ClC-1 compounds for treatment of multiple sclerosis and neuromuscular diseases

Abstract

The present invention relates to compounds capable of inhibiting the ClC-1 ion channel for use in the treatment, amelioration and / or prevention of multiple sclerosis and other neuromuscular diseases.

Description

TECHNICAL FIELD

[0001] The present invention relates to compounds capable of inhibiting the ClC-1 ion channel for the treatment, amelioration and / or prevention of multiple sclerosis and other neuromuscular diseases.

[0002] BACKGROUND

[0003] Multiple sclerosis (MS) is the most common demyelinating disease in which the insulating covering of nerve cells in the brain and spinal cord is damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical problems, mental problems, and sometimes psychological problems. Specific symptoms can include double vision, loss of vision, muscle weakness, and sensory or coordination disorders. MS has several forms, with new symptoms either appearing in isolated attacks (relapsing form) or accumulating over time (progressive form). In the relapsing form of MS, between attacks, symptoms can disappear completely, although some permanent neurological problems often remain, especially as the disease progresses.

[0004] Multiple sclerosis is the most common immune-mediated disorder affecting the central nervous system. In 2022, nearly 1 million people in the United States have MS, while in 2020, about 2.8 million people worldwide were affected, with varying incidence rates in different regions and different populations. The disease usually begins between the ages of 20 and 50, with twice as many women as men being affected.

[0005] Several phenotypes (often referred to as “types”) or patterns of progression have been described. Phenotypes use the past course of the disease to try to predict the future course. They are important not only for prognosis, but also for treatment decisions.

[0006] The International Advisory Committee on Clinical Trials of MS describes four types of MS, also known as the Lublin classification: Clinically isolated syndrome (CIS) Relapsing-remitting MS (RRMS) Primary progressive MS (PPMS) Secondary progressive MS (SPMS) RRMS is characterized by unpredictable relapses followed by periods of relative quiet (remission) of months to years with no new signs of disease activity. Functional deficits that appear during an attack can resolve or leave problems, and problems are left in about 40% of attacks, and are more common the longer a person has been ill. This describes the initial course of disease in 80% of MS patients.

[0007] The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a patient has one attack suggestive of demyelination, but does not meet the criteria for multiple sclerosis. 30% to 70% of CIS patients later develop MS.

[0008] PPMS has an incidence of about 10-20% in patients with this disease, and has no remission after the first symptoms. It is characterized by progression of disability from the onset of the disease, with no or only occasional and mild remissions and improvements. The usual age of onset of the primary progressive subtype is later than the relapsing-remitting subtype. This is similar to the age at which the secondary progressive subtype usually begins, around 40 years of age.

[0009] SPMS has an incidence of about 65% in patients with initial RRMS, who eventually develop progressive neurologic decline between acute attacks, without any clear remission period. Occasional relapses and mild remissions can occur. The most common length of time from onset of disease to conversion from RRMS to SPMS is 19 years.

[0010] Although several disease-modifying treatments have been approved by regulatory agencies in different countries, multiple sclerosis is known not to be curable. FDA-approved drugs include interferon beta-1a and beta-1b, monoclonal antibodies (such as natalizumab, alemtuzumab, and ocrelizumab), and immunomodulators (such as glatiramer acetate, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, diroximel fumarate, Siponimod, Cladribine, Ozanimod).

[0011] Although there is evidence that multiple sclerosis affects the peripheral nervous system (PNS), these treatments do not directly target or improve muscle weakness or coordination (Weir et al., 1979; Hopf and Eysholdt, 1978). Hopf and Eysholdt (1978) showed that the relative refractory period (RRP) of the median nerve sensory fibers was significantly prolonged in MS patients. Weir et al. (1979) showed that when measured using single-fiber electromyography (SFEMG), 6 out of 15 MS patients exhibited markedly abnormal tremors, and the SFEMGs of the other five patients showed borderline abnormalities.

[0012] Tremor refers to the time variability in the arrival of muscle fiber action potentials at the recording electrodes between consecutive discharges when measuring neuromuscular function using single-fiber electromyography (sfEMG). Blockage is the complete failure of NMJ transmission of muscle fiber action potentials to the recording electrodes between consecutive discharges when using sfEMG to measure neuromuscular function.

[0013] Normalization of tremors and / or reduction of blockade can improve neuromuscular function by ensuring that more muscle fibers in the muscle respond simultaneously, thereby improving muscle strength and control.

[0014] Therefore, safe and effective therapies are needed to improve muscle function in patients with various forms of multiple sclerosis. Summary of the Invention

[0015] This invention relates to ClC-1 inhibitors for the treatment, prevention, and / or improvement of multiple sclerosis and other neuromuscular diseases. Attached Figure Description

[0016] Figure 1

[0017] In a pharmacological rat model of neuromuscular dysfunction, NMD712 was used (( S 2-(p-bromophenoxy)butyric acid inhibits ClC-1 channels to restore muscle function and NMJ transmission. The figure shows stimulated muscle strength (A), compound muscle action potential (CMAP) (B), tremor (C), and blockade (D) in rats before (white, before NMBA) and during (grey, control) administration of a neuromuscular blocking agent (NMBA) to achieve a stable decline in neuromuscular function levels compared to pre-NMBA levels. NMD712 (50 mg / kg) was administered orally, and these four parameters were measured 60 minutes post-administration (grid). NMD712 resulted in the recovery of all four measured parameters: muscle strength (A), CMAP (B), tremor (C), and blockade (D). N = 4 animals, values ​​are mean ± SEM. Statistical significance based on two-way ANOVA with multiple comparisons ( p < 0.01, p < 0.001, p < 0.0001).

[0018] Figure 2

[0019] Figure 2 The study design of a clinical observational study is described, which enrolled CMT type 1 and 2 patients and age-matched healthy controls at two study sites. Clinical trials are listed in trial order. CMT ES2: CMT Examination Score 2. RNS: Repetitive Nerve Stimulation. SF EMG: Single Fiber EMG. CMT ES2 was performed only at Visit 1.

[0020] Figure 3

[0021] Figure 3 The tremor and block at Visit 1 of a clinical observational study of healthy subjects and Charcot-Marie-Tooth (CMT) patients is described, shown as individual data: median of healthy controls and CMT patients (A and B) and CMT1 and CMT2 patients (C and D). Mean consecutive difference (MCD).

[0022] Definitions

[0023] The nomenclature used in this application is based on the IUPAC system of nomenclature, unless otherwise specified.

[0024] The term "C 1-2 The terms "alkyl", "C 1-3 The terms "alkyl", "C 1-5 The terms "alkyl", "C

[0025] The terms "C2alkenyl" and "C 2-5 The terms "C2alkenyl" and "C

[0026] The terms "C2alkynyl" and "C 2-5"Alkynyl" refers to a branched or unbranched alkynyl group having two or two to five carbon atoms, 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-diyne, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, pent-2,4-diynyl, and pent-1,3-diynyl, respectively.

[0027] The term "C 3-5 "Cycloalkyl" and "C 3-6 "Cycloalkyl" and "C 3-5 Examples of cycloalkyl groups are oxirane-2-yl, oxetan-2-yl, oxetan-3-yl, oxolane-2-yl, and oxolane-3-yl.

[0028] The term "C 1-2 "Alkoxy" refers to an alkyl group having one to two carbon atoms attached to an oxygen atom, and the point of attachment is the oxygen atom. C 1-2 Examples of alkoxy groups are methoxy and ethoxy.

[0029] The term "C 1-2 "Alkylthio" refers to an alkyl group having one to two carbon atoms attached to a sulfur atom, and the point of attachment is the sulfur atom. C 1-2 Examples of alkylthio groups are methylthio and ethylthio.

[0030] The term "4-6 membered heterocycle" refers to a group having four, five, or six carbon atoms, respectively, wherein 1 to 3 carbon atoms in the ring have been replaced by a heteroatom selected from the group comprising nitrogen, sulfur, and oxygen. Attachment to the heterocycle can be at the position of the heteroatom or through a carbon atom of the heterocycle.

[0031] 4-membered heterocycles include, but are not limited to, oxetane, azetidine, and thietane.

[0032] 5-membered heterocycles include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, dihydrofuran, dihydrothiophene, 3-pyrroline, 2-pyrroline, 2-imidazoline, 2-pyrazolidine, dihydrooxazole, dihydrothiazole, dihydroisoxazole, dihydroisothiazole, dihydro-1,2,3-triazole, dihydro-1,2,4-triazole, dihydro-1,2,5-oxadiazole, dihydro-1,2,3-oxadiazole, dihydro-1,2,4-oxadiazole, dihydro-1,3,4-oxadiazole, dihydro-1,2,5-thiadiazole, dihydro-1,2,3-thiadiazole, dihydro-1,2,4-thiadiazole, dihydro-1,3,4-thiadiazole, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, thiazolidine, isoxazolidine, isothiazolidine, 1,2,3-triazolidine, 1,2,4-triazolidine, 1,2,5-oxadiazolidine, 1,2,3-oxadiazolidine, 1,3,4-oxadiazolidine, 1,2,5-thiadiazolidine, 1,2,3-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2-oxathiolane, 1,3-oxathiolane, 2-oxazolidinone, and 2-pyrrolidinone.

[0033] 6-membered heterocycles include, but are not limited to, pyridine, pyrazine, pyrimidine, pyridazine, tetrahydropyran, thiane, piperidine, 1,4-dioxane, morpholine, 1,4-oxathiane, 1,4-dithiane, and piperazine.

[0034] The term “5-membered aromatic heterocycle” refers to an aromatic group having five carbon atoms, in which 1 to 3 of the carbon atoms in the ring have been replaced by a heteroatom selected from the group comprising nitrogen, sulfur, and oxygen. The attachment to the heterocycle can be at the position of the heteroatom or through a carbon atom of the heterocycle.

[0035] 5-membered aromatic heterocycles include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2-thiazol-3-yl, 1,2-thiazol-4-yl, 1,2-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, and 1,2,5-oxadiazol-3-yl.

[0036] As used herein, the term "half-life" refers to the time required for a compound to lose half of its pharmacological activity. The term "plasma half-life" refers to the time required for a compound to lose half of its pharmacological activity in plasma.

[0037] The term "treatment" refers to the combating of a disease or disorder. As used herein, "treatment" or "treating" includes any desirable effect on the symptoms or pathology of the diseases or conditions described herein, and can include even minimal changes or improvements in one or more measurable markers of the disease or condition being treated. "Treatment" does not necessarily indicate complete eradication or cure of the disease or condition, or associated symptoms. In some embodiments, the term "treatment" includes amelioration and prevention.

[0038] The term "amelioration" refers to the lessening of the severity of symptoms of a disease or condition. An improvement in a patient's condition or an activity undertaken to correct an intolerable condition associated with a patient's condition or at least make it more acceptable, is considered "ameliorative" treatment.

[0039] The term "prevent" or "preventing" refers to precluding, obviating, averting, preventing, stopping or hindering the occurrence of something, especially by advance action.

[0040] The term "jitter" refers to the variability in the time of arrival of action potentials at a recording electrode between successive discharges when measuring neuromuscular function using single-fiber electromyography (sfEMG). For example, jitter can be measured by calculating the variation in the time interval between two action potentials of the same motor unit using a recording electrode.

[0041] The term "blocking" refers to the failure of full NMJ transmission of action potentials between successive discharges to a recording electrode when measuring neuromuscular function using sfEMG. Blocking of neuromuscular transmission can be detected by determining the percentage of paired successful action potentials of different muscle fibers of the same motor unit in neuromuscular tissue out of the total number of autonomous activations of said motor unit. For example, blocking can be detected by (i) first counting the number of paired successful action potentials of different muscle fibers of the same motor unit in neuromuscular tissue, (ii) dividing the number of paired successful action potentials by the total number of action potentials occurring in at least one muscle fiber of that motor unit, and (iii) multiplying the result of the division by 100. For example, if different muscle fibers of the same motor unit experienced 100 autonomous activations and 90 of those activations produced a detectable action potential in one muscle fiber and no action potential in the other muscle fiber, then the extent of blocking experienced by the motor unit was 10%. DETAILED DESCRIPTION

[0043] Skeletal muscle-specific ClC-1 chloride channels carry inhibitory currents that counteract neuromuscular transmission. Inhibition of ClC-1 reduces the inhibitory current, thereby increasing the excitability of the sarcolemma and enhancing neuromuscular transmission (Pedersen et al., 2021). Administration of a ClC-1 inhibitor will normalize tremor and increase the likelihood of action potential firing (i.e., reduce blocking) by making the sarcolemma more excitable. The reduction in blocking and normalization of tremor will reduce the incidence of NMJ transmission failure, enhance muscle function, and thereby result in increased muscle strength and control.

[0044] Thus, in a principal aspect, the present invention relates to ClC-1 inhibitors for use in the treatment, prevention and / or amelioration of multiple sclerosis and other neuromuscular diseases.

[0045] The compounds for use of the present disclosure include compounds capable of inhibiting ClC-1 channels and thereby ameliorating or restoring neuromuscular function, i.e., the compounds are ClC-1 inhibitors. In one embodiment, the 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. The EC 50 The assay can be performed, e.g., as described in Example 1.

[0046] In one embodiment, the force of the muscle with neuromuscular dysfunction is restored by > 5%, such as > 10%, such as > 15%, such as > 20%, such as > 25%, such as > 30%, such as > 35%. The force of the muscle with neuromuscular dysfunction can be determined, e.g., as described in Example 2.

[0047] In one embodiment, the compound can cause a positive shift in the half-activation voltage AV of the ClC-1 channel. The half-activation voltage of the ClC-1 channel can be determined, for example, as described in Example 3. 1 / 2

[0048] In one embodiment, the compound can increase twitch force in an in situ muscle contraction experiment. The increase in twitch force can be determined, for example, as described in Example 4.

[0049] ClC-1 inhibitors are described, for example, in WO 2016 / 202341, WO 2019 / 115777, WO 2019 / 115780, WO 2019 / 115781, EP19181263, WO 2020 / 254553, WO 2020 / 254558 and WO 2020 / 254559.

[0050] All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0051] In one aspect, the disclosure relates to a method of treating, preventing and / or ameliorating multiple sclerosis, comprising administering to a subject in need thereof a ClC-1 inhibitor. In one aspect, the disclosure relates to a method of treating, preventing and / or ameliorating multiple sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of use as defined herein. In one embodiment, the subject is a human.

[0052] In one aspect, the disclosure relates to the use of a ClC-1 inhibitor for the manufacture of a medicament for the treatment, prevention and / or amelioration of multiple sclerosis. In one aspect, the disclosure relates to the use of a compound as defined herein for the manufacture of a medicament for the treatment, prevention and / or amelioration of multiple sclerosis.

[0053] In one embodiment, the ClC-1 inhibitor restores the contractile force of a muscle of a subject. Ex vivo contractile force can be measured, for example, as described in Example 2 herein, while contractile force in a clinical setting can be measured, for example, as described in Scott et al., 2011.

[0054] ​In one aspect, the disclosure relates to a ClC-1 inhibitor for use in a method of restoring contractility of muscle in a subject having multiple sclerosis. In one aspect, the disclosure relates to a method of restoring contractility of muscle in a subject having multiple sclerosis, comprising administering a ClC-1 inhibitor to a subject in need thereof. In one aspect, the disclosure relates to the use of a ClC-1 inhibitor in the manufacture of a medicament for restoring contractility of muscle in a subject having multiple sclerosis. Ex vivo contractility can be measured, for example, as described in Example 2 herein, while contractility in a clinical setting can be measured, for example, as described in Scott et al., 2011.

[0055] In one embodiment, the ClC-1 inhibitor reduces the incidence of NMJ transmission failure in muscle of a subject. NMJ transmission failure can be measured, for example, as described in Example 5 herein, while contractility in a clinical setting can be measured, for example, as described in Scott et al., 2011.

[0056] In one aspect, the disclosure relates to a ClC-1 inhibitor for use in a method of reducing the incidence of NMJ transmission failure in muscle of a subject having multiple sclerosis. In one aspect, the disclosure relates to a method of reducing the incidence of NMJ transmission failure in muscle of a subject having multiple sclerosis, comprising administering a ClC-1 inhibitor to a subject in need thereof. In one aspect, the disclosure relates to the use of a ClC-1 inhibitor in the manufacture of a medicament for reducing the incidence of NMJ transmission failure in muscle of a subject having multiple sclerosis.

[0057] In one embodiment, the ClC-1 inhibitor increases the probability of action potential firing in muscle of a subject. The increase in probability of action potential firing can be determined in a subject as described in Example 6 or Weir et al., 1979.

[0058] In one aspect, the disclosure relates to a ClC-1 inhibitor for use in a method of increasing the probability of action potential firing in muscle of a subject having multiple sclerosis. In one aspect, the disclosure relates to a method of increasing the probability of action potential firing in muscle of a subject having multiple sclerosis, comprising administering a ClC-1 inhibitor to a subject in need thereof. In one aspect, the disclosure relates to the use of a ClC-1 inhibitor in the manufacture of a medicament for increasing the probability of action potential firing in muscle of a subject having multiple sclerosis.

[0059] In one embodiment, the ClC-1 inhibitor normalizes tremor of muscle of a subject. Normalization of tremor of muscle of a subject can be determined as described in Example 6.

[0060] In one aspect, the present disclosure relates to a ClC-1 inhibitor for use in a method of normalizing muscle twitch in a subject having multiple sclerosis. In one aspect, the present disclosure relates to a method of normalizing muscle twitch in a subject having multiple sclerosis, comprising administering to a subject in need thereof a ClC-1 inhibitor. In one aspect, the present disclosure relates to the use of a ClC-1 inhibitor for the manufacture of a medicament for normalizing muscle twitch in a subject having multiple sclerosis.

[0061] In some embodiments, the compound for use is a compound of formula (I):

[0062] Formula (I)

[0063] wherein: - R 1 is selected from C 1-2 alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 is selected from H, deuterium, F, Cl, Br, I, optionally substituted C 6 alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br, and I; 2-5 alkenyl, optionally substituted by one or more identical or different substituents R 6 alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br, and I; 2-5 alkynyl, optionally substituted by one or more identical or different substituents R 6 alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br, and I; 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 -CF2-C 1-5 alkyl and optionally substituted by one or more identical or different substituents R 7 5-membered aromatic heterocycle, optionally substituted by one or more identical or different substituents R - R 3 is selected from deuterium, Cl and F; - R 4 is selected from H, deuterium, C 1-5 alkyl, C 1-2 alkoxy-C 1-2 alkyl, C 1-2 alkylthio-C 1-2 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 3-5 cycloalkyl, each of which can be optionally substituted by one or more identical or different substituents R 6 ; - R 5 is selected from H, optionally substituted C 6 alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br, and I;1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 12 Selected from , , , , and ; - R 13 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 14 Selected from one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl groups and optionally substituted with one or more identical or different substituents R 8 Substituted phenyl; - R 15 Selected from -OH, optionally with one or more identical or different substituents R 6substituted -OC 1-5 alkyl and optionally substituted by one or more, same or different, substituents R 6 substituted -OC 3-5 cycloalkyl; - R 16 selected from H, optionally substituted by one or more, same or different, substituents R 6 substituted C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 3-5 cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-C 1-5 alkyl and optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-C 3-5 cycloalkyl; - R 17 selected from H, optionally substituted by one or more, same or different, substituents R 20 substituted C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 3-5 cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-C 1-5 alkyl and optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-C 3-5 cycloalkyl; - R 18 selected from H, optionally substituted by one or more, same or different, substituents R 19 substituted C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 19 substituted C 3-6 cycloalkyl, optionally substituted by one or more, same or different, substituents R 8 substituted phenyl and optionally substituted by one or more, same or different, substituents R 20 substituted 4-6 membered heterocyclic ring; - R 19 independently selected from F, Cl, Br, I, -CN, =0, optionally substituted by one or more, same or different, substituents R 6 substituted C 3-6 cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -0-C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -0-C3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SO-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SO-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SO2-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SO2-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 Substituted phenyl groups, optionally with one or more identical or different substituents R 20 Substituted pyrrolidine-1-yl and optionally with one or more identical or different substituents R 20 Substituted 4-6 membered heterocycles; - R 20independently selected from F, CI, Br, I, -CN, =0, optionally substituted C 6 substituted C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 3-6 cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-OC 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-C 3-5 cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -NH-C(=0)-C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -NH-C(=0)-C 3-5 cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-NH-C 1-5 alkyl and optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-NH-C 3-5 cycloalkyl; - R 21 selected from H, optionally substituted C 6 substituted C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 3-5 cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-C 1-5 alkyl and optionally substituted by one or more, same or different, substituents R 6 substituted -C(=0)-C 3-5 cycloalkyl; - R 22 selected from optionally substituted C 6 substituted C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 3-5 cycloalkyl and optionally substituted by one or more, same or different, substituents R 8 substituted phenyl; - X is selected from N and CR23 ; - Y is selected from NH, O and S; - R 23 is selected from H, NH2, optionally substituted C 6 alkyl, optionally substituted with one or more identical or different substituents R 1-5 alkyl, optionally substituted with one or more identical or different substituents R 6 alkyl, optionally substituted with one or more identical or different substituents R 3-5 cycloalkyl, optionally substituted with one or more identical or different substituents R 6 -OC 1-5 alkyl, optionally substituted with one or more identical or different substituents R 6 -OC 3-5 cycloalkyl, optionally substituted with one or more identical or different substituents R 6 -NH-C(=O)C 1-5 alkyl and optionally substituted with one or more identical or different substituents R 6 -NH-SO2-C 1-5 alkyl; - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0064] In some embodiments, the compound for use is a compound of formula (II):

[0065] formula (II)

[0066] wherein: - R 1 is selected from F, CI, Br and I; - R 2 is optionally substituted C 7 alkyl, optionally substituted with one or more identical or different substituents R - R 3 is selected from deuterium, F and CI; - R 4 is selected from H, deuterium, C 1-5 alkyl, C 1-2 alkoxy-C 1-2 alkyl, C 1-2 alkylthio-C 1-2 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 3-5 cycloalkyl, each of which can be optionally substituted with one or more identical or different substituents R 6 ; - R5 selected from H, deuterium, F, CI, Br and I, preferably CI or Br; 6 substituted C 1-5 alkyl, C 6 alkenyl, C 2-5 alkynyl, C 6 cycloalkyl, C5cycloalkenyl, each of which can optionally be substituted by one or more identical or different substituents R 2-5 substituted phenyl and optionally substituted benzyl; 6 substituted C 3-6 substituted C 8 substituted C 8 substituted C - R 6 is independently selected from deuterium and F; - R 7 is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 is independently selected from deuterium, methoxy, nitro, cyano, CI, Br, I and F; - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0067] In some embodiments, the compound for use is a compound of formula (IX):

[0068] formula (IX)

[0069] wherein: - R 1 is selected from H, deuterium, F, CI, Br and I, preferably CI or Br; - R 3 is selected from deuterium, F and CI; - R 4 is selected from H, deuterium, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C5cycloalkenyl, each of which can optionally be substituted by one or more identical or different substituents R 6 substituted; - R 5 is selected from H, deuterium, F, CI, Br and I, preferably CI or Br; 6 substituted C 1-5 alkyl, C 2-5 alkenyl, C 2-5alkynyl, optionally substituted with one or more, same or different, substituents R 6 substituted C 3-6 cycloalkyl, optionally substituted with one or more, same or different, substituents R 8 substituted phenyl and optionally substituted with one or more, same or different, substituents R 8 substituted benzyl; - R 6 is independently selected from the group consisting of deuterium and F; - R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl and cyclopropyl; - R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F; - m is an integer 0, 1 or 2; and - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0070] In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, m is 2.

[0071] In one embodiment, R 1 is selected from the group consisting of F, Cl, Br and I; R 3 is selected from the group consisting of deuterium, F and Cl; R 4 is selected from the group consisting of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C5cycloalkenyl, each of which can be optionally substituted with one or more, same or different, substituents R 6 substituted; R 5 is selected from the group consisting of H, C 1-5 alkyl, C 2-5 alkenyl and C 2-5 alkynyl; R 6 is independently selected from the group consisting of deuterium and F; and R 7 is independently selected from the group consisting of deuterium, F, methyl, ethyl and cyclopropyl.

