Kv7 modulators

Abstract

The present invention provides novel compounds (I) which modulate the Kv7 potassium channels. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat disorders responsive to the activation of Kv7 potassium channels.

Description

[0001] Kv7 modulators

[0002] Technical field

[0003] The present invention provides novel compounds which modulate the Kv7 potassium channels. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat disorders responsive to the activation of Kv7 potassium channels.

[0004] Background

[0005] Kv7 channels are voltage-dependent potassium channels that conduct potassium ions (K+) across cell membranes in response to depolarizations of the cell membrane potential. The Kv7 channel family consists of five proteins Kv7.1 , Kv7.2, Kv7.3, Kv7.4, Kv7.5 which are encoded by the human genes KCNQ1 , KCNQ2, KCNQ3, KCNQ4 and KCNQ5 or the rodent, dog or non-human primate equivalents. The Kv7 proteins have the traditional Kvstructure with six transmembrane helixes (S1-S6) and with the N and C termini located intracellularly. Functional Kv7 channels exists as homo- or hetero- tetrameric complexes of these subunits surrounding the K+conducting transmembrane pore. 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 Kv7 review, see Soldovieri et al 2011 ; Physiology, 26, 365-376).

[0006] Kv7.2-Kv7.5 has been detected in neurons of the central nervous system (CNS), where especially the Kv7.2 / Kv7.3 heteromeric channel plays an important role and underlies the so-called M-current (Brown and Adams, 1980; Nature, 283(5748), 673-676) a sustained and acetylcholine-sensitive K+current active in the range of action potential initiation and therefore a dominant conductance controlling neuronal excitability. The specific roles of Kv4 and Kv7.5 containing channels in the CNS seems less clear, but their wider expression, also in peripheral tissues such as smooth muscle cells, make especially Kv7.4 a potential off-target for development of 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 treatment of various pain conditions. In contrast to the neuronally expressed Kv7 channels, Kv7.1 is primarily expressed in cardiac cells and in some epithelia, typically in complex with different KCNE p-subunits. The pivotal role of the Kv7.2 / Kv7.3 channel in controlling the excitability of CNS neurons is well illustrated by the mutations in both KCNQ2 and KCNQ3, which is strongly linked to neonatal or pediatric epilepsy diseases ranging in severity from relative benign self- limiting cases to serious encephalopathies, whereas such associations are seen much less frequently for Kv7.5 and hardly ever for Kv7.4 (Maljevic and Lerche, 2014; Progress in Brain Research, 213, 17-53). In line with this, compounds with an activating effect on the neuronal Kv7 channels have for a long time been known as anti-epileptics and analgesics, exemplified by the drugs retigabine, which was registered for the management of treatment resistant focal epilepsies, and flupirtine, which was on the market as an analgesic in some countries including Germany. Retigabine and flupirtine are close chemical analogues and both have now been withdrawn from the marked due to long-term toxicities related to their unstable chemical structures (both are anilines) (Bock and Link, 2019; Future Med Chem, 11(4), 337-355). In addition to these chemical problems retigabine also showed adverse effects including both CNS and peripheral tissues of which the risk of causing urinary retention in sensitive patients was probably the most severe (Brickel et al, 2012; Epilepsia, 53(4), 606-612). Retigabine continued in new Ph 3 studies controlled by Xenon Pharmaceuticals under the name Xen496 with children diagnosed with KCNQ2 encephalopathies, but these studies were discontinued in May 2023 for yet unknown reasons. Since Kv7 activation is a clinically validated concept (with no drugs currently on the marked) for both epilepsy and pain, there is great interest in developing new Kv7 activators based on alternative chemical scaffolds. Fortunately, the scientific and patent literature reveals that other chemical classes can also act as Kv7 channel activators, either by interaction with the traditional retigabine activator site in the pore region (S5-6) or with an alternative site in the voltage sensor domains (S1-4). An added benefit of new chemical scaffolds may also be the possibility for better differentiation between Kv7 subtypes and thereby potentially improved efficacy and safety of the medicines. Approximately 1 / 3 of the epilepsy population is still not adequately treated with the existing medications. Similarly, several chronic pain conditions are poorly managed, which has led to the escalating opioid crisis in the USA. Thus, novel treatment principles are urgently needed for these diseases and improved Kv7 channel activating medicines represent a possible step to resolve these health issues. Summary

[0007] In one aspect, the present disclosure provides for a compound according to according to formula (I): formula (I) or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein,

[0008] R° is selected from the group consisting of -OH, and -CH3;

[0009] R1is aryl optionally substituted with one or more, identical or different, substituents R4, or heteroaryl optionally substituted with one or more, identical or different, substituents R4;

[0010] R4is selected from the group consisting of C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, halogen and CN;

[0011] R2is selected from the group consisting of -H, -CH3, and -CF3;

[0012] R3is selected from the group consisting of -H and -OH;

[0013] A is of formula (II): formula (II) wherein

[0014] A1is C-R5or N;

[0015] R5is -H or halogen;

[0016] A2is C-R6;

[0017] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more F; C1-5 alkyl optionally substituted with one or more F; halogen; and N(R10)(R11);

[0018] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0019] R11is -H; R12is selected from the group consisting of halogen, C3-5 cycloalkyl and C1-3 alkyl;

[0020] A3is C-R7or N;

[0021] R7is selected from the group consisting of -H, halogen and C1-5 alkyl;

[0022] A4is C-R8or N;

[0023] R8is selected from the group consisting of -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, and -CN;

[0024] A5is C-R9or N;

[0025] R9is -H or halogen; with the proviso that the compound is not

[0026] / V-[1-(3,5-Difluorophenyl)cyclopropyl]-p-methyl-1 / 7-imidazole-1-propanamide;

[0027] N-[1-(3-Chlorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide;

[0028] N-[1-(3-Fluorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide; or 3-Fluoro-N-[1-(3-fluorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide.

[0029] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as described herein.

[0030] In another aspect, the present disclosure provides a compound as described herein for use as a medicament.

[0031] In another aspect, the present disclosure provides a compound as described herein for use in a method of modulating the activity of a Kv7 channel in a subject, the method comprising administering an effective amount of the compound to the subject.

[0032] In another aspect, the present disclosure provides a compound as described herein for use in a method of modulating the activity of a Kv7.2 / Kv7.3 channel in a subject, the method comprising administering an effective amount of the compound to the subject.

[0033] In another aspect, the present disclosure provides a compound as described herein for use in the treatment of epilepsy or pain.

[0034] Definitions

[0035] The term “alkyl” as used herein refers to a linear or branched hydrocarbon moiety. The term "alkoxy" as used herein refers to a group of formula -O- alkyl, wherein alkyl is defined as above. In particular, C1-C3 -alkoxy is intended to indicate such hydrocarbon having 1 , 2 or 3 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy.

[0036] The term “haloalkyl” as used herein refers to an alkyl group wherein one or more hydrogen atoms have been replaced by a halogen atom, for example one or more hydrogen atoms replace by any of F, Cl, Br or I.

[0037] As used herein the term “cycloalkyl” refers to a monocyclic or polycyclic system. The term “cycloalkyl” also used herein can optionally contain one or more unsaturations or substituents.

[0038] The term "heteroatom" refers to sulfur, oxygen or nitrogen.

[0039] The term "heterocyclic" or “heterocycle” as used herein, alone or in combination, refers to saturated or unsaturated aromatic or nonaromatic rings containing from 3 to 20 ring atoms where at least one the ring atoms are heteroatom(s).

[0040] The term "aromatic" or “aryl” refers to a cyclic or polycyclic moiety having a conjugated unsaturated (4r|+2)TT electron system (where n is a positive integer), sometimes referred to as a delocalized TT electron system.

[0041] The term "heteroaromatic" or “heteroaryl” as used herein, alone or in combination, refers to an aromatic heterocycle containing 5 to 12 atoms of which 1 , 2, or 3 ring atoms are heteroatoms. Heteroaryl groups include monocyclic and biycyclic systems. For example, heteroaryl as used herein can be a C5-C10 monocyclic or C8-C12 bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring. Examples of heteroaryl groups include without limitation, pyridinyl, thiazolyl and indolyl.

[0042] The compounds described herein may contain one or more stereocenters. When referring to a chiral carbon or position, the term “stereochemistry configuration” as used herein refers to the absolute configuration of that center, which can be R or S, as determined by the Cahn-lngold-Prelog priority rules. A “heteromeric” channel or protein refers to an ion channel or protein that is composed of multiple different subunits. Some functional Kv7 channels exists in hetero-tetrameric complexes of subunits surrounding the K+conducting transmembrane pore, for example the Kv7.2 / Kv7.3 heteromeric channel. As used herein, the term “agonism” referring to a Kv7 channel, refers to activating, increasing or enhancing the activity of a Kv7 channel. Detailed description In one aspect, the present disclosure provides for a compound according to formula (I): formula (I) or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein, R0is selected from the group consisting of -OH, and -CH3; R1is aryl optionally substituted with one or more, identical or different, substituents R4, or heteroaryl optionally substituted with one or more, identical or different, substituents R4; R4is selected from the group consisting of C1-5alkyl optionally substituted with one or more F, C1-5alkoxy, halogen and CN; R2is selected from the group consisting of -H, -CH3, and -CF3; R3is selected from the group consisting of –H and -OH; A is of formula (II): formula (II) wherein A1is C-R5or N; R5is -H or halogen; A2is C-R6; R6is selected from the group consisting of C1-5alkoxy optionally substituted with one or more F; C1-5alkyl optionally substituted with one or more F; halogen; and N(R10)(R11); R10is C1-5alkyl optionally substituted with one or more, identical or different, substituents R12; R11is -H; R12is selected from the group consisting of halogen, C3-5cycloalkyl and C1-3alkyl; A3is C-R7or N; R7is selected from the group consisting of -H, halogen and C1-5alkyl; A4is C-R8or N; R8is selected from the group consisting of -H, halogen, C3-5cycloalkyl, C1-5alkyl optionally substituted with one or more F, C1-5alkoxy, and -CN; A5is C-R9or N; R9is -H or halogen; with the proviso that the compound is not 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. Thus, in one embodiment, the compound is not one of the group consisting of: . In one embodiment, the compound is of formula (la): formula (la) In one embodiment, the compound is of formula (lb): formula (lb)

[0043] In one embodiment, the compound is of formula (III): formula (III)

[0044] In one embodiment, the compound is of formula (Illa): formula (Illa)

[0045] In one embodiment, the compound is of formula (lllb): formula (I I lb)

[0046] In one embodiment, R° is -OH. In one embodiment, R° is -CH3.

[0047] In one embodiment R1is aryl, optionally substituted with one or more, identical or different substituents R4. In one embodiment R1is aryl substituted with one or two, identical or different substituents R4. In one embodiment R1is phenyl optionally substituted with one or more, identical or different, substituents R4. In one embodiment R1is phenyl substituted with 0 to 5, identical or different, substituents R4, wherein R4is -F, -Cl, -OCH3, -CH3, -CN or -CFs. In one embodiment R1is phenyl. In one embodiment R1is phenyl substituted with one or more, identical or different, substituents R4. In one embodiment R1is phenyl substituted with one R4. In one embodiment R1is phenyl substituted with two, identical or different, substituents R4. In one embodiment R1is phenyl substituted with three, identical or different, substituents R4

[0048] In one embodiment R1is heteroaryl, optionally substituted with one or more, identical or different substituents R4. In one embodiment R1is heteroaryl substituted with one or two, identical or different substituents R4. In one embodiment the heteroaryl is pyridinyl. In one embodiment the heteroaryl is pyridin-4-yl. In one embodiment the heteroaryl is pyridin-2-yl. In one embodiment the heteroaryl is pyridin-3-yl. In one embodiment R1is pyridinyl optionally substituted with one or more, identical or different, substituents R4. In one embodiment R1is pyridinyl. In one embodiment R1is pyridin-2-yl optionally substituted with one or more, identical or different substituents R4. In one embodiment R1is pyridin-2-yl substituted with one R4. In one embodiment R1is pyridin-3-yl optionally substituted with one or more, identical or different substituents R4. In one embodiment R1is pyridin-3-yl substituted with one R4. In one embodiment R1is pyridin- 4-yl optionally substituted with one or more, identical or different substituents R4. In one embodiment R1is pyridin-4-yl substituted with one R4. In one embodiment R1is pyridinyl substituted with 0 to 5, identical or different, substituents R4, wherein R4is -F, -Cl, -OCH3, -CH3, -CN or -CF3. In one embodiment the heteroaryl is thiazolyl. In one embodiment R1is thiazolyl optionally substituted with one or more, identical or different, substituents R4. In one embodiment R1is thiazol-2-yl optionally substituted with one or more, identical or different, substituents R4. In one embodiment R1is thiazol-5-yl optionally substituted with one or more, identical or different, substituents R4. In one embodiment R1is thiazolyl substituted with one or more, identical or different, substituents R4, wherein R4is individually halogen, such as Cl, or is C1-3 alkyl, such as -CH3. In one embodiment the thiazolyl is thiazol-2-yl. In one embodiment the thiazolyl is thiazol-5-yl. In one embodiment R1is thiazol-2-yl optionally substituted with one or more, identical or different, substituents R4. In one embodiment R1is thiazol-5-yl optionally substituted with one or more, identical or different, substituents R4. In one embodiment the heteroaryl is indolyl. In one embodiment the heteroaryl is indol-4-yl. In one embodiment R1is indolyl optionally substituted with one or more, identical or different, substituents R4. In one embodiment R1is indol-4-yl optionally substituted with one or more, identical or different, substituents R4. In one embodiment R1is indolyl optionally substituted with one or more, identical or different, substituents R4, wherein R4is C1-3 alkyl, such as - CH3. In one embodiment R1is indol-4-yl optionally substituted with one or more, identical or different, substituents R4, wherein R4is C1-3 alkyl, such as -CH3.

[0049] In one embodiment R4is halogen. In one embodiment R4is -F. In one embodiment R4is -Cl. In one embodiment R4is -Br. In one embodiment R4is C1-5 alkoxy. In one embodiment R4is C1-3 alkoxy. In one embodiment R4is -OCH3. In one embodiment R4is C1-5 alkyl. In one embodiment R4is C1-3 alkyl. In one embodiment R4is -CH3.

[0050] In one embodiment R4is -CN. In one embodiment R4is -CF3. In one embodiment R4is independently selected from the group consisting of -F, -Cl, -Br, -OCH3, -CH3, -CN and CF3.

[0051] In one embodiment R1is selected from: In one embodiment R1is selected from:

[0052] In one embodiment

[0053] In one embodiment In one embodiment R1is In one embodiment R1is

[0054] In one embodiment

[0055] In one embodiment, R2is selected from the group consisting of -H, -CHs and -CF3. In one embodiment R2is not H. In one embodiment, R2is selected from the group consisting of -CHs and -CF3. In one embodiment R2is -CH3. In one embodiment R2is - CF3.

[0056] In one embodiment of the present disclosure when R2is H then then at least one of A1, A3and A4is not -CH. In one embodiment R2is H and R° is OH. In one embodiment R2is -CH3 and R° is OH. In one embodiment, R2is -CF3 and R° is OH. In one embodiment, R2is H and R° is -CH3.

[0057] In one embodiment, R3is H. In one embodiment, R3is OH. In one embodiment R° is - OH, R2is -CH3, and R3is -H.

[0058] In one embodiment A is phenyl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9. In one embodiment A is phenyl optionally substituted with one substituent R5, R6, R7, R8and / or R9. In one embodiment A is phenyl optionally substituted with two substituent R5, R6, R7, R8and / or R9.

[0059] In one embodiment A is pyridinyl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9. In one embodiment A is pyridin-2-yl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9. In one embodiment A is pyridin-2-yl optionally substituted with one substituent R5, R6, R7, R8and / or R9. In one embodiment A is pyridin-2-yl optionally substituted with two substituent R5, R6, R7, R8and / or R9.

[0060] In one embodiment A is pyridin-3-yl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9. In one embodiment A is pyridin-3-yl optionally substituted with one substituent R5, R6, R7, R8and / or R9. In one embodiment A is pyridin-3-yl optionally substituted with two substituent R5, R6, R7, R8and / or R9. In one embodiment A is pyrimidinyl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9. In one embodiment A is pyrimidin-4-yl optionally substituted with one or more, substituents R5, R6, R7, R8and / or R9. In one embodiment A is pyrimidin-4-yl optionally substituted with one substituent R5, R6, R7, R8and / or R9.

[0061] In one embodiment A1is C-R5; A2is C-R6; A3is C-R7; A4is C-R8; and A5is C-R9.

[0062] In one embodiment at least one of A1, A3and A4is not -CH. In one embodiment of the present disclosure, at least two of A1, A2, A3and A4are not -CH.

[0063] In one embodiment one of A1, A3, A4, and A5is N. In one embodiment A1is N; A2is C- R6; A3is C-R7; A4is C-R8; and A5is C-R9. In one embodiment A1is C-R5; A2is C-R6; A3is N; A4is C-R8; and A5is C-R9. In one embodiment A1is C-R5; A2is C-R6; A3is C-R7; A4is N; and A5is C-R9. In one embodiment A1is N; A2is C-R6; A3is N; A4is C-R8; and A5is C-R9. In one embodiment A1is C-R5; A2is C-R6; A3is C-R7; A4is C-R8; and A5is N.

[0064] In one embodiment A1is N. In one embodiment A1is C-R5. In one embodiment R5is -H. In one embodiment A1is C(H). In one embodiment R5is halogen. In one embodiment R5is -F. In one embodiment A1is C(F).

[0065] In one embodiment A2is C-R6, wherein R6is selected from C1-5 alkoxy optionally substituted with one or more -F , -CF3, -CF2H, -Cl, -Br or -CH3. In one embodiment R6is selected from -CF3, -Cl, -Br or -CH3.

[0066] In one embodiment A2is C-R6, wherein R6is selected from C1-5 alkoxy optionally substituted with one or more F; C1-5 alkyl optionally substituted with one or more F; halogen and N(R10)(R11). In one embodiment R6is C1-5 alkoxy optionally substituted with one or more F. In one embodiment R6is C1-4 alkoxy optionally substituted with one or more F. In one embodiment R6is C1-3 alkoxy optionally substituted with one or more F. In one embodiment R6is Ci alkoxy optionally substituted with one or more F. In one embodiment R6is selected from -OCH2CF3, -OCF3, -OCH3, -OCH2CF2H and -OCF2H. In one embodiment R6is -OCH3. In one embodiment R6is -OCF3. In one embodiment R6is -OCH2CF3. In one embodiment R6is C1-5 alkyl optionally substituted with one or more F. In one embodiment R6is C1-3 alkyl optionally substituted with one or more F. In one embodiment R6is Ci alkyl optionally substituted with one or more F. In one embodiment R6is -CF3. In one embodiment R6is -CF2H.

[0067] In one embodiment R6is halogen. In one embodiment R6is Br. In one embodiment R6is Cl. In one embodiment R6is F.

[0068] In one embodiment R6N(R10)(R11), wherein R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12, R11is -H, and R12is selected from the group consisting of halogen, C3-5 cycloalkyl and C1-3 alkyl. In one embodiment R10is C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12. In one embodiment R12is halogen. In one embodiment R12is F. In one embodiment R10is -CH2CF3. In one embodiment R6is -N(H)(CH2CF3). In one embodiment R12is C3-5 . In one embodiment R6is . In one embodiment R12is C1-3 alkyl. In one embodiment R12is CH3. In one embodiment R10is -CH2C(CH3) 3. In one embodiment R6is -N(H)CH2C(CH3) 3. In one embodiment R10is -C(H)(CH3)2. In one embodiment R6is -

[0069] N(H)C(H)(CH3)2.

[0070] In one embodiment A3is C-R7, wherein R7is selected from the group consisting of -H, halogen and C1-5 alkyl. In one embodiment A3is C-R7, wherein R7is selected from -H, - F, -Cl, and -CH3. In one embodiment R7is -H. In one embodiment A3is C(H). In one embodiment R7is halogen. In one embodiment R7is -F. In one embodiment R7is -Cl. In one embodiment A3is C(F). In one embodiment R7is C1-5 alkyl. In one embodiment R7is C1-3 alkyl. In one embodiment R7is -CH3. In one embodiment, A3is N.

[0071] In one embodiment A4is C-R8, wherein R8is selected from the group consisting of H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, and -CN. In one embodiment A4is C-R8, wherein R8is selected from the group consisting of -H, C1-C5 cycloalkyl, -CN, -F, -Cl, -Br and -CF2H. In one embodiment A4is C-R8, wherein R8is selected from the group consisting of -H, cyclopropyl, methoxy, - CN, -F, -Cl, -Br and -CF2H. In one embodiment R8is selected from -H, -F and -Cl. In one embodiment R8is -H. In one embodiment A4is C(H). In one embodiment R8is - CN. In one embodiment A4is C(CN). In one embodiment R8is halogen. In one embodiment R8is F. In one embodiment A4is C(F). In one embodiment R8is -Br. In one embodiment A4is C(Br). In one embodiment R8is -Cl. In one embodiment A4is C(CI). In one embodiment R8is C1-5 alkyl optionally substituted with one or more F. In one embodiment R8is C1-3 alkyl optionally substituted with one or more F. In one embodiment R8is Ci alkyl optionally substituted with one or more F. In one embodiment R8is -CF2H. In one embodiment A4is C(CF2H). In one embodiment R8is - C3-C5 cycloalkyl. In one embodiment R8is cyclopropyl. In one embodiment A4is C(cyclopropyl). In one embodiment R8is C1-5 alkoxy. In one embodiment R8is C1-3 alkoxy. In one embodiment R8is -OCH3. In one embodiment A4is C(OCH3). In one embodiment A4is N.

[0072] In one embodiment A5is C-R9, wherein R9is -H or halogen. In one embodiment R9is - H or -F. In one embodiment R9is -H. In one embodiment A5is C(H). In one embodiment R9is halogen. In one embodiment R9is -F. In one embodiment A5is C(F). In one embodiment A5is N. embodiment one embodiment In one embodiment one embodiment A is

[0073] Br . In one embodiment A is CN . In one embodiment . . one embodiment A is . In one embodiment A is . In one embodiment A is

[0074] In one embodiment A is In one embodiment A is

[0075]

[0076] In one embodiment R° is -OH, R1is phenyl substituted with two or three -F, R2is -CH3, R3is -H, A1is C-R5, A2is C(OCH2CF3), A3is C-R7, A4is C-R8, and A5is C-R9, wherein one of R5, R7, R8, and R9is -F, -Cl, -Br, or -CH3, and the others are -H.

[0077] In one embodiment the stereochemistry configuration at positions 2 and 3, as defined by formulas (I) and (III), are independently selected from R and S. In one embodiment the stereochemistry configuration at position 3, as defined in formulas (I) and (III), is R. In one embodiment the stereochemistry configuration at position 3, as defined in formulas (I) and (III), is S. In one embodiment the stereochemistry configuration at position 2, as defined in formulas (I) and (III), is R. In one embodiment the stereochemistry configuration at position 2, as defined in formulas (I) and (III), is S.

[0078] In some embodiments, the compound is as shown in Table A.

[0079] In one aspect, the present invention relates to a compound shown in Table A, or a pharmaceutically acceptable salt thereof. Table A. List of compounds.

[0080]

[0081] 

[0082]

[0083] In one embodiment, the compound is selected from the group consisting of: 3-(6-chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclo- propyl)butanamide, 3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-butanamide, 3-hydroxy-3-(2-methoxypyridin-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclo- propyl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0084] 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)pyridin-4- yl)cyclopropyl)butanamide, 3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0085] 3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0086] 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-3-hydroxybutanamide,

[0087] 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[0088] 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,

[0089] 4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)- phenyl)-cyclopropyl)butanamide,

[0090] N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide,

[0091] 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,

[0092] N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0093] N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0094] N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0095] N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0096] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0097] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4- difluorophenyl)-3-hydroxybutanamide,

[0098] 3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl) cyclopropyl)-3-hydroxybutanamide,

[0099] N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-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,

[0100] N-(1-(4,6-dichloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0101] N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0102] 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl) amino) pyridin-2- yl)cyclopropyl)butanamide,

[0103] 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0104] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0105] N-(1-(4-chloro-6-(neopentylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide),

[0106] N-(1-(6-((cyclopropylmethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0107] N-(1-(4-chloro-6-(isopropylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0108] N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0109] N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0110] N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0111] 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,

[0112] 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,

[0113] 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridin-2- yl)cyclopropyl)butanamide,

[0114] N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4- fluorophenyl)-3-hydroxybutanamide,

[0115] 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)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0116] N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0117] N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-hydroxy-3-(1- methyl-1 H-indol-4-yl)butanamide,

[0118] 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidin-4- yl)cyclopropyl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- dimethylthiazol-5-yl)-3-hydroxybutanamide,

[0119] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4- methylthiazol-2-yl)butanamide,

[0120] 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)pyridin-2-yl)cyclopropyl)-3-(2,4,6- trifluorophenyl)butanamide, or a pharmaceutically acceptable salt thereof.

[0121] In one embodiment the compound of the present invention is selected from the group consisting of:

[0122] (R)-3-(6-chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclo-propyl)butanamide,

[0123] (R)-3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-butanamide,

[0124] (R)-3-hydroxy-3-(2-methoxypyridin-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,

[0125] (R)-3-(2,4-difluorophenyl)-N-(1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-3-hydroxybutanamide,

[0126] (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)pyridin-4- yl)cyclopropyl)butanamide,

[0127] (R)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[0128] (R)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-butanamide,

[0129] (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-3-hydroxybutanamide,

[0130] (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)- phenyl)cyclopropyl)butanamide,

[0131] (R)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-

[0132] 3-hydroxybutanamide,

[0133] (R)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0134] (R)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)- phenyl)cyclopropyl)butanamide,

[0135] (R)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0136] (R)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4- fluorophenyl)-3-hydroxybutanamide,

[0137] (R)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)- phenyl)cyclopropyl)-3-hydroxybutanamide,

[0138] (R)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0139] (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0140] (R)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0141] (R)-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0142] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0143] (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,

[0144] (R)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-(2,6- difluorophenyl) -3-hydroxybutanamide,

[0145] (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl) cyclopropyl)-3-hydroxybutanamide,

[0146] (R)-N-(1-(4,6-dichloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0147] (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0148] (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl) amino) pyridin-2-yl)cyclopropyl)butanamide,

[0149] (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0150] (R)- N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0151] (R)-N-(1-(4-chloro-6-(neopentylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide),

[0152] (R)-N-(1-(6-((cyclopropylmethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0153] (R)-N-(1-(4-chloro-6-(isopropylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0154] (R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0155] (R)-N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0156] (R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0157] (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,

[0158] (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,

[0159] (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridin-2- yl)cyclopropyl)butanamide, (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4- fluorophenyl)-3-hydroxybutanamide,

[0160] (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)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-hydroxy-3- (1-methyl-1 H-indol-4-yl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-4-yl)cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- dimethylthiazol-5-yl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4- methylthiazol-2-yl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5- chlorothiazol-2-yl)-3-hydroxybutanamide, and

[0161] (R)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4,6- trifluorophenyl)butanamide or a pharmaceutically acceptable salt thereof.

[0162] In one embodiment the compound is selected from the group consisting of:

[0163] (S)-3-(6-chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclo-propyl)butanamide, (S)-3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-butanamide, (S)-3-hydroxy-3-(2-methoxypyridin-4-yl)-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclo-propyl)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)pyridin-4- yl)cyclopropyl)butanamide,

[0164] (S)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0165] (S)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-butanamide,

[0166] (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0167] (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0168] (S)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-

[0169] 3-hydroxybutanamide,

[0170] (S)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0171] (S)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0172] (S)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0173] (S)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4- fluorophenyl)-3-hydroxybutanamide,

[0174] (S)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0175] (S)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0176] (S)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0177] (S)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0178] (S)-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0179] (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,

[0180] (S)-3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl) cyclopropyl)-3-hydroxybutanamide,

[0181] (S)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-(2,6- difluorophenyl) -3-hydroxybutanamide,

[0182] (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl) cyclopropyl)-3-hydroxybutanamide,

[0183] (S)-N-(1-(4,6-dichloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0184] (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0185] (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl) amino) pyridin-2-yl)cyclopropyl)butanamide,

[0186] (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0187] (S)- N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0188] (S)-N-(1-(4-chloro-6-(neopentylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide),

[0189] (S)-N-(1-(6-((cyclopropylmethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0190] (S)-N-(1-(4-chloro-6-(isopropylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0191] (S)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0192] (S)-N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0193] (S)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0194] (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,

[0195] (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridin-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)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0196] (S)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0197] (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-hydroxy-3- (1-methyl-1 H-indol-4-yl)butanamide,

[0198] (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-4-yl)cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- dimethylthiazol-5-yl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4- methylthiazol-2-yl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5- chlorothiazol-2-yl)-3-hydroxybutanamide, and

[0199] (S)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4,6- trifluorophenyl)butanamide, or a pharmaceutically acceptable salt thereof.

[0200] Kv7 modulation

[0201] As demonstrated in the examples, the compounds according to the present invention can produce activating effects of Kv7 channels. Thus, the compounds described herein are useful in the modulation of Kv7 channels, including Kv7 agonism.

[0202] In one embodiment, the compound according to the present disclosure can modulate the activity of a Kv7 channel. In one embodiment, the compound is able to increase the activity of a Kv7.2 / Kv7.3 heteromeric channel.

[0203] The activity of a compound on a Kv7 channel may be assessed through different in vitro assays in cells as known in the art. For example, fluorescence-based assays of channel activity assessing ion flux, such as Thallium ion (Tl+) influx assays, or other fluorescence based assays. The current examples demonstrate an example of a Tl+ion flux assay, other types of channel assay will be known to a person of skill in the art.

