Kv7 modulators

Abstract

The present invention provides novel compounds of formula (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 with B being defined as moiety of formula (II) and A being defined as moiety of formula (III).

Description

[0001] P6714PC00

[0002] Kv7 modulators

[0003] Technical field

[0004] 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.

[0005] Background

[0006] 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 heterotetrameric 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;

[0007] Physiology, 26, 365-376).

[0008] 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. P6714PC00

[0009] 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 selflimiting 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;

[0010] 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 antiepileptics 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).

[0011] 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.

[0012] 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. P6714PC00

[0013] Summary

[0014] In one aspect, the present disclosure provides for a compound according to according to formula (I):

[0015]

[0016] formula (I)

[0017] or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein

[0018] B is of formula (II):

[0019]

[0020] formula (II)

[0021] R1is selected from the group consisting of –OH and -CH3;

[0022] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0023] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0024] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0025] R3is -H or-CH3;

[0026] or R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0027] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;

[0028] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[0029] A is of formula (III): P6714PC00

[0030]

[0031] formula (III)

[0032] wherein

[0033] A1is C-R5or N;

[0034] R5is selected from -H, or halogen;

[0035] A2is C-R6;

[0036] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);

[0037] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0038] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[0039] A3is C-R7or N;

[0040] R7is -H, halogen, or C1-5 alkyl;

[0041] A4is C-R8or N;

[0042] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN;

[0043] A5is C-R9or N; and

[0044] R9is -H or halogen,

[0045] with the proviso that the compound is not

[0046] 3-Hydroxy--[1-(3-methoxyphenyl)cyclopropyl]-3-methylbutanamide.

[0047] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as described herein.

[0048] In another aspect, the present disclosure provides a compound as described herein for use as a medicament.

[0049] 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. P6714PC00

[0050] 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.

[0051] In another aspect, the present disclosure provides a compound as described herein for use in the treatment of epilepsy or pain.

[0052] Definitions

[0053] The term “alkyl” as used herein refers to a linear or branched hydrocarbon moiety.

[0054] The term "alkoxy" as used herein refers to a group of formula -O- alkyl, wherein alkyl is defined as above. In particular, C1-3 -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.

[0055] 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.

[0056] 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.

[0057] The term "heteroatom" refers to sulfur, oxygen or nitrogen.

[0058] 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).

[0059] 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.

[0060] 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 P6714PC00

[0061] atoms are heteroatoms. Heteroaryl groups include monocyclic and biycyclic systems. For example, heteroaryl as used herein can be a C5-10 monocyclic or Cs-12 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.

[0062] 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.

[0063] 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.

[0064] As used herein, the term “agonism” referring to a Kv7 channel, refers to activating, increasing or enhancing the activity of a Kv7 channel.

[0065] Detailed description

[0066] In one aspect, the present disclosure provides for a compound according to formula (I):

[0067]

[0068] formula (I)

[0069] or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein

[0070] B is of formula (II):

[0071]

[0072] formula (II)

[0073] R1is selected from the group consisting of –OH and -CH3; P6714PC00

[0074] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0075] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0076] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0077] R3is -H or-CH3;

[0078] or R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0079] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;

[0080] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[0081] A is of formula (III):

[0082] AKXA3

[0083]

[0084] formula (III)

[0085] wherein

[0086] A1is C-R5or N;

[0087] R5is selected from -H, or halogen;

[0088] A2is C-R6;

[0089] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);

[0090] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0091] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[0092] A3is C-R7or N;

[0093] R7is -H, halogen, or C1-5 alkyl;

[0094] A4is C-R8or N; P6714PC00

[0095] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN;

[0096] A5is C-R9or N; and

[0097] R9is -H or halogen.

[0098] In another aspect, the present disclosure provides for a compound according to formula (I):

[0099]

[0100] formula (I)

[0101] or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof;

[0102] wherein

[0103] B is of formula (II):

[0104] R1

[0105]

[0106] formula (II)

[0107] R1is selected from the group consisting of –OH and -CH3;

[0108] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0109] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0110] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0111] R3is -H or-CH3;

[0112] or R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0113] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl; P6714PC00

[0114] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[0115] A is of formula (III):

[0116]

[0117] formula (III)

[0118] wherein

[0119] A1is C-R5or N;

[0120] R5is selected from -H, or halogen;

[0121] A2is C-R6;

[0122] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);

[0123] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0124] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[0125] A3is C-R7or N;

[0126] R7is -H, halogen, or C1-5 alkyl;

[0127] A4is C-R8or N;

[0128] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN;

[0129] A5is C-R9or N; and

[0130] R9is -H or halogen;

[0131] with the proviso that the compound is not

[0132] 3-Hydroxy--[1-(3-methoxyphenyl)cyclopropyl]-3-methylbutanamide.

[0133] In some embodiments, the compound is not 3-Hydroxy--[1-(3-methoxyphenyl)cyclopropyl]-3-methylbutanamide. In some embodiments, the compound is not: P6714PC00

[0134]

[0135] In some embodiments, the compound is not / \ / -(1-(3-cyanophenyl)cyclopropyl)-3- hydroxy-3-methylbutanamide. In some embodiments, the compound is not:

[0136]

[0137] In some embodiments, the compound is not 3,3-dimethyl- / V-(1- phenylcyclopropyl)butanamide. In some embodiments, the compound is not:

[0138]

[0139] In some embodiments, the compound is not / \ / -(1-(4-fluorophenyl)cyclopropyl)-3,3- dimethylbutanamide. In some embodiments, the compound is not:

[0140]

[0141] In some embodiments, B is of formula (Ila):

[0142]

[0143] formula (Ila).

[0144] In some embodiments, B is of formula (lib):

[0145]

[0146] formula (lib).

[0147] In some embodiments, B is of formula (Ila), formula (lib) or a mixture thereof. P6714PC00

[0148] In some embodiments, the compound is of formula (la):

[0149]

[0150] formula (la).

[0151] In some embodiments, the compound is of formula (lb):

[0152]

[0153] formula (lb).

[0154] In some embodiments, the compound is of formula (la), formula (lb) or a mixture thereof.

[0155] In some embodiments, R1is -OH. In some embodiments, R1is -CH3.

[0156] In some embodiments, B is of formula (II):

[0157] R1

[0158]

[0159] formula (II)

[0160] wherein

[0161] R1is selected from the group consisting of –OH and -CH3;

[0162] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0163] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0164] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0165] R3is -H or -CH3. P6714PC00

[0166] In some embodiments, R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4.

[0167] In some embodiments, R2is C1-5 alkyl optionally substituted with one or more, identical or different substituents R4.

[0168] In some embodiments, R2is Ci alkyl optionally substituted with one or more, identical or different substituents R4. In some embodiments, R2is C2 alkyl optionally substituted with one or more, identical or different substituents R4. In some embodiments, R2is C3 alkyl optionally substituted with one or more, identical or different substituents R4. In some embodiments, R2is C4 alkyl optionally substituted with one or more, identical or different substituents R4. In some embodiments, R2is C5 alkyl optionally substituted with one or more, identical or different substituents R4.

[0169] In some embodiments, R2is C1-10 alkyl and has one to five R4substituents.

[0170] In some embodiments, R2is C1-2 alkyl and has two R4substituents. In some embodiments, R2is C1-2 alkyl and has three R4substituents.

[0171] In some embodiments, one or more R4substituents are on the same carbon.

[0172] In some embodiments, R2is a C1-2 alkyl and has two or three substituents R4on the same carbon.

[0173] In some embodiments, R4is selected from halogen, -CF3 and C1-5 alkyl.

[0174] In some embodiments, one or more R4is independently halogen. In some embodiments, R4is F.

[0175] In some embodiments, one or more R4is independently C1-5 haloalkyl. In some embodiments, one or more R4is independently Ci haloalkyl.

[0176] In some embodiments, R4is -CF3.

[0177] In some embodiments, R2is -CF3. In some embodiments, R2is -CH2CF3. P6714PC00

[0178] In some embodiments, one or more R4is independently C1-5 alkyl. In some embodiments, one or more R4is independently C1-3 alkyl. In some embodiments, R4is -CH3.

[0179] In some embodiments, R2is a C1-5 alkyl, such as a Ci, C2, C3, C4 or C5 alkyl.

[0180] In some embodiments, R2is tert-butyl. In some embodiments, R2is -CH3.

[0181] In some embodiments, R2is C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6-membered ring together with the intervening atom(s).

[0182] In some embodiments, R2is C3-6 cycloalkyl optionally substituted with one or more R4. In some embodiments, R2is C3 cycloalkyl optionally substituted with one or more R4. In some embodiments, R2is cyclopropyl.

[0183] In some embodiments, R2is C4 cycloalkyl optionally substituted with one or more R4. In some embodiments, R2is cyclobutyl substituted with one or more R4. In some embodiments, R2is cyclobutyl substituted with one or more halogen. In some embodiments, R2is cyclobutyl substituted with one or more F. In some embodiments, R2is cyclobutyl substituted with two F.

[0184] In some embodiments,

[0185]

[0186] R2is

[0187] In some embodiments, R2is cyclobutyl. In some embodiments, R2is C5 cycloalkyl optionally substituted with one or more R4.

[0188] In some embodiments, R2is cyclopentyl. In some embodiments, R2is selected from

[0189] cyclopropyl, cyclobutyl, cyclopentyl, or

[0190]

[0191] In some embodiments, R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 3- to 6-membered ring together with the intervening atom(s), P6714PC00

[0192] wherein G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4.

[0193] In some embodiments, R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 3-membered ring together with the intervening atom(s). In some embodiments, R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 4-membered ring together with the intervening atom(s). In some embodiments, R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 5-membered ring together with the intervening atom(s). In some embodiments, R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 6-membered ring together with the intervening atom(s). In some embodiments, R2is C4 cycloalkyl substituted with two substituents G1together forming a 3- to 6-membered ring together with the intervening atom(s).

