Kv7 regulator

Abstract

The present invention provides novel compounds that modulate the Kv7 potassium channel. Another aspect of the present invention relates to pharmaceutical compositions comprising the compound and to the use of the compound for treating disorders in response to activation of the Kv7 potassium channel.

Description

[Technical Field]

[0001] The present invention provides novel compounds that modulate the Kv7 potassium channel. Another aspect of the present invention relates to pharmaceutical compositions comprising the compound and to the use of the compound for treating disorders in response to activation of the Kv7 potassium channel. [Background technology]

[0002] The Kv7 channel responds to depolarization of the cell membrane potential by transmitting potassium ions (K) through the cell membrane. + It is a voltage-gated potassium channel that conducts K. The Kv7 channel family consists of five proteins, Kv7.1, Kv7.2, Kv7.3, Kv7.4, and Kv7.5, encoded by the human genes KCNQ1, KCNQ2, KCNQ3, KCNQ4, and KCNQ5, or their equivalent genes in rodents, dogs, or non-human primates. The Kv7 protein has a conventional Kv structure with six transmembrane helices (S1-S6) and its N and C termini are located intracellularly. Functional Kv7 channels are K + These subunits exist as homo- or heterotetrameric complexes surrounding conductive transmembrane pores. The functional heteromeric channels described are Kv7.2 / Kv7.3, Kv7.4 / Kv7.3, Kv7.5 / Kv7.3, and Kv7.4 / Kv7.5 (for a general review of Kv7, see Soldovieri et al., 2011; Physiology, 26, 365-376).

[0003] Kv7.2-Kv7.5 are detected in neurons of the central nervous system (CNS), with the Kv7.2 / Kv7.3 heteromeric channel playing a particularly important role, being persistent in the region of action potential initiation, and acetylcholine-sensitive K +Kv4 and Kv7.5-containing channels are active to electric currents and therefore form the basis of the so-called M-current (Brown and Adams, 1980; Nature, 283(5748), 673-676), which is the major conductance that controls neuronal excitability. The specific roles of Kv4 and Kv7.5-containing channels in the CNS do not appear to be clear, but they are widely expressed in terminal tissues such as smooth muscle cells, and Kv7.4 in particular is a potential off-target for developing Kv7 modulators for neuronal indications (Svaloe et al., 2011; Basic & Clinical Pharmacology & Toxicology, 110, 145-153). Kv7 channels are also expressed in primary sensory neurons and are thus targets for treating various pain symptoms. In contrast to Kv7 channels expressed in neurons, Kv7.1 is expressed mainly in cardiac cells and some epithelial cells, typically in complex with different KCNEβ-subunits.

[0004] The crucial role of Kv7.2 / Kv7.3 channels in regulating CNS neuronal excitability is well explained by mutations in both KCNQ2 and KCNQ3, which are strongly associated with neonatal or childhood epileptic disorders ranging from relatively benign, self-limiting cases to severe encephalopathy, whereas such associations are far less pronounced in Kv7.5 and almost absent in Kv7.4 (Maljevic and Lerche, 2014; Progress in Brain Research, 213, 17-53). Consequently, compounds that activate the action of neuronal Kv7 channels have long been known as antiepileptic and analgesic drugs, including retigabine, registered as a control agent for treatment-resistant focal epilepsy, and flupirtin, marketed as an analgesic in several countries, including Germany. Retigabin and flupirtin are chemically closely related analogs, and due to their unstable chemical structures (both aniline) and long-term toxicity, both have now been withdrawn from the market (Bock and Link, 2019; Future Med Chem, 11(4), 337-355). In addition to these chemical challenges, retigabine also exhibited side effects in both the CNS and peripheral tissues, with the risk of urinary retention being perhaps the most serious in susceptible patients (Brickel et al., 2012; Epilepsia, 53(4), 606-612). Retigabin was continued in a new phase 3 controlled study under the name Xen496 by Xenon Pharmaceuticals in children diagnosed with KCNQ2 encephalopathy, but these studies were terminated in May 2023 for reasons that remain unclear.

[0005] Activation of Kv7 is a clinically validated concept for both epilepsy and pain (there are currently no commercially available drugs), and there is great interest in developing new Kv7 activators based on alternative chemical scaffolds. Fortunately, the scientific and patent literature shows that other chemical substances can also act as Kv7 channel activators through their interaction with either the conventional retigabine activator site in the pore region (S5-6) or alternative sites in the voltage sensor domain (S1-4). The advantage of adding a new chemical scaffold is that it may enable better differentiation between Kv7 subtypes, potentially improving the efficacy and safety of the drug. Approximately one-third of epilepsy patients are still not adequately treated with existing drugs. Similarly, several chronic pain symptoms are poorly managed, contributing to the deepening opioid crisis in the United States. Thus, new treatment principles for these diseases are urgently needed, and improving Kv7 channel activating agents represents a potential step towards solving these health problems.

Summary of the Invention

[0006] In one aspect, the present disclosure provides a compound of formula (I):

Chemical Formula

[0007] In yet another embodiment, the present disclosure provides a pharmaceutical composition comprising the compounds described herein. In yet another embodiment, the present disclosure provides compounds described herein for use as pharmaceuticals. In yet another embodiment, the present disclosure provides a compound for use in a method for modulating the activity of a Kv7 channel in a subject, which includes administering an effective amount of the compound to the subject.

[0008] In yet another embodiment, the present disclosure provides a compound for use in a method that modulates the activity of Kv7.2 / Kv7.3 channels in a subject, which includes administering an effective amount of the compound to the subject. In yet another embodiment, the present disclosure provides compounds described herein for use in the treatment of epilepsy or pain.

[0009] definition As used herein, the term "alkyl" refers to the straight-chain or branched-chain hydrocarbon portion. As used herein, the term "alkoxy" refers to a group represented by the formula -O-alkyl, where alkyl is as described above. In particular, C 1- C3-alkoxy refers to a hydrocarbon having one, two, or three carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy. As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms, for example, one or more hydrogen atoms are replaced by F, Cl, Br, or I.

[0010] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic system. As used herein, the term "cycloalkyl" may also optionally include one or more unsaturated or substituted elements. The term "heteroatom" refers to sulfur, oxygen, or nitrogen. As used herein, the terms “heterocyclic formula” or “heterocyclic” refer to saturated or unsaturated aromatic or non-aromatic rings, either alone or in combination, that contain 3 to 20 ring atoms, where at least one ring atom is a heteroatom.

[0011] The terms "aromatic" or "aryl" refer to a cyclic or polycyclic part having a conjugated unsaturated (4η+2)π-electron system (where n is a positive integer), and are sometimes called a delocalized π-electron system. As used herein, the terms “heteroaromatic” or “heteroaryl” refer to aromatic heterocycles, which, individually or in combination, contain 5 to 12 atoms, of which 1, 2, or 3 ring atoms are heteroatoms. Heteroaryl groups include monocyclic or bicyclic systems. For example, as used herein, heteroaryls have 1 to 3 heteroatoms or heteroatomic groups in each ring, such as C 5- C10 Monocyclic or C 8- C 12 It may be a bicyclic aromatic ring system. Examples of heteroaryl groups include, but are not limited to, pyridinyl, thiazolyl, and indolyl groups.

[0012] The compounds used herein may contain one or more stereocenters. When referring to a chiral center or position, the term “stereochemical configuration” as used herein refers to the absolute configuration of the center, which may be R or S as determined by the Kahn-Ingold-Prelogue priority rule. A "heteromeric" channel or protein is an ion channel or protein composed of multiple different subunits. Some functional Kv7 channels exist in heterotetrameric complexes of subunits surrounding a K+-conducting transmembrane pore, such as the Kv7.2 / Kv7.3 heteromeric channel. As used herein, the term “agonism” in reference to the Kv7 channel means activation, enhancement, or strengthening of the Kv7 channel activity. [Modes for carrying out the invention]

[0013] In one embodiment, this disclosure relates to formula (I): [ka] [In formula; R 0 The group consisting of -OH and -CH3 is selected; R 1 R is one or more identical or different substituents 4 R may optionally be substituted with an aryl or one or more identical or different substituents. 4 It is a heteroaryl which may be substituted as desired; R 4 C may be optionally replaced with one or more Fs. 1-5 Alkyl, C 1-5 Selected from the group consisting of alkoxys, halogens, and CN; R2 It is selected from the group consisting of -H, -CH3, and -CF3; R 3 It is selected from the group consisting of -H and -OH; A is given by equation (II): [ka] (In the formula: A 1 CR 5 or N; R 5 is -H or halogen; A 2 CR 6 and; R 6 C may be optionally replaced with one or more Fs. 1-5 Alkoxy; C which may be optionally substituted with one or more F 1-5 alkyl; halogen; and N(R) 10 )(R 11 Selected from the group consisting of; R 10 R is one or more identical or different substituents 12 C may be replaced as desired. 1-5 It is alkyl; R 11 is -H; R 12 is halogen, C 3-5 Cycloalkyl and C 1-3 Selected from the group consisting of alkyl groups; A 3 CR 7 or N; R 7 -H, halogen and C 1-5 Selected from the group consisting of alkyl groups; A 4 CR 8 or N; R 8 -H, halogen, C 3-5 C which may optionally be substituted with cycloalkyl or one or more F 1-5 Alkyl, C 1-5Selected from the group consisting of alkoxy and -CN; A 5 CR 9 or N; R 9 (is -H or halogen) [The base shown by] The following provides compounds represented by [the specified symbol], or their tautomers, resonances, racemates, enantiomers or diastereomers, or mixtures thereof; or pharmaceutically acceptable salts thereof: However, the compound N-[1-(3,5-difluorophenyl)cyclopropyl]-β-methyl-1H-imidazole-1-propanamide; N-[1-(3-chlorophenyl)cyclopropyl]-β-hydroxybenzenepropanamide; N-[1-(3-fluorophenyl)cyclopropyl]-β-hydroxybenzenepropanamide; or 3-Fluoro-N-[1-(3-fluorophenyl)cyclopropyl]-β-hydroxybenzenepropanamide It is a compound other than those mentioned above.

[0014] Thus, in one embodiment, the compound is [ka] These are compounds other than those belonging to the group consisting of [the specified group].

[0015] In one embodiment, the compound is of formula (Ia): [ka] This is shown.

[0016] In one embodiment, the compound is of formula (Ib): [ka] This is shown.

[0017] In one embodiment, the compound has the formula (III): [Chemical Formula] as shown below.

[0018] In one embodiment, the compound has the formula (IIIa): [Chemical Formula] as shown below.

[0019] In one embodiment, the compound has the formula (IIIb): [Chemical Formula] as shown below.

[0020] In one embodiment, R 0 is OH. In one embodiment, R 0 is CH3. In one embodiment, R 1 is aryl optionally substituted with one or more identical or different substituents R 4 . In one embodiment, R 1 is aryl substituted with one or two identical or different substituents R 4 . In one embodiment, R 1 is phenyl optionally substituted with one or more identical or different substituents R 4 . In one embodiment, R 1 is phenyl substituted with 0 to 5 identical or different substituents R 4 , where R 4 is -F, -Cl, -OCH3, -CH3, -CN or -CF3. In one embodiment, R 1 is phenyl. In one embodiment, R 1 is phenyl substituted with one or more identical or different substituents R 4 . In one embodiment, R 1 is phenyl substituted with one R4 It is a phenyl substituted with R. In one embodiment, R 1 R is two identical or different substituents 4 It is a phenyl substituted with R. In one embodiment, R 1 R is one of three identical or different substituents. 4 It is a phenyl compound that is substituted with [a specific compound].

[0021] In one embodiment, R 1 R is one or more identical or different substituents 4 It is a heteroaryl which may be substituted as desired. In one embodiment, R 1 R has one or two identical or different substituents. 4 It is a heteroaryl that is substituted with. In one embodiment, the heteroaryl is pyridinyl. In one embodiment, the heteroaryl is pyridine-4-yl. In one embodiment, the heteroaryl is pyridine-2-yl. In one embodiment, the heteroaryl is pyridine-3-yl. In one embodiment, R 1 R is one or more identical or different substituents 4 It is a pyridinyl compound, which may be substituted as desired. In one embodiment, R 1 is pyridinyl. In one embodiment, R 1 R is one or more identical or different substituents 4 It is pyridine-2-yl, which may be substituted as desired. In one embodiment, R 1 is one R 4 It is pyridine-2-yl substituted with. In one embodiment, R 1 R is one or more identical or different substituents 4 Pyridine-3-yl, which may be substituted as desired. In one embodiment, R 1 is one R 4 It is pyridine-3-yl substituted with. In one embodiment, R 1 R is one or more identical or different substituents 4It is pyridine-4-yl, which may be substituted as desired. In one embodiment, R 1 is one R 4 It is pyridine-4-yl substituted with. In one embodiment, R 1 R has 0 to 5 identical or different substituents. 4 A pyridinyl substituted with, where R 4 These are -F, -Cl, -OCH3, -CH3, -CN, or -CF3.

[0022] In one embodiment, the heteroaryl is thiazolyl. In one embodiment, R 1 R is one or more identical or different substituents 4 Thiazolyl, which may be optionally substituted with R. In one embodiment, 1 R is one or more identical or different substituents 4 Thiazole-2-yl, which may be substituted as desired. In one embodiment, R 1 R is one or more identical or different substituents 4 Thiazole-5-yl, which may be substituted as desired. In one embodiment, R 1 R is one or more identical or different substituents 4 Thiazolyl is substituted with, where R 4 These are either halogens such as Cl, or C such as -CH3. 1-3 It is alkyl. In one embodiment, thiazolyl is thiazole-2-yl. In one embodiment, thiazolyl is thiazole-5-yl. In one embodiment, R 1 R is one or more identical or different substituents 4 Thiazole-2-yl, which may be substituted as desired. In one embodiment, R 1 R is one or more identical or different substituents 4 It is thiazole-5-yl, which may be substituted as desired. In one embodiment, the heteroaryl is indolyl. In one embodiment, the heteroaryl is indole-4-yl. In one embodiment, R1 R is one or more identical or different substituents 4 An indolyl which may be substituted as desired. In one embodiment, R 1 R is one or more identical or different substituents 4 Indole-4-yl, which may be substituted as desired. In one embodiment, R 1 R is one or more identical or different substituents 4 An indolyl which may be substituted as desired, where R 4 is C such as -CH3 1-3 It is alkyl. In one embodiment, R 1 R is one or more identical or different substituents 4 Indole-4-yl, which may be substituted as desired, where R 4 is C such as -CH3 1-3 It is alkyl.

[0023] In one embodiment, R 4 is a halogen. In one embodiment, R 4 is -F. In one embodiment, R 4 is -Cl. In one embodiment, R 4 is -Br. In one embodiment, R 4 is C 1-5 It is an alkoxy. In one embodiment, R 4 is C 1-3 It is an alkoxy. In one embodiment, R 4 is OCH3. In one embodiment, R 4 is C 1-5 It is alkyl. In one embodiment, R 4 is C 1-3 It is alkyl. In one embodiment, R 4 It is -CH3. In one embodiment, R 4 is -CN. In one embodiment, R 4 is -CF3. In one embodiment, R 4The group is independently selected from the group consisting of -F, -Cl, -Br, -OCH3, -CH3, -CN, and CF3.

[0024] In one embodiment, R 1 teeth: [ka] Selected from.

[0025] In one embodiment, R 1 teeth: [ka] Selected from.

[0026] In one embodiment, R 1 teeth [ka] That is the case.

[0027] In one embodiment, R 1 teeth [ka] That is the case.

[0028] In one embodiment, R 1 teeth [ka] That is the case.

[0029] In one embodiment, R 1 teeth [ka] That is the case.

[0030] In one embodiment, R 1 teeth [ka] That is the case.

[0031] In one embodiment, R 1 teeth [ka] That is the case.

[0032] In one embodiment, R 1 teeth [ka] That is the case.

[0033] In one embodiment, R 1 teeth [ka] That is the case.

[0034] In one embodiment, R 1 teeth [ka] That is the case.

[0035] In one embodiment, R 1 teeth [ka] That is the case.

[0036] In one embodiment, R 1 teeth [ka] That is the case.

[0037] In one embodiment, R 1 teeth [ka] That is the case.

[0038] In one embodiment, R 1 teeth [ka] That is the case.

[0039] In one embodiment, R 1 teeth [ka] That is the case.

[0040] In one embodiment, R 1 teeth [ka] That is the case.

[0041] In one embodiment, R 1 teeth [ka] That is the case.

[0042] In one embodiment, R 2 R is selected from the group consisting of -H, -CH3, and -CF3. In one embodiment, R 2 is a group other than H. In one embodiment, R 2 R is selected from the group consisting of -CH3 and -CF3. In one embodiment, R 2 is -CH3. In one embodiment, R 2 It is -CF3.

[0043] In one embodiment of this disclosure, R 2 If H, then at least 1 A 1 , A 3 and A 4 is a group other than -CH. In one embodiment, R 2 H is R 0 is OH. In one embodiment, R 2is -CH3, R 0 is OH. In one embodiment, R 2 is -CF3, R 0 is OH. In one embodiment, R 2 H is R 0 It is -CH3.

[0044] In one embodiment, R 3 is H. In one embodiment, R 3 is OH. In one embodiment, R 0 is -OH, and R 2 is -CH3, R 3 is -H. In one embodiment, A is R of one or more substituents. 5 , R 6 , R 7 , R 8 and / or R 9 It is a phenyl which may be optionally substituted. In one embodiment, A is R of one substituent. 5 , R 6 , R 7 , R 8 and / or R 9 It is phenyl, which may be optionally substituted. In one embodiment, A is R of two substituents. 5 , R 6 , R 7 , R 8 and / or R 9 It is a phenyl compound, which may be substituted as desired.

[0045] In one embodiment, A is R of one or more substituents. 5 , R 6 , R 7 , R 8 and / or R 9 A is a pyridinyl which may be optionally substituted. In one embodiment, A is R of one or more substituents. 5 , R 6 , R 7 , R 8 and / or R 9It is pyridine-2-yl, which may be optionally substituted. In one embodiment, A is R of one substituent. 5 , R 6 , R 7 , R 8 and / or R 9 Pyridine-2-yl, which may be optionally substituted. In one embodiment, A is R of two substituents. 5 , R 6 , R 7 , R 8 and / or R 9 It is pyridine-2-yl, which may be substituted as desired. In one embodiment, A is R of one or more substituents. 5 , R 6 , R 7 , R 8 and / or R 9 Pyridine-3-yl, which may be optionally substituted. In one embodiment, A is R with one substituent. 5 , R 6 , R 7 , R 8 and / or R 9 Pyridine-3-yl, which may be optionally substituted. In one embodiment, A is R of two substituents. 5 , R 6 , R 7 , R 8 and / or R 9 It is pyridine-3-yl, which may be substituted as desired.

[0046] In one embodiment, A is R of one or more substituents. 5 , R 6 , R 7 , R 8 and / or R 9 A pyrimidinyl which may be optionally substituted. In one embodiment, A R is one or more substituents 5 , R 6 , R 7 , R 8 and / or R 9It is pyrimidine-4-yl, which may be optionally substituted. In one embodiment, A is R with one substituent. 5 , R 6 , R 7 , R 8 and / or R 9 It is pyrimidine-4-yl, which may be substituted as desired. In one embodiment, A 1 CR 5 And; A 2 CR 6 And; A 3 CR 7 And; A 4 CR 8 And; A 5 CR 9 That is the case.

[0047] In one embodiment, at least one A 1 , A 3 and A 4 is a group other than -CH. In one embodiment of this disclosure, at least two A 1 , A 2 , A 3 and A 4 is a group other than -CH. In one embodiment, A 1 , A 3 , A 4 and A 5 is N. In one embodiment, A 1 is N and A 2 CR 6 And; A 3 CR 7 And; A 4 CR 8 And; A 5 CR 9 In one embodiment, A 1 CR 5 And; A 2 CR 6 And; A 3 is N and A 4 CR 8 And; A 5 CR 9In one embodiment, A 1 CR 5 And; A 2 CR 6 And; A 3 CR 7 And; A 4 is N and; A 5 CR 9 In one embodiment, A 1 is N and A 2 CR 6 And; A 3 is N and A 4 CR 8 And; A 5 CR 9 In one embodiment, A 1 CR 5 And; A 2 CR 6 And; A 3 CR 7 And; A 4 CR 8 And; A 5 It is N. In one embodiment, A 1 is N. In one embodiment, A 1 CR 5 In one embodiment, R 5 is H. In one embodiment, A 1 is C(H). In one embodiment, R 5 is a halogen. In one embodiment, R 5 is F. In one embodiment, A 1 C(F) is C(F).

[0048] In one embodiment, A 2 CR 6 And here R 6 C may be optionally replaced with one or more Fs. 1-5 Selected from alkoxy, -CF3, -CF2H, -Cl, -Br, or -CH3. In one embodiment, R 6 The group is selected from -CF3, -Cl, -Br, or -CH3. In one embodiment, A 2 CR 6 And here R 6 C may be optionally replaced with one or more Fs. 1-5 Alkoxy; C which may be optionally substituted with one or more F 1-5 Alkyl;halogen and N(R) 10 )(R 11 ) is selected from. In one embodiment, R 6 C may be optionally replaced with one or more Fs. 1-5 It is an alkoxy. In one embodiment, R 6 C may be optionally replaced with one or more Fs. 1-4 It is an alkoxy. In one embodiment, R 6 C may be optionally replaced with one or more Fs. 1-3 It is an alkoxy. In one embodiment, R 6 is a C1 alkoxy which may optionally be substituted with one or more F. In one embodiment, R 6 R is selected from -OCH2CF3, -OCF3, -OCH3, -OCH2CF2H and -OCF2H. In one embodiment, R 6 is -OCH3. In one embodiment, R 6 is -OCF3. In one embodiment, R 6 It is -OCH2CF3.

[0049] In one embodiment, R 6 C may be optionally replaced with one or more Fs. 1-5 It is alkyl. In one embodiment, R 6 C may be optionally replaced with one or more Fs. 1-3 It is alkyl. In one embodiment, R 6 is a C1 alkyl which may optionally be substituted with one or more F. In one embodiment, R 6 It is -CF3. In one embodiment, R 6 It is -CF2H. In one embodiment, R 6 is a halogen. In one embodiment, R 6 is Br. In one embodiment, R 6 is Cl. In one embodiment, R 6 It is F.

[0050] In one embodiment, R 6 is N(R 10 )(R 11 ) and here R 10 R is one or more identical or different substituents 12 C may be replaced as desired. 1-5 It is alkyl, R 11 is -H, and R 12 is halogen, C 3-5 Cycloalkyl and C 1-3 Selected from the group consisting of alkyl groups. In one embodiment, R 10 R is one or more identical or different substituents 12 C may be replaced as desired. 1-3 It is alkyl. In one embodiment, R 12 is a halogen. In one embodiment, R 12 is F. In one embodiment, R 10 is -CH2CF3. In one embodiment, R 6 is -N(H)(CH2CF3). In one embodiment, R 12 is C 3-5 It is cycloalkyl. In one embodiment, R 6 teeth [ka] In one embodiment, R 12 is C 1-3 It is alkyl. In one embodiment, R 12 is CH3. In one embodiment, R 10 is -CH2C(CH3)3. In one embodiment, R 6 is -N(H)CH2C(CH3)3. In one embodiment, R10 is -C(H)(CH3)2. In one embodiment, R 6 It is -N(H)C(H)(CH3)2.

[0051] In one embodiment, A 3 CR 7 And here R 7 -H, halogen and C 1-5 Selected from the group consisting of alkyl groups. In one embodiment, A 3 CR 7 And here R 7 R is selected from -H, -F, -Cl, and -CH3. In one embodiment, R 7 is -H. In one embodiment, A 3 is C(H). In one embodiment, R 7 is a halogen. In one embodiment, R 7 is -F. In one embodiment, R 7 is -Cl. In one embodiment, A 3 is C(F). In one embodiment, R 7 is C 1-5 It is alkyl. In one embodiment, R 7 is C 1-3 It is alkyl. In one embodiment, R 7 is -CH3. In one embodiment, A 3 It is N.

[0052] In one embodiment, A 4 CR 8 And here R 8 H, halogen, C 3-5 C which may optionally be substituted with cycloalkyl or one or more F 1-5 Alkyl, C 1-5 Selected from the group consisting of alkoxy and -CN. In one embodiment, A 4 CR 8 And here R 8 is -H, C 1-Selected from the group consisting of C5 cycloalkyl, -CN, -F, -Cl, -Br, and -CF2H. In one embodiment, A 4 CR 8 And here R 8 R is selected from the group consisting of -H, cyclopropyl, methoxy, -CN, -F, -Cl, -Br, and -CF2H. In one embodiment, R 8 R is selected from -H, -F, and -Cl. In one embodiment, R 8 is -H. In one embodiment, A 4 is C(H). In one embodiment, R 8 is -CN. In one embodiment, A 4 is C(CN). In one embodiment, R 8 is a halogen. In one embodiment, R 8 is F. In one embodiment, A 4 is C(F). In one embodiment, R 8 is -Br. In one embodiment, A 4 It is C(Br).

[0053] In one embodiment, R 8 is -Cl. In one embodiment, A 4 is C(Cl). In one embodiment, R 8 C may be optionally replaced with one or more Fs. 1-5 It is alkyl. In one embodiment, R 8 C may be optionally replaced with one or more Fs. 1-3 It is alkyl. In one embodiment, R 8 is a C1 alkyl which may optionally be substituted with one or more F. In one embodiment, R 8 is -CF2H. In one embodiment, A 4 is C(CF2H). In one embodiment, R 8 is -C 3- It is a C5 cycloalkyl. In one embodiment, R 8 A is cyclopropyl. In one embodiment, A 4is C (cyclopropyl). In one embodiment, R 8 is C 1-5 It is an alkoxy. In one embodiment, R 8 is C 1-3 It is an alkoxy. In one embodiment, R 8 is -OCH3. In one embodiment, A 4 is C(OCH3). In one embodiment, A 4 It is N.

[0054] In one embodiment, A 5 CR 9 And here R 9 is -H or halogen. In one embodiment, R 9 is -H or -F. In one embodiment, R 9 is -H. In one embodiment, A 5 is C(H). In one embodiment, R 9 is a halogen. In one embodiment, R 9 is -F. In one embodiment, A 5 is C(F). In one embodiment, A 5 It is N.

[0055] In one embodiment, A is [ka] That is the case.

[0056] In one embodiment, A is [ka] That is the case.

[0057] In one embodiment, A is [ka] That is the case.

[0058] In one embodiment, A is [ka] That is the case.

[0059] In one embodiment, A is [ka] That is the case.

[0060] In one embodiment, A is [ka] That is the case.

[0061] In one embodiment, A is [ka] That is the case.

[0062] In one embodiment, A is [ka] That is the case.

[0063] In one embodiment, A is [ka] That is the case.

[0064] In one embodiment, A is [ka] That is the case.

[0065] In one embodiment, A is [ka] That is the case.

[0066] In one embodiment, A is [ka] That is the case.

[0067] In one embodiment, A is [ka] That is the case.

[0068] In one embodiment, A is [ka] That is the case.

[0069] In one embodiment, A is [ka] That is the case.

[0070] In one embodiment, A is [ka] That is the case.

[0071] In one embodiment, A is [ka] That is the case.

[0072] In one embodiment, A is [ka] That is the case.

[0073] In one embodiment, A is [ka] That is the case.

[0074] In one embodiment, A is [ka] That is the case.

[0075] In one embodiment, A is [ka] That is the case.

[0076] In one embodiment, A is [ka] That is the case.

[0077] In one embodiment, A is [ka] That is the case.

[0078] In one embodiment, A is [ka] That is the case.

[0079] In one embodiment, A is [ka] That is the case.

[0080] In one embodiment, A is [ka] That is the case.

[0081] In one embodiment, A is [ka] That is the case.

[0082] In one embodiment, A is [ka] That is the case.

[0083] In one embodiment, A is [ka] That is the case.

[0084] In one embodiment, A is [ka] That is the case.

[0085] In one embodiment, A is [ka] That is the case.

[0086] In one embodiment, A is [ka] That is the case.

[0087] In one embodiment, R 0 is -OH, and R 1 R is a phenyl compound substituted with 2 or 3 -F atoms, 2 is -CH3, R 3 is -H, and A 1 CR 5 A 2 C(OCH2CF3) and A 3 CR 7 A 4 CR 8 And A 5 CR 9 And here, R of 1 5 , R 7 , R 8 , and R 9 is -F, -Cl, -Br, or -CH3, and the others are -H.

[0088] In one embodiment, R 0 is -OH, and R 1 teeth [ka] And R 2 is -CH3, R 3 is -H, and A 1 CR 5 A 2 C(OCH2CF3) and A 3 CR 7 A 4 CR 8 A 5 CR 9 And here R of 1 5 , R 7 , R 8 , and R 9 is -F, -Cl, -Br, or -CH3, and the others are -H.

[0089] In one embodiment, R 0 is -OH, and R 1 teeth [ka] And R 2 is -CH3, R 3 is -H, and A is [ka] That is the case.

[0090] In one embodiment, R 0 is -OH, and R 1 teeth [ka] And R 2 is -CH3, R 3 is -H, and A is [ka] That is the case.