[0204] In one embodiment, the compound is able to produce an increase in the activity of the Kv7.2 / Kv7.3 heteromeric channel, with an ECso of less than 50 pM, such as less than 20 pM, such as less than 10 pM, such as less than 1 pM, such as less than 0.1 pM, such as less than 0.06 pM, such as less than 0.01 pM, such as less than 0.001 pM.

[0205] In one embodiment, the compound is able to produce an increase in the activity of the Kv7.2 / Kv7.3 heteromeric channel, with an ECso from about 0.1 nM to about 20 pM, such as from about 0.1 nM to about 10 pM, such as from about 0.1 nM to about 1 pM, such as from about 0.1 nM to about 0.2 pM, such as from 0.1 nM to about 100 nM, such as from about 0.1 nM to about 10 nM.

[0206] Thus, in one aspect the present disclosure provides a compound as described herein for use in a method of modulating the activity of a Kv7 channel in a subject, the method comprising administering an effective amount of the compound to the subject.

[0207] In one embodiment, the compound is for use in a method of increasing the activity of a Kv7.2 / Kv7.3 heteromeric channel in a subject.

[0208] In one embodiment the compound is able to increase the activity of a Kv7.5 channel. In one embodiment, the compound is able to produce an increase in the activity of the Kv7.5 channel, with an ECso from about 0.1 nM to about 20 pM, such as from about 0.1 nM to about 10 pM, such as from about 0.1 nM to about 1 pM, such as from about 0.1 nM to about 0.2 pM, such as from 0.1 nM to about 100 nM, such as from about 0.1 nM to about 10 nM. In one embodiment, the compound is for use in a method of increasing the activity of a Kv7.5 channel in a subject. In one embodiment, the compound is for use in a method of increasing the activity of a Kv7.5 channel in a subject.

[0209] Selective Kv7 modulation

[0210] In some cases, differentiation between Kv7 subtypes is desired, as this potentially provides for improved efficacy and safety of medicines. In some embodiments, the compound can selectively increase the activity of a Kv7.2 / Kv7.3 heteromeric channel. In some embodiments, the compound is a subtype-selective Kv7 modulator. In one embodiment the compound is selective for Kv7.2 / Kv7.3. In some embodiments, the compound is selective for Kv7.2 / Kv7.3 over Kv7.5.

[0211] The selectivity for Kv7.2 / Kv7.3 over Kv7.5 of the compounds of the present invention can be observed either in terms of potency selectivity, efficiency selectivity or both.

[0212] The term ‘potency selectivity’ as used herein refers to that the ratio between Kv7.2 / Kv7.3 ECso and Kv7.5 EC50 is larger than 10. In one embodiment, the ratio is calculated according to the formula below:

[0213] In one embodiment the compound has a ratio between EC50 of Kv7.2 / Kv7.3 and EC50 of Kv7.5 of more than 2, such as more than 3, such as more than 5, such as more than 8, such as more than 10, such as more than 15, such as more than 20, such as more than 25, such as more than 30, such as more than 60, such as more than 75, such as more than 100, such as more than 150, such as more than 200, such as more than 230, such as more than 250, such as more than 500. In one embodiment the compound has a ratio between EC50 of Kv7.2 / Kv7.3 and EC50 of Kv7.5 of more than 10. In one embodiment, the Kv7.5 EC50 is more than 30 pM. In one embodiment, the compound has an ECsofor Kv7.2 / Kv7.3 of less than 10 pM and an EC50 for Kv7.5 of more than 30 pM.

[0214] In one embodiment the EC50 is measured in an in vitro cell-based assay of ion flux, such as a Thallium ion (Tl+) assay.

[0215] The term ‘efficacy selectivity’ as used refers to that the efficacy is larger than 50% at Kv7.2 / Kv7.3 and less than 25% at Kv7.5, relative to 10 uM retigabine.

[0216] In one embodiment the compound has an efficacy for Kv7.2 / Kv7.3 larger than 50%, such as larger than 60%, such as larger than 70%, such as larger than 75%, such as larger than 80%, such as larger than 85%, such as larger than 90%, such as larger than 95%, such as larger than 100%, such as larger than 110%. In one embodiment the compound has an efficacy for Kv7.5 of less than 60%, such as less than 50%, such as less than 40%, such as less than 30%, such as less than 20%, such as 0%. In one embodiment the compound has an efficacy for Kv7.5 of less than 25%. In one embodiment the compound has an efficacy for Kv7.2 / Kv7.3 larger than 50%, and an efficacy for Kv7.5 of less than 25%.

[0217] 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.

[0218] Preparation of compounds

[0219] Compounds according to the present invention may be prepared according to any conventional methods of chemical synthesis known by the skilled person, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods known by the skilled artisan from commercially available chemicals.

[0220] The end products of the reactions described herein may be isolated by conventional technique such as extraction, crystallisation, distillation, chromatography etc. Moreover the compounds according to the present invention may be separated into different stereoisomers, respectively (R) and (S), using chiral chromatography, such as chiral preparative HPLC.

[0221] The compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.

[0222] Pharmaceutically Acceptable Salts

[0223] The chemical compound of the invention may be provided in any form suitable for the intended administration, including pharmaceutically (i.e. physiologically) acceptable salts. Such salts may be formed by procedures well known and described in the art.

[0224] Pharmaceutical compositions

[0225] The present invention also relates to a pharmaceutical composition comprising, for example as an active ingredient, a pharmaceutically effective amount of a compound of Formula (I) as defined above. In one embodiment, said 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.

[0226] While the compound of Formula (I) of the present invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0227] In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and / or prophylactic ingredients, known and used in the art. The carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0228] A therapeutically effective dose refers to that amount of active ingredient, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, e.g. ED50, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by ratio between plasma levels resulting in therapeutic effects and plasma ratios resulting in toxic effects. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.

[0229] The dose administered may be adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage can be determined by the practitioner.

[0230] Medical use

[0231] Given the activity of the compounds in Kv7 channels, the compounds according to the present disclosure may be useful in treatment of conditions associated with Kv7 modulation. The examples demonstrate that compounds according to the present disclosure produce similar effects to the compound retigabine in Kv7 channels. Thus, in one aspect, the present disclosure provides a pharmaceutical composition comprising a compound as described herein. For example, the pharmaceutical composition may comprise one or more excipients as known in the art.

[0232] In another aspect, the present disclosure provides a compound as described herein for use as a medicament.

[0233] In another aspect, the present disclosure provides a compound as described herein for use in a method of treatment of one selected from epilepsy or pain in a subject, said method comprising administering a therapeutically effective amount of a compound as described herein to the subject.

[0234] In another aspect, the present disclosure provides for a method of treatment of epilepsy or pain in a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound as described herein to the subject.

[0235] In another aspect, the present disclosure provides for a use of a compound as described herein in the manufacture of a medicament for the treatment of epilepsy or pain in a subject in need thereof.

[0236] Items

[0237] 1. A compound according to formula (I): formula (I) or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein,

[0238] R° is selected from the group consisting of -OH, and -CH3;

[0239] R1is aryl optionally substituted with one or more, identical or different, substituents R4, or heteroaryl optionally substituted with one or more, identical or different, substituents R4;

[0240] R4is selected from the group consisting of C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, halogen and CN;

[0241] R2is selected from the group consisting of -H, -CH3, and -CF3; R3is selected from the group consisting of -H and -OH;

[0242] A is of formula (II): formula (II) wherein

[0243] A1is C-R5or N;

[0244] R5is -H or halogen;

[0245] A2is C-R6;

[0246] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more F; C1-5 alkyl optionally substituted with one or more F; halogen; and N(R10)(R11);

[0247] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0248] R11is -H;

[0249] R12is selected from the group consisting of halogen, C3-5 cycloalkyl and C1-3 alkyl;

[0250] A3is C-R7or N;

[0251] R7is selected from the group consisting of -H, halogen and C1-5 alkyl;

[0252] A4is C-R8or N;

[0253] R8is selected from the group consisting of -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, and -CN;

[0254] A5is C-R9or N;

[0255] R9is -H or halogen; with the proviso that the compound is not

[0256] / V-[1-(3,5-Difluorophenyl)cyclopropyl]-p-methyl-1 / 7-imidazole-1-propanamide;

[0257] N-[1-(3-Chlorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide;

[0258] N-[1-(3-Fluorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide; or 3-Fluoro-N-[1-(3-fluorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide.

[0259] 2. The compound according to item 1 , wherein the compound is of formula (la): formula (la)

[0260] 3. The compound according to item 1, wherein the compound is of formula (lb): formula (lb)

[0261] 4. The compound according to item 1, wherein the compound is of formula (III): formula (III) 5. The compound according to item 1 , wherein the compound is of formula (Illa): formula (Illa)

[0262] 6. The compound according to item 1 , wherein the compound is of formula (lllb): formula (I I lb)

[0263] 7. The compound according to any one of the preceding items, wherein R° is -OH.

[0264] 8. The compound according to any one of the preceding items, wherein R° is -CH3.

[0265] 9. The compound according to any one of the preceding items, wherein R1is aryl, optionally substituted with one or more, identical or different substituents R4.

[0266] 10. The compound according to any one of the preceding items, wherein R1is aryl substituted with one or two, identical or different substituents R4.

[0267] 11. The compound according to any one of the preceding items, wherein R1is phenyl optionally substituted with one or more, identical or different, substituents R4.

[0268] 12. The compound according to any one of the preceding items, wherein R1is phenyl.

[0269] 13. The compound according to any one of the preceding items, wherein R1is phenyl substituted with one or more, identical or different, substituents R4.

[0270] 14. The compound according to any one of the preceding items, wherein R1is phenyl substituted with one R4.

[0271] 15. The compound according to any one of the preceding items, wherein R1is phenyl substituted with two, identical or different, substituents R4.

[0272] 16. The compound according to any one of the preceding items, wherein R1is phenyl substituted with three, identical or different, substituents R4.

[0273] 17. The compound according to any one of the preceding items, wherein R1is heteroaryl, optionally substituted with one or more, identical or different substituents R4.

[0274] 18. The compound according to any one of the preceding items, wherein R1is heteroaryl substituted with one or two, identical or different substituents R4.

[0275] 19. The compound according to any one of the preceding items, wherein the heteroaryl is pyridinyl. 20. The compound according to any one of the preceding items, wherein the heteroaryl is pyridin-4-yl.

[0276] 21. The compound according to any one of the preceding items, wherein the heteroaryl is pyridin-2-yl.

[0277] 22. The compound according to any one of the preceding items, wherein the heteroaryl is pyridin-3-yl.

[0278] 23. The compound according to any one of the preceding items, wherein R1is pyridinyl optionally substituted with one or more, identical or different, substituents R4.

[0279] 24. The compound according to any one of the preceding items, wherein R1is pyridinyl.

[0280] 25. The compound according to any one of the preceding items, wherein R1is pyridin-2-yl optionally substituted with one or more, identical or different substituents R4.

[0281] 26. The compound according to any one of the preceding items, wherein R1is pyridin-2-yl substituted with one R4.

[0282] 27. The compound according to any one of the preceding items, wherein R1is pyridin-3-yl optionally substituted with one or more, identical or different substituents R4.

[0283] 28. The compound according to any one of the preceding items, wherein R1is pyridin-3-yl substituted with one R4.

[0284] 29. The compound according to any one of the preceding items, wherein R1is pyridin-4-yl optionally substituted with one or more, identical or different substituents R4.

[0285] 30. The compound according to any one of the preceding items, wherein R1is pyridin-4-yl substituted with one R4.

[0286] 31. The compound according to any one of the preceding items, wherein the heteroaryl is thiazolyl.

[0287] 32. The compound according to any one of the preceding items, wherein R1is thiazolyl optionally substituted with one or more, identical or different, substituents R4.

[0288] 33. The compound according to any one of the preceding items, wherein R1is thiazol-2-yl optionally substituted with one or more, identical or different, substituents R4. The compound according to any one of the preceding items, wherein R1is thiazol-5-yl optionally substituted with one or more, identical or different, substituents R4. The compound according to any one of the preceding items, wherein R1is thiazolyl substituted with one or more, identical or different, substituents R4, wherein R4is individually halogen, such as Cl, or is C1-3 alkyl, such as -CH3. The compound according to any one of the preceding items, wherein the thiazolyl is thiazol-2-yl. The compound according to any one of the preceding items, wherein the thiazolyl is thiazol-5-yl. The compound according to any one of the preceding items, wherein R1is thiazol-2-yl optionally substituted with one or more, identical or different, substituents R4. The compound according to any one of the preceding items, wherein R1is thiazol-5-yl optionally substituted with one or more, identical or different, substituents R4. The compound according to any one of the preceding items, wherein the heteroaryl is indolyl. The compound according to any one of the preceding items, wherein the heteroaryl is indol-4-yl. The compound according to any one of the preceding items, wherein R1is indolyl optionally substituted with one or more, identical or different, substituents R4. The compound according to any one of the preceding items, wherein R1is indol-4-yl optionally substituted with one or more, identical or different, substituents R4. The compound according to any one of the preceding items, wherein R1is indolyl optionally substituted with one or more, identical or different, substituents R4, wherein R4is C1-3 alkyl, such as -CH3. The compound according to any one of the preceding items, wherein R1is indol-4-yl optionally substituted with one or more, identical or different, substituents R4, wherein R4is C1-3 alkyl, such as -CH3. The compound according to any one of the preceding items, wherein one or more R4is halogen. 47. The compound according to any one of the preceding items, wherein one or more R4is -F.

[0289] 48. The compound according to any one of the preceding items, wherein one or more R4is -Cl.

[0290] 49. The compound according to any one of the preceding items, wherein one or more R4is -Br.

[0291] 50. The compound according to any one of the preceding items, wherein one or more R4is C1-5 alkoxy.

[0292] 51. The compound according to any one of the preceding items, wherein one or more R4is C1-3 alkoxy.

[0293] 52. The compound according to any one of the preceding items, wherein one or more R4is -OCH3.

[0294] 53. The compound according to any one of the preceding items, wherein one or more R4is C1-5 alkyl.

[0295] 54. The compound according to any one of the preceding items, wherein one or more R4is C1-3 alkyl.

[0296] 55. The compound according to any one of the preceding items, wherein one or more R4is -CH3.

[0297] 56. The compound according to any one of the preceding items, wherein one or more R4is -CN.

[0298] 57. The compound according to any one of the preceding items, wherein one or more R4is -CF3.

[0299] 58. The compound according to any one of the preceding items, wherein R4is independently selected from the group consisting of -F, -Cl, -Br, -OCH3, -CH3, - CN and CF3.

[0300] 59. The compound according to any one of the preceding items, wherein R1is selected from: 60. The compound according to any one of the preceding items, wherein R1is selected from:

[0301] 61. The compound according to any one of the preceding items, wherein R1is

[0302] 62. The compound according to any one of the preceding items, wherein R1is

[0303] 63. The compound according to any one of the preceding items, wherein R1is

[0304] 64. The compound according to any one of the preceding items, wherein R1is 65. The compound according to any one of the preceding items, wherein R1is

[0305] 66. The compound according to any one of the preceding items, wherein R1is 67. The compound according to any one of the preceding items, wherein R1is

[0306] 68. The compound according to any one of the preceding items, wherein R1is 69. The compound according to any one of the preceding items, wherein R1is

[0307] 70. The compound according to any one of the preceding items, wherein R1is

[0308] 71. The compound according to any one of the preceding items, wherein R1is

[0309] 72. The compound according to any one of the preceding items, wherein R1is

[0310] 73. The compound according to any one of the preceding items, wherein R1is . 74. The compound according to any one of the preceding items, wherein R1is . 75. The compound according to any one of the preceding items, wherein R1is . 76. The compound according to any one of the preceding items, wherein R1is . 77. The compound according to any one of the preceding items, wherein R2is selected from the group consisting of -H, -CH3and -CF3. 78. The compound according to any one of the preceding items, wherein R2is not H. 79. The compound according to any one of the preceding items, wherein R2is selected from –CH3 and -CF3. 80. The compound according to any one of the preceding items, wherein R2is -CH3. 81. The compound according to any one of the preceding items, wherein R2is -CF3. 82. The compound according to any one of the preceding items, wherein when R2is H then at least one of A1, A3and A4is not -CH. 83. The compound according to any one of the preceding items, wherein R2is – CH3 and R0is OH. 84. The compound according to any one of the preceding items, wherein R2is -CF3 and R° is OH.

[0311] 85. The compound according to any one of the preceding items, wherein R2is H and R° is OH.

[0312] 86. The compound according to any one of the preceding items, wherein R2is H and R° is -CH3.

[0313] 87. The compound according to any one of the preceding items, wherein R3is H.

[0314] 88. The compound according to any one of the preceding items, wherein R3is OH.

[0315] 89. The compound according to any one of the preceding items, wherein R° is -OH,

[0316] R2is -CH3, and R3is-H.

[0317] 90. The compound according to any one of the preceding items, wherein A is phenyl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9.

[0318] 91 . The compound according to any one of the preceding items, wherein A is phenyl optionally substituted with one substituent R5, R6, R7, R8and / or R9.

[0319] 92. The compound according to any one of the preceding items, wherein A is phenyl optionally substituted with two substituent R5, R6, R7, R8and / or R9.

[0320] 93. The compound according to any one of the preceding items, wherein A is pyridinyl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9.

[0321] 94. The compound according to any one of the preceding items, wherein A is pyridin-2-yl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9.

[0322] 95. The compound according to any one of the preceding items, wherein A is pyridin-2-yl optionally substituted with one substituent R5, R6, R7, R8and / or R9.

[0323] 96. The compound according to any one of the preceding items, wherein A is pyridin-2-yl optionally substituted with two substituent R5, R6, R7, R8and / or R9.

[0324] 97. The compound according to any one of the preceding items, wherein A is pyridin-3-yl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9.

[0325] 98. The compound according to any one of the preceding items, wherein A is pyridin-3-yl optionally substituted with one substituent R5, R6, R7, R8and / or R9.

[0326] 99. The compound according to any one of the preceding items, wherein A is pyridin-3-yl optionally substituted with two substituent R5, R6, R7, R8and / or R9. 100. The compound according to any one of the preceding items, wherein A is pyrimidinyl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9.

[0327] 101. The compound according to any one of the preceding items, wherein A is pyrimidin-4-yl optionally substituted with one or more, substituents R5, R6, R7, R8and / or R9.

[0328] 102. The compound according to any one of the preceding items, wherein A is pyrimidin-4-yl optionally substituted with one substituent R5, R6, R7, R8and / or R9.

[0329] 103. The compound according to any one of the preceding items, wherein A1is C-R5; A2is C-R6; A3is C-R7; A4is C-R8; and A5is C-R9.

[0330] 104. The compound according to any one of the preceding items, wherein at least one of A1, A3and A4is not -CH.

[0331] 105. The compound according to any one of the preceding items, wherein one of A1, A3, A4, and A5is N.

[0332] 106. The compound according to any one of the preceding items, wherein A1is N; A2is C-R6; A3is C-R7; A4is C-R8; and A5is C-R9.

[0333] 107. The compound according to any one of the preceding items, wherein A1is C-R5; A2is C-R6; A3is N; A4is C-R8; and A5is C-R9.

[0334] 108. The compound according to any one of the preceding items, wherein A1is C-R5; A2is C-R6; A3is C-R7; A4is N; and A5is C-R9.

[0335] 109. The compound according to any one of the preceding items, wherein A1is N; A2is C-R6; A3is N; A4is C-R8; and A5is C-R9.

[0336] 110. The compound according to any one of the preceding items, wherein A1is C-R5; A2is C-R6; A3is C-R7; A4is C-R8; and A5is N.

[0337] 111. The compound according to any one of the preceding items, wherein A1is N.

[0338] 112. The compound according to any one of the preceding items, wherein A1is C-R5.

[0339] 113. The compound according to any one of the preceding items, wherein R5is -H.

[0340] 114. The compound according to any one of the preceding items, wherein A1is

[0341] C(H). 115. The compound according to any one of the preceding items, wherein R5is halogen.

[0342] 116. The compound according to any one of the preceding items, wherein R5is -F.

[0343] 117. The compound according to any one of the preceding items, wherein A1is C(F).

[0344] 118. The compound according to any one of the preceding items, wherein A2is C-R6, wherein R6is selected from C1-5 alkoxy optionally substituted with one or more F , -CF3, -CF2H, -Cl, -Br or -CHs.The compound according to any one of items 1 to 0, wherein R6is selected from -CF3, -Cl, -Br or -CH3.

[0345] 119. The compound according to any one of the preceding items, wherein A2is C-R6, wherein R6is selected from C1-5 alkoxy optionally substituted with one or more F; C1-5 alkyl optionally substituted with one or more F; halogen and N(R10)(R11).

[0346] 120. The compound according to any one of the preceding items, wherein R6is C1-5 alkoxy optionally substituted with one or more F.

[0347] 121 . The compound according to any one of the preceding items, wherein R6is C1-4 alkoxy optionally substituted with one or more F.

[0348] 122. The compound according to any one of the preceding items, wherein R6is C1-3 alkoxy optionally substituted with one or more F.

[0349] 123. The compound according to any one of the preceding items, wherein R6is Ci alkoxy optionally substituted with one or more F.

[0350] 124. The compound according to any one of the preceding items, wherein R6is selected from -OCH2CF3, -OCF3, -OCH3, -OCH2CF2H and -OCF2H.

[0351] 125. The compound according to any one of the preceding items, wherein R6is -O-CH2-CF3.

[0352] 126. The compound according to any one of the preceding items, wherein R6is -OCH3.

[0353] 127. The compound according to any one of the preceding items, wherein R12is -CF3.

[0354] 128. The compound according to any one of the preceding items, wherein R6is C1-5 alkyl optionally substituted with one or more F. 129. The compound according to any one of the preceding items, wherein R6is C1-3 alkyl optionally substituted with one or more F.

[0355] 130. The compound according to any one of the preceding items, wherein R6is Ci alkyl optionally substituted with one or more F.

[0356] 131. The compound according to any one of the preceding items, wherein R6is -CF3.

[0357] 132. The compound according to any one of the preceding items, wherein R6is -CF2H.

[0358] 133. The compound according to any one of the preceding items, wherein R6is halogen.

[0359] 134. The compound according to any one of the preceding items, wherein R6is Br.

[0360] 135. The compound according to any one of the preceding items, wherein R6is Cl.

[0361] 136. The compound according to any one of the preceding items, wherein R6is F.

[0362] 137. The compound according to any one of the preceding items, wherein R6is -OCF3.

[0363] 138. The compound according to any one of the preceding items, wherein R6is -OCH2CF3.

[0364] 139. The compound according to any one of the preceding items, wherein R6N(R10)(R11), wherein R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12, R11is -H, and R12is selected from the group consisting of halogen, C3-5 cycloalkyl and C1-3 alkyl.

[0365] 140. The compound according to any one of the preceding items, wherein R10is C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12.

[0366] 141. The compound according to any one of the preceding items, wherein R12is halogen.

[0367] 142. The compound according to any one of the preceding items, wherein R12is F.

[0368] 143. The compound according to any one of the preceding items, wherein R10is -CH2CF3. 144. The compound according to any one of the preceding items, wherein R6is -N(H)(CH2CF3).

[0369] 145. The compound according to any one of the preceding items, wherein R12is C3-5 cycloalkyl.

[0370] 146. The compound according to any one of the preceding items, wherein R12is cyclopropyl.

[0371] 147. The compound according to any one of the preceding items, wherein R10 is

[0372] 148. The compound according to any one of the preceding items, wherein R6

[0373] 149. The compound according to any one of the preceding items, wherein R12is C1-3 alkyl.

[0374] 150. The compound according to any one of the preceding items, wherein R12is CH3.

[0375] 151. The compound according to any one of the preceding items, wherein R10is -CH2C(CH3) 3.

[0376] 152. The compound according to any one of the preceding items, wherein R6is -N(H)CH2C(CH3) 3.

[0377] 153. The compound according to any one of the preceding items, wherein R10is -C(H)(CH3)2.

[0378] 154. The compound according to any one of the preceding items, wherein R6is -N(H)C(H)(CH3)2.

[0379] 155. The compound according to any one of the preceding items, wherein A3is C-R7, and wherein R7is selected from the group consisting of -H, halogen and C1-5 alkyl.

[0380] 156. The compound according to any one of the preceding items, wherein A3is C-R7, wherein R7is selected from -H, -F, -Cl, and -CH3.

[0381] 157. The compound according to any one of the preceding items, wherein R7is -H.

[0382] 158. The compound according to any one of the preceding items, wherein A3is

[0383] C(H). 159. The compound according to any one of the preceding items, wherein R7is halogen.

[0384] 160. The compound according to any one of the preceding items, wherein R7is -F.

[0385] 161 . The compound according to any one of the preceding items, wherein R7is -Cl.

[0386] 162. The compound according to any one of the preceding items, wherein A3is C(F).

[0387] 163. The compound according to any one of the preceding items, wherein R7is C1-5 alkyl.

[0388] 164. The compound according to any one of the preceding items, wherein R7is C1-3 alkyl.

[0389] 165. The compound according to any one of the preceding items, wherein R7is -CH3.

[0390] 166. The compound according to any one of the preceding items, wherein A3is N.

[0391] 167. The compound according to any one of the preceding items, wherein A4is C-R8; wherein R8is selected from the group consisting of H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, and - CN.

[0392] 168. The compound according to any one of the preceding items, wherein A4is C-R8; wherein R8is selected from the group consisting of -H, C1-C5 cycloalkyl, - CN, -F, -Cl, -Br and -CF2H.

[0393] 169. The compound according to any one of the preceding items, wherein A4is C-R8; wherein R8is selected from the group consisting of -H, cyclopropyl, methoxy, -CN, -F, -Cl, -Br and -CF2H.

[0394] 170. The compound according to any one of the preceding items, wherein R8is selected from -H, -F and -Cl.

[0395] 171. The compound according to any one of the preceding items, wherein R8is -H.

[0396] 172. The compound according to any one of the preceding items, wherein A4is C(H).

[0397] 173. The compound according to any one of the preceding items, wherein R8is -CN. 174. The compound according to any one of the preceding items, wherein A4is C(CN).

[0398] 175. The compound according to any one of the preceding items, wherein R8is halogen.

[0399] 176. The compound according to any one of the preceding items, wherein R8is F.

[0400] 177. The compound according to any one of the preceding items, wherein A4is C(F).

[0401] 178. The compound according to any one of the preceding items, wherein R8is -Br.

[0402] 179. The compound according to any one of the preceding items, wherein A4is C(Br).

[0403] 180. The compound according to any one of the preceding items, wherein R8is -Cl.

[0404] 181. The compound according to any one of the preceding items, wherein A4is C(CI).

[0405] 182. The compound according to any one of the preceding items, wherein R8is C1-5 alkyl optionally substituted with one or more F.

[0406] 183. The compound according to any one of the preceding items, wherein R8is C1-3 alkyl optionally substituted with one or more F.

[0407] 184. The compound according to any one of the preceding items, wherein R8is Ci alkyl optionally substituted with one or more F.

[0408] 185. The compound according to any one of the preceding items, wherein R8is -CF2H.

[0409] 186. The compound according to any one of the preceding items, wherein A4is C(CF2H).

[0410] 187. The compound according to any one of the preceding items, wherein R8is -C3-C5 cycloalkyl.

[0411] 188. The compound according to any one of the preceding items, wherein R8is cyclopropyl.

[0412] 189. The compound according to any one of the preceding items, wherein A4is C(cyclopropyl).

[0413] 190. The compound according to any one of the preceding items, wherein R8is C1-5 alkoxy. 191. The compound according to any one of the preceding items, wherein R8is C1-3 alkoxy.

[0414] 192. The compound according to any one of the preceding items, wherein R8is -OCH3.

[0415] 193. The compound according to any one of the preceding items, wherein A4is C(OCH3).

[0416] 194. The compound according to any one of the preceding items, wherein A4is N.

[0417] 195. The compound according to any one of the preceding items, wherein A5is C-R9, and wherein R9is -H or -halogen.

[0418] 196. The compound according to any one of the preceding items, wherein A5is C-R9, and wherein R9is -H or -F.

[0419] 197. The compound according to any one of the preceding items, wherein R9is -H.

[0420] 198. The compound according to any one of the preceding items, wherein A5is C(H).

[0421] 199. The according to any one of the preceding items, wherein R9is -halogen.

[0422] 200. The compound according to any one of the preceding items, wherein R9is -F.

[0423] 201. The compound according to any one of the preceding items, wherein A5is C(F).

[0424] 202. The compound according to any one of the preceding items, wherein A5is N.

[0425] 203. The compound according to any one of the preceding items, wherein A is

[0426] 204. The compound according to any one of the preceding items, wherein A is 205. The compound according to any one of the preceding items, wherein A is

[0427] 206. The compound according to any one of the preceding items, wherein A is

[0428] 207. The compound according to any one of the preceding items, wherein A is

[0429] 208. The compound according to any one of the preceding items, wherein A is

[0430] 209. The compound according to any one of the preceding items, wherein A is

[0431] 210. The compound according to any one of the preceding items, wherein A is

[0432] 211. The compound according to any one of the preceding items, wherein A is

[0433] 212. The compound according to any one of the preceding items, wherein A is 213. The compound according to any one of the preceding items, wherein A is

[0434] 214. The compound according to any one of the preceding items, wherein A is

[0435] 215. The compound according to any one of the preceding items, wherein A is

[0436] 216. The compound according to any one of the preceding items, wherein A is

[0437] 217. The compound according to any one of the preceding items, wherein A is

[0438] 218. The compound according to any one of the preceding items, wherein A is

[0439] 219. The compound according to any one of the preceding items, wherein A is

[0440] 220. The compound according to any one of the preceding items, wherein A is 221. The compound according to any one of the preceding items, wherein A is

[0441] 222. The compound according to any one of the preceding items, wherein A is 223. The compound according to any one of the preceding items, wherein A is

[0442] 224. The compound according to any one of the preceding items, wherein A is

[0443] 225. The compound according to any one of the preceding items, wherein A is

[0444] 226. The compound according to any one of the preceding items, wherein A is

[0445] 227. The compound according to any one of the preceding items, wherein A is 228. The compound according to any one of the preceding items, wherein A is 229. The compound according to any one of the preceding items, wherein A is

[0446] 230. The compound according to any one of the preceding items, wherein A is

[0447] 231 . The compound according to any one of the preceding items, wherein A is

[0448] 232. The compound according to any one of the preceding items, wherein A is

[0449] 233. The compound according to any one of the preceding items, wherein A is

[0450] 234. The compound according to any one of the preceding items, wherein A is

[0451] 235. The compound according to item 1 , wherein

[0452] R° is -OH,

[0453] R1is phenyl substituted with two or three -F,

[0454] R2is -CH3,

[0455] R3is -H,

[0456] A1is C-R5,

[0457] A2is C(OCH2CF3),

[0458] A3is C-R7,

[0459] A4is C-R8, and

[0460] A5is C-R9, wherein one of R5, R7, R8, and R9is -F, -Cl, -Br, or -CH3, and the others are -H.