[0072] In some embodiments, the compound for use is a compound of formula (II):

[0073] formula (II)

[0074] wherein: - R 1 is selected from the group consisting of C 1-2 alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br and I; - R 2 is optionally substituted by one or more, same or different, substituents R 6 substituted -CF2-C 1-5 alkyl; - R 3 is selected from deuterium, Cl and F; - R 4 is selected from H, deuterium, C 1-5 alkyl, C 1-2 alkoxy-C 1-2 alkyl, C 1-2 alkylthio-C 1-2 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 3-5 cycloalkyl, each of which can be optionally substituted by one or more, same or different, substituents R 6 substituted; - R 5 is selected from H, optionally substituted by one or more, same or different, substituents R 6 substituted C 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 2-5 alkenyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 2-5 alkynyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 3-6 cycloalkyl, optionally substituted by one or more, same or different, substituents R 8 substituted phenyl and optionally substituted by one or more, same or different, substituents R 8 substituted benzyl; - R 6 is independently selected from deuterium and F; - R 8 is independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0075] In some embodiments, the compound for use is a compound of formula (X):

[0076] formula (X)

[0077] wherein: - R 1 is selected from C 1-2alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 3 is selected from the group consisting of deuterium, Cl, and F; - R 4 is selected from the group consisting of H, deuterium, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, and C 3-5 cycloalkyl, each of which can be optionally substituted with one or more substituents R 6 which are the same or different; - R 5 is selected from the group consisting of H, C 6 alkyl optionally substituted with one or more substituents R 1-5 which are the same or different; 6 alkenyl optionally substituted with one or more substituents R 2-5 which are the same or different; 6 alkynyl optionally substituted with one or more substituents R 2-5 which are the same or different; 6 cycloalkyl optionally substituted with one or more substituents R 3-6 phenyl optionally substituted with one or more substituents R 8 which are the same or different; and 8 benzyl optionally substituted with one or more substituents R - R 6 is independently selected from the group consisting of deuterium and F; - R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 9 is selected from the group consisting of C 6 alkyl optionally substituted with one or more substituents R 1-5 which are the same or different; and - n is an integer 0, 1, 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0078] In one embodiment, the compound for use has formula (X), and: - R 1 is selected from the group consisting of F, Cl, Br, and I; - R 3 is selected from the group consisting of deuterium and F; - R 4 is selected from the group consisting of H, deuterium, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, and C 3-5cycloalkyl, each of which can optionally be substituted with one or more, same or different, substituents R 6 substituted; - R 5 is selected from H, optionally substituted C 6 alkyl, optionally substituted C 1-5 alkyl, optionally substituted C 6 alkenyl, optionally substituted C 2-5 alkynyl, optionally substituted C 6 alkynyl, optionally substituted C 2-5 alkynyl, optionally substituted C B8 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 8 phenyl, optionally substituted C 8 benzyl, optionally substituted C - R 6 is independently selected from deuterium and F; - R 8 is independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; - R 9 is selected from optionally substituted C 6 alkyl; and 1-5 alkyl; and - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0079] In one embodiment, the compound for use has formula (X), and: - R 1 is selected from C2alkenyl, C2alkynyl, NO2, F, Cl, Br and I; - R 3 is selected from deuterium, Cl and F; - R 4 is selected from H, deuterium, C 1-5 alkyl and C 2-5 alkynyl, each of which can optionally be substituted with one or more, same or different, substituents R 6 substituted; - R 5 is H; - R 6 is independently selected from deuterium and F; - R 9 is optionally substituted C 6 alkyl; and 1-5alkyl; and - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0080] In some embodiments, the compound for use is a compound of formula (XI):

[0081] Formula (XI)

[0082] wherein: - R 1 is selected from C2alkenyl, C2alkynyl, NO2, F, Cl, Br and I; - R 3 is selected from H, deuterium, Cl and F; - R 4 is selected from H, deuterium, C 1-5 alkyl and C 2-5 alkynyl, each of which can be optionally substituted by one or more identical or different substituents R 6 ; - R 5 is selected from H, C 6 alkyl optionally substituted by one or more identical or different substituents R 1-5 ; 6 C2alkenyl optionally substituted by one or more identical or different substituents R 2-5 ; 6 C2alkynyl optionally substituted by one or more identical or different substituents R 2-5 ; B8 C3-cycloalkyl optionally substituted by one or more identical or different substituents R 3-6 ; 8 phenyl optionally substituted by one or more identical or different substituents R 8 ; - R 6 is independently selected from deuterium and F; - R 8 is independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and - R 9 is C 6 alkyl optionally substituted by one or more identical or different substituents R 1-5 ; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0083] In some embodiments, the compound for use is a compound of formula (XI):

[0084] Formula (XI)

[0085] wherein: - R 1 is selected from C2alkynyl, NO2, Cl, Br, and I; - R 3 is selected from deuterium, Cl, and F; - R 4 is selected from H, deuterium, C 1-3 alkyl, and C 2-3 alkynyl, each of which can be optionally substituted with one or more substituents R 6 which are the same or different; - R 5 is H; - R 6 is independently selected from deuterium and F; and - R 9 is C 6 alkyl optionally substituted with one or more substituents R 1-3 which are the same or different; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0086] In one embodiment, R 9 is methyl. In one embodiment, R 9 is ethyl. In one embodiment, R 9 is n-propyl. In one embodiment, R 9 is isopropyl. In one embodiment, R 9 is cyclopropyl.

[0087] In some embodiments, the compound for use is a compound of Formula (II):

[0088] Formula (II)

[0089] wherein: - R 1 is selected from F, Cl, Br, and I; - R 2 is selected from H, deuterium, F, Cl, Br, and I; - R 3 is selected from deuterium, Cl, and F - R 4 is selected from H, deuterium, C 1-5 alkyl, C 1-2 alkoxy-C 1-2 alkyl, C 1-2alkyl, C 1-2 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 3-5 cycloalkyl, each of which can optionally be substituted by one or more, same or different, substituents R 6 substituted; - R 5 is selected from H, C 6 alkyl, optionally substituted by one or more, same or different, substituents R 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 alkyl, optionally substituted by one or more, same or different, substituents R 2-5 alkenyl, optionally substituted by one or more, same or different, substituents R 6 alkenyl, optionally substituted by one or more, same or different, substituents R 2-5 alkynyl, optionally substituted by one or more, same or different, substituents R 6 alkynyl, optionally substituted by one or more, same or different, substituents R 3-6 cycloalkyl, optionally substituted by one or more, same or different, substituents R 8 phenyl, optionally substituted by one or more, same or different, substituents R 8 benzyl, optionally substituted by one or more, same or different, substituents R - R 6 is independently selected from deuterium and F; - R 8 is independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0090] In some embodiments, the compound for use is a compound of formula (II):

[0091] formula (II)

[0092] wherein: - R 1 is selected from F, Cl, Br and I; - R 2 is selected from hydrogen, deuterium, F, Cl and Br; - R 3 is deuterium; - R 4 is selected from C 6 alkyl, optionally substituted by one or more, same or different, substituents R 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 2-5 alkenyl, C 3-5 cycloalkyl, C5cycloalkenyl and phenyl, each of which is optionally substituted by one or more, same or different, substituents R 6 alkyl, optionally substituted by one or more, same or different, substituents R2-5 alkynyl group; and - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; and - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is 0, 1, 2 or 3; Or its pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate.

[0093] In some embodiments, the compound used is a compound of formula (II):

[0094] Equation (II)

[0095] in: - R 1 Selected from F, Cl, Br and I; - R 2 Selected from hydrogen, deuterium, F, Cl, and Br; - R 3 It is deuterium; - R 4 Selected from C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl and C5 cycloalkenyl groups, each being substituented by one or more identical or different R groups. 6 Replace; and - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 is independently selected from deuterium and F; and - R 8 is independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0096] In some embodiments, the compound for use is a compound of Formula (II):

[0097] Formula (II)

[0098] wherein: - R 1 is selected from H, Br, Cl, F, and I; - R 2 is H; - R 4 is selected from -CH3, -CH2-CH3, -CH(CH3)2, -CH2-F, -CH2-CH2F, and cyclopropyl; - R 5 is H; and - n is 0, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.

[0099] In some embodiments, the compound for use is a compound of Formula (II):

[0100] Formula (II)

[0101] wherein: - R 1 is selected from F, Cl, Br, I, -CN, and -CF3; - R 2 is selected from C 2-5 alkyl, C 2-5 alkenyl, C 3-5 alkynyl, and C 6 cycloalkyl, each of which can be optionally substituted by one or more substituents R 3 identical or different; - R 3 is selected from deuterium, F, and Cl; - R 4 is selected from C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, and C 3-5cycloalkyl, each of which can optionally be substituted with one or more, same or different, substituents R 6 substituted; - R 5 is selected from the group consisting of H, C 6 substituted C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, optionally substituted with one or more, same or different, substituents R 6 substituted C 3-6 cycloalkyl, optionally substituted with one or more, same or different, substituents R 8 substituted phenyl and optionally substituted with one or more, same or different, substituents R 8 substituted benzyl; - R 6 is independently selected from the group consisting of deuterium and F; - R 8 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0102] In some embodiments, the compound for use is a compound of Formula (XII):

[0103] Formula (XII)

[0104] wherein: - R 1 is selected from the group consisting of F, Cl, Br and I; - R 2 is optionally substituted C 6 substituted C 3-5 cycloalkyl; - R 3 is selected from the group consisting of deuterium, Cl and F; - R 10 is optionally substituted C 6 substituted C 1-2 alkanediyl; - R 5 is selected from the group consisting of H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 3-6 cycloalkyl, each of which can optionally be substituted with one or more, same or different, substituents R 6 substituted; optionally substituted with one or more, same or different, substituents R8 Substituted phenyl groups; and optionally substituted with one or more identical or different substituents R. 8 Substituted benzyl; - R 11 For optional addition of one or more identical or different substituents R 6 Replacement C 1-2 alkyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2, or 3; and - X a For O or S; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0105] In some embodiments, the compound used is a compound of formula (XIII):

[0106] Formula (XIII)

[0107] in: - R 1 Selected from Cl and Br; - R 2 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 cycloalkyl; - R 3 Selected from deuterium and F; - R 11 For optional addition of one or more identical or different substituents R 6 Replacement C 1-2 alkyl; - R 6 Independently selected from deuterium and F; - n is an integer 0, 1, 2, or 3; and - X a For O or S; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0108] In some embodiments, the compound used is a compound of formula (XIV):

[0109] Formula (XIV)

[0110] in: - R 1 is selected from Cl and Br; - R 3 is selected from deuterium and F; - R 11 is optionally substituted with one or more substituents R 6 substituted C 1-2 alkyl; - R 6 is independently selected from deuterium and F; - p is an integer 1 or 2; - n is an integer 0, 1, 2, or 3; and - X a is O or S; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0111] In one embodiment, X a is O. In one embodiment, X a is S. In one embodiment, p is 1. In one embodiment, p is 2.

[0112] In one embodiment, R 1 is C 1-2 alkyl. In one embodiment, R 1 is C2 alkenyl. In one embodiment, R 1 is C2 alkynyl. In one embodiment, R 1 is CN. In one embodiment, R 1 is CF3. In one embodiment, R 1 is NO2. In one embodiment, R 1 is Cl or Br. In one embodiment, R 1 is F. In one embodiment, R 1 is Cl. In one embodiment, R 1 is Br. In one embodiment, R 1 is I.

[0113] In one embodiment, R 2 is H. In one embodiment, R 2 is deuterium. In one embodiment, R 2 is F. In one embodiment, R 2 is Cl. In one embodiment, R 2 is Br. In one embodiment, R 2 is I. In one embodiment, R 2 is optionally substituted with one or more substituents R6 substituted C 2-5 alkenyl. In one embodiment, R 2 is vinyl. In one embodiment, R 2 is optionally substituted by one or more, same or different, substituents R 6 substituted C 2-5 alkynyl. In one embodiment, R 2 is ethynyl. In one embodiment, R 2 is optionally substituted by one or more, same or different, substituents R 6 substituted C 3-5 cycloalkyl. In one embodiment, R 2 is cyclopropyl. In one embodiment, R 2 is cyclobutyl.

[0114] In one embodiment, R 2 is optionally substituted by one or more, same or different, substituents R 6 substituted -CF2-C 1-5 alkyl. In one embodiment, R 2 is Me-CF2-. In one embodiment, R 2 is Et-CF2-. In one embodiment, R 2 is n Pr-CF2-. In one embodiment, R 2 is i Pr-CF2-. In one embodiment, R 2 is cyclopropyl-CF2-.

[0115] In one embodiment, R 2 is optionally substituted by one or more, same or different, substituents R 7 substituted 5-membered aromatic heterocycle. In one embodiment, R 2 is selected from 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. In one embodiment, R 2 is selected from thiophene, pyrrole, isoxazole, 1,2,4-oxadiazole and 1,3,4-oxadiazole. In one embodiment, R 2is selected from 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2-thiazol-3-yl, 1,2-oxazol-3-yl, 1,2-oxazol-5-yl and 1,3-oxazol-4-yl, each of which can optionally be substituted by one or more, same or different, substituents R 7 substituted. In one embodiment, R 2 is selected from 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2-thiazol-3-yl, 1,2-oxazol-3-yl, 1,2-oxazol-5-yl and 1,3-oxazol-4-yl, each of which can optionally be substituted by one or more, same or different, substituents R 7 substituted. In one embodiment, R 2 is selected from isoxazol-5-yl and isoxazol-3-yl. In one embodiment, R 2 is 1,2-oxazol-3-yl. In one embodiment, R 2 is 1,2-oxazol-4-yl. In one embodiment, R 2 is 1,2-oxazol-5-yl. In one embodiment, R 2 is 1,3-oxazol-2-yl. In one embodiment, R 2 is 1,3-oxazol-4-yl. In one embodiment, R 2 is 1,3-oxazol-5-yl. In one embodiment, R 2 is 1,2-thiazol-3-yl. In one embodiment, R 2 is 1,2-thiazol-4-yl. In one embodiment, R 2 is 1,2-thiazol-5-yl. In one embodiment, R 2 is 1,3-thiazol-2-yl. In one embodiment, R 2 is 1,3-thiazol-4-yl. In one embodiment, R 2 is 1,3-thiazol-5-yl. In one embodiment, R 2 is 1,2,3-thiadiazol-4-yl. In one embodiment, R 2It is 1,2,3-thiadiazole-5-yl. In one embodiment, R 2 It is 1,2,4-thiadiazole-3-yl. In one embodiment, R 2 It is 1,2,4-thiadiazole-5-yl. In one embodiment, R 2 It is 1,3,4-thiadiazole-2-yl. In one embodiment, R 2 It is 1,2,5-thiadiazole-3-yl. In one embodiment, R 2 It is 1,2,3-oxadiazol-4-yl. In one embodiment, R 2 It is 1,2,3-oxadiazol-5-yl. In one embodiment, R 2 It is 1,2,4-oxadiazol-3-yl. In one embodiment, R 2 It is 1,2,4-oxadiazol-5-yl. In one embodiment, R 2 It is 1,3,4-oxadiazol-2-yl. In one embodiment, R 2 It is 1,2,5-oxadiazol-3-yl.

[0116] In one implementation, R 3 For deuterium. In one implementation, R 3 For Cl. In one implementation, R 3 It is F.

[0117] In one implementation, R 4 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group. In one embodiment, R 4 Selected from methyl, ethyl, n-propyl, and isopropyl. In one embodiment, R 4 Selected from methyl, ethyl, n-propyl, and isopropyl, wherein the methyl, ethyl, n-propyl, or isopropyl group is modified by one or more identical or different substituents R. 6 Replacement. In one implementation, R 4 For Me. In one implementation, R 4 For Et. In one implementation, R 4 For -CH2F. In one implementation, R 4 For -CH2-CH2F. In one implementation, R 4 For optional addition of one or more identical or different substituents R 6 Replacement C 1-2 Alkoxy-C 1-2 Alkyl group. In one embodiment, R 4 For optional addition of one or more identical or different substituents R 6 Replacement C1-2 alkylthio-C 1-2 alkyl. In one embodiment, R 4 is selected from MeOCH2-, EtOCH2-, MeSCH2- and EtSCH2-. In one embodiment, R 4 is optionally substituted by one or more, same or different, substituents R 6 substituted C 2-5 alkenyl. In one embodiment, R 4 is optionally substituted by one or more, same or different, substituents R 6 substituted C 2-5 alkynyl. In one embodiment, R 4 is prop-2-ynyl. In one embodiment, R 4 is optionally substituted by one or more, same or different, substituents R 6 substituted -CH2-C 2-4 alkynyl. In one embodiment, R 4 is optionally substituted by one or more, same or different, substituents R 6 substituted C 3-5 cycloalkyl. In one embodiment, R 4 is selected from cyclopropyl and cyclobutyl. In one embodiment, R 4 is H. In one embodiment, R 4 is deuterium. When R 4 is H, the carbon to which R 4 is bound is not a stereogenic center.

[0118] In one embodiment, R 5 is H. In one embodiment, R 5 is optionally substituted by one or more, same or different, substituents R 8 substituted C 1-5 alkyl. In one embodiment, R 5 is optionally substituted by one or more, same or different, substituents R 8 substituted C 3-6 cycloalkyl. In one embodiment, R 5 is optionally substituted by one or more, same or different, substituents R 8 substituted phenyl. In one embodiment, R 5 is optionally substituted by one or more, same or different, substituents R 8 substituted benzyl.

[0119] In one embodiment, R 6 is deuterium. In one embodiment, R 6 is F.

[0120] In one embodiment, R7 For deuterium. In one implementation, R 7 For F. In one implementation, R 7 Selected from methyl, ethyl or cyclopropyl.

[0121] In one implementation, R 8 For deuterium. In one implementation, R 8 It is methoxylated. In one embodiment, R 8 It is a nitro group. In one embodiment, R 8 It is cyano. In one embodiment, R 8 For Cl. In one implementation, R 8 For Br. In one implementation, R 8 For I. In one implementation, R 8 It is F.

[0122] In one implementation, R 13 For H. In one implementation, R 13 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group. In one embodiment, R 13 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl. In one embodiment, R 13 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group. In one embodiment, R 13 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl.

[0123] In one implementation, R 14 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group. In one embodiment, R 14 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl. In one embodiment, R 14 For optional addition of one or more identical or different substituents R 8 Substituted phenyl groups.

[0124] In one implementation, R 15 For -OH. In one embodiment, R 15For optional addition of one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl group. In one embodiment, R 15 For optional addition of one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl.

[0125] In one implementation, R 16 For H. In one implementation, R 16 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group. In one embodiment, R 16 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl. In one embodiment, R 16 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group. In one embodiment, R 16 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl.

[0126] In one implementation, R 17 For H. In one implementation, R 17 For optional addition of one or more identical or different substituents R 20 Replacement C 1-5 Alkyl group. In one embodiment, R 17 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl. In one embodiment, R 17 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group. In one embodiment, R 17 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl.

[0127] In one implementation, R 18 For H. In one implementation, when R 18 When it is H, then R 17 Not H. In one implementation, R 18substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 1-5 substituted C1-C6-alkyl. In one embodiment, R 18 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 3-6 substituted C1-C6-alkyl. In one embodiment, R 18 substituted C1-C6-alkyl. In one embodiment, R 8 substituted C1-C6-alkyl. In one embodiment, R 18 substituted C1-C6-alkyl. In one embodiment, R 20 substituted C1-C6-alkyl. In one embodiment, R

[0128] substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 6 substituted C1-C6-alkyl. In one embodiment, R 3-6 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 6 substituted C1-C6-alkyl. In one embodiment, R 1-5 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 6 substituted C1-C6-alkyl. In one embodiment, R 3-5 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 6 substituted C1-C6-alkyl. In one embodiment, R 1-5 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 6 substituted C1-C6-alkyl. In one embodiment, R 3-5 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 6 substituted C1-C6-alkyl. In one embodiment, R 1-5 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 6 substituted C1-C6-alkyl. In one embodiment, R 3-5 substituted C1-C6-alkyl. In one embodiment, R 19 substituted C1-C6-alkyl. In one embodiment, R 6 substituted C1-C6-alkyl. In one embodiment, R 1-5alkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 6 substituted -SO2-C 3-5 cycloalkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 6 substituted -C(=0)-C 1-5 alkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 6 substituted -C(=0)-OC 1-5 alkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 6 substituted -NH-C(=0)-OC 1-5 alkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 6 substituted -C(=0)-C 3-5 cycloalkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 6 substituted -NH-C(=0)-C 1-5 alkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 6 substituted -NH-C(=0)-C 3-5 cycloalkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 6 substituted -C(=0)-NH-C 1-5 alkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 6 substituted -C(=0)-NH-C 3-5 cycloalkyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 8 substituted phenyl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 20 substituted pyrrolidin-1-yl. In one embodiment, R 19 substituted by one or more, identical or different, substituents R 20 4-6 membered heterocyclic ring.

[0129] substituted by one or more, identical or different, substituents R 20is -CN. In one embodiment, R 20 is -CN. In one embodiment, R 20 is =0. In one embodiment, R 20 is optionally substituted with one or more of the same or different substituents R 6 substituted C 1-5 alkyl. In one embodiment, R 20 is optionally substituted with one or more of the same or different substituents R 6 substituted C 3-6 cycloalkyl. In one embodiment, R 20 is optionally substituted with one or more of the same or different substituents R 6 substituted -C(=0)-C 1-5 alkyl. In one embodiment, R 20 is optionally substituted with one or more of the same or different substituents R 6 substituted -C(=0)-OC 1-5 alkyl. In one embodiment, R 20 is optionally substituted with one or more of the same or different substituents R 6 substituted -C(=0)-C 3-5 cycloalkyl. In one embodiment, R 20 is optionally substituted with one or more of the same or different substituents R 6 substituted -NH-C(=0)-C 1-5 alkyl. In one embodiment, R 20 is optionally substituted with one or more of the same or different substituents R 6 substituted -NH-C(=0)-C 3-5 cycloalkyl. In one embodiment, R 20 is optionally substituted with one or more of the same or different substituents R 6 substituted -C(=0)-NH-C 1-5 alkyl. In one embodiment, R 20 is optionally substituted with one or more of the same or different substituents R 6 substituted -C(=0)-NH-C 3-5 cycloalkyl.

[0130] is H. In one embodiment, R 21 is H. In one embodiment, R 21 is optionally substituted with one or more of the same or different substituents R 6 substituted C 1-5 alkyl. In one embodiment, R 21 is optionally substituted with one or more of the same or different substituents R 6 substituted C3-5 Cycloalkyl. In one embodiment, R 21 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group. In one embodiment, R 21 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl.

[0131] In one implementation, R 22 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group. In one embodiment, R 22 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl. In one embodiment, R 22 For optional addition of one or more identical or different substituents R 8 Substituted phenyl groups.

[0132] In one implementation, X is N. In another implementation, X is CR. 23 , where R 23 H is the variable. In one implementation, X is CR. 23 , where R 23 For example, X is NH2. In one implementation, X is CR. 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group. In one embodiment, X is CR. 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl. In one embodiment, X is CR. 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl group. In one embodiment, X is CR. 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl. In one embodiment, X is CR. 23 , where R 23 For optional addition of one or more identical or different substituents R6 Substituted -NH-C(=O)C 1-5 Alkyl group. In one embodiment, X is CR. 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Substituted -NH-SO2-C 1-5 alkyl.

[0133] In one embodiment, Y is NH. In one embodiment, Y is O. In one embodiment, Y is S.

[0134] In one implementation, n is 0. In one implementation, n is 1. In one implementation, n is 2. In one implementation, n is 3.

[0135] In one implementation, R 12 for In some embodiments, the compound used is a compound of formula (II):

[0136] Equation (II)

[0137] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, and C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C2-5 alkenyl, C 2-5 alkynyl and C 3-5 cycloalkyl, each of which can optionally be substituted by one or more, same or different, substituents R 6 substituted; - R 5 is selected from H, C 6 alkyl optionally substituted by one or more, same or different, substituents R 1-5 alkyl optionally substituted by one or more, same or different, substituents R 6 alkyl optionally substituted by one or more, same or different, substituents R 2-5 alkenyl optionally substituted by one or more, same or different, substituents R 6 alkenyl optionally substituted by one or more, same or different, substituents R 2-5 alkynyl optionally substituted by one or more, same or different, substituents R 6 alkynyl optionally substituted by one or more, same or different, substituents R 3-6 cycloalkyl optionally substituted by one or more, same or different, substituents R 8 phenyl optionally substituted by one or more, same or different, substituents R 8 benzyl optionally substituted by one or more, same or different, substituents R - R 6 is independently selected from deuterium and F; - R 7 is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 is independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0138] In some embodiments, the compound for use is a compound of formula (II):

[0139] formula (II)

[0140] wherein: - R 1 is selected from F, Cl, Br and I; - R 2 is selected from H, deuterium, F, Cl, Br and I; - R 3 is selected from deuterium, Cl and F; - R 4 is selected from H, deuterium, C 1-5 alkyl optionally substituted by one or more, same or different, substituents R 1-2 alkoxy-C 1-2 alkyl optionally substituted by one or more, same or different, substituents R 1-2 alkylthio-C 1-2 alkyl optionally substituted by one or more, same or different, substituents R2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - n is an integer 0, 1, 2 or 3; Or its pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate.

[0141] In one implementation, R 1 Selected from Cl and Br, R 2 Selected from H, deuterium, or F, and R 4 Selected from Me, Et and -CH2F.

[0142] In some embodiments, the compound used is a compound of formula (II):

[0143] Equation (II)

[0144] in: - R 1 Selected from F, Cl, Br and I; - R 2 For optional addition of one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, F and Cl; - R 4 Selected from H, deuterium, and C1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 3-5 cycloalkyl, each of which can optionally be substituted by one or more, same or different, substituents R 6 substituted; - R 5 is selected from H, C 6 substituted C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 3-6 cycloalkyl, optionally substituted by one or more, same or different, substituents R 8 substituted phenyl and optionally substituted benzyl; 8 substituted benzyl; - R 6 is independently selected from deuterium and F; - R 7 is independently selected from deuterium, F, methyl, ethyl and cyclopropyl; - R 8 is independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0145] In some embodiments, when R 1 is F, Cl or Br, R 2 is 1,2-oxazol-5-yl, R 4 is H, R 5 is H and R 6 is H, then n is 1, 2 or 3.

[0146] In one embodiment, the compound for use has formula (II), and

[0147] - R 1 is selected from F, Cl, Br and I, preferably Cl or Br; - R 2 is selected from 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2-thiazol-3-yl, 1,2-oxazol-3-yl, 1,2-oxazol-5-yl and 1,3-oxazol-4-yl, each of which can optionally be substituted by one or more, same or different, substituents R 7 substituted; - R 3 is selected from deuterium, F and Cl; - R 4 Selected from C 1-5 Alkyl and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 7 Independently selected from H, deuterium, F, Cl, Br, I, C 1-5 Alkyl and C 3-5 cycloalkyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0148] In some embodiments, the compound used is a compound of formula (II):

[0149] Equation (II)

[0150] in: - R 1 Selected from F, Cl, Br and I; - R 2 It can be optionally replaced by one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, F and Cl; - R 4 Selected from H, deuterium, and C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 3-5 cycloalkyl, each of which can optionally be substituted by one or more, same or different, substituents R 6 substituted; - R 5 is selected from H, optionally substituted C 6 alkyl, optionally substituted by one or more, same or different, substituents R 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 alkenyl, optionally substituted by one or more, same or different, substituents R 2-5 alkenyl, optionally substituted by one or more, same or different, substituents R 6 alkynyl, optionally substituted by one or more, same or different, substituents R 2-5 alkynyl, optionally substituted by one or more, same or different, substituents R 6 cycloalkyl, optionally substituted by one or more, same or different, substituents R 3-6 cycloalkyl, optionally substituted by one or more, same or different, substituents R 8 phenyl, optionally substituted by one or more, same or different, substituents R 8 benzyl, optionally substituted by one or more, same or different, substituents R - R 6 is independently selected from deuterium and F; - R 7 is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 is independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0151] In one embodiment, R 1 is selected from Cl and Br, R 2 is selected from 1,2-oxazol-3-yl, 1,2-oxazol-5-yl, 1,3-oxazol-4-yl and 1,2,3- thiadiazol-4-yl, and R 4 is selected from Me, Et and -CH2F.