[0091] In one embodiment, the stereochemical configurations at positions 2 and 3, as defined by formulas (I) and (III), are independently selected from R and S. In one embodiment, the stereochemical configuration at position 3, as defined by formulas (I) and (III), is R. In one embodiment, the stereochemical configuration at position 3, as defined by formulas (I) and (III), is S. In one embodiment, the stereochemical configuration at position 2, as defined by formulas (I) and (III), is R. In one embodiment, the stereochemical configuration at position 2, as defined by formulas (I) and (III), is S.

[0092] In some embodiments, the compounds are as shown in Table A. In one embodiment, the present invention relates to the compounds shown in Table A, or pharmaceutically acceptable salts thereof.

[0093] Table A. List of compounds [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

[0094] In one embodiment, the compound is: 3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-Hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, 3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide, 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide, 3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide, 3-Hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, 3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0095] 4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)-phenyl)-cyclopropyl)butanamide, N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide, 3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide,

[0096] N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide), N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide, N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide,

[0097] 3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide, and 3-Hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide or a pharmaceutically acceptable salt thereof Selected from the group consisting of .

[0098] In one embodiment, the compound of the present invention is: (R)-3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, (R)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide, (R)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide, (R)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide, (R)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)butanamide,

[0099] (R)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (R)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)butanamide, (R)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (R)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide,

[0100] (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide), (R)-N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide,

[0101] (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide, (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (R)-3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide, and (R)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide or a pharmaceutically acceptable salt thereof Selected from the group consisting of .

[0102] In one embodiment, the compound is: (S)-3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide, (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide, (S)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (S)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide,

[0103] (S)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide), (S)-N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide,

[0104] (S)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide, (S)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (S)-3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide, and (S)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide or a pharmaceutically acceptable salt thereof Selected from the group consisting of .

[0105] Kv7 regulation As demonstrated in the examples, the compounds of the present invention can generate Kv7 channel activation. Thus, the compounds described herein are useful in the modulation of Kv7 channels, including Kv7 agonism. In one embodiment, the compounds of the Disclosure can modulate the activity of a Kv7 channel. In one embodiment, the compounds can increase the activity of a Kv7.2 / Kv7.3 heteromeric channel.

[0106] The activity of a compound against the Kv7 channel may be evaluated through different in vitro assays in cells known in the field. For example, thallium ion (Tl + Examples include fluorescence assays of channel activity to evaluate ion influx, such as influx assays, or other fluorescence assays. Current examples are given as examples of Tl + This demonstrates an ion influx assay, and other types of channel assays will also be known to those skilled in the art.

[0107] In one embodiment, the compound increases the activity of the Kv7.2 / Kv7.3 heteromeric channel at EC levels of less than 50 μM, such as less than 20 μM, less than 10 μM, less than 1 μM, less than 0.1 μM, less than 0.06 μM, less than 0.01 μM, or less than 0.001 μM. 50 It can be generated using this method. In one embodiment, the compound increases the activity of the Kv7.2 / Kv7.3 heteromeric channel at EC levels of approximately 0.1 nM to 20 μM, such as approximately 0.1 nM to 10 μM, approximately 0.1 nM to 1 μM, approximately 0.1 nM to 0.2 μM, approximately 0.1 nM to 100 nM, and approximately 0.1 nM to 10 nM. 50 It can be generated using this method.

[0108] Thus, in one embodiment, the present disclosure provides compounds described herein for use in a method for modulating the activity of a Kv7 channel in a subject, the method comprising administering an effective amount of the compound to the subject. In one embodiment, the compound is intended for use in a method for increasing the activity of a Kv7.2 / Kv7.3 heteromeric channel in a subject.

[0109] In one embodiment, the compound can increase the activity of the Kv7.5 channel. In one embodiment, the compound can increase the activity of the Kv7.5 channel in EC2 concentrations of approximately 0.1 nM to approximately 20 μm, such as approximately 0.1 nM to approximately 10 μm, approximately 0.1 nM to approximately 1 μm, approximately 0.1 nM to approximately 0.2 μm, approximately 0.1 nM to approximately 100 nM, and approximately 0.1 nM to approximately 10 nM. 50 It can be produced by [method]. In one embodiment, the compound is intended for use in a method for increasing the activity of a Kv7.5 channel in a subject. In one embodiment, the compound is intended for use in a method for increasing the activity of the Kv7.5 channel in a subject.

[0110] Selective Kv7 adjustment In some cases, differences between Kv7 subtypes are desirable because these differences may provide improvements in the efficacy and safety of the drug. In some embodiments, the compound can selectively increase the activity of Kv7.2 / Kv7.3 heteromeric channels. In some embodiments, the compound is a subtype selective Kv7 regulator. In one embodiment, the compound is selective for Kv7.2 / Kv7.3. In some embodiments, the compound is more selective for Kv7.2 / Kv7.3 than for Kv7.5.

[0111] The selectivity of the compounds of the present invention for Kv7.2 / Kv7.3 over Kv7.5 can be observed in terms of efficacy selectivity, efficiency selectivity, or both. As used herein, the term "selective efficacy" refers to the EC of Kv7.2 / Kv7.3. 50 And, Kv7.5 EC 50 This means that the ratio between these two values ​​is greater than 10. In one embodiment, the ratio is given by the following formula:

number

[0112] In one embodiment, the compound has an EC of Kv7.2 / Kv7.3. 50 and Kv7.5 EC 50 The ratio between the two is greater than 2, such as 3, 5, 8, 10, 15, 20, 25, 30, 60, 75, 100, 150, 200, 230, 250, 500, etc. In one embodiment, the compound is EC7.2 / Kv7.3 50 And, Kv7.5 EC 50 The ratio between these two is greater than 10. In one embodiment, the EC of Kv7.5 50 The concentration exceeds 30 μM. In one embodiment, the compound has an EC of Kv7.2 / Kv7.3 50 The concentration is less than 10 μM, and the EC is less than 10 μM relative to Kv7.5. 50 The concentration exceeds 30 μM.

[0113] In one embodiment, EC 50This is measured by in vitro cell-type ion influx assays, such as the thallium ion (Tl+) assay. The term "efficacy selectivity" used here refers to the fact that, in relation to 10 μM retigabine, its efficacy is greater than 50% at Kv7.2 / Kv7.3 and less than 25% at Kv7.5.

[0114] In one embodiment, the compound has an efficacy of more than 50% against Kv7.2 / Kv7.3, such as more than 60%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 95%, more than 100%, or more than 110%. In one embodiment, the compound has an efficacy of less than 60% against Kv7.5, such as less than 50%, less than 40%, less than 30%, less than 20%, or 0%. In one embodiment, the compound has an efficacy of less than 25% against Kv7.5. In one embodiment, the compound has an efficacy of more than 50% against Kv7.2 / Kv7.3 and an efficacy of less than 25% against Kv7.5.

[0115] In one embodiment, the compound is potency-selective. In one embodiment, the compound is efficacy-selective. In one embodiment, the compound is potency-selective and efficacy-selective.

[0116] Manufacturing of compounds The compounds of the present invention can be produced according to any conventional chemical synthesis method known to those skilled in the art, for example, the method described in the examples. The starting materials for the method described herein can be readily produced from known or commercially available chemicals by conventional methods known to those skilled in the art.

[0117] The final products of the reactions described herein can be isolated by conventional techniques such as extraction, crystallization, distillation, and chromatography. Furthermore, the compounds of the present invention can be separated into different stereoisomers (R) and (S), respectively, using chiral chromatography such as chiral preparative HPLC.

[0118] The compounds of the present invention may exist in a non-solvated form and in a solvated form with pharmaceutically acceptable solvents such as water and ethanol. Generally, the solvated form is considered equivalent to the non-solvated form in order to achieve the objectives of the present invention.

[0119] Medicinally acceptable salts The compounds of the present invention may be provided in any form suitable for the intended administration, including pharmaceutically acceptable (i.e., pharmacologically) salts. Such salts are well known in the art and can be formed by the operations described herein.

[0120] Pharmaceutical composition The present invention also relates to a pharmaceutical composition comprising, for example, a pharmaceutically effective amount of the compound of formula (I) described above as an active ingredient. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier, excipient, or diluent.

[0121] The compounds of formula (I) of the present invention for use in therapy may be administered in the form of the raw material compounds, but it is preferable to introduce the active ingredient into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other conventional pharmaceutical adjuvants, which may optionally be in the form of physiologically acceptable salts.

[0122] In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, which may optionally also contain other therapeutic and / or prophylactic components known and used in the art. The carriers must be "acceptable" in the sense that they are compatible with the other components of the formulation and are not harmful to their recipients.

[0123] A medicinally effective dose refers to the amount of the active ingredient that improves a symptom or condition. This includes therapeutic efficacy and toxicity, such as ED. 50This can be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose-to-toxicity ratio is the therapeutic index, which can be expressed as the ratio between the plasma level that produces the therapeutic effect and the plasma level that produces the toxic effect. Pharmaceutical compositions exhibiting a large therapeutic index are preferred.

[0124] The dosage administered may be adjusted according to the age, weight, and condition of the patient being treated, as well as the route of administration, dosage form and regimen, and the desired outcome, and the exact dosage may be determined by a physician.

[0125] Pharmaceutical use Given the activity of the compound in the Kv7 channel, the compounds of this disclosure may be useful in treating symptoms associated with Kv7 modulation. Examples demonstrate that the compounds of this disclosure produce an effect in the Kv7 channel similar to that of the compound retigabine. Thus, in one embodiment, this disclosure provides a pharmaceutical composition comprising the compound described herein. For example, the pharmaceutical composition may comprise one or more excipients known in the art.

[0126] In yet another embodiment, the present disclosure provides compounds described herein for use as pharmaceuticals. In yet another embodiment, the Disclosure provides a compound described herein for use in a method for treating a condition selected from epilepsy or pain in a subject, the method comprising administering a therapeutically effective amount of the compound described herein to the subject.

[0127] In yet another embodiment, the present disclosure provides a method for treating epilepsy or pain in a subject requiring treatment, comprising administering a therapeutically effective amount of a compound described herein to the subject. In yet another embodiment, the Disclosure provides the use of the compounds described herein in the manufacture of a pharmaceutical product for the treatment of epilepsy or pain in a subject requiring treatment.

[0128] item 1. Equation (I): [ka] [In formula: R 0 It is selected from the group consisting of -OH and -CH3; R 1 R is one or more identical or different substituents 4 R may optionally be substituted with an aryl or one or more identical or different substituents. 4 It is a heteroaryl which may be substituted as desired; R 4 C may be optionally replaced with one or more Fs. 1-5 Alkyl, C 1-5 Selected from the group consisting of alkoxys, halogens, and CN; R 2 It is selected from the group consisting of -H, -CH3, and -CF3; R 3 It is selected from the group consisting of -H and -OH; A is given by equation (II): [ka] (In the formula: A 1 CR 5 or N; R 5 is -H or halogen; A 2 CR 6 and; R 6 C may be optionally replaced with one or more Fs. 1-5 Alkoxy; C which may be optionally substituted with one or more F 1-5 alkyl; halogen; and N(R) 10 )(R 11 Selected from the group consisting of; R 10 R is one or more identical or different substituents 12 C may be replaced as desired. 1-5It is alkyl; R 11 is -H; R 12 is halogen, C 3-5 Cycloalkyl and C 1-3 Selected from the group consisting of alkyl groups; A 3 CR 7 or N; R 7 -H, halogen and C 1-5 Selected from the group consisting of alkyl groups; A 4 CR 8 or N; R 8 -H, halogen, C 3-5 C which may optionally be substituted with cycloalkyl or one or more F 1-5 Alkyl, C 1-5 Selected from the group consisting of alkoxy and -CN; A 5 CR 9 or N; R 9 (is -H or halogen) [The base shown by] Compounds represented by, or their tautomers, resonances, racemates, enantiomers or diastereomers, or mixtures thereof; or pharmaceutically acceptable salts thereof; However, the compound N-[1-(3,5-difluorophenyl)cyclopropyl]-β-methyl-1H-imidazole-1-propanamide; N-[1-(3-chlorophenyl)cyclopropyl]-β-hydroxybenzenepropanamide; N-[1-(3-fluorophenyl)cyclopropyl]-β-hydroxybenzenepropanamide; or 3-Fluoro-N-[1-(3-fluorophenyl)cyclopropyl]-β-hydroxybenzenepropanamide It is a compound other than those mentioned above.

[0129] 2. Equation (Ia): [ka] The compound listed in item 1 shown.

[0130] 3. Formula (Ib): [ka] The compound listed in item 1 shown.

[0131] 4. Formula (III): [ka] The compound listed in item 1 shown.

[0132] 5. Formula (IIIa): [ka] The compound listed in item 1 shown.

[0133] 6. Formula (IIIb): [ka] The compound listed in item 1 shown.

[0134] 7. R 0 A compound described in any one of the above items, wherein the hydroxyl group (OH) is -OH. 8. R 0 A compound described in any one of the above items, wherein the group is -CH3. 9. R 1 R is one or more identical or different substituents 4 A compound according to any one of the above items, wherein the compound is an aryl which may be substituted as desired. 10. R 1 However, R has one or two identical or different substituents. 4 A compound described in any one of the above items, which is an aryl substituted with. 11. R 1However, R of one or more identical or different substituents 4 A compound according to any one of the above items, which is phenyl, which may be substituted as desired.

[0135] 12. R 1 A compound described in any one of the above items, wherein the compound is phenyl. 13. R 1 However, R of one or more identical or different substituents 4 A compound described in any one of the above items, which is phenyl substituted with. 14. R 1 However, one R 4 A compound described in any one of the above items, which is a phenyl substituted with. 15. R 1 However, two identical or different substituents R 4 A compound described in any one of the above items, which is phenyl substituted with. 16. R 1 However, the R of three identical or different substituents 4 A compound described in any one of the above items, which is phenyl substituted with.

[0136] 17. R 1 R is one or more identical or different substituents 4 A compound according to any one of the above items, which is a heteroaryl that may be optionally substituted. 18. R 1 However, R has one or two identical or different substituents. 4 A compound described in any one of the above items, which is a heteroaryl substituted with [the specified compound]. 19. A compound according to any one of the above items, wherein the heteroaryl group is pyridinyl. 20. A compound according to any one of the above items, wherein the heteroaryl is pyridine-4-yl. 21. A compound according to any one of the above items, wherein the heteroaryl is pyridine-2-yl.

[0137] 22. A compound according to any one of the above items, wherein the heteroaryl is pyridine-3-yl. 23. R 1 However, R of one or more identical or different substituents 4 A compound according to any one of the above items, which is a pyridinyl compound, which may be optionally substituted. 24. R 1 A compound described in any one of the above items, wherein the compound is pyridinyl. 25. R 1 However, R of one or more identical or different substituents 4 The compound according to any one of the above items, which is pyridine-2-yl, which may be substituted as desired. 26. R 1 is one R 4 A compound described in any one of the above items, which is pyridine-2-yl substituted with.

[0138] 27. R 1 However, R of one or more identical or different substituents 4 The compound according to any one of the above items, which is pyridine-3-yl, which may be substituted as desired. 28. R 1 is one R 4 A compound described in any one of the above items, which is pyridine-3-yl substituted with. 29. R 1 However, R of one or more identical or different substituents 4 The compound according to any one of the above items, which is pyridine-4-yl, which may be substituted as desired. 30. R 1 is one R 4 A compound described in any one of the above items, which is pyridine-4-yl substituted with. 31. A compound described in any one of the above items, wherein the heteroaryl is thiazolyl. 32. R 1 However, R of one or more identical or different substituents 4A compound according to any one of the above items, which is thiazolyl, which may be substituted as desired.

[0139] 33. R 1 However, R of one or more identical or different substituents 4 A compound according to any one of the above items, which is thiazole-2-yl, which may be substituted as desired. 34. R 1 However, R of one or more identical or different substituents 4 A compound according to any one of the above items, which is thiazole-5-yl, which may be substituted as desired. 35. R 1 However, R of one or more identical or different substituents 4 Thiazolyl is substituted with, where R 4 However, independently, halogens such as Cl, or C such as -CH3 1-3 A compound that is alkyl, as described in any one of the above items. 36. A compound according to any one of the above items, wherein thiazolyl is thiazol-2-yl. 37. A compound according to any one of the above items, wherein thiazolyl is thiazol-5-yl. 38. R 1 However, R of one or more identical or different substituents 4 A compound according to any one of the above items, which is thiazole-2-yl, which may be substituted as desired.

[0140] 39. R 1 However, R of one or more identical or different substituents 4 A compound according to any one of the above items, which is thiazole-5-yl, which may be substituted as desired. 40. A compound described in any one of the above items, wherein the heteroaryl is indolyl. 41. A compound according to any one of the above items, wherein the heteroaryl is indole-4-yl. 42. R 1However, R of one or more identical or different substituents 4 A compound according to any one of the above items, which is an indolyl and may be substituted as desired.

[0141] 43. R 1 However, R of one or more identical or different substituents 4 The compound according to any one of the above items, which is indole-4-yl, which may be substituted as desired. 44. R 1 However, R of one or more identical or different substituents 4 An indolyl which may be substituted as desired, where R 4 C such as -CH3 1-3 A compound that is alkyl, as described in any one of the above items. 45. R 1 However, R of one or more identical or different substituents 4 Indole-4-yl, which may be substituted as desired, where R 4 C such as CH3 1-3 A compound that is alkyl, as described in any one of the above items.

[0142] 46. ​​One or more R 4 A compound that is a halogen, as described in any one of the above items. 47. One or more R 4 A compound described in any one of the above items, wherein the compound is -F. 48. One or more R 4 A compound described in any one of the above items, wherein -Cl. 49. One or more R 4 A compound described in any one of the above items, wherein -Br. 50 One or more R 4 C 1-5 A compound that is an alkoxy, as described in any one of the above items. 51. One or more R 4 C 1-3 A compound that is an alkoxy, as described in any one of the above items. 52. One or more R 4 A compound described in any one of the above items, wherein OCH3 is present. 53. One or more R 4 C 1-5 A compound that is alkyl, as described in any one of the above items. 54. One or more R 4 C 1-3 A compound that is alkyl, as described in any one of the above items.

[0143] 55. One or more R 4 A compound described in any one of the above items, wherein the group is -CH3. 56. One or more R 4 A compound described in any one of the above items, wherein -CN. 57. One or more R 4 A compound described in any one of the above items, wherein the compound is -CF3. 58. R 4 However, the compound is independently selected from the group consisting of -F, -Cl, -Br, -OCH3, -CH3, -CN, and CF3, and is one of the compounds described in any one of the above items.

[0144] 59. R 1 but, [ka] A compound selected from any one of the above items.

[0145] 60. R 1 but, [ka] A compound selected from any one of the above items.

[0146] 61. R 1 but [ka] The compound described in any one of the above items.

[0147] 62. R 1 but [ka] The compound described in any one of the above items.

[0148] 63. R 1 but [ka] The compound described in any one of the above items.

[0149] 64. R 1 but [ka] The compound described in any one of the above items.

[0150] 65. R 1 but [ka] The compound described in any one of the above items.

[0151] 66. R 1 but [ka] The compound described in any one of the above items.

[0152] 67. R 1 but [ka] The compound described in any one of the above items.

[0153] 68. R 1 but [ka] The compound described in any one of the above items.

[0154] 69. R 1 but [ka] The compound described in any one of the above items.

[0155] 70. R 1 but [ka] The compound described in any one of the above items.

[0156] 71. R 1 but [ka] The compound described in any one of the above items.

[0157] 72. R 1 but [ka] The compound described in any one of the above items.

[0158] 73. R 1 but [ka] The compound described in any one of the above items.

[0159] 74. R 1 but [ka] The compound described in any one of the above items.

[0160] 75. R 1 but [ka] The compound described in any one of the above items.

[0161] 76. R 1 but [ka] The compound described in any one of the above items.

[0162] 77. R 2 The compound is selected from the group consisting of -H, -CH3, and -CF3, and is one of the compounds described in any one of the above items. 78. R 2 A compound according to any one of the above items, wherein the group is anything other than H. 79. R 2 A compound according to any one of the above items, wherein -CH3 and -CF3 are selected. 80. R 2 A compound described in any one of the above items, wherein the group is -CH3. 81. R 2 A compound described in any one of the above items, wherein the compound is -CF3. 82. R 2 If H, then at least 1 A 1 , A 3 and A 4 The compound is any one of the items listed above, wherein the group is not -CH.

[0163] 83. R 2 is -CH3, R 0 A compound described in any one of the above items, wherein the OH group is OH. 84. R 2 is -CF3, R 0 A compound described in any one of the above items, wherein the OH group is OH. 85. R 2 H is R 0A compound described in any one of the above items, wherein the OH group is OH. 86. R 2 H is R 0 A compound described in any one of the above items, wherein the group is -CH3. 87. R 3 A compound described in any one of the above items, wherein the element is H. 88. R 3 A compound described in any one of the above items, wherein the OH group is OH. 89. R 0 is -OH, and R 2 is -CH3, R 3 A compound described in any one of the above items, wherein -H.

[0164] 90. A is R of one or more substituents. 5 , R 6 , R 7 , R 8 and / or R 9 A compound according to any one of the above items, which is phenyl, which may be substituted as desired. 91. A has one substituent R 5 , R 6 , R 7 , R 8 and / or R 9 A compound according to any one of the above items, which is phenyl, which may be substituted as desired. 92. A has two substituents R 5 , R 6 , R 7 , R 8 and / or R 9 A compound according to any one of the above items, which is phenyl, which may be substituted as desired. 93. A is R of one or more substituents. 5 , R 6 , R 7 , R 8 and / or R 9 A compound according to any one of the above items, which is a pyridinyl compound, which may be optionally substituted. 94. A is R of one or more substituents.5 , R 6 , R 7 , R 8 and / or R 9 The compound according to any one of the above items, which is pyridine-2-yl, which may be substituted as desired. 95. A is R with one substituent. 5 , R 6 , R 7 , R 8 and / or R 9 The compound according to any one of the above items, which is pyridine-2-yl, which may be substituted as desired.

[0165] 96. A has two substituents R 5 , R 6 , R 7 , R 8 and / or R 9 The compound according to any one of the above items, which is pyridine-2-yl, which may be substituted as desired. 97. A is R of one or more substituents. 5 , R 6 , R 7 , R 8 and / or R 9 The compound according to any one of the above items, which is pyridine-3-yl, which may be substituted as desired. 98. A has one substituent R 5 , R 6 , R 7 , R 8 and / or R 9 The compound according to any one of the above items, which is pyridine-3-yl, which may be substituted as desired. 99. A has two substituents R 5 , R 6 , R 7 , R 8 and / or R 9 The compound according to any one of the above items, which is pyridine-3-yl, which may be substituted as desired. 100. A is R of one or more substituents. 5 , R 6 , R7 , R 8 and / or R 9 A compound according to any one of the above items, which is a pyrimidinyl and may be optionally substituted.

[0166] 101. A is R of one or more substituents. 5 , R 6 , R 7 , R 8 and / or R 9 A compound according to any one of the above items, which is pyrimidine-4-yl, which may be substituted as desired. 102. A is R with one substituent. 5 , R 6 , R 7 , R 8 and / or R 9 A compound according to any one of the above items, which is pyrimidine-4-yl, which may be substituted as desired. 103. A 1 CR 5 And; A 2 CR 6 And; A 3 CR 7 And; A 4 CR 8 And; A 5 CR 9 The compound described in any one of the above items. 104. At least 1 A 1 , A 3 and A 4 A compound described in any one of the above items, wherein the group is anything other than -CH. 105. 1A 1 , A 3 , A 4 , and A 5 A compound described in any one of the above items, wherein N is present.

[0167] 106. A 1 N is A 2 CR 6 And; A 3 CR 7 And; A4 CR 8 And; A 5 CR 9 The compound described in any one of the above items. 107. A 1 CR 5 And; A 2 CR 6 And; A 3 N is A 4 CR 8 And; A 5 CR 9 The compound described in any one of the above items. 108. A 1 CR 5 And; A 2 CR 6 And; A 3 CR 7 And; A 4 N is A 5 CR 9 The compound described in any one of the above items. 109. A 1 N is A 2 CR 6 And; A 3 N is A 4 CR 8 And; A 5 CR 9 The compound described in any one of the above items. 110. A 1 CR 5 And; A 2 CR 6 And; A 3 CR 7 And; A 4 CR 8 And; A 5 A compound described in any one of the above items, wherein N is present.

[0168] 111. A 1 A compound described in any one of the above items, wherein N is present. 112. A 1 CR 5The compound described in any one of the above items. 113. R 5 A compound described in any one of the above items, wherein the element is H. 114. A 1 A compound described in any one of the above items, wherein the parent element is C(H). 115. R 5 A compound that is a halogen, as described in any one of the above items. 116. R 5 A compound described in any one of the above items, wherein F is present. 117. A 1 A compound described in any one of the above items, wherein C(F).

[0169] 118. A 2 CR 6 And here R 6 However, C may be optionally replaced with one or more Fs. 1-5 Selected from alkoxy, -CF3, -CF2H, -Cl, -Br, or -CH3, or R 6 However, the compound is selected from -CF3, -Cl, -Br, or -CH3, as described in any one of the above items. 119. A 2 CR 6 And here R 6 However, C may be optionally replaced with one or more Fs. 1-5 Alkoxy; C which may be optionally substituted with one or more F 1-5 Alkyl;halogen and N(R) 10 )(R 11 A compound selected from any one of the above items.

[0170] 120. R 6 However, C may be optionally replaced with one or more Fs. 1-5 A compound that is an alkoxy, as described in any one of the above items. 121. R 6 However, C may be optionally replaced with one or more Fs. 1-4A compound that is an alkoxy, as described in any one of the above items. 122. R 6 However, C may be optionally replaced with one or more Fs. 1-3 A compound that is an alkoxy, as described in any one of the above items. 123. R 6 The compound according to any one of the above items, wherein the compound is a C1 alkoxy which may optionally be substituted with one or more F. 124. R 6 However, the compound is selected from -OCH2CF3, -OCF3, -OCH3, -OCH2CF2H, and -OCF2H, as described in any one of the above items. 125. R 6 A compound according to any one of the above items, wherein the group is -O-CH2CF3.

[0171] 126. R 6 A compound described in any one of the above items, wherein -OCH3. 127. R 12 A compound described in any one of the above items, wherein the compound is -CF3. 128. R 6 However, C may be optionally replaced with one or more Fs. 1-5 A compound that is alkyl, as described in any one of the above items. 129. R 6 However, C may be optionally replaced with one or more Fs. 1-3 A compound that is alkyl, as described in any one of the above items. 130. R 6 The compound according to any one of the above items, wherein the compound is a C1 alkyl group which may optionally be substituted with one or more F groups.

[0172] 131. R 6 A compound described in any one of the above items, wherein the compound is -CF3. 132. R 6 A compound described in any one of the above items, wherein is -CF2H. 133. R 6A compound that is a halogen, as described in any one of the above items. 134. R 6 A compound listed in any one of the above items, wherein Br is present. 135. R 6 A compound listed in any one of the above items, wherein the compound is Cl.

[0173] 136. R 6 A compound described in any one of the above items, wherein F is present. 137. R 6 A compound described in any one of the above items, wherein the compound is -OCF3. 138. R 6 A compound according to any one of the above items, wherein -OCH2CF3.

[0174] 139. R 6 ga-N(R 10 )(R 11 ) and here R 10 R is one or more identical or different substituents 12 C may be replaced as desired. 1-5 It is alkyl, R 11 is -H, R 12 However, halogen, C 3-5 Cycloalkyl and C 1-3 A compound selected from the group consisting of alkyl groups, as described in any one of the above items. 140. R 10 However, R of one or more identical or different substituents 12 C may be substituted as desired. 1-3 A compound that is alkyl, as described in any one of the above items. 141. R 12 A compound that is a halogen, as described in any one of the above items. 142. R 12 A compound described in any one of the above items, wherein F is present.

[0175] 143. R 10 A compound according to any one of the above items, wherein -CH2CF3. 144. R 6 A compound described in any one of the above items, wherein the group is -N(H)(CH2CF3). 145. R 12 C 3-5 A compound that is a cycloalkyl compound, as described in any one of the above items. 146. R 12 A compound according to any one of the above items, wherein the compound is cyclopropyl.

[0176] 147. R 10 but [ka] The compound described in any one of the above items.

[0177] 148. R 6 but [ka] The compound described in any one of the above items.

[0178] 149. R 12 C 1-3 A compound that is alkyl, as described in any one of the above items. 150. R 12 A compound described in any one of the above items, wherein the parent group is CH3. 151. R 10 A compound described in any one of the above items, wherein the parent compound is -CH2C(CH3)3. 152. R 6 A compound described in any one of the above items, wherein the parent compound is -N(H)CH2C(CH3)3. 153. R 10 A compound described in any one of the above items, wherein the compound is -C(H)(CH3)2. 154. R 6 A compound described in any one of the above items, wherein the compound is -N(H)C(H)(CH3)2. 155. A 3 CR 7where R 7 is selected from the group consisting of -H, halogen and C 1-5 alkyl, and the compound according to any one of the above items.

[0179] 156. A 3 is C-R 7 where R 7 is selected from -H, -F, -Cl, and -CH3, and the compound according to any one of the above items. 157. R 7 is -H, and the compound according to any one of the above items. 158. A 3 is C(H), and the compound according to any one of the above items. 159. R 7 is halogen, and the compound according to any one of the above items. 160. R 7 is -F, and the compound according to any one of the above items.