[0461] 236. The compound according to item 1 , wherein R° is -OH, wherein one of R5, R7, R8, and R9is -F, -Cl, -Br, or-CH3, and the others are -H.. The compound according to item 1, wherein . The compound according to item 1, wherein

[0462] R2is -CH3, R3is -H, and

[0463]

[0464] 239. The compound according to any one of the preceding items, wherein the stereochemistry configuration at positions 2 and 3, as defined by formulas (I) and (III), are independently selected from R and S.

[0465] 240. The compound according to any one of the preceding items, wherein the stereochemistry configuration at position 3, as defined in formulas (I) and (III), is

[0466] R.

[0467] 241 . The compound according to any one of the preceding items, wherein the stereochemistry configuration at position 3, as defined in formulas (I) and (III), is

[0468] S.

[0469] 242. The compound according to any one of the preceding items, wherein the compound is selected from the group consisting of: 3-(6-chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclo- propyl)butanamide, 3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-butanamide, 3-hydroxy-3-(2-methoxypyridin-4-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclo- propyl)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)pyridin-4- yl)cyclopropyl)butanamide, 3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0470] 3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0471] 3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-3-hydroxybutanamide,

[0472] 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[0473] 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,

[0474] 4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)- phenyl)-cyclopropyl)butanamide,

[0475] N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide,

[0476] 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,

[0477] N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0478] N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0479] N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0480] N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0481] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0482] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4- difluorophenyl)-3-hydroxybutanamide,

[0483] 3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl) cyclopropyl)-3-hydroxybutanamide,

[0484] N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-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,

[0485] N-(1-(4,6-dichloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0486] N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0487] 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl) amino) pyridin-2- yl)cyclopropyl)butanamide,

[0488] 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0489] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0490] N-(1-(4-chloro-6-(neopentylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide),

[0491] N-(1-(6-((cyclopropylmethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0492] N-(1-(4-chloro-6-(isopropylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0493] N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0494] N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0495] N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0496] 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,

[0497] 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,

[0498] 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridin-2- yl)cyclopropyl)butanamide,

[0499] N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4- fluorophenyl)-3-hydroxybutanamide,

[0500] 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)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-hydroxy-3-(1- methyl-1 H-indol-4-yl)butanamide, 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2-trifluoroethyl)amino)pyrimidin-4- yl)cyclopropyl)butanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- dimethylthiazol-5-yl)-3-hydroxybutanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4- methylthiazol-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)pyridin-2-yl)cyclopropyl)-3-(2,4,6- trifluorophenyl)butanamide or a pharmaceutically acceptable salt thereof.

[0501] 243. The compound according to any one of the preceding items, wherein the compound is selected from the group consisting of: (R)-3-(6-chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclo-propyl)butanamide, (R)-3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-butanamide, (R)-3-hydroxy-3-(2-methoxypyridin-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)pyridin-4- yl)cyclopropyl)butanamide,

[0502] (R)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[0503] (R)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-butanamide,

[0504] (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-3-hydroxybutanamide,

[0505] (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)- phenyl)cyclopropyl)butanamide,

[0506] (R)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-

[0507] 3-hydroxybutanamide,

[0508] (R)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0509] (R)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)- phenyl)cyclopropyl)butanamide,

[0510] (R)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0511] (R)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4- fluorophenyl)-3-hydroxybutanamide,

[0512] (R)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)- phenyl)cyclopropyl)-3-hydroxybutanamide,

[0513] (R)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0514] (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0515] (R)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0516] (R)-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0517] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0518] (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,

[0519] (R)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-(2,6- difluorophenyl) -3-hydroxybutanamide,

[0520] (R)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl) cyclopropyl)-3-hydroxybutanamide,

[0521] (R)-N-(1-(4,6-dichloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0522] (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0523] (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl) amino) pyridin-2-yl)cyclopropyl)butanamide,

[0524] (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0525] (R)- N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0526] (R)-N-(1-(4-chloro-6-(neopentylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide),

[0527] (R)-N-(1-(6-((cyclopropylmethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0528] (R)-N-(1-(4-chloro-6-(isopropylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0529] (R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0530] (R)-N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0531] (R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0532] (R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,

[0533] (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,

[0534] (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridin-2- yl)cyclopropyl)butanamide, (R)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4- fluorophenyl)-3-hydroxybutanamide,

[0535] (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)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-hydroxy-3- (1-methyl-1 H-indol-4-yl)butanamide, (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-4-yl)cyclopropyl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- dimethylthiazol-5-yl)-3-hydroxybutanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4- methylthiazol-2-yl)butanamide, (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5- chlorothiazol-2-yl)-3-hydroxybutanamide and

[0536] (R)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4,6- trifluorophenyl)butanamide or a pharmaceutically acceptable salt thereof.

[0537] 244. The compound according to anyone of the preceding items, wherein the compound is selected from the group consisting of:

[0538] (S)-3-(6-chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclo-propyl)butanamide, (S)-3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-butanamide, (S)-3-hydroxy-3-(2-methoxypyridin-4-yl)-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclo-propyl)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,

[0539] (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl) butanamide,

[0540] (S)-3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4- yl)cyclopropyl)butanamide,

[0541] (S)-3-hydroxy-3-(p-tolyl)-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0542] (S)-3-(4-cyanophenyl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-butanamide,

[0543] (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0544] (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(4-methyl-3-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0545] (S)-N-(1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropyl)-3-(2,4-difluorophenyl)-

[0546] 3-hydroxybutanamide,

[0547] (S)-3-(3,5-difluorophenyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0548] (S)-4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0549] (S)-N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0550] (S)-N-(1-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4- fluorophenyl)-3-hydroxybutanamide,

[0551] (S)-(3-(2,4-difluorophenyl)-N-(1-(3-fluoro-5-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0552] (S)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0553] (S)-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0554] (S)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0555] (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,

[0556] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(3,4- difluorophenyl)-3-hydroxybutanamide,

[0557] (S)-3-(2-bromo-6-fluorophenyl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl) cyclopropyl)-3-hydroxybutanamide,

[0558] (S)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-(2,6- difluorophenyl) -3-hydroxybutanamide,

[0559] (S)-3-(2,4-difluorophenyl)-N-(1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl) cyclopropyl)-3-hydroxybutanamide,

[0560] (S)-N-(1-(4,6-dichloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0561] (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0562] (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl) amino) pyridin-2-yl)cyclopropyl)butanamide,

[0563] (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(3-methoxy-5-(2,2,2- trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0564] (S)- N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,6- difluorophenyl)-3-hydroxybutanamide,

[0565] (S)-N-(1-(4-chloro-6-(neopentylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide),

[0566] (S)-N-(1-(6-((cyclopropylmethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0567] (S)-N-(1-(4-chloro-6-(isopropylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0568] (S)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0569] (S)-N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,

[0570] (S)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,

[0571] (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridin-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,

[0572] (S)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-hydroxy-3- (1-methyl-1 H-indol-4-yl)butanamide,

[0573] (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-4-yl)cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- dimethylthiazol-5-yl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4- methylthiazol-2-yl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(5- chlorothiazol-2-yl)-3-hydroxybutanamide and

[0574] (S)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4,6- trifluorophenyl)butanamide or a pharmaceutically acceptable salt thereof.

[0575] 245. The compound according to any one of the preceding items, wherein the compound is able to modulate the activity of a Kv7 channel.

[0576] 246. The compound according to any one of the preceding items, wherein the compound is an agonist of a Kv7 channel.

[0577] 247. The compound according to any one of the preceding items, wherein the compound is able to increase the activity of a Kv7.2 / Kv7.3 heteromeric channel

[0578] 248. The compound according to any one of the preceding items, wherein the compound is able to produce an increase in the activity of the Kv7.2 / Kv7.3 heteromeric channel, with an ECso of less than 50 pM, such as less than 20 pM, such as less than 10 pM, such as less than 1 pM, such as less than 0.1 pM, such as less than 0.06 pM, such as less than 0.01 pM, such as less than 0.001 pM.

[0579] 249. The compound according to any one of the preceding items, wherein the compound is able to produce an increase in the activity of the Kv7.2 / Kv7.3 heteromeric channel, with an ECso from about 0.1 nM to about 20 pM, such as from about 0.1 nM to about 10 pM, such as from about 0.1 nM to about 1 pM, such as from about 0.1 nM to about 0.2 pM, such as from 0.1 nM to about 100 nM, such as from about 0.1 nM to about 10 nM.

[0580] 250. The compound according to any one of the preceding items, wherein the compound is able to increase the activity of a Kv7.5 channel.

[0581] 251. The compound according to any one of the preceding items, wherein the Kv7.5 ECso is more than 30 pM.

[0582] 252. The compound according to any one of the preceding items, wherein the compound is able to produce an increase in the activity of the Kv7.5 channel, with an EC50 from about 0.1 nM to about 20 pM, such as from about 0.1 nM to about 10 pM, such as from about 0.1 nM to about 1 pM, such as from about 0.1 nM to about 0.2 pM, such as from 0.1 nM to about 100 nM, such as from about 0.1 nM to about 10 nM.

[0583] 253. The compound according to any one of the preceding items, wherein the compound is a subtype-selective Kv7 modulator.

[0584] 254. The compound according to any one of the preceding items, wherein the compound is selective for Kv7.2 / Kv7.3.

[0585] 255. The compound according to any one of the preceding items, wherein the compound is selective for Kv7.2 / Kv7.3 over Kv7.5.

[0586] 256. The compound according to any one of the preceding items, wherein the compound can selectively increase the activity of a Kv7.2 / Kv7.3 heteromeric channel.

[0587] 257. The compound according to any one of the preceding items, wherein the compound has an EC50 for Kv7.2 / Kv7.3 of less than 10 pM and an EC50 for Kv7.5 of more than 30 pM.

[0588] 258. The compound according to any one of the preceding items, wherein the compound has a ratio between EC50 of Kv7.2 / Kv7.3 and EC50 of Kv7.5 of more than 2, such as more than 3, such as more than 5, such as more than 8, such as more than 10, such as more than 15, such as more than 20, such as more than 25, such as more than 30, such as more than 60, such as more than 75, such as more than 100, such as more than 150, such as more than 200, such as more than 230, such as more than 250, such as more than 500.

[0589] 259. The compound according to any one of the preceding items, wherein the compound has a ratio between ECso of Kv7.2 / Kv7.3 and EC50 of Kv7.5 of more than 10.

[0590] 260. The compound according to any one of the preceding items, wherein the compound has a ratio between ECso of Kv7.2 / Kv7.3 and EC50 of Kv7.5 of more than 100.

[0591] 261. The compound according to items 257 to 260, wherein the ratio is calculated according to the formula below:

[0592] EC50 of Kv7.5 ratio between EC50 of Kv7.2 / Kv7.3 and EC50 of Kv7.5 = — - - - - - -

[0593] ’ EC50 of Kv7.2 / Kv7.3

[0594] 262. The compound according to any one of the preceding items, wherein the compound is potency selective.

[0595] 263. The compound according to any one of the preceding items, wherein the compound has an efficacy for Kv7.2 / Kv7.3 larger than 50%, such as larger than 60%, such as larger than 70%, such as larger than 75%, such as larger than 80%, such as larger than 85%, such as larger than 90%, such as larger than 95%, such as larger than 100%, such as larger than 110%.

[0596] 264. The compound according to any one of the preceding items, wherein the compound has an efficacy for Kv7.5 of less than 60%, such as less than 50%, such as less than 40%, such as less than 30%, such as less than 20%, such as 0%.

[0597] 265. The compound according to any one of the preceding items, wherein the compound has an efficacy for Kv7.5 of less than 25%.

[0598] 266. The compound according to any one of the preceding items, wherein the compound has an efficacy for Kv7.2 / Kv7.3 larger than 50%, and an efficacy for Kv7.5 of less than 25%.

[0599] 267. The compound according to any one of the preceding items, wherein the compound is efficacy selective.

[0600] 268. The compound according to any one of the preceding items, wherein the compound is potency selective and efficacy selective.

[0601] 269. The compound according to any one of the preceding items, wherein the ECso is measured in an in vitro cell-based assay of ion flux, such as a Thallium ion (Tl+) assay. 270. A pharmaceutical composition comprising the compound according to any one of items 1 to 269.

[0602] 271. A compound according to any one of items 1 to 269, or a pharmaceutical composition according to item 270, for use as a medicament.

[0603] 272. Use of a compound according to any one of items 1 to 269, or a pharmaceutical composition according to item 270, for the manufacture of a medicament for a disease or condition.

[0604] 273. A method of treatment of a disease or condition in a subject, the method comprising administering an effective amount of a compound according to any one of items 1 to 269, or a pharmaceutical composition according to item 270 to the subject.

[0605] 274. A compound according to any one of items 1 to 269, or a pharmaceutical composition according to item 270, for use in a method of modulating the activity of a Kv7 channel in a subject, the method comprising administering an effective amount of the compound to the subject.

[0606] 275. The compound or the pharmaceutical composition for use according to item 274, wherein the method is a method of increasing the activity of a Kv7.2 / Kv7.3 heteromeric channel.

[0607] 276. A compound according to any one of items one of items 1 to 269, or a pharmaceutical composition according to item 270, for use in an method of treatment, prevention or alleviation of epilepsy or pain in a subject, the method comprising administering an effective amount of the compound to the subject.

[0608] 277. Use of a compound according to any one of items 1 to 269, or a pharmaceutical composition according to item 270, for the manufacture of a medicament for the treatment, prevention or alleviation of epilepsy or pain.

[0609] 278. A method of treatment, prevention or alleviation of epilepsy or pain in a subject, the method comprising administering an effective amount of a compound according to any one of items 1 to 269, or a pharmaceutical composition according to item 270 to the subject.

[0610] Examples

[0611] General procedure for preparation of compounds according to the present disclosure:

[0612] The compounds of the present disclosure were prepared according to the below synthetic scheme 1 . Acid preparation

[0613] Scheme 1.

[0614] General procedures for compound-3:

[0615] Procedure A: To a stirred solution of compound-2 (1 eq) in THF (10 vol) added Zn (1.5 eq), I2 (0.02 eq) followed by dropwise addition of ethyl bromoacetate (1 eq). Resulting reaction mixture heated on preheated oil bath at 55 °C for 10 to 30 min. Resulting reaction mixture stirred under argon overnight. Reaction mixture was quenched using sat. NH4CI solution, filtered and extracted with EtOAc (3 x 20 vol) to get crude compound- 3. Crude compound-3 was purified using combiflash chromatography (EtOAc in hexane as eluent) to get compound-3 in 35 to 80% yield.

[0616] Procedure B: A combined solution of ethyl bromoacetate (1 eq), Zn (1.5 eq), Br2 (0.2 eq) in anhydrous THF heated in preheated bath for 30 min. The generated reagent supernatant solution added to a solution of compound-2 (1 eq) in anhydrous THF. Resulting reaction mixture stirred at rt for 1 h to overnight. Reaction mixture was quenched using sat. NH4CI solution, filtered and extracted with EtOAc (3 x 20 vol) to get crude compound-3. Crude compound-3 was purified using combiflash chromatography (EtOAc in hexane as eluent) to get compound-3 in 35 to 80% yield. General procedure for compound-4: To a stirred solution of compound-3 in THF : water : MeOH (10 vol, 3:2:1) added LiOH (1.5 eq). Reaction was monitored by TLC, quenched with water, extracted with EtOAc. Organic layer dried over anhydrous Na2SO4 to get crude compound-4. Crude compound-4 obtained further purified using combiflash chromatography.

[0617] General procedure for compound-6: To a stirred solution of compound-5 (1 eq) in DMF (10 vol) added CS2CO3 (3 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1 eq). Resulting reaction mixture stirred at rt overnight and quenched with water. Reaction mixture was extracted with EtOAc (3 x 20 vol). Organic layer dried over anhydrous Na2SO4and concentrated under high vacuo to get compound-6 which was purified using combiflash chromatography (5 to 10% EtOAc in hexane) to get pure enough compound- 6.

[0618] General procedure for compound-7: To a solution of compound-6 (1 eq) in Et20 added Ti(OiPr)4 (1 eq), at -78 °C followed by dropwise addition of EtMgBr (3 M in Et20, 2 eq). Resulting reaction stirred for 2 h and quenched using BFa:Et2O (2 eq). After overnight stirring added 1 N HCI and extracted reaction mixture with Et20. Aq. layer basified and extracted with Et20. Organic layer obtained after basification given brine wash, dried over anhydrous Na2SO4 and concentrated under vacuo to get crude compound-7. Crude compound-7 was purified using combiflash chromatography (20 to 60% EtOAc in hexane) to get pure enough compound-7.

[0619] General procedure for compound-8: To a stirred solution of compound-4 (1 eq) in DMF (10 vol) added HATLI (1.5 eq), DI PEA (3 eq). Resulting reaction mixture stirred for 15 min then added compound-7 (1 eq). The reaction mixture was diluted with cold water and extracted with EtOAc (2 x 10 vol). Combined organic layer given brine wash, dried over anhydrous Na2SO4 and concentrated under vacuo.

[0620] Chiral separation: The compounds according to the present disclosure were separated into different stereoisomers using Chiral preparative HPLC. Thus, for each example, two peaks are obtained: Peak-1 and Peak-2, each peak corresponding to a different stereoisomer. Each peak is isolated, characterized and tested for biological evaluation as described below. Example 1 : Synthesis of 3-(6-chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)butanamide

[0621] Synthesis of 3-(2,2,2-trifluoroethoxy)benzonitrile (6a): 3-Hydroxybenzonitrile (20 g, 168.01 mmol) converted to compound-6a (27.5 g, 83%) using general procedure for compound-6, H-NMR (DMSO-d6, 300 MHz): 5 7.60-7.53 (m, 3 H), 7.39-7.45 (m, 1 H), 4.87 (q, J = 9 Hz, 2 H).

[0622] 6a

[0623] Synthesis of 1 -(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1 -amine hydrochloride (7a): Compound-6a (20 g, 99.43 mmol) converted to 7a (7.5 g, 34%) using general procedure for compound-7. After acidification during work up compound- 7a extracted as HCI salt in diethyl ether, H-NMR (DMSO-de, 300 MHz): 5 8.78 (bs, 3 H), 7.38-7.42 (m, 1 H), 7.02 -7.10 (m, 3 H), 4.80 (q, J = 8.7 Hz, 2 H), 1.24-1.34 (m, 4

[0624] Synthesis of ethyl 3-(6-chloropyridin-3-yl)-3-hydroxybutanoate (3a): 1-(6-

[0625] Chloropyridin-3-yl)ethan-1-one (0.932 g, 5.99 mmol) converted to compound-3a (0.68 g, 47%) using general procedure A for compound-3, m / z (LC-MS): 243.95 [M+H]+.