[0194] In some embodiments, R2is C4 cycloalkyl substituted with two substituents G1together forming a 3- to 4-membered ring together with the intervening atom(s).ln some embodiments, R2is C4 cycloalkyl substituted with two substituents G1together forming a 3-membered ring together with the intervening atom(s). In some embodiments, two

[0195] G1are bound to the same carbon. In some embodiments, R2is

[0196]

[0197] . in some embodiments, R2is C4 cycloalkyl substituted with two substituents G1together forming a 4-membered ring together with the intervening atom(s). In some embodiments, R2is

[0198]

[0199] In some embodiments, R2is C6cycloalkyl substituted with two substituents G1together forming a 6-membered ring together with the intervening atom(s). In some embodiments, two G1are bound to different carbons. In some embodiments, R2is

[0200]

[0201] In some embodiments, R3is -CH3. In some embodiments, R3is H. P6714PC00

[0202] In some embodiments, R1is -OH or -CH3and R3is -CH3or H. In some embodiments, R1is -OH and R3is -CH3. In some embodiments, R1is -OH and R3is H. In some embodiments, R1is -CH3and R3is -CH3. In some embodiments, R1is -CH3and R3is H.

[0203] In some embodiments, B is of formula (II):

[0204] R1

[0205]

[0206] formula (II)

[0207] wherein

[0208] R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0209] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl; and

[0210] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11.

[0211] In some embodiments, R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s).

[0212] In some embodiments, the compound is of formula (IV):

[0213]

[0214] Formula (IV)

[0215] wherein

[0216] R1is selected from the group consisting of –OH and -CH3;

[0217] R2and R3form a 3- to 6-membered ring together with the intervening atom, P6714PC00

[0218] R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0219] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;

[0220] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[0221] A1is C-R5or N;

[0222] R5is selected from -H, or halogen;

[0223] A2is C-R6;

[0224] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);

[0225] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0226] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[0227] A3is C-R7or N;

[0228] R7is -H, halogen, or C1-5 alkyl;

[0229] A4is C-R8or N;

[0230] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN;

[0231] A5is C-R9or N; and

[0232] R9is -H or halogen.

[0233] In some embodiments, R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11.

[0234] In some embodiments, R11is halogen. In some embodiments, R11is F.

[0235] In some embodiments, two G2substituents on the same carbon are together forming a 3- to 6-membered ring. In some embodiments, two G2substituents on the same carbon are together forming a 3-membered ring. In some embodiments, two G2substituents on the same carbon are together forming a 4-membered ring. In some embodiments, two G2substituents on the same carbon are together forming a 5-membered ring. P6714PC00

[0236] In some embodiments, R2and R3are individually C1-3 alkanediyl and linked together to form a 3- to 6-membered ring, and the formed ring is substituted with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s).

[0237] In some embodiments, R2and R3are linked together to form a 4-membered ring substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s).

[0238] In some embodiments, R2and R3are linked together to form cyclobutyl substituted with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s). In some embodiments, R2and R3are linked together to form cyclobutyl substituted with two substituents G2together forming a 3- to 4-membered ring together with the intervening atom(s). In some embodiments, R2and R3are linked together to form cyclobutyl substituted with two substituents G2together forming a 3-membered ring together with the intervening atom(s). In some embodiments, R2and R3are linked together to form cyclobutyl substituted with two substituents G2together forming a 4-membered ring together with the intervening atom(s). In some embodiments, R2and R3are linked together to form cyclobutyl. In some embodiments, R2and R3are linked together to form cyclobutyl substituted with two R11. In some embodiments, R2and R3are linked together to form cyclobutyl substituted with one or more, identical or different substituents R11, wherein there are two R11substituents on the same carbon. In some embodiments, R2and R3are linked together to form cyclobutyl substituted with one or more, identical or different substituents R11. In some embodiments, R2and R3are linked together to form cyclobutyl substituted with one or more halogens. In some embodiments, R2and R3are linked together to form cyclobutyl substituted with one or more F.

[0239] In some embodiments, R2and R3are linked together to form a 5-membered ring substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s). In some embodiments, R2and R3are linked together to form cyclopentyl substituted with one or more, identical or different substituents R11. In some embodiments, R2and R3are linked together to form cyclopentyl. P6714PC00

[0240] R

[0241] F-1R1In some embodiments,

[0242]

[0243] B is F. In some embodiments,

[0244]

[0245] B is R1R1In some embodiments,

[0246]

[0247] B is In some embodiments,

[0248]

[0249] B is

[0250] OH

[0251] F- OH In some embodiments, B is

[0252]

[0253] F. In some embodiments, B is

[0254]

[0255] OH OH

[0256] In some embodiments, B is

[0257]

[0258] . In some embodiments,

[0259]

[0260] B is

[0261] In some embodiments, R2is C1-10 alkyl, optionally substituted with one or more, identical or different, substituents R4, wherein R4is selected from halogen, -CF3, C1-5 alkyl and R3is -CH3. In some embodiments, R2is C1-6 alkyl optionally substituted with one or more, identical or different, substituents R4, wherein R4is halogen, R3is -CH3, and R1is -OH. In some embodiments, R2is C1-6 alkyl optionally substituted with one or more -F, R3is -CH3, and R1is -OH.

[0262] In some embodiments, R1is -OH or -CH3, R2is -CH3, -tert-butyl, cyclopropyl,

[0263] ^ F cyclobutyl, cyclopentyl, -CF3,-CH2CF3,

[0264]

[0265] F XZ, XZ5, \ — f or

[0266]

[0267] , and R3is -H or -CH3. In some embodiments,, R3is H, and R1is -OH. In some embodiments, R2is -CH3, R3is -CH3, and R1is -CH3. In some embodiments, R2is -tert-butyl, R3is -CH3, and R1is -OH. In some embodiments, R2is -tert-butyl, R3is H, and R1is -CH3. In some embodiments, R2is -tert-butyl, R3is H, and R1is -OH. In some embodiments, R2is -CH2CF3, R3is -CH3, and R1is -OH. In some embodiments, R2is -CF3, R3is -CH3, and R1is -OH. In some embodiments, R2is C3-6 cycloalkyl optionally substituted with one or more R4, wherein R4is -F, and R3is -CH3. In some embodiments, R2is C3-6 cycloalkyl optionally substituted with one or more R4, wherein R4is F, R3is -CH3, and R1is -OH. In some embodiments, R2is cyclopropyl, R3is -CH3, and R1is -OH. In some embodiments, R2is cyclopropyl, R3is -H, and R1is -CH3. In some embodiments, R2is cyclopropyl, R3is -H, and R1is -OH. In some embodiments, R2is cyclobutyl, R3is -CH3, and R1is -OH. In some embodiments, R2is cyclopentyl, R3 P6714PC00

[0268] F\ Z\ is -CH3, and R1is -OH. In some embodiments, R

[0269]

[0270] 2is F xz, R3js -CH3, and R1is

[0271] -OH. In some embodiments, R2is

[0272]

[0273] 3is -CH3, and R1is -OH. In some

[0274] embodiments, R2is, R3is -CH3, and R1is -OH. In some embodiments, R2

[0275]

[0276] is R3is -CH3, and R1is -OH.

[0277] In one aspect, the present invention relates to a compound according to formula (I):

[0278]

[0279] formula (I)

[0280] or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof;

[0281] wherein

[0282] B is of formula (II):

[0283] R1

[0284] R2.

[0285]

[0286] R3

[0287] formula (II)

[0288] R1is selected from the group consisting of –OH and -CH3;

[0289] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0290] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0291] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0292] R3is -H or-CH3; P6714PC00

[0293] or R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0294] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;

[0295] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[0296] A is phenyl or pyridinyl, optionally substituted with one or more substituents R5, R6, R7, R8and / or R9,

[0297] R5is -H or halogen;

[0298] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);

[0299] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0300] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[0301] R7is -H, halogen, or C1-5 alkyl;

[0302] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN; and

[0303] R9is -H or halogen.

[0304] In one aspect, the present invention relates to a compound according to formula (I):

[0305] U

[0306]

[0307] n

[0308] formula (I)

[0309] or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof;

[0310] wherein

[0311] B is of formula (II):

[0312] R1

[0313]

[0314] P6714PC00

[0315] formula (II)

[0316] R1is selected from the group consisting of –OH and -CH3;

[0317] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0318] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0319] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0320] R3is -H or-CH3;

[0321] or R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0322] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;

[0323] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[0324] A is phenyl or pyridinyl, optionally substituted with one or more substituents R5, R6, R7, R8and / or R9,

[0325] R5is -H or halogen;

[0326] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);

[0327] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0328] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[0329] R7is -H, halogen, or C1-5 alkyl;

[0330] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN; and

[0331] R9is -H or halogen,

[0332] with the proviso that the compound is not 3-Hydroxy- / V-[1-(3-methoxyphenyl)cyclopropyl]-3-methylbutanamide, / \ / -(1-(3-cyanophenyl)cyclopropyl)-3-hydroxy-3-methylbutanamide, 3,3-dimethyl- / V-(1-phenylcyclopropyl)butanamide, or / V-(1-(4-fluorophenyl)cyclopropyl)-3,3-dimethylbutanamide. P6714PC00

[0333] In some embodiments, A is phenyl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9. In some embodiments, A is phenyl optionally substituted with one substituent R5, R6, R7, R8or R9. In some embodiments, A is phenyl optionally substituted with two substituents R5, R6, R7, R8and / or R9. In some embodiments, A is pyridinyl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9.

[0334] In some embodiments, A is pyridin-2-yl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9. In some embodiments, A is pyridin-2-yl optionally substituted with one substituent R5, R6, R7, R8and / or R9. In some embodiments, A is pyridin-2-yl optionally substituted with two substituents R5, R6, R7, R8and / or R9.

[0335] In some embodiments, A is pyridin-4-yl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9. In some embodiments, A is pyridin-4-yl optionally substituted with one substituent R5, R6, R7, R8and / or R9. In some embodiments, A is pyridin-4-yl optionally substituted with two substituents R5, R6, R7, R8and / or R9.

[0336] In some embodiments, at least one of R5, R6, R7, R8and R9, is not H. In some embodiments, at least one of R5, R7, R8and R9, is not H.

[0337] In some embodiments, A1is C-R5; A2is C-R6; A3is C-R7; A4is C-R8; and A5is C-R9. In some embodiments, one of A1or A3is N. In some embodiments, A1is N; A2is C-R6; A3is C-R7; A4is C-R8; and A5is C-R9. In some embodiments, A1is C-R5; A2is C-R6; A3is N; A4is C-R8; and A5is C-R9. In some embodiments, at least one of A1, A2, A3, A4and A5is not C(H). In some embodiments, at least one of A1, A3, A4, and A5is not C(H). In some embodiments, A1is N. In some embodiments, A1is C-R5.