[0180] 161. R 7 is -Cl, and the compound according to any one of the above items. 162. A 3 is C(F), and the compound according to any one of the above items. 163. R 7 is C 1-5 alkyl, and the compound according to any one of the above items. 164. R 7 is C 1-3 alkyl, and the compound according to any one of the above items. 165. R 7 is -CH3, and the compound according to any one of the above items.

[0181] 166. A 3 is N, and the compound according to any one of the above items. 167. A 4 is C-R 8 where; R 8 is H, halogen, C3-5 C which may optionally be substituted with cycloalkyl or one or more F 1-5 Alkyl, C 1-5 A compound selected from the group consisting of alkoxy and -CN, as described in any one of the above items. 168. A 4 CR 8 And here R 8 However, -H, C 1- A compound selected from the group consisting of C5 cycloalkyl, -CN, -F, -Cl, -Br, and -CF2H, as described in any one of the above items. 169. A 4 CR 8 And here R 8 The compound is selected from the group consisting of -H, cyclopropyl, methoxy, -CN, -F, -Cl, -Br, and -CF2H, as described in any one of the above items. 170. R 8 A compound according to any one of the above items, wherein is selected from -H, -F, and -Cl.

[0182] 171. R 8 A compound described in any one of the above items, wherein -H. 172. A 4 A compound described in any one of the above items, wherein the parent element is C(H). 173. R 8 A compound described in any one of the above items, wherein -CN. 174. A 4 A compound described in any one of the above items, wherein the element is C(CN). 175. R 8 A compound that is a halogen, as described in any one of the above items. 176. R 8 A compound described in any one of the above items, wherein F is present. 177. A 4 A compound described in any one of the above items, wherein C(F). 178. R 8 A compound described in any one of the above items, wherein -Br. 179. A 4 A compound listed in any one of the above items, wherein the compound is C(Br). 180. R 8 A compound described in any one of the above items, wherein -Cl.

[0183] 181. A 4 A compound described in any one of the above items, wherein the compound is C(Cl). 182. R 8 However, C may be optionally replaced with one or more Fs. 1-5 A compound that is alkyl, as described in any one of the above items. 183. R 8 However, C may be optionally replaced with one or more Fs. 1-3 A compound that is alkyl, as described in any one of the above items. 184. R 8 The compound according to any one of the above items, wherein the compound is a C1 alkyl group which may optionally be substituted with one or more F groups. 185. R 8 A compound described in any one of the above items, wherein is -CF2H. 186. A 4 A compound described in any one of the above items, wherein the parent compound is C(CF2H). 187. R 8 ga-C 3- A compound that is a C5 cycloalkyl group, as described in any one of the above items. 188. R 8 A compound according to any one of the above items, wherein the compound is cyclopropyl. 189. A 4 A compound described in any one of the above items, wherein C is cyclopropyl. 190. R 8 C 1-5 A compound that is an alkoxy, as described in any one of the above items.

[0184] 191. R 8 C 1-3The compound according to any one of the above items, which is an alkoxy. 192. R 8 The compound according to any one of the above items, wherein R is -OCH3. 193. A 4 The compound according to any one of the above items, wherein A is C(OCH3). 194. A 4 The compound according to any one of the above items, wherein A is N. 195. A 5 A is C-R 9 where R 9 is -H or -halogen, the compound according to any one of the above items. 196. A 5 A is C-R 9 where R 9 is -H or -F, the compound according to any one of the above items. 197. R 9 The compound according to any one of the above items, wherein R is -H. 198. A 5 The compound according to any one of the above items, wherein A is C(H). 199. R 9 The compound according to any one of the above items, wherein R is -halogen. 200. R 9 The compound according to any one of the above items, wherein R is -F.

[0185] 201. A 5 The compound according to any one of the above items, wherein A is C(F). 202. A 5 The compound according to any one of the above items, wherein A is N.

[0186] 203. A is

Chemical formula

[0187] 204. A is [ka] The compound described in any one of the above items.

[0188] 205. A [ka] The compound described in any one of the above items.

[0189] 206. A [ka] The compound described in any one of the above items.

[0190] 207. A [ka] The compound described in any one of the above items.

[0191] 208. A [ka] The compound described in any one of the above items.

[0192] 209. A [ka] The compound described in any one of the above items.

[0193] 210.A is [ka] The compound described in any one of the above items.

[0194] 211. A [ka] The compound described in any one of the above items.

[0195] 212. A [ka] The compound described in any one of the above items.

[0196] 213. A [ka] The compound described in any one of the above items.

[0197] 214. A [ka] The compound described in any one of the above items.

[0198] 215. A [ka] The compound described in any one of the above items.

[0199] 216. A [ka] The compound described in any one of the above items.

[0200] 217. A [ka] The compound described in any one of the above items.

[0201] 218. A [ka] The compound described in any one of the above items.

[0202] 219. A [ka] The compound described in any one of the above items.

[0203] 220. A [ka] The compound described in any one of the above items.

[0204] 221. A [ka] The compound described in any one of the above items.

[0205] 222. A [ka] The compound described in any one of the above items.

[0206] 223. A [ka] The compound described in any one of the above items.

[0207] 224. A [ka] The compound described in any one of the above items.

[0208] 225. A [ka] The compound described in any one of the above items.

[0209] 226. A [ka] The compound described in any one of the above items.

[0210] 227. A [ka] The compound described in any one of the above items.

[0211] 228. A [ka] The compound described in any one of the above items.

[0212] 229. A [ka] The compound described in any one of the above items.

[0213] 230. A [ka] The compound described in any one of the above items.

[0214] 231. A [ka] The compound described in any one of the above items.

[0215] 232. A [ka] The compound described in any one of the above items.

[0216] 233. A [ka] The compound described in any one of the above items.

[0217] 234. A [ka] The compound described in any one of the above items.

[0218] 235. R 0 is -OH, R 1 is a phenyl compound substituted with 2 or 3 -F atoms, R 2 is -CH3, R 3 is -H, A 1 CR 5 And, A 2 C(OCH2CF3) is, A 3 CR 7 And, A 4 CR 8 And, A 5 CR 9 And, Here R 5 , R 7 , R 8 , and R 9 One of them is -F, -Cl, -Br, or -CH3, and the others are -H. The compounds listed in item 1.

[0219] 236. R 0 is -OH, R 1 but [ka] And, R2 is -CH3, R 3 is -H, A 1 CR 5 And, A 2 C(OCH2CF3) is, A 3 CR 7 And, A 4 CR 8 And, A 5 CR 9 And, Here R 5 , R 7 , R 8 , and R 9 One of them is -F, -Cl, -Br, or -CH3, and the others are -H. The compounds listed in item 1.

[0220] 237. R 0 is -OH, R 1 but [ka] and R 2 is -CH3, R 3 is -H, A [ka] That is The compounds listed in item 1.

[0221] 238. R 0 is -OH, R 1 but [ka] And, R 2 is -CH3, R 3 is -H, A [ka] That is The compounds listed in item 1.

[0222] 239. A compound according to any one of the above items, wherein the stereochemical configuration at the 2nd and 3rd positions is independently selected from R and S, as defined by formulas (I) and (III). 240. A compound described in any one of the above items, having a stereochemical configuration of R at the 3-position as defined by formulas (I) and (III). 241. A compound described in any one of the above items, having a stereochemical configuration of S at the 3-position as defined by formulas (I) and (III).

[0223] 242. Compounds 3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, 3-Hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, 3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide, 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide, 3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide, 3-Hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, 3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)-phenyl)-cyclopropyl)butanamide, N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide,

[0224] (3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide, 3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide), N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide,

[0225] N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide, N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, 3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide and 3-Hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide A compound selected from the group consisting of a pharmaceutically acceptable salt thereof, as described in any one of the above items.

[0226] 243. Compounds (R)-3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, (R)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide, (R)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide, (R)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide, (R)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (R)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)butanamide, (R)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide,

[0227] (R)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide), (R)-N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide,

[0228] (R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide, (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (R)-3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide, and (R)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide A compound selected from the group consisting of a pharmaceutically acceptable salt thereof, as described in any one of the above items.

[0229] 244. Compounds (S)-3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide, (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide, (S)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (S)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (S)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0230] (S)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide), (S)-N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide,

[0231] (S)-N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide, (S)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (S)-3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide, and (S)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide A compound selected from the group consisting of a pharmaceutically acceptable salt thereof, as described in any one of the above items.

[0232] 245. A compound according to any one of the above items that can modulate the activity of the Kv7 channel. 246. A compound that is an agonist for the Kv7 channel, as described in any one of the above items. 247. A compound according to any one of the above items that can increase the activity of a Kv7.2 / Kv7.3 heteromeric channel. 248. Increase in Kv7.2 / Kv7.3 heteromeric channel activity at EC levels less than 50 μM, such as less than 20 μM, less than 10 μM, less than 1 μM, less than 0.1 μM, less than 0.06 μM, less than 0.01 μM, less than 0.001 μM, etc. 50 A compound described in any one of the above items, which can be produced by [method / method]. 249. Increased activity of Kv7.2 / Kv7.3 heteromeric channels was observed in EC2 levels ranging from approximately 0.1 nM to 10 μM, approximately 0.1 nM to 1 μM, approximately 0.1 nM to 0.2 μM, approximately 0.1 nM to 100 nM, approximately 0.1 nM to 10 nM, and approximately 0.1 nM to 20 μM. 50 A compound described in any one of the above items, which can be produced by [method / method].

[0233] 250. A compound described in any one of the above items that can increase the activity of Kv7.5 Nel. 251. EC of Kv7.5 50 A compound listed in any one of the above items, having a concentration exceeding 30 μM. 252. Activation of the Kv7.5 channel, EC 50 A compound described in any one of the above items, which can be increased in ranges such as approximately 0.1 nM to approximately 10 μM, approximately 0.1 nM to approximately 1 μM, approximately 0.1 nM to approximately 0.2 μM, approximately 0.1 nM to approximately 100 nM, approximately 0.1 nM to approximately 10 nM, or approximately 0.1 nM to approximately 20 μM. 253. A compound described in any one of the above items, which is a subtype selective Kv7 regulator. 254. A compound described in any one of the above items, which is selective for Kv7.2 / Kv7.3. 255. A compound described in any one of the above items, which is more selective to Kv7.2 / Kv7.3 than to Kv7.5.

[0234] 256. A compound according to any one of the above items that can selectively increase the activity of a Kv7.2 / Kv7.3 heteromeric channel. 257. EC for Kv7.2 / Kv7.3 50 The concentration is less than 10 μM, and the EC is less than 10 μM relative to Kv7.5. 50 A compound listed in any one of the above items, having a concentration exceeding 30 μM. 258. EC of compounds at Kv7.2 / Kv7.3 50 And, Kv7.5 EC 50Compounds listed in any one of the above items, where the ratio between the specified number and the specified number is greater than 2, such as 3, 5, 8, 10, 15, 20, 25, 30, 60, 75, 100, 150, 200, 230, 250, 500, etc. 259. EC of compounds at Kv7.2 / Kv7.3 50 And, Kv7.5 EC 50 A compound described in any one of the above items, wherein the ratio between the specified value and the specified value exceeds 10. 260. EC of compounds at Kv7.2 / Kv7.3 50 And, Kv7.5 EC 50 A compound listed in any one of the above items, wherein the ratio between the specified value and the specified value exceeds 100.

[0235] 261. The ratio is given by the following formula:

number

[0236] 262. A compound described in any one of the above items, which is potency-selective. 263. A compound described in any one of the above items, whose efficacy against Kv7.2 / Kv7.3 is greater than 50%, such as greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 100%, or greater than 110%. 264. A compound described in any one of the above items, whose efficacy against Kv7.5 is less than 60%, such as less than 50%, less than 40%, less than 30%, less than 20%, or 0%. 265. A compound listed in any one of the above items, having an efficacy of less than 25% against Kv7.5.

[0237] 266. A compound described in any one of the above items, wherein the efficacy against Kv7.2 / Kv7.3 is greater than 50% and the efficacy against Kv7.5 is less than 25%. 267. A compound described in any one of the above items, which is efficacy-selective. 268. A compound described in any one of the above items, which is potency-selective and efficacy-selective. 269. EC 50 However, thallium ions (Tl + A compound described in any one of the above items, measured by an in vitro cell type assay involving ion influx, such as an ) assay. 270. A pharmaceutical composition comprising any one of the compounds listed in items 1 to 269. 271. A compound described in any one of items 1 to 269, or a pharmaceutical composition described in item 270, for use as a pharmaceutical.

[0238] 272. Use of any one of the compounds described in items 1 to 269, or the pharmaceutical composition described in item 270, for the manufacture of a drug for a disease or symptom. 273. A method for treating a disease or symptom in a subject, comprising administering an effective amount of any one of items 1 to 269 or a pharmaceutical composition described in item 270 to the subject. 274. A method for modulating the activity of a Kv7 channel in a subject, comprising administering an effective amount of the compound to the subject, wherein the compound is one of items 1 to 269 or the pharmaceutical composition is one of item 270. 275. Compounds or pharmaceutical compositions described in item 274, used in methods for increasing the activity of Kv7.2 / Kv7.3 heteromeric channels. 276. A method for treating, preventing or alleviating epilepsy or pain in a subject, comprising administering an effective amount of the compound to the subject, wherein the method includes using one of the compounds described in items 1 to 269, or a pharmaceutical composition described in item 270. 277. Use of any one of the compounds described in items 1 to 269, or the pharmaceutical composition described in item 270, for the manufacture of a medicine for treating, preventing or alleviating epilepsy or pain. 278. A method for treating, preventing or alleviating epilepsy or pain in a subject, comprising administering an effective amount of any one of items 1 to 269 or a pharmaceutical composition described in item 270 to the subject.

[0239] Examples General operations for producing the compounds disclosed herein: The compounds of this disclosure were prepared according to the following synthesis scheme 1. [ka]

[0240] General procedures for compound-3: Procedure A: To a stirred solution of compound-2 (1 equivalent) in THF (10 volumes), Zn (1.5 equivalents) and I2 (0.02 equivalents) were added, followed by the dropwise addition of ethyl bromo (1 equivalent). The resulting reaction mixture was heated in a preheated oil bath at 55°C for 10-30 minutes. The resulting reaction mixture was stirred overnight under argon. The reaction mixture was quenched with a saturated NH4Cl solution, filtered, and extracted with RINKAN (3 x 20 volumes) to obtain crude compound-3. Crude compound-3 was purified by combiflash chromatography (eluent: RINKAN in RINKAN) to obtain compound-3 in yield of 35-80%.

[0241] Procedure B: A mixed solution of ethyl bromoacetate (1 equivalent), Zn (1.5 equivalents), and Br2 (0.2 equivalents) in anhydrous THF was heated in a preheated bath for 30 minutes. The resulting clarified solution was added to a solution of compound-2 (1 equivalent) in anhydrous THF. The resulting reaction mixture was stirred at room temperature for 1 hour or overnight. The reaction mixture was quenched with a saturated NH4Cl solution, filtered, and extracted with HCl (3 x 20 volumes) to obtain crude compound-3. Crude compound-3 was purified by combiflash chromatography (eluent: HCl in hexane) to obtain compound-3 in yield of 35-80%.

[0242] General procedure for compound-4: LiOH (1.5 equivalents) was added to a stirred solution of compound-3 in THF:water:MeOH (10 volumes, 3:2:1). The reaction was monitored by TLC, quenched with water, and extracted with RINKAN. The organic layer was dried over anhydrous Na2SO4 to obtain crude compound-4. The obtained crude compound-4 was further purified by combiflash chromatography.

[0243] General procedure for compound-6: To a stirred solution of compound-5 (1 equivalent) in DMF (10 volumes), Cs2CO3 (3 equivalents) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (1 equivalent) were added. The resulting reaction mixture was stirred overnight at room temperature and quenched with water. The reaction mixture was extracted with RINKAN (3 x 20 volumes). The organic layer was dried over anhydrous Na2SO4 and concentrated under high vacuum to obtain compound-6, which was then purified by combiflash chromatography (5-10% RINKAN in hexane) to obtain a sufficiently pure compound-6.

[0244] General procedure for compound-7: To a solution of compound-6 (1 equivalent) in Et2O, Ti(OiPr)4 (1 equivalent) was added at -78°C, followed by the dropwise addition of EtMgBr (3M, 2 equivalents in Et2O). The resulting reaction mixture was stirred for 2 hours and quenched with BF3:Et2O (2 equivalents). After stirring overnight, 1N HCl was added, and the reaction mixture was extracted with Et2O. The aqueous layer was made basic and extracted with Et2O. The organic layer obtained after basicization was washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum to obtain crude compound-7. Crude compound-7 was purified by combiflash chromatography (20-60% siRNA in hexane) to obtain a sufficiently pure compound-7.

[0245] General procedure for compound-8: To a stirred solution of compound-4 (1 equivalent) in DMF (10 volumes), HATU (1.5 equivalents) and DIPEA (3 equivalents) were added. The resulting reaction mixture was stirred for 15 minutes, and then compound-7 (1 equivalent) was added. The reaction mixture was diluted with cold water and extracted with SiO2 (2 x 10 volumes). The resulting organic layers were combined, washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum.

[0246] Chiral Separation: The compounds relating to this disclosure were separated into different stereoisomers using chiral preparative HPLC. Thus, in each example, two peaks, peak-1 and peak-2, were obtained, each corresponding to a different stereoisomer. Each peak was isolated, characterized, and tested for biological evaluation, as described below.

[0247] Example 1: Synthesis of 3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of 3-(2,2,2-trifluoroethoxy)benzonitrile (6a): Using the general procedure for compound-6, 3-hydroxybenzonitrile (20 g, 168.01 mmol) was converted to compound-6a (27.5 g, 83%). ¹H-NMR (DMSO-d6, 300 MHz): δ 7.60-7.53 (m, 3H), 7.39-7.45 (m, 1H), 4.87 (q, J=9 Hz, 2H) [ka]

[0248] Synthesis of 1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-amine hydrochloride (7a): Using the general procedure for compound-7, compound-6a (20 g, 99.43 mmol) was converted to 7a (7.5 g, 34%). During workup after acidification, compound-7a was extracted as an HCl salt in diethyl ether. ¹H-NMR (DMSO-d6, 300 MHz): δ 8.78 (bs, 3H), 7.38-7.42 (m, 1H), 7.02-7.10 (m, 3H), 4.80 (q, J=8.7 Hz, 2H), 1.24-1.34 (m, 4H) [ka]

[0249] Synthesis of ethyl 3-(6-chloropyridine-3-yl)-3-hydroxybutanoate (3a): Using general procedure A for compound-3, 1-(6-chloropyridine-3-yl)ethane-1-one (0.932 g, 5.99 mmol) was converted to compound-3a (0.68 g, 47%). m / z (LC-MS): 243.95 [M+H] + [ka]

[0250] Synthesis of 3-(6-chloropyridine-3-yl)-3-hydroxybutanoic acid (4a): Using the general procedure for compound-4, compound-3a (0.68 g, 2.79 mmol) was converted to the yellow, gum-like compound-4a (0.51 g, 85%). ¹H-NMR (DMSO-d6, 300 MHz): δ 1.51 (s, 3H), 2.73 (dd, J=14.7 Hz, 2H), 5.51 (bs, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.87 (dd, J=2.7 Hz, 8.7 Hz, 1H), 8.46 (d, J=2.7 Hz, 1H) [ka]

[0251] Example 1: Synthesis of 3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 1 Peak-1 & Example 1 Peak-2): [ka]

[0252] Following the general procedure for compound-8, compound-4a (0.2 g, 0.927 mmol) was converted to Example 1 (290 mg, 73%) using compound-7a. The enantiomers were separated using chiral preparative HPLC (column: Chiralpak IG, 250 mm x 21 mm, 5 μm; eluate: n-hexane (A) and EtOH:MeOH 1:1 (B); flow rate: 10 mL / min; isocratic: 70 (A):30 (B); diluent: EtOH:DCM, 3:1, 10 mL; injection volume: 0.5 mL; run time: 20 min), yielding peak-1 (104.9 mg) and peak-2 (101.3 mg); 1H-NMR (DMSO-d6, 300 MHz): δ 0.89-0.96(m,2H), 1.05-1.12(m,2H), 1.46(s,3H), 2.60(dd,J=13.8Hz,2H), 4.67(q,J=9Hz,2H), 5.79(s,1H), 6.43(d,J=8.1Hz,1H), 6.59(s,1 HRMS:[C 20 H 20 [CLF3N2O3+H] +Calculated value: 429.1187; Measured value: 429.1195 (Example 1 Peak-1), 429.1198 (Example 1 Peak-2); Chiral HPLC for analysis: ChiralPak-IG (150 x 4.6 mm x 5 μm); Mobile phase: (A) n-Hexane (B) 0.1% HCOOH in EtOH:MeOH (80:20) Isocratic: 80:20 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IG_8020_1_B_30MIN.amx.; Peak-1 (Rt: 4.961, 100%ee) Peak-2 (Rt: 11.357, 100%ee)

[0253] Example 2: Synthesis of 3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of ethyl 3-(5-fluoropyridine-2-yl)-3-hydroxybutanoate (3b): Using general procedure A for compound-3, 1-(5-fluoropyridine-2-yl)ethane-1-one (0.25 g, 1.797 mmol) was converted to compound-3b (80 mg, 20%) as a yellow oil. m / z (LC-MS): 228.1 [M+H] + [ka]

[0254] Synthesis of 3-(5-fluoropyridine-2-yl)-3-hydroxybutanoic acid (4b): Using the general procedure for compound-4, compound-3b (80 mg, 0.352 mmol) was converted to compound-4b (60 mg, 75%) as a yellow solid. m / z (LC-MS): 199.95 [M+H] + [ka]

[0255] Example 2: Synthesis of 3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 2 Peak-1 & Example 2 Peak-2): [ka]

[0256] Following the general procedure for compound-8, compound-4b (60 mg, 0.301 mmol) was converted to Example 2 (50 mg, 40%) using compound-7a. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 150 x 4.6 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH 1:1 (B); flow rate: 1 mL / min; isocratic: 85 (A):15 (B); diluent: EtOH), yielding peak-1 (20.3 mg) and peak-2 (24.9 mg). H-NMR (DMSO-d6, 400MHz):δ 0.98-1.09(m,2H), 1.10-1.18(m,2H), 1.42(s,3H), 2.58(d,J=14.4Hz,1H), 2.87(d,J=14.4Hz,1H), 4.68(q,J=9Hz,2H), 5.91(s,1H), 6.51(d, HRMS:[C 20 H 20 F4N2O3+H] +Calculated value: 413.1483; Measured value: 413.1492 (Example 2 Peak-1), 413.1551 (Example 2 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 85:15 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 10,000, Acq. method: IH_8515_7_C-30 min.amx. Peak-1 (Rt: 3.053, 100% ee) Peak-2 (Rt: 4.84, 100% ee)

[0257] Example 3: Synthesis of 3-hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of ethyl 3-hydroxy-3-(2-methoxypyridine-4-yl)butanoate (3c): Using general procedure A for compound-3, 1-(2-methoxypyridine-4-yl)ethane-1-one (0.55 g, 0.992 mmol) was converted to compound-3c (240 mg, 28%) as a colorless liquid. m / z (LC-MS): 239.90 [M+H] + [ka]

[0258] Synthesis of 3-hydroxy-3-(2-methoxypyridine-4-yl)butanoic acid (4c): Using the general procedure for compound-4, compound-3c (240 mg, 1.0031 mmol) was converted to compound-4c (98 mg, 46%) as an off-white solid. m / z (LC-MS): 212.10 [M+H] + [ka]

[0259] Example 3: Synthesis of 3-hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 3 Peak-1 & Example 3 Peak-2): [ka]

[0260] Following the general procedure for compound-8, compound-4c (0.2 g, 0.947 mmol) was converted to Example 3 using compound-7a, and purified by preparative HPLC (column: LUNA Phenomenex (250 x 21.2 mm, 5.0 μm), eluate: 0.1% HCOOH (A) and acetonitrile (B) in water, flow rate: 18 mL / min, time: %B, 0 / 50, 2 / 60, 6 / 85) to obtain a sufficiently pure Example 3a / b (75 mg, 19%), which was then subjected to chiral preparative HPLC (column: Chiral Pack IG, 250 x Separation was performed using a 21 mm, 5 μm filter, eluents: n-hexane (A) and EtOH (B), flow rate: 15 mL / min, isocratic: 90 (A):10 (B), and peak-1 (27 mg) and peak-2 (23 mg) were obtained as colorless gum-like oil. H-NMR (DMSO-d6, 400MHz):δ 0.97-1.02(m,2H), 1.05-1.25(m,2H), 1.43(s,3H), 2.59(d,J=14.1Hz,1H), 2.69(d,J=14.1Hz,1H), 3.84(s,3H), 4.68(q,J=8.6Hz,2 HRMS:[C 21 H 23 F3N2O4+H] +Calculated value: 425.1683; Measured value: 425.1698 (Example 3 Peak-1), 425.1697 (Example 3 Peak-2); Chiral HPLC for analysis: Chiral Pack-IG (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-hexane (B) 0.1% HCOOH:MeOH in EtOH (80:20) Isocratic: 70:30 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IG_7030_1_B_30MIN.amx.; Peak-1 (Rt: 3.097, 100%ee) Peak-2 (Rt: 3.607, 100%ee)

[0261] Example 4: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of ethyl 3-(2,4-difluorophenyl)-3-hydroxybutanoate (3d): Using general procedure A for compound-3, 1-(2,4-difluorophenyl)ethane-1-one (1g, 6.405 mmol) was converted to compound-3d (1g, 64%) as an off-white solid. ¹H-NMR (DMSO-d6, 400MHz): δ 0.96 (t, J=6.9Hz, 3H), 1.53 (s, 3H), 2.76 (dd, J=13.8Hz, 2H), 3.89 (q, J=6.6Hz, 2H), 6.99-7.05 (m, 1H), 7.08-7.16 (m, 1H), 7.54-7.62 (m, 1H) [ka]

[0262] Synthesis of 3-(2,4-difluorophenyl)-3-hydroxybutanoic acid (4d): Using the general procedure for compound-4, compound-3d (1 g, 4.409 mmol) was converted to compound-4d (800 mg, 90%) as a colorless solid. ¹H-NMR (DMSO-d6, 400 MHz): δ 1.51 (s, 3H), 2.69-2.78 (m, 2H), 5.53 (bs, 1H), 6.99-7.16 (m, 2H), 7.56-7.65 (m, 1H) [ka]

[0263] Synthesis of 3-chloro-5-(2,2,2-trifluoroethoxy)benzonitrile (6b): Using the general procedure for compound-6, 3-chloro-5-hydroxybenzonitrile (6g, 39.07 mmol) was converted to 6b (7.5g, 82%). ¹H-NMR (DMSO-d6, 400MHz): δ 4.92 (q, J=9Hz, 2H), 7.60-7.62 (m, 1H), 7.63-7.64 (m, 1H), 7.71-7.73 (m, 1H) [ka]

[0264] Synthesis of 1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-amine hydrochloride (7b): Using the general procedure for compound-7, compound-6b (9g, 38.20 mmol) was converted to compound-7b (5g, 43%) as an off-white solid. After acidification, the resulting solid was washed with hexane to obtain the desired compound as an HCl salt. m / z (LC-MS): 265.90 [M+H] + [ka]

[0265] Example 4: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (Example 4 Peak-1 & Example 4 Peak-2): [ka]

[0266] Following the general procedure for compound-8, compound-4d (100 mg, 0.462 mmol) was converted to Example 4 (103 mg, 43%) as an off-white solid using compound-7b. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and EtOH:IPA 1:1 (B); flow rate: 15 mL / min; isocratic: 80 (A):20 (B); diluent: EtOH:DCM (3:1, 5 mL); injection volume: 0.2 mL; run time: 15 min) to obtain peak-1 (34.8 mg) and peak-2 (38.7 mg) as colorless gum-like oils. H-NMR (DMSO-d6, 400MHz):δ 0.88-0.99(m,2H), 1.15-1.20(m,2H), 1.49(s,3H), 2.63(d,J=14Hz,1H), 2.75(d,J=14Hz,1H), 4.75(q,J=8.8Hz,2H), 5.96(s HRMS:[C 21 H 19 [ClF5NO3+H-H2O] + Calculated value: 446.0941; Measured value: 446.0956 (Example 4 Peak-1), 446.0954 (Example 4 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 85:15 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_8515_7_C-30 min.amx. Peak-1 (Rt: 2.68, 92%) Peak-2 (Rt: 3.46, 100%)

[0267] Example 5: Synthesis of 3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide Synthesis of 4-fluoro-3-(2,2,2-trifluoroethoxy)benzonitrile (6c): Using the general procedure for compound-6, 4-fluoro-3-hydroxybenzonitrile (1 g, 7.298 mmol) was converted to compound-6c (1 g, 63%) as a white solid. ¹H-NMR (DMSO-d6, 300 MHz): δ 4.90 (q, J=8.8 Hz, 2H), 7.50-7.64 (m, 2H), 7.88-7.92 (m, 1H) [ka]