[0626] Synthesis of 3-(6-chloropyridin-3-yl)-3-hydroxybutanoic acid (4a): Compound-3a (0.68 g, 2.79 mmol) converted to compound-4a (0.51 g, 85%) as yellow gummy using general procedure for compound-4, H-NMR (DMSO-de, 300 MHz): 5 1.51 (s, 3 H), 2.73 (dd, J = 14.7 Hz, 2 H), 5.51 (bs, 1 H), 7.42 (d, J = 8.7 Hz, 1 H), 7.87 (dd, J = 2.7 Hz, 8.7 Hz, 1 H), 8.46 (d, J = 2.7 Hz, 1 H). Example 1: Synthesis of 3-(6-chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 1 peak-1 & Example 1 peak-2): Following general procedure for compound-8, compound-4a (0.2 g, 0.927 mmol) converted to Example 1 (290 mg, 73%) using compound-7a. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IG, 250mmX21 mm, 5µm), Eluent: n-Hexane(A) and EtOH:MeOH 1:1 (B), Flow: 10 mL / min, Isocratic: 70(A):30(B), diluent EtOH:DCM, 3:1, 10 mL, Injection vol, 0.5 mL, run time 20 min, to get Peak-1 (104.9 mg), Peak-2: (101.3 mg); H-NMR (DMSO-d6, 300 MHz): δ 0.89-0.96 (m, 2 H), 1.05-1.12 (m, 2 H), 1.46 (s, 3H), 2.60 (dd, J = 13.8 Hz, 2 H), 4.67 (q, J = 9 Hz, 2 H), 5.79 (s, 1 H), 6.43 (d, J = 8.1 Hz. 1 H), 6.59 (s, 1 H), 6.78 (dd, J = 2.1 Hz, 8.1 Hz, 1 H), 7.03-7.09 (m 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 7.84 (dd, J = 2.7 Hz, 8.1 Hz, 1 H), = 2.7 Hz, 1 H), 8.52 (s, 1 H), HRMS calculated for: [C20H20ClF3N2O3+H]+429.1187; found: 429.1195 (Example 1 peak-1), 429.1198 (Example 1 peak-2). Analytical Chiral HPLC: CHIRALPAK-IG (150X4.6mmX5µm) Mobile Phase : (A) n-HEXANE (B) 0.1% HCOOH IN EtOH : MeOH (80:20) Isocratic : 80:20 (A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. 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) Example 2: Synthesis of 3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of ethyl 3-(5-fluoropyridin-2-yl)-3-hydroxybutanoate (3b): 1-(5- Fluoropyridin-2-yl)ethan-1-one (0.25 g, 1.797 mmol) converted to compound-3b (80 mg, 20%) as yellow oil using general procedure A for compound-3, m / z (LC-MS): 228.1 [M+H]+. Synthesis of 3-(5-fluoropyridin-2-yl)-3-hydroxybutanoic acid (4b): Compound-3b (80 mg, 0.352 mmol) converted to compound-4b (60 mg, 75%) as yellow solid using general procedure for compound-4, m / z (LC-MS): 199.95 [M+H]+. Example 2: Synthesis of 3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 2 peak-1 & Example 2 peak-2 ): Following general procedure for compound-8, compound-4b (60 mg, 0.301 mmol) converted to Example 2 (50 mg, 40%) using compound-7a. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 150x4.6mm, 5µm), Eluent: n-Hexane(A) and IPA:MeOH 1:1 (B), Flow: 1 mL / min, Isocratic: 85(A):15(B), diluent EtOH, to get Peak-1 (20.3 mg), Peak-2: (24.9 mg); H-NMR (DMSO-d6, 400 MHz): δ 0.98-1.09 (m, 2 H), 1.10-1.18 (m, 2 H), 1.42 (s, 3H), 2.58 (d, J = 14.4 Hz, 1 H), 2.87 (d, J = 14.4 Hz, 1 H), 4.68 (q, J = 9 Hz, 2 H), 5.91 (s, 1 H), 6.51 (d, J = 8.8 Hz, 1 H), 6.60- 6.61 (m, 1 H), 6.80 (dd, J = 2 Hz, 8.2 Hz, 1 H), 7.06-7.11 (m, 1 H), 7.68 (dd, J = 2 Hz, 8 Hz, 2 H), 8.48 (s, 1 H), 8.61 (s, 1 H), HRMS calculated for: [C + 20H20F4N2O3+H] 413.1483; found: 413.1492 (Example 2 peak-1), 413.1551 (Example 2 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase : (A) n- HEXANE (B) IPA: MeOH (50:50) Isocratic : 85:15(A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. volume: 10.000, Acq. method: IH_8515_7_C-30min.amx. Peak-1 (Rt: 3.053, 100% ee) Peak-2: (Rt: 4.84, 100% ee). Example 3: Synthesis of 3-hydroxy-3-(2-methoxypyridin-4-yl)-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)butanamide Synthesis of ethyl 3-hydroxy-3-(2-methoxypyridin-4-yl)butanoate (3c): 1-(2- Methoxypyridin-4-yl)ethan-1-one (0.55 g, 0.992 mmol) converted to compound-3c (240 mg, 28%) as colourless liquid using general procedure A for compound-3, m / z (LC- MS): 239.90 [M+H]+. Synthesis of 3-hydroxy-3-(2-methoxypyridin-4-yl)butanoic acid (4c): Compound- 3c (240 mg, 1.0031 mmol) converted to compound-4c (98 mg, 46%) as off white solid using general procedure for compound-4, m / z (LC-MS): 212.10 [M+H]+. Example 3: Synthesis of 3-hydroxy-3-(2-methoxypyridin-4-yl)-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 3 peak-1 & Example 3 peak-2): Following general procedure for compound-8, compound-4c (0.2 g, 0.947 mmol) converted to Example 3 using compound-7a and purified by prep HPLC, Column: LUNA Phenomenex (250x21.2mm, 5.0µ), Eluent: 0.1% HCOOH in water (A) and acetonitrile (B), Flow: 18 mL / min, Time: % B, 0 / 50, 2 / 60, 6 / 85 to get pure enough Example 3a / b (75 mg, 19%) which was separated using Chiral prep HPLC, Column: (Chiralpak IG, 250x21mm, 5µm), Eluent: n-Hexane(A) and EtOH (B), Flow: 15 mL / min, Isocratic: 90(A):10(B), to get Peak-1 (27 mg), Peak-2: (23 mg) as colourless gummy oil; H-NMR (DMSO-d6, 400 MHz): δ 0.97-1.02 (m, 2 H), 1.05-1.25 (m, 2 H), 1.43 (s, 3H), 2.59 (d, J = 14.1 Hz, 1 H), 2.69 (d, J= 14.1 Hz, 1 H), 3.84 (s, 3 H), 4.68 (q, J = 8.6 Hz, 2 H), 5.75 (s, 1 H), 6.48 (d, J = 8 Hz. 1 H), 6.60 (s, 1 H), 6.78-6.82 (m, 2 H), 7.00-7.07 (m, 2 H), 8.09 (d, J = 8 Hz, 1 H), 8.54 (bs, 1 H), HRMS calculated for: [C21H23F3N2O4+H]+425.1683; found: 425.1698 (Example 3 peak-1), 425.1697 (Example 3 peak-2). Analytical Chiral HPLC: CHIRALPAK-IG (150X4.6mmX5µm) Mobile Phase : (A) n-HEXANE (B) 0.1% HCOOH IN EtOH:MeOH (80:20) Isocratic : 70:30 (A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. 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) 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): 1-(2,4- Difluorophenyl)ethan-1-one (1 g, 6.405 mmol) converted to compound-3d (1 g, 64%) as off white solid using general procedure A for compound-3; H-NMR (DMSO-d6, 400 MHz): δ 0.96 (t, J = 6.9 Hz, 3 H), 1.53 (s, 3 H), 2.76 (dd, J = 13.8 Hz, 2 H), 3.89 (q, J = 6.6 Hz, 2 H), 6.99-7.05 (m, 1 H), 7.08-7.16 (m, 1 H), 7.54-7.62 (m, 1 H). FOHOO F Synthesis of 3-(2,4-difluorophenyl)-3-hydroxybutanoic acid (4d): Compound-3d (1 g, 4.409 mmol) converted to compound-4d (800 mg, 90%) as colourless liquid using general procedure for compound-4; H-NMR (DMSO-d6, 400 MHz): δ 1.51 (s, 3 H), 2.69-2.78 (m, 2 H), 5.53 (bs, 1 H), 6.99-7.16 (m, 2 H), 7.56-7.65 (m, 1 H). Synthesis of 3-chloro-5-(2,2,2-trifluoroethoxy)benzonitrile (6b): 3-Chloro-5- hydroxybenzonitrile (6 g, 39.07 mmol) converted to 6b (7.5 g, 82%) using general procedure for compound-6, H-NMR (DMSO-d6, 400 MHz): δ 4.92 (q, J = 9 Hz, 2 H), 7.60-7.62 (m, 1 H), 7.63-7.64 (m, 1 H), 7.71-7.73 (m, 1H). Synthesis of 1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine hydrochloride (7b): Compound-6b (9 g, 38.20 mmol) converted to compound-7b (5 g, 43%) as off white solid using general procedure for compound-7. After acidification solids obtained washed with hexane to get desired compound as HCl salt, m / z (LC- MS): 265.90 [M+H]+. 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): Following general procedure for compound-8, compound-4d (100 mg, 0.462 mmol) converted to Example 4 (103 mg, 43%) as off white solid using compound-7b. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and EtOH : IPA 1:1 (B), Flow: 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 get Peak-1 (34.8 mg), Peak-2: (38.7 mg) as colourless gummy oil; H- NMR (DMSO-d6, 400 MHz): δ 0.88-0.99 (m, 2 H), 1.15-1.20 (m, 2 H), 1.49 (s, 3 H), 2.63 (d, J = 14 Hz, 1 H), 2.75 (d, J= 14 Hz, 1 H), 4.75 (q, J = 8.8 Hz, 2 H), 5.96 (s, 1 H), 6.55 (s, 1 H), 6.70 (s, 1 H), 6.94 (s, 1 H), 6.98-7.02 (m, 1 H), 7.10-7.16 (m, 1 H), 7.58- 7.64 (m, 1 H), 8.59 (s, 1 H), HRMS calculated for: [C21H19ClF5NO3+H-H2O]+446.0941; found: 446.0956 (Example 4 peak-1), 446.0954 (Example 4 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase : (A) n-HEXANE (B) IPA :MeOH(50:50) Isocratic : 85:15(A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, Acq. method: IH_8515_7_C-30min.amx. Peak-1 (Rt: 2.68, 92%) Peak-2: (Rt: 3.46, 100%) 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): 4-Fluoro-3- hydroxybenzonitrile (1 g, 7.298 mmol) converted to compound-6c (1 g, 63%) as white solid using general procedure for compound-6, H-NMR (DMSO-d6, 300 MHz): δ 4.90 (q, J = 8.8 Hz, 2 H), 7.50-7.64 (m, 2 H), 7.88-7.92 (m, 1 H). Synthesis of 1-(4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7c): Compound-6c (600 mg, 2.738 mmol) converted to compound-7c (250 mg, 36%) as off white solid using general procedure for compound-7, m / z (LC-MS): 250.35 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): Following general procedure for compound-8, compound-4d (0.093 g, 0.432 mmol) converted to Example 5 (40 mg, 20%) using compound-7c. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH (1:1) (B), Flow: 15 mL / min, Isocratic: 90(A):10(B), diluent EtOH : DCM (1:1, 3 mL), Injection volume-0.5 mL, run time 14 min, to get Peak-1 (12 mg, ) Peak-2: (9 mg) as off white solid; H-NMR (DMSO-d6, 300 MHz): δ 0.87-0.99 (m, 2 H), 1.12-1-20 (m, 2 H), 1.48 (s, 3 H), 2.60 (d, J = 14.1 Hz, 1 H), 2.74 (d, J = 14.1 Hz, 1 H), 4.76 (q, J = 8.7 Hz, 2 H), 6.04 (bs, 1 H), 6.48-6.54 (m, 1 H), 6.79 (d, J = 6.6 Hz, 1 H), 6.92-7.07 (m, 2 H), 7.13-7.20 (m, 1 H), 7.54-7.62 (m, 1 H), 8.63 (bs, 1 H), HRMS calculated for: [C21H19F6NO3+H-H2O]+430.1236; found: 430.1246 (Example 5 peak-1), 430.1250 (Example 5 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (50:50) Isocratic : 85:15 (A:B) Flow : 1.0ml / min Diluent : EtOH Column Temp : 25°C, Inj. volume: 5.000, Acq. method: IH_8515_7_C-15min.amx. Peak-1 (Rt: 2.63, 100% ee) Peak-2: (Rt: 3.81, 100% ee) 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): 1-(4- Fluorophenyl)ethan-1-one (2 g, 14.478 mmol) converted to compound-3e (3 g, 94%) using general procedure A for compound-3, H-NMR (DMSO-d6, 300 MHz): δ 1.00 (t, J = 6.9 Hz, 3 H), 1.5 (s, 3 H), 2.51-2.70 (m, 2 H), 3.90 (q, J = 6 Hz, 2 H), 5.30 (s, 1 H), 7.04-7.11 (m, 2 H), 7.42-7.47 (m, 2 H). Synthesis of 3-(4-fluorophenyl)-3-hydroxybutanoic acid (4e): Compound-3e (3 g, 13.27 mmol) converted to compound-4e (1.1 g, 42%) as off white solid using general procedure for compound-4, H-NMR (DMSO-d6, 300 MHz): δ 1.49 (s, 3 H), 2.65 (s, 2 H), 5.25-5.30 (bs, 1 H), 7.05-7.11 (m, 2 H), 7.42-7.48 (m, 2 H). Synthesis of 1-(3-(trifluoromethyl)phenyl)cyclopropan-1-amine (7d): 3- (Trifluoromethyl)benzonitrile (2 g, 11.688 mmol) converted to compound-7d (350 mg, 15%) using general procedure for compound-7. After basification using NaHCO3, compound extracted as free base, m / z (LC-MS): 202.40 [M+H]+. Example 6: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3- (trifluoromethyl)phenyl)cyclopropyl)butanamide (Example 6 peak-1 & Example 6 peak-2): Following general procedure for compound-8, compound-4e (0.15 g, 0.757 mmol) converted to Example 6 (110 mg, 38%) using compound-7d. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 150mmX4.6 mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH 1:1 (B), Flow: 1.0 mL / min, Isocratic: 85(A):15(B) to get Peak-1 (37.9 mg) Peak-2: (42.8 mg). H-NMR (DMSO-d6, 400 MHz): δ 0.98-1.03 (m, 2 H), 1.05-1.24 (m, 2 H), 1.46 (s, 3H), 2.55 (d, J = 14.1 Hz, 1 H), 2.67 (d, J = 14.1 Hz, 1 H), 4.92 (q, J = 8.6 Hz, 2 H), 5.64 (s, 1 H), 7.08-7.13 (m, 3 H), 7.30-7.31 (m, 1 H), 7.33-7.37 (m, 1 H), 7.44-7.48 (m, 3 H), 8.60 (s, 1 H), HRMS calculated for: [C20H19F4NO2+H-H2O]+364.1319; found: 364.1329 (Example 6 peak-1), 364.1331 (Example 6 peak-2). Analytical Chiral HPLC : CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH(50:50) Isocratic: 93:07 (A:B) Flow: 1.0ml / min Diluent: EtOH Column Temp : 25°C, Inj. 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). Example 7: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3- (trifluoromethoxy)phenyl)cyclopropyl) butanamide Synthesis of 1-(3-(trifluoromethoxy)phenyl)cyclopropan-1-amine hydrochloride (7e): 3-(Trifluoromethoxy)benzonitrile (200 mg, 1.06 mmol) converted to 7e (160 g, crude) using general procedure for compound-7. After acidification during work up compound-7e extracted as HCl salt in diethyl ether, H-NMR (DMSO-d6, 400 MHz): δ 0.97-0.94 (m, 2H), 1.03-1.00 (m, 2 H), 7.11 -7.09 (m, 1 H), 7.22-7.20 (m, 1 H), 7.39- 7.30 (m, 2 H). Example 7: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(3- (trifluoromethoxy)phenyl)cyclopropyl) butanamide (Example 7 peak-1 & Example 7 peak-2): Following general procedure for compound-8, compound-4e (100 mg, 0.460 mmol) converted to Example 7 (135 mg, 74%) using compound-7e. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH 1:1 (B), Flow: 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, to get Peak-1 (41.2 mg) Peak-2: (29.8 mg) as off white solids; H-NMR (DMSO-d6, 400 MHz): δ 0.86-0.99 (m, 2 H), 1.17-1.24 (m, 2 H), 1.45 (s, 3 H), 2.53-2.71 (m, 2 H), 5.67 (s, 1 H), 6.78 (d, j = 8 Hz, 1 H), 6.85 (s, 1 H), 7.07-7.13 (m, 3 H), 7.24 (d, J = 8 Hz, 1 H), 7.45-7.48 (m, 2 H), 8.57 (s, 1H), HRMS calculated for: [C + 20H19F4NO3+H-H2O] 380.1268; found: 380.1281 (Example 7 peak-1), 380.1279 (Example 7 peak-2). Analytical Chiral HPLC : CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B)IPA : MeOH(50:50) Isocratic: 93:07 (A:B) Flow : 1.0ml / min Diluent: EtOH Column Temp: 25°C, Inj. 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) Example 8: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2- trifluoroethoxy)pyridin-4-yl)cyclopropyl)butanamide 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) at 00C added a solution of 2,2,2-trifluoroethan-1-ol (5.45 mL, 72.173 mmol) in anhydrous DMF (10 mL). After stirring at 00C for 10 min added a solution of 2-chloroisonicotinonitrile (5 g, 36.086 mmol) in anhydrous DMF (30 mL). Resulting reaction mixture stirred at rt overnight. Reaction was quenched using sat. solution of ammonium chloride and extracted using EtOAc (3 x 100 mL). Combined organic layer given brine wash and dried over anhydrous Na2SO4. Organic layer removed under vacuo to get crude product which was purified by flash chromatography (EtOAc:Hexane 5:95) as eluent to get compound-6f (2.5 g, 34%) as colourless gum; m / z (LC-MS): 203.1 [M+H]+. Synthesis of 1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropan-1-amine (7f): Compound-6f (0.1 g, 0.495 mmol) converted to compound-7f (80 mg, 71%) using general procedure for compound-7. After basification using NaHCO3, compound extracted as free base, m / z (LC-MS): 232.95 [M+H]+. Example 8: Synthesis of 3-(4-fluorophenyl)-3-hydroxy-N-(1-(2-(2,2,2- trifluoroethoxy)pyridin-4-yl)cyclopropyl)butanamide (Example 8 peak-1 & Example 8 peak-2): Following general procedure for compound-8, compound-4e (0.1 g, 0.303 mmol) converted to Example 8 (45 mg, 22%) using compound-7f. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21 mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH 1:1 (B), Flow: 15 mL / min, Isocratic: 85(A):15(B), diluent EtOH: : DCM, 3:1, 4 mL, Injection vol, 0.9 mL, run time 13 min, to get Peak-1 (16.7 mg) Peak-2: (15.9 mg). H-NMR (DMSO-d6, 400 MHz): δ 0.99-1.03 (m, 2 H), 1.05- 1.27 (m, 2 H), 1.47 (s, 3H), 2.60 (dd, J = 14.1 Hz, 2 H), 4.92 (q, J = 8.6 Hz, 2 H), 5.64 (s, 1 H), 6.43 (dd, J = 1.2 Hz, 9.4 Hz. 2 H), 7.11-7.15 (m, 2 H), 7.48 (dd, J = 5.6 Hz, 10.8Hz, 2 H), 7.88 (d, J = 5.6 Hz, 1 H), 8.537 (s, 1 H), HRMS calculated for: [C20H20F4N2O3+H]+413.1483; found: 413.1492 (Example 8 peak-1), 413.1494 (Example 8 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (50:50) Isocratic: 80:20(A:B) Flow: 1.0ml / min Diluent: EtOH, Column Temp: 25°C. Peak-1 (Rt: 2.59, 100% ee) Peak-2: (Rt: 3.50, 100% ee) 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): 1-(p-Tolyl)ethan-1-one (1 g, 7.453 mmol) converted to compound-3f (380 mg, 24%) using general procedure A for compound-3, H-NMR (DMSO-d6, 400 MHz): δ 1.04 (t, J = 7.2 Hz, 3 H), 1.51 (s, 3 H), 2.26 (s, 3 H), 2.68 (s, 2 H), 3.92 (q, J = 7.2 Hz, 2 H), 5.14 (s, 1 H), 7.08 (d, J = 8 Hz, 2 H), 7.31 (d, J = 8 Hz, 2 H). Synthesis of 3-hydroxy-3-(p-tolyl)butanoic acid (4f): Compound-3f (380 mg, 1.709 mmol) converted to compound-4f (300 mg, 90%) as reddish oil using general procedure for compound-4, H-NMR (DMSO-d6, 400 MHz): δ 1.49 (s, 3 H), 2.26 (s, 3 H), 2.65 (s, 2 H), 5.14 (bs, 1 H), 7.08 (d, J = 8 Hz, 2 H), 7.32 (d, J = 8 Hz, 2 H), 11.99 (bs, 1 H). 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): Following general procedure for compound-8, compound-4f (0.15 g, 0.772 mmol) converted to Example 9 (120 mg, 38%) using compound-7a. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21 mm, 5µm), Eluent: n-Hexane(A) and IPA (B), Flow: 15 mL / min, Isocratic: 80(A):20(B), diluent EtOH : DCM, 3:1, 5 mL, Injection vol, 0.5 mL, run time 22 min, to get Peak-1 (50 mg) Peak-2: (43 mg). H-NMR (DMSO-d6, 400 MHz): δ 0.70-1.00 (m, 2 H), 1.05-1.20 (m, 2 H), 1.42 (s, 3H), 2.67 (dd, J = 14.1 Hz, 2 H), 4.67 (q, J = 8.8 Hz, 2 H), 5.61 (s, 1 H), 6.43 (d, J = 7.6 Hz, 1 H), 6.58-6.59 (m, 1 H), 6.78 (dd, J = 2.4 Hz, 8.4 Hz, 1 H), 7.00-7.04 (m, 1 H), 7.12 (d, J = 8 Hz, 2 H), ), 7.32 (d, J = 8 Hz, 2 H), 8.50 (s, 1 H), HRMS calculated for: [C22H24F3NO3+H-H2O]+390.1675; found: 390.1682 (Example 9 peak-1), 390.1682 (Example 9 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA Isocratic: 95:05(A:B) Flow : 1.0ml / min Diluent: EtOH Column Temp: 25°C, Inj. 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). 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): 4- Acetylbenzonitrile (1 g, 6.889 mmol) converted to compound-3g (400 mg, 25%) using general procedure A for compound-3, H-NMR (DMSO-d6, 400 MHz): δ 1.01 (t, J = 7.2 Hz, 3 H), 1.52 (s, 3 H), 2.78 (dd, J = 14 Hz, 2 H), 3.90 (q, J = 7.2 Hz, 2 H), 5.53 (s, 1 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.76 (d, J = 8.4 Hz, 2 H). Synthesis of 3-(4-cyanophenyl)-3-hydroxybutanoic acid (4g): Compound-3g (400 mg, 1.715 mmol) converted to compound-4g (320 mg, 91%) as colourless oil using general procedure for compound-4, H-NMR (DMSO-d6, 400 MHz): δ 1.51 (s, 3 H), 2.74 (dd, J = 14.4 Hz, 2 H), 5.46 (bs, 1 H), 7.65 (d, J = 6.8 Hz, 2 H), 7.77 (d, J = 6.8 Hz, 2 H), 12.03 (bs, 1 H) 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): Following general procedure for compound-8, compound-4g (0.15 g, 0.731 mmol) converted to Example 10 (90 mg, 33%) using compound-7a. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21 mm, 5µm), Eluent: n-Hexane(A) and IPA: : MeOH, 1:1 (B), Flow: 15 mL / min, Isocratic: 80(A):20(B), diluent EtOH : DCM, 3:1, 6 mL, Injection vol, 0.9 mL, run time 18 min, to get Peak-1 (37 mg) Peak-2: (30 mg). H-NMR (DMSO-d6, 400 MHz): δ 0.85-0.95 (m, 2 H), 1.02-1.15 (m, 2 H), 1.47 (s, 3 H), 2.65 (dd, J = 14 Hz, 2 H), 4.68 (q, J = 8.8 Hz, 2 H), 5.86 (s, 1 H), 6.44 (d, J = 8.4 Hz, 1 H), 6.58-6.59 (m, 1 H), 6.80 (dd, J = 2.4 Hz, 8.4 Hz, 1 H), 7.00-7.04 (m, 1 H), 7.63 (d, J = 8.4 Hz, 2 H), ), 7.78 (d, J = 8.4 Hz, 2 H), 8.55 (s, 1 H), HRMS calculated for: [C22H21F3N2O3+H]+419.1577; found: 419.1586 (Example 10 peak-1), 419.1585 (Example 10 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (50:50) Isocratic: 90:10(A:B) Flow : 1.0ml / min Diluent: EtOH Column Temp: 25°C. Peak-1 (Rt: 7.02, 100% ee) Peak-2: (Rt: 12.84, 100% ee). 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 (6g): 2-Fluoro-3- hydroxybenzonitrile (2 g, 14.587 mmol) converted to 6g (2.3 g, 72%) using general procedure for compound-6, H-NMR (DMSO-d6, 300 MHz): δ 4.94 (q, J = 8.4 Hz, 2 H), 7.34-7.40 (m, 1 H), 7.52-7.57 (m, 1 H), 7.65-7.71 (m, 1H). Synthesis of 1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7g): Compound-6g (0.5 g, 2.282 mmol) converted to compound-7g (0.2 g, 35%) as yellowish oil using general procedure for compound-7, m / z (LC-MS): 249.95 [M+H]+. 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): Following general procedure for compound-8, compound-4d (0.087 g, 0.401 mmol) converted to Example 11 (100 mg, 56%) using compound-7g. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21 mm, 5µm), Eluent: n-Hexane(A) and EtOH (B), Flow: 15 mL / min, Isocratic: 90(A):10(B), diluent EtOH : DCM, 1:1, 5 mL, Injection vol, 0.3 mL, run time 13 min, to get Peak-1 (43.3 mg) Peak-2: (46.4 mg). H-NMR (DMSO-d6, 400 MHz): δ 0.76-0.80 (m, 2 H), 0.86-1.05 (m, 2 H), 1.40 (s, 3 H), 2.55 (dd, J = 14 Hz, 2 H), 4.75 (q, J = 8.8 Hz, 2 H), 5.96 (s, 1 H), 6.91-6.96 (m, 3 H), 7.03-7.12 (m, 2 H), 7.44-7.51 (m, 1 H), 8.64 (s, 1 H), HRMS calculated for: [C21H19F6NO3+H]+448.1342; found: 448.1347 (Example 11 peak-1), 448.1347 (Example 11 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm), Mobile Phase: (A) n-HEXANE (B) IPA: MeOH (50:50), Isocratic: 85:15 (A:B), Flow: 1.0ml / min, Diluent: EtOH, Column Temp: 25 °C, Inj. volume: 5.000, Acq. method: IH_8515_7_C-15min.amx. Peak-1 (Rt: 2.71, 100% ee) Peak-2: (Rt: 3.38, 100% ee). 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): 3-Hydroxy-4- methylbenzonitrile (2 g, 15.021 mmol) converted to 6h (2.9 g, 91%) using general procedure for compound-6, H-NMR (CDCl3, 300 MHz): δ 2.32 (s, 3 H), 4.38 (q, J = 8.4 Hz, 2 H), 7.01 (s, 1 H), 7.25.7.28 (m, 2 H). Synthesis of 1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7h): Compound-6h (1.5 g, 6.971 mmol) converted to compound-7h (550 mg, 31%) as yellowish oil using general procedure for compound-7, m / z (LC-MS): 246.00 [M+H]+. 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 ): Following general procedure for compound-8, compound-4d (0.132 g, 0.612 mmol) converted to Example 12 (150 mg, 55%) using compound-7h. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21 mm, 5µm), Eluent: n-Hexane(A) and IPA: : MeOH (1:1) (B), Flow: 15 mL / min, Isocratic: 90(A):10(B), diluent EtOH:DCM, 1:1, 5 mL, Injection vol, 0.25 mL, run time 11 min, to get Peak-1 (75.9 mg) Peak-2: (69.9 mg). H-NMR (DMSO-d6, 400 MHz): δ 0.76-0.95 (m, 2 H), 1.09-1.15 (m, 2 H), 1.48 (s, 3 H), 2.08 (s, 3 H), 2.70 (dd, J = 14 Hz, 2 H), 4.65 (q, J = 8.8 Hz, 2 H), 6.06 (s, 1 H), 6.37-6.39 (m, 1 H), 6.56 (s, 1 H), 6.88 (d, J = 8 Hz, 1 H), 7.01-7.06 (m, 1 H), 7.13-7.22 (m, 1 H), 7.55-7.62 (m, 1 H), 8.60 (s, 1 H), HRMS calculated for: [C22H22F5NO3+H]+444.1593; found: 444.1598 (Example 12 peak-1), 444.1600 (Example 12 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (50:50) Isocratic: 93:07(A:B) Flow: 1.0ml / min Diluent: EtOH, Column Temp: 25°C, Inj. 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). 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): To a solution of 3-chloro- 5-formylbenzonitrile (1 g, 6.04 mmol) in anhydrous dichloromethane (10 mL) at 00C dropwise added diethylaminosulfur trifluoride (1.4 mL, 12.08 mmol). Resulting reaction mixture stirred at rt for 4 h. Reaction was quenched using sat. solution of ammonium chloride and extracted using EtOAc (2 x 20 mL). Combined organic layer given brine wash and dried over anhydrous Na2SO4. Organic layer concentrated under vacuo to get compound-6i (1 g, 89%) as yellow oil, H-NMR (DMSO-d6, 400 MHz): δ 7.09 (t, J = 55.2 Hz, 1 H), 8.04 (d, J =1.2 Hz, 1 H), 8.10 (dd, J = 1.2 Hz, 1.2 Hz, 1 H), 8.27 (d, J = 1.2 Hz, 1 H). Synthesis of 1-(3-chloro-5-(difluoromethyl)phenyl)cyclopropan-1-amine (7i): Compound-6i (1 g, 5.331 mmol) converted to compound-7i (550 mg, 47%) as yellowish oil using general procedure for compound-7, m / z (LC-MS): 217.90 [M+H]+. 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): Following general procedure for compound-8, compound-4d (0.15 g, 0.694 mmol) converted to Example 13 (160 mg, 56%) as off white solid using compound-7i. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21 mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH (1:1) (B), Flow: 15 mL / min, Isocratic: 90(A):10(B), diluent EtOH : DCM, 1:1, 4.5 mL, Injection vol, 0.2 mL, run time 18 min, to get Peak-1 (47.2 mg) Peak-2: (69.9 mg). H-NMR (DMSO-d6, 400 MHz): δ 0.96-1.04 (m, 2 H), 1.18-1.23 (m, 2 H), 1.49 (s, 3 H), 2.65 (dd, J = 14 Hz, 2 H), 5.94 (s, 1 H), 6.93 (t, J = 55.6 Hz, 1 H), 6.98-7.02 (m, 1 H), 7.10-7.17 (m, 2 H), 7.16-7.23 (m, 1 H), 7.38 (s, 1 H), 7.58-7.62 (m, 1 H), 8.67 (s, 1 H), HRMS calculated for: [C20H18ClF4NO2+H-H2O]+398.0929; found: 398.0930 (Example 13 peak-1), 398.0934 (Example 13 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm), Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (50:50) Isocratic: 85:15(A:B), Flow: 1.0ml / min Diluent: EtOH, Column Temp: 25°C, Inj. volume: 5.000, Acq. method: IH_8515_7_C-20min.amx. Peak-1 (Rt: 2.97, 100% ee) Peak-2: (Rt: 4.27, 100% ee). 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)but-2-enoate (10): To a stirred suspension of sodium hydride (0.192 g, 4.803 mmol) in anhydrous THF (10 mL) at 00C added triethyl phosphonoacetate ( 1 g, 4.803 mmol). To a resulting reaction mixture added a dropwise solution of 1-(3,5-difluorophenyl)ethan-1-one (500 mg, 3.202 mmol) in anhydrous THF (2 mL) and stirred at rt for 30 min. Reaction was quenched using saturated solution of ammonium chloride and extracted using EtOAc (2 x 15 mL). Combined organic layer given brine wash, dried over anhydrous Na2SO4and concentrated under vacuo to get compound-10 (320 mg, 44%) as colourless liquid. m / z (LC-MS): 227.1 [M+H]+; H-NMR (DMSO-d6, 300 MHz): δ 1.23 (t, J = 6.9 Hz, 3 H), 2.47 (s, 3 H), 4.16 (q, J = 7.2 Hz & 14.4 Hz, 2 H), 6.26 (s, 1 H), 7.29-7.32 (m, 1 H), 7.32- 7.36 (m, 2 H ). Synthesis of Ethyl 3-(3,5-difluorophenyl)-3-hydroxypropanoate (3h): To a stirred solution of compound-10 in ethanol was added palladium on carbon (10%) at rt under argon atmosphere. The resulting mixture was allowed to stir under hydrogen balloon pressure until completion. The progress of the reaction monitored by TLC. After completion of the reaction, filtered through celite bed and washed with EtOH (2 x 10 mL). The resulting filtrate was concentrated under reduced pressure to afford the crude compound-3h which was used in next step without purification; H-NMR (DMSO-d6, 400 MHz): δ 1.09 (t, J = 7.2 Hz, 3 H), 1.20 (d, J = 6.8 Hz, 3 H), 2.61 (d, J = 7.6 Hz, 2 H), 3.15-3.11 (m, 1 H), 4.02 (q, J = 5.2 Hz, 2 H ), 6.99-7.06 (m, 3 H). Synthesis of 3-(3,5-difluorophenyl)butanoic acid (4h): Compound-3h (0.31 g, 1.35 mmol) converted to compound-4h (0.22 g, 1.1%) as off white solid using general procedure for compound-4, H-NMR (DMSO-d6, 300 MHz): δ 1.17-1.20 (m, 3 H), 2.49- 2.57 (m, 2 H), 3.16-3.1 (m, 1 H), 6.99-7.04 (m, 3 H); LCMS (ESI+, m / z): 198.95 (M+H)-. 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): Following general procedure for compound-8, compound-4h (0.22 g, 0.462 mmol) converted to Example 14 (0.22 g, 43%) as off white solid using compound-7a. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and EtOH : IPA 1:1 (B), Flow: 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 get Peak-1 (93.1 mg) Peak-2: (97.3 mg) as colourless gummy oil; H- NMR (DMSO-d6, 400 MHz): δ 0.91-0.97 (m, 2 H), 1.04-1.33 (m, 5 H), 2.37-2.49 (m, 2 H), 3.17-3.22 (m, 1 H), 4.68 (q, J = 8.8 Hz, 2 H), 6.55-6.57 (m, 2 H), 6.78-6.81 (m, 1 H), 6.94-6.97 (m, 2 H), 7.01-7.11 (m, 2 H), 8.49 (s, 1 H), HRMS calculated for: [C21H20F5NO2+H]+414.1487; found: 414.1495 (Example 14 peak-1), 414.1491 (Example 14 peak-2). Analytical Chiral HPLC: REGIS (S,S) WHELK- 01(150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOHL (50:50) Isocratic : 90:10(A:B) Flow: 1.0 ml / min, Diluent: EtOH, Column Temp: 25°C, Inj. 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). 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: 2,2,2- Trifluoro-1-(4-fluorophenyl)ethan-1-one (1 g, 6.405 mmol) converted to compound-3i (0.45 g, 62%) using general procedure A for compound-3; H-NMR (DMSO-d6, 400 MHz): δ 0.96 (t, J = 8 Hz, 2 H), 3.01 (d, J = 15.2 Hz, 1 H), 3.42 (dd, J = 15.2 Hz, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 6.93 (s, 1 H), 7.18-7.22 (m, 2 H), 7.60-7.63 (m, 2 H). Synthesis of 4,4,4-trifluoro-3-(4-fluorophenyl)-3-hydroxybutanoic acid (4i): Compound-3i (450 mg, 1.46 mmol) converted to compound-4i (250 mg, 61.80%) as off-white solid using general procedure for compound-4; m / z (LC-MS): 252.01 [M+H]-. 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): Following general procedure for compound-8, compound-4i (250 mg, 0.99 mmol) converted to Example 15 (250 mg, 54%) as off white solid using compound-7a. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and EtOH : IPA 1:1 (B), Flow: 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 get Peak-1 (110 mg) Peak-2: (108 mg) as colourless gummy oil; H- NMR (DMSO-d6, 400 MHz): δ 0.88-0.99 (m, 2 H), 1.15-1.20 (m, 2 H), 1.35 (d, J = 3.6 Hz, 3H), 3.16-3.22 (m, 1 H), 4.68 (d, J = 8.8 Hz, 2 H), 6.55-6.57 (m, 2 H), 6.78-6.81 (m, 1 H), 6.95-6.97 (m, 1 H), 7.01-7.11 (m, 2 H), 8.49 (s, 1 H), HRMS calculated for: [C21H18F7NO3+H]+466.1248; found: 466.1258 (Example 15 peak-1), 466.1260 (Example 15 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) 0.1% HCOOH IN EtOH:MeOH (80:20) Isocratic: 90:10 (A:B), Flow: 1.0 ml / min, Diluent: EtOH, Column Temp: 25°C, Inj. 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). Example 16: Synthesis of N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide Synthesis of 1-(3-bromophenyl)cyclopropan-1-amine hydrochloride (7j): 3- Bromobenzonitrile (1 g, 5.43 mmol) converted to compound-7j (600 mg, crude) using general procedure for compound-7. After acidification during work up compound-7j extracted as HCl salt in diethyl ether, m / z (LC-MS): 213.75 [M+H]+. Example 16: Synthesis of N-(1-(3-bromophenyl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide (Example 16 peak-1 & Example 16 peak-2): Following general procedure for compound-8, compound-4d (200 mg, 0.92 mmol) converted to Example 16 (80 mg, 21%) as off white solid using compound-7j. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and EtOH:IPA 1:1 (B), Flow: 20 mL / min, Isocratic: 85(A):15(B), diluent EtOH : DCM (1:1, 3 mL), Injection volume-0.5 mL, run time 11 min, to get Peak-1 (6.2 mg) Peak-2: (6.3 mg) as colourless gummy oil; H-NMR (DMSO-d6, 400 MHz): δ 0.85-0.97 (m, 2 H), 1.11-1.23 (m, 2 H), 1.48 (s, 3H), 2.49-2.78 (m, 2 H), 5.99 (s, 1 H), 4.73 (q, J = 8.8 Hz & 17.6 Hz, 2 H), 5.99 (s, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 7.01-7.14 m, 1 H), 7.15-7.19 (m, 1 H), 7.29 (d, J= 7.6 Hz, 1 H), 7.58-7.64 (m, 1 H), 7.59-7.60 (m, 1 H), 8.64 (s, 1 H), HRMS calculated for: [C19H18BrF2NO2+H- H2O]+392.0456; found: 392.0462 (Example 16 peak-1), 392.0471 (Example 16 peak- 2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n- HEXANE (B) IPA : MeOH (50:50), Isocratic: 85:15 (A:B), Flow: 1.0 ml / min, Diluent: EtOH, Column Temp: 25°C, Inj. volume: 10.000, Acq. method: IH_8515_7_C- 15min.amx. Peak-1 (Rt: 2.74, 100% ee) Peak-2: (Rt: 3.54, 100% ee). 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): 3-Bromo-5- hydroxybenzonitrile (10 g, 50.50 mmol) converted to 6k (15 g, 98%) using general procedure for compound-6, H-NMR (DMSO-d6, 400 MHz): δ 4.92 (q, J = 9 Hz, 2 H), 7.67 (s, 1 H), 7.73 (s, 1 H), 7.83 (s, 1H). Synthesis of 1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)102yclopropane-1-amine hydrochloride (7k): Compound-6k (100 mg, 0.32 mmol) converted to compound-7k (30 mg, 30%) as off white solid using general procedure for compound-7. After acidification solids obtained washed with hexane to get desired compound as HCl salt, m / z (LC-MS): 265.90 [M+H]+. Synthesis of N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(4- fluorophenyl) -3-hydroxybutanamide (8k): Following general procedure for compound-8, compound-4e (100 mg, 0.50 mmol) converted to compound-8k (60 mg, 24%) as colorless gummy using compound-7k, m / z (LC-MS): 489.95 [M+H]2+. Example 17: Synthesis of N-(1-(3-cyano-5-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-3-(4-fluorophenyl)-3-hydroxybutanamide In a seal tube charged compound-8k (60 mg, 0.12 mmol) in N,N-dimethylformamide at rt. Added zinc cyanide (14.5 mg, 0.12 mmol) at rt under argon atmosphere. The resulting mixture was degassed with argon for 15 min and then added tetrakis(triphenylphosphine)palladium(0) (565 mg, 0.48 mmol). Resulting reaction mixture was stirred at 1500C in MW for 2 h. The reaction mixture was diluted with cold water and extracted with EtOAc (3 x 15 mL). The combined organic layer given brine wash and dried over anhydrous Na2SO4.Organic layer concentrated under vacuo to afford crude Example 17 which was purified by prep TLC using 30% of EtOAc in hexane as mobile phase to isolate pure Example 17a / b (15 mg, 27%) as off white solid which was separated using Chiral prep HPLC, Column: (Regis (S,S) Whelk-01,, 250mmX21.1mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH(1:1) (B), Flow: 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, to get Peak-1 (7.8 mg) Peak-2: (6.2 mg) as colourless gummy oil; H-NMR (DMSO-d6, 400 MHz): δ 0.97-0.99 (m, 2 H), 1.11-1.15 (m, 2 H), 1.46 (s, 3H), 2.60-2.69 (m, 2 H), 4.80 (q, J= 8.8 Hz & 17.6 Hz, 2 H), 5.61 (s, 1 H), 6.92 (s, 1 H), 7.07-7.11 (m, 3 H), 7.35 (s, 1 H), 7.44-7.48 (m, 2 H), 8.49 (s, 1 H), HRMS calculated for: [C22H20F4N2O3+H-H2O]+419.1377; found: 419.1387 (Example 17 peak-1), 419.1386 (Example 17 peak-2). Analytical Chiral HPLC: REGIS(S,S) WHELK-01 (250X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (50:50), Isocratic: 80:20(A:B), Flow: 1.0 ml / min, Diluent: EtOH, Column Temp: 25°C, Inj. 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). 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): 3-Fluoro-5- hydroxybenzonitrile (4 g, 36.48 mmol) converted to compound-6l (5 g, 63%) using general procedure for compound-6, H-NMR (DMSO-d6, 400 MHz): δ 4.92 (q, J = 8.8 Hz, 2 H), 7.43-7.47 (m, 1 H), 7.52-7.56 (m, 2 H). Synthesis of 1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7l): Compound-6l (3 g, 13.69 mmol) converted to compound-7l (1.5 g, 44%) using general procedure for compound-7. After basification using NaHCO3, compound extracted as free base; H-NMR (DMSO-d6, 400 MHz): δ 0.93-0.99 (m, 4H), 2.35 (bs, 2 H), 4.73 (q, J = 8.8 Hz, 2 H), 6.72-6.73 (m, 1 H), 6.78-6.80 (m, 2 H). 