[0338] In some embodiments, R5is -H. In some embodiments, R5is halogen. In some embodiments, R5is -F. In some embodiments, R5is -H or-F."

[0339] In some embodiments, R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H); wherein R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12selected from halogen, C3-5 cycloalkyl or C1.3 alkyl. P6714PC00

[0340] In some embodiments, R6is C1-5 alkoxy optionally substituted with one or more F; C1-5 alkyl optionally substituted with one or more F; or N(R10)(H); wherein R10is C1-5 alkyl optionally substituted with one or more R12. In some embodiments, R6is C1-5 alkoxy optionally substituted with one or more halogen. In some embodiments, R6is C2-5 alkoxy optionally substituted with one or more halogen. In some embodiments, R6is C1- 5 alkoxy. In some embodiments, R6is C2-5 alkoxy. In some embodiments, R6is C1-5 alkoxy substituted with one or more halogen. In some embodiments, R6is C1-5 alkoxy substituted with one or more F. In some embodiments, R6is C1-2 alkoxy substituted with one or more F. In some embodiments, R6is C2 alkoxy substituted with one or more F. In some embodiments, R6is Ci alkoxy substituted with one or more F. In some embodiments, R6is C1-5 alkyl optionally substituted with one or more halogen. In some embodiments, R6is C1-5 alkyl. In some embodiments, R6is C1-5 alkyl substituted with one or more halogen. In some embodiments, R6is C1-5 alkyl substituted with one or more F. In some embodiments, R6is Ci alkyl substituted with one or more F. In some embodiments, R6is N(R10)(H) wherein R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12; and R12is halogen, C3-5 cycloalkyl or C1-3 alkyl. In some embodiments, R6is N(R10)(H), wherein R10is C1-5 alkyl optionally substituted with one or more F. In some embodiments, R6is -CF3, -OCF3, -OCH₂CF₃, or -NHCH₂CF₃. In some embodiments, R6is -CF3. In some embodiments, R6is -OCF3. In some embodiments, R6is -OCH2CF3. In some embodiments, R6is -NHCH2CF3.

[0341] In some embodiments, R10is C1-5 alkyl substituted with one or more, identical or different, substituents R12. In some embodiments, R10is C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12. In some embodiments, R10is C2 alkyl optionally substituted with one or more, identical or different, substituents R12.

[0342] In some embodiments, R12is halogen. In some embodiments, R12is F.

[0343] In some embodiments, A3is N. In some embodiments, A3is C-R7. In some embodiments, R7is -H, halogen, or C1-5 alkyl. In some embodiments, R7is -H, -F, -Cl or -CH3. In some embodiments, R7is -H. In some embodiments, R7is halogen. In some embodiments, R7is -F. In some embodiments, R7is- Cl. In some embodiments, R7is C1-5 alkyl. In some embodiments, R7is -CH3. P6714PC00

[0344] In some embodiments, A4is N. In some embodiments, A4is C-R8. In some embodiments, R8is -H, halogen, C3-5 cycloalkyl, or C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN. In some embodiments, R8is -H, halogen, C3- 5 cycloalkyl, or C1-5 alkyl optionally substituted with one or more F. In some embodiments, R8is H. In some embodiments, R8is halogen. In some embodiments, R8is F. In some embodiments, R8is Cl. In some embodiments, R8is Br. In some embodiments, R8is C3-5 cycloalkyl. In some embodiments, R8is cyclopropyl. In some embodiments, R8is C1-5 alkyl optionally substituted with one or more halogen. In some embodiments, R8is C1-5 alkyl substituted with one or more F. In some embodiments, R8is Ci alkyl substituted with one or more F. In some embodiments, R8is -CF2H. In some embodiments, R8is C1-5 alkyl. In some embodiments, R8is -CH3. In some embodiments, R8is -H, -F, -Cl, -Br, -CH3, -CF2H, or cyclopropyl.

[0345] In some embodiments, A5is N. In some embodiments, A5is C-R9. In some embodiments, R9is halogen. In some embodiments, R9is -H.

[0346]

[0347] P6714PC00

[0348] Cl

[0349] OCF3

[0350]

[0351] In some embodiments

[0352]

[0353] some embodiments, A is. In some

[0354] embodiments, A

[0355]

[0356] is embodiments, A is

[0357]

[0358] embodiments, A is P6714PC00

[0359] . In some

[0360]

[0361] CF3

[0362] . In some embodiments, A is

[0363] CF3

[0364]

[0365] Cl

[0366] . In some embodiments, A is. In some embodiments, A is

[0367] H

[0368] N^CF3CF3

[0369]

[0370]

[0371] . In some embodiments, A is. In some embodiments, A is

[0372] O^ / CF3

[0373]

[0374] ci

[0375] In some embodiments, R1is -OH or-CH3:

[0376] R2is -CH3, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF3,-CH2CF3: F

[0377] F

[0378]

[0379] R3is -H or-CH3;

[0380] A1is N or C-R5;

[0381] R5is -H or-F;

[0382] A2is C-R6;

[0383] R6is -CF3, -OCF3, -OCH2CF3, -NHCH2CF3;

[0384] A3is C-R7;

[0385] R7is -H, -F, -Cl or-CH3;

[0386] A4is C-R8; P6714PC00

[0387] R8is -H, -F, -Cl, -Br, -CH3, -CF2H, or cyclopropyl;

[0388] A5is C-R9; and

[0389] R9is -H.

[0390] In some embodiments, R1is -OH or -CH3;

[0391] R2is -CH3, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF₃,-CH₂CF₃;

[0392] R3is -H or-CH3; and

[0393]

[0394] In some embodiments, B is

[0395]

[0396] P6714PC00

[0397]

[0398] In some embodiments, R1is -OH or -CH₃,

[0399] R2is -CH3, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF3.-CH2CF3, F F

[0400] R3is -H or -CH3, and

[0401] CF3

[0402]

[0403] In some embodiments, R1is -OH,

[0404] R2is -CH3, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF3,-CH2CF3,

[0405] R

[0406]

[0407] 3is -CH3, and P6714PC00

[0408]

[0409] In some embodiments, R1is -OH,

[0410] R2is -CH3, tert-butyl, -CF3, or -CH2CF3,

[0411] R3is -CH3, and

[0412]

[0413] In some embodiments, R1is -OH,

[0414] R2is cyclopropyl, cyclobutyl, cyclopentyl,

[0415] R3is -CH3, and

[0416]

[0417] In some embodiments, R1is -OH, R2is cyclopropyl, R3is -CH3, and A is

[0418]

[0419] P6714PC00

[0420] In some embodiments, R1is -OH, R2is -CF3, R3is -CH3, and A is

[0421]

[0422] In some embodiments, R1is -OH;

[0423] R2is C1-5alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6cycloalkyl optionally substituted with one or more R4; R3is -CH3;

[0424] R4is halogen;

[0425] A1is C(H) or N;

[0426] R6is C1-5alkoxy optionally substituted with one or more halogen;

[0427] A3is C(H) or N;

[0428] A4is C-R8;

[0429] R8is H or halogen; and

[0430] A1is C(H).

[0431] In some embodiments, R1is -OH; R2is -CF3 or cyclopropyl; R3is -CH3; A1is C(H) or N; A2is C(OCH2CF3); A3is C(H) or N; A4is C-R8; R8is H or halogen; and A1is C(H).

[0432] In some embodiments, the halogen is F. In some embodiments, the halogen is Cl. In some embodiments, the halogen is Br. In some embodiments, the C1-10alkyl is C1-5alkyl. In some embodiments, the C1-10alkyl is C1-3alkyl. In some embodiments, the C1-5alkyl is C1-3alkyl.

[0433] In some embodiments, the compound of the present invention is selected from the group consisting of:

[0434] N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4- dimethylpentan-amide,

[0435] 2-(1-hydroxycyclopentyl)-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)- acetamide,

[0436] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(3,3-difluoro-1- hydroxy-cyclobutyl)acetamide, P6714PC00

[0437] 3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,

[0438] 3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,

[0439] 3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,

[0440] 3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-pentanamide,

[0441] 5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)pentanamide,

[0442] 2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-methyl-5-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)acetamide,

[0443] 2-(2-hydroxyspiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)acetamide,

[0444] 3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclo-propyl)butanamide,

[0445] N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxy-butanamide,

[0446] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxy-butanamide,

[0447] 3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0448] 3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide,

[0449] N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0450] 3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-butanamide,

[0451] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,3-dimethylbutanamide,

[0452] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide,

[0453] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(5-hydroxyspiro- [2.3]hexan-5-yl)acetamide, P6714PC00

[0454] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4- trimethylpentanamide,

[0455] 3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3- hydroxybutanamide,

[0456] 3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3- hydroxybutanamide,

[0457] N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3- hydroxybutanamide,

[0458] 3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[0459] 3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[0460] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3- hydroxy-3-methylbutanamide,

[0461] 3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)- cyclopropyl)butanamide,

[0462] 3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)- phenyl)cyclopropyl)-3-hydroxybutanamide,

[0463] 4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,

[0464] 3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,

[0465] 4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)cyclopropyl)butanamide, and

[0466] N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4-trifluoro-3- hydroxy-3-methylbutanamide,

[0467] or a pharmaceutically acceptable salt thereof.

[0468] In some embodiments, the compound of the present invention is selected from is selected from the group consisting of:

[0469] (R)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4- dimethylpentanamide,

[0470] (R)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide, P6714PC00

[0471] (R)-3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,

[0472] (R)-3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,

[0473] (R)-3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-pentanamide,

[0474] (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)pentanamide,

[0475] (R)-3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0476] (R)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0477] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0478] (R)-3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0479] (R)-3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)-3-hydroxybutanamide,

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

[0481] (R)-3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)butanamide,

[0482] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide,

[0483] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide,

[0484] (R)-3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0485] (R)-3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide,

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

[0487] (R)-3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide, P6714PC00

[0488] (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[0489] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3- hydroxy-3-methylbutanamide,

[0490] (R)-3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)cyclopropyl)butanamide,

[0491] (R)-3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-3-hydroxybutanamide,

[0492] (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,

[0493] (R)-3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,

[0494] (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)- pyridin-2-yl)cyclopropyl)butanamide, and

[0495] (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4- trifluoro-3-hydroxy-3-methylbutanamide,

[0496] or a pharmaceutically acceptable salt thereof.