[0268] Synthesis of 1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-amine (7c): Using the general procedure for compound-7, compound-6c (600 mg, 2.738 mmol) was converted to compound-7c (250 mg, 36%) as an off-white solid. m / z (LC-MS): 250.35 [M+H] + [ka]

[0269] Example 5: Synthesis of 3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 5 Peak-1 & Example 5 Peak-2): [ka]

[0270] Following the general procedure for compound-8, compound-4d (0.093 g, 0.432 mmol) was converted to Example 5 (40 mg, 20%) using compound-7c. The enantiomers were separated by chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH (1:1) (B); flow rate: 15 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM (1:1, 3 mL); injection volume: 0.5 mL; run time: 14 min), and peak-1 (12 mg) and peak-2 (9 mg) were obtained as off-white solids. H-NMR (DMSO-d6, 300MHz):δ 0.87-0.99(m,2H), 1.12-1-20(m,2H), 1.48(s,3H), 2.60(d,J=14.1Hz,1H), 2.74(d,J=14.1Hz,1H), 4.76(q,J=8.7Hz,2H), 6.04(b HRMS:[C 21 H 19 [F6NO3+H-H2O] + Calculated value: 430.1236; Measured value: 430.1246 (Example 5 Peak-1), 430.1250 (Example 5 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 85:15 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_8515_7_C-15 min.amx. Peak-1 (Rt: 2.63, 100% ee) Peak-2 (Rt: 3.81, 100% ee)

[0271] Example 6: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide Synthesis of ethyl 3-(4-fluorophenyl)-3-hydroxybutanoate (3e): Using general procedure A for compound-3, 1-(4-fluorophenyl)ethane-1-one (2g, 14.478 mmol) was converted to compound-3e (3g, 94%). ¹H-NMR (DMSO-d6, 300MHz): δ 1.00 (t, J=6.9Hz, 3H), 1.5 (s, 3H), 2.51-2.70 (m, 2H), 3.90 (q, J=6Hz, 2H), 5.30 (s, 1H), 7.04-7.11 (m, 2H), 7.42-7.47 (m, 2H) [ka]

[0272] Synthesis of 3-(4-fluorophenyl)-3-hydroxybutanoic acid (4e): Using the general procedure for compound-4, compound-3e (3g, 13.27 mmol) was converted to compound-4e (1.1g, 42%) as an off-white solid. ¹H-NMR (DMSO-d6, 300MHz): δ 1.49(s,3H), 2.65(s,2H), 5.25-5.30(bs,1H), 7.05-7.11(m,2H), 7.42-7.48(m,2H) [ka] [ka]

[0273] Synthesis of 1-(3-(trifluoromethyl)phenyl)cyclopropan-1-amine (7d): Using the general procedure for compound-7, 3-(trifluoromethyl)benzonitrile (2 g, 11.688 mmol) was converted to compound-7d (350 mg, 15%). After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 202.40 [M+H] + [ka]

[0274] Example 6: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide (Example 6 Peak-1 & Example 6 Peak-2): [ka]

[0275] Following the general procedure for compound-8, compound-4e (0.15 g, 0.757 mmol) was converted to Example 6 (110 mg, 38%) using compound-7d. The enantiomers were separated by chiral preparative HPLC (column: Chiral Pack IH, 150 mm x 4.6 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH 1:1 (B); flow rate: 1.0 mL / min; isocratic: 85 (A):15 (B)) to obtain peak-1 (37.9 mg) and peak-2 (42.8 mg). H-NMR (DMSO-d6, 400MHz):δ 0.98-1.03(m,2H), 1.05-1.24(m,2H), 1.46(s,3H), 2.55(d,J=14.1Hz,1H), 2.67(d,J=14.1Hz,1H), 4.92(q,J=8.6Hz) HRMS:[C 20 H 19 [F4NO2+H-H2O] + Calculated value: 364.1319; Measured value: 364.1329 (Example 6 Peak-1), 364.1331 (Example 6 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 93:07 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH Column temperature: 25°C, Injection volume: 10,000, Acq. method: IH_9307_7_C_30MIN.amx.; Peak-1 (Rt: 7.293, 100%ee) Peak-2 (Rt: 7.286, 100%ee)

[0276] Example 7: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide Synthesis of 1-(3-(trifluoromethoxy)phenyl)cyclopropane-1-amine hydrochloride (7e): Using the general procedure for compound-7, 3-(trifluoromethoxy)benzonitrile (200 mg, 1.06 mmol) was converted to 7e (160 g, crude). During work-up after acidification, compound-7e was extracted as an HCl salt in diethyl ether. ¹H-NMR (DMSO-d6, 400 MHz): δ 0.97-0.94 (m, 2H), 1.03-1.00 (m, 2H), 7.11-7.09 (m, 1H), 7.22-7.20 (m, 1H), 7.39-7.30 (m, 2H) [ka]

[0277] Example 7: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide (Example 7 Peak-1 & Example 7 Peak-2): [ka]

[0278] Following the general procedure for compound-8, compound-4e (100 mg, 0.460 mmol) was converted to Example 7 (135 mg, 74%) using compound-7e. The enantiomers were separated by chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH 1:1 (B); flow rate: 15 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM (1:1, 3.5 mL); injection volume: 0.5 mL; run time: 13 min), and peak-1 (41.2 mg) and peak-2 (29.8 mg) were obtained as white solids. H-NMR (DMSO-d6, 400MHz):δ 0.86-0.99(m,2H), 1.17-1.24(m,2H), 1.45(s,3H), 2.53-2.71(m,2H), 5.67(s,1H), 6.78(d,J=8Hz HRMS:[C 20 H 19 [F4NO3+H-H2O] + Calculated value: 380.1268; Measured value: 380.1281 (Example 7 Peak-1), 380.1279 (Example 7 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 93:07 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH Column temperature: 25°C, Injection volume: 10,000, Acq. method: IH_9307_7_C_30MIN.amx.; Peak-1 (Rt: 7.293, 100%ee) Peak-2 (Rt: 7.286, 100%ee)

[0279] Example 8: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide [ka]

[0280] Synthesis of 2-(2,2,2-trifluoroethoxy)isonicotinonitrile (6f): To a stirred suspension of sodium hydride (2.89 g, 72.173 mmol) in anhydrous DMF (10 mL), a solution of 2,2,2-trifluoroethane-1-ol (5.45 mL, 72.173 mmol) in anhydrous DMF (10 mL) was added at 0°C. After stirring for 10 minutes at 0°C, a solution of 2-chloroisonicotinonitrile (5 g, 36.086 mmol) in anhydrous DMF (30 mL) was added. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated ammonium chloride solution and extracted with RINKAN (3 x 100 mL). The resulting organic layers were combined, washed with brine, and dried on anhydrous Na2SO4. The organic layer was removed under vacuum to obtain the crude product, which was purified by flash chromatography (eluent: HCl:hexane 5:95) to obtain compound-6f (2.5 g, 34%) as a colorless gum. m / z (LC-MS): 203.1 [M+H] +

[0281] Synthesis of 1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropan-1-amine (7f): Using the general procedure for compound-7, compound-6f (0.1 g, 0.495 mmol) was converted to compound-7f (80 mg, 71%). After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 232.95 [M+H] +

[0282] Example 8: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide (Example 8 Peak-1 & Example 8 Peak-2): [ka]

[0283] Following the general procedure for compound-8, compound-4e (0.1 g, 0.303 mmol) was converted to Example 8 (45 mg, 22%) using compound-7f. The enantiomers were separated by chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH 1:1 (B); flow rate: 15 mL / min; isocratic: 85 (A):15 (B); diluent: EtOH::DCM, 3:1, 4 mL; injection volume: 0.9 mL; run time: 13 min), yielding peak-1 (16.7 mg) and peak-2 (15.9 mg). H-NMR (DMSO-d6, 400MHz):δ 0.99-1.03(m,2H), 1.05-1.27(m,2H), 1.47(s,3H), 2.60(dd,J=14.1Hz,2H), 4.92(q,J=8.6Hz,2H), 5.64(s,1H), 6.43(d d,J=1.2Hz,9.4Hz,2H), 7.11-7.15(m,2H), 7.48(dd,J=5.6Hz,10.8Hz,2H), 7.88(d,J=5.6Hz,1H), 8.537(s,1H);HRMS:[C 20 H 20 F4N2O3+H] + Calculated value: 413.1483; Measured value: 413.1492 (Example 8 Peak-1), 413.1494 (Example 8 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 80:20 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25℃; Peak-1 (Rt: 2.59, 100% ee) Peak-2 (Rt: 3.50, 100% ee)

[0284] Example 9: Synthesis of 3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of ethyl 3-hydroxy-3-(p-tolyl)butanoate (3f): Using general procedure A for compound-3, 1-(p-tolyl)ethane-1-one (1 g, 7.453 mmol) was converted to compound-3f (380 mg, 24%). ¹H-NMR (DMSO-d6, 400 MHz): δ 1.04 (t, J=7.2 Hz, 3H), 1.51 (s, 3H), 2.26 (s, 3H), 2.68 (s, 2H), 3.92 (q, J=7.2 Hz, 2H), 5.14 (s, 1H), 7.08 (d, J=8 Hz, 2H), 7.31 (d, J=8 Hz, 2H) [ka]

[0285] Synthesis of 3-hydroxy-3-(p-tolyl)butanoic acid (4f): Using the general procedure for compound-4, compound-3f (380 mg, 1.709 mmol) was converted to compound-4f (300 mg, 90%) as a reddish oil. ¹H-NMR (DMSO-d6, 400 MHz): δ 1.49 (s, 3H), 2.26 (s, 3H), 2.65 (s, 2H), 5.14 (bs, 1H), 7.08 (d, J=8 Hz, 2H), 7.32 (d, J=8 Hz, 2H), 11.99 (bs, 1H) [ka]

[0286] Example 9: Synthesis of 3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 9 Peak-1 & Example 9 Peak-2): [ka]

[0287] Following the general procedure for compound-8, compound-4f (0.15 g, 0.772 mmol) was converted to Example 9 (120 mg, 38%) using compound-7a. The enantiomers were separated by chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm; eluate: n-hexane (A) and IPA (B); flow rate: 15 mL / min; isocratic: 80 (A):20 (B); diluent: EtOH:DCM, 3:1, 5 mL; injection volume: 0.5 mL; run time: 22 min) to obtain peak-1 (50 mg) and peak-2 (43 mg). H-NMR (DMSO-d6, 400MHz):δ 0.70-1.00(m,2H), 1.05-1.20(m,2H), 1.42(s,3H), 2.67(dd,J=14.1Hz,2H), 4.67(q,J=8.8Hz,2H), 5.61(s,1H), 6.43(d,J=7.6Hz,1H) HRMS:[C 22 H 24 [F3NO3+H-H2O] + Calculated value: 390.1675; Measured value: 390.1682 (Example 9 Peak-1), 390.1682 (Example 9 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA Isocratic: 95:05 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH Column temperature: 25°C, Injection volume: 3.000, Acq. method: IH_9505_7_C_30MIN.amx.; Peak-1 (Rt: 8.65, 100%ee) Peak-2 (Rt: 12.54, 100%ee)

[0288] Example 10: Synthesis of 3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of ethyl 3-(4-cyanophenyl)-3-hydroxybutanoate (3g): Using general procedure A for compound-3, 4-acetylbenzonitrile (1g, 6.889 mmol) was converted to compound-3g (400mg, 25%). ¹H-NMR (DMSO-d6, 400MHz): δ 1.01 (t, J=7.2Hz, 3H), 1.52 (s, 3H), 2.78 (dd, J=14Hz, 2H), 3.90 (q, J=7.2Hz, 2H), 5.53 (s, 1H), 7.65 (d, J=8.4Hz, 2H), 7.76 (d, J=8.4Hz, 2H) [ka]

[0289] Synthesis of 3-(4-cyanophenyl)-3-hydroxybutanoic acid (4g): Using the general procedure for compound-4, 3g (400mg, 1.715 mmol) of compound-4 was converted to 4g (320mg, 91%) of compound-4 as a colorless oil. ¹H-NMR (DMSO-d6, 400MHz): δ 1.51(s,3H), 2.74(dd,J=14.4Hz,2H), 5.46(bs,1H), 7.65(d,J=6.8Hz,2H), 7.77(d,J=6.8Hz,2H), 12.03(bs,1H) [ka]

[0290] Example 10: Synthesis of 3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 10 Peak-1 & Example 10 Peak-2): [ka]

[0291] Following the general procedure for compound-8, compound-4 g (0.15 g, 0.731 mmol) was converted to Example 10 (90 mg, 33%) using compound-7a. The enantiomer was separated by chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH, 1:1 (B); flow rate: 15 mL / min; isocratic: 80 (A):20 (B); diluent: EtOH:DCM, 3:1, 6 mL; injection volume: 0.9 mL; run time: 18 min) to obtain peak-1 (37 mg) and peak-2 (30 mg). H-NMR (DMSO-d6, 400MHz):δ 0.85-0.95(m,2H), 1.02-1.15(m,2H), 1.47(s,3H), 2.65(dd,J=14Hz,2H), 4.68(q,J=8.8Hz,2H), 5.86(s,1H), 6.44(d,J=8.4Hz,1H), 6. 58-6.59(m,1H), 6.80(dd,J=2.4Hz,8.4Hz,1H), 7.00-7.04(m,1H), 7.63(d,J=8.4Hz,2H), ), 7.78(d,J=8.4Hz,2H), 8.55(s,1H);HRMS:[C 22 H 21 F3N2O3+H] + Calculated value: 419.1577; Measured value: 419.1586 (Example 10 Peak-1), 419.1585 (Example 10 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 90:10 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH Column temperature: 25℃; Peak-1 (Rt: 7.02, 100% ee) Peak-2 (Rt: 12.84, 100% ee)

[0292] Example 11: Synthesis of 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide Synthesis of 2-fluoro-3-(2,2,2-trifluoroethoxy)benzonitrile (6 g): Using the general procedure for compound-6, 2-fluoro-3-hydroxybenzonitrile (2 g, 14.587 mmol) was converted to 6 g (2.3 g, 72%). ¹H-NMR (DMSO-d6, 300 MHz): δ 4.94 (q, J=8.4 Hz, 2H), 7.34-7.40 (m, 1H), 7.52-7.57 (m, 1H), 7.65-7.71 (m, 1H) [ka]

[0293] Synthesis of 1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-amine (7g): Using the general procedure for compound-7, 6g (0.5g, 2.282 mmol) of compound-7 was converted to 7g (0.2g, 35%) of compound-7 as a yellowish oil. m / z (LC-MS): 249.95 [M+H] + [ka]

[0294] Example 11: Synthesis of 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 11 Peak-1 & Example 11 Peak-2): [ka]

[0295] Following the general procedure for compound-8, compound-4d (0.087 g, 0.401 mmol) was converted to Example 11 (100 mg, 56%) using compound-7 g. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm; eluate: n-hexane (A) and EtOH (B); flow rate: 15 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM, 1:1, 5 mL; injection volume: 0.3 mL; run time: 13 min) to obtain peak-1 (43.3 mg) and peak-2 (46.4 mg). H-NMR (DMSO-d6, 400MHz):δ 0.76-0.80(m,2H), 0.86-1.05(m,2H), 1.40(s,3H), 2.55(dd,J=14Hz,2H), 4.75(q,J=8.8Hz,2H ), 5.96(s,1H), 6.91-6.96(m,3H), 7.03-7.12(m,2H), 7.44-7.51(m,1H), 8.64(s,1H);HRMS:[C 21 H 19 F6NO3+H] + Calculated value: 448.1342; Measured value: 448.1347 (Example 11 Peak-1), 448.1347 (Example 11 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm), Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50), Isocratic: 85:15 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_8515_7_C-15 min.amx. Peak-1 (Rt: 2.71, 100% ee) Peak-2 (Rt: 3.38, 100% ee)

[0296] Example 12: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of 4-methyl-3-(2,2,2-trifluoroethoxy)benzonitrile (6h): Using the general procedure for compound-6, 3-hydroxy-4-methylbenzonitrile (2g, 15.021 mmol) was converted to 6h (2.9g, 91%). ¹H-NMR (CDCl3, 300MHz): δ 2.32 (s, 3H), 4.38 (q, J=8.4Hz, 2H), 7.01 (s, 1H), 7.25, 7.28 (m, 2H) [ka]

[0297] Synthesis of 1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7h): Using the general procedure for compound-7, compound-6h (1.5g, 6.971 mmol) was converted to compound-7h (550mg, 31%) as a yellowish oil. m / z (LC-MS): 246.00 [M+H] + [ka]

[0298] Example 12: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 12 Peak-1 & Example 12 Peak-2): [ka]

[0299] Following the general procedure for compound-8, compound-4d (0.132 g, 0.612 mmol) was converted to Example 12 (150 mg, 55%) using compound-7h. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH (1:1) (B); flow rate: 15 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM, 1:1, 5 mL; injection volume: 0.25 mL; run time: 11 min) to obtain peak-1 (75.9 mg) and peak-2 (69.9 mg). H-NMR (DMSO-d6, 400MHz):δ 0.76-0.95(m,2H), 1.09-1.15(m,2H), 1.48(s,3H), 2.08(s,3H), 2.70(dd,J=14Hz,2H), 4.65(q,J=8.8Hz,2H), 6.06(s,1H), 6.3 7-6.39(m,1H), 6.56(s,1H), 6.88(d,J=8Hz,1H), 7.01-7.06(m,1H), 7.13-7.22(m,1H), 7.55-7.62(m,1H), 8.60(s,1H);HRMS:[C 22 H 22 F5NO3+H] + Calculated value: 444.1593; Measured value: 444.1598 (Example 12 Peak-1), 444.1600 (Example 12 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 93:07 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_9307_7_C_30MIN.amx.; Peak-1 (Rt: 2.98, 100%ee) Peak-2 (Rt: 3.44, 100%ee)

[0300] Example 13: Synthesis of N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 3-chloro-5-(difluoromethyl)benzonitrile (6i): 3-chloro-5-formylbenzonitrile (1 g, 6.04 mmol) was dissolved in anhydrous dichloromethane (10 mL), to which diethylaminosulfur trifluoride (1.4 mL, 12.08 mmol) was added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction product was quenched with a saturated ammonium chloride solution and extracted with toluene (2 x 20 mL). The resulting organic layers were combined, washed with brine, and dried on anhydrous sodium 2SO4. The organic layers were concentrated under vacuum to obtain compound-6i (1 g, 89%) as a yellow oil. H-NMR (DMSO-d6, 400MHz): δ 7.09(t,J=55.2Hz,1H), 8.04(d,J=1.2Hz,1H), 8.10(dd,J=1.2Hz,1.2Hz,1H), 8.27(d,J=1.2Hz,1H) [ka]

[0301] Synthesis of 1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropan-1-amine (7i): Using the general procedure for compound-7, compound-6i (1 g, 5.331 mmol) was converted to compound-7i (550 mg, 47%) as a yellowish oil. m / z (LC-MS): 217.90 [M+H] + [ka]

[0302] Example 13: Synthesis of N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (Example 13 Peak-1 & Example 13 Peak-2): [ka]

[0303] Following the general procedure for compound-8, compound-4d (0.15 g, 0.694 mmol) was converted to Example 13 (160 mg, 56%) as an off-white solid using compound-7i. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH (1:1) (B); flow rate: 15 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM, 1:1, 4.5 mL; injection volume: 0.2 mL; run time: 18 min) to obtain peak-1 (47.2 mg) and peak-2 (69.9 mg). H-NMR (DMSO-d6, 400MHz):δ 0.96-1.04(m,2H), 1.18-1.23(m,2H), 1.49(s,3H), 2.65(dd,J=14Hz,2H), 5.94(s,1H), 6.93(t,J=55.6Hz,1H), 6.98-7.02(m,1H), 7.10-7.17(m,2H), 7.16-7.23(m,1H), 7.38(s,1H), 7.58-7.62(m,1H), 8.67(s,1H);HRMS:[C 20 H 18 [ClF4NO2+H-H2O] + Calculated value: 398.0929; Measured value: 398.0930 (Example 13 Peak-1), 398.0934 (Example 13 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm), Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 85:15 (A:B), Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_8515_7_C-20 min. amx. Peak-1 (Rt: 2.97, 100% ee) Peak-2 (Rt: 4.27, 100% ee)

[0304] Example 14: Synthesis of 3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of ethyl (E)-3-(3,5-difluorophenyl)buta-2-enoate (10): Triethyl phosphonoacetate (1 g, 4.803 mmol) was added at 0°C to a stirred suspension of sodium hydride (0.192 g, 4.803 mmol) in anhydrous THF (10 mL). To the resulting reaction mixture, a solution of 1-(3,5-difluorophenyl)ethane-1-one (500 mg, 3.202 mmol) in anhydrous THF (2 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction product was quenched with a saturated ammonium chloride solution and extracted with RINKAN (2 x 15 mL). The resulting organic layers were combined, washed with brine, dried on anhydrous Na₂SO₄, and concentrated under vacuum to obtain compound-10 (320 mg, 44%) as a colorless liquid. m / z (LC-MS): 227.1 [M + H] + ;H-NMR (DMSO-d6, 300MHz): δ 1.23(t,J=6.9Hz,3H), 2.47(s,3H), 4.16(q,J=7.2Hz&14.4Hz,2H), 6.26(s,1H), 7.29-7.32(m,1H), 7.32-7.36(m,2H) [ka]

[0305] Synthesis of ethyl 3-(3,5-difluorophenyl)-3-hydroxypropanoate (3h): To a stirred solution of compound-10 in ethanol, palladium on carbon (10%) was added at room temperature under an argon atmosphere. The resulting mixture was stirred under hydrogen balloon pressure until complete. The progress of the reaction was monitored by TLC. After the reaction was complete, the mixture was filtered through a Celite bed and washed with EtOH (2 x 10 mL). The resulting filtrate was concentrated under reduced pressure to obtain crude compound-3h, which was used in the next step without purification. H-NMR (DMSO-d6, 400MHz):δ 1.09(t,J=7.2Hz,3H), 1.20(d,J=6.8Hz,3H), 2.61(d,J=7.6Hz,2H), 3.15-3.11(m,1H), 4.02(q,J=5.2Hz,2H), 6.99-7.06(m,3H) [ka]

[0306] Synthesis of 3-(3,5-difluorophenyl)butanoic acid (4h): Using the general procedure for compound-4, compound-3h (0.31 g, 1.35 mmol) was converted to compound-4h (0.22 g, 1.1%) as an off-white solid. ¹H-NMR (DMSO-d6, 300 MHz): δ 1.17-1.20 (m,3H), 2.49-2.57 (m,2H), 3.16-3.1 (m,1H), 6.99-7.04 (m,3H); LC-MS (ESI+, m / z): 198.95 (M+H) - [ka]

[0307] Example 14: Synthesis of 3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 14 Peak-1 & Example 14 Peak-2): [ka]

[0308] Following the general procedure for compound-8, compound-4h (0.22 g, 0.462 mmol) was converted to Example 14 (0.22 g, 43%) as an off-white solid using compound-7a. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and EtOH:IPA 1:1 (B); flow rate: 15 mL / min; isocratic: 80 (A):20 (B); diluent: EtOH:DCM (3:1, 5 mL); injection volume: 0.2 mL; run time: 15 min), and peak-1 (93.1 mg) and peak-2 (97.3 mg) were obtained as colorless gum-like oil; 1H-NMR (DMSO-d6, 400 MHz): δ 0.91-0.97(m,2H), 1.04-1.33(m,5H), 2.37-2.49(m,2H), 3.17-3.22(m,1H), 4.68(q,J=8.8Hz,2H) , 6.55-6.57(m,2H), 6.78-6.81(m,1H), 6.94-6.97(m,2H), 7.01-7.11(m,2H), 8.49(s,1H);HRMS:[C 21 H 20 F5NO2+H] + Calculated value: 414.1487; Measured value: 414.1495 (Example 14 Peak-1), 414.1491 (Example 14 Peak-2); Chiral HPLC for analysis: REGIS (S,S) WHELK-01 (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-hexane (B) IPA:MeOH (50:50) Isocratic: 90:10 (A:B) Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: REG_9010_8_C_30MIN.amx.; Peak-1 (Rt: 11.93, 100%ee) Peak-2 (Rt: 13.62, 100%ee)

[0309] Example 15: Synthesis of 4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of ethyl 4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxybutanoate: Using general procedure A for compound-3, 2,2,2-trifluoro-1-(4-fluorophenyl)ethane-1-one (1 g, 6.405 mmol) was converted to compound-3i (0.45 g, 62%). ¹H-NMR (DMSO-d6, 400 MHz): δ 0.96 (t, J=8 Hz, 2H), 3.01 (d, J=15.2 Hz, 1H), 3.42 (dd, J=15.2 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 6.93 (s, 1H), 7.18-7.22 (m, 2H), 7.60-7.63 (m, 2H) [ka]

[0310] Synthesis of 4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxybutanoic acid (4i): Using the general procedure for compound-4, compound-3i (450 mg, 1.46 mmol) was converted to compound-4i (250 mg, 61.80%) as an off-white solid. m / z (LC-MS): 252.01[M+H]- [ka]

[0311] Example 15: Synthesis of 4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 15 Peak-1 & Example 15 Peak-2): [ka]

[0312] Following the general procedure for compound-8, compound-4i (250 mg, 0.99 mmol) was converted to Example 15 (250 mg, 54%) as an off-white solid using compound-7a. The enantiomer was separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and EtOH:IPA 1:1 (B); flow rate: 15 mL / min; isocratic: 80 (A):20 (B); diluent: EtOH:DCM (3:1, 5 mL); injection volume: 0.2 mL; run time: 15 min) to obtain peak-1 (110 mg) and peak-2 (108 mg) as colorless gum-like oil. H-NMR (DMSO-d6, 400MHz):δ 0.88-0.99(m,2H), 1.15-1.20(m,2H), 1.35(d,J=3.6Hz,3H), 3.16-3.22(m,1H), 4.68(d,J=8.8Hz,2H ), 6.55-6.57(m,2H), 6.78-6.81(m,1H), 6.95-6.97(m,1H), 7.01-7.11(m,2H), 8.49(s,1H);HRMS:[C 21 H 18 F7NO3+H] + Calculated value: 466.1248; Measured value: 466.1258 (Example 15 Peak-1), 466.1260 (Example 15 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-hexane (B) 0.1% HCOOH:MeOH in EtOH (80:20) Isocratic: 90:10 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_9010_7_B_10MIN.amx.; Peak-1 (Rt: 3.19, 100%ee), Peak-2 (Rt: 4.09, 100%ee)

[0313] Example 16: Synthesis of N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 1-(3-bromophenyl)cyclopropane-1-amine hydrochloride (7j): Using the general procedure for compound-7, 3-bromobenzonitrile (1 g, 5.43 mmol) was converted to compound-7j (600 mg, crude). During work-up after acidification, compound-7j was extracted as an HCl salt in diethyl ether. m / z (LC-MS): 213.75 [M+H] + [ka]

[0314] Example 16: Synthesis of N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (Example 16 Peak-1 & Example 16 Peak-2): [ka]

[0315] Following the general procedure for compound-8, compound-4d (200 mg, 0.92 mmol) was converted to Example 16 (80 mg, 21%) as an off-white solid using compound-7j. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and EtOH:IPA 1:1 (B); flow rate: 20 mL / min; isocratic: 85 (A):15 (B); diluent: EtOH:DCM (1:1, 3 mL); injection volume: 0.5 mL; run time: 11 min), and peak-1 (6.2 mg) and peak-2 (6.3 mg) were obtained as colorless gum-like oil; 1H-NMR (DMSO-d6, 400 MHz): δ 0.85-0.97(m,2H), 1.11-1.23(m,2H), 1.48(s,3H), 2.49-2.78(m,2H), 5.99(s,1H), 4.73(q,J=8.8Hz&17.6Hz,2H), 5.99(s,1H), 6.79(d HRMS: 19 H 18 [BrF2NO2+H-H2O] + Calculated value: 392.0456; Measured value: 392.0462 (Example 16 Peak-1), 392.0471 (Example 16 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm), Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50), Isocratic: 85:15 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 10.000, Acq. method: IH_8515_7_C-15 min.amx. Peak-1 (Rt: 2.74, 100% ee) Peak-2 (Rt: 3.54, 100% ee)

[0316] Example 17: Synthesis of N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide Synthesis of 3-bromo-5-(2,2,2-trifluoroethoxy)benzonitrile (6k): Using the general procedure for compound-6, 3-bromo-5-hydroxybenzonitrile (10g, 50.50 mmol) was converted to 6k (15g, 98%). ¹H-NMR (DMSO-d6, 400MHz): δ 4.92 (q, J=9Hz, 2H), 7.67 (s, 1H), 7.73 (s, 1H), 7.83 (s, 1H) [ka]

[0317] Synthesis of 1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-amine hydrochloride (7k): Using the general procedure for compound-7, compound-6k (100 mg, 0.32 mmol) was converted to compound-7k (30 mg, 30%) as an off-white solid. After acidification, the resulting solid was washed with hexane to obtain the desired compound as an HCl salt. m / z (LC-MS): 265.90 [M+H] + [ka]