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): Following general procedure for compound-8, compound-4d (150 mg, 0.60 mmol) converted to Example 18 (220 mg, 82%) as off-white solid using compound-7l. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and EtOH : IPA 1:1 (B), Flow: 15 mL / min, Isocratic: 90(A):10(B), diluent EtOH : DCM (3:1, 6 mL), Injection volume-0.5 mL, run time 17 min, to get Peak-1 (97.1 mg) Peak-2: (93.5 mg) as colourless gummy oil; H- NMR (DMSO-d6, 400 MHz): δ 0.97-0.98 (m, 2 H), 1.14-1.23 (m, 2 H), 1.49 (s, 3H), 2.60-2.79 (m, 2 H), 4.73 (q, J= 8.8 Hz & 17.6 Hz, 2 H), 5.99 (s, 1 H), 6.34 (d, J= 10.4 Hz, 1 H), 6.41 (s, 1 H), 6.74 (d, J= 10.4 Hz, 1 H), 6.98-7.02 (m, 1 H), 7.11-7.17 (m, 1 H), 7.59-7.60 (m, 1 H), 8.60 (s, 1 H), HRMS calculated for: [C21H19F6NO3+H]+ 448.1342; found: 448.1350 (Example 18 peak-1), 448.1350 (Example 18 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n- HEXANE (B) IPA : MeOH (50:50), Isocratic: 80:20 (A:B), Flow: 1.0 ml / min Diluent: EtOH, Column Temp: 25°C, Inj. 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). 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): 4-Chloro-3- hydroxybenzonitrile (3 g, 19.53 mmol) converted to 6m (4 g, 87%) as white solid using general procedure for compound-6, H-NMR (DMSO-d6, 300 MHz): δ 4.98 (q, J = 8.8 Hz, 2 H), 7.55-7.58 (dd, J = 1.6 Hz & 8.4 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H) 7.84 (d, J = 1.6 Hz, 1 H), Cl Synthesis of 1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)105yclopropane-1-amine (7m): Compound-6m (1 g, 4.24 mmol) converted to compound-7m (350 mg, crude) using general procedure for compound-7. After basification using NaHCO3, compound extracted as free base, m / z (LC-MS): 266.1 [M+H]+; H-NMR (DMSO-d6, 400 MHz): δ 0.97-0.98 (m, 4H), 2.77 (bs, 2 H), 4.86 (q, J = 8.4 Hz, 2 H), 6.96-6.98 (dd, J = 2.4 Hz & 8.4 Hz, 1 H), 7.14 (d, J = 2.4 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H). Example 19: Synthesis of 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): Following general procedure for compound-8, compound-4d (100 mg, 0.37 mmol) converted to Example 19 (100 mg, 57%) as off-white solid using compound-7m. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and MeOH : IPA 1:1 (B), Flow: 15 mL / min, Isocratic: 88(A):12(B), diluent EtOH : DCM (1:1, 5 mL), Injection volume-0.4 mL, run time 15 min, to get Peak-1 (30 mg) Peak-2: (31 mg) as colourless gummy oil; H-NMR (DMSO-d6, 400 MHz): δ 0.93-0.97 (m, 2 H), 1.13-1.24 (m, 2 H), 1.49 (s, 3H), 2.59-2.77 (m, 2 H), 4.76 (q, J= 8.8 Hz & 17.6 Hz, 2 H), 5.99 (s, 1 H), 6.47-6.50 (dd, J= 4 Hz, 1 H), 6.74-6.75 (m, 1 H), 7.03-7.07 (m, 1 H), 7.13-7.21 (m, 2 H), 7.55-7.62 (m, 1 H), 8.63 (s, 1 H), HRMS calculated for: [C21H19ClF5NO3+H-H2O]+446.0941; found: 446.0949 (Example 19 peak-1), 446.0947 (Example 19 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (50:50) Isocratic: 90:10 (A:B), Flow: 1.0ml / min, Diluent: EtOH, Column Temp: 25°C, Inj. 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). 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): 3- (Difluoromethyl)-5-hydroxybenzonitrile (1 g, 2.95 mmol) converted to 6n (550 mg, 74%) using general procedure for compound-6, H-NMR (DMSO-d6, 400 MHz): δ 4.95 (q, J = 8.7 Hz, 2 H), 7.05 (t, J = 55.2 Hz, 1 H), 7.62 (s, 1 H), 7.75 (s, 1 H), 7.81 (s, 1 H). Synthesis of 1-(3-(difluoromethyl)-5-(2,2,2- trifluoroethoxy)phenyl)106yclopropane-1-amine (7n): Compound-6n (700 mg, 2.78 mmol) converted to compound-7n (170 mg, 22%) using general procedure for compound-7. After basification using NaHCO3, compound extracted as free base, m / z (LC-MS): 282.1 [M+H]+; H-NMR (DMSO-d6, 400 MHz): δ 0.98-1.17 (m, 4H), 2.93 (bs, 2 H), 4.82 (q, J = 8.8 Hz, 2 H), 6.94 (t, J = 50.4 Hz, 1 H), 6.93 (s, 1 H), 7.13 (s, 1 H), 7.17 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): Following general procedure for compound-8, compound-4d (80 mg, 0.28 mmol) converted to Example 20 (50 mg, 37%) as off white solid using compound-7n. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH 1:1(B), Flow: 15 mL / min, Isocratic: 85(A):15(B), diluent EtOH : DCM (1:1, 4 mL), Injection volume-0.4 mL, run time 11 min, to get Peak-1 (15 mg) Peak-2: (14 mg) as colourless gummy oil; H-NMR (DMSO-d6, 400 MHz): δ 0.99-1.06 (m, 2 H), 1.14 (s, 2 H), 1.49 (s, 3H), 2.66-2.74 (m, 2 H), 4.76 (q, J= 8.8 Hz & 17.6 Hz, 2 H), 5.94 (s, 1 H), 6.73-7.01 (m, 5 H), 7.09-7.15 (m, 1 H), 7.57-7.63 (m, 1 H), 8.63 (s, 1 H), HRMS calculated for: [C + 22H20F7NO3+H-H2O] 462.1299; found: 462.1306 (Example 20 peak-1), 462.1306 (Example 20 peak-2). Analytical chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n- HEXANE (B) IPA : MeOH (50:50), Isocratic: 90:10 (A:B), Flow: 1.0ml / min, Diluent : EtOH, Column Temp: 25°C, Inj. 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). 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’): Compound-6k (1 g, 3.57 mmol) converted to compound-7k’ (300 mg, 35%) using general procedure for compound-7. After basification using NaHCO3, compound extracted as free base, m / z (LC-MS): 311.1 [M+H]+. 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): Following general procedure for compound-8, compound-4d (100 mg, 0.462 mmol) converted to Example 21 (25 mg, 18%) as off white solid using compound-7k’. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and MeOH : IPA 1:1 (B), Flow: 15 mL / min, Isocratic: 90(A):10(B), diluent EtOH : DCM (1:1, 2 mL), Injection volume-0.5 mL, run time 14 min, to get Peak-1 (7.7 mg) Peak-2: (7.8 mg) as colourless gummy oil; H-NMR (DMSO-d6, 400 MHz): δ 0.90-0.94 (m, 2 H), 1.15-1.23 (m, 2 H), 1.49 (s, 3 H), 2.61-2.72 (m, 2 H), 4.76 (q, J = 8.8 Hz, 2 H), 5.94 (s, 1 H), 6.60 (s, 1 H), 6.88 (s, 1 H), 6.99-7.02 (m, 1 H), 7.07-7.12 (m, 2 H), 7.61-7.62 (m, 1 H), 8.58 (s, 1 H), HRMS calculated for: [C21H19BrF5NO3+H-H2O]+490.0436; found: 490.0443 (Example 21 peak-1), 490.0443 (Example 21 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (50:50) Isocratic: 85:15 (A:B), Flow: 1.0ml / min, Diluent: EtOH, Column Temp: 25°C, Inj. volume: 5.000, Acq. method: IH_8515_7_C-30min.amx. Peak-1 (Rt: 2.74, 100% ee) Peak-2: (Rt: 3.54, 100% ee). 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 tube charged 3-bromo-5-(2,2,2-trifluoroethoxy)benzonitrile (500 mg, 1.78 mmol) in toluene : water (5:1), was added 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) at rt under argon atmosphere. The resulting mixture was purged under argon atmosphere for 10 min and stirred at 100 °C for 12 h. After completion of the reaction, added water and extracted with EtOAc (3 x 10 mL). Combined all organic layers washed with brine and concentrated under reduced pressure to afford crude compound-6o. The crude material was purified by combiflash (12 g column, 0-10% EtOAc in Hexane as eluent) to afford pure compound-6o as off white solid (300 mg, 80%); H-NMR (DMSO-d6, 400 MHz): δ 0.78-0.79 (m, 2 H), 0.97- 0.99 (m, 2 H), 1.96 (bs, 1 H), 4.84 (q, J = 8.8 Hz, 2 H), 7.09 (s, 1 H), 7.24 (s, 1 H), 7.32 (s, 1 H). Synthesis of 1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl))cyclopropane-1- amine (7o): Compound-6o (300 mg, 1.24 mmol) converted to compound-7o (150 mg, 38%) using general procedure for compound-7. After basification using NaHCO3, compound extracted as free base, m / z (LC-MS): 272.0 [M+H]+. 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): Following general procedure for compound-8, compound-4d (100 mg, 0.368 mmol) converted to Example 22 (40 mg, 35%) as off white solid using compound-7o. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane(A) and EtOH : IPA 1:1 (B), Flow: 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 get Peak-1 (13.2 mg) Peak-2: (10 mg) as colourless gummy oil; H-NMR (DMSO-d6, 400 MHz): δ 0.28-0.37 (m, 2 H), 0.88-0.92 (m, 4 H), 1.09 (s, 1 H), 1.48 (s, 3 H), 1.73-1.79 (m, 1 H), 2.51-2.76 (m, 3 H), 4.68 (d, J= 8.8 Hz, 2 H), 6.02 (s, 1 H), 6.38- 6.45 (m, 3 H), 6.98-7.03 (m, 1 H), 7.10-7.16 (m, 1 H), 7.57-7.69 (m, 1 H), 8.56 (s, 1 H), HRMS calculated for: [C24H24F5NO3+H]+470.1749; found: 470.1757 (Example 22 peak-1), 470.1755 (Example 22 peak-2). Analytical chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA: MeOH (50:50) Isocratic: 85:15(A:B) Flow: 1.0ml / min Diluent: EtOH, Column Temp: 25°C, Inj. volume: 5.000, Acq. method: IH_8515_7_C-15min.amx. Peak-1 (Rt: 2.612, 100% ee) Peak-2: (Rt: 3.426, 100% ee). 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): 1-(2,6- difluorophenyl)ethan-1-one (1 g, 6.40 mmol) converted to compound-3j (1.7 g, Crude) using general procedure A for compound-3, used for the next step without purification. H-NMR (DMSO-d6, 400 MHz): δ 1.16 (t, J = 7.2, 3 H), 1.69 (s, 3 H), 2.77 (d, J = 15 Hz, 1 H), 3.25 (d, J = 15 Hz, 1 H), 4.06-4.11 (q, J = 7.2 Hz, 2 H), 4.56 (bs, 1 H), 6.88-6.81 (m, 2 H), 6.97-6.95 (m, 1 H). Synthesis of 3-(2,6-difluorophenyl)-3-hydroxybutanoic acid (4j): Compound-3j (1.5 g, 6.14 mmol) converted to compound-4j (1 g, 76.92%) as yellow gummy using general procedure for compound-4, H-NMR (CDCl3, 400 MHz): δ 1.70 (s, 3 H), 2.85 (d, J = 16.8 Hz, 1 H), 3.30 (d, J = 16.8 Hz, 1 H), 6.88-6.83 (m, 2 H), 7.26-7.18 (m, 1 H). 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): Following general procedure for compound-8, compound-4j (0.2 g, 0.927 mmol) converted to Example 23 (180 mg, 42%) using compound-7b. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21 mm, 5µm), Eluent: n-Hexane(A) and IPA : EtOH 1:1 (B), Flow: 15 mL / min, Isocratic: 90(A):10(B), diluent EtOH : DCM, 1:1, 3.5 mL, Injection vol, 0.4 mL, run time 20 min, to get Peak-1 (58.18 mg), Peak-2: (62.05 mg); 1H NMR (400 MHz, CDCl3) δ ppm 0.87-1.01 (m, 1 H), 1.10-1.22 (m, 3 H), 1.67 (s, 3 H), 2.71 (d, J = 15.11 Hz, 1 H), 3.06 (d, J = 15.11 Hz, 1 H), 4.27 (q, J = 8.07 Hz, 2 H), 4.94 (bs, 1 H), 6.45 (bs, 1 H), 6.63-6.64 (m, 1 H), 6.70- 6.73 (m, 2 H), 6.80-6.86 (m, 2 H), 7.13-7.20 (m, 1 H), HRMS calculated for: [C21H19ClF5NO3+H]+464.1052; found: 464.1055 (Example 23 peak-1), 464.1067 (Example 23 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : EtOH (50:50) Isocratic : 85:15 (A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, Acq. method: IH_8515_7_C-30min.amx. Peak-1 (Rt: 4.961, 100% ee) Peak-2: (Rt: 11.357, 100% ee). 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): 1-(3,4-difluorophenyl)ethan-1-one (1 g, 6.40 mmol) converted to compound-3k (0.5 g, 33.33%) as colourless gummy using general procedure A for compound-3,1H NMR (300 MHz, DMSO-d6) δ 1.04 (q, J = 7.2 Hz, 3 H), 1.51 (s, 3 H), 2.77 (dd, J = 14 Hz, 2 H), 3.92 (q, J = 7.2 Hz, 2 H), 5.44 (bs, 1 H), 7.36-7.24 (m, 2 H), 7.48-7.42 (m, 1 H). Synthesis of 3-(3,4-difluorophenyl)-3-hydroxybutanoic acid (4k): Compound-3k (0.5 g, 2.047 mmol) converted to compound-4k (0.4 g, 90.47%) as pale reddish gummy using general procedure for compound-4,1H NMR (300 MHz, DMSO- d6) δ 1.47 (s, 3 H), 2.67 (dd, J = 14 Hz, 2 H), 7.30-7.25 (m, 2 H), 7.47-7.40 (m, 1 H). 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): Following general procedure for compound-8, compound-4k (0.15 g, 0.693 mmol) converted to Example 24 (190 mg, 59.37%) using compound-7b. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 150mmX4.6 mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH 1:1 (B), Flow: 1 mL / min, Isocratic: 90(A):10(B), diluent EtOH, Injection vol, 5 mL, run time 15 min, to get Peak-1 (75.8 mg), Peak-2: (80.5 mg);1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-0.97 (m, 2 H), 1.17- 1.20 (m, 2 H), 1.45 (s, 3 H), 2.56 (d, J = 14 Hz, 1 H), 2.70 (d, J = 14 Hz, 1 H), 4.75 (q, J = 8.8 Hz, 2 H), 5.75 (s, 1 H), 6.53-6.54 (m, 1 H), 6.64-6.65 (m, 1 H), 6.94-6.95 (m, 1 H), 7.23-7.34 (m, 2 H), 7.40-7.46 (m, 1 H), 8.52 (bs, 1 H), HRMS calculated for: [C21H19ClF5NO3+H-H2O]+446.0941; found: 446.0955 (Example 24 peak-1), 446.0957 (Example 24 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA: MeOH (50:50) Isocratic: 90:10 (A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25 °C, Inj. volume: 5.000, Peak-1 (Rt: 3.613, 100% ee) Peak-2: (Rt: 5.134, 100% ee). 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)ethan-1-one (0.5 g, 2.30 mmol) converted to compound-3l (0.36 g, 51.30%) using general procedure A used for compound-3, m / z (LC-MS): 288.90 [M-17+H]+.1H NMR (400 MHz, DMSO-d6) δ 1.16 (t, J = 7.2 Hz, 3 H), 1.57 (s, 3 H), 2.79 (dd, J = 4.4 Hz & 16.4 Hz, 1 H), 2.83 (dd, J = 4.4 Hz & 16.4 Hz, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 4.50 (bs, 1 H), 6.94-7.07 (m, 2 H), 7.43-7.45 (m, 1 H). Synthesis of 3-(2-bromo-6-fluorophenyl)-3-hydroxybutanoic acid (4l): Compound-3l (0.54 g, 1.769 mmol) hydrolysed to get 4l (0.450 g, 91.83%) using general procedure used for compound-4, m / z (LC-MS): 274.95 [M-H]+. 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): Following general procedure used for compound-8, compound-4l (0.45 g, 1.62 mmol) converted to Example 25 (0.68 g, 59.37%) using compound-7b. The enantiomers were separated on 30 mg scale using Chiral SFC, Column: (CHIRALPAK-IG, 4.6 MM x150MM x 5µm), Co-Solvent Name : IPA : EtOH : MeOH (1:1:1); Flow: 3 mL / min, Injection vol, 15 µl, Outlet Pressure: 100 bar; Temperature : 40 °C to get Peak-1 (8.8 mg), Peak-2: (8.2 mg);1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.18 (m, 2 H), 1.21- 1.33 (m, 2 H), 1.60 (s, 3 H), 2.70-2.74 (dd, J = 2.8 Hz & 14.8 Hz, 1 H), 3.07-3.02 (dd, J = 2.8 Hz & 14.8 Hz, 1 H), 4.75 (q, J = 8.8 Hz, 2 H), 5.70 (s, 1 H), 6.58 (bs, 1 H), 6.74 (s, 1 H), 7.10-7.19 (m, 2 H), 7.43-7.45 (m, 2 H), 8.52 (s, 1 H), HRMS calculated for: [C21H19BrClF4NO3+H]+524.0251; found: 524.0243 (Example 25 peak-1), 524.0260 (Example 25 peak-2). Analytical Chiral HPLC: (CHIRALPAK-IG, 4.6 MM x150MM x 5µm), Co-Solvent Name : IPA : EtOH : MeOH (1 : 1 : 1); Flow: 3 mL / min, Injection vol, 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). Example 26: Synthesis of N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4- yl)cyclopropyl)-3-(2,6-difluorophenyl) -3-hydroxybutanamide Synthesis of 2-chloro-6-(2,2,2-trifluoroethoxy)isonicotinonitrile (6p): To a stirred solution 2,6-dichloroisonicotinonitrile (1 g, 5.7803 mmol) in acetonitrile (10 vol) added K2CO3 (0.798 g, 5.7803 mmol) and 2,2,2-trifluoroethanol (0.34 mL, 4.6242 mmol). Resulting reaction mixture stirred at room temperature for overnight and quenched with water. Reaction mixture was extracted with EtOAc (3 X 10 vol). Organic layer dried over anhydrous Na2SO4and concentrated under high vacuo to get crude compound which was purified using combi flash chromatography (5 to 10% EtOAc in Hexane) to get pure enough compound-6p (600 mg, 44.11%) as off white solid,1H NMR (400 MHz, DMSO-d6) δ ppm 5.05 (q, J = 8.8 Hz, 2 H), 7.6 (s, 1 H), 7.9 (s, 1 H). Synthesis of 1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropan-1- amine (7p): Compound-6p (0.4 g, 1.60 mmol mmol) converted to compound-7p (60 mg, 26.66%) using general procedure used for compound-7. After basification using NaHCO3, compound extracted as free base. m / z (LC-MS): 266.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.09 (m, 4 H), 4.94 (q, J = 9.2 Hz, 2 H), 6.87 (d, J = 1.2 Hz, 1 H), 7.07 (d, J = 1.2 Hz, 1 H). Example 26: Synthesis of N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4- yl)cyclopropyl)-3-(2,6-difluorophenyl) -3-hydroxybutanamide (Example 26 peak-1 & Example 26 peak-2): Following general procedure for compound-8, compound-4k (0.48 g, 0.22 mmol) converted to Example 26 (70 mg, 47.61%) using compound-7p. The enantiomers were separated using Chiral prep HPLC, Column Column: CHIRALPAK IH, 250mmX20mm, 5µm, Eluent: n-Hexane(A) and IPA:MeOH 1:1 (B), Flow: 15 ml / min, Isocratic: 90(A):10(B), diluent EtOH:DCM, 1:1, 3 mL, Injection vol, 0.5 mL, run time 20 min, to get Peak-1 (14.6 mg, Rt: 4.315) and Peak-2 (13.1 mg, Rt: 5.080).1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.06 (m, 2 H), 1.23-1.34 (m, 2 H), 1.63 (s, 3 H), 2.74 (d, J = 14.4 Hz, 1 H), 2.86 (d, J = 14.4 Hz, 1 H), 4.92 (q, J = 8.95 Hz, 2 H), 5.72 (bs, 1 H), 6.45 (d, J = 1 Hz, 1 H), 6.76 (d, J = 1 Hz, 1 H), 6.96-6.99 (m, 2 H), 7.26-7.32 (m, 1 H), 8.72 (s, 1 H), HRMS calculated for: [C20H18ClF5N2O3+H]+465.1004; found: 465.1011 (Example 26 peak-1), found: 465.1014 (Example 26 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : METHANOL (50:50), Isocratic : 90:10 (A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, Peak-1 (Rt: 4.315, 100% ee) Peak-2: (Rt: 5.080, 100% ee). 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 g, 0.365 mmol mmol) converted to compound- 6q (380 mg, 79.33%) as white crystalline solid using general procedure used for compound-6. m / z (LC-MS): 250.05 [M+H]+. H NMR (300 MHz, DMSO-d6) δ ppm 4.85 (q, J = 8.7 Hz, 2 H), 7.48-7.53 (m, 2 H), 7.68-7.71 (m, 1 H). Synthesis of 1-(2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7q): Compound-6q (0.08 g, 0.365 mmol mmol) converted to compound-7q (45 mg, 7.9%) using general procedure used for compound-7. After basification using NaHCO3, compound extracted as free base. m / z (LC-MS): 250.05 [M+H]+. 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): Following general procedure for compound-8, compound-4d (0.043 g,0.198 mmol) converted to Example 27 (20 mg, 22%) using compound-7q. The enantiomers were separated using Chiral prep HPLC, Column: CHIRALPAK-IG(250X4.6mmX5µm), Mobile Phase: (A) n-HEXANE (B)IPA : METHANOL(50:50), Flow: 15 mL / min, Isocratic: 93 (A):07 (B), diluent: EtOH : DCM, 1:1, 2 mL, Injection vol: 0.35 mL, run time 14 min, to get Peak-1 (1.5 mg), Peak-2: (2.1 mg); H NMR (400 MHz, CDCl3) δ ppm 0.83-0.96 (m, 2 H), 0.92-1.02 (m, 2 H), 1.47 (s, 3 H), 2.55 (d, J = 14.4, 1 H), 2.80 (d, J = 14.4, 1 H), 4.28 (q, J = 6.8 Hz, 2 H), 5.39 (s, 1 H), 6.28 (bs, 1 H), 6.59-6.67 (m, 2 H), 6.72-6.76 (m, 1 H), 6.82-6.92 (m, 2 H), 7.46-7.53 (m, 1 H). HRMS calculated for: [C21H19F6NO3+H-H2O]+430.1242; found: 430.1246 (Example 27 peak-1), 430.1245 (Example 27 peak-2). Analytical Chiral HPLC: CHIRALPAK-IG (150X4.6mmX5µm), Mobile Phase: (A) n-HEXANE (B) IPA : METHANOL(50:50), Isocratic : 95:05 (A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, Peak-1 (Rt: 5.00, 100% ee) Peak-2: (Rt: 7.60, 100% ee). Example 28: Synthesis of (R)-N-(1-(4,6-dichloropyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide Synthesis of 1-(4,6-dichloropyridin-2-yl)cyclopropan-1-amine (7r): 4,6-dichloropicolinonitrile (0.5 g, 2.890 mmol mmol) converted to compound-7r (45 mg, 7.9%) using general procedure used for compound-7. After basification using NaHCO3, compound extracted as free base. m / z (LC-MS): 202.95 [M+H]+. Synthesis of (R)-3-(2,4-difluorophenyl)-3-hydroxybutanoic acid (R-4d) Synthesis of (R)-3-acetyl-4-benzyloxazolidin-2-one (2): To a stirred solution of (R)-4-benzyloxazolidin-2-one (50 g, 1.0 eq, 282.16 mmol) in anhydrous tetrahydrofuran (10 vol) was stirred for 10 minutes. The reaction mixture was cooled to -78°C and was added n-Butyllithium (2.5 M in Hexane) (113.99 mL, 1.01 eq, 284.98 mmol) dropwise (30 min) and the reaction mixture was stirred for about 30 minutes. A solution of Acetyl chloride (22.29 mL, 1.1 eq, 310.38 mmol) was added dropwise (15 min) at the same temperature. Then the reaction mixture was warmed to room temperature and stirred for further 1 h. The resulting mixture was monitored by TLC and LCMS. After completion of the reaction quenched with sat. NH4Cl solution (2 vol) was extracted with EtOAc (3 X 10 vol). The organic layer was washed with water (3 x 100 mL) and brine solution (1 X 10 vol). Resulting organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to give off white product (55.6 g, 253.18 mmol, 89.88%). m / z (LC-MS): 220.15 [M+H]+; H NMR (300 MHz, CDCl3) δ ppm 2.55 (s, 3 H), 2.73-2.81 (m, 1 H), 3.27-3.32 (m, 1 H), 4.17-4.23 (m, 2 H), 4.64-4.69 (m, 1 H), 7.19-7.21 (m, 2 H), 7.25-7.36 (m, 3 H). Synthesis of (R)-4-benzyl-3-((R)-3-(2,4-difluorophenyl)-3- hydroxybutanoyl)oxazolidin-2-one (3a): To a stirred solution of Lithium bis(trimethylsilyl)amide (228.06 mL, 228.06 mmol, 1eq) under argon atmosphere at -78°C was added compound-2 (50 g, 228.06 mmol, 1 eq) in anhydrous THF (10 vol) dropwise for 45 min. Then reaction mixture was stirred for 2 h at -78°C followed by addition of 2, 4-Difluoro acetophenone (32.37 mL, 228.06 mmol, 1 eq) in anhydrous THF ( 6 vol) at -78° C for 30 min. Then reaction mixture was stirred for 1 h at -78°C. The resulting mixture was monitored by TLC and LCMS. After completion of the reaction was quenched with 0.5M HCl (2 vol) at -78°C, temperature was slowly raised to rt (30 min) and extracted with ethyl acetate (3 x 10 vol), Combined all organic layers washed with water (2 x 10 vol) and brine solution (2 x vol) and concentrated under vacuo to afford crude material. To obtain a clear solution, the crude material was recrystallized in a 1: 1 ratio of IPA and t-Butanol (10 vol) and heated at 50°C h for 10 minutes. The resulting solution was left for 24 hours to form crystals. It was filtered through a Buchner funnel and washed with 1 vol of 1: 1 IPA and t-Butanol to obtain pure (R)-4-benzyl-3-((R)-3-(2,4-difluorophenyl)-3-hydroxybutanoyl)oxazolidin- 2-one 3a (19.1 g, 22.31%). Filtrate contains a mixture of diastereomers (44 g crude, ~1:1 ratio), m / z (LC-MS): 358.1 [M-17]+; Chiral HPLC: 99.41%, Rt = 11.70 min, H NMR (300 MHz, CDCl3) δ ppm 1.63 (s, 3 H), 2.56-2.63 (m, 1 H), 2.96 (d, J = 13.2 Hz, 1 H), 3.28 (d, J = 17.1 Hz, 1 H), 4.08-4.23 (m, 3 H), 4.60-4.63 (m, 2 H), 6.79 (t, J = 9 Hz, 1 H), 6.89 (t, J = 7.8 Hz, 1 H), 7.04-7.05 (m, 2 H), 7.27-7.29 (m, 3 H), 7.67-7.75 (m, 1 H). Synthesis of (R)-3-(2,4-difluorophenyl)-3-hydroxybutanoic acid (R-4d): To a solution of 3a (9 g, 23.97 mmol, 1 eq) in Tetrahydrofuran and Water (4 : 1, 15 vol) was added Hydrogen peroxide (9.8 mL, 95.90 mmol, 4 eq) , The reaction mixture was cooled to 0°C and added Lithium Hydroxide Monohydrate (4.02 g, 95.90 mmol, 4 eq). The resulting mixture was stirred at RT for 2h. Progress reaction mass was monitored by TLC and LCMS. After completion of reaction was diluted with water (3 x 10 vol) and extracted with Dichloromethane (5 x 3 vol) to remove biproduct impurities. Aqueous was acidified by 1N HCl and extracted with Dichloromethane (4 x 20 vol). Combined all organic layer washed with water (3 x 2 vol), and brine (1 x 5 vol) and concentrated by reduce pressure to afford crude title compound as pale-yellow gummy (5 g, 96.52%) was used to next step without any purification.m / z (LC-MS): 215.1 [M-1]+; Chiral HPLC: 11.70 min, 93.12%; H NMR (300 MHz, DMSO-d6) δ ppm 1.52 (s, 3 H), 2.68-2.78 (m, 2 H), 5.56 (bs, 1 H), 7.01-7.16 (m, 2 H), 7.57-7.66 (m, 1 H), 12.10 (bs, 1 H). Example 28: Synthesis of (R)-N-(1-(4,6-dichloropyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide: Following general procedure for compound-8, enantiopure compound-4d (0.047 g, 0.221 mmol) converted to Example 28 (3 mg, 5.05%) using compound-7r. It was purified using prep HPLC Column: X SELECT (250mmx20.0mm), 5.0µ, Eluent: 0.1%HCOOH in water (A) and ACN (B), Flow: 15 ml / min, Gradient Programmer: Time (%B): 0 / 30, 2 / 40, 6 / 75, H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.09 (m, 2 H), 1.32- 1.36 (m, 2 H), 1.52 (s, 3 H), 2.65 (d, J = 14.4 Hz, 1 H), 2.70 (d, J = 14.4 Hz, 1 H), 5.97 (s, 1 H), 7.01-7.06 (m, 1 H), 7.14-7.20 (m, 2 H), 7.49 (d, J = 1.6 Hz, 1 H), 7.62-7.69 (m, 1 H), 8.69 (bs, 1 H), HRMS calculated for: [C18H16Cl2F2N2O2+H]+401.0635; found: 401.0644, Analytical Chiral HPLC: Column: REGIS(S,S) WHELK-01 (250X4.6mmX5µm), Mobile Phase: (A) n-HEXANE (B) 0.1% HCOOH IN ETHANOL : METHANOL (80:20), Isocratic : 70:30 (A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 10, (Rt: 4.40, 97.11%) Example 29: Synthesis of (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-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) at 00C added a solution of 2,2,2-trifluoroethan-1-ol (7.6055 g, 76.0244 mmol) in anhydrous DMF (10 mL). After stirring at 00C for 15 min added a solution of 4- chloro-2-fluoropyridine (10 g, 76.0244 mmol) in anhydrous DMF (20 mL). Resulting reaction mixture stirred at room temperature overnight. Reaction was quenched using sat. solution of ammonium chloride and extracted using EtOAc (3 x 200 mL). Combined Organic layer given brine wash and dried over anhydrous Na2SO4. Organic layer removed under vacuo to get crude product which was purified by flash chromatography (EtOAc : Hexane 5 : 95) as eluent to get 4-chloro-2-(2,2,2-trifluoroethoxy)pyridine (10.2 g, 63.43%) as colourless liquid; m / z (LC-MS): 211.95 [M+H]+. 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) at 0oC was added Hydrogen peroxide (22 mL). Reaction mixture was stirred for overnight at 80oC. The reaction mixture was concentrated under vacuo and diluted with water and cooled to 0 °C, then slowly basified with ammonium hydroxide solution till pH = 7-8. The resulting solution was extracted with DCM. The combined organic layers were washed with brine solution, dried over Na2SO4 and concentrated under vacuo to afford crude 4-chloro-2-(2,2,2-trifluoroethoxy) pyridine 1- oxide (7.6 g, 69.27%) as off white solid; m / z (LC-MS): 227.90 [M+H]+. Synthesis of 4-chloro-6-(2,2,2-trifluoroethoxy) picolinonitrile: In 250 ml seal tube a stirred solution of 4-chloro-2-(2,2,2-trifluoroethoxy) pyridine 1- oxide (7.5 g, 32.957 mmol) in Acetonitrile (70 mL) were added Trimethylsilyl cyanide (22.65 mL, 164.78 mmol), Triethylamine (22.96 mL, 164.78 mmol) at room temperature. The reaction mixture was stirred for overnight at 80 °C. the reaction mixture was concentrated under vacuo and filtered through celite bed. The filtrate was diluted with water and extracted wit EtOAc (3 x 200 mL). The combined organic layers were washed with brine solution and concentrated under vacuo to obtained crude product which was purified by flash chromatography (EtOAc:Hexane 20:80) as eluent to get 4-chloro-6-(2,2,2-trifluoroethoxy) picolinonitrile (2.5 g, 32.09%) as yellow liquid; H-NMR (CDCl3, 400 MHz) δ ppm 4.79 (s, 2 H), 7.15 (d, J = 1.47 Hz,1 H), 7.41 (d, J = 1.47 Hz,1 H). Synthesis of 1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropan-1- amine (7s): 4-Chloro-6-(2,2,2-trifluoroethoxy) picolinonitrile (1.2 g, 5.072 mmol) converted to compound-7s (700 mg, 51.85%) using general procedure used for compound-7. After acidification using 4M HCl in Dioxane, compound extracted as HCl salt, m / z (LC-MS): 166.85 [M+H]+. Example 29: Synthesis of (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: Following general procedure for compound- 8, enantiopure compound-4d (0.040 g, 0.187 mmol) converted to Example 29 (13.3 mg, 44.33%) using compound-7s, using prep HPLC, Column: (X SELECT (250mmx20.0mm), 5.0µ,), Eluent: A= 0.1%HCOOH IN WATER, B= ACN, Flow: 15 ml / min, to get Example 29. H-NMR (DMSO-d6, 400 MHz): δ ppm 0.96-1.01 (m, 2 H), 1.44-1.47 (m, 2 H), 1.52 (s, 3 H), 2.68 (d, J = 14 Hz, 1 H), 2.81 (d, J = 14 Hz, 1 H), 4.9 (q, J = 9.10 Hz, 2 H), 6.01 (s, 1 H), 6.78 (d, J = 1.61 Hz, 1 H), 6.89 (d, J = 1.61 Hz, 1 H), 7.01-7.06 (m, 1 H), 7.14-7.20 (m, 1 H), 7.62-7.69 (m, 1 H), 8.65 (s, 1 H). HRMS calculated for: [C20H18ClF5N2O3+H]+465.1004; found: 465.1010, Analytical Chiral HPLC: Column: REGIS(S,S) WHELK-01 (250X4.6mmX5µm), Mobile Phase: (A) n-HEXANE (B) 0.1%DEA IN EtOH : MeOH (70:30), Isocratic : 70:30 (A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, (Rt: 4.08, 98.90%). Example 30: Synthesis of 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl) amino) pyridin-2-yl)cyclopropyl)butanamide Synthesis of 6-((2,2,2-trifluoroethyl)amino)picolinonitrile: To a stirred solution 6-fluoropicolinonitrile (1 g, 8.18 mmol, 1 eq) in DMSO (10 vol) added 2,2,2-trifluoroethylamine (0.97 mL, 9.82 mmol). Resulting reaction mixture was heated on preheated oil bath at 1500C for 16 h. Reaction mixture was quenched using water and extracted with EtOAc (3 x 20 vol) to get crude compound. It was purified using combiflash chromatography (EtOAc : Hexane 1:3 as eluent) to get 6-((2,2,2- trifluoroethyl)amino)picolinonitrile (0.8 g, 50 % ) as an off white solid ; m / z (LC-MS): 201.95 [M+H]+. Synthesis of 6-(1-aminocyclopropyl)-N-(2,2,2-trifluoroethyl)pyridin-2-amine : 6-((2,2,2-trifluoroethyl)amino)picolinonitrile (0.4 g, 1.98 mmol) converted to get 7t (0.2 g, 44 %) as a yellow solid, using general procedure used for compd-7. m / z (LC-MS): 232.15 [M+H]+. Example 30: Synthesis of 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2- trifluoroethyl) amino) pyridin-2-yl)cyclopropyl)butanamide (Example 30 peak-1 & Example 30 peak-2): Following general procedure 8, Compound-4j (0.103 g, 0.472 mmol) converted to Example 30 (33 mg, 17.83%) using compound-7t. The enantiomers were separated using chiral prep HPLC, Column: (Chiralpak IH, 150mmX4.6 mm, 5µm), Eluent: n- Hexane(A) and IPA : MeOH 1:1 (B), Flow: 1 mL / min, Isocratic: 90(A):10(B), diluent: EtOH, Injection vol, 5 mL, run time 20 min, to get Peak-1 (8.9 mg), Peak-2: (6.4 mg) as off white solid,1H NMR (400 MHz, DMSO-d6) δ ppm 0.81-0.86 (m, 2 H), 1.23-1.35 (m, 2 H), 1.63 (s, 3 H), 2.69 (d, J = 14 Hz, 1 H), 2.9 (d, J = 14 Hz, 1 H), 3.98-4.05 (m, 2 H), 5.75 (s, 1 H), 5.98 (d, J = 7.6 Hz, 1 H), 6.27 (d, J = 7.6 Hz, 1 H), 6.95-7.03 (m, 3 H), 7.07-7.12 (m, 1 H), 7.33-7.38 (m, 1 H), 8.66 (s, 1 H). HRMS : m / z (LC-MS): 430.05 [M+H]+. HRMS calculated for: [C20H20F5N3O2+H]+430.1554; found: 430.1554 (Example 30 peak-1), 430.1558 (Example 30 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (50:50) Isocratic : 85:15 (A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. volume: 12.000,. Peak-1 (Rt: 9.549, 100% ee) Peak-2: (Rt: 12.546, 100% ee). 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: 3-bromo-5-methoxyphenol (1 g, 4.92 mmol) converted to 1-bromo-3-methoxy-5-(2,2,2- trifluoroethoxy)benzene (1.6 g, Crude) using general procedure for compound-6. H-NMR (CDCl3, 300 MHz): δ 3.77 (s, 3 H), 4.30 (q, J = 8.7 Hz, 2 H), 6.42 (s, 1 H), 6.67 (s,1 H), Hz, 2 H), 6.74 (s, 1 H). 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 eq) in DMF (10 vol) added ZnCN2(1.16 g, 9.82 mmol, 4 eq), Resulting reaction mixture was degassed with argon and added Tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.240.1 eq). Reaction mixture was heated at 1200C in MW for 1h. The reaction mixture was diluted with cold water and extracted with EtOAc (3 X 5 vol) then combined layers are separated. The combined organic phases are dried over anhydrous Na2SO4, concentrated under vacuum. Residue purified by column chromatography using silica gel as ethyl acetate and hexane solvent system to afford title compound 6u as off white solid. H-NMR (DMSO- d6, 300 MHz): δ 3.82 (s, 3 H), 4.36 (q, J = 8 Hz, 2 H), 6.72-6.71 (m, 1 H), 6.79-6.78 (m, 1 H), 6.87-6.86 (m, 1 H). Synthesis of 1-(3-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropan-1-amine (7u): 3-methoxy-5-(2,2,2-trifluoroethoxy)benzonitrile 6u (0.75 g, 3.24 mmol) converted to compound-7u (0.3 g, 35.41%) using general procedure A for compound-7, m / z (LC- MS): 262.0 [M+H]+. 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): Following general procedure for compound-8, compound-4d (0.13 g, 0.49 mmol) converted to Example 31 (45 mg, 20.20%) using compound-7u. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 150mmX4.6 mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH 1:1 (B), Flow: 1 mL / min, Isocratic: 90(A):10(B), diluent: EtOH, Injection vol, 10 mL, run time 15 min, to get Peak-1 (10.9 mg), Peak-2: (11 mg); H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.88 (m, 2 H), 1.01-1.15 (m, 2 H), 1.56 (s, 3 H), 2.63 (d, J = 14 Hz, 1 H), 2.92 (d, J = 14 Hz, 1 H), 3.72 (s, 3 H), 4.24 (q, J = 8.4 Hz, 2 H), 5.55 (bs, 1 H), 6.14 (bs, 1H), 6.22-6.28 (m, 3 H), 6.66-6.69 (m, 1 H), 6.79-6.84 (m, 1 H), 7.61-7.65 (m, 1 H), HRMS calculated for: [C22H22F5NO4+H]+ 460.1547; found: 460.1558 (Example 31 peak-1), 460.1555 (Example 31 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm) Mobile Phase: (A) n- HEXANE (B) IPA : MeOH (50:50) Isocratic : 90:10 (A:B) Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, Peak-1 (Rt: 4.0, 100% ee) Peak-2: (Rt: 5.888, 100% ee). 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)but-2-enoate: To a stirred suspension of sodium hydride (0.768 g, 19.214mmol) in anhydrous THF (20 mL) at 00C added triethyl phosphonoacetate (4.02 g, 17.93 mmol). To a resulting reaction mixture added a dropwise solution of 1-(2,4-difluorophenyl)ethan-1-one (2 g, 12.81 mmol) in anhydrous THF (20 mL) and stirred at room temperature for 30 min. Reaction was quenched using saturated solution of ammonium chloride and extracted using EtOAc (2 x 50 mL). Combined organic layer given brine wash, dried over anhydrous Na2SO4 and concentrated under vacuo to get ethyl 3-(2,4-difluorophenyl)but-2-enoate (2.4 g, 82.84%) as colourless liquid. m / z (LC-MS): 226.95 [M+H]+. H-NMR (CDCl3, 300 MHz): δ 1.31 (t, J = 6.9 Hz, 3 H), 2.50 (s, 3 H), 4.21 (q, J = 6.9 Hz, 2 H), 5.96 (s, 3 H), 6.79- 6.95 (m, 2 H), 7.21-7.29 (m, 1 H). Synthesis of ethyl 3-(2,4-difluorophenyl)butanoate: To a stirred solution of ethyl 3- (2,4-difluorophenyl)but-2-enoate (500 mg, 2.210 mmol) in anhydrous EtOAc (10 mL) under nitrogen added Pd-C (10%, 0.047 g, 0.442 mmol). Resulting reaction mixture flushed with hydrogen and hydrogenated under balloon pressure of hydrogen for 16 h. After completion of the reaction, filtered through celite bed and washed with EtOAc (2 x 10 mL). The resulting filtrated was concentrated under reduced pressure to get ethyl 3- (2,4-difluorophenyl)butanoate (410 mg, 81.34%) as crude oil, m / z (LC-MS): 229.0 [M+H]+. H-NMR (CDCl3, 300 MHz): δ 1.1.7 (t, J = 7.2 Hz, 3 H), 1.30 (d, J = 6.8 Hz, 3 H), 2.53-2.67 (m, 2 H), 3.51 (q, J = 7.52 Hz, 2 H), 4.08 (q, J = 7.2 Hz, 2 H), 6.73-6.83 (m, 2 H), 7.14-7.19 (m, 1 H).