[0497] In some embodiments, the compound of the present invention is selected from the group consisting of:

[0498] (S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4- dimethylpentanamide,

[0499] (S)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0500] (S)-3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0501] (S)-3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[0502] (S)-3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- pentanamide,

[0503] (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)pentanamide,

[0504] (S)-3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide, P6714PC00

[0505] (S)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0506] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0507] (S)-3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0508] (S)-3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0509] (S)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0510] (S)-3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0511] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide,

[0512] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide,

[0513] (S)-3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0514] (S)-3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0515] (S)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0516] (S)-3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0517] (S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0518] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[0519] (S)-3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide,

[0520] (S)-3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0521] (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide, P6714PC00

[0522] (S)-3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,

[0523] (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2- trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide, and

[0524] (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4- trifluoro-3-hydroxy-3-methylbutanamide,

[0525] or a pharmaceutically acceptable salt thereof.

[0526] In some embodiments, the compound is as shown in Table A.

[0527] In one aspect, the present invention relates to a compound shown in Table A, or a pharmaceutically acceptable salt thereof.

[0528] Table A. List of compounds:

[0529] Compound ID. Structure

[0530] °Ho

[0531] H, C. JL V. ^CF,

[0532] A1a H, O

[0533] 3H

[0534] CH, A.

[0535] T OH ° w

[0536] H, C X 11 V OF,

[0537] A1b

[0538] H3C7H H N T

[0539] / - 0

[0540] A2 ^^OCF3

[0541] OHHI Jt

[0542] A3

[0543] 0H H

[0544] Cl

[0545] 0V7

[0546] A4a X^x.0. _CF3

[0547] v HU

[0548]

[0549] P6714PC00

[0550] H3CZX? V7

[0551] A4b < — N iX

[0552] V H I I]

[0553] H3CXOH ° V7

[0554] A5a z\ X YA ^CF,

[0555] V-JHk JJ

[0556] A5b

[0557] \ 7 I

[0558] Ao

[0559] < I

[0560] H3C OH O F JL ° /

[0561] A6anIZ JY o

[0562] f i v F X H H I

[0563] H3CZOH O F O

[0564] A6b

[0565] X / H [I I

[0566] v

[0567] H3CSOH° vy

[0568] H3C^ JL >4 ^CF A7a3

[0569] H-CIH,HXJ

[0570] H3CZOH ° V- 7

[0571] H, C Ji / JL J / CF, A7b

[0572] H,< XH

[0573] CH3

[0574] FH C OH O — F F^ l3< " X.#■ J ILI V y7. o x I ^F A8a

[0575] H [I I

[0576] FH C OH O — F A8b X < X5X °X

[0577] H H I

[0578] OH? V7FF kk NT XL ^o. ^ J^< F A9 F H [I I

[0579] CH3

[0580]

[0581] P6714PC00

[0582] A10

[0583] ry- °H

[0584] HO CH O

[0585] A 11a JY Yx X / x / kA-F,

[0586] Y rJr ^N H T H YI

[0587] HO CH O _

[0588] A11b 3x. Xx YC^\ / O CF3r-A

[0589] 1J H 1 HYVl

[0590] A o.

[0591] H3CS0O (

[0592] \ I

[0593] X. H A2

[0594] ° X Y7

[0595] / ^°x. CF, I z

[0596] A12a V H I I]

[0597] Br

[0598] o A12b < o

[0599] HO CH3O v-7

[0600] A13a \ V / NH T [I Y 1

[0601] Cl

[0602] HO CH, O v-,

[0603] ^3CY-NY^^^°^CF3 A13b V H H I

[0604] Cl

[0605] HO CH3O 5— 7

[0606] JL 34 JDF,, A14a V H H I

[0607] F HO CH O,

[0608] YYxY Yx ^^^O CF3A14b V H I Hl Y 1

[0609] F

[0610] V-7^ ^x N >4

[0611] V >f

[0612] H3A15a [I I

[0613] ^

[0614]

[0615] P6714PC00

[0616] HO CH30

[0617] v— r N _ ^CF,3A15bv HL J

[0618] HO CH3O

[0619] A16a v~ r N >< — _CF3

[0620] V H H I

[0621] \^ci

[0622] b HO CH3O

[0623] > O 0 0 A16b v—< N >< > > _

[0624] 0CF3 03V H |l \

[0625] | HZ

[0626] LO"

[0627] ( 0 < O \ \ I ZE zz

[0628] \ ^o=O Z T

[0629] A17a \ T IZ

[0630] ZZ

[0631] v °

[0632] T 11 o*

[0633] ^^20

[0634] < R>

[0635] 0

[0636] < 0 A17b 0

[0637] <

[0638] 0 CH, O „

[0639] H n3CC,^^N N^> f^5^ HrO^CF3A18HU. J

[0640] Cl

[0641] A19a

[0642] A19b

[0643] A20

[0644] CH, O. _,

[0645] H

[0646] HnCHJ^ II V

[0647] 3CXLA ><.<0, CF, - A21a3CH3H

[0648] Cl

[0649]

[0650] P6714PC00

[0651] CH, O. _,

[0652] M r II \7 _O.. CF, A21b T

[0653] CH3N

[0654] HL JI

[0655] Cl

[0656] A22a

[0657] HO^H3? V I

[0658] A22b

[0659] VO \. H l |]

[0660] / 3 (

[0661] HO \_ I CH

[0662] ^ yo3O

[0663] v~7 N 77x'- / '^CF3

[0664] V3A23a [I I

[0665] HO ^CH3O

[0666] ^ A X o

[0667] A23b V H [I I

[0668] <

[0669] o

[0670] jn

[0671] HO CH, Ox / < ANXrvo^CF, A24aV HL^N

[0672] Cl

[0673] HO CH, O

[0674] A24b

[0675] HC*

[0676] Cl

[0677] =JH v

[0678] A25a

[0679] vhr II ^^CH3

[0680] J ICMXNX v ^VO^CF3A25b

[0681] VH1 II ^XXH3

[0682] HO, 0 _FA26a F X"FF H<>°F

[0683]

[0684] P6714PC00

[0685] HO o

[0686] A26b FF HO-°^FHO CH3O

[0687] CF3z^X3A27a H L JI

[0688] Cl

[0689] HO CH3O

[0690] JD.. CF, CF3N- "r^> T 5 ■ A27b IZ

[0691] H I J

[0692] Cl

[0693] ZI

[0694] A28a

[0695] £< °

[0696] / 0

[0697] OX H'

[0698] OH O „ ij F.. CHy V7H| F A28b

[0699] V H I I]

[0700] HO CH3O „

[0701] _ CF, A29a | > J H H I

[0702] Cl

[0703] HO CH3O

[0704] _ CF3A29b l y| H H I

[0705] Cl

[0706] HO CH3O

[0707] A30a CF3X^ ^N^ >4>< X^. OF,

[0708] 'Y'3HI I]

[0709] HO CH3O

[0710] A30b r C'cFX3X^^JX\.N / >4^^ X y ^CF33

[0711] HI I]

[0712] HO CH3O

[0713] J-U^ JSL CL ^CF, A31a

[0714] VH l |]

[0715]

[0716] P6714PC00

[0717] HO CH3O

[0718] X JL JSL, O. ^CF,

[0719] A31b

[0720] v H I H

[0721] HO CH,0 ^—7 i_i

[0722] A32CXXX / VN^CF3

[0723] HOH O v—, F

[0724] \7 | > F

[0725] CF^^^ N A.7^ / N. X F

[0726] A33a H L I]

[0727] Cl

[0728] OH O — F

[0729] r*

[0730] -KC

[0731] AHy V i /

[0732] ^o. XF

[0733] CF^ — >< — F

[0734] A33b H L I]

[0735] Cl

[0736]

[0737] In some embodiments, the compound is selected from the group consisting of:

[0738] N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4-dimethylpentan-amide,

[0739] 2-(1-hydroxycyclopentyl)-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)acetamide, N-(1 -(3-chloro-5-(2, 2, 2-trifluoroethoxy)phenyl)cyclopropyl)-2-(3,3-difluoro-1 -hydroxy-cyclobutyl)acetamide,

[0740] 3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, 3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pentan-amide,

[0741] 5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-pentanamide,

[0742] 2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-methyl-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)acetamide,

[0743] 2-(2-hydroxyspiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-acetamide,

[0744] 3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclo-propyl)butanamide,

[0745] N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxy-butanamide, P6714PC00

[0746] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxy-butanamide,

[0747] 3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0748] 3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0749] N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0750] 3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,

[0751] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,3-dimethylbutanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide, N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(5-hydroxyspiro-[2.3]hexan-5-yl)acetamide,

[0752] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide, 3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0753] 3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0754] N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0755] 3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0756] 3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[0757] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[0758] 3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)-cyclopropyl)butanamide,

[0759] 3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- 3-hydroxybutanamide,

[0760] 4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,

[0761] 3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)

[0762] cyclopropyl)butanamide, P6714PC00

[0763] 4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide, and

[0764] N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[0765] or a pharmaceutically acceptable salt thereof.

[0766] In some embodiments, the compound is selected from the group consisting of:

[0767] (R)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4-dimethylpentanamide,

[0768] (R)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0769] (R)-3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0770] (R)-3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0771] (R)-3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pentanamide,

[0772] (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pentanamide,

[0773] (R)-3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0774] (R)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0775] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0776] (R)-3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0777] (R)-3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0778] (R)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0779] (R)-3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0780] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide, P6714PC00

[0781] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide,

[0782] (R)-3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0783] (R)-3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0784] (R)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0785] (R)-3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0786] (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0787] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[0788] (R)-3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide,

[0789] (R)-3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0790] (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,

[0791] (R)-3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,

[0792] (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide, and

[0793] (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[0794] or a pharmaceutically acceptable salt thereof..