[0318] Synthesis of N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide (8k): Following the general procedure for compound-8, compound-4e (100 mg, 0.50 mmol) was converted to compound-8k (60 mg, 24%) as a colorless gum-like substance using compound-7k. m / z (LC-MS): 489.95 [M+H] 2+ [ka]

[0319] Example 17: Synthesis of N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide (Example 17 Peak-1 & Example 17 Peak-2): [ka]

[0320] Compound-8k (60 mg, 0.12 mmol) was packed into a sealed test tube at room temperature in N,N-dimethylformamide. Zinc cyanide (14.5 mg, 0.12 mmol) was added at room temperature under an argon atmosphere. The resulting mixture was degassed with argon for 15 minutes, and then tetrakis(triphenylphosphine)palladium(0) (565 mg, 0.48 mmol) was added. The resulting reaction mixture was stirred in a MW at 150°C for 2 hours. The reaction mixture was diluted with cold water and extracted with ethyl acetate (3 x 15 mL). The resulting organic layers were combined, washed with brine, and dried on anhydrous sodium 2SO4. The organic layer was concentrated under vacuum to obtain crude Example 17, which was purified by preparative TLC (using 30% siRNA in hexane as the mobile phase). Pure Example 17a / b (15 mg, 27%) was isolated as an off-white solid and separated using chiral preparative HPLC (column: Regis(S,S) Whelk-01, 250 mm x 21.1 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH (1:1) (B); flow rate: 15 ml / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM (1:1, 3.5 mL); injection volume: 0.25 mL; run time: 33 min). Peak-1 (7.8 mg) and Peak-2 (6.2 mg) were obtained as colorless gum-like oil; 1H-NMR (DMSO-d6, 400 MHz): δ 0.97-0.99(m,2H), 1.11-1.15(m,2H), 1.46(s,3H), 2.60-2.69(m,2H), 4.80(q,J=8.8Hz&17.6Hz,2H) , 5.61(s,1H), 6.92(s,1H), 7.07-7.11(m,3H), 7.35(s,1H), 7.44-7.48(m,2H), 8.49(s,1H);HRMS:[C 22 H 20 [F4N2O3+H-H2O] +Calculated value: 419.1377; Measured value: 419.1387 (Example 17 Peak-1), 419.1386 (Example 17 Peak-2); Chiral HPLC for analysis: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50), Isocratic: 80:20 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 10.000, Acq. method: REG_8020_8_C_20MIN.amx.; Peak-1 (Rt: 9.40, 100%ee) Peak-2 (Rt: 10.04, 100%ee)

[0321] Example 18: Synthesis of 3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide Synthesis of 3-fluoro-5-(2,2,2-trifluoroethoxy)benzonitrile (6L): Using the general procedure for compound-6, 3-fluoro-5-hydroxybenzonitrile (4g, 36.48 mmol) was converted to compound-6L (5g, 63%). ¹H-NMR (DMSO-d6, 400MHz): δ 4.92 (q, J=8.8Hz, 2H), 7.43-7.47 (m, 1H), 7.52-7.56 (m, 2H) [ka]

[0322] Synthesis of 1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-amine (7L): Using the general procedure for compound-7, compound-6L (3g, 13.69 mmol) was converted to compound-7L (1.5g, 44%). After basicization with NaHCO3, the compound was extracted as a free base. ¹H-NMR (DMSO-d6, 400MHz): δ 0.93-0.99 (m,4H), 2.35 (bs,2H), 4.73 (q,J=8.8Hz,2H), 6.72-6.73 (m,1H), 6.78-6.80 (m,2H) [ka]

[0323] Example 18: Synthesis of 3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 18 Peak-1 & Example 18 Peak-2): [ka]

[0324] Following the general procedure for compound-8, compound-4d (150 mg, 0.60 mmol) was converted to Example 18 (220 mg, 82%) as an off-white solid using compound-7l. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and EtOH:IPA 1:1 (B); flow rate: 15 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM (3:1, 6 mL); injection volume: 0.5 mL; run time: 17 min), and peak-1 (97.1 mg) and peak-2 (93.5 mg) were obtained as colorless gum-like oil; 1H-NMR (DMSO-d6, 400 MHz): δ 0.97-0.98(m,2H), 1.14-1.23(m,2H), 1.49(s,3H), 2.60-2.79(m,2H), 4.73(q,J=8.8Hz&17.6Hz,2H), 5.99(s,1H), 6.34(d,J=1 HRMS:[C 21 H 19 F6NO3+H] +Calculated value: 448.1342; Measured value: 448.1350 (Example 18 Peak-1), 448.1350 (Example 18 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50), Isocratic: 80:20 (A:B), Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_8020_7_C_20MIN.amx.; Peak-1 (Rt: 2.40, 100%ee) Peak-2 (Rt: 3.00, 100%ee)

[0325] Example 19: Synthesis of N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 4-chloro-3-(2,2,2-trifluoroethoxy)benzonitrile (6m): Using the general procedure for compound-6, 4-chloro-3-hydroxybenzonitrile (3g, 19.53 mmol) was converted to 6m (4g, 87%) as a white solid. ¹H-NMR (DMSO-d6, 300MHz): δ 4.98 (q, J=8.8Hz, 2H), 7.55-7.58 (dd, J=1.6Hz & 8.4Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.84 (d, J=1.6Hz, 1H) [ka]

[0326] Synthesis of 1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7m): Using the general procedure for compound-7, compound-6m (1g, 4.24 mmol) was converted to compound-7m (350mg, crude). After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 266.1 [M+H] + ;H-NMR (DMSO-d6, 400MHz):δ 0.97-0.98(m,4H), 2.77(bs,2H), 4.86(q,J=8.4Hz,2H), 6.96-6.98(dd,J=2.4Hz&8.4Hz,1H), 7.14(d,J=2.4Hz,1H), 7.34(d,J=8.4Hz,1H) [ka]

[0327] Example 19: N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (Example 19 Peak-1 & Example 19 Peak-2): [ka]

[0328] Following the general procedure for compound-8, compound-4d (100 mg, 0.37 mmol) was converted to Example 19 (100 mg, 57%) as an off-white solid using compound-7m. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and MeOH:IPA 1:1 (B); flow rate: 15 mL / min; isocratic: 88 (A):12 (B); diluent: EtOH:DCM (1:1, 5 mL); injection volume: 0.4 mL; run time: 15 min), and peak-1 (30 mg) and peak-2 (31 mg) were obtained as colorless gum-like oil; 1H-NMR (DMSO-d6, 400 MHz): δ 0.93-0.97(m,2H), 1.13-1.24(m,2H), 1.49(s,3H), 2.59-2.77(m,2H), 4.76(q,J=8.8Hz&17.6Hz,2H), 5.99(s,1H), 6.47 -6.50(dd,J=4Hz,1H), 6.74-6.75(m,1H), 7.03-7.07(m,1H), 7.13-7.21(m,2H), 7.55-7.62(m,1H), 8.63(s,1H);HRMS:[C 21 H 19 [ClF5NO3+H-H2O] +Calculated value: 446.0941; Measured value: 446.0949 (Example 19 Peak-1), 446.0947 (Example 19 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 90:10 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_9010_7_C_30MIN.amx.; Peak-1 (Rt: 3.321, 100%ee) Peak-2 (Rt: 5.602, 100%ee)

[0329] Example 20: Synthesis of N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)benzonitrile (6n): Using the general procedure for compound-6, 3-(difluoromethyl)-5-hydroxybenzonitrile (1 g, 2.95 mmol) was converted to 6n (550 mg, 74%). ¹H-NMR (DMSO-d6, 400 MHz): δ 4.95 (q, J=8.7 Hz, 2H), 7.05 (t, J=55.2 Hz, 1H), 7.62 (s, 1H), 7.75 (s, 1H), 7.81 (s, 1H) [ka]

[0330] Synthesis of 1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7n): Using the general procedure for compound-7, compound-6n (700 mg, 2.78 mmol) was converted to compound-7n (170 mg, 22%). After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 282.1 [M+H] + ;H-NMR (DMSO-d6, 400MHz): δ 0.98-1.17(m,4H), 2.93(bs,2H), 4.82(q,J=8.8Hz,2H), 6.94(t,J=50.4Hz,1H), 6.93(s,1H), 7.13(s,1H), 7.17(s,1H) [ka]

[0331] Example 20: Synthesis of N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (Example 20 Peak-1 & Example 20 Peak-2): [ka]

[0332] Following the general procedure for compound-8, compound-4d (80 mg, 0.28 mmol) was converted to Example 20 (50 mg, 37%) as an off-white solid using compound-7n. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH 1:1 (B); flow rate: 15 mL / min; isocratic: 85 (A):15 (B); diluent: EtOH:DCM (1:1, 4 mL); injection volume: 0.4 mL; run time: 11 min), and peak-1 (15 mg) and peak-2 (14 mg) were obtained as colorless gum-like oil; 1H-NMR (DMSO-d6, 400 MHz): δ 0.99-1.06(m,2H), 1.14(s,2H), 1.49(s,3H), 2.66-2.74(m,2H), 4.76(q,J=8.8Hz&17.6Hz,2H ), 5.94(s,1H), 6.73-7.01(m,5H), 7.09-7.15(m,1H), 7.57-7.63(m,1H), 8.63(s,1H);HRMS:[C 22 H 20 [F7NO3+H-H2O] +Calculated value: 462.1299; Measured value: 462.1306 (Example 20 Peak-1), 462.1306 (Example 20 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50), Isocratic: 90:10 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_9010_7_C_30MIN.amx.; Peak-1 (Rt: 3.72, 100%ee) Peak-2 (Rt: 6.011, 100%ee)

[0333] Example 21: Synthesis of N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-amine (7k'): Using the general procedure for compound-7, compound-6k (1g, 3.57 mmol) was converted to compound-7k' (300mg, 35%). After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 311.1 [M+H] + [ka]

[0334] Example 21: Synthesis of N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (Example 21 Peak-1 & Example 21 Peak-2): [ka]

[0335] Following the general procedure for compound-8, compound-4d (100 mg, 0.462 mmol) was converted to Example 21 (25 mg, 18%) as an off-white solid using compound-7k'. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and MeOH:IPA 1:1 (B); flow rate: 15 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM (1:1, 2 mL); injection volume: 0.5 mL; run time: 14 min), and peak-1 (7.7 mg) and peak-2 (7.8 mg) were obtained as colorless gum-like oil; 1H-NMR (DMSO-d6, 400 MHz): δ 0.90-0.94(m,2H), 1.15-1.23(m,2H), 1.49(s,3H), 2.61-2.72(m,2H), 4.76(q,J=8.8Hz,2H), 5.94(s,1H) ,6.60(s,1H),6.88(s,1H),6.99-7.02(m,1H),7.07-7.12(m,2H),7.61-7.62(m,1H),8.58(s,1H);HRMS:[C 21 H 19 [BrF5NO3+H-H2O] + Calculated value: 490.0436; Measured value: 490.0443 (Example 21 Peak-1), 490.0443 (Example 21 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm), Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 85:15 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_8515_7_C-30 min. amx. Peak-1 (Rt: 2.74, 100% ee) Peak-2 (Rt: 3.54, 100% ee)

[0336] Example 22: Synthesis of N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 3-Cyclopropyl-5-(2,2,2-trifluoroethoxy)benzonitrile (6o): In a sealed test tube, 3-bromo-5-(2,2,2-trifluoroethoxy)benzonitrile (500 mg, 1.78 mmol) was packed in toluene:water (5:1). Cyclopropylboronic acid (766 mg, 8.92 mmol), K3PO4 (1.13 g, 3.35 mmol), tricyclohexylphosphine (25.8 mg, 0.08 mmol), and palladium(II) acetate (20.3 mg, 0.08 mmol) were added at room temperature under an argon atmosphere. The resulting mixture was purged under an argon atmosphere for 10 minutes and stirred at 100°C for 12 hours. After the reaction was complete, water was added and extracted with RINKAN (3 x 10 mL). All organic layers were combined, washed with brine, and concentrated under reduced pressure to obtain crude compound-6o. The crude material was purified by combifling (12g column, eluate with 0-10% phenylethylamine in hexane) to obtain pure compound-6o (300mg, 80%) as an off-white solid; 1H-NMR (DMSO-d6, 400MHz): δ 0.78-0.79 (m,2H), 0.97-0.99 (m,2H), 1.96 (bs,1H), 4.84 (q,J=8.8Hz,2H), 7.09 (s,1H), 7.24 (s,1H), 7.32 (s,1H) [ka]

[0337] Synthesis of 1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl))cyclopropane-1-amine (7o): Using the general procedure for compound-7, compound-6o (300 mg, 1.24 mmol) was converted to compound-7o (150 mg, 38%). After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 272.0 [M+H] + [ka]

[0338] Example 22: Synthesis of N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (Example 22 Peak-1 & Example 22 Peak-2): [ka]

[0339] Following the general procedure for compound-8, compound-4d (100 mg, 0.368 mmol) was converted to Example 22 (40 mg, 35%) as an off-white solid using compound-7o. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and EtOH:IPA 1:1 (B); flow rate: 15 mL / min; isocratic: 80 (A):20 (B); diluent: EtOH:DCM (3:1, 5 mL); injection volume: 0.2 mL; run time: 15 min), and peak-1 (13.2 mg) and peak-2 (10 mg) were obtained as colorless gum-like oil; 1H-NMR (DMSO-d6, 400 MHz): δ 0.28-0.37(m,2H), 0.88-0.92(m,4H), 1.09(s,1H), 1.48(s,3H), 1.73-1.79(m,1H), 2.51-2.76(m,3H), 4.68(d,J=8.8H) HRMS:[C 24 H 24 F5NO3+H] +Calculated value: 470.1749; Measured value: 470.1757 (Example 22 Peak-1), 470.1755 (Example 22 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 85:15 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_8515_7_C-15 min.amx. Peak-1 (Rt: 2.612, 100% ee) Peak-2 (Rt: 3.426, 100% ee)

[0340] Example 23: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide Synthesis of ethyl 3-(2,6-difluorophenyl)-3-hydroxybutanoate (3j): Using general procedure A for compound-3, 1-(2,6-difluorophenyl)ethane-1-one (1 g, 6.40 mmol) was converted to compound-3j (1.7 g, crude product) and used in the next step without purification. ¹H-NMR (DMSO-d6, 400 MHz): δ 1.16 (t, J=7.2, 3H), 1.69 (s, 3H), 2.77 (d, J=15 Hz, 1H), 3.25 (d, J=15 Hz, 1H), 4.06-4.11 (q, J=7.2 Hz, 2H), 4.56 (bs, 1H), 6.88-6.81 (m, 2H), 6.97-6.95 (m, 1H) [ka]

[0341] Synthesis of 3-(2,6-difluorophenyl)-3-hydroxybutanoic acid (4j): Using the general procedure for compound-4, compound-3j (1.5g, 6.14 mmol) was converted to compound-4j (1g, 76.92%) as a yellow gum. ¹H-NMR (CDCl3, 400MHz): δ 1.70 (s, 3H), 2.85 (d, J=16.8Hz, 1H), 3.30 (d, J=16.8Hz, 1H), 6.88-6.83 (m, 2H), 7.26-7.18 (m, 1H) [ka]

[0342] Example 23: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide (Example 23 Peak-1 & Example 23 Peak-2): [ka]

[0343] Following the general procedure for compound-8, compound-4j (0.2 g, 0.927 mmol) was converted to Example 23 (180 mg, 42%) using compound-7b. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm; eluate: n-hexane (A) and IPA:EtOH 1:1 (B); flow rate: 15 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM, 1:1, 3.5 mL; injection volume: 0.4 mL; run time: 20 min), yielding peak-1 (58.18 mg) and peak-2 (62.05 mg). 1 H NMR (400MHz, CDCl3)δ ppm 0.87-1.01(m,1H), 1.10-1.22(m,3H), 1.67(s,3H), 2.71(d,J=15.11Hz,1H), 3.06(d,J=15.11Hz,1H), 4.27(q,J=8.07Hz) HRMS:[C 21 H 19 ClF5NO3+H] +Calculated value: 464.1052; Measured value: 464.1055 (Example 23 Peak-1), 464.1067 (Example 23 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:EtOH (50:50) Isocratic: 85:15 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Acq. method: IH_8515_7_C-30 min. amx. Peak-1 (Rt: 4.961, 100% ee) Peak-2 (Rt: 11.357, 100% ee)

[0344] Example 24: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide Synthesis of ethyl 3-(3,4-difluorophenyl)-3-hydroxybutanoate (3K): Using the general procedure A for compound-3, 1-(3,4-difluorophenyl)ethane-1-one (1 g, 6.40 mmol) was converted to compound-3k (0.5 g, 33.33%) as a colorless gum. 1 H NMR (300MHz, DMSO-d6)δ 1.04(q,J=7.2Hz,3H), 1.51(s,3H), 2.77(dd,J=14Hz,2H), 3.92(q,J=7.2Hz,2H), 5.44(bs,1H), 7.36-7.24(m,2H), 7.48-7.42(m,1H) [ka]

[0345] Synthesis of 3-(3,4-difluorophenyl)-3-hydroxybutanoic acid (4k): Using the general procedure for compound-4, compound-3k (0.5g, 2.047 mmol) was converted to compound-4k (0.4g, 90.47%) as a pale reddish gum. 1 H NMR (300MHz, DMSO-d6)δ 1.47(s,3H), 2.67(dd,J=14Hz,2H), 7.30-7.25(m,2H), 7.47-7.40(m,1H) [ka]

[0346] Example 24: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide (Example 24 Peak-1 & Example 24 Peak-2): [ka]

[0347] Following the general procedure for compound-8, compound-4k (0.15 g, 0.693 mmol) was converted to Example 24 (190 mg, 59.37%) using compound-7b. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 150 mm x 4.6 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH 1:1 (B); flow rate: 1 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH; injection volume: 5 mL; run time: 15 min) to obtain peak-1 (75.8 mg) and peak-2 (80.5 mg). 1 H NMR (400MHz, DMSO-d6) δ ppm 0.94-0.97(m,2H), 1.17-1.20(m,2H), 1.45(s,3H), 2.56(d,J=14Hz,1H), 2.70(d,J=14Hz,1H), 4.75(q,J=8.8Hz,2H), 5.75(s HRMS:[C 21 H 19 [ClF5NO3+H-H2O] +Calculated value: 446.0941; Measured value: 446.0955 (Example 24 Peak-1), 446.0957 (Example 24 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 90:10 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Peak-1 (Rt: 3.613, 100% ee) Peak-2 (Rt: 5.134, 100% ee)

[0348] Example 25: Synthesis of 3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide Synthesis of ethyl 3-(2-bromo-6-fluorophenyl)-3-hydroxybutanoate (3L): 1-(2-bromo-6-fluorophenyl)ethane-1-one (0.5 g, 2.30 mmol) was converted to compound-3l (0.36 g, 51.30%) using the general procedure A used for compound-3. m / z (LC-MS): 288.90 [M-17+H] + ; 1 H NMR (400MHz, DMSO-d6)δ 1.16(t,J=7.2Hz,3H), 1.57(s,3H), 2.79(dd,J=4.4Hz&16.4Hz,1H), 2.83(dd,J=4.4Hz& 16.4Hz,1H), 4.09(q,J=7.2Hz,2H), 4.50(bs,1H), 6.94-7.07(m,2H), 7.43-7.45(m,1H) [ka]

[0349] Synthesis of 3-(2-bromo-6-fluorophenyl)-3-hydroxybutanoic acid (4L): Compound-4 was subjected to hydrolysis using the same general procedure as for Compound-4, yielding 4L (0.450g, 91.83%). m / z (LC-MS): 274.95 [MH] + [ka]

[0350] Example 25: Synthesis of 3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 25 Peak-1 & Example 25 Peak-2): [ka]

[0351] Following the general procedure used for compound-8, compound-4l (0.45g, 1.62 mmol) was converted to Example 25 (0.68g, 59.37%) using compound-7b. The enantiomer was separated on a 30 mg scale using a chiral SFC (column: Chiral Pack-IG, 4.6 mm x 150 mm x 5 μm, cosolvent: IPA:EtOH:MeOH (1:1:1); flow rate: 3 mL / min, injection volume: 15 μl, outlet pressure: 100 bar; temperature: 40 °C), yielding peak-1 (8.8 mg) and peak-2 (8.2 mg). 1 H NMR (400MHz, DMSO-d6) δ ppm 1.15-1.18(m,2H), 1.21-1.33(m,2H), 1.60(s,3H), 2.70-2.74(dd,J=2.8Hz&14.8Hz,1H), 3.07-3.02(dd,J=2.8Hz&14.8Hz,1H ), 4.75(q,J=8.8Hz,2H), 5.70(s,1H), 6.58(bs,1H), 6.74(s,1H), 7.10-7.19(m,2H), 7.43-7.45(m,2H), 8.52(s,1H);HRMS:[C 21 H 19 [BrClF4NO3+H] +Calculated value: 524.0251; Measured value: 524.0243 (Example 25 Peak-1), 524.0260 (Example 25 Peak-2); Chiral HPLC for analysis: (Chiral Pack-IG, 4.6 mm x 150 mm x 5 μm), Cosolvent name: IPA:EtOH:MeOH (1:1:1); Flow rate: 3 mL / min, Injection volume: 15 μl, Outlet pressure: 100 bar; Temperature: 40°C. Acq. Method: C: / Pic Solution / Methode / Analytical / 3-20-30Min.met. Peak-1 (Rt: 1.86, 100%ee) Peak-2 (Rt: 2.51, 100%ee)

[0352] Example 26: N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl ) Synthesis of -3-hydroxybutanamide Synthesis of 2-chloro-6-(2,2,2-trifluoroethoxy)isonicotinonitrile (6p): To a stirred solution of 2,6-dichloroisonicotinonitrile (1 g, 5.7803 mmol) in acetonitrile (10 vol.), K2CO3 (0.798 g, 5.7803 mmol) and 2,2,2-trifluoroethanol (0.34 mL, 4.6242 mmol) were added. The resulting reaction mixture was stirred overnight at room temperature and quenched with water. The reaction mixture was extracted with toluene (3 x 10 vol.). The organic layer was dried over anhydrous sodium toluene (Na2SO4) and concentrated under high vacuum to obtain the crude compound, which was purified by combiflash chromatography (5-10% toluene in hexane) to obtain a sufficiently pure compound-6p (600 mg, 44.11%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ ppm 5.05(q,J=8.8Hz,2H), 7.6(s,1H), 7.9(s,1H) [ka]

[0353] Synthesis of 1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropan-1-amine (7p): Compound-6p (0.4 g, 1.60 mmol) was converted to compound-7p (60 mg, 26.66%) using the general procedure used for compound-7. After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 266.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ ppm 1.07-1.09(m,4H), 4.94(q,J=9.2Hz,2H), 6.87(d,J=1.2Hz,1H), 7.07(d,J=1.2Hz,1H) [ka]

[0354] Example 26: Synthesis of N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide (Example 26 Peak-1 & Example 26 Peak-2): [ka]

[0355] Following the general procedure for compound-8, compound-4k (0.48 g, 0.22 mmol) was converted to Example 26 (70 mg, 47.61%) using compound-7p. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 20 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH 1:1 (B); flow rate: 15 ml / min; isocratic: 90 (A):10 (B); diluent: EtOH:DCM, 1:1, 3 mL; injection volume: 0.5 mL; run time: 20 min) to obtain peak-1 (14.6 mg, Rt: 4.315) and peak-2 (13.1 mg, Rt: 5.080). 1H NMR (400MHz, DMSO-d6) δ ppm 1.02-1.06(m,2H), 1.23-1.34(m,2H), 1.63(s,3H), 2.74(d,J=14.4Hz,1H), 2.86(d,J=14.4Hz,1H), 4.92(q,J=8.95Hz, HRMS:[C 20 H 18 [CLF5N2O3+H] + Calculated value: 465.1004; Measured value: 465.1011 (Example 26 Peak-1), Measured value: 465.1014 (Example 26 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-hexane (B) IPA: methanol (50:50), Isocratic: 90:10 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Peak-1 (Rt: 4.315, 100% ee) Peak-2 (Rt: 5.080, 100% ee)

[0356] Example 27: Synthesis of 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide Synthesis of 2-fluoro-5-(2,2,2-trifluoroethoxy)benzonitrile (6q): 2-Fluoro-5-hydroxybenzonitrile (300 mg, 0.365 mmol) was converted to compound-6q (380 mg, 79.33%) as a white crystalline solid using the general procedure used for compound-6. m / z (LC-MS): 250.05 [M+H] + ;H NMR(300MHz, DMSO-d6)δ ppm 4.85(q,J=8.7Hz,2H), 7.48-7.53(m,2H), 7.68-7.71(m,1H) [ka]

[0357] Synthesis of 1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7q): Compound-6q (0.08 g, 0.365 mmol) was converted to compound-7q (45 mg, 7.9%) using the general procedure used for compound-7. After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 250.05 [M+H] + [ka]

[0358] Example 27: Synthesis of 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 27 Peak-1 & Example 27 Peak-2): [ka]

[0359] Following the general procedure for compound-8, compound-4d (0.043 g, 0.198 mmol) was converted to Example 27 (20 mg, 22%) using compound-7q. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack-IG (250 x 4.6 mm x 5 μm), mobile phase: (A)n-hexane(B)IPA:methanol (50:50), flow rate: 15 mL / min, isocratic: 93(A):07(B), diluent: EtOH:DCM, 1:1, 2 mL, injection volume: 0.35 mL, run time: 14 min), yielding peak-1 (1.5 mg) and peak-2 (2.1 mg); 1H NMR (400 MHz, CDCl3) δ ppm 0.83-0.96(m,2H), 0.92-1.02(m,2H), 1.47(s,3H), 2.55(d,J=14.4, 1H), 2.80(d,J=14.4, 1H), 4.28(q,J=6.8Hz,2H ), 5.39(s,1H), 6.28(bs,1H), 6.59-6.67(m,2H), 6.72-6.76(m,1H), 6.82-6.92(m,2H), 7.46-7.53(m,1H);HRMS:[C 21 H 19 [F6NO3+H-H2O] + Calculated value: 430.1242; Measured value: 430.1246 (Example 27 Peak-1), 430.1245 (Example 27 Peak-2); Chiral HPLC for analysis: Chiral Pack-IG (150 x 4.6 mm x 5 μm), Mobile phase: (A) n-Hexane (B) IPA:Methanol (50:50), Isocratic: 95:05 (A:B), Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Peak-1 (Rt: 5.00, 100% ee) Peak-2 (Rt: 7.60, 100% ee)

[0360] Example 28: Synthesis of (R)-N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 1-(4,6-dichloropyridine-2-yl)cyclopropane-1-amine(7r): 4,6-Dichloropicolinonitrile (0.5 g, 2.890 mmol) was converted to compound-7r (45 mg, 7.9%) using the general procedure used for compound-7. After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 202.95 [M+H] + [ka]

[0361] Synthesis of (R)-3-(2,4-difluorophenyl)-3-hydroxybutanoic acid (R-4d) [ka]

[0362] Synthesis of (R)-3-acetyl-4-benzyloxazolidine-2-one (2): A stirring solution of (R)-4-benzyloxazolidine-2-one (50 g, 1.0 equivalent, 282.16 mmol) in anhydrous tetrahydrofuran (10 vols) was stirred for 10 minutes. The reaction mixture was cooled to -78°C, and n-butyllithium (2.5 M in hexane) (113.99 mL, 1.01 equivalent, 284.98 mmol) was added dropwise (30 minutes), and the reaction mixture was stirred for approximately 30 minutes. Acetyl chloride solution (22.29 mL, 1.1 equivalent, 310.38 mmol) was added dropwise at the same temperature (15 minutes). The reaction mixture was then heated to room temperature and stirred for a further 1 hour. The resulting mixture was monitored by TLC and LCMS. After the reaction was quenched with saturated NH4Cl solution (2 vols), it was extracted with RINKAN (3 x 10 vols). The organic layer was washed with water (3 x 100 mL) and brine solution (1 x 10 volumes). The resulting organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain an off-white product (55.6 g, 253.18 mmol, 89.88%). m / z (LC-MS): 220.15 [M+H] +;H NMR (300MHz, CDCl3)δ ppm 2.55(s,3H), 2.73-2.81(m,1H), 3.27-3.32(m,1H), 4.17-4.23(m,2H), 4.64-4.69(m,1H), 7.19-7.21(m,2H), 7.25-7.36(m,3H) [ka]