[0627] Synthesis of ethyl 3-(2,4-difluorophenyl)-2-hydroxybutanoate:

[0628] To a stirred solution of ethyl 3-(2,4-difluorophenyl)butanoate (400 mg, 1.75 mmol) in anhydrous THF (5 mL) under argon atmosphere cooled to -78 °C followed by added KHMDS (704 mg, 3.50 mmol) was added dropwise. Then reaction mixture was stirred for 30 min at -78°C followed by addition of 3-phenyl-2-(phenylsulfonyl)-1 ,2-oxaziridine (544 mg, 2.104 mmol) in THF at -78° C. Then reaction mixture was stirred for 2 h at - 78°C. Progress of the reaction was monitored by TLC. After Completion of the reaction, it was quenched with NH4CI then diluted with water and extracted with EtOAc (4 X 10 ml). Combined all organic layers washed with brine and concentrated under reduced pressure to afford crude material which was purified using combiflash chromatography (10% EtOAc in hexane) to get racemic trans ethyl 3-(2,4-difluorophenyl)-2- hydroxybutanoate (240 mg, 56.07%)

[0629] Synthesis of 3-(2,4-difluorophenyl)-2-hydroxybutanoic acid (4I):

[0630] To a stirred solution of ethyl 3-(2,4-difluorophenyl)butanoate (240 mg, 0.983 mmol) in THF : water (10 vol, 1 :1) added LiOH (164.9 mg, 3.930 mmol) at 0 °C. Reaction mixture stirred at 0 °C- ethyl 3-(2,4-difluorophenyl)-2-hydroxybutanoate rt for 4 h. It was quenched with water (3 mL), extracted with EtOAc (2 x 20 mL). Organic layer dried over anhydrous Na2SO4 and concentrated under vacuo to get crude compound-41 (165 mg, 77.67%); m / z (LC-MS): 215.0 [M-H]+.

[0631] 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): Following general procedure for compound-8, compound-4l (160 mg, 0.740 mmol) 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, 250mmX21.1mm, 5µm), Mobile Phase: CO2(A) and IPA: EtOH:MeOH,1:1:1(B), Flow: 50 mL, Isocratic: 90(A):10(B), diluent EtOH : DCM, 1:1, 3 mL, Injection vol, 0.2 mL, run time 22 min, to get Peak-1 (22.2 mg), Peak-2: (23.8 mg); H-NMR (DMSO-d6, 400 MHz): δ 0.89-1.05 (m, 2 H), 1.13 (d, J = 7.2 Hz, 2 H), 1.20-1.23 (m, 2 H), 3.31-3.42 (m, 1 H), 3.94-3.96 (m, 1 H), 4.77 (q, J = 8.8 Hz, 2 H), 5.72 (bs, 1 H), 6.67-6.68 (m, 1 H), 6.85-6.86 (m,, 1 H), 6.98-7.03 (m, 2 H), 7.09-7.15 (m, 1 H), 7.34-7.41 (m, 1 H), 8.57 (s, 1 H), HRMS calculated for: [C21H19ClF5NO3+H]+464.1052; found: 464.1056 (Example 32 peak-1), 464.1050 (Example 32 peak-2). Analytical Chiral SFC: REGIS(S,S) WHELK-01, 4.6 MM x150MM x 5µm, Flow Rate : 3 ml / min, Co-Solvent : 10%, Co-Solvent Name : IPA: EtOH: MeOH (1:1:1), Temperature : 40 °C. Peak-1 (Rt: 5.41, 100% ee), Peak-2: (Rt: 5.8, 100% ee). Example 33: Synthesis of (R)-N-(1-(4-chloro-6-(neopentylamino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide) Synthesis of 4-chloro-N-neopentylpyridin-2-amine: To a sealed tube containing stirred solution of 4-chloro-2-fluoropyridine (1 g, 7.602 mmol) in DMSO (5 mL) added neopentylamine (1.325 g, 15.205 mmol). Resulting reaction mixture heated at 1500C for overnight. After completion of the reaction it was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL), Combined all organic layers washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude material. It was purified further using combi flash (30% EtOAc in Hexane as eluent, 24 g column) to get pure enough 4-chloro-N-neopentylpyridin-2-amine (1.25 g, 82.78%) as yellow solid. m / z (LC-MS): 199.00 [M-H]+. Synthesis of 4-chloro-2-(neopentylamino)pyridine 1-oxide : To a stirred solution of 4-chloro-N-neopentylpyridin-2-amine (1.2 g, 6.038 mmol) in anhydrous DCM (12 mL) at 00C under argon atmosphere added m-CPBA (2.083 g, 12.077 mmol). Resulting reaction mixture stirred at room temperature for 4 h. Reaction mixture was quenched with aq. NaHCCh solution (PH = 8). Reaction mixture was extracted with MeOH : DCM (1 :10, 2 x 15 mL). Organic layer given brine wash dried over anhydrous Na2SO4 and concentrated under vacuo to get crude 4-chloro-2-(neopentylamino)pyridine 1 -oxide 215.00 [M-H]+.

[0632] 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) added triethylamine (14.367 g, 141.984 mmol) followed by trimethylsilylcyanide (14.521 g, 141.984 mmol) at room temperature. Resulting reaction mixture stirred at 80 °C for 16 h. After completion of the reaction, solvent was removed under vacuo, quenched using aq. NaHCCh and extracted with EtOAc (3 x 20 mL). Combined organic layer given brine wash, dried over anhydrous Na2SO4. Combined organic layer concentrated under vacuo to get crude compound which was purified using combiflash chromatography (10-20% EtOAc : Hexane as eluent) to get pure enough 4-chloro-6- (neopentylamino)picolinonitrile (152 mg, 7.67%) (m / z (LC-MS): 224.20 [M-H]+.

[0633] Synthesis of 6-(1-aminocyclopropyl)-4-chloro-N-neopentylpyridin-2-amine (7v):

[0634] Using general procedure for compound-7, 4-chloro-6-(neopentylamino)picolinonitrile (100 mg, 0.447 mmol) converted to crude compound-7v (60 mg, 46.15%) as brown solid, (m / z (LC-MS): 224.20 [M-H]+.

[0635] Example 33: Synthesis of (R)-N-(1-(4-chloro-6-(neopentylamino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide): Following general procedure for compound-8, enantiopure compound-4d (40 mg, 0.185 mmol) converted to crude Example 33 using compound-7v (47 mg, 0.185 mmol). Crude compound purified using combiflash chromatography followed by prep HPLC, Column (X SELECT (250 mm x 20mm), 5.0 µ, Mobile Phase: A = 0.1% HCOOH in water and B = Acetonitrile, Flow: 15 mL / min to get pure compound (4.4 mg, 5.3%); H- NMR (DMSO-d6, 400 MHz): δ 0.85 (s, 9 H), 0.86-0.90 (m, 2 H), 1.23-1.27 (m, 2 H), 1.49 (s, 3 H), 2.70 (dd, J = 13.8 Hz, 2 H), 3.02 (d, J = 6.4 Hz, 2 H), 6.06 (d, J = 1.6 Hz, 2 H), 6.30 (s, 1 H), 6.61-6.63 (m, 1 H), 6.99-7.05 (m 1 H), 7.13-7.19 (m, 1 H), 7.60-7.66 (m, 1 H), 8.56 (s, 1 H), HRMS calculated for: [C23H28ClF2N3O2+H]+452.1916; found: 452.1926, Analytical Chiral HPLC: Column: REGIS(S,S) WHELK-01 (250X4.6mmX5µm), Mobile Phase: (A) n-HEXANE (B) 0.1% HCOOH IN EtOH : MeOH (80:20), Isocratic : 70:30 (A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, (Rt: 4.79, 98.88%). Example 34: Synthesis of (R)-N-(1-(6-((cyclopropylmethyl)amino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 6-((cyclopropylmethyl)amino)picolinonitrile: To a sealed tube containing stirred solution of 6-chloropicolinonitrile (0.5 g, 3.608 mmol) in acetonitrile (5 mL) under argon added DIPEA (0.95 mL, 5.413 mmol) and cyclopropyl methylamine (0.33 g, 4.69 mmol). Resulting reaction mixture heated at 1600C in MW for 3 h. Reaction mixture was concentrated under vacuo, diluted with water and extracted with EtOAc (3 X 15 ml), Combined all organic layers dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford as crude product. Crude product was purified using combiflash (40 g column, 15% EtOAc:Hexane as eluent) to get 6- ((cyclopropylmethyl)amino)picolinonitrile (270 mg, 43.2%), as off white gum. (m / z (LC- MS): 174.10 [M-H]+. Synthesis of 6-(1-aminocyclopropyl)-N-(cyclopropylmethyl)pyridin-2-amine (7w): Using general procedure used for compound-7, 6- ((cyclopropylmethyl)amino)picolinonitrile (200 mg, 1.155 mmol) converted to compound-7w (47 mg, 20.08%) as yellow gum. (m / z (LC-MS): 204.25 [M-H]+. Example 34: Synthesis of (R)-N-(1-(6-((cyclopropylmethyl)amino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: Following general procedure for compound-8, enantiopure compound-4d (50 mg, 0.2313 mmol) converted to crude Example 34 using compound-7w (47 mg, 0.2313 mmol). Crude compound purified using combiflash chromatography followed by prep HPLC, Column (X SELECT (250 mm x 20mm), 5.0 µ, Mobile Phase: A = 0.1% HCOOH in water and B = Acetonitrile, Flow: 15 mL / min to get pure compound (3.5 mg, 5.3%); H-NMR (DMSO-d6, 400 MHz): δ 0.11-0.15 (m, 2 H), 0.35-0.39 (m, 2 H), 0.76-0.82 (m, 2 H), 0.95-0.98 (m, 1 H), 1.23-1.26 (m, 1 H), 1.33-1.36 (m, 1 H), 1.49 (s, 3 H), 2.58 (d, J = 14.4 Hz, 1 H), 2.83 (d, J = 14.4 Hz, 1 H), 2.98-3.00 (m, 2 H), 5.78 (d, J = 7.2 Hz, 1 H), 6.14-6.16 (m, 2 H), 6.34-6.37 (m, 1 H), 6.94-6.98 (m, 1 H), 7.03-7.07 (m, 1 H). 7.18-7.24 (m, 1 H), 7.57-7.64 (m, 1 H), 8.63 (bs, 1 H), HRMS calculated for: [C22H25F2N3O2+H]+402.1993; found: 402.1994.1051, Analytical Chiral HPLC: Column: CHIRALPAK-IK 250X4.6mm, 5,0µm, Mobile Phase: (A) D)0.1% DEA IN n-Hexane: ETHNAOL: DCM (60:20:20), Isocratic : (C) 100%;Flow : 1.0ml / min, Column Temp : 25°C, Inj. volume: 5.000, (Rt: 4.55, 99.13%). Example 35: Synthesis of (R)-N-(1-(4-chloro-6-(isopropylamino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 4-chloro-N-neopentylpyridin-2-amine: To a sealed tube containing stirred solution of 4-chloro-2-fluoropyridine (1 g, 7.602 mmol) in DMSO (5 mL) added isopropylamine (0.654 mL, 7.602 mmol). Resulting reaction mixture heated at 1500C for 8 h. After completion of the reaction, added water and extracted with EtOAc (3 x 20 mL), Combined all organic layers washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude material. It was purified further using combi flash (10% Ethyl acetate in Hexane as eluen, 24 g column) to get pure enough 4-chloro-N-neopentylpyridin-2-amine (1.1 g, 85.26%) as colourless liquid. m / z (LC-MS): 171.15 [M-H]+. Synthesis of 4-chloro-2-(isopropylamino)pyridine 1-oxide: To a stirred solution of 4-chloro-N-neopentylpyridin-2-amine (1.1 g, 6.446 mmol) in anhydrous DCM (12 mL) at 0 °C under argon atmosphere added m-CPBA (2.225 g, 12.892 mmol). Resulting reaction mixture stirred at room temperature for 3 h. Reaction mixture was quenched with aq. NaHCCh solution (PH = 8). Reaction mixture was extracted with MeOH: DCM (1 :10, 2 x 15 mL). Organic layer given brine wash dried over anhydrous Na2SO4 and concentrated under vacuo to get crude 4-chloro-2-(isopropylamino)pyridine 1-oxide

[0636] 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) added triethylamine (1.87 mL, 40.184 mmol) followed by trimethylsilylcyanide (5.35 mL, 40.184 mmol) at room temperature. Resulting reaction mixture stirred at 80 °C for 16 h. After completion of the reaction, solvent was removed under vacuo, quenched using aq. NaHCOs and extracted using EtOAc (3 x 10 mL). Combined organic layer given brine wash. Organic layer dried over anhydrous Na2SO4. and concentrated under vacuo to get crude compound which was purified using combiflash chromatography (24 g column, 0-15% EtOAc: Hexane as eluent) to get pure enough 4-chloro-6- (isopropylamino)picolinonitrile (209 mg, 39.88%) (m / z (LC-MS): 195.95 [M-H]+.