[0152] In some embodiments, the compound for use is a compound of formula (II):

[0153] formula (II)

[0154] wherein: - R 1 is selected from C 1-2 alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br and I; - R2 For optional addition of one or more identical or different substituents R 6 Replacement -CF2-C 1-5 alkyl; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, and C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - n is an integer 0, 1, 2 or 3; Or its pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate.

[0155] In one implementation, R 1 Selected from Cl and Br, R 2 Selected from -CF2Me and -CF2Et, and R 4 Selected from Me, Et and -CH2F.

[0156] In one implementation, R 12 for In some embodiments, the compound used is a compound of formula (III):

[0157] Equation (III)

[0158] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, and C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - X is selected from N and CR 23 ; - Y is selected from NH, O, and S; - R 23 Selected from H, NH2, and optionally substituents R (one or more of the same or different). 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -OC 1-5 alkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -OC 3-5 cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -NH-C(=O)C 1-5 alkyl and optionally substituted by one or more, same or different, substituents R 6 substituted -NH-SO2-C 1-5 alkyl; - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0159] In one embodiment, the compound for use has formula (IVa) or formula (IVb)

[0160] formula (IVa) formula (IVb)

[0161] wherein: - R 1 is selected from C 1-2 alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br and I; - R 2 is selected from H, deuterium, F, Cl, Br, I, optionally substituted by one or more, same or different, substituents R 6 substituted C 2-5 alkenyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 2-5 alkynyl, optionally substituted by one or more, same or different, substituents R 6 substituted C 3-5 cycloalkyl, optionally substituted by one or more, same or different, substituents R 6 substituted -CF2-C 1-5 alkyl and optionally substituted by one or more, same or different, substituents R 7 substituted 5-membered aromatic heterocycle; - R 3 is selected from deuterium, Cl and F; - R 4 is selected from H, deuterium, C 1-5 alkyl, C 1-2 alkoxy-C 1-2 alkyl, C 1-2 alkylthio-C 1-2 alkyl, C 2-5alkenyl, C 2-5 alkynyl and C 3-5 cycloalkyl, each of which can optionally be substituted by one or more, same or different, substituents R 6 substituted; - R 6 is independently selected from deuterium and F; - R 7 is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0162] The skilled person understands that formula (IXa) and (IXb) are tautomers of each other.

[0163] In one embodiment, R 12 is In some embodiments, the compound for use is a compound of formula (V):

[0164] (V)

[0165] wherein: - R 1 is selected from C 1-2 alkyl, C2alkenyl, C2alkynyl, CN, CF3, NO2, F, Cl, Br and I; - R 2 is selected from H, deuterium, F, Cl, Br, I, C 6 alkyl optionally substituted by one or more, same or different, substituents R 2-5 alkenyl optionally substituted by one or more, same or different, substituents R 6 alkynyl optionally substituted by one or more, same or different, substituents R 2-5 cycloalkyl optionally substituted by one or more, same or different, substituents R 6 -CF2-C 3-5 alkyl optionally substituted by one or more, same or different, substituents R 6 5-membered aromatic heterocycle optionally substituted by one or more, same or different, substituents R 1-5 alkyl optionally substituted by one or more, same or different, substituents R 7 5-membered aromatic heterocycle optionally substituted by one or more, same or different, substituents R - R 3 is selected from deuterium, Cl and F; - R 4 is selected from H, deuterium, C 1-5 alkyl, C 1-2 alkoxy-C 1-2 alkyl, C 1-2 alkyl, C 1-2 alkyl, C2-5 alkenyl, C 2-5 alkynyl and C 3-5 cycloalkyl, each of which can optionally be substituted by one or more, same or different, substituents R 6 substituted; - R 6 is independently selected from deuterium and F; - R 7 is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 is independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I and F; - R 13 is selected from H, C 6 alkyl optionally substituted by one or more, same or different, substituents R 1-5 alkyl optionally substituted by one or more, same or different, substituents R 6 cycloalkyl optionally substituted by one or more, same or different, substituents R 3-5 cycloalkyl optionally substituted by one or more, same or different, substituents R 6 -C(=O)-C 1-5 alkyl and optionally substituted by one or more, same or different, substituents R 6 -C(=O)-C 3-5 cycloalkyl; - R 14 is selected from C 6 alkyl optionally substituted by one or more, same or different, substituents R 1-5 alkyl optionally substituted by one or more, same or different, substituents R 6 cycloalkyl and optionally substituted by one or more, same or different, substituents R 3-5 cycloalkyl and optionally substituted by one or more, same or different, substituents R 8 phenyl; - R 15 is selected from -OH, -OC 6 alkyl and optionally substituted by one or more, same or different, substituents R 1-5 alkyl and optionally substituted by one or more, same or different, substituents R 6 -OC 3-5 cycloalkyl; - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0166] In one embodiment, R 12 is In some embodiments, the compound for use is a compound of formula (VI):

[0167] Formula (VI)

[0168] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, and C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 16 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C3-5 cycloalkyl; - n is an integer 0, 1, 2 or 3; Or its pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate.

[0169] In one implementation, R 12 for In some embodiments, the compound used is a compound of formula (VII):

[0170] Equation (VII)

[0171] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, and C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8independently selected from the group consisting of deuterium, methoxy, nitro, cyano, CI, Br, I and F; - R 17 selected from the group consisting of H, optionally substituted C 20 substituted C 1-5 alkyl, 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 6 substituted -C(=0)-C 1-5 alkyl and optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-C 3-5 cycloalkyl; - R 18 selected from the group consisting of H, optionally substituted C 19 substituted C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 19 substituted C 3-6 cycloalkyl, optionally substituted by one or more identical or different substituents R 8 substituted phenyl and optionally substituted by one or more identical or different substituents R 20 substituted 4- to 6-membered heterocyclic ring; - R 19 independently selected from the group consisting of F, CI, Br, I, -CN, =0, optionally substituted C 6 substituted C 3-6 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 substituted -0-C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -0-C 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 substituted -S-C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -S-C 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 substituted -SO-C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -SO-C 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 substituted -SO2-C 1-5 alkyl, optionally substituted by one or more identical or different substituents R6 substituted -SO2-C 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-OC 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -NH-C(=0)-OC 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-C 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 substituted -NH-C(=0)-C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -NH-C(=0)-C 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-NH-C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-NH-C 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 8 substituted phenyl, optionally substituted by one or more identical or different substituents R 20 substituted pyrrolidin-1-yl and optionally substituted by one or more identical or different substituents R 20 substituted 4-6 membered heterocyclic ring; - R 20 independently selected from F, Cl, Br, I, -CN, =0, 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 3-6 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-OC 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-C 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 6substituted -NH-C(=0)-C 1-5 alkyl, optionally substituted by one or more identical or different substituents R 6 substituted -NH-C(=0)-C 3-5 cycloalkyl, optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-NH-C 1-5 alkyl and optionally substituted by one or more identical or different substituents R 6 substituted -C(=0)-NH-C 3-5 cycloalkyl; - n is an integer 0, 1, 2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate thereof.

[0172] In one embodiment, R 12 is In some embodiments, the compound for use is a compound of formula (VIII):

[0173] (VIII)

[0174] wherein: - R 1 is selected from C 1-2 alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, N02, F, CI, Br and I; - R 2 is selected from H, deuterium, F, CI, Br, I, 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 6 substituted -CF2-C 1-5 alkyl and optionally substituted by one or more identical or different substituents R 7 substituted 5-membered aromatic heterocycle; - R 3 is selected from deuterium, CI and F; - R 4 is selected from H, deuterium, C 1-5 alkyl, C 1-2 alkoxy-C 1-2 alkyl, C 1-2 alkylthio-C 1-2 alkyl, C2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 21 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 22 Selected from one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl groups and optionally substituted with one or more identical or different substituents R 8 Substituted phenyl; - n is an integer 0, 1, 2 or 3; Or its pharmaceutically acceptable salt, hydrate, polymorph, tautomer or solvate.

[0175] In one embodiment, the compound used is selected from: ( S )-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)-3-methoxypropionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propionic acid; ( R )-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropionic acid; ( S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutyric acid; ( S )-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propionic acid; ( R )-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-(4-chloro-2-cyclopropyl-5-fluorophenoxy)-3-methoxypropionic acid; ( S )-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butyric acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butyric acid; ( S )-2-[2-(1,1-difluoropropyl)-5-fluoro-4-styryloxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutyric acid; ( R )-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid; ( R )-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propionic acid; ( R )-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propionic acid; [4-Chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; [4-Bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid; ( S)-2-[2-(1,1-difluoropropyl)-4-phenylsulfinyl]propionic acid; [4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-phenylsulfinyl]propionic acid; ( R )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid; [4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propionic acid; 2 H3)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propionic acid; ( R )-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-cyano-2-(1,1-difluoropropyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propionic acid; ( R )-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2- 2 H)propionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propionic acid; ( S )-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-4-pentynoic acid; ( S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-pentyneic acid; ( R )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-pentyneic acid; ( S )-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid; ( S )-2-[4-bromo-2-(cyclopropyldifluoromethyl)phenoxy]propionic acid; ( R )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propionic acid; ( S )-[4-bromo-2-(1,1-difluoroethyl)phenoxy]cyclopropylacetic acid; ( S )-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propionic acid; [4-Bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid; ( S )-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid; ( S 2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propionic acid; ( S )-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid; ( S )-(4-bromo-2-cyclopropylphenoxy)cyclopropylacetic acid; ( S )-Cyclopropyl(2,4-dibromophenoxy)acetic acid; ( S)-(4-bromo-2-chlorophenoxy)cyclopropylacetic acid; (2R,3R)-2-(p-bromophenoxy)-3-fluorobutyric acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-ethoxypropionic acid; [4-Bromo-2-(1,3-oxazol-4-yl)phenoxy]acetic acid; [4-Bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]acetic acid; [4-Chloro-2-(5-isoxazolyl)phenoxy]acetic acid; ( S )-[4-bromo-2-(5-isoxazolyl)phenoxy]cyclopropylacetic acid; ( S )-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]cyclopropylacetic acid; (S,E)-2-(p-bromophenoxy)-4-fluoro-3-butenoic acid; (2R,3R)-2-(4-bromo-2-fluorophenoxy)-3-fluorobutyric acid; (4-Bromo-2-cyclopropylphenoxy)acetic acid; ( S )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]-3-cyclopropylpropionic acid; [4-Bromo-2-(4-methyl-3-isoxazolyl)phenoxy]acetic acid; [4-Bromo-5-fluoro-2-(5-isoxazolyl)phenoxy]acetic acid; ( S 2-[4-bromo-5-fluoro-2-(5-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-cyclobutylpropionic acid; ( S )-2-[4-bromo-5-fluoro-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid; [4-Bromo-2-(5-isoxazolyl)phenoxy]acetic acid; ( S )-2-(p-bromophenoxy)(2- 2 H) Butyric acid; ( S )-2-(p-bromophenoxy)-4-pentyneic acid; [4-Bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]acetic acid; (4-Bromo-2-ethynylphenoxy)acetic acid; ( S 2-(4-bromo-2-fluorophenoxy)valerate; ( S 2-(2,4-dibromophenoxy)valerate; ( S 2-(4-bromo-2-chlorophenoxy)valerate; ( S 2-(p-bromophenoxy)-3-cyclopropylpropionic acid; ( S )-2-(2,4-dibromophenoxy)-4-pentyneic acid; ( S )-2-(4-bromo-2-chlorophenoxy)-4-pentyneic acid; ( S )-(p-bromophenoxy)cyclopropylacetic acid; ( S )-2-(4-bromo-2-fluorophenoxy)-4-pentyneic acid; ( S )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]butyric acid; ( S 2-(p-bromophenoxy)valerate; ( R )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,3,4-thiadiazol-2-yl)phenoxy]propionic acid; ( S )-(4-bromo-2-chlorophenoxy)cyclobutylacetic acid; ( S 2-(4-bromo-2-chlorophenoxy)-3-cyclopropylpropionic acid; ( S 2-(4-bromo-2-chlorophenoxy)-3-methylbutyric acid; [4-Bromo-2-(3-isoxazolyl)phenoxy]acetic acid; ( R )-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid; ( S )-2-(p-bromophenoxy)-3-butenoic acid; ( S )-2-[4-bromo-2-(1H-1,2,3-triazol-5-yl)phenoxy]propionic acid; (2S)-2-(p-bromophenoxy)(3,4- 2 H2) Butyric acid; ( R 2-(4-bromo-2-chlorophenoxy)-3-fluoropropionic acid; ( S 2-(4-bromo-2-chlorophenoxy)butyric acid; ( S 2-(4-bromo-3-fluorophenoxy)-3-methylbutyric acid; ( S 2-(4-bromo-2-chlorophenoxy)-4-fluorobutyric acid; ( S 2-(p-ethynylphenoxy)-4-fluorobutyric acid; ( S )-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]-4-fluorobutyric acid; ( S )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,3-oxazol-5-yl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-4-fluorobutyric acid; ( R )-2-(p-bromophenoxy)-3-fluoro(2- 2 H) propionic acid; ( R )-2-[4-chloro-5-fluoro-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S 2-(4-bromo-5-fluoro-2-styryloxy)propionic acid; ( S )-2-[4-bromo-2-(1,3-thiazolyl-4-yl)phenoxy]propionic acid; ( S )-2-[4-bromo-5-fluoro-2-(1,3-oxazol-4-yl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-methylbutyric acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid; ( R )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-5-fluoro-2-(5-isoxazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)propionic acid; ( S )-2-[4-bromo-2-(2,2-difluorovinyl)-5-fluorophenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]butyric acid; ( S )-2-(4-bromo-2-iodophenoxy)-4-fluorobutyric acid; ( S )-(4-bromo-2-ethynylphenoxy)cyclobutylacetic acid; ( S 2-(4-bromo-2-ethynyl-5-fluorophenoxy)propionic acid; ( S 2-(4-chloro-2-ethynyl-5-fluorophenoxy)propionic acid; ( S )-2-[4-bromo-2-(4-isoxazolyl)phenoxy]propionic acid; ( R )-2-[4-chloro-5-fluoro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-(p-bromophenoxy)cyclobutylacetic acid; ( S )-2-(4-bromo-2-cyclopropylphenoxy)-4-fluorobutyric acid; ( S )-2-(4-bromo-2-fluorophenoxy)-4-fluorobutyric acid; ( S )-2-(4-bromo-2-ethynylphenoxy)-4-fluorobutyric acid; ( S )-2-(4-bromo-2-styryloxy)-4-fluorobutyric acid; ( S )-(4-bromo-2-fluorophenoxy)cyclobutylacetic acid; ( S )-2-[4-chloro-2-(1,3-oxazol-4-yl)phenoxy]propionic acid; ( S )-2-[4,5-dichloro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S 2-(p-bromophenoxy)-4-fluorobutyric acid; ( S )-2-{2-[(E)-2-fluorovinyl]-4-bromophenoxy}propionic acid; ( S )-2-[4-bromo-2-(1,3-oxazol-4-yl)phenoxy]propionic acid; ( S )-2-{2-[(E)-2-fluorovinyl]-4-chlorophenoxy}propionic acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid; ( S )-2-[4-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid; ( R )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(4-methyl-3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-cyclopropyl-3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-methylbutyric acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]butyric acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid; ( S )-2-[4-chloro-2-(1,3-oxazol-2-yl)phenoxy]propionic acid; ( S )-2-(4-bromo-2-iodophenoxy)-3-methylbutyric acid; ( S )-(4-bromo-2-fluorophenoxy)cyclopropylacetic acid; ( R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(3-isothiazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-ethynylphenoxy)butyric acid; ( S 2-(4-bromo-2-iodophenoxy)butyric acid; ( S 2-(4-chloro-2-fluorophenoxy)butyric acid; ( S 2-(p-bromophenoxy)butyric acid; ( S )-2-[4-bromo-2-(2,2-difluorovinyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(5-isoxazolyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-methylbutyric acid; ( S )-2-[4-bromo-2-(4-methyl-3-isoxazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-fluorophenoxy)butyric acid; ( S )-2-[4-bromo-2-(5-methyl-3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxy]propionic acid; ( R )-2-[p-bromo(3,5- 2 [H2)phenoxy]-3-fluoropropionic acid; ( S )-2-[p-bromo(3,5- 2 [H2)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(5-cyclopropyl-3-isoxazolyl)phenoxy]propionic acid; ( S ethyl 2-(4-bromo-2-fluorophenoxy)-3-methyl-3-butenoate; ( R2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid; ( R )-2-[p-bromo(2,6- 2 [H2)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(1,3-thiazolyl-2-yl)phenoxy]propionic acid; ( S )-2-[p-bromo(2,6- 2 [H2)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-methyl-5-isoxazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-iodophenoxy)propionic acid; ( S 2-[4-bromo-2-(2-imidazolyl)phenoxy]propionic acid; ( S 2-[4-bromo-2-(5-imidazolyl)phenoxy]propionic acid; ( R )-2-(4-bromo-2-cyclobutylphenoxy)-3-fluoropropionic acid; ( R )-2-(4-bromo-2-fluorophenoxy)-3,3-difluoropropionic acid; ( S 2-(4-bromo-2-ethynylphenoxy)propionic acid; ( S 2-(2-bromo-4-chlorophenoxy)-3-methylbutyric acid; ( S 2-(2-fluoro-4-iodophenoxy)propionic acid; ( S 2-(2-bromo-4-iodophenoxy)propionic acid; ( R )-2-[4-bromo-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S 2-(2-chloro-4-iodophenoxy)propionic acid; ( S 2-(2-bromo-4-chlorophenoxy)propionic acid; ( S 2-(4-bromo-2-cyclopropylphenoxy)propionic acid; ( S2-(4-bromo-2-styryloxy)propionic acid; ( S )-2-[4-chloro-2-(1-methyl-3-methyl-4-pyrazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-pyrazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid; ( S 2-(2-cyclopropyl-4-fluorophenoxy)propionic acid; ( S )-2-[4-chloro-2-(1-methyl-4-pyrazolyl)phenoxy]propionic acid; ( S 2-(2-cyclobutyl-4-fluorophenoxy)propionic acid; ( S 2-(4-bromo-2-cyclobutylphenoxy)propionic acid; ( R 2-(4-bromo-2-fluorophenoxy)-3-fluoropropionic acid; ( S 2-(4-chloro-2-fluorophenoxy)-3-methylbutyric acid; ( S 2-(4-chloro-2-cyclobutylphenoxy)propionic acid; ( S )-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]propionic acid; ( R 2-(2-bromo-4-chlorophenoxy)-3-fluoropropionic acid; ( R 2-(p-chlorophenoxy)-3-fluoropropionic acid; ( R )-2-(4-chloro-2-fluorophenoxy)-3-fluoropropionic acid; ( R )-2-(2,4-dibromophenoxy)-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid; ( R 2-(p-bromophenoxy)-3-fluoropropionic acid; ( S 2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid; ( S 2-(4-bromo-2-fluorophenoxy)propionic acid; (S 2-(4-chloro-2-fluorophenoxy)propionic acid; ( S 2-(2,4-dibromophenoxy)propionic acid; ( S 2-(4-chloro-2-ethynylphenoxy)propionic acid; ( S 2-(4-chloro-2-styryloxy)propionic acid; ( S 2-(4-chloro-2-cyclopropylphenoxy)propionic acid; ( S 2-(p-chlorophenoxy)butyric acid; ( S Sodium 2-(2,4-dichlorophenoxy)propionate; ( S 2-(p-chlorophenoxy)-3-methylbutyric acid; ( S 2-(p-cyanophenoxy)propionic acid; ( S methyl 2-(p-bromophenoxy)propionate; ( S 2-(p-chlorophenoxy)butyrate methyl ester; ( S Isopropyl 2-(p-chlorophenoxy)propionate; ( S 2-(p-chlorophenoxy)propionate methyl ester, (2 S )-2-(4-bromo-2-fluorophenoxy)- N -{1-[(cyclopropylmethoxy)imino]ethyl}propionamide; (2 S )-2-(4-bromophenoxy)- N -[1-(methoxyimino)ethyl]propionamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -[(4-fluorophenyl)(hydroxyimino)methyl]-3-methylbutyramide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -[1-(hydroxyimino)ethyl]-3-methylbutyramide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -[1-(hydroxyimino)ethyl]propionamide; (2 S)-2-(4-bromophenoxy)- N -[1-(hydroxyimino)ethyl]acrylamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -Cyanopropionamide; (2 S )- N -Cyano-2-(2,4-dibromophenoxy)propionamide; (2 S )-2-(4-bromophenoxy)- N -Cyanopropionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyanopropionamide; (2 S )-2-(4-bromophenoxy)- N -Cyano-3-methylbutyramide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -Cyclobutoxypropionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -Methoxypropionamide; (2 S )- N -acetyl- N -[(1-acetylazetane-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylazetane-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -(azacyclobutane-3-yloxy)-2-(4-chlorophenoxy)propionamide; (2 S )- N -acetyl- N -[(1-acetylpyrrolidone-3-yl)methoxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylpyrrolidone-3-yl)methoxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N-[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-bromophenoxy)propionamide; N -(2-{[(2 S 2-(4-chlorophenoxy)propamido]oxy]propyl)carbamate tert-butyl ester; (2 S )- N -acetyl-2-(4-chlorophenoxy)- N -[(1-acetamidopropyl-2-yl)oxy]propionamide; (2 S )-2-(4-bromophenoxy)- N -(pyrrolidine-3-yloxy)propionamide; (2 S )- N -acetyl- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-bromophenoxy)propionamide; 3-{[(2 S 2-(4-chlorophenoxy)propamido]oxy}azacyclobutane-1-carboxylic acid tert-butyl ester; (2 S )-2-(4-chlorophenoxy)- N -[(pyrrolidone-3-yl)methoxy]propionamide; 3-({[(2 S 2-(4-chlorophenoxy)propamido]oxy}methyl)pyrrolidine-1-carboxylic acid tert-butyl ester; (2 S )- N -acetyl- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(pyrrolidine-3-yloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2,2-Dimethylpropyl)- N -Hydroxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-(pyrrolidone-1-yl)ethoxy]propionamide; (2S )-2-(4-chlorophenoxy)- N -[2-(2-oxopyrrolidone-1-yl)ethoxy]propionamide; (2 S )- N -acetyl-2-(4-chlorophenoxy)- N -(2-acetamidoethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-acetamidoethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(4,4,4-trifluoro-2-methylbutoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(3-Cyclopentylpropyl)- N -Hydroxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -{[(2E)-2-methyl-3-phenylprop-2-en-1-yl]oxy}propionamide; (2 S )-2-(4-chlorophenoxy)- N -{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethoxy}propionamide; N -(2-{[(2 S 2-(4-chlorophenoxy)propamido]oxyethyl)carbamate tert-butyl ester; (2 S )-2-(4-chlorophenoxy)- N -[(2-methyl-1H-imidazol-4-yl)methoxy]propionamide; 4-({[(2 S 2-(4-chlorophenoxy)propamido]oxy}methyl)-2-methyl-1H-imidazol-1-carboxylic acid tert-butyl ester; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-bromophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N-[2-oxo-2-(pyrrolidone-1-yl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -[1-(4-fluorophenyl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -[1-(1,3-thiazolyl-2-yl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -{1-[4-(trifluoromethyl)phenyl]ethoxy}propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-Methylsulfinylethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-Methanesulfonylethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(1,2-oxazol-3-yl)methoxy]propionamide; (2 S )-2-(4-chloro-2-fluorophenoxy)- N -Methoxypropionamide; (2 S )-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]- N -(cyclopropylmethoxy)propionamide; (2 S )-2-[4-chloro-2-(trifluoromethyl)phenoxy]- N -(cyclopropylmethoxy)propionamide; (2 S )- N -(tert-butoxy)-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-(methylthio)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -(1-Phenylacetyl)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(1-methyl-1H-imidazol-2-yl)methoxy]propionamide; (2S )-2-(4-chlorophenoxy)- N -(2-methoxyethoxy)propionamide; (2 S )-2-(4-chloro-2-fluorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]- N -Methoxypropionamide; (2 S )-2-[4-chloro-2-(trifluoromethyl)phenoxy]- N -Methoxypropionamide; (2 S )- N -(benzyloxy)-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(2-methoxycyclopentyl)oxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxy-5-methylhexanoamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxy- N -Methylpropionamide; (2 S )-2-(4-chloro-2-methylphenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chloro-3-fluorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chloro-2-methylphenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chloro-3-fluorophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxy-4-methylpentanamide; (2 S )-2-(4-chlorophenoxy)- N -[(3-methylbut-2-en-1-yl)oxy]propionamide; (2 S)-2-(4-chlorophenoxy)- N -Cyclobutoxyhexylamide; (2 S )-2-(4-chlorophenoxy)- N -[(1,3-oxazol-2-yl)methoxy]propionamide; (2 S )-2-(2,4-dibromophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(oxane-2-yloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(1,3-thiazolyl-2-yl)methoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -(3,3-difluorocyclobutoxy)propionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]- N -Cyclobutoxypropionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(cyclopentyloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-Cyclopentylethoxy)propionamide; (2 S )-2-(4-bromo-2-chlorophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-bromo-2-methylphenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(cyclopropylmethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N-(cyclobutylmethoxy)propionamide; (2 S )- N -(2-aminoethoxy)-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-bromophenoxy)- N -Methoxy-3-methylbutyramide; 2-{[(2 S 2-(4-chlorophenoxy)propamido]oxy]methyl acetate; (2 S )-2-(4-chlorophenoxy)- N -[2-(2-methoxyethoxy)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-hydroxyethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -Ethoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -Propoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(prop-2-yloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -Methoxypropionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -(cyclopropanesulfonyl)acrylamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -Methanesulfonylpropionamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -(cyclopropanesulfonyl)acrylamide; (2 S )-2-(4-chlorophenoxy)- N -Methanesulfonylpropionamide; (2 S )-2-(4-bromophenoxy)- N-Methanesulfonyl-3-methylbutyramide; 5-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-fluoropropyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-fluorophenoxy)propyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-fluorophenoxy)-2-methylpropyl]-2H-1,2,3,4-tetraazole; 5-[(1 R )-1-(4-bromophenoxy)-2-fluoroethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromophenoxy)propyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromophenoxy)ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-cyclopropylphenoxy)ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-vinylphenoxy)ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-ethylphenoxy)ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-methylphenoxy)ethyl]-2H-1,2,3,4-tetraazole; 5-[(1S )-1-(4-chlorophenoxy)ethyl]-1H-1,2,3,4-tetraazole; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-thiadiazol-5-yl]acetamide; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-thiadiazol-5-yl]methanesulfonamide; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-thiadiazole-5-amine; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-oxadiazol-5-yl]acetamide; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-oxadiazol-5-yl]methanesulfonamide; 3-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-(trifluoromethyl)-4H-1,2,4-triazole; 3-[(1 S )-1-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-(trifluoromethyl)-4H-1,2,4-triazole; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-5-methoxy-1,2,4-oxadiazole; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-oxadiazole-5-amine; 3-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-methyl-4H-1,2,4-triazole; 3-[(1 S )-1-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-methyl-4H-1,2,4-triazole; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-5-methyl-4H-1,2,4-triazole; 5-[(1 S)-1-(4-chlorophenoxy)ethyl]-1H-1,2,4-triazole; (2 S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]- N -Cyanopropionamide; (2 S )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]- N -Cyanopropionamide; (2 S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]- N -Methanesulfonylpropionamide; (2 S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]- N -(cyclopropanesulfonyl)acrylamide; 5-[(1 S )-1-[4-bromo-2-(1,1-difluoroethyl)phenoxy]ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-bromo-2-(1,1-difluoropropyl)phenoxy]ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-cyclobutylphenoxy)-2-methoxyethyl]-1H-1,2,3,4-tetraazole; and 5-[(1 S )-1-(4-bromo-2-cyclopropylphenoxy)-2-methoxyethyl]-1H-1,2,3,4-tetraazole, Or its pharmaceutically acceptable salt.