[0363] Synthesis of (R)-4-benzyl-3-((R)-3-(2,4-difluorophenyl)-3-hydroxybutanoyl)oxazolidine-2-one (3a): Compound-2 (50 g, 228.06 mmol, 1 equivalent) was added dropwise to a stirred solution of lithium bis(trimethylsilyl)amide (228.06 mL, 228.06 mmol, 1 equivalent) under an argon atmosphere at -78°C over 45 minutes using 10 volumes of anhydrous THF. The reaction mixture was then stirred at -78°C for 2 hours, followed by the addition of 2,4-difluoroacetophenone (32.37 mL, 228.06 mmol, 1 equivalent) in 6 volumes of anhydrous THF over 30 minutes at -78°C. The reaction mixture was then stirred at -78°C for 1 hour. The resulting mixture was monitored by TLC and LCMS. After completion, the reaction mixture was quenched at -78°C with 0.5 M HCl (2 volumes), the temperature was slowly raised to room temperature (30 minutes), extracted with ethyl acetate (3 x 10 volumes), all organic layers were combined, washed with water (2 x 10 volumes) and brine solution (2 x volumes), and concentrated under vacuum to obtain the crude material. To obtain a clarified solution, the crude material was recrystallized with 1:1 IPA and t-butanol (10 volumes) and heated at 50°C for 10 minutes. The resulting solution was allowed to stand for 24 hours to form crystals. It was filtered through a Buchner funnel and washed with 1 volume of 1:1 IPA and t-butanol to obtain pure (R)-4-benzyl-3-((R)-3-(2,4-difluorophenyl)-3-hydroxybutanoyl)oxazolidine-2-one 3a (19.1 g, 22.31%). The filtrate contained a mixture of diastereomers (44 g crude, approximately 1:1 ratio). m / z (LC-MS): 358.1 [M-17] + ;Chiral HPLC: 99.41%, Rt=11.70 min;H NMR (300MHz, CDCl3)δ ppm 1.63(s,3H), 2.56-2.63(m,1H), 2.96(d,J=13.2Hz,1H), 3.28(d,J=17.1Hz,1H), 4.08-4.23(m,3H), 4.60-4.6 3(m,2H), 6.79(t,J=9Hz,1H), 6.89(t,J=7.8Hz,1H), 7.04-7.05(m,2H), 7.27-7.29(m,3H), 7.67-7.75(m,1H) [ka]

[0364] Synthesis of (R)-3-(2,4-difluorophenyl)-3-hydroxybutanoic acid (R-4d): To a solution of 3a (9 g, 23.97 mmol, 1 equivalent) in tetrahydrofuran and water (4:1, 15 vol.), hydrogen peroxide (9.8 mL, 95.90 mmol, 4 equivalents) was added. The reaction mixture was cooled to 0°C, and lithium hydroxide monohydrate (4.02 g, 95.90 mmol, 4 equivalents) was added. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction product was diluted with water (3 x 10 vol.) and extracted with dichloromethane (5 x 3 vol.) to remove impurities from by-products. The aqueous solution was acidified with 1N HCl and extracted with dichloromethane (4 x 20 vol.). All organic layers were combined, washed with water (3x2 volume) and brine (1x5 volume), and concentrated under reduced pressure to obtain the crude compound as a pale yellow gum (5g, 96.52%), which was used in the next step without any purification. m / z (LC-MS): 215.1 [M-1] + ;Chiral HPLC: 11.70 min, 93.12%;H NMR (300MHz, DMSO-d6)δ ppm 1.52(s,3H), 2.68-2.78(m,2H), 5.56(bs,1H), 7.01-7.16(m,2H), 7.57-7.66(m,1H), 12.10(bs,1H) [ka]

[0365] Example 28: Synthesis of (R)-N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: [ka]

[0366] Following the general procedure for compound-8, enantiopurine compound-4d (0.047 g, 0.221 mmol) was converted to Example 28 (3 mg, 5.05%) using compound-7r. This was then purified by preparative HPLC (column: X SELECT (250 mm x 20.0 mm), 5.0 μm, eluate: 0.1% HCOOH (A) and ACN (B) in water, flow rate: 15 ml / min, gradient programmer: time (%B): 0 / 30, 2 / 40, 6 / 75). H NMR (400MHz, DMSO-d6) δ ppm 1.02-1.09(m,2H), 1.32-1.36(m,2H), 1.52(s,3H), 2.65(d,J=14.4Hz,1H), 2.70(d,J=14.4Hz,1H), 5.97(s, HRMS:[C 18 H 16 Cl2F2N2O2+H] + Calculated value: 401.0635; Measured value: 401.0644; Chiral HPLC for analysis: Column: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm), Mobile phase: (A) n-hexane (B) 0.1% HCOOH in methanol: methanol (80:20), Isocratic: 70:30 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 10, (Rt: 4.40, 97.11%)

[0367] Example 29: Synthesis of (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 4-chloro-2-(2,2,2-trifluoroethoxy)pyridine: To a stirred suspension of sodium hydride (3.04 g, 76.0244 mmol) in anhydrous DMF (80 mL), a solution of 2,2,2-trifluoroethane-1-ol (7.6055 g, 76.0244 mmol) in anhydrous DMF (10 mL) was added at 0°C. After stirring at 0°C for 15 minutes, a solution of 4-chloro-2-fluoropyridine (10 g, 76.0244 mmol) in anhydrous DMF (20 mL) was added. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated ammonium chloride solution and extracted with siRNA (3 x 200 mL). The resulting organic layers were combined, washed with brine, and dried on anhydrous Na₂SO₄. The organic layer was removed under vacuum to obtain the crude product, which was purified by flash chromatography (eluent: HCl:hexane 5:95) to obtain 4-chloro-2-(2,2,2-trifluoroethoxy)pyridine (10.2 g, 63.43%) as a colorless liquid; m / z (LC-MS): 211.95 [M+H] + [ka]

[0368] Synthesis of 4-chloro-2-(2,2,2-trifluoroethoxy)pyridine 1-oxide: To a stirred solution of 4-chloro-2-(2,2,2-trifluoroethoxy)pyridine (10.2 g, 48.211 mmol) in TFA (42 mL), hydrogen peroxide (22 mL) was added at 0°C. The reaction mixture was stirred overnight at 80°C. The reaction mixture was concentrated under vacuum, diluted with water, cooled to 0°C, and then slowly stabilized with ammonium hydroxide solution until the pH was 7-8. The resulting solution was extracted by DCM. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain crude 4-chloro-2-(2,2,2-trifluoroethoxy)pyridine·1-oxide (7.6 g, 69.27%) as an off-white solid; m / z (LC-MS): 227.90 [M+H] + [ka]

[0369] Synthesis of 4-chloro-6-(2,2,2-trifluoroethoxy)picolinonitrile: In a 250 ml sealed test tube, 4-chloro-2-(2,2,2-trifluoroethoxy)pyridine·1-oxide (7.5 g, 32.957 mmol) was stirred in acetonitrile (70 mL), to which trimethylsilyl cyanide (22.65 mL, 164.78 mmol) and triethylamine (22.96 mL, 164.78 mmol) were added at room temperature. The reaction mixture was stirred overnight at 80 °C. The reaction mixture was concentrated under vacuum and filtered through a Celite bed. The filtrate was diluted with water and extracted with ethylethanol (3 x 200 mL). The organic layers were combined, washed with brine, and concentrated under vacuum to obtain the crude product, which was purified by flash chromatography (eluent:ethylethanol:hexane 20:80) to obtain 4-chloro-6-(2,2,2-trifluoroethoxy)picolinonitrile (2.5 g, 32.09%) as a yellow liquid. H-NMR (CDCl3, 400MHz) δ ppm 4.79(s,2H), 7.15(d,J=1.47Hz,1H), 7.41(d,J=1.47Hz,1H) [ka]

[0370] Synthesis of 1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropan-1-amine(7s): 4-Chloro-6-(2,2,2-trifluoroethoxy)picolinonitrile (1.2 g, 5.072 mmol) was converted to compound-7s (700 mg, 51.85%) using the general procedure used for compound-7. After acidification with 4 M HCl in dioxane, the compound was extracted as the HCl salt; m / z (LC-MS): 166.85 [M+H] + [ka]

[0371] Example 29: Synthesis of (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: [ka]

[0372] Following the general procedure for compound-8, enantiopurine compound-4d (0.040 g, 0.187 mmol) was converted to Example 29 (13.3 mg, 44.33%) using compound-7s, and Example 29 was obtained by preparative HPLC (column: X-Select (250 mm x 20.0 mm), 5.0 μm), eluate: A = 0.1% HCOOH in water, B = ACN, flow rate: 15 ml / min). H-NMR (DMSO-d6, 400MHz): δ ppm 0.96-1.01(m,2H), 1.44-1.47(m,2H), 1.52(s,3H), 2.68(d,J=14Hz,1H), 2.81(d,J=14Hz,1H), 4.9(q,J=9.10Hz,2H), 6.01(s,1H) ), 6.78(d,J=1.61Hz,1H), 6.89(d,J=1.61Hz,1H), 7.01-7.06(m,1H), 7.14-7.20(m,1H), 7.62-7.69(m,1H), 8.65(s,1H);HRMS:[C 20 H 18 [CLF5N2O3+H] + Calculated value: 465.1004; Measured value: 465.1010; Chiral HPLC for analysis: Column: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm), Mobile phase: (A) n-hexane (B) EtOH with 0.1% DEA:MeOH (70:30), Isocratic: 70:30 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, (Rt: 4.08, 98.90%)

[0373] Example 30: Synthesis of 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide Synthesis of 6-((2,2,2-trifluoroethyl)amino)picolinonitrile: 6-fluoropiccolinonitrile (1 g, 8.18 mmol, 1 equivalent) was stirred in DMSO (10 vol.), to which 2,2,2-trifluoroethylamine (0.97 mL, 9.82 mmol) was added. The resulting reaction mixture was heated in a preheated oil bath at 150°C for 16 hours. The reaction mixture was quenched with water and extracted with toluene (3 x 20 vol.) to obtain the crude compound. This was purified by combiflash chromatography (eluent: toluene:hexane 1:3) to obtain 6-((2,2,2-trifluoroethyl)amino)piccolinonitrile (0.8 g, 50%) as an off-white solid; m / z (LC-MS): 201.95 [M+H] + [ka]

[0374] Synthesis of 6-(1-aminocyclopropyl)-N-(2,2,2-trifluoroethyl)pyridine-2-amine: 6-((2,2,2-trifluoroethyl)amino)picolinonitrile (0.4 g, 1.98 mmol) was converted using the general procedure used for compound-7, yielding 7t (0.2 g, 44%) as a yellow solid. m / z (LC-MS): 232.15 [M+H] + [ka]

[0375] Example 30: Synthesis of 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide (Example 30 Peak-1 & Example 30 Peak-2): [ka]

[0376] Following general procedure 8, compound-4j (0.103 g, 0.472 mmol) was converted to Example 30 (33 mg, 17.83%) using compound-7t. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 150 mm x 4.6 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH 1:1 (B); flow rate: 1 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH; injection volume: 5 mL; run time: 20 min), and peak-1 (8.9 mg) and peak-2 (6.4 mg) were obtained as off-white solids. 1 H NMR (400MHz, DMSO-d6) δ ppm 0.81-0.86(m,2H), 1.23-1.35(m,2H), 1.63(s,3H), 2.69(d,J=14Hz,1H), 2.9(d,J=14Hz,1H), 3.98-4.05(m,2H), 5.75(s,1H), 5.98(d, J=7.6Hz,1H), 6.27(d,J=7.6Hz,1H), 6.95-7.03(m,3H), 7.07-7.12(m,1H), 7.33-7.38(m,1H), 8.66(s,1H);HRMS:m / z(LC-MS):430.05 [M+H] + ;HRMS:[C 20 H 20 F5N3O2+H] + Calculated value: 430.1554; Measured value: 430.1554 (Example 30 Peak-1), 430.1558 (Example 30 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 85:15 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 12.000; Peak-1 (Rt: 9.549, 100% ee) Peak-2 (Rt: 12.546, 100% ee)

[0377] Example 31: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of 1-bromo-3-methoxy-5-(2,2,2-trifluoroethoxy)benzene: Using the general procedure for compound-6, 3-bromo-5-methoxyphenol (1 g, 4.92 mmol) was converted to 1-bromo-3-methoxy-5-(2,2,2-trifluoroethoxy)benzene (1.6 g, crude product). H-NMR (CDCl3, 300MHz): δ 3.77(s,3H), 4.30(q,J=8.7Hz,2H), 6.42(s,1H), 6.67(s,1H), Hz,2H), 6.74(s,1H) [ka]

[0378] Synthesis of 3-methoxy-5-(2,2,2-trifluoroethoxy)benzonitrile (6u): To a stirred solution of 1-bromo-3-methoxy-5-(2,2,2-trifluoroethoxy)benzene (0.7 g, 2.45 mmol, 1 equivalent) in DMF (10 vol.), ZnCN2 (1.16 g, 9.82 mmol, 4 equivalents) was added. The resulting reaction mixture was degassed with argon, and tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.240.1 equivalents) was added. The reaction mixture was heated in a MW at 120°C for 1 hour. The reaction mixture was diluted with cold water and extracted with siRNA (3 x 5 vol.), and the combined layers were separated. The organic phases were combined, dried on anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography using silica gel and ethyl acetate and hexane as solvents to obtain the compound 6u as an off-white solid. H-NMR (DMSO-d6, 300MHz): δ 3.82(s,3H), 4.36(q,J=8Hz,2H), 6.72-6.71(m,1H), 6.79-6.78(m,1H), 6.87-6.86(m,1H) [ka]

[0379] Synthesis of 1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-amine (7u): 6u (0.75g, 3.24 mmol) of 3-methoxy-5-(2,2,2-trifluoroethoxy)benzonitrile was converted to compound-7u (0.3g, 35.41%) according to general procedure A for compound-7. m / z (LC-MS): 262.0[M+H] + [ka]

[0380] Example 31: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 31 Peak-1 & Example 31 Peak-2): [ka]

[0381] Following the general procedure for compound-8, compound-4d (0.13 g, 0.49 mmol) was converted to Example 31 (45 mg, 20.20%) using compound-7u. The enantiomers were separated using chiral preparative HPLC (column: Chiral Pack IH, 150 mm x 4.6 mm, 5 μm; eluate: n-hexane (A) and IPA:MeOH 1:1 (B); flow rate: 1 mL / min; isocratic: 90 (A):10 (B); diluent: EtOH; injection volume: 10 mL; run time: 15 min) to obtain peak-1 (10.9 mg) and peak-2 (11 mg). H NMR (400MHz, DMSO-d6) δ ppm 0.77-0.88(m,2H), 1.01-1.15(m,2H), 1.56(s,3H), 2.63(d,J=14Hz,1H), 2.92(d,J=14Hz,1H), 3.72(s,3H), 4.24(q,J=8.4 HRMS:[C 22 H 22 F5NO4+H]+ Calculated value: 460.1547; Measured value: 460.1558 (Example 31 Peak-1), 460.1555 (Example 31 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm) Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50) Isocratic: 90:10 (A:B) Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Peak-1 (Rt: 4.0, 100% ee) Peak-2 (Rt: 5.888, 100% ee)

[0382] Example 32: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide Synthesis of ethyl 3-(2,4-difluorophenyl)buta-2-enoate: Triethyl phosphonoacetate (4.02 g, 17.93 mmol) was added to a stirred suspension of sodium hydride (0.768 g, 19.214 mmol) in anhydrous THF (20 mL) at 0°C. To the resulting reaction mixture, a stirred solution of 1-(2,4-difluorophenyl)ethane-1-one (2 g, 12.81 mmol) in anhydrous THF (20 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction product was quenched with a saturated ammonium chloride solution and extracted with SiO2 (2 x 50 mL). The resulting organic layers were combined, washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum to obtain ethyl 3-(2,4-difluorophenyl)buta-2-enoate (2.4 g, 82.84%) as a colorless liquid. m / z (LC-MS): 226.95 [M+H] + ;H-NMR (CDCl3, 300MHz): δ 1.31(t,J=6.9Hz,3H), 2.50(s,3H), 4.21(q,J=6.9Hz,2H), 5.96(s,3H), 6.79-6.95(m,2H), 7.21-7.29(m,1H) [ka]

[0383] Synthesis of ethyl 3-(2,4-difluorophenyl)butanoate: To a stirred solution of ethyl 3-(2,4-difluorophenyl)buta-2-enoate (500 mg, 2.210 mmol) in anhydrous HCl (10 mL), Pd-C (10%, 0.047 g, 0.442 mmol) was added under nitrogen. The resulting reaction mixture was flushed with hydrogen and hydrogenated under hydrogen balloon pressure for 16 hours. After the reaction was complete, the mixture was filtered through a Celite bed and washed with HCl (2 x 10 mL). The resulting filtrate was concentrated under reduced pressure to obtain ethyl 3-(2,4-difluorophenyl)butanoate (410 mg, 81.34%) as a crude oil. m / z (LC-MS): 229.0 [M+H] + ;H-NMR(CDCl3, 300MHz):δ 1.1.7(t,J=7.2Hz,3H), 1.30(d,J=6.8Hz,3H), 2.53-2.67(m,2H), 3.51(q, J=7.52Hz,2H), 4.08(q,J=7.2Hz,2H), 6.73-6.83(m,2H), 7.14-7.19(m,1H) [ka]

[0384] Synthesis of ethyl 3-(2,4-difluorophenyl)-2-hydroxybutanoate: A stirred solution of ethyl 3-(2,4-difluorophenyl)butanoate (400 mg, 1.75 mmol) in anhydrous THF (5 mL) was cooled to -78°C under an argon atmosphere, and then KHMDS (704 mg, 3.50 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 30 minutes, and then 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (544 mg, 2.104 mmol) in THF was added at -78°C. The reaction mixture was then stirred at -78°C for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, it was quenched with NH4Cl, then diluted with water, and extracted with siRNA (4 x 10 ml). All organic layers were combined, washed with brine, and concentrated under reduced pressure to obtain the crude material, which was then purified by combiflash chromatography (10% ethyl hexane) to obtain racemic trans-3-(2,4-difluorophenyl)-2-hydroxybutanoate ethyl (240 mg, 56.07%). [ka]

[0385] Synthesis of 3-(2,4-difluorophenyl)-2-hydroxybutanoic acid (4L): To a stirred solution of ethyl 3-(2,4-difluorophenyl)butanoate (240 mg, 0.983 mmol) in THF:water (10 vol, 1:1), LiOH (164.9 mg, 3.930 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 4 hours to obtain ethyl 3-(2,4-difluorophenyl)-2-hydroxybutanoate. This was quenched with water (3 mL) and extracted with RINKAN (2 x 20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to obtain 4 L of crude compound (165 mg, 77.67%); m / z (LC-MS): 215.0 [MH] + [ka]

[0386] Example 32: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide (Example 32 Peak-1 & Example 32 Peak-2): [ka]

[0387] Following the general procedure for compound-8, compound-4l (160 mg, 0.740 mmol) was converted to Example 32 (60 mg, 17.49%) using compound-7b. The enantiomers were separated using chiral SFC (column: (2 x Regis(S,S) Whelk-01, 250 mm x 21.1 mm, 5 μm), mobile phase: CO2 (A) and IPA:EtOH:MeOH 1:1:1 (B), flow rate: 50 mL, isocratic: 90 (A):10 (B), diluent EtOH:DCM, 1:1, 3 mL, injection volume 0.2 mL, run time 22 min), yielding peak-1 (22.2 mg) and peak-2 (23.8 mg); 1H-NMR (DMSO-d6, 400 MHz): δ 0.89-1.05(m,2H), 1.13(d,J=7.2Hz,2H), 1.20-1.23(m,2H), 3.31-3.42(m,1H), 3.94-3.96(m,1H), 4.77(q,J=8.8Hz,2H), 5.72 (bs,1H), 6.67-6.68(m,1H), 6.85-6.86(m,1H), 6.98-7.03(m,2H), 7.09-7.15(m,1H), 7.34-7.41(m,1H), 8.57(s,1H);HRMS:[C 21 H 19 ClF5NO3+H] + Calculated value: 464.1052; Measured value: 464.1056 (Example 32 Peak-1), 464.1050 (Example 32 Peak-2); Chiral SFC for analysis: REGIS(S,S) WHELK-01, 4.6mm x 150mm x 5μm, Flow rate: 3ml / min, Cosolvent: 10%, Cosolvent name: IPA:EtOH:MeOH (1:1:1), Temperature: 40℃, Peak-1 (Rt: 5.41, 100%ee), Peak-2 (Rt: 5.8, 100%ee)

[0388] Example 33: Synthesis of (R)-N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide) Synthesis of 4-chloro-N-neopentylpyridine-2-amine: Neopentylamine (1.325 g, 15.205 mmol) was added to a stirred solution of 4-chloro-2-fluoropyridine (1 g, 7.602 mmol) in DMSO (5 mL) in a sealed test tube. The resulting reaction mixture was heated overnight at 150°C. After the reaction was complete, it was diluted with water (10 mL), extracted with RINKAN (3 x 20 mL), all organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude material. This was further purified using a combiflush (eluent: 30% RINKAN in hexane, 24 g column) to obtain well-pure 4-chloro-N-neopentylpyridine-2-amine (1.25 g, 82.78%) as a yellow solid. m / z (LC-MS): 199.00 [MH] + [ka]

[0389] Synthesis of 4-chloro-2-(neopentylamino)pyridine 1-oxide: 4-chloro-N-neopentylpyridine-2-amine (1.2 g, 6.038 mmol) was stirred in anhydrous DCM (12 mL) and m-CPBA (2.083 g, 12.077 mmol) was added under an argon atmosphere at 0°C. The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with an aqueous solution of NaHCO3 (pH=8). The reaction mixture was extracted with MeOH:DCM (1:10, 2 x 15 mL). The resulting organic layer was washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum to obtain crude 4-chloro-2-(neopentylamino)pyridine 1-oxide (1.9 g); m / z (LC-MS): 215.00 [MH] + [ka]

[0390] Synthesis of 4-chloro-6-(neopentylamino)picolinonitrile: To a stirred solution of 4-chloro-2-(neopentylamino)pyridine·1-oxide (1.9 g, 8.874 mmol) in acetonitrile (20 mL), triethylamine (14.367 g, 141.984 mmol) was added, followed by trimethylsilyl cyanide (14.521 g, 141.984 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the solvent was removed under vacuum, the mixture was quenched with aqueous NaHCO3 solution, and extracted with toluene (3 x 20 mL). The resulting organic layers were combined, washed with brine, and dried on anhydrous Na2SO4. The organic layers were combined and concentrated under vacuum to obtain the crude compound, which was then purified using combiflash chromatography (with 10-20% toluene:hexane as eluate) to obtain a sufficiently pure 4-chloro-6-(neopentylamino)picolinonitrile (152 mg, 7.67%). m / z (LC-MS): 224.20 [MH] + [ka]

[0391] Synthesis of 6-(1-aminocyclopropyl)-4-chloro-N-neopentylpyridine-2-amine (7v): Using the general procedure for compound-7, 4-chloro-6-(neopentylamino)picolinonitrile (100 mg, 0.447 mmol) was converted to crude compound-7v (60 mg, 46.15%) as a brown solid. m / z (LC-MS): 224.20 [MH] + [ka]

[0392] Example 33: Synthesis of (R)-N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide): [ka]

[0393] Following the general procedure for compound-8, enantiopurine compound-4d (40 mg, 0.185 mmol) was converted to crude Example 33 using compound-7v (47 mg, 0.185 mmol). The crude compound was purified by combiflash chromatography and then by preparative HPLC (column: X-Select (250 mm x 20 mm), 5.0 μm, mobile phase: A = 0.1% HCOOH in water, and B = acetonitrile, flow rate: 15 mL / min) to obtain the pure compound (4.4 mg, 5.3%); 1H-NMR (DMSO-d6, 400 MHz): δ 0.85(s,9H), 0.86-0.90(m,2H), 1.23-1.27(m,2H), 1.49(s,3H), 2.70(dd,J=13.8Hz,2H), 3.02(d,J=6.4Hz,2H), 6.06(d,J= HRMS:[C 23 H 28 [CLF2N3O2+H] + Calculated value: 452.1916; Measured value: 452.1926; Chiral HPLC for analysis: Column: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm), Mobile phase: (A) n-hexane (B) EtOH with 0.1% HCOOH:MeOH (80:20), Isocratic: 70:30 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, (Rt: 4.79, 98.88%)

[0394] Example 34: Synthesis of (R)-N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 6-((cyclopropylmethyl)amino)picolinonitrile: A stirred solution of 6-chloropicolinonitrile (0.5 g, 3.608 mmol) in acetonitrile (5 mL) was placed in a sealed test tube. Under argon, DIPEA (0.95 mL, 5.413 mmol) and cyclopropylmethylamine (0.33 g, 4.69 mmol) were added. The resulting reaction mixture was heated in a MW at 160°C for 3 hours. The reaction mixture was concentrated under vacuum, diluted with water, extracted with toluene (3 x 15 ml), and all organic layers were combined. The mixture was dried over anhydrous sodium 2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified using a combiflush (40 g column, eluate 15% toluene:hexane) to obtain 6-((cyclopropylmethyl)amino)picolinonitrile (270 mg, 43.2%) as an off-white gum. m / z (LC-MS): 174.10 [MH] + [ka]

[0395] Synthesis of 6-(1-aminocyclopropyl)-N-(cyclopropylmethyl)pyridine-2-amine (7w): Using the general procedure for compound-7, 6-((cyclopropylmethyl)amino)picolinonitrile (200 mg, 1.155 mmol) was converted to compound-7w (47 mg, 20.08%) as a yellow gum. m / z (LC-MS): 204.25 [MH] + [ka]

[0396] Example 34: Synthesis of (R)-N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: [ka]

[0397] Following the general procedure for compound-8, enantiopurine compound-4d (50 mg, 0.2313 mmol) was converted to crude Example 34 using compound-7w (47 mg, 0.2313 mmol). The crude compound was purified by combiflash chromatography followed by preparative HPLC (column: X-Select (250 mm x 20 mm), 5.0 μm, mobile phase: A = 0.1% HCOOH in water, B = acetonitrile, flow rate: 15 mL / min) to obtain pure compound (3.5 mg, 5.3%); 1H-NMR (DMSO-d6, 400 MHz): δ 0.11-0.15(m,2H), 0.35-0.39(m,2H), 0.76-0.82(m,2H), 0.95-0.98(m,1H), 1.23-1.26( m,1H), 1.33-1.36(m,1H), 1.49(s,3H), 2.58(d,J=14.4Hz,1H), 2.83(d,J=14.4Hz,1H), 2 .98-3.00(m,2H), 5.78(d,J=7.2Hz,1H), 6.14-6.16(m,2H), 6.34-6.37(m,1H), 6.94-6.9 8(m,1H), 7.03-7.07(m,1H), 7.18-7.24(m,1H), 7.57-7.64(m,1H), 8.63(bs,1H);HRMS:[C 22 H 25 F2N3O2+H] + Calculated value: 402.1993; Measured value: 402.1994.1051; Chiral HPLC for analysis: Column: Chiral Pack-IK 250 x 4.6 mm, 5.0 μm, Mobile phase: (A)D) 0.1% DEA in n-hexane; Ethanol: DCM (60:20:20), Isocratic: (C) 100%; Flow rate: 1.0 ml / min, Column temperature: 25°C, Injection volume: 5.000, (Rt: 4.55, 99.13%)

[0398] Example 35: Synthesis of (R)-N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 4-chloro-N-neopentylpyridine-2-amine: Isopropylamine (0.654 mL, 7.602 mmol) was added to a stirred solution of 4-chloro-2-fluoropyridine (1 g, 7.602 mmol) in DMSO (5 mL) in a sealed test tube. The resulting reaction mixture was heated at 150°C for 8 hours. After the reaction was complete, water was added and extracted with RINKAN (3 x 20 mL). All organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude material. This was further purified using a combiflush (eluent: 10% ethyl acetate in hexane, 24 g column) to obtain a sufficiently pure 4-chloro-N-neopentylpyridine-2-amine (1.1 g, 85.26%) as a colorless liquid. m / z (LC-MS): 171.15 [MH] + [ka]

[0399] Synthesis of 4-chloro-2-(isopropylamino)pyridine·1-oxide: 4-chloro-N-neopentylpyridine-2-amine (1.1 g, 6.446 mmol) was stirred in anhydrous DCM (12 mL) and m-CPBA (2.225 g, 12.892 mmol) was added under an argon atmosphere at 0°C. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with an aqueous solution of NaHCO3 (pH=8). The reaction mixture was extracted with MeOH:DCM (1:10, 2 x 15 mL). The resulting organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain crude 4-chloro-2-(isopropylamino)pyridine·1-oxide (1.4 g); m / z (LC-MS): 187.15 [MH] + [ka]

[0400] Synthesis of 4-chloro-6-(isopropylamino)picolinonitrile: To a stirred solution of 4-chloro-2-(isopropylamino)pyridine·1-oxide (0.5 g, 2.679 mmol) in acetonitrile (5 mL), triethylamine (1.87 mL, 40.184 mmol) was added, followed by trimethylsilyl cyanide (5.35 mL, 40.184 mmol) at room temperature. The resulting reaction mixture was stirred at 80°C for 16 hours. After the reaction was complete, the solvent was removed under vacuum, the mixture was quenched with aqueous NaHCO3 solution, and extracted with toluene (3 x 10 mL). The resulting organic layers were combined and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to obtain the crude compound. This was purified by combiflash chromatography (24g column, eluate with 0-15% toluene:hexane) to obtain well-pure 4-chloro-6-(isopropylamino)picolinonitrile (209 mg, 39.88%). m / z (LC-MS): 195.95 [MH] + [ka]