[0637] Synthesis of 6-(1-aminocyclopropyl)-4-chloro-N-isopropylpyridin-2-amine (7x):

[0638] To a solution of 4-chloro-6-(isopropylamino)picolinonitrile (100 mg, 0.511 mmol) in anhydrous diethylether (2 mL) added Ti(OiPr)4 (0.470 mmol, 1.533 mmol), at -78 °C followed by dropwise addition of EtMgBr (3 M in Et20, 0.852 mL, 2.555 mmol). Resulting reaction mixture stirred for 2 h and quenched using BF3:Et2O (2 eq). After overnight stirring added 1 N HCI and extracted reaction mixture with Et20. Aq. layer basified and extracted with Et20. Organic layer obtained after basification given brine wash, dried over anhydrous Na2SO4 and concentrated under vacuo to get crude compound-7x (100 mg, 86.95%) as orange gum. (m / z (LC-MS): 226.05 [M-H]+. Example 35: Synthesis of (R)-N-(1-(4-chloro-6-(isopropylamino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: Following general procedure for compound-8, enantiopure compound-4d (96 mg, 0.443 mmol) converted to crude Example 35 using compound-7x (100 mg, 0.443 mmol). Crude compound purified using combiflash chromatography followed by prep HPLC, Column (X SELECT (250 mm x 20mm), 5.0 µ, Mobile Phase: A = 0.02% NH4OH in water and B = Acetonitrile, Flow: 15 mL / min to get pure compound (15 mg, 8%); H- NMR (DMSO-d6, 400 MHz): δ 0.82-0.88 (m, 2 H), 1.08 (d, J = 6.50 Hz, 6 H), 1.31-1.35 (m, 2 H), 1.51 (s, 3 H), 2.64 (d, J = 14.38 Hz, 1 H), 2.83 (d, J = 14.38 Hz, 1 H), 3.78- 3.83 (m, 1 H), 6.07-6.10 (m, 2 H), 6.19 (d, J = 1.63 Hz, 1 H), 6.49 (d, J = 7.13 Hz, 1 H), 7.01-7.06 (m, 1 H), 7.14-7.17 (m, 1 H), 7.61-7.67 (m, 1 H), 8.58 (s, 1 H), HRMS calculated for: [C21H24ClF2N3O2+H]+424.1603; found: 424.1607, Analytical Chiral HPLC: Column: REGIS(S,S) WHELK-01 (250X4.6mmX5µm, Mobile Phase : (A) n- HEXANE (B) 0.1% HCOOH IN EtOH : MeOH (80:20), Isocratic : 70:30(A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, (Rt: 5.03, 97.81%). Example 36: (R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)cyclopropyl)- 3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 2-chloro-6-((2,2,2-trifluoroethyl)amino)isonicotinonitrile (6y): To a stirred solution of 2,6-dichloroisonicotinonitrile (1.0 g, 5.7803 mmol) in anhydrous DMSO (10 mL) was added N,N-Diisopropyl ethylamine (2.51 mL, 14.4507 mmol) and 2,2,2-Trifluoroethylamine (0.57 g, 5.7803 mmol) at room temperature. Resulting reaction mixture stirred at 100 °C for 16 h. Reaction was quenched using ice cold water and extracted using EtOAc (3 x 20 mL). Combined Organic layer given brine wash and dried over anhydrous Na2SO4. Organic layer removed under vacuo to get crude product which was purified by flash chromatography (EtOAc:Hexane 20:80) as eluent to get 2-chloro-6-((2,2,2-trifluoroethyl)amino)isonicotinonitrile 6y (0.75 g, 54.17%) as brownish solid; m / z (LC-MS): 235.90 [M+H]+. 4-(1-aminocyclopropyl)-6-chloro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (7y): 2-chloro-6-((2,2,2-trifluoroethyl)amino)isonicotinonitrile 6y (0.1 g, 0.4245 mmol) converted to compound-7y (60 mg, Crude) using general procedure used for compound-7, m / z (LC-MS): 264.9 [M+H]+. Example 36: (R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: Following general procedure 8, enantiopure compound-4d (0.03 g, 0.1129 mmol) converted to Example 36 using compound-7y which was subsequently purified by prep HPLC. Mobile Phase:A= 0.2%HCOOH IN WATER, B= Acetonitrile, Column: X SELECT (250mmx20.0mm), 5.0µ, Flow: 15ml / min; Gradient Programmer: Time %B,0 30,130, 870 as Off white solid; 1H NMR (400 MHz, CDCl3) δ ppm 0.85-0.98 (m, 1 H), 1.10-1.30 (m, 6 H), 2.71 (d, J = 14.5 Hz, 1 H), 3.01 (d, J = 14.5 Hz, 1 H), 3.99-4.07 (m, 2 H), 4.37 (t, J = 6.31 Hz, 1 H), 5.4 (s, 1 H), 5.7 (d, J = 1.17 Hz, 1 H), 6.08 (s, 1 H), 6.14 (s, 1 H), 6.78-6.83 (m, 1 H), 6.89-6.95 (m, 1 H), 7.69-7.7573 (m, 1 H), HRMS calculated for: [C20H19ClF2N3O2+H]+464.1164; found: 464.1177; Analytical Chiral HPLC: Column: REGIS(S,S) WHELK-01 (250X4.6mmX5µm, Mobile Phase : (A) n- HEXANE (B) IPA : MeOH (50:50), Isocratic : 90 : 10 (A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, (Rt: 16.54, 95.34%). Example 37: Synthesis of N-(1-(6-chloropyridin-2-yl)cvclopropyl)-3-(2,4-difluorophenyl)- 3-hydroxybutanamide

[0639] Synthesis of 1-(6-chloropyridin-2-yl)cyclopropan-1 -amine (7t)

[0640] To a solution of 6-chloropicolinonitrile (5 g, 36.086 mmol) in anhydrous diethyl ether (50 mL) added Ti(OiPr)4 (12.18 mL, 39.70 mmol), at -78 °C followed by dropwise addition of EtMgBr (3 M in Et20, 30.07 mL, 90.2126 mmol). Resulting reaction mixture stirred for 2 h and quenched using BF3:Et2O (4.233 mL, 36.086 mmol). After overnight stirring added 1 N HCI and extracted reaction mixture with Et20. Aq. layer basified and extracted with Et20. Organic layer obtained after basification using 2 N NaOH, given brine wash, dried over anhydrous Na2SO4 and concentrated under vacuo to get crude compound-7t which was purified using combiflash chromatography (24 g column, 30% EtOAc : Hexane) to get pure enough compound-7t (470 mg, 7.8%) as yellow solid. H- NMR (DMSO-d6, 300 MHz): 5 0.99 1.00 (m, 2 H), 1.16-1.17 (m, 2 H), 7.17-7.21 (m, 1 H), 7.72-7.80 (m, 2 H),

[0641] Synthesis of N-(1 -(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide:

[0642] Following general procedure for compound-8, compounded (150 mg, 0.694 mmol) converted to crude N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide using compound-7t (117 mg, 0.694 mmol). Crude compound purified using combiflash chromatography (30% EtOAc: Hexane as eluent) to get pure enough N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide (130 mg, 51.08%) as brownish gummy.

[0643] Example 37: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2- trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide To sealed tube containing a stirred solution of N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3- (2,4-difluorophenyl)-3-hydroxybutanamide (100 mg, 0.273 mmol) in dioxane : DME (1 mL, 1:1) added Cs2CO3(222 mg, 0.682 mmol) followed by 2,2,2-Trifluoroethylamine hydrochloride (55.4 mg, 0.409 mmol). Resulting reaction mixture purged with argon for 15 min. then added XPhos-Pd-G2(21.5 mg, 0.0273 mmol) and again purged with argon for 5 min. Reaction mixture heated at 1100C for 16 h. After completion of the reaction added water and extracted with EtOAc (3 x 5 mL). All organic layers dried given brine wash and over anhydrous Na2SO4and concentrated under vacuo to get crude compound which was purified using prep HPLC (X-SELECT (C18 , 21.2mm X 150mm), Eluent: 0.1% HCOOH IN WATER (A) and Acetonitrile (B), Flow: 18 mL / min to get pure enough racemic compound (25 mg, 21.34%) which was further purified using chiral HPLC, (CHIRALPAK IH, 250mmX21mm, 5µm), Eluent: n-Hexane(A) and IPA : MeOH 1:1 (B), Isocratic; 85 (A): 15 (B), Flow: 15 mL / min, Injection vol, 0.6 mL, run time 20 min, to get Peak-1 (14 mg), Peak-2: (13 mg); H-NMR (DMSO-d6, 400 MHz): δ 0.80-.0.85 (m, 2 H), 1.23-1.38 (m, 2 H), 1.49 (s, 3 H), 2.60 (dd, J = 13.8 Hz, 2 H), 3.95-4.05 (m, 2 H), 5.92 (d, J = 7.2 Hz, 1 H), 6.12 (bs, 1 H), 6.30 (d, J = 8 Hz, 1 H), 6.96-7.00 (m, 1 H), 7.05-7.09 (m, 2 H), 7.19-7.25 (m, 1 H), 7.58-7.64 (m, 1 H), 8.65 (bs, 1 H), HRMS calculated for: [C20H20F5N3O2+H]+430.1554; found: 430.1564 (Example 37 peak-1), 430.1559 (Example 37 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (150X4.6mmX5µm), Mobile Phase: (A) n-HEXANE (B) 0.1% HCOOH IN EtOH : MeOH (80:20) Isocratic : 90:10 (A:B) Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 10.000, Peak-1 (Rt: 5.87, 100% ee), Peak-2: (Rt: 9.60, 100% ee). Example 38: Synthesis of (R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Synthesis of 4-chloro-N-(2,2,2-trifluoroethyl)pyridin-2-amine To a sealed tube containing stirred solution of 4-chloro-2-fluoropyridine (1 g, 7.602 mmol) in DMSO (5 mL) added 2,2,2-trifluoroethan-1-amine (0.72 mL, 9.123 mmol). Resulting reaction mixture heated at 1500C for 4 h. After completion of the reaction, added water and extracted with EtOAc (3 x 20 mL), Combined all organic layers washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude material. It was purified further using combiflash (10% EtOAc in Hexane as eluent, 24 g column) to get pure enough 4-chloro-N-(2,2,2- trifluoroethyl)pyridin-2-amine (150 mg, 9.36%) as white solid. m / z (LC-MS): 211.05 [M- H]+. 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)pyridin-2-amine (150 mg, 0.712 mmol) in anhydrous DCM (2 mL) at 00C under argon atmosphere added m-CPBA (0.246 g, 1.425 mmol). Resulting reaction mixture stirred at room temperature for 3 h. Reaction mixture was quenched with aq. NaHCO3solution (PH = 8). Reaction mixture was extracted with MeOH : DCM (1:10, 2 x 5 mL). Organic layer given brine wash dried over anhydrous Na2SO4and concentrated under vacuo to get crude 4-chloro-2-((2,2,2- trifluoroethyl)amino)pyridine 1-oxide (145 mg); m / z (LC-MS):227.10 [M-H]+. 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) added triethylamine (1.43 mL, 10.24 mmol) followed by trimethylsilylcyanide (1.41 mL, 10.24 mmol) at room temperature. Resulting reaction mixture stirred at 800C for 16 h. After completion of the reaction, solvent was removed under vacuo, quenched using aq. NaHCO3and extracted using EtOAc (3 x 5 mL). Combined organic layer given brine wash, dried over anhydrous Na2SO4 .Combined organic layer concentrated under vacuo to get crude compound which was purified using combiflash chromatography (4 g column, 0-15% EtOAc : Hexane as eluent) to get pure enough 4-chloro-6-(isopropylamino)picolinonitrile (69 mg, 39.78%) (m / z (LC- MS): 234.00 [M-H]+. Synthesis of 6-(1-aminocyclopropyl)-4-chloro-N-(2,2,2-trifluoroethyl)pyridin-2- amine (7z) To a solution of 4-chloro-6-(isopropylamino)picolinonitrile (50 mg, 0.212 mmol) in anhydrous diethyl ether (2 mL) added Ti(OiPr)4(0.098 mmol, 0.318 mmol),at -780C followed by dropwise addition of EtMgBr (3 M in Et2O, 0.14 mL, 0.414 mmol). Resulting reaction mixture stirred for 2 h at room temperature and quenched using BF3:Et2O (0.033 mL, 0.424 mmol). After overnight stirring added 1 N HCl and extracted reaction mixture with Et2O. Aq. layer basified and extracted with Et2O. Organic layer obtained after basification given brine wash, dried over anhydrous Na2SO4and concentrated under vacuo to get crude compound-7z (30 mg, 53.56%) as brownish solid, (m / z (LC-MS): 266.05 [M+H]+. Example 38: Synthesis of (R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin- 2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide Following general procedure for compound-8, enantiopure compound-4d (24 mg, 0.113 mmol) converted to crude Example 38 using compound-7z (30 mg, 0.113 mmol). Crude compound purified by prep HPLC, Column (X-BRIDGE (C18, 20mm X 150mm), Mobile Phase: A = 0.1% HCOOH in water and B = Acetonitrile, Flow: 16 mL / min to get pure compound (2.1 mg, 4.03%) as off white solid; H-NMR (DMSO-d6, 400 MHz): δ 0.89-093 (m, 2 H), 132-1.36 (m, 2 H), 1.50 (s, 3 H), 2.66 (d, J = 14 Hz, 1 H), 2.80 (d, J = 14 Hz, 1 H), 3.98-4.07 (m, 2 H), 6.03 (s, 1 H), 6.26 (d, J = 1.2 Hz, 1 H), 6.39 (d, J = 1.2 Hz, 1 H), 7.01-7.05 (m, 1 H), 7.13-7.20 (m, 1 H), 7.26-7.30 (m, 1 H), 7.61-7.67 (m, 1 H), 8.59 (s, 1 H), HRMS calculated for: [C20H19ClF5N3O2+H]+464.1164; found: 464.1177; Analytical Chiral HPLC: Column: REGIS(S,S) WHELK-01 (250X4.6mmX5µm, Mobile Phase : (A) n-HEXANE (B) 0.1%HCOOH IN ETHANOL : METHANOL(80:20) Isocratic : 70 : 30 (A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, (Rt: 4.88, 98.15%). Example 39: Synthesis of 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2- trifluoroethoxy)pyridin-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) was added K2CO3(39.89 g, 288.6905 mmol) and 2,2,2-trifluoroethan-1-ol (3.61g, 267.0387 mmol) at RT. Resulting reaction mixture stirred at 60 °C for 24 h. Reaction was quenched using ice cold water and extracted using EtOAc (3 x 500 mL). Combined Organic layer given brine wash and dried over anhydrous Na2SO4. Organic layer removed under vacuo to get crude product which was purified by flash chromatography (EtOAc:Hexane 5:95) as eluent to get 2-(2,2,2- trifluoroethoxy)isonicotinonitrile (11.5 g, 79.3%) as off white crystalline solid; m / z (LC- MS): 202.90 [M+H]+. 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropan-1-amine (7aa): 2-(2,2,2-trifluoroethoxy)isonicotinonitrile (6 g, 29.6833 mmol) converted to compound- 7aa (5.1 g, 64.55%) using general procedure used for compound-7. After basification using NaHCO3, compound extracted as free base, m / z (LC-MS): 233.00 [M+H]+. Example 39: Synthesis of 3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2- trifluoroethoxy)pyridin-2-yl)cyclopropyl)butanamide (Example 39 peak-1 & Example 39 peak-2): Following general procedure 8, compound-4j (0.11 g, 0.5088 mmol) converted to Example 39 (175 mg, 80.19%) using compound 7aa (0.141 g, 0.610 mmol). The products were separated using Chiral prep HPLC, Column: CHIRALPAK IH, 250mmX20mm,5µm; Mobile Phase :n-Hexane(A) and 10mM ;Ammonia in IPA:EtOH(1:1)(B); Flow :15 ml, Isocratic : 90(A) : 10(B), Diluents: EtOH : DCM, 1:1, 3ml, Injection: Volume-0.4 ml; Run Time-21 min; to get Peak-1 (63.8 mg, Rt: 5.41) Peak-2: (55.3 mg, Rt: 7.47).1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-0.98 (m, 2 H), 1.35-1.48 (m, 2 H), 1.66 (s, 3 H), 2.72 (d, J = 14.53 Hz, 1 H), 2.92 (d, J = 14.53 Hz, 1 H), 4.86 (q, J = 9.15 Hz, 2 H), 5.84 (s, 1 H), 6.45 (d, J = 7.48 Hz, 1 H), 6.65 (d, J = 8.22 Hz, 1 H), 6.99-7.04 (m, 2 H), 7.35-7.39 (m, 1 H), 7.42-7.46 (m, 1 H), 8.75 (bs, 1 H); HRMS calculated for: [C20H19F5N2O3+H]+431.1394; found: 431.1402 (Example 39 peak-1), 431.1395 (Example 39 peak-2). Analytical Chiral HPLC: REGIS(S,S) WHELK-01 (250X4.6mmX5µm), Mobile Phase: (A) n-HEXANE (B) 0.1% HCOOH IN EtOH : MeOH (80 : 20), Isocratic : 70:30 (A:B) Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 10.000, Peak-1 (Rt: 4.55, 100% ee), Peak-2: (Rt: 4.40, 100% ee). Example 40: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2- trifluoroethoxy)pyridin-2-yl)cyclopropyl)butanamide Example 40: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2- trifluoroethoxy)pyridin-2-yl)cyclopropyl)butanamide (Example 40 peak-1 & Example 40 peak-2): Following general procedure 8, Compound-4d (0.25 g, 1.1564 mmol) converted to Example 40 (220 mg, 44.89%) using compound 7aa (0.295 g, 1.272 mmol). The products were separated using Chiral prep HPLC, Column: Chiralpak IH,250mmX20mm, 5µm, Mobile Phase : n-Hexane(A) and 0.1%HCOOH in IPA:MeOH (1:1)(B), Flow :15ml ,Isocratic :80(A):20(B), Diluents: EtOH:DCM,1:1,3.5.ml, Injection: Volume-0.2ml, Run Time-10min, Instrument Make and Model: Agilent-1200 Series, to get Peak-1 (101 mg, Rt: 2.13) Peak-2: (90 mg, Rt: 2.63).1H NMR (400 MHz, DMSO- d6) δ 0.87-1.02 (m, 2 H), 1.34-1.48 (m, , 2 H), 1.51 (s, 3 H), 2.66 (d, J = 14.4 Hz, 1 H), 2.85 (d, J = 14.4 Hz, 1 H), 4.88 (q, J = 9.1 Hz, 2H), 6.06 (s, 1 H), 6.39 (d, J = 7.6 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 7.06-7.11 (m, 1 H), 7.20-7.27 (m, 1 H), 7.40-7.44 (m, 1 H), 7.61-7.66 (m, 1 H), 8.73 (s, 1 H); HRMS calculated for: [C20H19F5N2O3+H]+431.1394; found: 431.1404 (Example 40 peak-1), 431.1406 (Example 40 peak-2). Analytical Chiral HPLC: REGIS(S,S) WHELK-01 (250X4.6mmX5µm), Mobile Phase: (A) n- HEXANE (B) 0.1% HCOOH IN ETHANOL : METHNAOL(80:20), Isocratic : 70:30 (A:B) Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. 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). Example 41: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6- (trifluoromethyl)pyridin-2-yl)cyclopropyl)butanamide 1-(6-(trifluoromethyl)pyridin-2-yl)cyclopropan-1-amine (7ab): 2-Cyano-6-trifluoromethylpyridine (0.8 g, 4.648 mmol) converted to compound-7ab (300 mg, 32.25 %) using general procedure used for compound-7, m / z (LC-MS): 202.18 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 1.03-1.06 (m, 2 H), 1.22-1.24 (m, 2 H), 2.78 (bs, 2 H), 7.59-7.61 (dd, J = 1.2 Hz & 7.6 Hz, 1H), 8.00-8.06 (m, 2H). Example 41: Synthesis of 3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6- (trifluoromethyl)pyridin-2-yl)cyclopropyl)butanamide (Example 41 peak-1 & Example 41 peak-2 ): Following general procedure 8, Compound-4d (100 mg, 0.462 mmol) converted to Example 41 (105 mg, 56.75% yield) using compound 7ab (0.093 mg, 0.462 mmol). The products were separated using chiral prep HPLC; Column: Chiralpak IH, 250mmX21mm, 5µm, Eluent: A: n-Hexane, B: 10mM Ammonia in IPA : MeOH (1:1), Flow: 15 ml / min, Isocratic: 90(A):10(B) to get Peak-1 (36 mg, Rt: 3.44), Peak-2: (40 mg, Rt: 5.75).1H NMR (400 MHz, DMSO-d6) δ 0.981.07 (m, 2 H), 1.32-1.44 (m, 2 H), 1.52 (s, 3 H), 2.69 (d, J = 14.4 Hz, 1 H), 2.85 (d, J = 14.4 Hz, 1 H), 5.98 (s, 1 H), 7.06- 7.12 (m, 2 H), 7.19-7.26 (m, 1 H ), 7.59- 7.67 (m, 2 H), 7.73-7.77 (m, 1 H), 8.82 (bs, 1 H), HRMS: 401.00 [M+H]+, HRMS calculated for: [C19H17F5N2O2+H]+401.1288; found: 401.1296 (Example 41 peak-1), 401.1295 (Example 41 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (250X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) 0.1% NH4OH IN IPA : EtOH : MeOH (1:1:1), Flow : 1.0 ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, Peak-1 (Rt: 3.40, 100% ee) Peak-2: (Rt: 5.66, 100% ee). 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 ): Following general procedure for compound-8, compound-4e (59.2 mg, 0.298 mmol) converted to crude Example 42 using compound 7n (70 mg, 0.249 mmol). The products were purified using prep HPLC Column: X SELECT (250mmx20.0mm), 5.0 µ Mobile Phase: A = 0.1% HCOOH in water and B = Acetonitrile, Flow: 15 mL / min to get pure compound (11 mg, 9.64%) as brownish solid, which was separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5µm), Eluent: n-Hexane (A) and IPA : EtOH : MeOH,1:1:1 (B), Flow: 15 ml / min, Isocratic: 85(A):15(B), diluent EtOH : DCM (1:1, 2 ML), Injection volume-0.3 mL, run time 11 min, to get Peak-1 (2.5 mg, Rt: 3.03, 100% ee) Peak-2: (1.1 mg, Rt: 3.99, 100% ee) as off white solid; H-NMR (CDCl3, 400 MHz): δ 0.99-1.33 (m, 4 H), 1.49 (s, 3 H), 2.66 (s, 2 H), 4.28-4.35 (m, 2 H), 4.85 (s, 1 H), 6.24 (bs, 1 H), 6.50 (t, J = 56.4 Hz, 1 H), 6.80 (s, 1 H), 6.83-6.85 (m, 2 H), 6.94- 6.99 (m, 2 H), 7.35-7.38 (m, 2 H), HRMS calculated for: [C22H21F6NO3+H-H2O]+ 444.1398; found: 444.1399 (Example 42 peak-1), 444.1406 (Example 42 peak-2). Analytical chiral HPLC; Column : CHIRALPAK-IH(150X4.6mmX5µm) Mobile Phase : (A) n-HEXANE (B)IPA : MeOH (50:50), Isocratic : 85:15 (A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 10.000. Peak-1 (Rt: 3.03, 100% ee) Peak-2: (Rt: 3.99, 100% ee) 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 ): Following general procedure for compound-8, compound-4e (119 mg, 0.602 mmol) converted to Example 43 using compound 7g (150 mg, 0.602 mmol). The products were purified using combiflash (20% EtOAc : Hexane, 4 g column) to get pure compound (120 mg, 46.51%) as yellowish solid, which was separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21 mm, 5µm), Eluent: n-Hexane(A) and IPA: MEOH (1:1) (B), Flow: 15 ml / min, Isocratic: 93(A):07(B), diluent EtOH:DCM, 1:1, 3.5 mL, Injection vol, 0.35 mL, run time 18 min, to get Peak-1 (33.6 mg, Rt: 3.18, 100% ee) Peak-2: (46.5 mg, Rt: 3.21, 100% ee), H-NMR (DMSO-d6, 400 MHz): δ 0.74-0.81 (m, 2 H), 1.01-1.04 (m, 2 H), 1.36 (s, 3 H), 2.55 (dd, J = 14 Hz, 2 H), 4.75 (q, J = 8.8 Hz, 2 H), 5.59 (s, 1 H), 6.97-7.04 (m, 4 H), 7.08-7.11 (m, 1 H), 7.32-7.37 (m, 2 H), 8.54 (s, 1 H), HRMS calculated for: [C21H20F5NO3+H-H2O]+412.1330; found: 412.1338 (Example 43 peak-1), 412.1344 (Example 43 peak-2). Chiral HPLC Column : CHIRALPAK-IH (150X4.6mmX5µm), Mobile Phase : (A) n-HEXANE (B)IPA: MeOH (50:50), Isocratic : 85:15(A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25 °C, Inj. volume: 5.000. Peak-1 (Rt: 3.18, 100% ee) Peak-2: (Rt: 3.21, 100% ee) Example 44: Synthesis of (R)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: Synthesis of ((R)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: To a solution of Example-28 (40 mg, 0.0997 mmol) in dioxane : DME (1:1, 1 mL) added Cs2CO3(81.2 mg, 0.249 mmol),at rt followed by 2,2,2-Trifluoroethylamine.HCl Salt (20.3 mg, 1.495 mmol). Resulting reaction mixture purged with argon for 15 min then added XPhosPdG2 (7.9 mg, 0.01 mmol). Resulting reaction mixture again purged with argon for 5 min and heated at 1100C for 16 h. After completion of the reaction added water and extracted with EtOAc, Combined all organic layers washed with brine and dried over anhydrous Na2SO4.Organic layer concentrated under reduced pressure to get crude compound which was purified using prep HPLC, Gemini NX (250mmx21.2mm), 5.0µ, (A) 10 Mm (NH4)HCO3in water (B) Acetonitrile, Flow: 18 mL / min to get pure ((R)-N-(1-(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide (3.3 mg, 7.14%) as off white solid; H-NMR (DMSO-d6, 400 MHz): δ 0.79-0.82 (m, 2 H), 1.24-1.25 (m, 2 H), 1.52 (s, 3 H), 2.68 (s, 2 H), 4.00-4.06 (m, 2 H), 5.91 (bs, 1 H), 6.56 (bs, 1 H), 6.64-6.66 (m, 1 H,), 7.02-7.06 (m, 1 H), 7.15-7.19 (m, 1 H), 7.22-7.26 (m, 1 H), 7.58-7.64 (m, 1 H), 8.58 (bs, 1 H), HRMS calculated for: [C20H19ClF5N3O2+H]+464.1164; found: 464.1174; Analytical Chiral HPLC: Column: REGIS(S,S) WHELK-01 (250X4.6mmX5µm, Mobile Phase : (A) n-HEXANE (B) 0.1%HCOOH IN EtOH : MeOH (80:20), Isocratic : 70 : 30 (A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, (Rt: 4.47, 98.91%). Example 45: Synthesis of (R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: Example 45: Synthesis of (R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)-3-(2,4-difluorophenyl)-3-hydroxybutanamide: To a solution of Example 28 (40 mg, 0.0997 mmol) in anhydrous DMF (1 mL) added K2CO3 (13.8 mg, 0.249 mmol), at rt followed by 2,2,2-Trifluoroethanol (25 mg, 1.495 mmol). Resulting reaction mixture heated at 800C for 16 h. After completion of the reaction added water and extracted with EtOAc, Combined all organic layers washed with brine and dried over anhydrous Na2SO4.Organic layer concentrated under reduced pressure to get crude compound which was purified using prep HPLC, Gemini NX (250mmx21.2mm), 5.0µ, (A) 10 Mm (NH4)HCO3in water (B) Acetonitrile : MeOH, Flow: 18 mL / min to get pure compound (7.7 mg, 16.%) as off white solid; H-NMR (DMSO-d6, 400 MHz): δ 0.93-1.01 (m, 2 H), 1.29-1.35 (m, 2 H), 1.52 (s, 3 H), 2.70 (dd, J = 14 Hz, 2 H), 4.87-4.94 (m, 2 H), 5.94 (bs, 1 H), 6.77 (d, J = 2 Hz, 1 H), 6.96-7.00 (m, 1 H), 7.09 (d, J = 2 Hz, 1 H), 7.10-7.15 (m, 1 H), 7.59-7.65 (m, 1 H), 8.61 (bs, 1 H), HRMS calculated for: [C20H18ClF5N2O3+H]+465.1004; found: 465.1015; Analytical Chiral HPLC: Column: REGIS(S,S) WHELK-01 (250X4.6mmX5µm, Mobile Phase : (A) n-HEXANE (B) 0.1%HCOOH IN EtOH : MeOH (80:20), Isocratic : 70 : 30 (A:B), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, (Rt: 4.62, 99.38%). Example 46: Synthesis of N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indol-4-yl)butanamide: Synthesis of ethyl 3-hydroxy-3-(1-methyl-1H-indol-4-yl)butanoate: 1-(1-methyl-1H-indol-4-yl)ethan-1-one (0.1 g, 2.30 mmol) 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]+. oxy-3-(1-methyl-1H-indol-4-yl)butanoic acid (4m): methyl-1H-indol-4-yl)butanoate (0.15 g, 0.57 mmol) hydrolysed to using general procedure used for compound-4, m / z (LC-MS): Example 46: Synthesis of N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1H-indol-4-yl)butanamide (Example 46 peak-1 & Example 46 peak-2 ): By ffollowing general procedure for compound-8, compound-4m (120 mg, 0.514 mmol) converted to Example 46 using compound 7s (100 mg, 0.249 mmol). The products were purified using prep HPLC Column: REGIS(S,S) WHELK-01 (250X4.6mmX5µm), Eluent: n-Hexane(A) and IPA : MeOH 1:1 (B), Flow: 1 mL / min, Isocratic: 70(A):30(B), diluent: EtOH, Injection vol, 5 mL, run time 15 min, to get Peak-1 (25.5 mg), Peak-2: (23.3 mg);1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-94 (m, 2 H), 1.13-1.24 (m, 2 H), 1.58 (s, 3 H), 2.83 (q, J = 14 Hz, 2 H), 3.76 (s, 3 H), 4.75 (q, J = 8.8 Hz, 2 H), 5.70 (bs, 1 H), 6.63 (s, 1 H), 6.68 (d, J = 2.8 Hz, 1H), 6.77 (bs, 1 H), 6.94 (s, 1 H), 7.06-7.12 (m, 2 H), 7.28-7.31 (m, 2 H), 8.53 (bs, 1 H); HRMS : m / z (LC-MS): 430.05 [M+H]+. HRMS calculated for: [C24H24ClF3N2O3+H-H2O]+463.1400; found: 463.1403 (Example 46 peak-1), 463.1405 (Example 46 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH (250X4.6mmX5µm) Mobile Phase: (A) n-HEXANE (B) IPA : MeOH (70:30), Flow : 1.0ml / min Diluent : EtOH, Column Temp : 25°C, Inj. volume: 5.000, Peak-1 (Rt: 8.406, 100% ee) Peak-2: (Rt: 7.529, 100% ee). Example 47: (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-4-yl)cyclopropyl)butanamide Synthesis of Methyl 1-(2-chloropyrimidin-4-yl)cyclopropane-1-carboxylate: To a stirred solution of methyl 2-(2-chloropyrimidin-4-yl)acetate (1 g, 5.399 mmol) in anhydrous N,N-Dimethylformamide (10 mL) was added Sodium hydroxide (5.399 mmol), at room temperature under argon atmosphere. Stirred the reaction mixture for 20 min then added 1,2-dibromoethane (0.924 mL, 10.72 mmol) at room temperature. Resulting reaction mixture stirred fat room temperature for 4 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtAOc (3 x 20 mL), to get crude compound which was purified using combi flash chromatography (EtOAc : Hexane, 3:7 as eluent) to get Methyl 1-(2-chloropyrimidin-4-yl)cyclopropane-1-carboxylate (580 mg, 51.32%) as colourless liquid, m / z (LC-MS): 212.90 [M+H]+. Synthesis of 1-(2-chloropyrimidin-4-yl)cyclopropane-1-carboxylic acid: To stirred solution of Methyl 1-(2-chloropyrimidin-4-yl)cyclopropane-1-carboxylate (0.580 g, 2.7276 mmol) in Tetrahydrofuran at 00C was added aqueous Lithium Hydroxide Monohydrate dropwise (1 ml), and reaction mixture was maintain same temperature 10 mins. Reaction mixture then allowed to stir at room temperature for 4. The reaction mixture was diluted with water and extracted with EtOAc (3 x 5 mL) to remove impurities. Aqueous was acidified by 1N HCl and extracted with EtOAc, then the organic layer was washed with water (3 x 5ml), to get crude 1-(2-chloropyrimidin-4- yl)cyclopropane-1-carboxylic acid (0.390 g, 72.08%), m / z (LC-MS): 199.15 [M+H]+. Synthesis of 1-(2-chloropyrimidin-4-yl)cyclopropane-1-carboxamide: To a stirred solution of 1-(2-chloropyrimidin-4-yl)cyclopropane-1-carboxylic acid (0.390 g, 1.9637 mmol) in N,N-dimethylformamide at 00C, was added DIPEA (1.03 mL, 5.90 mmol) and HATU (1.12 g, 2.945 mmol). Resulting reaction mixture was stirred for 30 mins under argon atmosphere then added Ammonium chloride (1.072 g, 19.64 mmol). Resulting homogeneous brown solution was stirred at room temperature for 4 h under argon atmosphere. The reaction mixture was quenched with ice cold water and extracted with EtOAc (3 x 10 mL). Combined all organic layers washed with brine to get crude compound which was purified using combi flash chromatography (EtOAc : Hexane as eluent) to get 1-(2-chloropyrimidin-4-yl)cyclopropane-1 -carboxamide (0.210 197.95 [M+H]+.