[0176] In one aspect, this disclosure relates to a method for treating neuromuscular disorders, comprising at least one or more of the following: repeatedly activating different muscle fibers of the same motor unit in the neuromuscular tissue of a patient undergoing a neuromuscular disorder examination; detecting the number of paired successful action potentials from the number of activations using a medical device and recording electrodes; determining whether the patient has a block or is at risk of a block by dividing the number of paired successful action potentials by the total number of activations; and administering a ClC-1 inhibitor to the patient when the percentage of the number of paired successful action potentials relative to the total number of activations is less than a threshold of 95%, wherein the administration of the ClC-1 inhibitor increases the percentage of the number of paired successful action potentials relative to the total number of activations by at least 5%.

[0177] "Paired successful action potentials" are detected by recording electrodes when voluntary activation of a muscle generates action potentials in both muscle fibers within the same motor unit. It can be measured as time (tremor) and / or the success of generating action potentials in both muscle fibers (blockage). A motor unit can be defined as "a motor neuron and all its associated muscle fibers".

[0178] Examples of medical devices and recording electrodes include a clinical electrodiagnostic system, which consists of a Cadwell Sierra Wave (Kennewick, WA, USA), concentric recording electrodes (25 mm × 30 gauge, Dantec), and a 1–10 kHz high-pass and low-pass filter setup.

[0179] Examples of neuromuscular tissues examined in patients include the abductor pollicis brevis, trapezius, frontalis, and extensor digitorum muscles.

[0180] In an exemplary embodiment, the method includes administering a ClC-1 inhibitor to a patient when the percentage of the number of paired successful action potentials relative to the total number of activations is below a threshold of 90%, below a threshold of 85%, below a threshold of 80%, below a threshold of 75%, below a threshold of 70%, below a threshold of 65%, below a threshold of 60%, below a threshold of 55%, or below a threshold of 50%.

[0181] In an exemplary embodiment, administration of the ClC-1 inhibitor increases the percentage of the number of paired successful action potentials relative to the total number of activations by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 75%, any percentage or range between 5% and 75%, any percentage or range between 10% and 50%, or any percentage or range between 10% and 30%.

[0182] In an exemplary implementation, administration of a ClC-1 inhibitor to a patient can restore the patient’s muscle contractility to at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 75%, at least 100%, at least 150%, at least 200%, any percentage or range between 10% and 400%, any percentage or range between 15% and 200%, or any percentage or range between 20% and 100%.

[0183] In an exemplary implementation, administration of a ClC-1 inhibitor to a patient reduces the incidence of neuromuscular junction transmission failure in the patient's muscles by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 75%, any percentage or range between 5% and 75%, any percentage or range between 10% and 50%, or any percentage or range between 10% and 30%.

[0184] In one aspect, this disclosure relates to a method for treating neuromuscular disorders, comprising at least one or more of the following: acquiring, using a medical device and recording electrodes, a change in the time interval between two action potentials of the same motor unit in the neuromuscular tissue of a patient undergoing examination for neuromuscular disorders; determining whether the change in the time interval between two action potentials of the same motor unit exceeds or meets a threshold of 40 µs; and administering a ClC-1 inhibitor to the patient when the change in the time interval between two action potentials exceeds or meets the threshold, wherein the administration of the ClC-1 inhibitor reduces the change in the time interval between two action potentials between consecutive discharges by at least 10%.

[0185] In an exemplary embodiment, the method includes determining whether the change in time interval between two action potentials of the same motor unit exceeds or satisfies a threshold of at least 40 µs, at least 45 µs, at least 50 µs, at least 55 µs, at least 60 µs, at least 65 µs, at least 70 µs, at least 75 µs, at least 80 µs, at least 85 µs, at least 90 µs, at least 95 µs, at least 100 µs, at least 150 µs, at least 200 µs, or at least 250 µs.

[0186] In an exemplary embodiment, the administration of the ClC-1 inhibitor reduces the variation in the time interval between two action potentials between consecutive discharges by 5 µs, at least 10 µs, at least 15 µs, at least 20 µs, at least 25 µs, at least 30 µs, at least 40 µs, at least 50 µs, at least 75 µs, at least 100 µs, any point or range between 5 µs and 200 µs, any point or range between 5 µs and 100 µs, or any point or range between 10 µs and 50 µs.

[0187] In an exemplary implementation, single-fiber electromyography (SFEMG) is used to measure the change in the time interval between two action potentials.

[0188] In an exemplary implementation, administration of a ClC-1 inhibitor to a patient reduces the variation in the time interval between two action potentials between consecutive discharges by at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 75%, at least 100%, at least 150%, at least 200%, any percentage or range between 10% and 400%, any percentage or range between 15% and 200%, or any percentage or range between 20% and 100%.

[0189] In an exemplary embodiment, the method for treating neuromuscular disorders can also be used to prevent and / or improve neuromuscular disorders.

[0190] In an exemplary embodiment, the neuromuscular disease is at least one of the following: sarcopenia, myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle specific kinase myasthenia gravis (MuSK-MG), Lambert-Eaton syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie Tooth disease, diabetic polyneuropathy, or periodic paralysis. The neuromuscular disorders include hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy, Duchenne muscular dystrophy, Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disorder, multiple sclerosis, and multifocal motor neuropathy. In other exemplary embodiments, the neuromuscular disorder is multiple sclerosis.

[0191] Any of the ClC-1 inhibitors disclosed herein can be used in the disclosed methods.

[0192] project

[0193] 1. A compound for treating, preventing, and / or improving multiple sclerosis, wherein the compound is a ClC-1 inhibitor.

[0194] 2. A compound in a method for restoring muscle contractility in a subject with multiple sclerosis, wherein the compound is a ClC-1 inhibitor.

[0195] 3. A compound in a method for reducing the incidence of NMJ delivery failure in the muscles of a subject with multiple sclerosis, wherein the compound is a ClC-1 inhibitor.

[0196] 4. A compound in a method for increasing the probability of action potential firing in the muscles of a subject with multiple sclerosis, wherein the compound is a ClC-1 inhibitor.

[0197] 5. A compound in a method for normalizing muscle tremors in a subject with multiple sclerosis, wherein the compound is a ClC-1 inhibitor.

[0198] 6. The compound for use according to Project 1, wherein the ClC-1 inhibitor restored the contractile force of the subject's muscles.

[0199] 7. The compound for use according to any one of the preceding items, wherein the ClC-1 inhibitor reduces the incidence of NMJ delivery failure in the muscle of a subject.

[0200] 8. The compound for use according to any one of the preceding items, wherein the ClC-1 inhibitor increases the probability of action potential firing in the muscles of the subject.

[0201] 9. The compound for use according to any one of the preceding items, wherein the ClC-1 inhibitor normalizes muscle tremors in the subject.

[0202] 10. The compound for use according to any one of the preceding items, wherein the compound has the formula (I):

[0203] Formula (I)

[0204] in: - R 1 Selected from C 1-2Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 12 Selected from: , , , , and ; - R 13 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 14 Selected from one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl groups and optionally substituted with one or more identical or different substituents R 8 Substituted phenyl; - R 15 Selected from -OH, optionally with one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Replacement -OC 3-5 cycloalkyl; - R 16 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 17 Selected from H, optionally with one or more identical or different substituents R 20 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 18 Selected from H, optionally with one or more identical or different substituents R 19 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 19 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 20 Substituted 4-6 membered heterocycles; - R 19 Independently selected from F, Cl, Br, I, -CN, =O, and optionally by one or more identical or different substituents R. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SO-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SO-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SO2-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SO2-C 3-5Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 Substituted phenyl groups, optionally with one or more identical or different substituents R 20 Substituted pyrrolidine-1-yl and optionally with one or more identical or different substituents R 20 Substituted 4-6 membered heterocycles; - R 20 Independently selected from F, Cl, Br, I, -CN, =O, and optionally by one or more identical or different substituents R. 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 1-5Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 3-5 cycloalkyl; - R 21 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 22 Selected from one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl groups and optionally substituted with one or more identical or different substituents R 8 Substituted phenyl; - X is selected from N and CR 23 ; - Y is selected from NH, O, and S; - R 23 Selected from H, NH2, and optionally substituents R (one or more of the same or different). 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)C 1-5 Alkyl groups and optionally one or more identical or different substituents R6 Substituted -NH-SO2-C 1-5 alkyl; - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0205] 11. The compound for use according to any one of items 1 to 9, wherein the compound has formula (II):

[0206] Equation (II)

[0207] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 7 Independently selected from deuterium, F, methyl, ethyl and cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0208] 12. The compound for use according to any one of items 1 to 9, wherein the compound has formula (III):

[0209] Equation (III)

[0210] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - X is selected from N and CR 23 ; - Y is selected from NH, O, and S; - R 23 Selected from H, NH2, and optionally substituents R (one or more of the same or different). 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -NH-SO2-C 1-5 Alkyl; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0211] 13. The compound for use according to any one of items 1 to 9, wherein the compound has formula (IVa) or formula (IVb):

[0212] Formula (IVa) Formula (IVb)

[0213] in: - R 1 Selected from C 1-2Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 Independently selected from deuterium, F, methyl, ethyl, or cyclopropyl; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0214] 14. The compound for use according to any one of items 1 to 9, wherein the compound has the formula (V):

[0215] Formula (V)

[0216] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 13 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 14 Selected from one or more identical or different substituents R 6 Replacement C 1-5Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl groups and optionally substituted with one or more identical or different substituents R 8 Substituted phenyl; - R 15 Selected from -OH, optionally with one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Replacement -OC 3-5 cycloalkyl; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0217] 15. The compound for use according to any one of items 1 to 9, wherein said compound has formula (VI):

[0218] Formula (VI)

[0219] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 16 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0220] 16. The compound for use according to any one of items 1 to 9, wherein the compound has formula (VII):

[0221] Equation (VII)

[0222] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 17 Selected from H, optionally with one or more identical or different substituents R 20 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 18 Selected from H, or arbitrarily substituted by one or more identical or different R. 19 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 19 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 20 Substituted 4-6 membered heterocycles; - R 19 Independently selected from F, Cl, Br, I, -CN, =O, and optionally by one or more identical or different substituents R. 6 Replacement C 3-6Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SO-C 1-5 Alkyl groups, optionally substituted with one or more identical or different substituents R6, of the -SO-C group. 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SO2-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SO2-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 Substituted phenyl groups, optionally with one or more identical or different substituents R 20Substituted pyrrolidine-1-yl and optionally with one or more identical or different substituents R 20 Substituted 4-6 membered heterocycles; - R 20 Independently selected from F, Cl, Br, I, -CN, =O, and optionally by one or more identical or different substituents R. 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 3-5 cycloalkyl; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0223] 17. The compound for use according to any one of items 1 to 9, wherein said compound has formula (VIII):

[0224] Formula (VIII)

[0225] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 21 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 22 Selected from one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C3-5 Cycloalkyl groups and optionally substituted with one or more identical or different substituents R 8 Substituted phenyl; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0226] 18. A compound for use according to any one of items 1 to 9, wherein said compound has formula (II):

[0227] Equation (II)

[0228] in: - R 1 Selected from F, Cl, Br and I; - R 2 It is a 5-membered aromatic heterocycle, which can be optionally replaced by one or more identical or different substituents R. 7 replace; - R 3 Selected from deuterium, F and Cl; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0229] 19. The compound for use according to any one of the preceding items, wherein R 2 For optional addition of one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles.

[0230] 20. The compound for use according to item 11, wherein: - R 1 Selected from F, Cl, Br and I; - R 2 For optional addition of one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, F and Cl; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 7 Independently selected from deuterium, F, methyl, ethyl and cyclopropyl; - R 6 Independently selected from deuterium and F; - R 8Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0231] 21. The compound for use according to item 18, provided that R 1 For F, Cl or Br, R 2 It is 1,2-oxazol-5-yl, R 4 For H, R 5 For H and R 6 When the value is H, then n is 1, 2, or 3.

[0232] 22. The compound for use according to any one of items 11 or 18 to 21, wherein: - R 1 Selected from F, Cl, Br and I, with Cl or Br preferred; - R 2 The group is selected from 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2-thiazol-3-yl, 1,2-oxazol-3-yl, 1,2-oxazol-5-yl, and 1,3-oxazol-4-yl, each of which may be optionally substituented by one or more of the same or different substituents R. 7 replace; - R 3 Selected from deuterium, F and Cl; - R 4 Selected from C 1-5 Alkyl and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 7 Independently selected from H, deuterium, F, Cl, Br, I, C 1-5 Alkyl and C 3-5 cycloalkyl; - R6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0233] 23. The compound for use according to any one of items 10 to 22, wherein R 1 Selected from Cl and Br, R 2 Selected from 1,2-oxazol-3-yl, 1,2-oxazol-5-yl, 1,3-oxazol-4-yl and 1,2,3-thiadiazol-4-yl, and R 4 Selected from Me, Et and -CH2F.

[0234] 24. The compound for use according to any one of items 10 to 22, wherein R 2 Selected from 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.

[0235] 25. The compound for use according to any one of items 10 to 21, wherein R 2 Selected from thiophene, pyrrole, isoxazole, 1,2,4-oxadiazole and 1,3,4-oxadiazole.

[0236] 26. The compound for use according to any one of items 10 to 22, wherein R 2Selected from 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2-thiazol-3-yl, 1,2-thiazol-4-yl, 1,2-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 1,2,3-thiadiazole-4-yl, 1,2,3-thiadiazole-5-yl, 1,2,4-Thiadiazole-3-yl, 1,2,4-Thiadiazole-5-yl, 1,3,4-Thiadiazole-2-yl, 1,2,5-Thiadiazole-3-yl, 1,2,3-Oxadiazole-4-yl, 1,2,3-Oxadiazole-5-yl, 1,2,4-Oxadiazole-3-yl, 1,2,4-Oxadiazole-5-yl, 1,3,4-Oxadiazole-2-yl, and 1,2,5-Oxadiazole-3-yl, each of which may be optionally substituented by one or more of the same or different substituents R. 7 replace.

[0237] 27. The compound for use according to any one of items 10 to 22, wherein R 2 The group is selected from 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2-thiazol-3-yl, 1,2-oxazol-3-yl, 1,2-oxazol-5-yl, and 1,3-oxazol-4-yl, each of which may be optionally substituented by one or more of the same or different substituents R. 7 replace.

[0238] 28. The compound for use according to any one of items 10 to 22, wherein R 2 Selected from isoxazol-5-yl and isoxazol-3-yl.

[0239] 29. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2-oxazol-3-yl.

[0240] 30. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2-oxazol-4-yl.

[0241] 31. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2-oxazol-5-yl.

[0242] 32. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,3-oxazol-2-yl.

[0243] 33. The compound for use according to any one of items 10 to 22, wherein R 2It is 1,3-oxazol-4-yl.

[0244] 34. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,3-oxazol-5-yl.

[0245] 35. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2-thiazolyl-3-yl.

[0246] 36. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2-thiazolyl-4-yl.

[0247] 37. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2-thiazolyl-5-yl.

[0248] 38. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,3-thiazolyl-2-yl.

[0249] 39. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,3-thiazolyl-4-yl.

[0250] 40. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,3-thiazolyl-5-yl.

[0251] 41. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,3-thiadiazole-4-yl.

[0252] 42. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,3-thiadiazole-5-yl.

[0253] 43. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,4-thiadiazole-3-yl.

[0254] 44. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,4-thiadiazole-5-yl.

[0255] 45. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,3,4-thiadiazole-2-yl.

[0256] 46. ​​The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,5-thiadiazole-3-yl.

[0257] 47. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,3-oxadiazol-4-yl.

[0258] 48. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,3-oxadiazol-5-yl.

[0259] 49. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,4-oxadiazol-3-yl.

[0260] 50. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,4-oxadiazol-5-yl.

[0261] 51. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,3,4-oxadiazol-2-yl.

[0262] 52. The compound for use according to any one of items 10 to 22, wherein R 2 It is 1,2,5-oxadiazol-3-yl.

[0263] 53. The compound for use according to any one of items 1 to 9, wherein the compound has formula (IX):

[0264] Formula (IX)

[0265] in: - R 1 Selected from H, deuterium, F, Cl, Br and I, with Cl or Br preferred; - R 3 Selected from deuterium, F and Cl; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl and C5 cycloalkenyl groups, each of which may be optionally replaced by one or more identical or different substituents R. 6 replace; R 5Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 7 Independently selected from deuterium, F, methyl, ethyl and cyclopropyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - m is an integer 0, 1, or 2; and - n is an integer 0, 1, 2 or 3.

[0266] 54. The compound for use as described in item 53, wherein m is 0.

[0267] 55. The compound for use as described in item 53, wherein m is 1.

[0268] 56. The compound for use as described in item 53, wherein m is 2.

[0269] 57. The compound for use according to any one of items 53 to 56, wherein; - R 1 Selected from F, Cl, Br and I; - R 3 Selected from deuterium, F and Cl; - R 4 Selected from C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl and C5 cycloalkenyl groups, each of which may be optionally replaced by one or more identical or different substituents R. 6 replace; - R 5 Selected from H, C 1-5 Alkyl, C 2-5 alkenyl and C 2-5 alkynyl group; - R 7 Independently selected from deuterium, F, methyl, ethyl, and cyclopropyl; and - R6 It is independently selected from deuterium and F.

[0270] 58. The compound for use according to any one of items 10 to 17, wherein R 2 For optional addition of one or more identical or different substituents R 6 Replacement -CF2-C 1-5 alkyl.

[0271] 59. The compound for use according to any one of items 1 to 9, wherein the compound has formula (II):

[0272] Equation (II)

[0273] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 For optional addition of one or more identical or different substituents R 6 Replacement -CF2-C 1-5 alkyl; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0274] 60. The compound for use according to any one of items 10 to 17 or 59, wherein R 2 It is Me-CF2-.

[0275] 61. The compound for use according to any one of items 10 to 17 or 59, wherein R 2 It is Et-CF2-.

[0276] 62. The compound for use according to any one of items 10 to 17 or 59, wherein R 2 for n Pr-CF2-.

[0277] 63. The compound for use according to any one of items 10 to 17 or 59, wherein R 2 for i Pr-CF2-.

[0278] 64. The compound for use according to any one of items 10 to 17 or 59, wherein R 2 It is cyclopropyl-CF2-.

[0279] 65. The compound for use according to any one of items 10 to 17 or 59, wherein R 1 Selected from Cl and Br, R 2 Selected from -CF2Me and -CF2Et, and R 4 Selected from Me, Et and -CH2F.

[0280] 66. The compound for use according to any one of items 1 to 9, wherein the compound has the formula (X):

[0281] Formula (X)

[0282] in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 9 Selected from one or more identical or different substituents R 6 Replacement C 1-5 alkyl; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0283] 67. The compound for use according to item 66, wherein: - R 1 Selected from F, Cl, Br and I; - R 3 Selected from deuterium and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. B8 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 9 Selected from one or more identical or different substituents R 6 Replacement C 1-5 Alkyl; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0284] 68. The compound for use according to item 66, wherein: - R 1 Selected from C2-alkenyl, C2-alkynyl, NO2, F, Cl, Br, and I; - R 9 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl and C 2-5 The alkynyl groups, each of which may be optionally replaced by one or more identical or different substituents R, 6 replace; - R 5 For H; - R 6 Independently selected from deuterium and F; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0285] 69. The compound for use according to any one of items 1 to 9, wherein the compound has the formula (XI):

[0286] Formula (XI)

[0287] in: - R 1 Selected from C2 alkynyl groups, NO2, Cl, Br, and I; - R 3 Selected from H, deuterium, Cl and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl and C 2-5 The alkynyl groups, each of which may be optionally replaced by one or more identical or different substituents R, 6 replace; - R 5 For H; - R 6 Independently selected from deuterium and F; and - R 9 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0288] 70. The compound for use according to item 69, wherein: - R 1 Selected from C2-alkenyl, C2-alkynyl, NO2, F, Cl, Br, and I; - R 9 For optional addition of one or more identical or different substituents R 6 Replacement C 1-3 alkyl; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-3 Alkyl and C 2-3 The alkynyl groups, each of which may be optionally replaced by one or more identical or different substituents R, 6 Replace; and - R 6 Independently selected from deuterium and F; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0289] 71. The compound for use according to any one of items 66 to 70, wherein R 9 It is a methyl group.

[0290] 72. The compound for use according to any one of items 66 to 70, wherein R 9 It is an ethyl group.

[0291] 73. The compound for use according to any one of items 66 to 70, wherein R 9 It is n-propyl.

[0292] 74. The compound for use according to any one of items 66 to 70, wherein R 9 It is isopropyl.

[0293] 75. The compound for use according to any one of items 66 to 70, wherein R 9 It is cyclopropyl.

[0294] 76. The compound for use according to any one of items 1 to 9, wherein the compound has formula (II):

[0295] Equation (II)

[0296] in: - R 1 Selected from F, Cl, Br and I; - R 2 Selected from H, deuterium, F, Cl, Br, and I; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0297] 77. The compound for use according to item 11, wherein: - R 1 Selected from F, Cl, Br and I; - R 2 Selected from hydrogen, deuterium, F, Cl, and Br; - R 4 Selected from each of one or more identical or different substituents R 6 Replacement C 1-5 Alkyl, C 2-5 alkenyl, C 3-5 Cycloalkyl, C5 cycloalkenyl, and optionally substituents R, either the same or different. 6 Replacement C 2-5 alkynyl group; and - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; and - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 3 It is deuterium; and - n is 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0298] 78. The compound for use according to item 11, wherein: - R 1 Selected from F, Cl, Br and I; - R 2 Selected from hydrogen, deuterium, F, Cl, and Br; - R 4 Selected from C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl and C5 cycloalkenyl groups, each being substituented by one or more of the same or different R groups. 6 Replace; and - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; and - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 3 It is deuterium; and - n is 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0299] 79. The compound for use according to any one of items 10 to 17 or 76 to 78, wherein R 2 For H.

[0300] 80. The compound for use according to any one of items 10 to 17 or 76 to 78, wherein R 2 It is deuterium.

[0301] 81. The compound for use according to any one of items 10 to 17 or 76 to 78, wherein R 2 It is F.

[0302] 82. The compound for use according to any one of items 10 to 17 or 76 to 78, wherein R 2 It is Cl.

[0303] 83. The compound for use according to any one of items 10 to 17 or 76 to 78, wherein R 2 It is Br.

[0304] 84. The compound for use according to any one of items 10 to 17 or 76 to 78, wherein R 2 For I.

[0305] 85. The compound for use according to item 11, wherein: - R 1 Selected from H, Br, Cl, F, and I; - R 2 For H; - R 4 Selected from -CH3, -CH2-CH3, -CH(CH3)2, -CH2F, -CH2-CH2F, -, and cyclopropyl; - R 5 For H; and - n is 0, Or its pharmaceutically acceptable salts, solvates, polymorphs or tautomers.

[0306] 86. The compound for use according to item 11, wherein: - R 1 Selected from F, Cl, Br, I, -CN and -CF3; - R 2 Selected from C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 3 Selected from deuterium, F and Cl; - R 4 Selected from C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl, C2-5 alkenyl, C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0307] 87. The compound for use according to any one of items 10 to 17 or 86, wherein R 2 For optional addition of one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group.

[0308] 88. The compound for use according to any one of items 10 to 17 or 86, wherein R 2 It is vinyl.