[0795] In some embodiments, the compound is selected from the group consisting of:

[0796] (S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4-dimethylpentanamide,

[0797] (S)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0798] (S)-3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, P6714PC00

[0799] (S)-3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0800] (S)-3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pentanamide,

[0801] (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pentanamide,

[0802] (S)-3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0803] (S)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0804] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0805] (S)-3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0806] (S)-3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0807] (S)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0808] (S)-3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0809] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide,

[0810] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide,

[0811] (S)-3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0812] (S)-3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0813] (S)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[0814] (S)-3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[0815] (S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide, P6714PC00

[0816] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[0817] (S)-3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide,

[0818] (S)-3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[0819] (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,

[0820] (S)-3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,

[0821] (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide, and

[0822] (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[0823] or a pharmaceutically acceptable salt thereof.

[0824] Kv7 modulation

[0825] As demonstrated in Example 34, 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.

[0826] In some embodiments, the compound is able to modulate the activity of a Kv7 channel. In some embodiments, the compound is able to increase the activity of a Kv7.2 / Kv7.3 heteromeric channel. In some embodiments, the compound is an agonist of a Kv7 channel.

[0827] 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. In some embodiments, the compound is for use in a method of increasing the activity of a Kv7.2 / Kv7.3 heteromeric channel in a subject.

[0828] 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 P6714PC00

[0829] 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.

[0830] In some embodiments, the EC50is measured in an in vitro cell-based assay of ion flux, such as a Thallium ion (Tl+) assay, such as described in Example 34.

[0831] In some embodiments, the compound is able to produce an increase in the activity of the Kv7.2 / Kv7.3 heteromeric channel, with an EC50of less than 50 µM, such as less than 20 µM, such as less than 10 µM, such as less than 1 µM, such as less than 0.1 µM, such as less than 0.06 µM, such as less than 0.01 µM, such as less than 0.001 µM.

[0832] In some embodiments, the compound is able to produce an increase in the activity of the Kv7.2 / Kv7.3 heteromeric channel, with an EC50from about 0.1 nM to about 20 µM, such as from about 0.1 nM to about 10 µM, such as from about 0.1 nM to about 1 µM, such as from about 0.1 nM to about 0.2 µM, such as from 0.1 nM to about 100 nM, such as from about 0.1 nM to about 10 nM.

[0833] In some embodiments, the compound has an efficacy, for example determined as described in Example 34, 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%.

[0834] In some embodiments, the compound is able to increase in the activity of the Kv7.5 channel, with an EC50from about 0.1 nM to about 20 µM, such as from about 0.1 nM to about 10 µM, such as from about 0.1 nM to about 1 µM, such as from about 0.1 nM to about 0.2 µM, such as from 0.1 nM to about 100 nM, such as from about 0.1 nM to about 10 nM. In some embodiments, the Kv7.5 ECso is more than 30 pM. In some embodiments, the compound is for use in a method of increasing the activity of a Kv7.5 channel in a subject. In some embodiments, the compound is for use in a method of increasing the activity of a Kv7.5 channel in a subject. In some embodiments, 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 some embodiments, the compound has an efficacy for Kv7.5 of less than 25%. P6714PC00

[0835] Selective Kv7 modulation

[0836] 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 some embodiments, the compound is selective for Kv7.2 / Kv7.3.

[0837] In some embodiments, the compound is selective for Kv7.2 / Kv7.3 over Kv7.5. Selectivity for Kv7.2 / Kv7.3 over Kv7.5 may for example be observed in terms of efficacy selectivity. Efficacy may for example be determined as in Example 34. In some embodiments, the compound is efficacy selective. The term ‘efficacy selectivity’ as used herein refers to that the efficacy is larger than 50% at Kv7.2 / Kv7.3 and less than 25% at Kv7.5, relative to 30 uM retigabine.

[0838] In some embodiments, 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 some embodiments, 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 some embodiments, the compound has an efficacy for Kv7.5 of less than 25%. In some embodiments, the compound has an efficacy for Kv7.2 / Kv7.3 larger than 50%, and an efficacy for Kv7.5 of less than 25%. In some embodiments, the compound has an efficacy for Kv7.2 / Kv7.3 larger than 50%, such as larger than 60%, and an efficacy for Kv7.5 of less than 25%.

[0839] In some embodiments, the compound has an EC50for Kv7.2 / Kv7.3 of less than 10 µM and an EC50for Kv7.5 of more than 20 µM, such as more than 30 µM.

[0840] Preparation of compounds

[0841] 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 P6714PC00

[0842] 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.

[0843] 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.

[0844] 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.

[0845] Pharmaceutically Acceptable Salts

[0846] 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.

[0847] Pharmaceutical compositions

[0848] 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 aspect, the present disclosure provides a pharmaceutical composition comprising a compound as described herein. In some embodiments, 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.

[0849] 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. P6714PC00

[0850] 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.

[0851] 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.

[0852] 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.

[0853] Medical use

[0854] 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.

[0855] In another aspect, the present disclosure provides a compound as described herein for use as a medicament. In another aspect, the present disclosure provides a use of a compound or a pharmaceutical composition comprising a compound as described herein, for the manufacture of a medicament for a disease or condition. P6714PC00

[0856] In another aspect, the present disclosure provides a method of treatment of a disease or condition in a subject, the method comprising administering an effective amount of a compound as described herein, or a pharmaceutical composition thereof, to the subject.

[0857] In another aspect, the present disclosure provides a compound as described herein, or a pharmaceutical composition thereof, for use in a method of modulating the activity of a Kv7 channel in a subject, said method comprising administering an effective amount of the compound as described herein to the subject.

[0858] In some embodiments, the method increases the activity of a Kv7.2 / Kv7.3 heteromeric channel.

[0859] 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.

[0860] 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.

[0861] 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.

[0862] In another aspect, the present disclosure provides a compound as described herein, or a pharmaceutical composition thereof, for use in a 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.

[0863] In another aspect, the present disclosure provides a use of a compound as described herein, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment, prevention or alleviation of epilepsy or pain. P6714PC00

[0864] In another aspect, the present disclosure provides a method of treatment, prevention or alleviation of epilepsy or pain in a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound as described herein, or a pharmaceutical composition thereof to the subject in need thereof.

[0865] The term " treatment" as used herein to describe the present invention, means that the compound or pharmaceutical composition is administered to a subject to stop or reduce the relevant condition or symptom of said condition from occurring in a subject. Thus, unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition (or any symptom thereof), or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment").

[0866] The term "preventive treatment" or “prevention”, as used herein to describe the present invention, means that the compound, or pharmaceutical composition, is administered to a subject to reduce the extent of or development of the relevant condition or symptom of said condition from occurring in a subject. The term "preventive treatment" thus also refers to the compound, or pharmaceutical composition, being administered to a subject to inhibit or stop or reduce the risk of the relevant condition or symptom of said condition from occurring in a subject.

[0867] Items

[0868] 1. A compound according to formula (I):

[0869]

[0870] formula (I)

[0871] or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein

[0872] B is of formula (II): P6714PC00

[0873] R1

[0874]

[0875] formula (II)

[0876] R1is selected from the group consisting of –OH and -CH3;

[0877] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0878] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0879] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0880] R3is -H or-CH3;

[0881] or R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0882] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;

[0883] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[0884] A is of formula (III):

[0885] A3

[0886]

[0887] ^A4"

[0888] formula (III)

[0889] wherein

[0890] A1is C-R5or N;

[0891] R5is selected from -H, or halogen;

[0892] A2is C-R6;

[0893] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H); P6714PC00

[0894] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0895] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[0896] A3is C-R7or N;

[0897] R7is -H, halogen, or C1-5 alkyl;

[0898] A4is C-R8or N;

[0899] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN;

[0900] A5is C-R9or N; and

[0901] R9is -H or halogen.

[0902] 2. A compound according to formula (I):

[0903]

[0904] formula (I)

[0905] or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein

[0906] B is of formula (II):

[0907]

[0908] formula (II)

[0909] R1is selected from the group consisting of –OH and -CH3;

[0910] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0911] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0912] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0913] R3is -H or-CH3; P6714PC00

[0914] or R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0915] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;

[0916] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[0917] A is of formula (III):

[0918]

[0919] formula (III)

[0920] wherein

[0921] A1is C-R5or N;

[0922] R5is selected from -H, or halogen;

[0923] A2is C-R6;

[0924] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);

[0925] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0926] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[0927] A3is C-R7or N;

[0928] R7is -H, halogen, or C1-5 alkyl;

[0929] A4is C-R8or N;

[0930] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN;

[0931] A5is C-R9or N; and

[0932] R9is -H or halogen;

[0933] with the proviso that the compound is not

[0934] 3-Hydroxy--[1-(3-methoxyphenyl)cyclopropyl]-3-methylbutanamide. P6714PC00

[0935] 3. The compound according to any one of the preceding items, wherein B is of formula (II):

[0936] R1

[0937]

[0938] formula (II)

[0939] wherein

[0940] R1is selected from the group consisting of –OH and -CH3;

[0941] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0942] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0943] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0944] R3is -H or -CH3.

[0945] 4. A compound according to formula (I):

[0946]

[0947] formula (I)

[0948] or a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer thereof, or a mixture thereof; or a pharmaceutically acceptable salt thereof; wherein

[0949] B is of formula (II):

[0950] R1

[0951]

[0952] formula (II)

[0953] R1is selected from the group consisting of –OH and -CH3; P6714PC00

[0954] R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);

[0955] R4is C1-5 alkyl, halogen or C1-5 haloalkyl;

[0956] G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; and

[0957] R3is -H or-CH3;

[0958] or R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[0959] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;

[0960] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[0961] A is phenyl or pyridinyl, optionally substituted with one or more substituents R5, R6, R7, R8and / or R9,

[0962] R5is -H or halogen;

[0963] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);

[0964] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[0965] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[0966] R7is -H, halogen, or C1-5 alkyl;

[0967] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN; and

[0968] R9is -H or halogen.

[0969] 5. The compound according to items 1 or 2, wherein the compound is of formula (la), formula (lb) or a mixture thereof P6714PC00

[0970] formula (la)

[0971]

[0972] formula (lb).

[0973] 6. The compound according to items 1 or 2, wherein the compound is of formula (la)

[0974]

[0975] formula (la)

[0976] 7. The compound according to items 1 or 2, wherein the compound is of formula (lb)

[0977]

[0978] formula (lb).

[0979] 8. The compound according to any one of the preceding items, wherein R1is -OH.

[0980] 9. The compound according to any one of the preceding items, wherein R1is - CH3.