[0644] Synthesis of tert-butyl (1 -(2-chloropyrimidin-4-yl)cyclopropyl)carbamate:

[0645] To stirred solution of 1-(2-chloropyrimidin-4-yl)cyclopropane-1 -carboxamide (100 mg, 0.506 mmol) in t-Butanol (10 vol) added Lead Tetraacetate (0.673 g, 1.518 mmol) was added under argon atmosphere. Resulting reaction mixture was heated at 70 °C for 6 h, The reaction mass was monitored by TLC. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate (3 x 5 mL). Organic layer collected given brine wash and dried over anhydrous Na2SO4. Organic layer concentrated and crude compound purified using combi flash chromatography (EtOAc: Hexane as eluent, 20% EtOAc in Hexane) to get tert-butyl (1-(2-chloropyrimidin-4-yl)cyclopropyl)carbamate (70 mg, 51.475), m / z (LC-MS): 269.95 [M+H]+.

[0646] Synthesis of tert-butyl (1 -(2-((2,2,2-trifluoroethyl)amino)pyrimidin-4- yl)cyclopropyl)carbamate:

[0647] To a sealed tube containing stirred solution of tert-butyl (1-(2-chloropyrimidin-4- yl)cyclopropyl)carbamate (50 mg, 0.1854 mmol) in Toluene : Dioxane (1:1, 1 mL) added Cs2CO3 (121 mg, 0.371 mmol), XANTPHOS (10.7 mg, 0.0185 mmol). Resulting reaction mixture purged with argon for 10 mins, then added 2,2,2-Trifluoroethylamine (0.022 g, 0.222 mmol) and Pd(OAc)2(4.2 mg, 00185 mmol). Reaction mixture was purged with argon again for 5 min and heated 80 °C at 5 h. The reaction mass was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc (3 x 5 mL). Combined organic layer given brine wash and dried over anhydrous Na2SO4. Organic layer concentrated under vacuo to get crude compound which was purified using combi flash chromatography (EtOAc : Hexane as eluent, 3:7 as eluent) to get tert-butyl (1-(2-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)cyclopropyl)carbamate (42 mg, 68.18%); m / z (LC-MS): 333.1 [M+H]+. Synthesis of 4-(1-aminocyclopropyl)-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine (7ae): To stirred solution of tert-butyl (1-(2-((2,2,2-trifluoroethyl)amino)pyrimidin-4- yl)cyclopropyl)carbamate (0.042 g, 0.1264 mmol) in Dichloromethane (1 mL) at 00C was added Trifluoroacetic acid dropwise (0.1 mL). Reaction mixture was allowed stirr at rt for 4 h and concentrated under vacuo to get crude compound which was washed with hexane to get pure enough 4-(1-aminocyclopropyl)-N-(2,2,2- trifluoroethyl)pyrimidin-2-amine 7ae (40 mg, Crude%); m / z (LC-MS): 233.00 [M+H]+. Example 47: (R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-4-yl)cyclopropyl)butanamide: Following general procedure for compound-8, compound-4d (30 mg, 0.139 mmol) converted to crude Example 47 using compound-7ae (38.7 mg, 0.166 mmol). Crude compound purified by prep HPLC, Column: Gemini NX (250mmx21.2mm), 5.0µ, Mobile Phase: A = 0.1% HCOOH in water and B = Acetonitrile, Flow: 18 mL / min to get pure compound-48 (27 mg, 45.22%) as off white solid; H-NMR (DMSO-d6, 400 MHz): δ 0.93-0.97 (m, 2 H), 1.33-1.36 (m, 1 H), 1.42-1.45 (m, 1 H), 1.53 (s, 3 H), 2.63 (d, J = 14.0 Hz, 1 H), 2.81 (d, J = 14.4 Hz, 1 H), 3.99-4.03 (m, 2 H), 5.99 (s, 1 H), 6.12 (d, J = 5.2 Hz, 1 H), 7.06-7.11 (m, 1H), 7.18-7.24 (m, 1 H), 7.53 (bs, 1 H), 7.58-7.65 (m, 1 H), 7.98 (d, J = 5.2 Hz, 1 H), 8.68 (bs, 1 H); HRMS calculated for: [C19H19F5N4O2+H]+430.14; found:; Analytical Chiral HPLC: Column: CHIRALPAK-IG 250X4.6mm,5µm, Mobile Phase : (A) n-HEXANE (B) 0.1% NH4OH IN (ETHANOL: :DCM)(50:50), Isocratic : (A:B) (50:50), Flow : 1.0ml / min, Diluent : EtOH, Column Temp : 25 °C, Inj. volume: 10.000, (Rt: 5.38, 98%). Example 48: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3- (2,4-dimethylthiazol-5-yl)-3-hydroxybutanamide Synthesis of Ethyl 3-(2,4-dimethylthiazol-5-yl)-3-hydroxybutanoate (3n): 1-(2,4- dimethylthiazol-5-yl)ethan-1-one (2 g, 12.885 mmol) 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]+. Synthesis of 3-(2,4-dimethylthiazol-5-yl)-3-hydroxybutanoic acid (4n): Compound- 3n (2.4 g, 9.863 mmol) hydrolysed to get 4n (0.5 g, 23.80%) as reddish gum using general procedure used for compound-4, m / z (LC-MS): 216 [M+H]+. Example 48: Synthesis of N-(1-(3-chloro-5-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4-dimethylthiazol-5-yl)-3- hydroxybutanamide (Example 48 peak-1 & Example 48 peak-2 ): Following general procedure for compd-8, compound-4n (100 mg, 0.465 mmol) converted to Example 48 (60 mg, 27.90%) using compound 7b. The products were separated using Chiral prep HPLC, Column: CHIRALPAK IH, 250mmX20mm, 5µm, Mobile Phase : n-Hexane (A) and 0.2% HCOOH in EtOH(B), Flow: 15ml, Isocratic :90(A):10(B), Diluents: EtOH:DCM,1:1, 4 ml, Injection: Volume-0.05 ml, Run Time: 17 min, to get Peak-1 (11 mg) and Peak-2 (13.5 mg), 1H NMR (400 MHz, DMSO-d6) δ 0.99-1.06 (m, 2 H), 1.17-1.26 (m, 2 H), 1.52 (s, 3 H), 2.33 (s, 3 H), 2.47 (s, 3 H), 2.66 (dd, J = 14 Hz, 2 H), 4.76 (q, J = 8.9 Hz, 2 H), 6.10 (bs, 1 H), 6.64 (m, 1 H), 6.81 (m, 1 H), 6.96 (m, 1 H), 8.64 (bs, 1 H); HRMS calculated for: [C20H22ClF3N2O3S+H]+463.1070; found: 463.1072 (Example 48 peak-1), 463.1089 (Example 48 peak-2). Analytical Chiral HPLC: CHIRALPAK-IH(150X4.6mmX5µm), Mobile Phase : (A) n- Hexane (B) EtOH (B), Flow : 1.0ml / min, Isocratic : 90:10(A:B), Column Temp : 25 °C, Diluent : EtOH, Inj. volume: 5 µl; Peak-1 (Rt: 3.08, 100% ee) Peak-2: (Rt: 3.52, 100% ee). Example 49: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3- hydroxy-3-(4-methylthiazol-2-yl)butanamide Synthesis of Ethyl 3-hydroxy-3-(4-methylthiazol-2-yl)butanoate (3o): 1-(4-methylthiazol-2-yl)ethan-1-one (0.5 g, 3.5413 mmol) 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]+. Synthesis of 3-hydroxy-3-(4-methylthiazol-2-yl)butanoic acid (4o): Compound-3o (0.1 g, 0.4361 mmol) hydrolysed to get 4o (0.048 g, 55.17%) using general procedure used for compound-4, m / z (LC-MS): 201.95 [M+H]+. Example 49: Synthesis of N-(1-(3-chloro-5-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4-methylthiazol-2- yl)butanamide (Example 49 peak-1 & Example 49 peak-2): Following general procedure for compound-8, compound-4o (0.048 g, 0.2385 mmol) converted Example 49 (0.037 g, 33.33%) using compound 7b. The products were separated using Chiral SFC, Column: Chiralpak IG, 250mmX21mm, 5µm, Mobile Phase : CO2(A) and IPA : MeOH (1:1) (B), Flow:50ml, Isocratic :85(A):15(B), Diluents: EtOH:DCM,1:1,3.5ml, Injection: Volume-0.75ml, Run Time: 8 min, to get Peak-1 (10.5 mg) and Peak-2 (9.8 mg), 1H NMR (400 MHz, DMSO-d6) δ 0.97-1.10 (m, 2 H), 1.15- 1.23 (m, 2 H), 1.49 (s, 3 H), 2.32 (s, 3 H), 2.63 (d, J = 14 Hz, 1H), 2.81 (d, J = 14 Hz, 1 H), 4.76 (q, J = 8.9 Hz, 2 H), 6.38 (bs, 1 H), 6.59 (s, 1H), 6.75 (s, 1 H), 6.94-6.96 (m, 1 H), 7.20 (s, 1 H), 8.67 (s, 1 H); HRMS calculated for: [C19H20ClF3N2O3S+H]+449.0914; found: 449.0919 (Example 49 peak-1), 449.0920 (Example 49 peak-2). Analytical Chiral SFC: CHIRALPAK-IG (150X4.6mmX5µm), Mobile Phase : CO2(A) and IPA : EtOH: MeOH (1:1:1) (B), Flow : 3.0ml / min, Column Temp : 40°C, Inj. volume: 15 µl; Peak-1 (Rt: 1.45, 100% ee), Peak-2: (Rt: 2.21, 100% ee). Example 50: Synthesis of N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3- (5-chlorothiazol-2-yl)-3-hydroxybutanamide Synthesis of tert-butyl 3-(5-chlorothiazol-2-yl)-3-hydroxybutanoate (3p): Using general procedure B used for compound-3 (using Ether as solvent instead of THF and terbutyl bromoacetate instead of ethyl bromoacetate) 1-(5-chlorothiazol-2- yl)ethan-1-one (0.250 g, 1.5469 mmol) converted to compound-3p (0.4 g Crude). m / z (LC-MS): 277.85 [M+H]+. Synthesis of 3-(5-chlorothiazol-2-yl)-3-hydroxybutanoic acid (4p): To a stirred solution of Compound-3p (0.2 g, 0.72 mmol) in Dichloromethane at 00C, was added HCl in dioxane dropwise. Reaction mixture was stirred at room temperature for 2 h. Excess of HCl in dioxane removed under vacuo and triturated with ether to get crude product (0.150 g, Crude). m / z (LC-MS): 221.90 [M+H]+. 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): Following general procedure for compd-8, compound-4p (0.150 g, 0.6767 mmol) converted to Example 50 (0.110 g, 34.70%) using compound 7b. The products were separated using Chiral SFC, Column : 2 X LUX AMYLOSE 2-, 250mmX19mm, 5µm, Mobile Phase : CO2(A) and IPA (B) Flow:50ml, ISO-90:10, Diluents: EtOH:DCM,1:1 5ml, Injection: Volume-0.3ml, Run Time:16 min, to get Peak-1 (44 mg) and peak-2 (41 mg), 1H NMR (400 MHz, DMSO-d6) δ 1.08-1.17 (m, 2 H), 1.19-1.26 (m, 2 H), 1.50 (s, 3 H), 2.64 (d, J = 14 Hz, 1H), 2.80 (d, J = 14 Hz, 1 H), 4.75 (q, J = 8.9 Hz, 2 H), 6.61-6.64 (m, 2 H), 6.77-6.78 (m, 1 H), 6.96-6.97 (m, 1 H), 7.67 (s, 1H), 8.70 (s, 1H), HRMS calculated for: [C18H17Cl2F3N2O3S+H]+469.0367; found: 469.0381 (Example 50 peak-1), 469.0372 (Example 50 peak-2). Analytical Chiral SFC: LUX AMYLOSE 2-, 250mmX19mm, 5µm, Mobile Phase : CO2(A) and 10mM Ammonia in IPA:EtOH:MeOH(1:1:1) (B), Flow : 3.0ml / min, Column Temp : 40°C, Inj. volume: 15 µl; Peak-1 (Rt: 2.18, 100% ee), Peak-2: (Rt: 2.58, 100% ee). Example 51: Synthesis of 3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide Synthesis of ethyl 3-hydroxy-3-(2,4,6-trifluorophenyl)butanoate (3q): Using general procedure A used for compound-3, 1-(2,4,6-trifluorophenyl)ethan-1-one (500 mg, 2.872 mmol) converted to compound-3q (0.9 g Crude). m / z (LC-MS): 244.95 [M-18]+. Synthesis of 3-hydroxy-3-(2,4,6-trifluorophenyl)butanoic acid (4q): Compound-3q (750 mg, 2.860 mmol) hydrolysed to get 4q (600 mg, 90.9%) using general procedure used for compound-4, m / z (LC-MS): 232.85 [M-H]+. Example 51: Synthesis of 3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)-3-(2,4,6-trifluorophenyl)butanamide (Example 51 peak-1 & Example 51 peak-2): Following general procedure for compd-8, compound-4q (0.1 g, 0.427 mmol) converted to Example 51 (0.125 g, 65.78%) using 7aa, which was separated using chiral HPLC, Column Chiralpak IH, 250mmX21mm, 5µm, Mobile Phase : n-Hexane(A) and 10mM Ammonia in IPA:EtOH(1:1)(B), Flow: 15 ml, Isocratic: 90 (A) :10 (B), Diluents: EtOH:DCM,1:13 ml, Injection: Volume-0.2ml, Run Time:19 min, to get Peak-1 (45 mg) and peak-2 (48.4 mg) as off white gum, 1H NMR (400 MHz, DMSO-d6) δ 0.99-1.01 (m, 2 H), 1.19-1.26 (m, 2 H), 1.38-1.48 (m, 2 H), 1.64 (s, 3 H), 2.73 (d, J = 14.4 Hz, 1H), 2.83 (d, J = 14.4 Hz, 1 H), 4.86 (q, J = 8.8 Hz, 2 H), 5.82 (s, 1 H), 6.58 (d, J = 7.2 Hz, 1 H), 6.67 (d, J = 7.2 Hz, 1 H), 7.08-7.13 (m, 2 H), 7.46-750 (m, 1 H), 8.77 (bs, 1 H), HRMS calculated for: [C20H18F6N2O3+H]+448.12; found: 448. (Example 51 peak-1), 448. (Example 51 peak-2). Analytical Chiral HPLC: Column: CHIRALPAK-IH (150X4.6mmX5µm), Mobile Phase : (A) n-HEXANE (B) 0.1% NH4OH IN IPA : EtOH: MeOH (1:1:1), Isocratic: 95 (A) :05 (B), Flow : 1.0 ml / min, Diluent: EtOH, Column Temp : 25 °C, Inj. volume: 5 µl; Peak-1 (Rt: 3.47, 100% ee), Peak-2: (Rt: 4.37, 95.28% ee). Example 52: Kv7 modulating activity Aim To demonstrate the ability of the compounds according to the present disclosure to modulate the activity of Kv7 potassium channels. Materials and Methods Cell seeding. HEK293 cells stably expressing concatenated hKv7.3−hKv7.2 were seeded on poly-D-lysine (10 µg / ml) coated 384-well, clear bottomed, black-walled Corning Optiplates. The cells were seeded at a density of approximately 3x106cells / ml in 20 µl DMEM containing 10% FCS per well and left overnight at 37 °C in a 5% CO2 incubator. Fluorescence-based Tl+ influx assay (FLIPR). Prior to an experiment, the cells were loaded with the fluorescent dye benzothiazolecoumarin-acetoxymethyl ester (BTC-AM. In brief, the cells were washed thrice in Cl−-free assay buffer (in mM: 140 Na+- gluconate, 2.5 K+-gluconate, 6 Ca2+-gluconate, 1 Mg2+-gluconate, 5 glucose, 10 HEPES, pH 7.3). Hereafter, the buffer was aspirated, and 25 µl Cl−-free loading buffer (assay buffer containing an additional 2 µM BTC-AM, 2 mM amaranth and 1 mM tartrazine) was added to each well. The cells were incubated at 37 °C for 1 h and, subsequently, transferred to a fluorometric imaging plate reader (FLIPR). Assay plates were tested using a two-addition protocol (1st add.: test compound, 2nd add.: stimulus buffer). 10 mM DMSO stock solution of the compounds were diluted in Cl"-free assay buffer and 14 log serial dilutions (31.6 pM-0.316 nM) were prepared in 384-well plates. In the hKv7.3-hKv7.2 assay the stimulus buffer consisted of Cl"-free assay buffer supplemented with 2 mM TI2SO4 (Thallium sulphate) and 5 mM K2SO4 (final concentrations) as well as the quenchers amaranth (2 mM) and tartrazine (1 mM). The stimulus buffer in the hKv7.5 assay was similar to the stimulus buffer used in the hKv7.3-hKv7.2 assay, but with a final K2SO4 concentration of 10 mM. The cells were stimulated in quadruplicate, i.e. , four individual wells were stimulated per compound test concentration. In addition, 16 wells / plate served as negative controls (buffer addition) and another 16 wells / plate as positive controls (30 pM retigabine).

[0648] Data analysis. The data from the individual wells were expressed as fold increase (maximal signal (after addition of stimulus buffer) divided by the average baseline value (immediately prior to the addition)). Next, the data were background corrected by subtraction of the averaged value of the fold increase for the negative control wells. The data were subsequently analyzed by normalizing the corrected fold increase values to the maximal positive control response and fitting the data to the Hill equation. EC50 and efficacy (% of positive control) values are reported, where positive control is defined as response to 30 pM retigabine.

[0649] Results

[0650] Table 1 below displays the results obtained when assessing the compounds according to the present disclosure to modulate the activity of Kv7 potassium channels, respectively Kv7.2 / 7.3 and Kv7.5.

[0651] Table 1:

[0652] Conclusion

[0653] The compounds according to the present disclosure are able to modulate the activity of Kv7 channels.

[0654] As demonstrated in the example, the compounds of the present invention provides for smaller EC50 values for Kv7.2 / Kv7.3 channels compared to Kv7.5 channels. As also demonstrated in the example, the compounds of the present invention provides larger efficacy values for Kv7.2 / Kv7.3 channels compared to Kv7.5 channels. Thus it can be concluded that the compounds of the current invention are subtype-selective Kv7 modulators, selective for Kv7.2 / Kv7.3 over Kv7.5.

Claims

Claims1 . A compound according to formula (I):formula (I) or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein,R° is selected from the group consisting of -OH, and -CH3;R1is aryl optionally substituted with one or more, identical or different, substituents R4, or heteroaryl optionally substituted with one or more, identical or different, substituents R4;R4is selected from the group consisting of C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, halogen and CN;R2is selected from the group consisting of -H, -CH3, and -CF3;R3is selected from the group consisting of -H and -OH;A is of formula (II):formula (II) whereinA1is C-R5or N;R5is -H or halogen;A2is C-R6;R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more F; C1-5 alkyl optionally substituted with one or more F; halogen; and N(R10)(R11);R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;R11is -H;R12is selected from the group consisting of halogen, C3-5 cycloalkyl and C1-3 alkyl;A3is C-R7or N;R7is selected from the group consisting of -H, halogen and C1-5 alkyl;A4is C-R8or N;R8is selected from the group consisting of -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more F, C1-5 alkoxy, and -CN;A5is C-R9or N;R9is -H or halogen; with the proviso that the compound is not / V-[1-(3,5-Difluorophenyl)cyclopropyl]-p-methyl-1 / 7-imidazole-1-propanamide;N-[1-(3-Chlorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide;N-[1-(3-Fluorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide; or 3-Fluoro-N-[1-(3-fluorophenyl)cyclopropyl]-p-hydroxybenzenepropanamide.

2. The compound according to claim 1 , wherein the compound is of formula (Illa):formula (Illa)3. The compound according to claim 1 , wherein the compound is of formula (111 b) :formula (I I lb)4. The compound according to any one of the preceding claims, wherein R1is phenyl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, thiazol-2-yl or thiazol-5-yl optionally substituted with one or more, identical or different substituents R4selected from the group consisting of -F, -Cl, -Br, C1-5 alkoxy, C1-5 alkyl, and -CN.

5. The compound according to any one of claims 1 to 3, wherein R1is phenyl substituted with one or more, identical or different, substituents R4selected from the group consisting of -F, -Cl, -Br, C1-5 alkoxy, C1-5 alkyl, and -CN.

6. The compound according to any one of claims 1 to 3, wherein R1is phenyl substituted with one or more, identical or different, substituents R4selected from the group consisting of -F, -Br, C1-5 alkyl, and -CN.

7. The compound according to any one of claims 1 to 3, wherein R1is phenyl substituted with one or more -F.

8. The compound according to any one of claims 1 to 3, wherein R1is pyridinyl substituted with one or more, identical or different, substituents R4selected from the group consisting of -F, -Cl, -Br, C1-5 alkoxy, C1-5 alkyl, and -CN.

9. The compound according to any one of claims 1 to 3, wherein R1is pyridinyl substituted with one or more, identical or different, substituents R4selected from the group consisting of -F, -Cl, -Br, and C1-5 alkoxy.

10. The compound according to any one of claims 1 to 3, wherein R1is thiazolyl substituted with one or more, identical or different substituents R4selected from the group consisting of -F, -Cl, -Br, and C1-5 alkyl.11 . The compound according to any one of claims 1 to 3, wherein R1is thiazolyl substituted with one or more, identical or different substituents R4selected from the group consisting of -F, -Cl, -Br, and C1-5 alkyl,12. The compound according to any one of claims 1 to 3, wherein R1is indolyl substituted with one or more, identical or different substituents R4selected from the group consisting of -F, -Cl, -Br, and C1-5 alkyl.

13. The compound according to any one of claims 1 to 3, wherein R1is selected from:

14. The compound according to any one of the preceding claims, wherein R2is -CH3and R° is -OH.

15. The compound according to any one of the preceding claims, wherein R° is - OH, R2is -CH3, and R3is -H.

16. The compound according to any one of claims 1 to 12, wherein R2is -CF3 and R° is -OH.

17. The compound according to any one of the preceding claims, wherein R3is -H.

18. The compound according to any one of the preceding claims, wherein A is of formula (II),formula (II) wherein: a) A1is C-R5; A2is C-R6; A3is C-R7; A4is C-R8; and A5is C-R9, or b) A1is N; A2is C-R6; A3is C-R7; A4is C-R8; and A5is C-R9, orc) A1is C-R5; A2is C-R6; A3is N; A4is C-R8; and A5is C-R9, or d) A1is C-R5; A2is C-R6; A3is C-R7; A4is N; and A5is C-R9, or e) A1is N; A2is C-R6; A3is N; A4is C-R8; and A5is C-R9, or f) A1is C-R5; A2is C-R6; A3is C-R7; A4is C-R8; and A5is N.

19. The compound according to any one of the preceding claims, whereinR5is -H or -F,R6is -CF3, -Cl, -Br, -CH3-OCH2CF3, -OCF3, -OCH3, -OCH2CF2H, -R8is -H, -F, -Cl, - Br, -CN, -CF2H, cyclopropyl, or -OCH3.R9is -H or -F.

20. The compound according to any one of the preceding claims, wherein A1is C(H), A2is C(OCH2CF3) and A5is C(H).21 . The compound according to any one of claims 1 to 17, wherein A1is N, A3is C(H) and A5is C(H).

22. The compound according to any one of the preceding claims, wherein at least one of A1, A3and A4is not -C(H).

23. The compound according to any one of claims 1 to 17, wherein A is selected from:

24. The compound according to claim 1 , wherein the compound is (R)-3-(6- chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclo- propyl)butanamide, (R)-3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-butanamide, (R)-3-hydroxy-3-(2-methoxypyridin-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)pyridin-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)pyridin-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-dichloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,(R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl) amino) pyridin-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)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide),(R)-N-(1-(6-((cyclopropylmethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(R)-N-(1-(4-chloro-6-(isopropylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(R)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(R)-N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,(R)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(R)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,(R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide,(R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridin-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)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(R)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-hydroxy-3-(1-methyl-1 H-indol-4-yl)butanamide,(R)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-4-yl)cyclopropyl)butanamide,(R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- dimethylthiazol-5-yl)-3-hydroxybutanamide,(R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4- methylthiazol-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)pyridin-2-yl)cyclopropyl)-3-(2,4,6- trifluorophenyl)butanamide,(S)-3-(6-chloropyridin-3-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclo-propyl)butanamide,(S)-3-(5-fluoropyridin-2-yl)-3-hydroxy-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)-butanamide,(S)-3-hydroxy-3-(2-methoxypyridin-4-yl)-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclo-propyl)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)pyridin-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)pyridin-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-dichloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,(S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl) amino) pyridin-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)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide),(S)-N-(1-(6-((cyclopropylmethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(S)-N-(1-(4-chloro-6-(isopropylamino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(S)-N-(1-(2-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide,(S)-N-(1-(6-chloropyridin-2-yl)cyclopropyl)-3-(2,4-difluorophenyl)-3- hydroxybutanamide,(S)-N-(1-(4-chloro-6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, (S)-3-(2,6-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl)cyclopropyl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(6-(trifluoromethyl)pyridin-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)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(6-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-(2,4- difluorophenyl)-3-hydroxybutanamide, (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-3-hydroxy-3- (1-methyl-1 H-indol-4-yl)butanamide, (S)-3-(2,4-difluorophenyl)-3-hydroxy-N-(1-(2-((2,2,2- trifluoroethyl)amino)pyrimidin-4-yl)cyclopropyl)butanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-(2,4- dimethylthiazol-5-yl)-3-hydroxybutanamide, (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxy-3-(4- methylthiazol-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)pyridin-2-yl)cyclopropyl)-3-(2,4,6- trifluorophenyl)butanamide or a pharmaceutically acceptable salt thereof.

25. The compound according to any one of the preceding claims, wherein the compound is able to produce an increase in the activity of the Kv7.2 / Kv7.3 heteromeric channel with an ECso of less than 20 pM, as measured by a thallium ion (TI+) influx assay.

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

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