[0309] 89. The compound for use according to any one of items 10 to 17 or 86, wherein R 2 For optional addition of one or more identical or different substituents R 6 Replacement C 2-5 Alkyne group.

[0310] 90. The compound for use according to any one of items 10 to 17 or 86, wherein R 2 It is an acetylene group.

[0311] 91. The compound for use according to any one of items 1 to 9, wherein the compound has the formula (XII):

[0312] Formula (XII)

[0313] in: - R 1 Selected from F, Cl, Br and I; - R 2 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 cycloalkyl; - R 3 Selected from deuterium, Cl, and F; - R 10 It can be optionally replaced by one or more identical or different substituents R 6 Replacement C 1-2 Alkyl; - R 5 Selected from H, C 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-6 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 Substitution; optionally by one or more identical or different substituents R 8 Substituted phenyl groups; and optionally substituted with one or more identical or different substituents R. 8 Substituted benzyl; - R 11 For optional addition of one or more identical or different substituents R 6 Replacement C 1-2 alkyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2, or 3; and - X a For O or S; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0314] 92. A compound for use according to any one of items 1 to 9, wherein said compound has the formula (XIII):

[0315] Formula (XIII)

[0316] in: - R 1 Selected from Cl and Br; - R 2 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 cycloalkyl; - R 3 Selected from deuterium and F; - R 11 For optional addition of one or more identical or different substituents R 6 Replacement C1-2 alkyl; - R 6 Independently selected from deuterium and F; - n is an integer 0, 1, 2, or 3; and - X a For O or S; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0317] 93. The compound for use according to any one of items 11 to 17, 86, 91 or 92, wherein R 2 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl.

[0318] 94. The compound for use according to any one of items 11 to 17, 86, 91 or 92, wherein R 2 It is cyclopropyl.

[0319] 95. The compound for use according to any one of items 11 to 17, 86, 91 or 92, wherein R 2 It is cyclobutyl.

[0320] 96. A compound for use according to any one of items 1 to 9, wherein said compound has the formula (XIV):

[0321] Formula (XIV)

[0322] in: - R 1 Selected from Cl and Br; - R 3 Selected from deuterium and F; - R 11 For optional addition of one or more identical or different substituents R 6 Replacement C 1-2 alkyl; - R 6 Independently selected from deuterium and F; - p is an integer, either 1 or 2; - n is an integer 0, 1, 2, or 3; and - X a For O or S; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0323] 97. The compound for use according to any one of items 91 to 96, wherein X a It is O.

[0324] 98. The compound for use according to any one of items 91 to 96 above, wherein X a Let it be S.

[0325] 99. The compound for use according to any one of items 96 to 98, wherein p is 1.

[0326] 100. The compound for use according to any one of items 96 to 98, wherein p is 2.

[0327] 101. The compound for use according to any one of items 10, 11, or 18 to 100, wherein R 5 For H.

[0328] 102. The compound for use according to any one of items 10, 11, or 18 to 100, wherein R 5 For optional addition of one or more identical or different substituents R 8 Replacement C 1-5 alkyl.

[0329] 103. The compound for use according to any one of items 10, 11, or 18 to 100, wherein R 5 For optional addition of one or more identical or different substituents R 8 Replacement C 3-6 Cycloalkyl.

[0330] 104. The compound for use according to any one of items 10, 11, or 18 to 100, wherein R 5 For optional addition of one or more identical or different substituents R 8 Substituted phenyl groups.

[0331] 105. The compound for use according to any one of items 10, 11, or 18 to 100, wherein R 5 For optional addition of one or more identical or different substituents R 8 Substituted benzyl group.

[0332] 106. The compound for use according to any one of items 10 or 12, wherein X is N.

[0333] 107. The compound for use according to any one of items 10 or 12, wherein X is CR 23 , where R 23 For H.

[0334] 108. The compound for use according to any one of items 10 or 12, wherein X is CR 23 , where R 23 It is NH2.

[0335] 109. The compound for use according to any one of items 10 or 12, wherein X is a CR 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl.

[0336] 110. The compound for use according to any one of items 10 or 12, wherein X is CR 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl.

[0337] 111. The compound for use according to any one of items 10 or 12, wherein X is CR 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Replacement -OC 1-5 alkyl.

[0338] 112. The compound for use according to any one of items 10 or 12, wherein X is CR 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl.

[0339] 113. The compound for use according to any one of items 10 or 12, wherein X is a CR 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Substituted -NH-C(=O)C 1-5 alkyl.

[0340] 114. The compound for use according to any one of items 10 or 12, wherein X is CR 23 , where R 23 For optional addition of one or more identical or different substituents R 6 Substituted -NH-SO2-C 1-5 alkyl.

[0341] 115. The compound for use according to any one of items 10, 12 or 106 to 114, wherein Y is NH.

[0342] 116. The compound for use according to any one of items 10, 12 or 106 to 114, wherein Y is O.

[0343] 117. The compound for use according to any one of items 10, 12 or 106 to 114, wherein Y is S.

[0344] 118. The compound for use according to any one of items 10 or 14, wherein R 13 For H.

[0345] 119. The compound for use according to any one of items 10 or 14, wherein R 13 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl.

[0346] 120. The compound for use according to any one of items 10 or 14, wherein R 13 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl.

[0347] 121. The compound for use according to any one of items 10 or 14, wherein R 13 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 alkyl.

[0348] 122. The compound for use according to any one of items 10 or 14, wherein R 13 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl.

[0349] 123. The compound for use according to any one of items 10, 14 or 118 to 122, wherein R 14 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl.

[0350] 124. The compound for use according to any one of items 10, 14 or 118 to 122, wherein R 14 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl.

[0351] 125. The compound for use according to any one of items 10, 14 or 118 to 122, wherein R 14 For optional addition of one or more identical or different substituents R 8 Substituted phenyl groups.

[0352] 126. The compound for use according to any one of items 10, 14 or 118 to 125, wherein R 15 It is -OH.

[0353] 127. The compound for use according to any one of items 10, 14 or 118 to 125, wherein R 15 For optional addition of one or more identical or different substituents R 6 Replacement -OC 1-5 alkyl.

[0354] 128. The compound for use according to any one of items 10, 14 or 118 to 125, wherein R 15 For optional addition of one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl.

[0355] 129. The compound for use according to any one of items 10 or 15, wherein R 16 For H.

[0356] 130. The compound for use according to any one of items 10 or 15, wherein R 16 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl.

[0357] 131. The compound for use according to any one of items 10 or 15, wherein R 16 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl.

[0358] 132. The compound for use according to any one of items 10 or 15, wherein R 16 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 alkyl.

[0359] 133. The compound for use according to any one of items 10 or 15, wherein R 16 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5Cycloalkyl.

[0360] 134. The compound for use according to any one of items 10 or 16, wherein R 17 For H.

[0361] 135. The compound for use according to any one of items 10 or 16, wherein R 17 For optional addition of one or more identical or different substituents R 20 Replacement C 1-5 alkyl.

[0362] 136. The compound for use according to any one of items 10 or 16, wherein R 17 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl.

[0363] 137. The compound for use according to any one of items 10 or 16, wherein R 17 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 alkyl.

[0364] 138. The compound for use according to any one of items 10 or 16, wherein R 17 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl.

[0365] 139. The compound for use according to any one of items 10, 16, or 134 to 138, wherein R 18 For H.

[0366] 140. The compound for use according to any one of items 10, 16, or 134 to 138, wherein when R 18 When it is H, then R 17 Not H.

[0367] 141. The compound for use according to any one of items 10, 16, or 134 to 138, wherein R 18 For optional addition of one or more identical or different substituents R 19 Replacement C 1-5 alkyl.

[0368] 142. The compound for use according to any one of items 10, 16, or 134 to 138, wherein R 18 For optional addition of one or more identical or different substituents R 19 Replacement C3-6 Cycloalkyl.

[0369] 143. The compound for use according to any one of items 10, 16, or 134 to 138, wherein R 18 For optional addition of one or more identical or different substituents R 8 Substituted phenyl groups.

[0370] 144. The compound for use according to any one of items 10, 16, or 134 to 138, wherein R 18 For optional addition of one or more identical or different substituents R 20 Replaced 4-6 membered heterocycles.

[0371] 145. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 It can be F, Cl, Br or I.

[0372] 146. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For -CN.

[0373] 147. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 =O.

[0374] 148. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Replacement C 3-6 Cycloalkyl.

[0375] 149. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Replacement -OC 1-5 alkyl.

[0376] 150. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl.

[0377] 151. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R6 Replacement -SC 1-5 alkyl.

[0378] 152. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Replacement -SC 3-5 Cycloalkyl.

[0379] 153. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Replacement -SO-C 1-5 alkyl.

[0380] 154. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Replacement -SO-C 3-5 Cycloalkyl.

[0381] 155. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Replacement -SO2-C 1-5 alkyl.

[0382] 156. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Replacement -SO2-C 3-5 Cycloalkyl.

[0383] 157. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 alkyl.

[0384] 158. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Replacement -C(=O)-OC 1-5 alkyl.

[0385] 159. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Substituted -NH-C(=O)-OC 1-5 alkyl.

[0386] 160. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl.

[0387] 161. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 1-5 alkyl.

[0388] 162. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 3-5 Cycloalkyl.

[0389] 163. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 1-5 alkyl.

[0390] 164. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 3-5 Cycloalkyl.

[0391] 165. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 8 Substituted phenyl groups.

[0392] 166. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19For optional addition of one or more identical or different substituents R 20 Substituted pyrrolidine-1-yl.

[0393] 167. The compound for use according to any one of items 10, 16, or 134 to 144, wherein R 19 For optional addition of one or more identical or different substituents R 20 Replaced 4-6 membered heterocycles.

[0394] 168. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 It can be F, Cl, Br or I.

[0395] 169. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For -CN.

[0396] 170. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 =O.

[0397] 171. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl.

[0398] 172. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For optional addition of one or more identical or different substituents R 6 Replacement C 3-6 Cycloalkyl.

[0399] 173. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 alkyl.

[0400] 174. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For optional addition of one or more identical or different substituents R 6 Replacement -C(=O)-OC 1-5 alkyl.

[0401] 175. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl.

[0402] 176. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For optional addition of one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 1-5 alkyl.

[0403] 177. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For optional addition of one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 3-5 Cycloalkyl.

[0404] 178. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 1-5 alkyl.

[0405] 179. The compound for use according to any one of items 10, 16, or 134 to 167, wherein R 20 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 3-5 Cycloalkyl.

[0406] 180. The compound for use according to any one of items 10 or 17, wherein R 21 For H.

[0407] 181. The compound for use according to any one of items 10 or 17, wherein R 21 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl.

[0408] 182. The compound for use according to any one of items 10 or 17, wherein R 21 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl.

[0409] 183. The compound for use according to any one of items 10 or 17, wherein R 21 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 alkyl.

[0410] 184. The compound for use according to any one of items 10 or 17, wherein R 21 For optional addition of one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl.

[0411] 185. The compound for use according to any one of items 10, 17 or 180 to 184, wherein R 22 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl.

[0412] 186. The compound for use according to any one of items 10, 17 or 180 to 184, wherein R 22 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl.

[0413] 187. The compound for use according to any one of items 10, 17 or 180 to 184, wherein R 22 For optional addition of one or more identical or different substituents R 8 Substituted phenyl groups.

[0414] 188. The compound for use according to any one of items 10 to 187, wherein R 1 C 1-2 alkyl.

[0415] 189. The compound for use according to any one of items 10 to 187, wherein R 1 It is a C2-olefinic compound.

[0416] 190. The compound for use according to any one of items 10 to 187, wherein R 1 It is a C2 acetylene group.

[0417] 191. The compound for use according to any one of items 10 to 187, wherein R 1 For CN.

[0418] 192. The compound for use according to any one of items 10 to 187, wherein R 1It is CF3.

[0419] 193. The compound for use according to any one of items 10 to 187, wherein R 1 It is NO2.

[0420] 194. The compound for use according to any one of items 10 to 187, wherein R 1 It can be Cl or Br.

[0421] 195. The compound for use according to any one of items 10 to 187, wherein R 1 It is F.

[0422] 196. The compound for use according to any one of items 10 to 187, wherein R 1 It is Cl.

[0423] 197. The compound for use according to any one of items 10 to 187, wherein R 1 It is Br.

[0424] 198. The compound for use according to any one of items 10 to 187, wherein R 1 For I.

[0425] 199. The compound for use according to any one of items 10 to 198, wherein R 3 It is deuterium.

[0426] 200. The compound for use according to any one of items 10 to 198, wherein R 3 It is Cl.

[0427] 201. The compound for use according to any one of items 10 to 198, wherein R 3 It is F.

[0428] 202. The compound for use according to any one of items 10 to 201, wherein R 4 For optional addition of one or more identical or different substituents R 6 Replacement C 1-5 alkyl.

[0429] 203. The compound for use according to any one of items 10 to 201, wherein R 4 Selected from methyl, ethyl, n-propyl and isopropyl.

[0430] 204. The compound for use according to any one of items 10 to 201, wherein R 4 Selected from methyl, ethyl, n-propyl, and isopropyl, wherein the methyl, ethyl, n-propyl, or isopropyl group is modified by one or more identical or different substituents R.6 replace.

[0431] 205. The compound for use according to any one of items 10 to 201, wherein R 4 For Me.

[0432] 206. The compound for use according to any one of items 10 to 201, wherein R 4 It is an ethyl group.

[0433] 207. The compound for use according to any one of items 10 to 201, wherein R 4 C replaced by one or more F 1-5 alkyl.

[0434] 208. The compound for use according to any one of items 10 to 201, wherein R 4 For being substituents R by one or more identical or different substituents 6 Substituted methyl group.

[0435] 209. The compound for use according to any one of items 10 to 201, wherein R 4 Selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2 and -CH2CF3.

[0436] 210. The compound for use according to any one of items 10 to 201, wherein R 4 It is -CH2F.

[0437] 211. The compound for use according to any one of items 10 to 201, wherein R 4 It is -CH2-CH2F.

[0438] 212. The compound for use according to any one of items 10 to 201, wherein R 4 For optional addition of one or more identical or different substituents R 6 Replacement C 1-2 Alkoxy-C 1-2 alkyl.

[0439] 213. The compound for use according to any one of items 10 to 201, wherein R 4 For optional addition of one or more identical or different substituents R 6 Replacement C 1-2 Alkylthio-C 1-2 alkyl.

[0440] 214. The compound for use according to any one of items 10 to 201, wherein R 4Selected from MeOCH2-, EtOCH2-, MeSCH2-, and EtSCH2-.

[0441] 215. The compound for use according to any one of items 10 to 201, wherein R 4 For optional addition of one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group.

[0442] 216. The compound for use according to any one of items 10 to 201, wherein R 4 For optional addition of one or more identical or different substituents R 6 Replacement C 2-5 Alkyne group.

[0443] 217. The compound for use according to any one of items 10 to 201, R 4 It is prop-2-ynyl.

[0444] 218. The compound for use according to any one of items 10 to 201, wherein R 4 For optional addition of one or more identical or different substituents R 6 Replaced -CH2-C 2-4 Alkyne group.

[0445] 219. The compound for use according to any one of items 10 to 201, wherein R 4 For optional addition of one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl.

[0446] 220. The compound for use according to any one of items 10 to 201, wherein R 4 Selected from cyclopropyl and cyclobutyl.

[0447] 221. The compound for use according to any one of items 10 to 201, wherein R 4 It is deuterium.

[0448] 222. The compound for use according to any one of items 10 to 201, wherein R 4 For H.

[0449] 223. The compound for use according to any one of items 10 to 201, wherein when R 4 When it is H, it is related to R. 4 The bonded carbon is not a stereoisomer source center.

[0450] 224. The compound for use according to any one of items 10 to 223, wherein R6 It is deuterium.

[0451] 225. The compound for use according to any one of items 10 to 223, wherein R 6 It is F.

[0452] 226. The compound for use according to any one of items 10 to 225, wherein R 7 It is deuterium.

[0453] 227. The compound for use according to any one of items 10 to 225, wherein R 7 It is F.

[0454] 228. The compound for use according to any one of items 10 to 225, wherein R 7 Selected from methyl, ethyl or cyclopropyl.

[0455] 229. The compound for use according to any one of items 10 to 227, wherein R 8 It is deuterium.

[0456] 230. The compound for use according to any one of items 10 to 227, wherein R 8 It is a methoxy group.

[0457] 231. The compound for use according to any one of items 10 to 227, wherein R 8 It is a nitro group.

[0458] 232. The compound for use according to any one of items 10 to 227, wherein R 8 It is a cyano group.

[0459] 233. The compound for use according to any one of items 10 to 227, wherein R 8 It is Cl.

[0460] 234. The compound for use according to any one of items 10 to 227, wherein R 8 It is Br.

[0461] 235. The compound for use according to any one of items 10 to 227, wherein R 8 For I.

[0462] 236. The compound for use according to any one of items 10 to 227, wherein R 8 It is F.

[0463] 237. The compound for use according to any one of items 10 to 236, wherein n is 0.

[0464] 238. The compound for use according to any one of items 10 to 236, wherein n is 1.

[0465] 239. The compound for use according to any one of items 10 to 236, wherein n is 2.

[0466] 240. The compound for use according to any one of items 10 to 236, wherein n is 3.