[0981] 10. The compound according to any one of the preceding items, wherein R2is -C1-10alkyl optionally substituted with one or more, identical or different, substituents R4. P6714PC00

[0982] 11. The compound to any one of the preceding items, wherein R2is C1-5alkyl optionally substituted with one or more, identical or different substituents R4.

[0983] 12. The compound according to any one of the preceding items, wherein R2is C1alkyl optionally substituted with one or more, identical or different substituents R4.

[0984] 13. The compound according to any one of the preceding items, wherein R2is C2alkyl optionally substituted with one or more, identical or different substituents R4.

[0985] 14. The compound according to any one of the preceding items, wherein R2is C3alkyl optionally substituted with one or more, identical or different substituents R4.

[0986] 15. The compound according to any one of the preceding items, wherein R2is C4alkyl optionally substituted with one or more, identical or different substituents R4.

[0987] 16. The compound according to any one of the preceding items, wherein R2is C5alkyl optionally substituted with one or more, identical or different substituents R4.

[0988] 17. The compound according to any one of the preceding items, wherein R2is C1-10 alkyl and has 1 to 5 R4substituents.

[0989] 18. The compound according to any one of the preceding items, wherein R2is C1-2 alkyl and has two R4substituents.

[0990] 19. The compound according to any one of the preceding items, wherein R2is C1-2 alkyl and has three R4substituents.

[0991] 20. The compound according to any one of the preceding items, wherein the one or more R4substituents are on the same carbon.

[0992] 21. The compound according to any one of the preceding items, wherein R2is a C1- 2 alkyl and has two or three substituents R4on the same carbon.

[0993] 22. The compound according to any one of the preceding items, wherein R4is selected from halogen, -CF3 and C1-5 alkyl.

[0994] 23. The compound according to any one of the preceding items, wherein R4is independently halogen.

[0995] 24. The compound according any one of the preceding items, wherein R4is F. P6714PC00

[0996] 25. The compound according to any one of the preceding items, wherein R4is independently C1-5 haloalkyl.

[0997] 26. The compound according to any one of the preceding items, wherein R4is independently Ci haloalkyl.

[0998] 27. The compound according to any one of the preceding items, wherein R4is -CF3.

[0999] 28. The compound according to any one of the preceding items, wherein R2is - CF3.

[1000] 29. The compound according to any one of the preceding items, wherein R2is – CH2CF3.

[1001] 30. The compound according to any one of the preceding items, wherein R4is independently C1-5 alkyl.

[1002] 31. The compound according to any one of the preceding items, wherein R4is independently C1-3 alkyl.

[1003] 32. The compound according to any one of the preceding items, wherein R4is - CH3.

[1004] 33. The compound according to any one of the preceding items, wherein R2is a C1- 5 alkyl, such as a Ci, C2, C3, C4 or C5 alkyl.

[1005] 34. The compound according to any one of the preceding items, wherein R2is tert-butyl.

[1006] 35. The compound according to any one of the preceding items, wherein R2is - CH3.

[1007] 36. The compound according to any one of the preceding items, wherein R2is C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6-membered ring together with the intervening atom(s).

[1008] 37. The compound according to any one of the preceding items, wherein R2is C3-6 cycloalkyl optionally substituted with one or more R4.

[1009] 38. The compound according to any one of the preceding items, wherein R2is C3 cycloalkyl optionally substituted with one or more R4. P6714PC00

[1010] 39. The compound according to any one of the preceding items, wherein R2is cyclopropyl.

[1011] 40. The compound according to any one of the preceding items, wherein R2is C4 cycloalkyl optionally substituted with one or more R4.

[1012] 41. The compound according to any one of the preceding items wherein R2is cyclobutyl substituted with one or more R4.

[1013] 42. The compound according to any one of the preceding items wherein R2is cyclobutyl substituted with one or more halogen.

[1014] 43. The compound according to any one of the preceding items wherein R2is cyclobutyl substituted with one or more F.

[1015] 44. The compound according to any one of the preceding items wherein R2is cyclobutyl substituted with two F.

[1016] 45. The compound according to any one of the preceding items wherein R2is / e_

[1017] F^ XZ

[1018] 46. The compound according to any one of the preceding items, wherein R2is cyclobutyl.

[1019] 47. The compound according to any one of the preceding items, wherein R2is C5 cycloalkyl optionally substituted with one or more R4.

[1020] 48. The compound according to any one of the preceding items, wherein R2is cyclopentyl.

[1021] 49. The compound according to any one of the preceding items, wherein R2is F^ / X e selected from cyclopropyl, cyclobutyl, cyclopentyl, or F XZ P6714PC00

[1022] 50. The compound according to any one of the preceding items, wherein R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s), wherein G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4.

[1023] 51. The compound according to any one of the preceding items, wherein R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 3-membered ring together with the intervening atom(s).

[1024] 52. The compound according to any one of the preceding items, wherein R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 4-membered ring together with the intervening atom(s).

[1025] 53. The compound according to any one of the preceding items, wherein R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 5-membered ring together with the intervening atom(s).

[1026] 54. The compound according to any one of the preceding items, wherein R2is C3-6 cycloalkyl substituted with two substituents G1together forming a 6-membered ring together with the intervening atom(s).

[1027] 55. The compound according to any one of the preceding items, wherein R2is C4 cycloalkyl substituted with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s).

[1028] 56. The compound according to any one of the preceding items, wherein R2is C4 cycloalkyl substituted with two substituents G1together forming a 3- to 4- membered ring together with the intervening atom(s).

[1029] 57. The compound according to any one of the preceding items, wherein R2is C4 cycloalkyl substituted with two substituents G1together forming a 3-membered ring together with the intervening atom(s).

[1030] 58. The compound according to any one of the preceding items, wherein the two G1are bound to the same carbon. P6714PC00

[1031] 59. The compound according to any one of the preceding items, wherein R2is

[1032]

[1033] 60. The compound according to any one of the preceding items, wherein R2is C4 cycloalkyl substituted with two substituents G1together forming a 4-membered ring together with the intervening atom(s).

[1034] 61. The compound according to any one of the preceding items, wherein R2is

[1035]

[1036] 62. The compound according to any one of the preceding items, wherein R2is C6cycloalkyl substituted with two substituents G1together forming a 6-membered ring together with the intervening atom(s).

[1037] 63. The compound according to any one of the preceding items, wherein the two G1are bound to different carbons.

[1038] 64. The compound according to any one of the preceding items, wherein R2is

[1039]

[1040] 65. The compound according any one of the preceding items, wherein R3is -CH3.

[1041] 66. The compound according to any one of the preceding items, wherein R3is H.

[1042] 67. The compound according to any one of the preceding items, wherein R1is -OH or -CH3and R3is -CH3or H.

[1043] 68. The compound according to any one of the preceding items, wherein R1is -OH and R3is -CH3.

[1044] 69. The compound according to any one of the preceding items, wherein R1is -OH and R3is H.

[1045] 70. The compound according to any one of the preceding items, wherein R1is -CH3 and R3is -CH3. P6714PC00

[1046] 71. The compound according to any one of the preceding items, wherein R1is -CH3 and R3is H.

[1047] 72. The compound according to any one of the preceding items, wherein B is of formula (II):

[1048] R1

[1049] R2

[1050]

[1051] R3

[1052] formula (II)

[1053] wherein

[1054] R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[1055] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl; and

[1056] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11.

[1057] 73. The compound according to any one of the preceding items, wherein R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s).

[1058] 74. The compound for use according to any one of the preceding items, wherein the compound is of formula (IV):

[1059]

[1060] Formula (IV)

[1061] wherein

[1062] R1is selected from the group consisting of –OH and -CH3;

[1063] R2and R3form a 3- to 6-membered ring together with the intervening atom, P6714PC00

[1064] R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);

[1065] R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;

[1066] G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;

[1067] A1is C-R5or N;

[1068] R5is selected from -H, or halogen;

[1069] A2is C-R6;

[1070] R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);

[1071] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;

[1072] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;

[1073] A3is C-R7or N;

[1074] R7is -H, halogen, or C1-5 alkyl;

[1075] A4is C-R8or N;

[1076] R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN;

[1077] A5is C-R9or N; and

[1078] R9is -H or halogen.

[1079] 75. The compound according to any one of the preceding items, wherein R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11.

[1080] 76. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl.

[1081] 77. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form a 4-membered ring substituted with one or P6714PC00

[1082] more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s).

[1083] 78. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl substituted with one or more, identical or different substituents R11.

[1084] 79. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl substituted with one or more halogens.

[1085] 80. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl substituted with one or more F.

[1086] 81. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl substituted with two R11.

[1087] 82. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl substituted with one or more, identical or different substituents R11, wherein there are two R11substituents on the same carbon.

[1088] 83. The compound according to items any one of the preceding items, wherein R11is halogen.

[1089] 84. The compound according to items any one of the preceding items, wherein R11is F.

[1090] 85. The compound according to any one of the preceding items, wherein R2and R3are individually C1-3 alkanediyl and linked together to form a 3- to 6-membered ring, and the formed ring is substituted with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s).

[1091] 86. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl substituted with two substituents P6714PC00

[1092] G2together forming a 3- to 6-membered ring together with the intervening atom(s).

[1093] 87. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl substituted with two substituents G2together forming a 3- to 4-membered ring together with the intervening atom(s).

[1094] 88. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl substituted with two substituents G2together forming a 3-membered ring together with the intervening atom(s).

[1095] 89. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclobutyl substituted with two substituents G2together forming a 4-membered ring together with the intervening atom(s).

[1096] 90. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form a 5-membered ring substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s).

[1097] 91. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclopentyl substituted with one or more, identical or different substituents R11.

[1098] 92. The compound according to items any one of the preceding items, wherein R2and R3are linked together to form cyclopentyl.

[1099] 93. The compound according to any one of the preceding items, wherein two G2substituents on the same carbon are together forming a 3- to 6-membered ring.

[1100] 94. The compound according to any one of the preceding items, wherein two G2substituents on the same carbon are together forming a 3-membered ring. P6714PC00

[1101] 95. The compound according to any one of the preceding items, wherein two G2substituents on the same carbon are together forming a 4-membered ring.