[0401] Synthesis of 6-(1-aminocyclopropyl)-4-chloro-N-isopropylpyridine-2-amine (7x): To a solution of 4-chloro-6-(isopropylamino)picolinonitrile (100 mg, 0.511 mmol) in anhydrous diethyl ether (2 mL), Ti(OiPr)4 (0.470 mmol, 1.533 mmol) was added at -78°C, followed by dropwise addition of EtMgBr (3 M in Et2O, 0.852 mL, 2.555 mmol). The resulting reaction mixture was stirred for 2 hours and quenched with BF3:Et2O (2 equivalents). After stirring overnight, 1N HCl was added, and the reaction mixture was extracted with Et2O. The aqueous layer was made basic and extracted with Et2O. The organic layer obtained after basicization was washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum to obtain crude compound-7x (100 mg, 86.95%) as an orange gum. m / z (LC-MS): 226.05 [MH] + [ka]

[0402] Example 35: Synthesis of (R)-N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: [ka]

[0403] Following the general procedure for compound-8, enantiopurine compound-4d (96 mg, 0.443 mmol) was converted to crude Example 35 using compound-7x (100 mg, 0.443 mmol). The crude compound was subjected to combiflash chromatography, followed by preparative HPLC (column: X-Select (250 mm x 20 mm), 5.0 μm, mobile phase: A = 0.02% NH4OH in water and B = acetonitrile, flow rate: 15 mL / min) to obtain the pure compound (15 mg, 8%); 1H-NMR (DMSO-d6, 400 MHz): δ 0.82-0.88(m,2H), 1.08(d,J=6.50Hz,6H), 1.31-1.35(m,2H), 1.51(s,3 H), 2.64(d,J=14.38Hz,1H), 2.83(d,J=14.38Hz,1H), 3.78-3.83(m,1H), 6.07-6.10(m,2H), 6.19(d,J=1.63Hz,1H), 6.49(d,J=7.13Hz,1H), 7.01- 7.06(m,1H), 7.14-7.17(m,1H), 7.61-7.67(m,1H), 8.58(s,1H);HRMS:[C 21 H 24 [CLF2N3O2+H] +Calculated value: 424.1603; Measured value: 424.1607; Chiral HPLC for analysis: Column: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm, Mobile phase: (A) n-hexane (B) EtOH with 0.1% HCOOH:MeOH (80:20), Isocratic: 70:30 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, (Rt: 5.03, 97.81%)

[0404] Example 36: (R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 2-chloro-6-((2,2,2-trifluoroethyl)amino)isonicotinonitrile (6y): [ka]

[0405] To a stirred solution of 2,6-dichloroisonicotinonitrile (1.0 g, 5.7803 mmol) in anhydrous DMSO (10 mL), N,N-diisopropylethylamine (2.51 mL, 14.4507 mmol) and 2,2,2-trifluoroethylamine (0.57 g, 5.7803 mmol) were added at room temperature. The resulting reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 x 20 mL). The resulting organic layers were combined, washed with brine, and dried on anhydrous Na₂SO₄. The organic layer was removed under vacuum to obtain the crude product, which was purified by flash chromatography (eluent: ethyl acetate:hexane 20:80) to obtain 2-chloro-6-((2,2,2-trifluoroethyl)amino)isonicotinonitrile (6y) (0.75 g, 54.17%) as a brownish solid. m / z (LC-MS): 235.90 [M+H] +

[0406] 4-(1-aminocyclopropyl)-6-chloro-N-(2,2,2-trifluoroethyl)pyridine-2-amine(7y): 2-Chloro-6-((2,2,2-trifluoroethyl)amino)isonicotinonitrile (6y) (0.1 g, 0.4245 mmol) was converted to compound-7y (60 mg, crude) using the general procedure used for compound-7. m / z (LC-MS): 264.9 [M+H] + [ka]

[0407] Example 36: (R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: [ka]

[0408] Following general procedure 8, enantiopurine compound-4d (0.03 g, 0.1129 mmol) was converted to Example 36 using compound-7y, and then purified by preparative HPLC. Mobile phase: A = 0.2% HCOOH in water, B = acetonitrile, Column: X-Select (250 mm x 20.0 mm), 5.0 μm, Flow rate: 15 ml / min; Gradient programmer: Time %B, 0 30, 1 30, 8 70. As an off-white solid; 1 H NMR (400MHz, CDCl3)δ ppm 0.85-0.98(m,1H), 1.10-1.30(m,6H), 2.71(d,J=14.5Hz,1H), 3.01(d,J=14.5Hz,1H), 3.99-4.07(m,2H), 4.37(t,J=6.31Hz,1H), HRMS:[C 20 H 19 [CLF2N3O2+H] +Calculated value: 464.1164; Measured value: 464.1177; Chiral HPLC for analysis: Column: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm, Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50), Isocratic: 90:10 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, (Rt: 16.54, 95.34%)

[0409] Example 37: Synthesis of N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 1-(6-chloropyridine-2-yl)cyclopropane-1-amine (7t): To a solution of 6-chloropicolinonitrile (5 g, 36.086 mmol) in anhydrous diethyl ether (50 mL), Ti(OiPr)4 (12.18 mL, 39.70 mmol) was added at -78°C, followed by dropwise addition of EtMgBr (3 M in Et2O, 30.07 mL, 90.2126 mmol). The resulting reaction mixture was stirred for 2 hours and quenched with BF3:Et2O (4.233 mL, 36.086 mmol). After stirring overnight, 1N HCl was added, and the reaction mixture was extracted with Et2O. The aqueous layer was made basic and extracted with Et2O. The organic layer obtained after basicization with a specified 2N NaOH was washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum to obtain crude compound-7t. This was purified by combiflash chromatography (24g column, 30% HCl:hexane) to obtain a sufficiently pure compound-7t (470mg, 7.8%) as a yellow solid. ¹H-NMR (DMSO-d6, 300MHz): δ 0.99-1.00 (m,2H), 1.16-1.17 (m,2H), 7.17-7.21 (m,1H), 7.72-7.80 (m,2H) [ka]

[0410] Synthesis of N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: [ka]

[0411] Following the general procedure for compound-8, compound-4d (150 mg, 0.694 mmol) was converted to crude N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide using compound-7t (117 mg, 0.694 mmol). The crude compound was purified by combiflash chromatography (with 30% HCl:hexane as eluate) to obtain well-pure N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (130 mg, 51.08%) as a brownish gum-like substance.

[0412] Example 37: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide [ka]

[0413] In a sealed test tube containing a stirred solution of N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (100 mg, 0.273 mmol) in dioxane:DME (1 mL, 1:1), Cs2CO3 (222 mg, 0.682 mmol) was added, followed by 2,2,2-trifluoroethylamine hydrochloride (55.4 mg, 0.409 mmol). The resulting reaction mixture was purged with argon for 15 minutes, then XPhos-Pd-G2 (21.5 mg, 0.0273 mmol) was added, and the mixture was purged again with argon for 5 minutes. The reaction mixture was heated at 110°C for 16 hours. After the reaction was complete, water was added and the mixture was extracted with Âr (3 x 5 mL). All obtained organic layers were dried, washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum to obtain the crude compound. This was purified by preparative HPLC (X-Select (C18, 21.2 mm x 150 mm), eluate: 0.1% HCOOH (A) and acetonitrile (B) in water, flow rate: 18 mL / min) to obtain a sufficiently pure racemic compound (25 mg, 21.34%). This was further purified by chiral HPLC ((Chiral Pack IH, 250 mm x 21 mm, 5 μm), eluate: n-hexane (A) and IPA:MeOH 1:1 (B), isocratic; 85 (A):15 (B), flow rate: 15 mL / min, injection volume 0.6 mL, run time 20 min) to obtain peak-1 (14 mg) and peak-2 (13 mg); 1H-NMR (DMSO-d6, 400 MHz): δ 0.80-.0.85(m,2H), 1.23-1.38(m,2H), 1.49(s,3H), 2.60(dd,J=13.8Hz,2H), 3.95-4.05(m,2H), 5.92(d,J=7.2Hz,1H), 6.12(b HRMS:[C 20 H 20 F5N3O2+H] +Calculated value: 430.1554; Measured value: 430.1564 (Example 37 Peak-1), 430.1559 (Example 37 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm), Mobile phase: (A) n-hexane (B) 0.1% HCOOH:MeOH in EtOH (80:20) Isocratic: 90:10 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 10.000, Peak-1 (Rt: 5.87, 100% ee), Peak-2 (Rt: 9.60, 100% ee)

[0414] Example 38: Synthesis of (R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 4-chloro-N-(2,2,2-trifluoroethyl)pyridine-2-amine: A stirred solution of 4-chloro-2-fluoropyridine (1 g, 7.602 mmol) in DMSO (5 mL) was placed in a sealed test tube, to which 2,2,2-trifluoroethane-1-amine (0.72 mL, 9.123 mmol) was added. The resulting reaction mixture was heated at 150 °C for 4 hours. After the reaction was complete, water was added, and the mixture was extracted with RINKAN (3 x 20 mL). All organic layers were combined, washed with brine, dried on anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude material. This was further purified using a combiflush (eluent: 10% RINKAN in hexane, 24 g column) to obtain a sufficiently pure 4-chloro-N-(2,2,2-trifluoroethyl)pyridine-2-amine (150 mg, 9.36%) as a white solid. m / z (LC-MS): 211.05 [MH] + [ka]

[0415] Synthesis of 4-chloro-2-((2,2,2-trifluoroethyl)amino)pyridine·1-oxide: To a stirred solution of 4-chloro-N-(2,2,2-trifluoroethyl)pyridine-2-amine (150 mg, 0.712 mmol) in anhydrous DCM (2 mL), m-CPBA (0.246 g, 1.425 mmol) was added under argon at 0°C. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with an aqueous solution of NaHCO3 (pH=8). The reaction mixture was extracted with MeOH:DCM (1:10, 2 x 5 mL). The resulting organic layer was washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum to obtain crude 4-chloro-2-((2,2,2-trifluoroethyl)amino)pyridine·1-oxide (145 mg); m / z (LC-MS): 227.10 [MH] + [ka]

[0416] Synthesis of 4-chloro-6-(isopropylamino)picolinonitrile: To a stirred solution of 4-chloro-2-((2,2,2-trifluoroethyl)amino)pyridine·1-oxide (145 mg, 0.64 mmol) in acetonitrile (5 mL), triethylamine (1.43 mL, 10.24 mmol) was added, followed by trimethylsilyl cyanide (1.41 mL, 10.24 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the solvent was removed under vacuum, the mixture was quenched with aqueous NaHCO3, and extracted with toluene (3 x 5 mL). The resulting organic layers were combined, washed with brine, and dried on anhydrous sodium 2SO4. The organic layers were combined and concentrated under vacuum to obtain the crude compound, which was purified by combiflash chromatography (4 g column, eluent 0-15% toluene:hexane) to obtain well-pure 4-chloro-6-(isopropylamino)picolinonitrile (69 mg, 39.78%). m / z (LC-MS): 234.00 [MH] + [ka]

[0417] Synthesis of 6-(1-aminocyclopropyl)-4-chloro-N-(2,2,2-trifluoroethyl)pyridine-2-amine (7z): To a solution of 4-chloro-6-(isopropylamino)picolinonitrile (50 mg, 0.212 mmol) in anhydrous diethyl ether (2 mL), Ti(OiPr)4 (0.098 mmol, 0.318 mmol) was added at -78°C, followed by dropwise addition of EtMgBr (3 M in Et2O, 0.14 mL, 0.414 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours and quenched with BF3:Et2O (0.033 mL, 0.424 mmol). After stirring overnight, 1N HCl was added, and the reaction mixture was extracted with Et2O. The aqueous layer was made basic and extracted with Et2O. The organic layer obtained after adjusting to the specified basicity was washed with brine, dried on anhydrous Na2SO4, and concentrated under vacuum to obtain the crude compound -7z (30 mg, 53.56%) as a brownish solid. m / z (LC-MS): 266.05 [M+H] + [ka]

[0418] Example 38: Synthesis of (R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide [ka] Following the general procedure for compound-8, enantiopurine compound-4d (24 mg, 0.113 mmol) was converted to crude Example 38 using compound-7z (30 mg, 0.113 mmol). The crude compound was purified by preparative HPLC (column (X-BRIDGE) (C18, 20 mm x 150 mm), mobile phase: A = 0.1% HCOOH in water and B = acetonitrile, flow rate: 16 mL / min) to obtain the pure compound (2.1 mg, 4.03%) as an off-white solid; 1H-NMR (DMSO-d6, 400 MHz): δ 0.89-093(m,2H), 132-1.36(m,2H), 1.50(s,3H), 2.66(d,J=14Hz,1H), 2.80(d,J=14Hz,1H), 3.98-4.07(m,2H), 6.03(s,1H), 6.26(d,J HRMS:[C 20 H 19 [CLF5N3O2+H] + Calculated value: 464.1164; Measured value: 464.1177; Chiral HPLC for analysis: Column: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm, Mobile phase: (A) n-hexane (B) 0.1% HCOOH in ethanol: methanol (80:20) isocratic: 70:30 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, (Rt: 4.88, 98.15%)

[0419] Example 39: Synthesis of 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide Synthesis of 2-(2,2,2-trifluoroethoxy)isonicotinonitrile: To a stirred solution of 6-chloropicolinonitrile (10 g, 72.1726 mmol) in anhydrous DMF (80 mL), K2CO3 (39.89 g, 288.6905 mmol) and 2,2,2-trifluoroethane-1-ol (3.61 g, 267.0387 mmol) were added at room temperature. The resulting reaction mixture was stirred at 60°C for 24 hours. The reaction mixture was quenched with ice-cold water and extracted with toluene (3 x 500 mL). The resulting organic layers were combined, washed with brine, and dried on anhydrous sodium 2SO4. The organic layer was removed under vacuum to obtain the crude product, which was purified by flash chromatography (eluent: Depositphotos:hexane 5:95) to obtain 2-(2,2,2-trifluoroethoxy)isonicotinonitrile (11.5 g, 79.3%) as an off-white crystalline solid; m / z (LC-MS): 202.90 [M+H] + [ka]

[0420] 1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropan-1-amine(7aa): 2-(2,2,2-trifluoroethoxy)isonicotinonitrile (6 g, 29.6833 mmol) was converted to compound-7aa (5.1 g, 64.55%) using the general procedure used for compound-7. After basicization with NaHCO3, the compound was extracted as a free base. m / z (LC-MS): 233.00 [M+H] + [ka]

[0421] Example 39: Synthesis of 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide (Example 39 Peak-1 & Example 39 Peak-2): [ka]

[0422] Following general procedure 8, compound-4j (0.11 g, 0.5088 mmol) was converted to Example 39 (175 mg, 80.19%) using compound 7aa (0.141 g, 0.610 mmol). The product was separated using chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 20 mm, 5 μm; mobile phase: n-hexane (A) and 10 mM ammonia (B) in IPA:EtOH (1:1); flow rate: 15 ml, isocratic: 90 (A):10 (B), diluent: EtOH:DCM, 1:1, 3 ml, injection volume - 0.4 ml; run time - 21 min), yielding peak-1 (63.8 mg, Rt: 5.41) and peak-2 (55.3 mg, Rt: 7.47). 1 H NMR (400MHz, DMSO-d6) δ ppm 0.94-0.98(m,2H), 1.35-1.48(m,2H), 1.66(s,3H), 2.72(d,J=14.53Hz,1H), 2.92(d,J=14.53Hz,1H), 4.86(q,J=9.15Hz,2H), 5.84(s HRMS:[C 20 H 19 F5N2O3+H] + Calculated value: 431.1394; Measured value: 431.1402 (Example 39 Peak-1), 431.1395 (Example 39 Peak-2); Chiral HPLC for analysis: REGIS (S,S) WHELK-01 (250 x 4.6 mm x 5 μm), Mobile phase: (A) n-hexane (B) 0.1% HCOOH:MeOH in EtOH (80:20), Isocratic: 70:30 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 10.000, Peak-1 (Rt: 4.55, 100% ee), Peak-2 (Rt: 4.40, 100% ee)

[0423] Example 40: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide Example 40: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide (Example 40 Peak-1 & Example 40 Peak-2): [ka]

[0424] Following general procedure 8, compound-4d (0.25 g, 1.1564 mmol) was converted to Example 40 (220 mg, 44.89%) using compound 7aa (0.295 g, 1.272 mmol). The product was separated using chiral preparative HPLC (column: Chiralpak IH, 250 mm x 20 mm, 5 μm; mobile phase: n-hexane (A) and 0.1% HCOOH:MeOH in IPA (1:1) (B); flow rate: 15 ml; isocratic: 80 (A):20 (B); diluent: EtOH:DCM 1:1, 3.5 ml; injection volume - 0.2 ml; run time - 10 min; manufacturing apparatus and model: Agilent-1200 series), yielding peak-1 (101 mg, Rt: 2.13) and peak-2 (90 mg, Rt: 2.63). 1 H NMR (400MHz, DMSO-d6)δ 0.87-1.02(m,2H), 1.34-1.48(m,2H), 1.51(s,3H), 2.66(d,J=14.4Hz,1H), 2.85(d,J=14.4Hz,1H), 4.88(q,J=9.1Hz,2H), 6.06(s,1H), 6.3 9(d,J=7.6Hz,1H), 6.66(d,J=8.0Hz,1H), 7.06-7.11(m,1H), 7.20-7.27(m,1H), 7.40-7.44(m,1H), 7.61-7.66(m,1H), 8.73(s,1H);HRMS:[C 20 H 19 F5N2O3+H] +Calculated value: 431.1394; Measured value: 431.1404 (Example 40 Peak-1), 431.1406 (Example 40 Peak-2); Chiral HPLC for analysis: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm), Mobile phase: (A) n-hexane (B) 0.1% HCOOH in ethanol: methanol (80:20), Isocratic: 70:30 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 10.000, Acq. method: REG_7030_8_B_15MIN.amx, Peak-1 (Rt: 4.40, 100% ee), Peak-2 (Rt: 4.44, 100% ee)

[0425] Example 41: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide 1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropan-1-amine(7ab): 2-Cyano-6-trifluoromethylpyridine (0.8 g, 4.648 mmol) was converted to compound-7ab (300 mg, 32.25%) using the general procedure for compound-7; m / z (LC-MS): 202.18 [M+H] +1 H NMR (400MHz, DMSO-d6) δ=1.03-1.06(m,2H), 1.22-1.24(m,2H), 2.78(bs,2H), 7.59-7.61(dd,J=1.2Hz&7.6Hz,1H), 8.00-8.06(m,2H) [ka]

[0426] Example 41: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide (Example 41 Peak-1 & Example 41 Peak-2): [ka]

[0427] Following general procedure 8, compound-4d (100 mg, 0.462 mmol) was converted to Example 41 (105 mg, yield 56.75%) using compound 7ab (0.093 mg, 0.462 mmol). The product was separated using chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm, eluate: A: n-hexane, B: 10 mM ammonia in IPA: MeOH (1:1), flow rate: 15 ml / min, isocratic: 90(A):10(B)) to obtain peak-1 (36 mg, Rt: 3.44) and peak-2 (40 mg, Rt: 5.75). 1 H NMR (400MHz, DMSO-d6)δ 0.981.07(m,2H), 1.32-1.44(m,2H), 1.52(s,3H), 2.69(d,J=14.4Hz,1H), 2.85(d,J=14.4Hz,1H), 5.98(s,1H) , 7.06-7.12(m,2H), 7.19-7.26(m,1H), 7.59-7.67(m,2H), 7.73-7.77(m,1H), 8.82(bs,1H);HRMS:401.00[M+H] + ;HRMS:[C 19 H 17 F5N2O2+H] + Calculated value: 401.1288; Measured value: 401.1296 (Example 41 Peak-1), 401.1295 (Example 41 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (250 x 4.6 mm x 5 μm), Mobile phase: (A) n-hexane (B) 0.1% NH4OH:EtOH:MeOH in IPA (1:1:1), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Peak-1 (Rt: 3.40, 100% ee) Peak-2 (Rt: 5.66, 100% ee)

[0428] Example 42: Synthesis of N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide Example 42: Synthesis of N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide (Example 42 Peak-1 & Example 42 Peak-2): [ka]

[0429] Following the general procedure for compound-8, compound-4e (59.2 mg, 0.298 mmol) was converted to crude example 42 using compound-7n (70 mg, 0.249 mmol). The product was purified by preparative HPLC (column: X-Select (250 mm x 20.0 mm), 5.0 μm; mobile phase: A = 0.1% HCOOH in water and B = acetonitrile; flow rate: 15 mL / min) to obtain a pure compound (11 mg, 9.64%) as a brownish solid, which was then separated using chiral preparative HPLC (column: Chiral Pack IH, 250 x 21 mm, 5 μm; eluate: n-hexane (A) and IPA:EtOH:MeOH 1:1:1 (B); flow rate: 15 ml / min; isocratic: 85 (A):15 (B); diluent: EtOH:DCM (1:1, 2 mL); injection volume -0.3 mL; run time 11 min), and peak-1 (2.5 mg, Rt: 3.03, 100% ee) was identified. Peak-2 (1.1 mg, Rt: 3.99, 100% ee) was obtained as an off-white solid; 1H-NMR (CDCl3, 400 MHz): δ 0.99-1.33 (m, 4H), 1.49 (s, 3H), 2.66 (s, 2H), 4.28-4.35 (m, 2H), 4.85 (s, 1H), 6.24 (bs, 1H), 6.50 (t, J=56.4 Hz, 1H), 6.80 (s, 1H), 6.83-6.85 (m, 2H), 6.94-6.99 (m, 2H), 7.35-7.38 (m, 2H); HRMS: [C 22 H 21 [F6NO3+H-H2O] +Calculated value: 444.1398; Measured value: 444.1399 (Example 42 Peak-1), 444.1406 (Example 42 Peak-2); Chiral HPLC for analysis; Column: Chiral Pack-IH (150 x 4.6 mm x 5 μm); Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50), Isocratic: 85:15 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 10.000; Peak-1 (Rt: 3.03, 100% ee) Peak-2 (Rt: 3.99, 100% ee)

[0430] Example 43: Synthesis of 3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide Example 43: Synthesis of 3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 43 Peak-1 & Example 43 Peak-2): [ka]

[0431] Following the general procedure for compound-8, compound-4e (119 mg, 0.602 mmol) was converted to Example 43 using 7 g of compound (150 mg, 0.602 mmol). The product was purified using a combiflash (20% siRNA:hexane, 4g column) to obtain a pure compound (120 mg, 46.51%) as a yellow solid, which was separated using a chiral preparative HPLC (column (Chiral Pack IH, 250 mm x 21 mm, 5 μm), eluate: n-hexane (A) and IPA:MeOH (1:1) (B), flow rate: 15 ml / min, isocratic: 93 (A):07 (B), diluent EtOH:DCM, 1:1, 3.5 mL, injection volume 0.35 mL, run time 18 min) to obtain peak-1 (33.6 mg, Rt: 3.18, 100% ee) and peak-2 (46.5 mg, Rt: 3.21, 100% ee); 1H-NMR (DMSO-d6, 400 MHz): δ 0.74-0.81(m,2H), 1.01-1.04(m,2H), 1.36(s,3H), 2.55(dd,J=14Hz,2H), 4.75(q,J=8.8Hz,2H ), 5.59(s,1H), 6.97-7.04(m,4H), 7.08-7.11(m,1H), 7.32-7.37(m,2H), 8.54(s,1H);HRMS:[C 21 H 20 [F5NO3+H-H2O] + Calculated value: 412.1330; Measured value: 412.1338 (Example 43 Peak-1), 412.1344 (Example 43 Peak-2); Chiral HPLC column: Chiral Pack-IH (150 x 4.6 mm x 5 μm), Mobile phase: (A) n-Hexane (B) IPA:MeOH (50:50), Isocratic: 85:15 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000; Peak-1 (Rt: 3.18, 100% ee) Peak-2 (Rt: 3.21, 100% ee)

[0432] Example 44: Synthesis of (R)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: Synthesis of ((R)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: [ka]

[0433] To a solution of dioxane (40 mg, 0.0997 mmol) in Example-28 (1:1, 1 mL) in DME, Cs2CO3 (81.2 mg, 0.249 mmol) was added at room temperature, followed by 2,2,2-trifluoroethylamine·HCl salt (20.3 mg, 1.495 mmol). The resulting reaction mixture was purged with argon for 15 minutes, and then XPhosPdG2 (7.9 mg, 0.01 mmol) was added. The resulting reaction mixture was again purged with argon for 5 minutes and heated at 110°C for 16 hours. After the reaction was complete, water was added and extracted with RINKAN. All organic layers were combined, washed with brine, and dried on anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to obtain the crude compound, which was purified using preparative HPLC (Gemini NX (250 mm x 21.2 mm), 5.0 μm, (A) 10 mM (NH4)HCO3 in water and (B) acetonitrile, flow rate: 18 mL / min) to obtain pure ((R)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (3.3 mg, 7.14%) as an off-white solid; 1H-NMR (DMSO-d6, 400 MHz): δ 0.79-0.82(m,2H), 1.24-1.25(m,2H), 1.52(s,3H), 2.68(s,2H), 4.00-4.06(m,2H), 5.91(bs,1H), 6.56(bs,1H), 6. 64-6.66(m,1H), 7.02-7.06(m,1H), 7.15-7.19(m,1H), 7.22-7.26(m,1H), 7.58-7.64(m,1H), 8.58(bs,1H);HRMS:[C 20 H 19 [CLF5N3O2+H]+ Calculated value: 464.1164; Measured value: 464.1174; Chiral HPLC for analysis: Column: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm, Mobile phase: (A) n-hexane (B) EtOH with 0.1% HCOOH:MeOH (80:20), Isocratic: 70:30 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, (Rt: 4.47, 98.91%)

[0434] Example 45: Synthesis of (R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: Example 45: Synthesis of (R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: [ka]

[0435] To a solution of Example 28 (40 mg, 0.0997 mmol) in anhydrous DMF (1 mL), K2CO3 (13.8 mg, 0.249 mmol) was added at room temperature, followed by 2,2,2-trifluoroethanol (25 mg, 1.495 mmol). The resulting reaction mixture was heated at 80°C for 16 hours. After the reaction was complete, water was added and extracted with RINKAN. All organic layers were combined, washed with brine, and dried on anhydrous Na2SO4. The organic layers were concentrated under reduced pressure to obtain the crude compound, which was purified by preparative HPLC (Gemini NX (250 mm x 21.2 mm), 5.0 μm, (A) 10 mM (NH4)HCO3 in water and (B) acetonitrile: MeOH, flow rate: 18 mL / min) to obtain the pure compound (7.7 mg, 16%) as an off-white solid; 1H-NMR (DMSO-d6, 400 MHz): δ 0.93-1.01(m,2H), 1.29-1.35(m,2H), 1.52(s,3H), 2.70(dd,J=14Hz,2H), 4.87-4.94(m,2H), 5.94(bs,1H), 6.77( d,J=2Hz,1H), 6.96-7.00(m,1H), 7.09(d,J=2Hz,1H), 7.10-7.15(m,1H), 7.59-7.65(m,1H), 8.61(bs,1H);HRMS:[C 20 H 18 [CLF5N2O3+H] + Calculated value: 465.1004; Measured value: 465.1015; Chiral HPLC for analysis: Column: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm, Mobile phase: (A) n-hexane (B) EtOH with 0.1% HCOOH:MeOH (80:20), Isocratic: 70:30 (A:B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, (Rt: 4.62, 99.38%)

[0436] Example 46: Synthesis of N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide: Synthesis of ethyl 3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanoate: 1-(1-methyl-1H-indole-4-yl)ethane-1-one (0.1 g, 2.30 mmol) was converted to compound-3m (0.08 g, 51.30%) using general procedure A used for compound-3. m / z (LC-MS): 244.1[M-17+H] + [ka]

[0437] Synthesis of 3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanoic acid (4m): Ethyl 3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanoate (0.15 g, 0.57 mmol) was hydrolyzed using the general procedure used for compound-4 to obtain 4m (0.12 g, 80%). m / z (LC-MS): 232.15 [MH] + [ka]

[0438] Example 46: Synthesis of N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide (Example 46 Peak-1 & Example 46 Peak-2): [ka]

[0439] Following the general procedure for compound-8, compound-4m (120 mg, 0.514 mmol) was converted to Example 46 using compound-7s (100 mg, 0.249 mmol). The product was purified by preparative HPLC (column: REGIS(S,S) WHELK-01 (250 x 4.6 mm x 5 μm), eluate: n-hexane (A) and IPA:MeOH 1:1 (B), flow rate: 1 mL / min, isocratic: 70 (A):30 (B), diluent: EtOH, injection volume: 5 mL, run time: 15 min) to obtain peak-1 (25.5 mg) and peak-2 (23.3 mg). 1 H NMR (400MHz, DMSO-d6) δ ppm 0.80-94(m,2H), 1.13-1.24(m,2H), 1.58(s,3H), 2.83(q,J=14Hz,2H), 3.76(s,3H), 4.75(q,J=8.8Hz,2H), 5.70(bs,1H), 6.63(s,1H) ), 6.68(d,J=2.8Hz,1H), 6.77(bs,1H), 6.94(s,1H), 7.06-7.12(m,2H), 7.28-7.31(m,2H), 8.53(bs,1H);HRMS:m / z(LC-MS):430.05 [M+H] + ;HRMS:[C 24 H 24 [ClF3N2O3+H-H2O] + Calculated value: 463.1400; Measured value: 463.1403 (Example 46 Peak-1), 463.1405 (Example 46 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (250 x 4.6 mm x 5 μm), Mobile phase: (A) n-Hexane (B) IPA: MeOH (70:30), Flow rate: 1.0 ml / min; Diluent: EtOH, Column temperature: 25°C, Injection volume: 5.000, Peak-1 (Rt: 8.406, 100% ee), Peak-2 (Rt: 7.529, 100% ee)

