ethyl (2S)-2-(4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy)propanoate B.5 (9.15 g, 22.90 mmol) in aqueous formic acid (90%) (100 mL, 2.39 mol) was heated at 100° C. for 6 h.

[0430] The reaction mixture is cooled to room temperature and desolventized under vacuum. Crude material is azeotropically dried in vacuo for 1h with acetonitrile. The isolated oil is distributed between methyl tert-butyl ether and water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a yellow oil. The oil is ground in dichloromethane (20mL) and hexane (400mL) and the isolated solid is dried overnight in a vacuum oven to provide the desired product (2S) -2- (4- bromo- 2- (isoxazole -3- bases) phenoxy) propionic acid B.6, which is a beige solid (5.52g, 78% yield).

[0431] 1H NMR (400MHz, CDCl 3)δ8.49(d,J=1.8Hz,1H),7.77(d,J=2.4Hz,1H),7.53(dd,J=8.8,2.4Hz,1H),6.90(d ,J=8.8Hz,1H),6.78(d,J=1.8Hz,1H),4.91(q,J=6.9Hz,1H),1.73(d,J=6.9Hz,3H). LC / MS(Agilent)m / z312.0(M+H) + , at 2.40min.

[0432] The overall yield starting from 5-bromo-2-hydroxybenzaldehyde B.1 was 48% and the purity of the product was >98% as judged by LC / MS and 1 H NMR.

[0433] Chiral SCF method: (S)-enantiomer, 2.12 min; (R)-enantiomer, 2.79 min.

[0434] Example 2: Synthesis of (2S)-2-(4-bromo-2-(isoxazol-3-yl)phenoxy)propionic acid (2S)-2-(4-bromo-2- Synthesis of methyl (4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy)propionate B.5

[0435] DMF (595 mL) was added to methyl (S,E)-2-(4-bromo-2-((hydroxyimino)methyl)phenoxy)propanoate B.4 (119 g) and the temperature was adjusted to 20°C. N-Chlorosuccinimide (16.0 g, 0.3 eq) was added and the reaction was stirred at 15-30°C for 20 minutes. N-Chlorosuccinimide (4 x 10.5 g, 4 x 0.2 eq) was added in 4 equal portions every 5 minutes, keeping the temperature between 20-30°C, and the reaction was stirred at 15-30°C for 20 minutes. The reaction was cooled to 0-5°C and butyl vinyl ether (56.6 mL, 1.1 eq) was added, followed by triethylamine (54.9 mL, 1.0 eq) dropwise at 0-5°C over 1 hour. The reaction was stirred at 0-5°C for 12 hours, then water (1.19 L) was added over 5 minutes. The product was extracted with methyl tert-butyl ether (2 x 600 mL), and the organic phase was washed with 10% w / w brine (2 x 350 mL), dried over magnesium sulfate, filtered and concentrated to give methyl (2S)-2-(4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy)propanoate B.5 as a approximately 1:1 mixture of diastereomers (157.1 g, quantitative) as an amber oil.

[0436] Synthesis of (2S)-2-(4-bromo-2-(isoxazol-3-yl)phenoxy)propionic acid B.6

[0437] (2S)-2-(4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy)propanoate B.5 (151 g) was dissolved in acetic acid (755 mL) and water (226 mL) was added at 15-25°C. The reaction was heated to reflux (about 107°C) for 48 hours or until in-process control indicated the reaction was complete. The reaction was cooled to 15-25°C and water (1.5 L) was added. The product was extracted with methyl tert-butyl ether (755 mL then 450 mL) and the combined organic phases were washed with 10% w / w brine (3 x 450 mL). The organic phase was distilled leaving about 4 volumes and toluene (1.5 L) was then added. The organic phase was distilled leaving about 5 volumes and toluene (750 mL) was then added. The organic phase was distilled leaving about 4 volumes and then cooled to 80-90°C and filtered. The organic phase was cooled to 50-55°C and seeded. The solution was stirred at 50-55°C for 30 minutes, cooled to 0-5°C over 12 hours, stirred at 0-5°C for 5 hours, then filtered and washed with toluene (150 mL) and n-heptane (2 x 300 mL). The solid was dried at 40°C until no further mass change was obtained to afford (2S)-2-(4-bromo-2-(isoxazol-3-yl)phenoxy)propanoic acid B.6 as a beige solid (83.9 g, 71%) with a purity of >98% by LC / MS and 1H NMR and an enantiomeric excess of >98% by chiral HPLC.