[0467] 241. The compound for use according to Item 1, wherein the compound is selected from: ( S )-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)-3-methoxypropionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propionic acid; ( R )-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutyric acid; ( S )-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propionic acid; ( R )-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-(4-chloro-2-cyclopropyl-5-fluorophenoxy)-3-methoxypropionic acid; ( S )-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butyric acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butyric acid; ( S )-2-[2-(1,1-difluoropropyl)-5-fluoro-4-styryloxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutyric acid; (R )-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid; ( R )-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propionic acid; ( R )-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propionic acid; [4-Chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; [4-Bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-tolyloxy]propionic acid; [4-Bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-styryloxy]propionic acid; ( R )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid; [4-Bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)(3,5,6- 2 [H3)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propionic acid; ( R )-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-cyano-2-(1,1-difluoropropyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propionic acid; ( R )-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2- 2 H) propionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propionic acid; ( S )-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-4-pentyneic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-pentyneic acid; ( R )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-pentyneic acid; ( S )-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid; ( S )-2-[4-bromo-2-(cyclopropyldifluoromethyl)phenoxy]propionic acid; ( R )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propionic acid; ( S )-[4-bromo-2-(1,1-difluoroethyl)phenoxy]cyclopropylacetic acid; ( S )-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propionic acid; [4-Bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid; ( S )-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propionic acid; ( S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid; ( S 2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propionic acid; ( S )-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid; ( S )-(4-bromo-2-cyclopropylphenoxy)cyclopropylacetic acid; ( S )-Cyclopropyl(2,4-dibromophenoxy)acetic acid; ( S )-(4-bromo-2-chlorophenoxy)cyclopropylacetic acid; (2R,3R)-2-(p-bromophenoxy)-3-fluorobutyric acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-ethoxypropionic acid; [4-Bromo-2-(1,3-oxazol-4-yl)phenoxy]acetic acid; [4-Bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]acetic acid; [4-Chloro-2-(5-isoxazolyl)phenoxy]acetic acid; ( S )-[4-bromo-2-(5-isoxazolyl)phenoxy]cyclopropylacetic acid; ( S )-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]cyclopropylacetic acid; (S,E)-2-(p-bromophenoxy)-4-fluoro-3-butenoic acid; (2R,3R)-2-(4-bromo-2-fluorophenoxy)-3-fluorobutyric acid; (4-Bromo-2-cyclopropylphenoxy)acetic acid; ( S )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]-3-cyclopropylpropionic acid; [4-Bromo-2-(4-methyl-3-isoxazolyl)phenoxy]acetic acid; [4-Bromo-5-fluoro-2-(5-isoxazolyl)phenoxy]acetic acid; ( S2-[4-bromo-5-fluoro-2-(5-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-cyclobutylpropionic acid; ( S )-2-[4-bromo-5-fluoro-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid; [4-Bromo-2-(5-isoxazolyl)phenoxy]acetic acid; ( S )-2-(p-bromophenoxy)(2- 2 H) Butyric acid; ( S )-2-(p-bromophenoxy)-4-pentyneic acid; [4-Bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]acetic acid; (4-Bromo-2-ethynylphenoxy)acetic acid; ( S 2-(4-bromo-2-fluorophenoxy)valerate; ( S 2-(2,4-dibromophenoxy)valerate; ( S 2-(4-bromo-2-chlorophenoxy)valerate; ( S 2-(p-bromophenoxy)-3-cyclopropylpropionic acid; ( S )-2-(2,4-dibromophenoxy)-4-pentyneic acid; ( S )-2-(4-bromo-2-chlorophenoxy)-4-pentyneic acid; ( S )-(p-bromophenoxy)cyclopropylacetic acid; ( S )-2-(4-bromo-2-fluorophenoxy)-4-pentyneic acid; ( S )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]butyric acid; ( S 2-(p-bromophenoxy)valerate; ( R )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,3,4-thiadiazol-2-yl)phenoxy]propionic acid; ( S)-(4-bromo-2-chlorophenoxy)cyclobutylacetic acid; ( S 2-(4-bromo-2-chlorophenoxy)-3-cyclopropylpropionic acid; ( S 2-(4-bromo-2-chlorophenoxy)-3-methylbutyric acid; [4-Bromo-2-(3-isoxazolyl)phenoxy]acetic acid; ( R )-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid; ( S )-2-(p-bromophenoxy)-3-butenoic acid; ( S )-2-[4-bromo-2-(1H-1,2,3-triazol-5-yl)phenoxy]propionic acid; (2S)-2-(p-bromophenoxy)(3,4- 2 H2) Butyric acid; ( R 2-(4-bromo-2-chlorophenoxy)-3-fluoropropionic acid; ( S 2-(4-bromo-2-chlorophenoxy)butyric acid; ( S 2-(4-bromo-3-fluorophenoxy)-3-methylbutyric acid; ( S 2-(4-bromo-2-chlorophenoxy)-4-fluorobutyric acid; ( S 2-(p-ethynylphenoxy)-4-fluorobutyric acid; ( S )-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]-4-fluorobutyric acid; ( S )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,3-oxazol-5-yl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-4-fluorobutyric acid; ( R )-2-(p-bromophenoxy)-3-fluoro(2- 2 H) propionic acid; (R )-2-[4-chloro-5-fluoro-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S 2-(4-bromo-5-fluoro-2-styryloxy)propionic acid; ( S )-2-[4-bromo-2-(1,3-thiazolyl-4-yl)phenoxy]propionic acid; ( S )-2-[4-bromo-5-fluoro-2-(1,3-oxazol-4-yl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-methylbutyric acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid; ( R )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-5-fluoro-2-(5-isoxazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)propionic acid; ( S )-2-[4-bromo-2-(2,2-difluorovinyl)-5-fluorophenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]butyric acid; ( S )-2-(4-bromo-2-iodophenoxy)-4-fluorobutyric acid; ( S )-(4-bromo-2-ethynylphenoxy)cyclobutylacetic acid; ( S 2-(4-bromo-2-ethynyl-5-fluorophenoxy)propionic acid; ( S 2-(4-chloro-2-ethynyl-5-fluorophenoxy)propionic acid; ( S )-2-[4-bromo-2-(4-isoxazolyl)phenoxy]propionic acid; ( R )-2-[4-chloro-5-fluoro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-(p-bromophenoxy)cyclobutylacetic acid; ( S)-2-(4-bromo-2-cyclopropylphenoxy)-4-fluorobutyric acid; ( S )-2-(4-bromo-2-fluorophenoxy)-4-fluorobutyric acid; ( S )-2-(4-bromo-2-ethynylphenoxy)-4-fluorobutyric acid; ( S )-2-(4-bromo-2-styryloxy)-4-fluorobutyric acid; ( S )-(4-bromo-2-fluorophenoxy)cyclobutylacetic acid; ( S )-2-[4-chloro-2-(1,3-oxazol-4-yl)phenoxy]propionic acid; ( S )-2-[4,5-dichloro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S 2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S 2-(p-bromophenoxy)-4-fluorobutyric acid; ( S )-2-{2-[(E)-2-fluorovinyl]-4-bromophenoxy}propionic acid; ( S )-2-[4-bromo-2-(1,3-oxazol-4-yl)phenoxy]propionic acid; ( S )-2-{2-[(E)-2-fluorovinyl]-4-chlorophenoxy}propionic acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid; ( S )-2-[4-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid; ( R )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(4-methyl-3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-cyclopropyl-3-isoxazolyl)phenoxy]propionic acid; ( S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-methylbutyric acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]butyric acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid; ( S )-2-[4-chloro-2-(1,3-oxazol-2-yl)phenoxy]propionic acid; ( S )-2-(4-bromo-2-iodophenoxy)-3-methylbutyric acid; ( S )-(4-bromo-2-fluorophenoxy)cyclopropylacetic acid; ( R )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(3-isothiazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-ethynylphenoxy)butyric acid; ( S 2-(4-bromo-2-iodophenoxy)butyric acid; ( S 2-(4-chloro-2-fluorophenoxy)butyric acid; ( S 2-(p-bromophenoxy)butyric acid; ( S )-2-[4-bromo-2-(2,2-difluorovinyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(5-isoxazolyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-methylbutyric acid; ( S )-2-[4-bromo-2-(4-methyl-3-isoxazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-fluorophenoxy)butyric acid; ( S)-2-[4-bromo-2-(5-methyl-3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxy]propionic acid; ( R )-2-[p-bromo(3,5- 2 [H2)phenoxy]-3-fluoropropionic acid; ( S )-2-[p-bromo(3,5- 2 [H2)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(5-cyclopropyl-3-isoxazolyl)phenoxy]propionic acid; ( S ethyl 2-(4-bromo-2-fluorophenoxy)-3-methyl-3-butenoate; ( R 2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid; ( R )-2-[p-bromo(2,6- 2 [H2)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(1,3-thiazolyl-2-yl)phenoxy]propionic acid; ( S )-2-[p-bromo(2,6- 2 [H2)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-methyl-5-isoxazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-iodophenoxy)propionic acid; ( S 2-[4-bromo-2-(2-imidazolyl)phenoxy]propionic acid; ( S 2-[4-bromo-2-(5-imidazolyl)phenoxy]propionic acid; ( R )-2-(4-bromo-2-cyclobutylphenoxy)-3-fluoropropionic acid; ( R )-2-(4-bromo-2-fluorophenoxy)-3,3-difluoropropionic acid; ( S 2-(4-bromo-2-ethynylphenoxy)propionic acid; ( S 2-(2-bromo-4-chlorophenoxy)-3-methylbutyric acid; ( S 2-(2-fluoro-4-iodophenoxy)propionic acid; ( S 2-(2-bromo-4-iodophenoxy)propionic acid; ( R )-2-[4-bromo-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S 2-(2-chloro-4-iodophenoxy)propionic acid; ( S 2-(2-bromo-4-chlorophenoxy)propionic acid; ( S 2-(4-bromo-2-cyclopropylphenoxy)propionic acid; ( S 2-(4-bromo-2-styryloxy)propionic acid; ( S )-2-[4-chloro-2-(1-methyl-3-methyl-4-pyrazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-pyrazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid; ( S 2-(2-cyclopropyl-4-fluorophenoxy)propionic acid; ( S )-2-[4-chloro-2-(1-methyl-4-pyrazolyl)phenoxy]propionic acid; ( S 2-(2-cyclobutyl-4-fluorophenoxy)propionic acid; ( S 2-(4-bromo-2-cyclobutylphenoxy)propionic acid; ( R 2-(4-bromo-2-fluorophenoxy)-3-fluoropropionic acid; ( S 2-(4-chloro-2-fluorophenoxy)-3-methylbutyric acid; ( S 2-(4-chloro-2-cyclobutylphenoxy)propionic acid; ( S )-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]propionic acid; ( R2-(2-bromo-4-chlorophenoxy)-3-fluoropropionic acid; ( R 2-(p-chlorophenoxy)-3-fluoropropionic acid; ( R )-2-(4-chloro-2-fluorophenoxy)-3-fluoropropionic acid; ( R )-2-(2,4-dibromophenoxy)-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid; ( R 2-(p-bromophenoxy)-3-fluoropropionic acid; ( S 2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid; ( S 2-(4-bromo-2-fluorophenoxy)propionic acid; ( S 2-(4-chloro-2-fluorophenoxy)propionic acid; ( S 2-(2,4-dibromophenoxy)propionic acid; ( S 2-(4-chloro-2-ethynylphenoxy)propionic acid; ( S 2-(4-chloro-2-styryloxy)propionic acid; ( S 2-(4-chloro-2-cyclopropylphenoxy)propionic acid; ( S 2-(p-chlorophenoxy)butyric acid; ( S Sodium 2-(2,4-dichlorophenoxy)propionate; ( S 2-(p-chlorophenoxy)-3-methylbutyric acid; ( S 2-(p-cyanophenoxy)propionic acid; ( S methyl 2-(p-bromophenoxy)propionate; ( S 2-(p-chlorophenoxy)butyrate methyl ester; ( S Isopropyl 2-(p-chlorophenoxy)propionate; ( S 2-(p-chlorophenoxy)propionate methyl ester, (2 S )-2-(4-bromo-2-fluorophenoxy)- N-{1-[(cyclopropylmethoxy)imino]ethyl}propionamide; (2 S )-2-(4-bromophenoxy)- N -[1-(methoxyimino)ethyl]propionamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -[(4-fluorophenyl)(hydroxyimino)methyl]-3-methylbutyramide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -[1-(hydroxyimino)ethyl]-3-methylbutyramide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -[1-(hydroxyimino)ethyl]propionamide; (2 S )-2-(4-bromophenoxy)- N -[1-(hydroxyimino)ethyl]acrylamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -Cyanopropionamide; (2 S )- N -Cyano-2-(2,4-dibromophenoxy)propionamide; (2 S )-2-(4-bromophenoxy)- N -Cyanopropionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyanopropionamide; (2 S )-2-(4-bromophenoxy)- N -Cyano-3-methylbutyramide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -Cyclobutoxypropionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -Methoxypropionamide; (2 S )- N -acetyl- N -[(1-acetylazetane-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylazetane-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -(azacyclobutane-3-yloxy)-2-(4-chlorophenoxy)propionamide; (2 S )- N -acetyl- N -[(1-acetylpyrrolidone-3-yl)methoxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylpyrrolidone-3-yl)methoxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-bromophenoxy)propionamide; N -(2-{[(2 S 2-(4-chlorophenoxy)propamido]oxy]propyl)carbamate tert-butyl ester; (2 S )- N -acetyl-2-(4-chlorophenoxy)- N -[(1-acetamidopropyl-2-yl)oxy]propionamide; (2 S )-2-(4-bromophenoxy)- N -(pyrrolidine-3-yloxy)propionamide; (2 S )- N -acetyl- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-bromophenoxy)propionamide; 3-{[(2 S 2-(4-chlorophenoxy)propamido]oxy}azacyclobutane-1-carboxylic acid tert-butyl ester; (2 S )-2-(4-chlorophenoxy)- N -[(pyrrolidone-3-yl)methoxy]propionamide; 3-({[(2 S 2-(4-chlorophenoxy)propamido]oxy}methyl)pyrrolidine-1-carboxylic acid tert-butyl ester; (2 S )- N -acetyl-N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(pyrrolidine-3-yloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2,2-Dimethylpropyl)- N -Hydroxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-(pyrrolidone-1-yl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-(2-oxopyrrolidone-1-yl)ethoxy]propionamide; (2 S )- N -acetyl-2-(4-chlorophenoxy)- N -(2-acetamidoethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-acetamidoethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(4,4,4-trifluoro-2-methylbutoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(3-Cyclopentylpropyl)- N -Hydroxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -{[(2E)-2-methyl-3-phenylprop-2-en-1-yl]oxy}propionamide; (2 S )-2-(4-chlorophenoxy)- N -{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethoxy}propionamide; N -(2-{[(2 S2-(4-chlorophenoxy)propamido]oxyethyl)carbamate tert-butyl ester; (2 S )-2-(4-chlorophenoxy)- N -[(2-methyl-1H-imidazol-4-yl)methoxy]propionamide; 4-({[(2 S 2-(4-chlorophenoxy)propamido]oxy}methyl)-2-methyl-1H-imidazol-1-carboxylic acid tert-butyl ester; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-bromophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-oxo-2-(pyrrolidone-1-yl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -[1-(4-fluorophenyl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -[1-(1,3-thiazolyl-2-yl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -{1-[4-(trifluoromethyl)phenyl]ethoxy}propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-Methylsulfinylethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-Methanesulfonylethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(1,2-oxazol-3-yl)methoxy]propionamide; (2 S )-2-(4-chloro-2-fluorophenoxy)- N -Methoxypropionamide; (2 S )-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]- N -(cyclopropylmethoxy)propionamide; (2 S )-2-[4-chloro-2-(trifluoromethyl)phenoxy]- N -(cyclopropylmethoxy)propionamide; (2 S )- N -(tert-butoxy)-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-(methylthio)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -(1-Phenylacetyl)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(1-methyl-1H-imidazol-2-yl)methoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-methoxyethoxy)propionamide; (2 S )-2-(4-chloro-2-fluorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]- N -Methoxypropionamide; (2 S )-2-[4-chloro-2-(trifluoromethyl)phenoxy]- N -Methoxypropionamide; (2 S )- N -(benzyloxy)-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(2-methoxycyclopentyl)oxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxy-5-methylhexanoamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxy- N -Methylpropionamide; (2 S )-2-(4-chloro-2-methylphenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chloro-3-fluorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chloro-2-methylphenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chloro-3-fluorophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxy-4-methylpentanamide; (2 S )-2-(4-chlorophenoxy)- N -[(3-methylbut-2-en-1-yl)oxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxyhexylamide; (2 S )-2-(4-chlorophenoxy)- N -[(1,3-oxazol-2-yl)methoxy]propionamide; (2 S )-2-(2,4-dibromophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(oxane-2-yloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(1,3-thiazolyl-2-yl)methoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -(3,3-difluorocyclobutoxy)propionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]- N -Cyclobutoxypropionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]- N -Methoxypropionamide; (2S )-2-(4-chlorophenoxy)- N -(cyclopentyloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-Cyclopentylethoxy)propionamide; (2 S )-2-(4-bromo-2-chlorophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-bromo-2-methylphenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(cyclopropylmethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(cyclobutylmethoxy)propionamide; (2 S )- N -(2-aminoethoxy)-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-bromophenoxy)- N -Methoxy-3-methylbutyramide; 2-{[(2 S 2-(4-chlorophenoxy)propamido]oxy]methyl acetate; (2 S )-2-(4-chlorophenoxy)- N -[2-(2-methoxyethoxy)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-hydroxyethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -Ethoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -Propoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(prop-2-yloxy)propionamide; (2S )-2-(4-chlorophenoxy)- N -Methoxypropionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -(cyclopropanesulfonyl)acrylamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -Methanesulfonylpropionamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -(cyclopropanesulfonyl)acrylamide; (2 S )-2-(4-chlorophenoxy)- N -Methanesulfonylpropionamide; (2 S )-2-(4-bromophenoxy)- N -Methanesulfonyl-3-methylbutyramide; 5-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-fluoropropyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-fluorophenoxy)propyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-fluorophenoxy)-2-methylpropyl]-2H-1,2,3,4-tetraazole; 5-[(1 R )-1-(4-bromophenoxy)-2-fluoroethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromophenoxy)propyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromophenoxy)ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S)-1-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-cyclopropylphenoxy)ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-vinylphenoxy)ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-ethylphenoxy)ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-methylphenoxy)ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chlorophenoxy)ethyl]-1H-1,2,3,4-tetraazole; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-thiadiazol-5-yl]acetamide; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-thiadiazol-5-yl]methanesulfonamide; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-thiadiazole-5-amine; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-oxadiazol-5-yl]acetamide; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-oxadiazol-5-yl]methanesulfonamide; 3-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-(trifluoromethyl)-4H-1,2,4-triazole; 3-[(1 S)-1-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-(trifluoromethyl)-4H-1,2,4-triazole; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-5-methoxy-1,2,4-oxadiazole; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-oxadiazole-5-amine; 3-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-methyl-4H-1,2,4-triazole; 3-[(1 S )-1-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-methyl-4H-1,2,4-triazole; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-5-methyl-4H-1,2,4-triazole; 5-[(1 S )-1-(4-chlorophenoxy)ethyl]-1H-1,2,4-triazole; (2 S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]- N -Cyanopropionamide; (2 S )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]- N -Cyanopropionamide; (2 S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]- N -Methanesulfonylpropionamide; (2 S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]- N -(cyclopropanesulfonyl)acrylamide; 5-[(1 S )-1-[4-bromo-2-(1,1-difluoroethyl)phenoxy]ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-bromo-2-(1,1-difluoropropyl)phenoxy]ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-cyclobutylphenoxy)-2-methoxyethyl]-1H-1,2,3,4-tetraazole; and 5-[(1 S )-1-(4-bromo-2-cyclopropylphenoxy)-2-methoxyethyl]-1H-1,2,3,4-tetraazole, Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0468] 242. A method for treating neuromuscular disorders, comprising at least one or more of the following: repeatedly activating different muscle fibers of the same motor unit in the neuromuscular tissue of a patient undergoing examination for neuromuscular disorders; detecting the number of paired successful action potentials from the number of activations using a medical device and recording electrodes; determining whether the patient has a block or is at risk of a block by dividing the number of paired successful action potentials by the total number of activations; and administering a ClC-1 inhibitor to the patient when the percentage of the number of paired successful action potentials relative to the total number of activations is less than a threshold of 95%, wherein the administration of the ClC-1 inhibitor increases the percentage of the number of paired successful action potentials relative to the total number of activations by at least 5%.

[0469] 243. The method according to item 242, wherein the ClC-1 inhibitor is a compound according to any one of items 10 to 241.

[0470] 244. The method according to item 242, wherein the method is used to treat, prevent and / or improve neuromuscular disorders.

[0471] 245. The method according to Item 243, wherein the neuromuscular disease is at least one of the following: sarcopenia, myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle-specific kinase myasthenia gravis (MuSK-MG), Lambert-Eton syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie-Toos disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotube myopathy, Duchenne muscular dystrophy, Guillain-Barré syndrome, poliomyelitis, post-poliomyelitis syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disease, multiple sclerosis, and multifocal motor neuropathy.

[0472] 246. The method according to item 245, wherein the neuromuscular disease is multiple sclerosis.

[0473] 247. The method according to item 242, wherein administration of the ClC-1 inhibitor restores at least 5% of the contractile force of the patient's muscles.

[0474] 248. The method according to item 242, wherein administration of the ClC-1 inhibitor reduces the incidence of neuromuscular junction transmission failure in the patient's muscles by at least 5%.

[0475] 249. The method described in Item 242, wherein single-fiber electromyography is used to measure the change in the time interval between two action potentials.

[0476] 250. A method for treating neuromuscular disorders, comprising at least one or more of the following: acquiring, using a medical device and recording electrodes, a change in the time interval between two action potentials of the same motor unit in the neuromuscular tissue of a patient undergoing examination for neuromuscular disorders; determining whether the change in the time interval between two action potentials of the same motor unit exceeds or meets a threshold of 40 µs; and administering a ClC-1 inhibitor to the patient when the change in the time interval between two action potentials exceeds or meets the threshold, wherein the administration of the ClC-1 inhibitor reduces the change in the time interval between two action potentials between consecutive discharges by at least 10%.

[0477] 251. The method according to item 250, wherein the ClC-1 inhibitor is a compound according to any one of items 10 to 241.

[0478] 252. The method according to item 250, wherein the method is used to treat, prevent and / or improve neuromuscular disorders.

[0479] 253. The method according to item 250, wherein the neuromuscular disease is at least one of the following: sarcopenia, myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle-specific kinase myasthenia gravis (MuSK-MG), Lambert-Eton syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie-Toos disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotube myopathy, Duchenne muscular dystrophy, Guillain-Barré syndrome, poliomyelitis, post-poliomyelitis syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disease, multiple sclerosis, and multifocal motor neuropathy.

[0480] 254. The method described in Item 253, wherein the neuromuscular disease is multiple sclerosis.

[0481] 255. The method according to item 250, wherein the administration of the ClC-1 inhibitor restores at least 5% of the contractile force of the patient's muscles.

[0482] 256. The method according to item 250, wherein administration of the ClC-1 inhibitor reduces the incidence of neuromuscular junction transmission failure in the patient's muscles by at least 5%.

[0483] 257. The method described in Item 250, wherein single-fiber electromyography is used to measure the change in the time interval between two action potentials.

[0484] result

[0485] Example 1: Electrophysiological measurements of the inhibitory effect of the compound on ClC-1 in rat muscle

[0486] The goal of these experiments was to evaluate whether compounds inhibited ClC-1 channels in the native tissue of rat skeletal muscle fibers. The concentration at which the compounds achieved 50% complete inhibition of ClC-1 was determined by observation. 50 The apparent ClC-1 affinity was reported (see also WO2019 / 115777).

[0487] Experimentally, G was measured in individual fibers of the entire rat soleus muscle using the three-microelectrode technique described in this embodiment and elsewhere. m (Riisager et al., Determination of cable parameters inskeletal muscle fibers during repetitive firing of action potentials. Journal of Physiology, 2014, 592 (4417-4429). In short, complete rat soleus muscles were dissected 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 mM MgSO4, 1.3 mM CaCl2, and 5.0 mM D-glucose. During the experiment, the solution was maintained at approximately 30°C and continuously equilibrated with a mixture of 95% O2 and 5% CO2 (pH ~7.4). The experimental chamber was placed in a Nikon vertical microscope for observation of individual muscle fibers and three electrodes (glass pipettes filled with 2 M potassium citrate). For G... mMeasurements were performed by inserting electrodes into the same fibers, with known inter-electrode distances of 0.35–0.5 mm (V1–V2, X1) and 1.1–1.5 mm (V1–V3, X3). Membrane potentials of the punctured muscle fibers were recorded using all electrodes. Furthermore, a 50 ms current pulse of -30 nA was injected using two of the electrodes. Given the electrode positions, three distinct inter-electrode distances (X1–X2, X1–X3, X2–X3) can be determined, thus allowing the membrane potential response to current injection to be obtained at three distances from the injection point. The steady-state voltage deflection at each distance was divided by the injected current magnitude (-30 nA), and the resulting transfer resistance was plotted against the inter-electrode distance. The data were fitted to a single exponential function, and G was calculated from this single exponential function using linear slew theory. m .

[0488] To establish the dose-response relationship, G was first measured in 10 muscle fibers in the absence of the compound. m Then, measurements were performed at four increasing compound concentrations, with 5-10 fibers subjected to G at each concentration. m Determined. The average G at each concentration was... m Plotting values ​​relative to compound concentration and fitting the data to an sigmoid function to obtain EC values. 50 value.

[0489] ECG of various ClC-1 inhibitors 50 Values ​​are given in WO 2019 / 115777, WO 2019 / 115780, WO 2019 / 115781, WO 2020 / 254553, WO 2020 / 254558 and WO 2020 / 254559.

[0490] Example 2: Force Measurement in an In Vitro Model

[0491] This disclosure relates to compounds that improve muscle function by inhibiting ClC-1 ion channels and increasing muscle excitability in clinical conditions of muscle activation failure. These clinical conditions result in loss of skeletal muscle contractile function, weakness, and excessive fatigue. In this series of experiments, the ability of the compounds to restore isolated rat muscle contractile function in cases of neuromuscular transmission impairment similar to neuromuscular disorders was tested.

[0492] In the experiments, soleus muscle from 4-5 week old rats was isolated, with motor nerves still attached. A neuromuscular preparation was installed in an experimental device capable of electrically stimulating the motor nerves. Stimulation of the motor nerves led to activation of the muscle fibers and the generation of force, which was recorded. In these experiments, the neuromuscular preparation was also incubated in a standard Krebs Ringer (see Example 15), the solution was heated to 30°C, and continuously equilibrated with a mixture of 95% O2 and 5% CO2 (pH ~7.4).

[0493] After loading the neuromuscular preparation into the experimental setup, muscle contractile function was first assessed under control conditions. Then, a submaximal concentration of tubocurarine (115 nM) (an acetylcholine receptor antagonist) was added to the experimental bath to partially inhibit the ability of motor nerves to activate muscle fibers. The experimental conditions simulated failed neuromuscular transmission in a range of neuromuscular disorders. Following the addition of tubocurarine, contractile force decreased to 10–50% of the control force over the next 90 minutes. The test compound was then added to obtain the desired compound concentration in the experimental bath, and the recovered contractile force was measured. To quantify the compound's ability to recover, the percentage of the initial force recovered was determined 40 minutes after compound exposure.

[0494] The percentage increase in initial force restored by various ClC-1 inhibitors is given in WO 2016 / 202341, WO 2019 / 115777, WO 2019 / 115780, WO 2019 / 115781, EP19181253, WO 2020 / 254553, WO 2020 / 254558 and WO 2020 / 254559.

[0495] Example 3: Screening of compounds on human C1C-1 isoforms expressed in CHO cells using automated patch clamp

[0496] The goal of these experiments was to evaluate how compounds affect the opening probability and current amplitude of human ClC-1 channels expressed in CHO cells. Experiments were conducted using an automated patch-clamp system, which allows for high-throughput testing of whole-cell patches and allows for the addition of compounds both intracellularly and extracellularly.

[0497] Automated voltage clamp measurements

[0498] Automated whole-cell patch-clamp experiments were performed at room temperature using a Qpatch 16 system (Sophion Bioscience, Ballerup, Denmark). Data acquisition and analysis were performed using Qassay software (version 5.6, Odense).

[0499] Voltage protocol and analysis of whole-cell ClC-1 currents

[0500] To induce ClC-1 currents in the whole-cell membrane sheet, the membrane potential was first stepped from a holding potential of -30 mV to +60 mV for 100 ms, and then stepped in 20 mV increments to various test voltages (scans) within the range of +120 mV to -140 mV for 300 ms. To obtain the tail current, after each test voltage, the membrane potential was stepped to -100 mV for 300 ms, and then relaxed to -30 mV for 2 seconds between scans.

[0501] By plotting the average current density relative to membrane potential at the start and end of a 300 ms step, the I / V relationship of the instantaneous and steady-state current amplitudes in the whole cell was obtained.

[0502] To determine the relative total activation probability (P0), the instantaneous tail current was normalized relative to the maximum tail current obtained after the most positive voltage step and plotted against the test voltage. Then, the normalized tail current plot for each whole-cell sheet was fitted to a Boltzmann function to determine the half-activation voltage (V). 1 / 2 ).

[0503] Solutions

[0504] For automated patch-clamp experiments, the extracellular solution contained: 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 4 mM KCl, 145 mM NaCl, and 10 mM glucose. The pH was adjusted to 7.4 using NaOH (2 M). The osmolality was adjusted to approximately 320 using sucrose.

[0505] The intracellular solution contained: 80 mM CsF, 60 mM CsCl, 5 / 1 mM KOH / EGTA, 10 mM HEPES, and 10 mM NaCl. The pH was adjusted to 7.2 with NaOH (2 M). The osmotic pressure was adjusted to approximately 320 mOsm using sucrose.

[0506] Cell line information: The cells used in patch-clamp experiments were constitutively expressed human ClC-1 channel Chinese hamster ovary cells (CHO). The amino acid sequence encoded by the cDNA used to create this cell line was identical to the translational sequence of GenBank accession number NM_000083.2. Cells were produced cryopreserved by Charles River (catalog CT6175, Cleveland OH, USA). After thawing, cells were used directly for experiments (3 × 10⁶ cells per experiment). 6 (cells).

[0507] Test protocol

[0508] To evaluate the effect of the compound on ClC-1 when directly applied to the intracellular side of the cell membrane, the half-activation voltage V was measured from whole-cell membrane sheets in which the compound was added to the intracellular solution. 1 / 2 Then, it was compared with the V measured in control cell membranes in which only the intracellular solution contained solvent. 1 / 2 Comparisons were made. Furthermore, the levels of V were measured before and after changing the extracellular solution to contain the compound. 1 / 2 The effects of extracellularly added compounds were evaluated using steady-state current amplitude.

[0509] The half-activation voltage difference ΔV of the ClC-1 channel 1 / 2 The difference between cell membranes treated intracellularly with the compound and control cell membranes was identified, and the ΔV of various ClC-1 inhibitors was reported in WO 2019 / 115777, WO 2019 / 115780, WO 2019 / 115781, EP19181253, WO 2020 / 254554, and WO 2020 / 254558. 1 / 2 ΔV 1 / 2 The positive shift reflects the inhibition of the ClC-1 channel by the tested compound. A p-value < 0.05 is considered significant.

[0510] Example 4: Measurement of in situ muscle contraction characteristics

[0511] Isometric hindlimb force was measured in 12-week-old female Lewis rats in the presence and absence of the compound.

[0512] Rats were anesthetized with isoflurane (2-4%), 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 near the ankle to expose the Achilles tendon, which was tied with cotton thread and connected to a position-adjustable (vernier-controlled) force sensor (Fort250, World Precision Instruments). The Achilles tendon was then severed distal to the tying point. The rats were placed on a heating pad, and to prevent motion artifacts caused by ankle dorsiflexor contraction, the feet were secured to a footplate with tape.

[0513] The nature of muscle contraction was assessed by applying an electric current (under supermaximal voltage conditions) to the nerve and recording the force generated by the muscle. When assessed with a 2 Hz stimulus, the muscle was stretched until maximum force was achieved. Isometric force was measured every 30 seconds at 12 Hz (twitching), 10 pulses, and every 5 minutes for 1 second (80 pulses) at 80 Hz (tetany). This stimulation pattern was used throughout the experiment, except in a few cases where 12 Hz (10 pulses) was used instead of 80 Hz. Neuromuscular transmission was partially inhibited by continuous infusion of 0.1 mg / kg cisatracurium (Nimbex, GlaxoSmithKline) at an adjustable infusion rate, with the infusion rate individually adjusted for each animal to achieve an inhibition level of approximately 50% of the force generated at the 4th pulse of the 12 Hz stimulus. Once the neuromuscular inhibition level stabilized, the test substance was administered intravenously, intraperitoneally, or orally at a selected concentration. The effect of the test substance was assessed based on its ability to increase the force produced by the applied stimulus pattern. The effect was assessed by the ratio between the ability to increase the force itself (tetany, 80 Hz, stimulus) and the peak of individual convulsion (12 Hz stimulus). The effect was monitored for at least 1 hour after injection of the test substance. Additionally, the time from injection of the test substance to the maximal effect on the force (both convulsions and tetany) was recorded, as well as, if possible, the time to the loss of effect (return to baseline). When appropriate, the infusion of the neuromuscular blocking agent was stopped, the stimulus pattern was continued, and the force was monitored to return to control levels. Animals were euthanized by cervical dislocation while still fully sedated.

[0514] The percentage increase in tetanic force restored by various ClC-1 inhibitors is given in WO 2019 / 115777, WO 2019 / 115780, WO 2019 / 115781, WO 2020 / 254553, WO 2020 / 254554, WO 2020 / 254558 and WO 2020 / 254559.

[0515] Example 5: Pharmacological model of neuromuscular dysfunction in sedated WT rats

[0516] Experimental setup

[0517] In a pharmacological model of neuromuscular dysfunction, experiments were conducted on sedated and mechanically ventilated female Wistar rats. The device was designed to achieve simultaneous electromyographic recording of the complex muscle action potential (CMAP, EMG) of the triceps surae muscle and simultaneous measurement of muscle strength and single-fiber EMG stimulation (SSFEMG; to evaluate tremors and blockade). Neuromuscular dysfunction was pharmacologically induced by intravenous infusion of the neuromuscular blocking agent (NMBA) cisatracurium.