[0440] Example 47: (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide Synthesis of methyl 1-(2-chloropyrimidine-4-yl)cyclopropane-1-carboxylate: To a stirred solution of methyl 2-(2-chloropyrimidine-4-yl)acetate (1 g, 5.399 mmol) in anhydrous N,N-dimethylformamide (10 mL), sodium hydroxide (5.399 mmol) was added at room temperature under an argon atmosphere. The reaction mixture was stirred for 20 minutes, and then 1,2-dibromoethane (0.924 mL, 10.72 mmol) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous solution of NH4Cl, extracted with ethyl acetate (3 x 20 mL) to obtain the crude compound, which was purified by combiflash chromatography (eluent:ethyl acetate:hexane 3:7) to obtain methyl 1-(2-chloropyrimidine-4-yl)cyclopropane-1-carboxylate (580 mg, 51.32%) as a colorless liquid. m / z (LC-MS): 212.90 [M+H] + [ka]

[0441] Synthesis of 1-(2-chloropyrimidine-4-yl)cyclopropane-1-carboxylic acid: To a stirred solution of methyl 1-(2-chloropyrimidine-4-yl)cyclopropane-1-carboxylate (0.580 g, 2.7276 mmol) in tetrahydrofuran, lithium hydroxide monohydrate (1 ml) was added dropwise at 0°C, and the reaction mixture was maintained at the same temperature for 10 minutes. The reaction mixture was then stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 5 mL) to remove impurities. The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was then washed with water (3 x 5 ml) to obtain crude 1-(2-chloropyrimidine-4-yl)cyclopropane-1-carboxylic acid (0.390 g, 72.08%). m / z (LC-MS): 199.15 [M+H] + [ka]

[0442] Synthesis of 1-(2-chloropyrimidine-4-yl)cyclopropane-1-carboxamide: To a stirred solution of 1-(2-chloropyrimidine-4-yl)cyclopropane-1-carboxylic acid (0.390 g, 1.9637 mmol) in N,N-dimethylformamide, DIPEA (1.03 mL, 5.90 mmol) and HATU (1.12 g, 2.945 mmol) were added at 0°C. The resulting reaction mixture was stirred under an argon atmosphere for 30 minutes, and then ammonium chloride (1.072 g, 19.64 mmol) was added. The resulting homogeneous brown solution was stirred under an argon atmosphere at room temperature for 4 hours. The reaction mixture was quenched with ice-cold water and extracted with SiO2 (3 x 10 mL). All organic layers were combined, washed with brine, and the crude compound was obtained. This was then purified by combiflash chromatography (eluting with HCl:hexane) to obtain 1-(2-chloropyrimidine-4-yl)cyclopropane-1-carboxamide (0.210 g, 54.10%); m / z (LC-MS): 197.95 [M+H] + [ka]

[0443] Synthesis of tert-butyl (1-(2-chloropyrimidine-4-yl)cyclopropyl)carbamate: To a stirred solution of 1-(2-chloropyrimidine-4-yl)cyclopropane-1-carboxamide (100 mg, 0.506 mmol) in t-butanol (10 vol.), lead tetraacetate (0.673 g, 1.518 mmol) was added under an argon atmosphere. The resulting reaction mixture was heated at 70°C for 6 hours. The reaction mixture was monitored by TLC. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 x 5 mL). The organic layer was collected, washed with a predetermined brine, and dried on anhydrous Na2SO4. The organic layer was concentrated, and the crude compound was purified by combiflash chromatography (eluent: ethyl acetate:hexane, 20% ethyl acetate in hexane) to obtain (1-(2-chloropyrimidine-4-yl)cyclopropyl)carbamate tert-butyl (70 mg, 51.475 mg); m / z (LC-MS): 269.95 [M+H] + [ka]

[0444] Synthesis of (1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)carbamate tert-butyl: A sealed test tube containing a stirred solution of (1-(2-chloropyrimidine-4-yl)cyclopropyl)carbamate tert-butyl (50 mg, 0.1854 mmol) in toluene:dioxane (1:1, 1 mL) was mixed with Cs2CO3 (121 mg, 0.371 mmol) and xanthophos (10.7 mg, 0.0185 mmol). The resulting reaction mixture was purged with argon for 10 minutes, and then 2,2,2-trifluoroethylamine (0.022 g, 0.222 mmol) and Pd(OAc)2 (4.2 mg, 0.0185 mmol) were added. The reaction mixture was again purged with argon for 5 minutes and heated at 80°C for 5 hours. The reaction mixture was monitored by TLC. The reaction mixture was quenched with water and extracted with RINKAN (3 x 5 mL). The resulting organic layers were combined, washed with brine, and dried on anhydrous sodium 2SO4. The organic layers were concentrated under vacuum to obtain the crude compound, which was purified by combiflash chromatography (eluent: ethyl hexane, 3:7) to obtain tert-butyl (1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)carbamate (42 mg, 68.18%); m / z (LC-MS): 333.1 [M+H] + [ka]

[0445] Synthesis of 4-(1-aminocyclopropyl)-N-(2,2,2-trifluoroethyl)pyrimidine-2-amine (7ae): 0.042 g, 0.1264 mmol of (1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)carbamate tert-butyl was added dropwise to a stirred solution in dichloromethane (1 mL) at 0°C, with trifluoroacetic acid (0.1 mL) added dropwise. The reaction mixture was stirred at room temperature for 4 hours and concentrated under vacuum to obtain the crude compound, which was washed with hexane to obtain a sufficiently pure 4-(1-aminocyclopropyl)-N-(2,2,2-trifluoroethyl)pyrimidine-2-amine 7ae (40 mg, crude %); m / z (LC-MS): 233.00 [M+H] + [ka]

[0446] Example 47: (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide: [ka]

[0447] Following the general procedure for compound-8, compound-4d (30 mg, 0.139 mmol) was converted to crude example 47 using compound-7ae (38.7 mg, 0.166 mmol). The crude compound was purified by preparative HPLC (column: Gemini NX (250 mm x 21.2 mm), 5.0 μm, mobile phase: A = 0.1% HCOOH in water and B = acetonitrile, flow rate: 18 mL / min) to obtain pure compound-48 (27 mg, 45.22%) as an off-white solid; 1H-NMR (DMSO-d6, 400 MHz): δ 0.93-0.97(m,2H), 1.33-1.36(m,1H), 1.42-1.45(m,1H), 1.53(s,3H), 2 .63(d,J=14.0Hz,1H), 2.81(d,J=14.4Hz,1H), 3.99-4.03(m,2H), 5.99(s ,1H), 6.12(d,J=5.2Hz,1H), 7.06-7.11(m,1H), 7.18-7.24(m,1H), 7.53( bs,1H), 7.58-7.65(m,1H), 7.98(d,J=5.2Hz,1H), 8.68(bs,1H);HRMS:[C 19 H 19 F5N4O2+H] + Calculated value: 430.14; Measured value:; Chiral HPLC for analysis: Column: Chiral Pack-IG 250 x 4.6 mm, 5 μm, Mobile phase: (A) n-Hexane (B) 0.1% NH4OH (ethanol: DCM 50:50), Isocratic: (A:B) (50:50), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 10,000, (Rt: 5.38, 98%)

[0448] Example 48: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide Synthesis of 3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanoate ethyl (3n): 1-(2,4-dimethylthiazole-5-yl)ethane-1-one (2 g, 12.885 mmol) was converted to compound-3n (2.4 g, 76.92%) using general procedure A used for compound-3. m / z (LC-MS): 243.95 [M+H] + [ka]

[0449] Synthesis of 3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanoic acid (4n): Compound 3n (2.4 g, 9.863 mmol) was hydrolyzed, and 4n (0.5 g, 23.80%) was obtained as a reddish gum using the general procedure used for compound 4. m / z (LC-MS): 216 [M+H] + [ka]

[0450] Example 48: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide (Example 48 Peak-1 & Example 48 Peak-2): [ka]

[0451] Following the general procedure for compound-8, compound-4n (100 mg, 0.465 mmol) was converted to Example 48 (60 mg, 27.90%) using compound-7b. The product was separated using chiral preparative HPLC (column: Chiral Pack IH, 250 mm x 20 mm, 5 μm; mobile phase: n-hexane (A) and 0.2% HCOOH in EtOH (B), flow rate: 15 ml, isocratic: 90 (A):10 (B), diluent: EtOH:DCM 1:1, 4 ml, injection volume - 0.05 ml, run time: 17 min) to obtain peak-1 (11 mg) and peak-2 (13.5 mg); 1H NMR (400MHz, DMSO-d6)δ 0.99-1.06(m,2H), 1.17-1.26(m,2H), 1.52(s,3H), 2.33(s,3H), 2.47(s,3H), 2.66(dd,J=14Hz,2H) , 4.76(q,J=8.9Hz,2H), 6.10(bs,1H), 6.64(m,1H), 6.81(m,1H), 6.96(m,1H), 8.64(bs,1H);HRMS:[C 20 H 22 [CLF3N2O3S+H] + Calculated value: 463.1070; Measured value: 463.1072 (Example 48 Peak-1), 463.1089 (Example 48 Peak-2); Chiral HPLC for analysis: Chiral Pack-IH (150 x 4.6 mm x 5 μm), Mobile phase: (A) n-Hexane (B) EtOH, Flow rate: 1.0 ml / min, Isocratic: 90:10 (A:B), Column temperature: 25°C, Diluent: EtOH, Injection volume: 5 μl; Peak-1 (Rt: 3.08, 100% ee) Peak-2 (Rt: 3.52, 100% ee)

[0452] Example 49: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide Synthesis of ethyl 3-hydroxy-3-(4-methylthiazole-2-yl)butanoate (3O): 1-(4-methylthiazole-2-yl)ethane-1-one (0.5 g, 3.5413 mmol) was converted to compound-3o (0.1 g, 12.31%) using general procedure A used for compound-3. m / z (LC-MS): 230.00 [M+H] + [ka]

[0453] Synthesis of 3-hydroxy-3-(4-methylthiazole-2-yl)butanoic acid (4o): Compound 3o (0.1 g, 0.4361 mmol) was subjected to hydrolysis, and 4o (0.048 g, 55.17%) was obtained using the general procedure used for compound 4. m / z (LC-MS): 201.95 [M+H] + [ka]

[0454] Example 49: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide (Example 49 Peak-1 & Example 49 Peak-2): [ka]

[0455] Following the general procedure for compound-8, compound-4o (0.048 g, 0.2385 mmol) was converted to Example 49 (0.037 g, 33.33%) using compound-7b. The product was separated using chiral SFC (column: Chiral Pack IG, 250 mm x 21 mm, 5 μm, mobile phase: CO2 (A) and IPA:MeOH (1:1) (B), flow rate: 50 ml, isocratic: 85 (A):15 (B), diluent: EtOH:DCM 1:1, 3.5 ml, injection volume - 0.75 ml, run time: 8 min) to obtain peak-1 (10.5 mg) and peak-2 (9.8 mg). 1 H NMR (400MHz, DMSO-d6)δ 0.97-1.10(m,2H), 1.15-1.23(m,2H), 1.49(s,3H), 2.32(s,3H), 2.63(d,J=14Hz,1H), 2.81(d,J=14Hz,1H), 4.76 (q,J=8.9Hz,2H), 6.38(bs,1H), 6.59(s,1H), 6.75(s,1H), 6.94-6.96(m,1H), 7.20(s,1H), 8.67(s,1H);HRMS:[C 19 H 20 [CLF3N2O3S+H] +Calculated value: 449.0914; Measured value: 449.0919 (Example 49 Peak-1), 449.0920 (Example 49 Peak-2); Chiral SFC for analysis: Chiral Pack-IG (150 x 4.6 mm x 5 μm), Mobile phase: CO2 (A) and IPA:EtOH:MeOH (1:1:1) (B), Flow rate: 3.0 ml / min, Column temperature: 40°C, Injection volume: 15 μl; Peak-1 (Rt: 1.45, 100% ee), Peak-2 (Rt: 2.21, 100% ee)

[0456] Example 50: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide Synthesis of 3-(5-chlorothiazol-2-yl)-3-hydroxybutanoate tert-butyl(3p): Using the general procedure B used for compound-3 (using ether as the solvent instead of THF, and tert-butyl bromoacetate instead of ethyl bromoacetate), 1-(5-chlorothiazole-2-yl)ethane-1-one (0.250 g, 1.5469 mmol) was converted to compound-3p (0.4 g crude product). m / z (LC-MS): 277.85 [M+H] + [ka]

[0457] Synthesis of 3-(5-chlorothiazol-2-yl)-3-hydroxybutanoic acid (4p): Compound-3p (0.2 g, 0.72 mmol) was added dropwise to a stirred solution in dichloromethane at 0°C by adding HCl in dioxane. The reaction mixture was stirred at room temperature for 2 hours. The excess HCl in dioxane was removed under vacuum, and the mixture was triturated with ether to obtain the crude product (0.150 g, crude). m / z (LC-MS): 221.90 [M+H] + [ka]

[0458] Example 50: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide (Example 50 Peak-1 & Example 50 Peak-2): [ka]

[0459] Following the general procedure for compound-8, compound-4p (0.150 g, 0.6767 mmol) was converted to Example 50 (0.110 g, 34.70%) using compound-7b. The product was separated using chiral SFC (column: 2 X LUX AMYLOSE 2-, 250 mm x 19 mm, 5 μm, mobile phase: CO2 (A) and IPA (B); flow rate: 50 ml, ISO-90:10, diluent: EtOH:DCM, 1:1 5 ml, injection volume: 0.3 ml, run time: 16 min) to obtain peak-1 (44 mg) and peak-2 (41 mg). 1 H NMR (400MHz, DMSO-d6)δ 1.08-1.17(m,2H), 1.19-1.26(m,2H), 1.50(s,3H), 2.64(d,J=14Hz,1H), 2.80(d,J=14Hz,1H), 4.75(q,J =8.9Hz,2H),6.61-6.64(m,2H),6.77-6.78(m,1H),6.96-6.97(m,1H),7.67(s,1H),8.70(s,1H);HRMS:[C 18 H 17 Cl2F3N2O3S+H] + Calculated value: 469.0367; Measured value: 469.0381 (Example 50 Peak-1), 469.0372 (Example 50 Peak-2); Chiral SFC for analysis: LUX AMYLOSE 2-, 250mm x 19mm, 5μm, Mobile phase: CO2 (A) and 10mM ammonia:EtOH:MeOH (1:1:1) (B) in IPA, Flow rate: 3.0 ml / min, Column temperature: 40℃, Injection volume: 15μl; Peak-1 (Rt: 2.18, 100%ee), Peak-2 (Rt: 2.58, 100%ee)

[0460] Example 51: Synthesis of 3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide Synthesis of ethyl 3-hydroxy-3-(2,4,6-trifluorophenyl)butanoate (3q): Using the general procedure A used for compound-3, 1-(2,4,6-trifluorophenyl)ethane-1-one (500 mg, 2.872 mmol) was converted to compound-3q (0.9 g crude product). m / z (LC-MS): 244.95 [M-18] + [ka]

[0461] Synthesis of 3-hydroxy-3-(2,4,6-trifluorophenyl)butanoic acid (4q): Compound-3q (750 mg, 2.860 mmol) was subjected to hydrolysis, and compound-4q (600 mg, 90.9%) was obtained using the general procedure used for compound-4. m / z (LC-MS): 232.85 [MH] + [ka]

[0462] Example 51: Synthesis of 3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide (Example 51 Peak-1 & Example 51 Peak-2): [ka]

[0463] Following the general procedure for compound-8, compound-4q (0.1 g, 0.427 mmol) was converted to Example 51 (0.125 g, 65.78%) using 7aa, and separated using chiral HPLC (column: Chiral Pack IH, 250 mm x 21 mm, 5 μm, mobile phase: n-hexane (A) and 10 mM ammonia in IPA:EtOH (1:1) (B), flow rate: 15 ml, isocratic: 90 (A):10 (B), diluent: EtOH:DCM 1:1 3 ml, injection volume - 0.2 ml, run time: 19 min), yielding peak-1 (45 mg) and peak-2 (48.4 mg) as off-white gum. 1 H NMR (400MHz, DMSO-d6)δ 0.99-1.01(m,2H), 1.19-1.26(m,2H), 1.38-1.48(m,2H), 1.64(s,3H), 2.73(d,J=14.4Hz,1H), 2.83(d,J=14.4Hz,1H), 4.86(q,J= HRMS:[C 20 H 18 F6N2O3+H] + Calculated value: 448.12; Measured value: 448. (Example 51 Peak-1), 448. (Example 51 Peak-2); Chiral HPLC for analysis: Column: Chiral Pack-IH (150 x 4.6 mm x 5 μm), Mobile phase: (A) n-hexane (B) 0.1% NH4OH in IPA: EtOH: MeOH (1:1:1), Isocratic: 95(A):05(B), Flow rate: 1.0 ml / min, Diluent: EtOH, Column temperature: 25°C, Injection volume: 5 μl; Peak-1 (Rt: 3.47, 100% ee), Peak-2 (Rt: 4.37, 95.28% ee)

[0464] Example 52: Kv7 regulatory activity the purpose To demonstrate the regulatory ability of the compounds related to this disclosure to Kv7 potassium channel activity.

[0465] material and method Cell seeding: HEK293 cells stably expressing ligated hKv7.3-hKv7.2 were seeded into 384-well Corning Optiplates with clear bottoms and black walls coated with poly-D-lysine (10 μg / ml). Approximately 3 x 10 cells were added to each well in 20 μl of DMEM containing 10% FCS. 6 The cells were seeded at a density of 1 cell / ml and left to stand overnight in a 5% CO2 incubator at 37°C.

[0466] Fluorescent TI + Influx assay (FLIPR): Before the experiment, cells were loaded with the fluorescent dye benzothiazole coumarin acetoxymethyl ester (BTC-AM). In short, cells were loaded with Cl - -Free assay buffer (mM: 140Na) + -Gluconate, 2.5K + -Gluconate, 6Ca 2+ -Gluconate, 1 mg 2+ Washed three times with gluconate, 5 glucose, 10 HEPES, pH 7.3). Then, aspirate the buffer and add 25 μl of Cl. - - Free loading buffer (assay buffer further containing 2 μM BTC-AM, 2 mM amaranth, and 1 mM tartrazine) was added to each well. Cells were incubated at 37°C for 1 hour, then transferred to a fluorometric image plate reader (FLIPR). Assay plates were tested using a two-addition protocol (first addition: test compound, second addition: stimulating buffer). A 10 mM DMSO stock solution of the compound was added to Cl - -Diluted with free assay buffer, 1 / 2 log serial dilutions (31.6 μM-0.316 nM) were prepared in 384-well plates. In the hKv7.3-hKv7.2 assay, the stimulating buffer was supplemented with 2 mM Tl2SO4 (thallium sulfate) and 5 mM K2SO4 (final concentration), as well as the quenchers amaranth (2 mM) and tartrazine (1 mM) in Cl -- Composed of free assay buffer. The stimulation buffer in the hKv7.5 assay was the same as the stimulation buffer used in the hKv7.3-hKv7.2 assay, but the final concentration of K2SO4 was 10 mM. Cells were stimulated in quadruple duplication, i.e., four individual wells were stimulated for each test concentration of the compound. In addition, a 16-well / plate was used as a negative control (with buffer added), and another 16-well / plate was used as a positive control (30 μM retigabine).

[0467] Data Analysis: Data from individual wells were expressed as multiplication factors (the maximum signal (after stimulus buffer addition) divided by the mean baseline value (immediately before addition)). Next, the data were background-corrected by subtracting the mean multiplication factor from the negative control well. Finally, the data were analyzed by normalizing the corrected multiplication factor to the maximum positive control response and fitting the data to Hill's equation. EC 50 The efficacy (percentage of the positive control) is reported, with the positive control defined as the response to 30 μM retigabine.

[0468] result Table 1 below shows the results obtained when evaluating the ability of the compounds of this disclosure to modulate the activity of Kv7 potassium channels, specifically Kv7.2 / 7.3 and Kv7.5.

[0469] Table 1: [Table 14] [Table 15] [Table 16]

[0470] conclusion The compounds of this disclosure can modulate the activity of the Kv7 channel. As shown in the examples, the compounds of the present invention exhibit lower EC values ​​for Kv7.2 / Kv7.3 channels compared to Kv7.5 channels. 50 The compounds of the present invention provide a value. Furthermore, as shown in the examples, the compounds of the present invention provide a greater efficacy value for the Kv7.2 / Kv7.3 channel compared to the Kv7.5 channel. Thus, it can be concluded that the compounds of the present invention are a subtype of selective Kv7 modulator that is more selective for the Kv7.2 / Kv7.3 channel than for the Kv7.5 channel.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula: R ０ -OH and -CH ３ Selected from the group consisting of; R １ R is one or more identical or different substituents ４ An aryl that may be substituted with, or one or more identical or different substituents R ４ It is a heteroaryl that may be substituted with; R ４ C may be replaced by one or more Fs. １－５ Alkyl, C １－５ Selected from the group consisting of alkoxys, halogens, and CN; R ２ is selected from the group consisting of -H, -CH ３ and -CF ３ ; selected from the group consisting of R ３ It is selected from the group consisting of -H and -OH; A is equation (II): 【Chemistry 2】 (In the formula: A １ CR ５ or N; R ５ is -H or halogen; A ２ CR ６ And; R ６ C may be replaced by one or more Fs. １－５ Alkoxy; C which may be substituted with one or more F １－５ alkyl; halogen; and N(R) １０ ) (Caution １１ Selected from the group consisting of; R １０ R is one or more identical or different substituents １２ C may be replaced by １－５ It is alkyl; R １１ is -H; R １２ is halogen, C ３－５ Cycloalkyl and C １－３ Selected from the group consisting of alkyl groups; A ３ CR ７ or N; R ７ is -H, halogen and C １－５ Selected from the group consisting of alkyl groups; A ４ CR ８ or N; R ８ is -H, halogen, C ３－５ C may be substituted with cycloalkyl or one or more F atoms. １－５ Alkyl, C １－５ Selected from the group consisting of alkoxy and -CN; A ５ CR ９ or N; R ９ (is -H or halogen) [This is the base shown by] Compounds represented by, or their tautomers, resonances, racemates, enantiomers or diastereomers, or mixtures thereof; or pharmaceutically acceptable salts thereof: however, N-[1-(3,5-difluorophenyl)cyclopropyl]-β-methyl-1H-imidazole-1-propanamide; N-[1-(3-chlorophenyl)cyclopropyl]-β-hydroxybenzenepropanamide; N-[1-(3-fluorophenyl)cyclopropyl]-β-hydroxybenzenepropanamide; or 3-Fluoro-N-[1-(3-fluorophenyl)cyclopropyl]-β-hydroxybenzenepropanamide Other compounds.

2. Formula (IIIa): 【Transformation 3】 The compound according to claim 1, which is a compound represented by [the formula shown].

3. Formula (IIIb): 【Chemistry 4】 The compound according to claim 1, which is a compound represented by [the formula shown].

4. R １ However, -F, -Cl, -Br, C １－５ Alkoxy, C １－５ R is one or more identical or different substituents selected from the group consisting of alkyl and -CN. ４ The compound according to any one of the above claims, which is phenyl, pyridine-4-yl, pyridine-3-yl, pyridine-2-yl, thiazole-2-yl, or thiazole-5-yl, which may be substituted with.

5. R １ However, -F, -Cl, -Br, C １－５ Alkoxy, C １－５ R is one or more identical or different substituents selected from the group consisting of alkyl and -CN. ４ The compound according to any one of claims 1 to 3, wherein the compound is a phenyl compound substituted with [the specified compound].

6. R １ However, -F, -Br, C １－５ R is one or more identical or different substituents selected from the group consisting of alkyl and -CN. ４ The compound according to any one of claims 1 to 3, wherein the compound is a phenyl compound substituted with [the specified compound].

7. R １ The compound according to any one of claims 1 to 3, wherein is a phenyl substituted with one or more -F.

8. R １ However, -F, -Cl, -Br, C １－５ Alkoxy, C １－５ R is one or more identical or different substituents selected from the group consisting of alkyl and -CN. ４ The compound according to any one of claims 1 to 3, wherein the compound is a pyridinyl substituted with

9. R １ However, -F, -Cl, -Br, and C １－５ R is one or more identical or different substituents selected from the group consisting of alkoxys. ４ The compound according to any one of claims 1 to 3, wherein the compound is a pyridinyl substituted with

10. R １ However, -F, -Cl, -Br, and C １－５ R is one or more identical or different substituents selected from the group consisting of alkoxys. ４ The compound according to any one of claims 1 to 3, wherein the compound is a thiazolyl substituted with

11. R １ However, -F, -Cl, -Br, and C １－５ R is one or more identical or different substituents selected from the group consisting of alkyl groups. ４ The compound according to any one of claims 1 to 3, wherein the compound is a thiazolyl substituted with

12. R １ However, -F, -Cl, -Br, and C １－５ R is one or more identical or different substituents selected from the group consisting of alkyl groups. ４ The compound according to any one of claims 1 to 3, which is an indolyl that is substituted with

13. R １ but 【Transformation 5】 A compound according to any one of claims 1 to 3, selected from the above.

14. R ２ ga-CH ３ And R ０ The compound according to any one of the above claims, wherein is -OH.

15. R ０ is -OH, and R ２ ga-CH ３ And R ３ The compound according to any one of the above claims, wherein is -H.

16. R ２ ga-CF ３ And R ０ The compound according to any one of claims 1 to 12, wherein the OH group is -OH.

17. R ３ The compound according to any one of the above claims, wherein is -H.

18. A is equation (II): 【Transformation 6】 [In the formula: a) A １ is C-R ５ ; A ２ is C-R ６ ; A ３ is C-R ７ ; A ４ is C-R ８ ; and A ５ is C-R ９ or b) A １ is N; A ２ is C-R ６ ; A ３ is C-R ７ ; A ４ is C-R ８ ; A ５ is C-R ９ ; or c) A １ CR ５ A ２ CR ６ A ３ is N; A ４ CR ８ And; A ５ CR ９ is, or d) A １ CR ５ A ２ CR ６ A ３ CR ７ A ４ is N; A ５ CR ９ is, or e) A １ is N; A ２ CR ６ A ３ is N; A ４ CR ８ And; A ５ CR ９ is, or f) A １ CR ５ A ２ CR ６ A ３ CR ７ A ４ CR ８ And; A ５ [is N] The compound according to any one of the above claims, wherein the group is represented by .

19. ・R ５ If it is H or -F, ・R ６ が-CF ３ 、-Cl、-Br、-CH ３ ,-OCH ２ CF ３ 、-OCF ３ ,-OCH ３ ,-OCH ２ CF ２ H、-OCF ２ H、-N(H)(CH ２ CF ３ ) 【Transformation 7】 -N(H)CH ２ C (CH ３ ) ３ , or -N(H)C(H)(CH ３ ) ２ And, ・R ７ is -H, -Cl, -F, or -CH ３ And, ・R ８ -H, -F, -Cl, -Br, -CN, -CF ２ H, cyclopropyl, or -OCH ３ And, ・R ９ is -H or -F The compound according to any one of the above claims.

20. A １ C(H) and A ２ is C(OCH) ２ CF ３ ) and A ５ The compound according to any one of the above claims, wherein is C(H).

21. A １ N is A ３ C(H) and A ５ The compound according to any one of claims 1 to 17, wherein is C(H).

22. At least 1 A １ A ３ and A ４ The compound according to any one of the above claims, wherein is a group other than -C(H).

23. A 【Transformation 8】 A compound according to any one of claims 1 to 17, selected from the above.

24. (R)-3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, (R)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide, (R)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide, (R)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide, (R)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (R)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)butanamide, (R)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (R)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide), (R)-N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide, (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (R)-3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide, (R)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide, (S)-3-(6-chloropyridine-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(5-fluoropyridine-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-hydroxy-3-(2-methoxypyridine-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)butanamide, (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)butanamide, (S)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, (S)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (S)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (S)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridine-4-yl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(4,6-dichloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(neopentylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide), (S)-N-(1-(6-((cyclopropylmethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(isopropylamino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloropyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridine-2-yl)cyclopropyl)butanamide, (S)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide, (S)-3-(4-fluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indole-4-yl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidine-4-yl)cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazole-2-yl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5-chlorothiazol-2-yl)-3-hydroxybutanamide, or (S)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridine-2-yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide or a pharmaceutically acceptable salt thereof The compound according to claim 1.

25. Thallium ion (Tl ＋ When measured by an influx assay, the activity of the Kv7.2 / Kv7.3 heteromeric channel is measured at an EC of less than 20 μM. ５０ The compound according to any one of the above claims, which can be increased by

26. A compound according to any one of claims 1 to 25 for use in a method for increasing the activity of a Kv7.2 / Kv7.3 heteromeric channel in a subject, comprising administering an effective amount of the compound to the subject.

27. A compound according to any one of claims 1 to 25 for use in a method for treating, preventing or alleviating epilepsy or pain in a subject, comprising administering an effective amount of the compound to the subject.

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