[1102] 96. The compound according to items any one of the preceding items, wherein B is

[1103]

[1104] 97. The compound according to items any one of the preceding items, wherein B is

[1105]

[1106] 98. The compound according to items any one of the preceding items, wherein B is

[1107] R1

[1108]

[1109] 99. The compound according to items any one of the preceding items, wherein B is

[1110]

[1111] 100. The compound according to items any one of the preceding items,

[1112] OH

[1113] wherein

[1114]

[1115] B is

[1116] 101. The compound according to items any one of the preceding items,

[1117] OH

[1118] wherein

[1119]

[1120] B is

[1121] 102. The compound according to items any one of the preceding items,

[1122] OH

[1123] wherein

[1124]

[1125] B is P6714PC00

[1126] 103. The compound according to items any one of the preceding items, wherein B is

[1127] _ _ OH

[1128]

[1129] 104. The compound according to any one of the preceding items, wherein R2is C1-10 alkyl, optionally substituted with one or more, identical or different, substituents R4, wherein R4is selected from halogen, -CF3, C1-5 alkyl and R3is - CH3.

[1130] 105. The compound according to any one of the preceding items, wherein R2is C1-6 alkyl optionally substituted with one or more, identical or different, substituents R4, wherein R4is halogen, R3is -CH3, and R1is -OH.

[1131] 106. The compound according to any one of the preceding items, wherein R2is C1-6 alkyl optionally substituted with one or more F, R3is -CH3, and R1is -OH.

[1132] 107. The compound according to any one of the preceding items, wherein R1is -OH or -CH3,

[1133] R2is -CH3, -tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF3,-CH2CF3,

[1134]

[1135] R3is -H or -CH3.

[1136] 108. The compound according to any one of the preceding items, wherein R2is -CH3, R3is -CH3, and R1is -CH3.

[1137] 109. The compound according to any one of the preceding items, wherein R2is – tert-butyl, R3is -CH3, and R1is –OH.

[1138] 110. The compound according to any one of the preceding items, wherein R2is – tert-butyl, R3is H, and R1is –CH3. P6714PC00

[1139] 111. The compound according to any one of the preceding items, wherein R2is - tert-butyl, R3is H, and R1is -OH.

[1140] 112. The compound according to any one of the preceding items, wherein R2is -CH2CF3, R3is -CH3, and R1is –OH.

[1141] 113. The compound according to any one of the preceding items, wherein R2is -CF3, R3is -CH3, and R1is -OH.

[1142] 114. The compound according to any one of the preceding items, wherein R2is C3-6 cycloalkyl optionally substituted with one or more R4, wherein R4is -F, and R3is -CH3.

[1143] 115. The compound according to any one of the preceding items, wherein R2is C3-6 cycloalkyl optionally substituted with one or more R4, wherein R4is -F, R3is -CH3, and R1is -OH.

[1144] 116. The compound according to any one of the preceding items, wherein R2is cyclopropyl, R3is -CH3, and R1is -OH.

[1145] 117. The compound according to any one of the preceding items, wherein R2is cyclopropyl, R3is -H, and R1is -CH3.

[1146] 118. The compound according to any one of the preceding items, wherein R2is cyclopropyl, R3is -H, and R1is -OH.

[1147] 119. The compound according to any one of the preceding items, wherein R2is cyclobutyl, R3is -CH3, and R1is -OH.

[1148] 120. The compound according to any one of the preceding items, wherein R2is cyclopentyl, R3is -CH3, and R1is -OH.

[1149] 121. The compound according to any one of the preceding items, wherein R2is F-

[1150]

[1151] F, R3is -CH3, and R1is -OH. P6714PC00

[1152] 122. The compound according to any one of the preceding items, wherein R2is

[1153]

[1154] , R3is -CH3, and R1is -OH.

[1155] 123. The compound according to any one of the preceding items, wherein R2is

[1156]

[1157] , R3is -CH3, and R1is -OH.

[1158] 124. The compound according to any one of the preceding items, wherein R2is

[1159]

[1160] , R3is -CH3, and R1is -OH.

[1161] 125. 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.

[1162] 126. The compound according to any one of the preceding items, wherein A is phenyl optionally substituted with one substituent R5, R6, R7, R8or R9.

[1163] 127. The compound according to any one of the preceding items, wherein A is phenyl optionally substituted with two substituents R5, R6, R7, R8and / or R9. 128. 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.

[1164] 129. 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.

[1165] 130. 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.

[1166] 131. The compound according to any one of the preceding items, wherein A is pyridin-2-yl optionally substituted with two substituents R5, R6, R7, R8and / or R9.

[1167] 132. The compound according to any one of the preceding items, wherein A is pyridin-4-yl optionally substituted with one or more substituents R5, R6, R7, R8and / or R9.

[1168] 133. The compound according to any one of the preceding items, wherein A is pyridin-4-yl optionally substituted with one substituent R5, R6, R7, R8and / or R9. P6714PC00

[1169] 134. The compound according to any one of the preceding items, wherein A is pyridin-4-yl optionally substituted with two substituents R5, R6, R7, R8and / or R9.

[1170] 135. The compound according to any one of the preceding items, wherein at least one of R5, R6, R7, R8and / or R9are not H.

[1171] 136. 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.

[1172] 137. The compound according to any one of the preceding items, wherein one of A1or A3is N.

[1173] 138. 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.

[1174] 139. 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.

[1175] 140. The compound according to any one of the preceding items, wherein at least one of A1, A2, A3, A4and A5is not -CH.

[1176] 141. The compound according to any one of the preceding items, wherein at least one of A1, A3, A4and A5is not -CH.

[1177] 142. The compound according to any one of the preceding items, wherein A1is N.

[1178] 143. The compound according to any one of the preceding items, wherein A1is C-R5.

[1179] 144. The compound according to any one of the preceding items, wherein R5is -H.

[1180] 145. The compound according to any one of the preceding items, wherein R5is halogen.

[1181] 146. The compound according to any one of the preceding items, wherein R5is -F."

[1182] 147. The compound according to any one of the preceding items, wherein R5is -H or-F."

[1183] 148. The compound according to any one of the preceding items, wherein R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H); wherein P6714PC00

[1184] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12selected from halogen, C3-5 cycloalkyl or C1-3 alkyl.

[1185] 149. The compound according to any one of the preceding items, wherein R6is C1-5 alkoxy optionally substituted with one or more -F; C1-5 alkyl optionally substituted with one or more -F; or N(R10)(H);

[1186] wherein R10is C1-5 alkyl optionally substituted with one or more R12.

[1187] 150. The compound according to any one of the preceding items, wherein R6is C1-5 alkoxy optionally substituted with one or more halogen.

[1188] 151. The compound according to any one of the preceding items, wherein R6is C2-5 alkoxy optionally substituted with one or more halogen.

[1189] 152. The compound according to any one of the preceding items, wherein R6is C1-5 alkoxy.

[1190] 153. The compound according to any one of the preceding items, wherein R6is C2-5 alkoxy.

[1191] 154. The compound according to any one of the preceding items, wherein R6is C1-5 alkoxy substituted with one or more halogen.

[1192] 155. The compound according to any one of the preceding items, wherein R6is C1-5 alkoxy substituted with one or more -F.

[1193] 156. The compound according to any one of the preceding items, wherein R6is C1-2 alkoxy substituted with one or more -F.

[1194] 157. The compound according to any one of the preceding items, wherein R6is C2 alkoxy substituted with one or more -F.

[1195] 158. The compound according to any one of the preceding items, wherein R6is Ci alkoxy substituted with one or more -F.

[1196] 159. The compound according to any one of the preceding items, wherein R6is C1-5 alkyl optionally substituted with one or more halogen.

[1197] 160. The compound according to any one of the preceding items, wherein R6is C1-5alkyl.

[1198] 161. The compound according to any one of the preceding items, wherein R6is C1-5 alkyl substituted with one or more halogen. P6714PC00

[1199] 162. The compound according to any one of the preceding items, wherein R6is C1-5alkyl substituted with one or more -F.

[1200] 163. The compound according to any one of the preceding items, wherein R6is C1alkyl substituted with one or more -F.

[1201] 164. The compound according to any one of the preceding items, wherein R6is N(R10)(H) wherein

[1202] R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12; and

[1203] R12is halogen, C3-5 cycloalkyl or C1-3 alkyl.

[1204] 165. The compound according to any one of the preceding items, wherein R10is C1-5 alkyl substituted with one or more, identical or different, substituents R12.

[1205] 166. 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.

[1206] 167. The compound according to any one of the preceding items, wherein R10is C2 alkyl optionally substituted with one or more, identical or different, substituents R12.

[1207] 168. The compound according to any one of the preceding items, wherein R12is halogen.

[1208] 169. The compound according to any one of the preceding items, wherein R12is -F.

[1209] 170. The compound according to any one of the preceding items, wherein R6is N(R10)(H), wherein R10is C1-5 alkyl optionally substituted with one or more -F.

[1210] 171. The compound according to any one of the preceding items, wherein R6is -CF3, -OCF3, -OCH2CF3,or -NHCH2CF3.

[1211] 172. The compound according to any one of the preceding items, wherein R6is -CF3.

[1212] 173. The compound according to any one of the preceding items, wherein R6is -OCF3. P6714PC00

[1213] 174. The compound according to any one of the preceding items, wherein R6is -OCH2CF3.

[1214] 175. The compound according to any one of the preceding items, wherein R6is -NHCH2CF3.

[1215] 176. The compound according to any one of the preceding items, wherein A3is N.

[1216] 177. The compound according to any one of the preceding items, wherein A3is C-R7.

[1217] 178. The compound according to any one of the preceding items, wherein R7is -H, halogen, or C1-5 alkyl.

[1218] 179. The compound according to any one of the preceding items, wherein R7is -H, -F, -Cl or-CH3.

[1219] 180. The compound according to any one of the preceding items, wherein R7is -H.

[1220] 181. The compound according to any one of the preceding items, wherein R7is halogen.

[1221] 182. The compound according to any one of the preceding items wherein, R7is -F.

[1222] 183. The compound according to any one of the preceding items, wherein R7is -Cl.

[1223] 184. The compound according to any one of the preceding items, wherein R7is C1-5 alkyl.

[1224] 185. The compound according to any one of the preceding items, wherein R7is -CH3.

[1225] 186. The compound according to item any one of the preceding items, wherein A4is N.