[0518] Animal surgery

[0519] Anesthesia was administered subcutaneously to rats using a 1:1 mixture of fentanyl (Hypnorm) and midazolam (Dormicum 5 mg / mL) (Hameln Pharma Plus GmbH, DE), at a dose volume of 1 mL / kg. Subsequently, rats were intubated and mechanically ventilated to ensure adequate pulmonary gas exchange (Hallowell MicroVent 1 rodent anesthesia ventilator, Dre Veterinary, KY, USA), and anesthesia was maintained by mixing isoflurane (2–3%) into the ventilation gas. A gastric tube was inserted through the esophagus to allow oral (PO) administration. Blood samples were collected via jugular vein cannulation to verify effective plasma exposure levels. Core body temperature was continuously monitored and maintained at 37°C by placing a heating pad under the animal.

[0520] Stimulating muscle strength and CMAPs

[0521] While the animal was under stable anesthesia, preparations for measuring CMAP (EMG) and force in the right hind limb began: the distal portion of the triceps surae muscle was surgically exposed, a suture was securely tied to the Achilles tendon, and the tendon was then severed from a position away from the suture. The suture was connected to a force sensor (FORT 1000, World Precision Instruments, FL, USA). Two stimulating electrodes (monopolar EMG needle electrodes 25 mm × 27 g, Chalgren, London, UK) were then inserted near the sciatic nerve to elicit a neurostimulatory contraction response in the triceps surae muscle upon electrical stimulation of the nerve. The force generated was then recorded and quantified by the force sensor. Finally, two EMG electrodes (subcutaneous needle electrodes, Cadwell Kennewick, WA, USA) were placed subcutaneously, with the active recording electrode positioned above the proximal portion of the triceps surae muscle distal to the knee joint, and the reference electrode placed in the metatarsal region of the foot. The acquisition program (Signal version 6.4, Cambridge Electronics Design Ltd, Cambridge, UK) is used to control the stimulation delivered by the isostim 01D NPI electronics, DE, and to record the data via an analog-to-digital converter (Micro 1401 Cambridge Electronics Design Ltd, Cambridge, UK).

[0522] After the device was set up, the sciatic nerve was stimulated with 10 pulses of 12 Hz (12-15 V) every 30 seconds. After 9 stimulations (5 minutes), the 12 Hz stimulation was replaced with a 1-second 80 Hz stimulation, and after another 9 stimulations, it was replaced again with a 1-second 80 Hz stimulation. This cycle was repeated until the end of the experiment. The muscle strength data from the 80 Hz stimulation were quantified as the area under the curve (AUC) of the principal force (g). s). For CMAP analysis, the amplitudes of the first and tenth peaks in the 12 Hz stimulation sequence were used, and... Figure 1 A and Figure 1 Section B describes the amplitude ratio of the 10th peak to the 1st peak.

[0523] Stimulated single fiber EMG (SSFEMG)

[0524] SSFEMG was performed concurrently with force and CMAP in the same rats to assess tremors and NMJ blockade in the presence and absence of a ClC-1 inhibitor compound. SSFEMG was performed on the gastrocnemius muscle (left limb) using the Sierra Summit clinical electrodiagnostic system (Cadwell, Kennewick, WA, USA). 18 The hair on the left hind leg was shaved, and the foot was secured with tape, with the hip joint in abduction and the ankle in plantar flexion. Two stimulating electrodes (monopolar EMG needle electrodes, 25 mm × 27 g, Chalgren, London, UK) were then percutaneously placed at different locations in the gastrocnemius muscle to stimulate branches from the sciatic nerve to the muscle fibers. A grounding electrode (subcutaneous needle electrode, Cadwell Kennewick, WA, USA) was inserted subcutaneously at the base of the tail. A highly selective SFEMG recording needle (25 × 0.30 mm, SEI EMG srl, Cittadella, IT) was inserted into the gastrocnemius muscle to record single-fiber AP evoked during stimulation. The recording was performed at a frequency of 10 Hz and a frequency of 50... The pulse duration and the varying current intensity (mA) for each rat were adjusted to stimulate the nerve branches. The standard for capturing AP was a minimum amplitude of 200. V, rise time < 500 s, and all-or-nothing response. One hundred (100) potentials were captured from each synapse. Flickering (mean continuous delay, MCD) was reported as an average per animal, and blockade was reported as the percentage of synapses with blockade in each animal out of the total number of synapses. SSFEMG parameters were quantified: flickering, which is the temporal variability of AP reaching the recording electrode between consecutive discharges; and intermittent pulse blockade (i.e., complete NMJ transmission failure). Figure 1 C and Figure 1 D).

[0525] Record all four readings (force, CMAP, tremor, and block) while maintaining stability (white bars). Figure 1 Following AD, NMBA was introduced as a continuous IV infusion to achieve a stable level of neuromuscular blockade, producing a relative level compared to before NMBA (gray bar). Figure 1 AD) approximately 30% of the power, and oral administration of NMD712 (( S 2-(p-bromophenoxy)butyric acid (50 mg / kg). Recording was performed 60 minutes after compound administration (grid column). Figure 1 (AD). The NMD compound resulted in the recovery of all four parameters, indicating improved neuromuscular transmission and muscle function.

[0526] Example 6: Measurement methods for tremors and blockades in a clinical setting

[0527] Single-fiber electromyography (SFEMG) was performed using a clinical electrodiagnostic system [Ohio State University: Cadwell Sierra Wave (Kennewick, WA, USA)], concentric recording electrodes (25 mm × 30 gauge, Dantec), and high-pass and low-pass filter settings of 1–10 kHz to record and analyze up to 22 apparent single-fiber action potential pairs during voluntary contraction. A total of 50–100 consecutive discharge analyses were performed on each apparent single-fiber pair to determine parameters of jitter (variability in NMJ transmission) and blockade (i.e., NMJ transmission failure). Repetitive nerve stimulation (RNS) was performed on the trapezius and abductor pollicis brevis muscles at a stimulation rate of 3 Hz. The attenuation of the amplitude and area of ​​the compound muscle action potential (CMAP) of the 1st–5th and 1st–10th stimulations was quantified. See also Weir et al., 1979.

[0528] Example 7: Observational Clinical Trial

[0529] I. Introduction

[0530] An observational clinical trial was conducted to identify and characterize the presence of NMJ transmission abnormalities in patients with CMT1 or CMT2. The primary objective was to investigate the NMJ transmission deficits in patients with CMT types 1 and 2 compared to age-matched healthy controls.

[0531] II.1. Study overview and timeline

[0532] This study protocol was reviewed and approved by the Institutional Review Board of The Ohio State University Wexner Medical Center and the Central Denmark Health Research Ethics Committee. All participants (two types of CMT patients and healthy controls) provided written informed consent before participation in the study. CMT participants underwent four clinical evaluations. Following baseline visits, the interval between visits was 2 weeks ± 10 days. Figure 2 Each visit involved clinical and electrophysiological testing. Healthy controls underwent electrophysiological testing during one visit (Visit 1). Figure 2 This study was conducted in accordance with the Declaration of Helsinki and registered in the database Clinicaltrials.gov (NCT04980807).

[0533] II.2. Participants

[0534] The study recruited participants with CMT type 1 and 2, as well as age-matched healthy controls. Inclusion and exclusion criteria for CMT participants and healthy controls are listed in Tables 1 and 2, respectively. Inclusion and exclusion criteria were defined to ensure that the CMT diagnosis was definitive, participants could complete physical tests, and their condition was stable, thus eliminating factors that might potentially affect NMJ function.

[0535] Table 1: Inclusion and exclusion criteria for CMT participants

[0536] Table 2: Inclusion and exclusion criteria for healthy control participants

[0537] II.3. Study outcomes

[0538] Outcome measures included NMJ electrophysiological testing, isometric muscle strength testing, manual muscle strength testing, 10-meter walk / run time, timed standing walk, 6-minute walk test, Berger Balance Scale (total score), six-point step test, 9-well column test, and CMT examination score (CMTES2). Adverse events (AEs) were collected throughout the study. Tolerance to outcome tests was assessed at all study visits for healthy control participants (electrophysiological testing) and CMT participants (electrophysiological and clinical testing) using a 0-9 scale, where 0 indicates no discomfort and 9 indicates the most severe possible discomfort.

[0539] II.3.A. NMJ electrophysiology

[0540] Single-fiber electromyography (SFEMG) was performed using a clinical electrodiagnostic system [Ohio State University: Cadwell Sierra Wave (Kennewick, WA, USA)], concentric recording electrodes (25 mm × 30 gauge, Dantec), and high-pass and low-pass filter settings of 1–10 kHz to record and analyze up to 22 apparent single-fiber action potential pairs during voluntary contraction. A total of 50–100 consecutive discharges were analyzed for each apparent single-fiber pair to determine parameters of jitter (variability in NMJ transmission) and blockade (i.e., NMJ transmission failure). Repetitive nerve stimulation (RNS) at a stimulation rate of 3 Hz was performed on the trapezius and abductor pollicis brevis muscles. The attenuation of the amplitude and area of ​​the compound muscle action potential (CMAP) of the 1st–5th and 1st–10th stimulations was quantified.

[0541] Manual Muscle Testing (MMT)

[0542] Manual muscle testing (MMT) was performed on 15 muscle groups, including shoulder abduction, elbow flexion / extension, wrist flexion / extension, flexor pollicis longus, hip flexors / extensors, hip abductors, knee flexors / extensors, ankle dorsiflexors / plantar flexors, and neck flexors / extensors. All muscle groups except the neck muscles were tested bilaterally. Posture determination and grading were standardized and applied as previously described (Personius, 1994; Kendall, 2005). The Modified Medicine Research Council (MRC) scale was converted to a 0-10 ordinal scale for analysis (Table 3).

[0543] Table 3: Conversion table to convert MRC scores to ordinal scale scores

[0544] Isometric Dynamometry

[0545] Isometric muscle strength measurements were performed using equipment available at each center. Ohio State University used the Accurate Test of Limb Isometric Strength (ATLIS) chair, a fixed-frame device with adjustable wireless load sensors. Ankle dorsiflexion was tested in an upright seated position; other positioning was standardized and applied as previously described (Andres et al., 2012). Aarhus University Hospital used a Biodex isokinetic dynamometer SYSTEM 3 PRO (Biodex Medical Systems, Inc.). Ankle dorsiflexion was tested on the non-dominant side. Positioning was standardized and applied as previously described (Harbo et al., 2012). At least two trials were performed; additional trials were performed if the variability was greater than 15%. Due to the different methodologies used, data collected from the two centers were not combined for analysis. The highest values ​​for each muscle group were recorded.

[0546] II.3.B. Function and assessments

[0547] Nine-hole Peg Test (9HPT)

[0548] The nine-hole column test (9HPT) is a timed test of finger dexterity and hand function. Participants place nine columns from a reservoir into holes arranged in a 3×3 grid and then move them back into the reservoir one at a time. The 9HPT has been shown to have good reliability and responsiveness in patients with CMT (Svensson et al., 2006; Solari et al., 2008; Piscosquito et al., 2015). The setup and procedure were standardized as previously described (Mathiowetz et al., 1985). Two trials were performed on each hand; the average of the trials was used for analysis.

[0549] Six-spot Step Test (SSST)

[0550] The Six-Point Step Test (SSST) is a timed test of lower limb function and balance. Participants walk in a standard zigzag pattern across a 1 x 5-meter route, sliding cylindrical blocks off the route with their test feet as they move through it (Nieuwenhuis et al., 2006). This test has been shown to be effective and reliable in neurodegenerative conditions and older adults (Sandroff et al., 2015; Brincks et al., 2019; Kondori et al., 2020); it also demonstrates responsiveness to polyneuropathy (Kreutzfeldt et al., 2017). Two trials were performed on each foot; the average of the trials was used for analysis. Participants were allowed to use their typical supportive and / or assistive devices, and their use was recorded at each visit.

[0551] Ten-meter Walk / Run Test (10mWRT)

[0552] The 10-meter walk / run test (10mWRT) is a timed assessment designed to capture maximum performance over short distances and is not subject to the same ceiling effect as tests that only allow walking regardless of ability (Krosschell et al., 2022). It has been proven reliable in CMT (Bray et al., 2020). Two trials were conducted and the average was used for analysis. Participants were allowed to use their typical support and / or assistive devices, and their use was recorded at each visit.

[0553] Timed Up and Go (TUG)

[0554] The timed stand-up walking test (TUG) is a timed assessment of mobility, involving standing up from a chair, walking 3 meters at a comfortable pace, and then returning to the chair to sit down (Podsiadlo et al., 1991). It has been validated in neurological disorders, neuromuscular diseases, and older populations (Dunaway et al., 2014). Two trials were conducted, and the average was used for data analysis. Participants were allowed to use their typical supportive and / or assistive devices, and their use was recorded at each visit.

[0555] Six-minute Walk Test (6MWT)

[0556] The six-minute walk test (6MWT) is an indicator of endurance and can also provide a fatigue index (Montes et al., 2010). Its effectiveness has been demonstrated in patients with chronic thromboembolism (CMT) (Mori et al., 2020). The test is conducted using standardized cues along a 30-meter route according to American Thoracic Society guidelines (ATS, 2002). Participants are allowed to use their typical support and / or assistive devices, which are recorded at each visit. A 10-minute rest is required before the test begins. Analysis is performed using the total walking distance from the first to the sixth minute and the percentage change in walking distance.

[0557] Berg Balance Scale (BBS)

[0558] The Berg Balance Scale (BBS) is a 14-item assessment of balance ability during a functional task. Each item is scored from 0 to 4, with higher scores indicating better performance. The total score used for analysis is the sum of the individual scores for each item, with a maximum score of 56. Its validity has been demonstrated in CMT (Bragadin et al., 2015). Participants were allowed to wear support but were not permitted to use mobile devices. The items were administered as previously described (Berg et al., 1989).

[0559] CMT Examination Score (CMTES2)

[0560] The CMT Assessment Scale, Version 2 is a composite scoring system for assessing sensory and motor impairments in subjects with CMT. It is a subscale of the CMT Neuropathy Scale. Each item is scored on an ordinal scale of 0-4, with higher scores indicating greater severity of impairment. It has demonstrated excellent inter-rater and intra-rater reliability in CMT patients (Murphy et al., 2011).

[0561] II.4. Statistical analysis

[0562] The independent statistical consulting group Phastar used SAS for statistical analysis. Statistical coding was performed before database locking and according to the statistical analysis plan for the study. For the primary objective of comparing NMJ delivery in CMT patients and controls, unpaired t-tests were used to analyze data following a parametric (normal) distribution. For data with unequal variances, Welch's test was used. For data not following a parametric distribution, the Mann-Whitney test was applied. For the secondary objective of test-retest reliability, the intraclass correlation coefficient (ICC) was calculated. For the exploratory analysis investigating the association between electrophysiological and clinical outcomes, Spearman's correlation coefficient was calculated. Due to the exploratory nature of this study, no correction was made for multiple tests.

[0563] III. Results

[0564] III.1. Study participants, demographics, baseline characteristics, and adverse events

[0565] A total of 23 CMT patients and 10 healthy controls were screened. A total of 21 CMT patients and 10 healthy controls were recruited. Of these, 18 CMT patients and 10 healthy controls completed all visits, while 2 CMT patients withdrew after the third visit (one patient was unable to attend the final visit within the allowed timeframe, and the other was participating in a drug study), and 1 patient withdrew consent for personal reasons before the first visit. Data available for these 3 participants are included in the analysis. Table 4 lists demographics and baseline characteristics. No adverse events (AEs) were reported in the healthy controls. Four AEs were reported among the CMT patients: one patient fell during a 6MWT – rated as mild, one patient fell during a 10MWT – rated as mild, one patient experienced knee pain after an isometric muscle strength test – rated as moderate, and one patient experienced syncope – rated as mild.

[0566] Table 4: Demographics and clinical baseline characteristics

[0567] Data are average ± SD.

[0568] III.2. CMT patients demonstrated significant NMJ transmission dysfunction compared to healthy controls

[0569] For the primary objective of comparing NMJ transmission on SFEMG and RNS between CMT patients and healthy controls, data from study visit 1 (baseline) were used. Median SFEMG tremor (a measure of NMJ transmission reliability) was increased by >90% in CMT patients compared to healthy controls [CMT: median tremor 56.3 µs (range: 35.3; 196.6) vs healthy controls: median 29.4 µs (range: 18.6; 35.6), p < 0.05]. Figure 3 A). Similarly, patients with CMT showed increased SFEMG blockade (a measure of NMJ transmission failure) [CMT: median blockade 13.39% (range: 0; 90.9) vs healthy controls: median 0% (range: 0; 4.5), p < 0.05]. In addition to comparing CMT patients to healthy controls, SFEMG tremor was also compared between CMT1 and CMT2. Tremor was increased in CMT2 compared to CMT1 [CMT2: median tremor 100.2 µs (range: 62.2; 152.2) vs CMT1: median tremor 49.3 µs (range: 35.3; 196.6), p < 0.05]. Figure 3C). Similarly, compared to CMT1, SFEMG hindrance increased in CMT2 [CMT2: median hindrance 75.0% (range: 12.5; 87.5) vs CMT1: median hindrance 10.0% (range: 0.0; 90.9), p<0.05] Figure 3 D).

[0570] The amplitude of compound muscle action potentials (CMAP) was assessed after a single supermaximal stimulation and a 10-repetition 3Hz stimulation sequence. Following a single stimulation, CMAP amplitude in CMT patients was ~40% lower than in healthy controls, based on recordings from the abductor pollicis brevis (APB), while it was ~35% lower in CMT patients compared to healthy controls, based on recordings from the trapezius muscle. Compared to SFEMG, no significant increase in RNS at 3Hz was observed when comparing the first, fifth, and tenth stimulations in a 10-repetition stimulation sequence with both the APB and trapezius muscles. No difference was found in CMAP amplitude after a single stimulation or in the attenuation after the stimulation sequence between CMT1 and CMT2 for either the APB or trapezius muscles.

[0571] IV.3. Secondary analysis - Test-Retest Reliability

[0572] Test-retest reliability of electrophysiological and clinical outcomes was assessed by calculating intergroup correlation coefficients (ICC) based on data from visits 1–4 of the CMT patient study. Table 5 summarizes the estimated test-retest reliability values ​​between visits.

[0573] Table 5: Test-Retest Reliability

[0574] Data are presented as mean ± SD and within-group correlation coefficient (ICC).

[0575] IV.4. Secondary analysis - Tolerability of electrophysiology outcomes and clinical outcomes

[0576] Table 6 summarizes the tolerance scores of different procedures for CMT patients and healthy controls at each visit. Tolerance was evaluated on a 0-9 subscale, where 0 indicates no discomfort and 9 indicates the most severe possible discomfort.

[0577] Table 6: Tolerability of electrophysiology outcomes and clinical outcomes

[0578] The data includes the median and range.

[0579] IV.5. NMJ transmission defects correlate with measures of strength and function in CMT

[0580] Table 7 summarizes the associations between electrophysiological and clinical endpoints. Clinical parameters related to strength, balance, and mobility were associated with tremor and blockade. The 6-point step test, 10-meter walk / run test, and timed stand-up walk were positively correlated with tremor and blockade, indicating that longer completion times (worse performance) on these tasks were associated with higher levels of tremor and blockade (worse NMJ transmission). Isometric ankle dorsiflexor strength, Berg Balance Scale total score, and 6-minute walk test were negatively correlated with tremor and blockade, indicating that lower performance on these tasks was associated with higher levels of tremor and blockade. CMTES2, manual muscle strength tests, and 9-hole column tests were not associated with tremor and blockade. Overall, contrary to SFEMG measurements, clinical endpoints were not associated with CMAP decay assessed using RNS (data not shown).

[0581] Table 7: Association of clinical outcomes with tremor and block

[0582] The association between SFEMG parameters and clinical outcomes was a Spearman correlation. Isometric muscle strength measurements were performed by Aarhus and Ohio using separate procedures, therefore these data were analyzed centroidally.

[0583] V. Discussion and conclusion

[0584] As the final link between the nervous system and skeletal muscle, reliable NMJ transmission is crucial for neural control of muscle contraction. Based on sporadic animal studies and findings in other motor axonal and motor neuron disorders, we hypothesized that patients with chronic motor neuron disease (CMT) would exhibit deficits in NMJ transmission. We further hypothesized that NMJ transmission deficits correlated with disease severity and functional assessment. Using SFEMG, we confirmed significant NMJ transmission deficits in CMT patients compared to age-matched healthy controls. Furthermore, NMJ transmission deficits showed significant correlations with clinical outcome measures of strength, mobility, and balance.

[0585] This study further provides reliability and tolerability estimates for clinical and electrophysiological outcomes in CMT patients. Overall, the clinical outcome measures were well tolerable and demonstrated moderate to excellent reliability. SFEMG showed better reliability and tolerability than RNS, but both tests were associated with greater discomfort in patient subgroups.

[0586] Notably, SFEMG demonstrated clear indications of impaired NMJ transmission function. The fact that tremor and blockade are significantly associated with clinical outcomes increases the likelihood of targeting NMJ transmission dysfunction to improve symptoms in CMT patients.

[0587] References

[0588] Pedersen et al., 2021. Pedersen TH, Macdonald WA, Broch-Lips M, Halldorsdottir O, Baekgaard Nielsen O. Chloride channel inhibition improves neuromuscular function under conditions mimicking neuromuscular disorders. Acta Physiol (Oxf). 2021 Oct;233(2):e13690. The entire contents of the foregoing document are incorporated herein by reference.

[0589] Weir et al., 1979. Weir A, Hansen S, Ballantyne JP. Single fibreelectromyographic jitter in multiple sclerosis. J Neurol NeurosurgPsychiatry. 1979 Dec;42(12):1146-50. PMID: 533854; PMCID: PMC490431. The entire contents of the foregoing document are incorporated herein by reference.

[0590] Hopf and Eysholdt, 1978. Hopf HC, Eysholdt M. Impaired refractory periods of peripheral sensory nerves in multiple sclerosis. Ann Neurol. 1978 Dec;4(6):499-501. PMID: 742849. The entire contents of the foregoing document are incorporated herein by reference.

[0591] Scott et al., 2011. Surface EMG characteristics of people with multiplesclerosis during static contractions of the knee extensors, Clin PhysiolFunct Imaging (2011), 31:11–17. PMID: 20807227. The entire contents of the foregoing document are incorporated herein by reference.

Claims

1. A compound for treating, preventing, and / or improving multiple sclerosis, wherein the compound is a ClC-1 inhibitor.

2. The compound of claim 1, wherein the ClC-1 inhibitor restores the contractile force of the subject's muscles.

3. The compound of claim 1, wherein the ClC-1 inhibitor reduces the incidence of NMJ delivery failure in the muscle of the subject.

4. The compound of claim 1, wherein the ClC-1 inhibitor increases the probability of action potential firing in the subject's muscles.

5. The compound of claim 1, wherein the ClC-1 inhibitor normalizes muscle tremors in the subject.

6. The compound for use according to any one of claims 1 to 5, wherein the compound has formula (I): Formula (I) in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; - R 12 Selected from: , , , , and ; - R 13 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 14 Selected from one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl groups and optionally substituted with one or more identical or different substituents R 8 Substituted phenyl; - R 15 Selected from -OH, optionally with one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Replacement -OC 3-5 cycloalkyl; - R 16 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 17 Selected from H, optionally with one or more identical or different substituents R 20 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 18 Selected from H, optionally with one or more identical or different substituents R 19 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 19 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 20 Substituted 4-6 membered heterocycles; - R 19 Independently selected from F, Cl, Br, I, -CN, =O, and optionally by one or more identical or different substituents R. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SO-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SO-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -SO2-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -SO2-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 Substituted phenyl groups, optionally with one or more identical or different substituents R 20 Substituted pyrrolidine-1-yl and optionally with one or more identical or different substituents R 20 Substituted 4-6 membered heterocycles; - R 20 Independently selected from F, Cl, Br, I, -CN, =O, and optionally by one or more identical or different substituents R. 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -C(=O)-OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)-C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-NH-C 3-5 cycloalkyl; - R 21 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -C(=O)-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -C(=O)-C 3-5 cycloalkyl; - R 22 Selected from one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl groups and optionally substituted with one or more identical or different substituents R 8 Substituted phenyl; - X is selected from N and CR 23 ; - Y is selected from NH, O, and S; - R 23 Selected from H, NH2, and optionally substituents R (one or more of the same or different). 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement -OC 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Substituted -NH-C(=O)C 1-5 Alkyl groups and optionally one or more identical or different substituents R 6 Substituted -NH-SO2-C 1-5 alkyl; - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

7. The compound of claim 6, wherein the compound has formula (II): Equation (II) in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2 or 3; Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

8. The compound for use according to any one of claims 6 to 7, wherein: - R 1 Selected from F, Cl, Br and I; - R 2 Selected from H, deuterium, F, Cl, Br, and I; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2 or 3.

9. The compound for use according to any one of claims 6 to 7, wherein: - R 1 Selected from F, Cl, Br and I; - R 2 It can be optionally replaced by one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, F and Cl; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 7 It is independently selected from deuterium, F, methyl, ethyl or cyclopropyl; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2 or 3.

10. The compound for use according to any one of claims 6 to 7, wherein: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 For optional addition of one or more identical or different substituents R 6 Replacement -CF2-C 1-5 alkyl; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 5 Selected from H, optionally with one or more identical or different substituents R 6 Replacement C 1-5 Alkyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-6 Cycloalkyl, optionally substituted with one or more identical or different substituents R 8 The substituted phenyl group and optionally the same or different substituents R 8 Substituted benzyl; - R 6 Independently selected from deuterium and F; - R 8 Independently selected from deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; and - n is an integer 0, 1, 2 or 3.