[0438] Example 3: Screening of compounds on human ClC-1 isoforms expressed in CHO cells using automated patch clamp

[0439] The research goal of these experiments was to evaluate how compounds affect the open probability and current amplitude of human ClC-1 channels expressed in CHO cells. Experiments were performed using an automated patch clamp system that allows high-throughput testing of whole-cell patches as well as intracellular and extracellular addition of compounds.

[0440] Automatic voltage clamp measurements

[0441] Automated whole-cell patch clamp experiments were performed at room temperature using the Qpatch 16 system (Sophion Bioscience, Ballerup, Denmark). Data acquisition and analysis were performed in Qassay software (version 5.6, Odense).

[0442] Voltage protocol and analysis of whole-cell ClC-1 currents

[0443] To elicit ClC-1 currents in whole-cell patches, the membrane potential was initially stepped from a holding potential of -30 mV to +60 mV for 100 ms and then stepped to various test voltages (sweeps) ranging from +120 mV to -140 mV in 20 mV steps for 300 ms. To obtain tail currents, after each test voltage, the membrane potential was stepped to -100 mV for 300 ms and then relaxed to -30 mV for 2 sec between sweeps ( Figure 1 ).

[0444] The I / V relationship of whole-cell transient and steady-state current amplitudes was obtained by plotting the average current density at the beginning and end of the 300 ms step versus the membrane potential ( Figure 2 ).

[0445] In order to determine the relative total open probability (P 0 ), the instantaneous tail current was normalized to the maximum tail current obtained after the most positive voltage step and plotted against the test voltage. The normalized tail current plots from each whole-cell patch were then fitted to a Boltzmann function, allowing the determination of the half-activation voltage (V 1 / 2 , Figure 3 ).

[0446] Solution

[0447] For automated patch clamp experiments, the extracellular solution contained: 2 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, 4 mM KCl, 145 mM NaCl, 10 mM glucose, pH adjusted to 7.4 with NaOH (2 M). Osmolality was adjusted to ~320 with sucrose.

[0448] The intracellular solution contained: 80 mM CsF, 60 mM CsCl, 5 / 1 mM KOH / EGTA, 10 mM HEPES, 10 mM NaCl, pH was adjusted to 7.2 with NaOH (2 M). The osmolarity was adjusted to ∼320 mOsm using sucrose.

[0449] Cell line information:

[0450] The cell used in the patch clamp experiment is a Chinese hamster ovary cell (CHO) that constitutively expresses people's ClC-1 channel. The amino acid sequence encoded by the cDNA that is used to produce this cell line is identical to the translation sequence of GenBank accession number NM_000083.2. Cell is produced by Charles River (catalog CT6175, Cleveland OH, USA) in the form of cryopreservation. After thawing, directly cells are tested (3x 10 are used in each experiment) and the cell culture medium is used for lysine hydrochloride. 6 cells).

[0451] Test plan

[0452] To evaluate the effects of compounds on ClC-1, when applied directly to the intracellular side of the cell membrane, the half-activation voltage V was determined from whole-cell membrane patches in which the compounds were added to the intracellular solution. 1 / 2 , which was then compared to the V determined from control cell membranes in which only the vehicle was added to the intracellular solution. 1 / 2 In addition, V was determined before and after exchanging the extracellular solution to contain the compound. 1 / 2 and steady-state current amplitude to evaluate the effects of extracellularly added compounds.

[0453] The difference in the half-activation voltage of ClC-1 channels ΔV 1 / 2 It was determined as the difference between cell membrane slices treated intracellularly with compound and control cell membrane slices and is reported in Table 1 below. ΔV 1 / 2 A positive shift in reflects inhibition of ClC-1 channels by the tested compound. P-values ​​< 0.05 were considered significant.

[0454] Table 1: Half-activation voltage V 1 / 2 Offset

[0455]

[0456] Example 4: Measurement of in situ muscle contraction properties

[0457] Isometric hindlimb force was measured in 12 week old female Lewis rats in the presence and absence of compound.

[0458] Rats were placed under isoflurane (2-4%) anesthesia, intubated and subsequently connected to a microventilator (Microvent 1, Hallowell EMC, US). Two stimulating electrodes were inserted through the skin to stimulate the sciatic nerve. A small incision was made proximally at the ankle to expose the Achilles tendon, which was tied with cotton thread and connected to a position-adjustable (vernier-controlled) force transducer (Fort250, World Precision Instruments). The Achilles tendon was then cut at the distal end of the connected cotton thread. Rats were placed on a heating pad and their feet were fixed to a pedal with tape to prevent movement artefacts caused by contraction of the ankle dorsiflexor.