11. The compound for use according to claim 6, wherein the compound has formula (IVa) or formula (IVb): Formula (IVa) Formula (IVb) in: - R 1 Selected from C 1-2 Alkyl, C2 alkenyl, C2 alkynyl, CN, CF3, NO2, F, Cl, Br, and I; - R 2 Selected from H, deuterium, F, Cl, Br, I, optionally with one or more identical or different substituents R 6 Replacement C 2-5 Alkenyl group, optionally substituted with one or more identical or different substituents R 6 Replacement C 2-5 The alkynyl group, optionally substituented by one or more identical or different R groups. 6 Replacement C 3-5 Cycloalkyl, optionally substituted with one or more identical or different substituents R 6 Replacement -CF2-C 1-5 Alkyl groups and optionally one or more identical or different substituents R 7 Replaced 5-membered aromatic heterocycles; - R 3 Selected from deuterium, Cl, and F; - R 4 Selected from H, deuterium, C 1-5 Alkyl, C 1-2 Alkoxy-C 1-2 Alkyl, C 1-2 Alkylthio-C 1-2 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group and C 3-5 Cycloalkyl groups, each of which may optionally be substituented by one or more identical or different substituents R 6 replace; - R 6 Independently selected from deuterium and F; - R 7 Independently selected from deuterium, F, methyl, ethyl, or cyclopropyl; and - n is an integer, which can be 0, 1, 2, or 3. Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

12. The compound for use according to any one of claims 6 to 12, wherein R 1 Selected from Br and Cl.

13. The compound for use according to any one of claims 6 to 13, wherein R 4 Selected from methyl, -CH2F, ethyl, -CH2CH2F, n-propyl and isopropyl.

14. The compound for use according to any one of claims 6 to 14, wherein n is 0 or 1.

15. The compound for use according to claim 1, wherein the compound is selected from: ( S )-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)-3-methoxypropionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propionic acid; ( R )-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-methoxybutyric acid; ( S )-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propionic acid; ( R )-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-(4-chloro-2-cyclopropyl-5-fluorophenoxy)-3-methoxypropionic acid; ( S )-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butyric acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butyric acid; ( S )-2-[2-(1,1-difluoropropyl)-5-fluoro-4-styryloxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-fluorobutyric acid; ( R )-2-[4,5-dichloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid; ( R )-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-[4,5-dichloro-2-(1,1-difluoropropyl)phenoxy]propionic acid; ( R )-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propionic acid; [4-Chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; [4-Bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]acetic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-tolyloxy]propionic acid; [4-Bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-styryloxy]propionic acid; ( R )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid; [4-Bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)(3,5,6- 2 [H3)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propionic acid; ( R )-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-cyano-2-(1,1-difluoropropyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propionic acid; ( R )-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy](2- 2 H) propionic acid; ( S )-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propionic acid; ( S )-2-[4-chloro-2-(1,1-difluoroethyl)phenoxy]-4-pentyneic acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-4-pentyneic acid; ( R )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-4-pentyneic acid; ( S )-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid; ( S )-2-[4-bromo-2-(cyclopropyldifluoromethyl)phenoxy]propionic acid; ( R )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,1-difluorobutyl)phenoxy]propionic acid; ( S )-[4-bromo-2-(1,1-difluoroethyl)phenoxy]cyclopropylacetic acid; ( S )-2-[4-chloro-2-(1,1-difluoropropyl)phenoxy]propionic acid; [4-Bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid; ( S )-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropionic acid; ( S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid; ( S 2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propionic acid; ( S )-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid; ( S )-(4-bromo-2-cyclopropylphenoxy)cyclopropylacetic acid; ( S )-Cyclopropyl(2,4-dibromophenoxy)acetic acid; ( S )-(4-bromo-2-chlorophenoxy)cyclopropylacetic acid; (2R,3R)-2-(p-bromophenoxy)-3-fluorobutyric acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-ethoxypropionic acid; [4-Bromo-2-(1,3-oxazol-4-yl)phenoxy]acetic acid; [4-Bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]acetic acid; [4-Chloro-2-(5-isoxazolyl)phenoxy]acetic acid; ( S )-[4-bromo-2-(5-isoxazolyl)phenoxy]cyclopropylacetic acid; ( S )-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]cyclopropylacetic acid; (S,E)-2-(p-bromophenoxy)-4-fluoro-3-butenoic acid; (2R,3R)-2-(4-bromo-2-fluorophenoxy)-3-fluorobutyric acid; (4-Bromo-2-cyclopropylphenoxy)acetic acid; ( S )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]-3-cyclopropylpropionic acid; [4-Bromo-2-(4-methyl-3-isoxazolyl)phenoxy]acetic acid; [4-Bromo-5-fluoro-2-(5-isoxazolyl)phenoxy]acetic acid; ( S 2-[4-bromo-5-fluoro-2-(5-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-cyclobutylpropionic acid; ( S )-2-[4-bromo-5-fluoro-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid; [4-Bromo-2-(5-isoxazolyl)phenoxy]acetic acid; ( S )-2-(p-bromophenoxy)(2- 2 H) Butyric acid; ( S )-2-(p-bromophenoxy)-4-pentyneic acid; [4-Bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]acetic acid; (4-Bromo-2-ethynylphenoxy)acetic acid; ( S 2-(4-bromo-2-fluorophenoxy)valerate; ( S 2-(2,4-dibromophenoxy)valerate; ( S 2-(4-bromo-2-chlorophenoxy)valerate; ( S 2-(p-bromophenoxy)-3-cyclopropylpropionic acid; ( S )-2-(2,4-dibromophenoxy)-4-pentyneic acid; ( S )-2-(4-bromo-2-chlorophenoxy)-4-pentyneic acid; ( S )-(p-bromophenoxy)cyclopropylacetic acid; ( S )-2-(4-bromo-2-fluorophenoxy)-4-pentyneic acid; ( S )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]butyric acid; ( S 2-(p-bromophenoxy)valerate; ( R )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(1,3,4-thiadiazol-2-yl)phenoxy]propionic acid; ( S )-(4-bromo-2-chlorophenoxy)cyclobutylacetic acid; ( S 2-(4-bromo-2-chlorophenoxy)-3-cyclopropylpropionic acid; ( S 2-(4-bromo-2-chlorophenoxy)-3-methylbutyric acid; [4-Bromo-2-(3-isoxazolyl)phenoxy]acetic acid; ( R )-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid; ( S )-2-(p-bromophenoxy)-3-butenoic acid; ( S )-2-[4-bromo-2-(1H-1,2,3-triazol-5-yl)phenoxy]propionic acid; (2S)-2-(p-bromophenoxy)(3,4- 2 H2) Butyric acid; ( R 2-(4-bromo-2-chlorophenoxy)-3-fluoropropionic acid; ( S 2-(4-bromo-2-chlorophenoxy)butyric acid; ( S 2-(4-bromo-3-fluorophenoxy)-3-methylbutyric acid; ( S 2-(4-bromo-2-chlorophenoxy)-4-fluorobutyric acid; ( S 2-(p-ethynylphenoxy)-4-fluorobutyric acid; ( S )-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]-4-fluorobutyric acid; ( S )-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(1,3-oxazol-5-yl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-4-fluorobutyric acid; ( R )-2-(p-bromophenoxy)-3-fluoro(2- 2 H) propionic acid; ( R )-2-[4-chloro-5-fluoro-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S 2-(4-bromo-5-fluoro-2-styryloxy)propionic acid; ( S )-2-[4-bromo-2-(1,3-thiazolyl-4-yl)phenoxy]propionic acid; ( S )-2-[4-bromo-5-fluoro-2-(1,3-oxazol-4-yl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-methylbutyric acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid; ( R )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-5-fluoro-2-(5-isoxazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)propionic acid; ( S )-2-[4-bromo-2-(2,2-difluorovinyl)-5-fluorophenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]butyric acid; ( S )-2-(4-bromo-2-iodophenoxy)-4-fluorobutyric acid; ( S )-(4-bromo-2-ethynylphenoxy)cyclobutylacetic acid; ( S 2-(4-bromo-2-ethynyl-5-fluorophenoxy)propionic acid; ( S 2-(4-chloro-2-ethynyl-5-fluorophenoxy)propionic acid; ( S )-2-[4-bromo-2-(4-isoxazolyl)phenoxy]propionic acid; ( R )-2-[4-chloro-5-fluoro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-(p-bromophenoxy)cyclobutylacetic acid; ( S )-2-(4-bromo-2-cyclopropylphenoxy)-4-fluorobutyric acid; ( S )-2-(4-bromo-2-fluorophenoxy)-4-fluorobutyric acid; ( S )-2-(4-bromo-2-ethynylphenoxy)-4-fluorobutyric acid; ( S )-2-(4-bromo-2-styryloxy)-4-fluorobutyric acid; ( S )-(4-bromo-2-fluorophenoxy)cyclobutylacetic acid; ( S )-2-[4-chloro-2-(1,3-oxazol-4-yl)phenoxy]propionic acid; ( S )-2-[4,5-dichloro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S 2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S 2-(p-bromophenoxy)-4-fluorobutyric acid; ( S )-2-{2-[(E)-2-fluorovinyl]-4-bromophenoxy}propionic acid; ( S )-2-[4-bromo-2-(1,3-oxazol-4-yl)phenoxy]propionic acid; ( S )-2-{2-[(E)-2-fluorovinyl]-4-chlorophenoxy}propionic acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid; ( S )-2-[4-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid; ( R )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(4-methyl-3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-cyclopropyl-3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-methylbutyric acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]butyric acid; ( S )-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid; ( S )-2-[4-chloro-2-(1,3-oxazol-2-yl)phenoxy]propionic acid; ( S )-2-(4-bromo-2-iodophenoxy)-3-methylbutyric acid; ( S )-(4-bromo-2-fluorophenoxy)cyclopropylacetic acid; ( R )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(3-isothiazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-ethynylphenoxy)butyric acid; ( S 2-(4-bromo-2-iodophenoxy)butyric acid; ( S 2-(4-chloro-2-fluorophenoxy)butyric acid; ( S 2-(p-bromophenoxy)butyric acid; ( S )-2-[4-bromo-2-(2,2-difluorovinyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(5-isoxazolyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]butyric acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-methylbutyric acid; ( S )-2-[4-bromo-2-(4-methyl-3-isoxazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-fluorophenoxy)butyric acid; ( S )-2-[4-bromo-2-(5-methyl-3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxy]propionic acid; ( R )-2-[p-bromo(3,5- 2 [H2)phenoxy]-3-fluoropropionic acid; ( S )-2-[p-bromo(3,5- 2 [H2)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(5-cyclopropyl-3-isoxazolyl)phenoxy]propionic acid; ( S ethyl 2-(4-bromo-2-fluorophenoxy)-3-methyl-3-butenoate; ( R 2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid; ( R )-2-[p-bromo(2,6- 2 [H2)phenoxy]-3-fluoropropionic acid; ( S )-2-[4-chloro-2-(1,3-thiazolyl-2-yl)phenoxy]propionic acid; ( S )-2-[p-bromo(2,6- 2 [H2)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid; ( S )-2-[4-bromo-2-(3-methyl-5-isoxazolyl)phenoxy]propionic acid; ( S 2-(4-bromo-2-iodophenoxy)propionic acid; ( S 2-[4-bromo-2-(2-imidazolyl)phenoxy]propionic acid; ( S 2-[4-bromo-2-(5-imidazolyl)phenoxy]propionic acid; ( R )-2-(4-bromo-2-cyclobutylphenoxy)-3-fluoropropionic acid; ( R )-2-(4-bromo-2-fluorophenoxy)-3,3-difluoropropionic acid; ( S 2-(4-bromo-2-ethynylphenoxy)propionic acid; ( S 2-(2-bromo-4-chlorophenoxy)-3-methylbutyric acid; ( S 2-(2-fluoro-4-iodophenoxy)propionic acid; ( S 2-(2-bromo-4-iodophenoxy)propionic acid; ( R )-2-[4-bromo-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid; ( S 2-(2-chloro-4-iodophenoxy)propionic acid; ( S 2-(2-bromo-4-chlorophenoxy)propionic acid; ( S 2-(4-bromo-2-cyclopropylphenoxy)propionic acid; ( S 2-(4-bromo-2-styryloxy)propionic acid; ( S )-2-[4-chloro-2-(1-methyl-3-methyl-4-pyrazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-pyrazolyl)phenoxy]propionic acid; ( S )-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid; ( S 2-(2-cyclopropyl-4-fluorophenoxy)propionic acid; ( S )-2-[4-chloro-2-(1-methyl-4-pyrazolyl)phenoxy]propionic acid; ( S 2-(2-cyclobutyl-4-fluorophenoxy)propionic acid; ( S 2-(4-bromo-2-cyclobutylphenoxy)propionic acid; ( R 2-(4-bromo-2-fluorophenoxy)-3-fluoropropionic acid; ( S 2-(4-chloro-2-fluorophenoxy)-3-methylbutyric acid; ( S 2-(4-chloro-2-cyclobutylphenoxy)propionic acid; ( S )-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]propionic acid; ( R 2-(2-bromo-4-chlorophenoxy)-3-fluoropropionic acid; ( R 2-(p-chlorophenoxy)-3-fluoropropionic acid; ( R )-2-(4-chloro-2-fluorophenoxy)-3-fluoropropionic acid; ( R )-2-(2,4-dibromophenoxy)-3-fluoropropionic acid; ( S )-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid; ( R 2-(p-bromophenoxy)-3-fluoropropionic acid; ( S 2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid; ( S 2-(4-bromo-2-fluorophenoxy)propionic acid; ( S 2-(4-chloro-2-fluorophenoxy)propionic acid; ( S 2-(2,4-dibromophenoxy)propionic acid; ( S 2-(4-chloro-2-ethynylphenoxy)propionic acid; ( S 2-(4-chloro-2-styryloxy)propionic acid; ( S 2-(4-chloro-2-cyclopropylphenoxy)propionic acid; ( S 2-(p-chlorophenoxy)butyric acid; ( S Sodium 2-(2,4-dichlorophenoxy)propionate; ( S 2-(p-chlorophenoxy)-3-methylbutyric acid; ( S 2-(p-cyanophenoxy)propionic acid; ( S methyl 2-(p-bromophenoxy)propionate; ( S 2-(p-chlorophenoxy)butyrate methyl ester; ( S Isopropyl 2-(p-chlorophenoxy)propionate; ( S 2-(p-chlorophenoxy)propionate methyl ester, (2 S )-2-(4-bromo-2-fluorophenoxy)- N -{1-[(cyclopropylmethoxy)imino]ethyl}propionamide; (2 S )-2-(4-bromophenoxy)- N -[1-(methoxyimino)ethyl]propionamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -[(4-fluorophenyl)(hydroxyimino)methyl]-3-methylbutyramide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -[1-(hydroxyimino)ethyl]-3-methylbutyramide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -[1-(hydroxyimino)ethyl]propionamide; (2 S )-2-(4-bromophenoxy)- N -[1-(hydroxyimino)ethyl]acrylamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -Cyanopropionamide; (2 S )- N -Cyano-2-(2,4-dibromophenoxy)propionamide; (2 S )-2-(4-bromophenoxy)- N -Cyanopropionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyanopropionamide; (2 S )-2-(4-bromophenoxy)- N -Cyano-3-methylbutyramide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -Cyclobutoxypropionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -Methoxypropionamide; (2 S )- N -acetyl- N -[(1-acetylazetane-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylazetane-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -(azacyclobutane-3-yloxy)-2-(4-chlorophenoxy)propionamide; (2 S )- N -acetyl- N -[(1-acetylpyrrolidone-3-yl)methoxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylpyrrolidone-3-yl)methoxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-bromophenoxy)propionamide; N -(2-{[(2 S 2-(4-chlorophenoxy)propamido]oxy]propyl)carbamate tert-butyl ester; (2 S )- N -acetyl-2-(4-chlorophenoxy)- N -[(1-acetamidopropyl-2-yl)oxy]propionamide; (2 S )-2-(4-bromophenoxy)- N -(pyrrolidine-3-yloxy)propionamide; (2 S )- N -acetyl- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-bromophenoxy)propionamide; 3-{[(2 S 2-(4-chlorophenoxy)propamido]oxy}azacyclobutane-1-carboxylic acid tert-butyl ester; (2 S )-2-(4-chlorophenoxy)- N -[(pyrrolidone-3-yl)methoxy]propionamide; 3-({[(2 S 2-(4-chlorophenoxy)propamido]oxy}methyl)pyrrolidine-1-carboxylic acid tert-butyl ester; (2 S )- N -acetyl- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )- N -[(1-acetylpyrrolidone-3-yl)oxy]-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(pyrrolidine-3-yloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2,2-Dimethylpropyl)- N -Hydroxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-(pyrrolidone-1-yl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-(2-oxopyrrolidone-1-yl)ethoxy]propionamide; (2 S )- N -acetyl-2-(4-chlorophenoxy)- N -(2-acetamidoethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-acetamidoethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(4,4,4-trifluoro-2-methylbutoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(3-Cyclopentylpropyl)- N -Hydroxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -{[(2E)-2-methyl-3-phenylprop-2-en-1-yl]oxy}propionamide; (2 S )-2-(4-chlorophenoxy)- N -{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1-yl]ethoxy}propionamide; N -(2-{[(2 S 2-(4-chlorophenoxy)propamido]oxyethyl)carbamate tert-butyl ester; (2 S )-2-(4-chlorophenoxy)- N -[(2-methyl-1H-imidazol-4-yl)methoxy]propionamide; 4-({[(2 S 2-(4-chlorophenoxy)propamido]oxy}methyl)-2-methyl-1H-imidazol-1-carboxylic acid tert-butyl ester; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-bromophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-oxo-2-(pyrrolidone-1-yl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -[1-(4-fluorophenyl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -[1-(1,3-thiazolyl-2-yl)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -{1-[4-(trifluoromethyl)phenyl]ethoxy}propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-Methylsulfinylethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-Methanesulfonylethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(1,2-oxazol-3-yl)methoxy]propionamide; (2 S )-2-(4-chloro-2-fluorophenoxy)- N -Methoxypropionamide; (2 S )-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]- N -(cyclopropylmethoxy)propionamide; (2 S )-2-[4-chloro-2-(trifluoromethyl)phenoxy]- N -(cyclopropylmethoxy)propionamide; (2 S )- N -(tert-butoxy)-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[2-(methylthio)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -(1-Phenylacetyl)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(1-methyl-1H-imidazol-2-yl)methoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-methoxyethoxy)propionamide; (2 S )-2-(4-chloro-2-fluorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]- N -Methoxypropionamide; (2 S )-2-[4-chloro-2-(trifluoromethyl)phenoxy]- N -Methoxypropionamide; (2 S )- N -(benzyloxy)-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(2-methoxycyclopentyl)oxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxy-5-methylhexanoamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxy- N -Methylpropionamide; (2 S )-2-(4-chloro-2-methylphenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chloro-3-fluorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chloro-2-methylphenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chloro-3-fluorophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxy-4-methylpentanamide; (2 S )-2-(4-chlorophenoxy)- N -[(3-methylbut-2-en-1-yl)oxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxyhexylamide; (2 S )-2-(4-chlorophenoxy)- N -[(1,3-oxazol-2-yl)methoxy]propionamide; (2 S )-2-(2,4-dibromophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(oxane-2-yloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -[(1,3-thiazolyl-2-yl)methoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -(3,3-difluorocyclobutoxy)propionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]- N -Cyclobutoxypropionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(cyclopentyloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-Cyclopentylethoxy)propionamide; (2 S )-2-(4-bromo-2-chlorophenoxy)- N -Methoxypropionamide; (2 S )-2-(4-bromo-2-methylphenoxy)- N -Methoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(cyclopropylmethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -(cyclobutylmethoxy)propionamide; (2 S )- N -(2-aminoethoxy)-2-(4-chlorophenoxy)propionamide; (2 S )-2-(4-bromophenoxy)- N -Methoxy-3-methylbutyramide; 2-{[(2 S 2-(4-chlorophenoxy)propamido]oxy]methyl acetate; (2 S )-2-(4-chlorophenoxy)- N -[2-(2-methoxyethoxy)ethoxy]propionamide; (2 S )-2-(4-chlorophenoxy)- N -Cyclobutoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(2-hydroxyethoxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -Ethoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -Propoxypropionamide; (2 S )-2-(4-chlorophenoxy)- N -(prop-2-yloxy)propionamide; (2 S )-2-(4-chlorophenoxy)- N -Methoxypropionamide; (2 S )-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]- N -(cyclopropanesulfonyl)acrylamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -Methanesulfonylpropionamide; (2 S )-2-(4-bromo-2-fluorophenoxy)- N -(cyclopropanesulfonyl)acrylamide; (2 S )-2-(4-chlorophenoxy)- N -Methanesulfonylpropionamide; (2 S )-2-(4-bromophenoxy)- N -Methanesulfonyl-3-methylbutyramide; 5-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-fluoropropyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-fluorophenoxy)propyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-fluorophenoxy)-2-methylpropyl]-2H-1,2,3,4-tetraazole; 5-[(1 R )-1-(4-bromophenoxy)-2-fluoroethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromophenoxy)propyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromophenoxy)ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-cyclopropylphenoxy)ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-vinylphenoxy)ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-ethylphenoxy)ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chloro-2-methylphenoxy)ethyl]-2H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-chlorophenoxy)ethyl]-1H-1,2,3,4-tetraazole; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-thiadiazol-5-yl]acetamide; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-thiadiazol-5-yl]methanesulfonamide; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-thiadiazole-5-amine; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-oxadiazol-5-yl]acetamide; N -{3-[(1 S [1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-oxadiazol-5-yl]methanesulfonamide; 3-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-(trifluoromethyl)-4H-1,2,4-triazole; 3-[(1 S )-1-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-(trifluoromethyl)-4H-1,2,4-triazole; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-5-methoxy-1,2,4-oxadiazole; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-1,2,4-oxadiazole-5-amine; 3-[(1 S )-1-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-methyl-4H-1,2,4-triazole; 3-[(1 S )-1-[4-chloro-2-(1,2-oxazol-3-yl)phenoxy]ethyl]-5-methyl-4H-1,2,4-triazole; 3-[(1 S )-1-(4-bromo-2-fluorophenoxy)ethyl]-5-methyl-4H-1,2,4-triazole; 5-[(1 S )-1-(4-chlorophenoxy)ethyl]-1H-1,2,4-triazole; (2 S )-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]- N -Cyanopropionamide; (2 S )-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]- N -Cyanopropionamide; (2 S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]- N -Methanesulfonylpropionamide; (2 S )-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]- N -(cyclopropanesulfonyl)acrylamide; 5-[(1 S )-1-[4-bromo-2-(1,1-difluoroethyl)phenoxy]ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-[4-bromo-2-(1,1-difluoropropyl)phenoxy]ethyl]-1H-1,2,3,4-tetraazole; 5-[(1 S )-1-(4-bromo-2-cyclobutylphenoxy)-2-methoxyethyl]-1H-1,2,3,4-tetraazole; and 5-[(1 S )-1-(4-bromo-2-cyclopropylphenoxy)-2-methoxyethyl]-1H-1,2,3,4-tetraazole, Or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

16. A method for treating neuromuscular disorders: Multiple activations were performed on different muscle fibers of the same motor unit in the neuromuscular tissue of patients undergoing neuromuscular disease examinations. The number of paired successful action potentials is detected from the number of activations using medical equipment and recording electrodes; The patient’s presence of block or risk of block is determined by dividing the number of the paired successful action potentials by the total number of activations. as well as When the percentage of the number of paired successful action potentials relative to the total number of activations is below a threshold of 95%, the patient is given a ClC-1 inhibitor, wherein the administration of the ClC-1 inhibitor increases the percentage of the number of paired successful action potentials relative to the total number of activations by at least 5%.

17. The method of claim 16, wherein the ClC-1 inhibitor is a compound according to any one of claims 1 to 15.

18. The method of claim 16, wherein the method is used to treat, prevent and / or improve neuromuscular disorders.

19. The method of claim 16, wherein the neuromuscular disease is selected from one of the following: sarcopenia, myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle-specific kinase myasthenia gravis (MuSK-MG), Lambert-Eton syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie-Toos disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotube myopathy, Duchenne muscular dystrophy, Guillain-Barré syndrome, poliomyelitis, post-poliomyelitis syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disease, multiple sclerosis, and multifocal motor neuropathy.

20. The method of claim 19, wherein the neuromuscular disease is multiple sclerosis.

21. The method of claim 16, wherein administration of the ClC-1 inhibitor restores at least 5% of the contractile force of the patient's muscles.

22. The method of claim 16, wherein administration of the ClC-1 inhibitor reduces the incidence of neuromuscular junction transmission failure in the patient's muscles by at least 5%.

23. A method for treating neuromuscular disorders, comprising: Using medical equipment and recording electrodes, the time interval between two action potentials of the same motor unit in the neuromuscular tissue of patients undergoing examination for neuromuscular diseases is obtained; Determine whether the time interval change between two action potentials of the same motion unit exceeds or meets a threshold of 40 µs; as well as When the time interval between the two action potentials changes more than or meets the threshold, the patient is given a ClC-1 inhibitor, wherein the administration of the ClC-1 inhibitor reduces the time interval between the two action potentials between consecutive discharges by at least 10%.

24. The method of claim 23, wherein the ClC-1 inhibitor is a compound according to any one of claims 1 to 15.

25. The method of claim 23, wherein the method is used to treat, prevent and / or improve neuromuscular disorders.

26. The method of claim 25, wherein the neuromuscular disease is selected from one of the following: sarcopenia, myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle-specific kinase myasthenia gravis (MuSK-MG), Lambert-Eton syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie-Toos disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotube myopathy, Duchenne muscular dystrophy, Guillain-Barré syndrome, poliomyelitis, post-poliomyelitis syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disease, multiple sclerosis, and multifocal motor neuropathy.

27. The method of claim 26, wherein the neuromuscular disease is multiple sclerosis.

28. The method of claim 23, wherein administration of the ClC-1 inhibitor restores at least 5% of the contractile force of the patient's muscles.

29. The method of claim 23, wherein administration of the ClC-1 inhibitor reduces the incidence of neuromuscular junction transmission failure in the patient's muscles by at least 5%.

30. The method of claim 23, wherein single-fiber electromyography is used to measure the change in the time interval between two action potentials.

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