[0459] The muscle contractile properties are assessed by applying an electric current to the nerve (under supermaximal voltage conditions) and recording the force generated 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 was used throughout the experiment, except that in a few cases 80Hz stimulation was replaced by 12Hz (10 pulses). Neuromuscular transmission is partially inhibited by constant rate infusion of Cisatracurium (Nimbex, GlaxoSmithKline) at a concentration of 0.1mg / kg with an adjustable infusion rate, and each animal is individually adjusted to obtain an inhibition level of about 50% of the force generated by 12Hz stimulation at the 4th pulse. When the neuromuscular inhibition level is stable, the test article is injected intravenously at a selected concentration. The effect of the test article is evaluated according to its ability to increase the force generated by the applied stimulation mode. Effects were assessed in terms of the ability to increase the force itself (tonic, 80 Hz, stimulation) and the ratio between the peak values ​​of individual twitches (12 Hz stimulation). Effects were monitored for at least 1 hour after injection of the test article. In addition, if possible, the time from injection of the test article to the maximum effect on force (twitch and twitch) and the time when the effect disappeared (returned to baseline) were recorded. When appropriate, the infusion of neuromuscular blockers was stopped, the stimulation mode was continued, and the force was monitored to recover to the control level. Animals were killed by cervical dislocation while still fully sedated.

[0460] (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propionic acid was administered intravenously at 24.6 mg / kg. The average increase in tetanic force was 46.2% (3 experiments).

[0461] 2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]acetic acid was administered intravenously at 44.8 mg / kg. The average increase in tetanic force was 57.7% (2 experiments).

[0462] This indicates that the compounds of the invention can restore force in vivo to muscles that have been partially inhibited by neuromuscular blockers.

Claims

1. A method for preparing a compound of formula I It comprises step a), wherein i) reacting the compound of formula II with an acid or a base as well as ii) isolating the compound of formula I from the reaction mixture, in -R 1 is selected from the group consisting of H, F, Cl, Br and I; -R 2 Selected from C 1-5 Alkyl and C 3-5 Cycloalkyl; -R 3 is selected from the group consisting of deuterium, F, Cl, Br and I; -R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl and C 5 cycloalkenyl, each of which is optionally substituted by one or more identical or different substituents R 7 replace; -R 5 is selected from optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 Alkyl, C 2-5 Alkenyl, 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; -R 6 Selected from H, deuterium, C 1-5 Alkyl and C 3-5 Cycloalkyl; -R 7 independently selected from deuterium, tritium, F, Cl, Br, I, CN, isocyano, optionally substituted by one or more identical or different substituents R 8 Substituted C 3-5 Cycloalkyl, optionally substituted by one or more identical or different substituents R 8 Replaced OC 1-3 alkyl, optionally substituted by one or more identical or different substituents R 8 Replaced SC 1-3 alkyl, optionally substituted by one or more identical or different substituents R 8 Substituted CH 2 -OC 1-3 alkyl and optionally substituted by one or more identical or different substituents R 8 Substituted CH 2 -SC 1-3 alkyl; -R 8 are independently selected from deuterium and F; -R 9 are independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and -n is an integer 0, 1, 2, or 3.

2. The method of claim 1, wherein R 1 It is Cl or Br.

3. The method of claim 1, wherein R 2 It is C 1-5 alkyl.

4. The method of claim 1, wherein R 3 It's F.

5. The method of claim 1, wherein R 4 is optionally substituted by one or more identical or different substituents R 7 Substituted C 1-5 alkyl.

6. The method of claim 1, wherein R 5 is optionally substituted by one or more identical or different substituents R 8 Substituted C 1-5 alkyl.

7. The method of claim 1, wherein R 6 It's H. The method of claim 1 , wherein n is 0.

9. The process of claim 1, wherein the compound of formula II is reacted with an acid.

10. The process of claim 1, wherein the acid in step a) i) is formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, hydrochloric acid or sulfuric acid or a mixture thereof.

11. The method of claim 1, wherein step a)i) is performed at a temperature of 70°C to 140°C.

12. The method of claim 1, wherein step a)i) is performed at a temperature of 90°C to 120°C.

13. The process of claim 1, wherein the compound of formula II is reacted with a base.

14. The method of claim 1, wherein the reaction time of step a) i) is 12 to 96 hours.

15. The method of claim 1, wherein the reaction time of step a) i) is 36 to 60 hours.

16. The process of claim 1, wherein in step a) ii) the compound of formula I is isolated from the reaction mixture by adding water and extracting the product into an organic solvent.

17. The process of claim 1, wherein the compound of formula I is purified by crystallization from an organic solvent selected from the group consisting of toluene, ethyl acetate, isopropyl acetate and methyl tert-butyl ether.

18. The method of claim 1, wherein the compound of formula I is an inhibitor of the ClC-1 chloride channel.

19. The method of claim 1, wherein the compound of formula I is selected from: (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]-2-cyclopropylacetic acid; (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid; 2-[4-Bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]acetic acid; 2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]acetic acid; (2S)-2-[4,5-dichloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-Chloro-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid; (2S)-2-[4-Fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-chloro-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid; (2S)-2-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid; (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid; (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid; (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid; (2S)-2-[4-Bromo-2-(5-methyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-bromo-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; and (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid.

20. The method according to any one of claims 1 to 19, wherein the method further comprises step b), wherein i) making a compound of formula III Reaction with N-chlorosuccinimide in an organic solvent; ii) the compound of formula IV and a base are added to the reaction mixture; and iii) isolating the compound of formula II from the reaction mixture, Where R 1 To R 9 and n is as defined in claim 1.

21. A compound of formula (II) as defined in claim 1 selected from: (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-tert-butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-tert-butyl 2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-tert-butyl 2-[4-chloro-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-bromo-2-(5-methyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-bromo-2-(5-cyclopropyl-4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-methyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid methyl ester; Methyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; Methyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; (2S)-2-[4,5-dichloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-methyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-methyl 2-[4-chloro-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid methyl ester; (2S)-2-[4-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid methyl ester; (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid methyl ester; (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; Ethyl (2S)-2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropionic acid ethyl ester; Ethyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; Ethyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; (2S)-2-[4,5-dichloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-chloro-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropionic acid ethyl ester; (2S)-2-[4-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid ethyl ester; (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid ethyl ester; (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropionic acid ethyl ester; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid ethyl ester; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid ethyl ester; (2S)-2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; tert-Butyl (2S)-2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate; (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropanoate; tert-Butyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; tert-Butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; tert-Butyl (2S)-2-[4,5-dichloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-bromo-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-chloro-5-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoate; (2S)-tert-butyl 2-[4-fluoro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; tert-Butyl (2S)-2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoate; (2S)-tert-butyl 2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoate; (2S)-tert-butyl 2-[4-chloro-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoate; (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoate; (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoate; (2S)-tert-butyl 2-[4-bromo-2-(4-butoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-methyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid methyl ester; Methyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; Methyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; (2S)-2-[4,5-dichloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-methyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-methyl 2-[4-chloro-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid methyl ester; (2S)-2-[4-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid methyl ester; (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid methyl ester; (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid methyl ester; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid methyl ester; Ethyl (2S)-2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropionic acid ethyl ester; Ethyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; Ethyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; (2S)-2-[4,5-dichloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-chloro-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropionic acid ethyl ester; (2S)-2-[4-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid ethyl ester; (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid ethyl ester; (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropionic acid ethyl ester; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoic acid ethyl ester; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoic acid ethyl ester; (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoic acid ethyl ester; tert-Butyl (2S)-2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-2-cyclopropylacetate; (2S)-tert-butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclobutylpropanoate; tert-Butyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; tert-Butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]acetate; tert-Butyl (2S)-2-[4,5-dichloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-bromo-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; Tert-butyl (2S)-2-[4-chloro-5-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoate; Tert-butyl (2S)-2-[4-fluoro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; tert-Butyl (2S)-2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoate; (2S)-tert-butyl 2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoate; (2S)-tert-butyl 2-[4-chloro-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate; (2S)-tert-butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-cyclopropylpropanoate; (2S)-tert-butyl 2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]butanoate; tert-Butyl (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]-3-methylbutanoate; and Tert-butyl (2S)-2-[4-bromo-2-(4-ethoxy-4,5-dihydroisoxazol-3-yl)phenoxy]propanoate.

22. A method for preparing a pharmaceutical composition, The following steps are involved: i) preparing a compound of formula I by a method according to any one of claims 1 to 19, wherein the compound of formula I is selected from: (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]-2-cyclopropylacetic acid; (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclobutylpropanoic acid; 2-[4-Bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]acetic acid; 2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]acetic acid; (2S)-2-[4,5-dichloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-Chloro-5-fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid; (2S)-2-[4-Fluoro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-chloro-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid; (2S)-2-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid; (2S)-2-[4-Chloro-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-cyclopropylpropanoic acid; (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid; (2S)-2-[4-Bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid; (2S)-2-[4-Bromo-2-(5-methyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; (2S)-2-[4-bromo-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid; and (2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid, as well as ii) formulating the compound into a pharmaceutical composition.

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