[1226] 187. The compound according to item any one of the preceding items, wherein A4is C-R8. P6714PC00

[1227] 188. The compound according to item any one of the preceding items, wherein R8is -H, halogen, C3-5 cycloalkyl, or C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN.

[1228] 189. The compound according to item any one of the preceding items, wherein R8is -H, halogen, C3-5 cycloalkyl, or C1-5 alkyl optionally substituted with one or more -F.

[1229] 190. The compound according to any one of the preceding items, wherein R8is H.

[1230] 191. The compound according to any one of the preceding items, wherein R8is halogen.

[1231] 192. The compound according to any one of the preceding items, wherein R8is -F.

[1232] 193. The compound according to any one of the preceding items, wherein R8is Cl.

[1233] 194. The compound according to any one of the preceding items, wherein R8is Br.

[1234] 195. The compound according to item any one of the preceding items, wherein R8is C3-5 cycloalkyl.

[1235] 196. The compound according to any one of the preceding items, wherein R8is cyclopropyl.

[1236] 197. The compound according to item any one of the preceding items, wherein R8is C1-5 alkyl optionally substituted with one or more halogen.

[1237] 198. The compound according to item any one of the preceding items, wherein R8is C1-5 alkyl substituted with one or more -F.

[1238] 199. The compound according to item any one of the preceding items, wherein R8is C1alkyl substituted with one or more -F.

[1239] 200. The compound according to any one of the preceding items, wherein R8is -CF2H.

[1240] 201. The compound according to item any one of the preceding items, wherein R8is C1-5 alkyl.

[1241] 202. The compound according to any one of the preceding items, wherein R8is -CH3.

[1242] 203. The compound according to any one of the preceding items, wherein R8is -H, -F, -Cl, -Br, -CH3, -CF2H, or cyclopropyl. P6714PC00

[1243] 204. The compound according to item any one of the preceding items, wherein A5is N.

[1244] 205. The compound according to item any one of the preceding items, wherein A5is C-R9.

[1245] 206. The compound according to any one of the preceding items, wherein R9is halogen.

[1246] 207. The compound according to any one of the preceding items, wherein R9is -H.

[1247] 208. The compound according to any one of the preceding items, wherein A is

[1248]

[1249] 209. The compound according to any one of the preceding items, wherein A is P6714PC00

[1250]

[1251] 210. The compound according to any one of the preceding items, wherein A is

[1252]

[1253] 211. The compound according to any one of the preceding items, wherein A is

[1254]

[1255] 212. The compound according to any one of the preceding items, wherein A is

[1256]

[1257] 213. The compound according to any one of the preceding items, wherein A is

[1258]

[1259] Cl

[1260] 214. The compound according to any one of the preceding items, wherein A is

[1261]

[1262] Br

[1263] 215. The compound according to any one of the preceding items, wherein A is

[1264]

[1265] Cl

[1266] 216. The compound according to any one of the preceding items, wherein A is

[1267]

[1268] 217. The compound according to any one of the preceding items, wherein A is P6714PC00

[1269] 218. The compound according to any one of the preceding items, wherein A is [structure image] 219. The compound according to any one of the preceding items, wherein A is

[1270]

[1271] 220. The compound according to any one of the preceding items, wherein A is [structure image] 221. The compound according to any one of the preceding items, wherein A is

[1272] 222. The compound according to any one of the preceding items, wherein A is

[1273]

[1274] Cl 223. The compound according to any one of the preceding items, wherein A is [structure image]

[1275] 224. The compound according to any one of the preceding items, wherein A is [structure image]

[1276]

[1277] 225. The compound according to any one of the preceding items, wherein A is P6714PC00

[1278]

[1279] Cl

[1280] 226. The compound according to any one of the preceding items, wherein R1is -OH or-CH3:

[1281] R2is -CH3, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF3,-CH2CF3:

[1282]

[1283] R3is -H or-CH3;

[1284] A1is N or C-R5;

[1285] R5is -H or-F;

[1286] A2is C-R6;

[1287] R6is -CF3, -OCF3, -OCH2CF3, -NHCH2CF3;

[1288] A3is C-R7;

[1289] R7is -H, -F, -Cl or-CH3;

[1290] A4is C-R8;

[1291] R8is -H, -F, -Cl, -Br, -CH3, -CF2H, or cyclopropyl;

[1292] A5is C-R9; and

[1293] R9is -H.

[1294] 227. The compound according to any one of the preceding items, wherein R1is -OH or-CH3;

[1295] R2is -CH3, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF3,-CH2CF3;

[1296] R3is -H or -CH3; and

[1297]

[1298] P6714PC00

[1299]

[1300] P6714PC00

[1301]

[1302] 229. The compound according to any one of the preceding items, wherein R1is -OH or -CH3,

[1303] R2is -CH3, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF3.-CH2CF3,

[1304] R3is -H or -CH3, and

[1305]

[1306] 230. The compound according to any one of the preceding items, wherein R1is -OH,

[1307] R2is -CH3, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF3.-CH2CF3,

[1308] R3is -CH3, and

[1309]

[1310] 231. The compound according to any one of the preceding items, wherein R1is -OH,

[1311] R2is -CH3, tert-butyl, -CF3, or -CH2CF3, P6714PC00

[1312] R3is -CH3, and

[1313]

[1314] 232. The compound according to any one of the preceding items, wherein R1is -OH,

[1315] R2is cyclopropyl, cyclobutyl, cyclopentyl,

[1316] R3is -CH3, and

[1317]

[1318] 233. The compound according to any one of the preceding items, wherein R1is -OH,

[1319] R2is cyclopropyl,

[1320] R3is -CH3, and

[1321]

[1322] 234. The compound according to any one of the preceding items, wherein R1is -OH,

[1323] R2is -CF3, P6714PC00

[1324] R3is -CH3, and

[1325]

[1326] 235. The compound according to any one of the preceding items, wherein R1is -OH;

[1327] R2is C1-5alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6cycloalkyl optionally substituted with one or more R4; R3is -CH3;

[1328] R4is halogen;

[1329] A1is C(H) or N;

[1330] R6is C1-5alkoxy optionally substituted with one or more halogen;

[1331] A3is C(H) or N;

[1332] A4is C-R8;

[1333] R8is H or halogen; and

[1334] A1is C(H).

[1335] 236. The compound according to any one of the preceding items, wherein R1is -OH;

[1336] R2is -CF3 or cyclopropyl;

[1337] R3is -CH3;

[1338] A1is C(H) or N;

[1339] A2is C(OCH2CF3);

[1340] A3is C(H) or N;

[1341] A4is C-R8;

[1342] R8is H or halogen; and

[1343] A1is C(H).

[1344] 237. The compound according to any one of the preceding items, wherein the halogen is -F.

[1345] 238. The compound according to any one of the preceding items, wherein the halogen is -Cl.

[1346] 239. The compound according to any one of the preceding items, wherein P6714PC00

[1347] the halogen is -Br.

[1348] 240. The compound according to any one of the preceding items, wherein the C1-10alkyl is C1-5alkyl.

[1349] 241. The compound according to any one of the preceding items, wherein the C1-10alkyl is C1-3alkyl.

[1350] 242. The compound according to any one of the preceding items, wherein the C1-5alkyl is C1-3alkyl.

[1351] 243. The compound according to any one of the preceding items, wherein the pyridinyl is pyridin-2-yl.

[1352] 244. The compound according to any one of the preceding items, wherein the pyridinyl is pyridin-4-yl.

[1353] 245. The compound according to any one of the preceding items, wherein the compound is not 3-Hydroxy- / V-[1-(3-methoxyphenyl)cyclopropyl]-3- methylbutanamide.

[1354] 246. The compound according to any one of the preceding items, wherein the compound is not / \ / -(1-(3-cyanophenyl)cyclopropyl)-3-hydroxy-3- methylbutanamide.

[1355] 247. The compound according to any one of the preceding items, wherein the compound is not 3,3-dimethyl- / V-(1-phenylcyclopropyl)butanamide.

[1356] 248. The compound according to any one of the preceding items, wherein the compound is not / V-(1-(4-fluorophenyl)cyclopropyl)-3,3-dimethylbutanamide.

[1357] 249. The compound according to any one of the preceding items, wherein the compound is selected from the group consisting of:

[1358] N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4- dimethylpentan-amide,

[1359] 2-(1-hydroxycyclopentyl)-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)- acetamide,

[1360] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(3,3-difluoro-1- hydroxy-cyclobutyl)acetamide,

[1361] 3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[1362] 3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[1363] 3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide, P6714PC00

[1364] 3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-pentanamide,

[1365] 5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)pentanamide,

[1366] 2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-methyl-5-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)acetamide,

[1367] 2-(2-hydroxyspiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)acetamide,

[1368] 3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclo-propyl)butanamide,

[1369] N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxy-butanamide,

[1370] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxy-butanamide,

[1371] 3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[1372] 3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide,

[1373] N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[1374] 3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-butanamide,

[1375] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,3-dimethylbutanamide,

[1376] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide,

[1377] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(5-hydroxyspiro- [2.3]hexan-5-yl)acetamide,

[1378] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide,

[1379] 3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[1380] 3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide, P6714PC00

[1381] N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3- hydroxybutanamide,

[1382] 3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[1383] 3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[1384] N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3- hydroxy-3-methylbutanamide,

[1385] 3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)- cyclopropyl)butanamide,

[1386] 3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)- phenyl)cyclopropyl)-3-hydroxybutanamide,

[1387] 4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,

[1388] 3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,

[1389] 4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2- yl)cyclopropyl)butanamide, and

[1390] N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4-trifluoro-3- hydroxy-3-methylbutanamide,

[1391] or a pharmaceutically acceptable salt thereof.

[1392] 250. The compound according to any one of the preceding items, wherein the compound is selected from the group consisting of:

[1393] (R)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4- dimethylpentanamide,

[1394] (R)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[1395] (R)-3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[1396] (R)-3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[1397] (R)-3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- pentanamide, P6714PC00

[1398] (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)pentanamide,

[1399] (R)-3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[1400] (R)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[1401] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[1402] (R)-3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[1403] (R)-3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)-3-hydroxybutanamide,

[1404] (R)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[1405] (R)-3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)butanamide,

[1406] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide,

[1407] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide,

[1408] (R)-3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[1409] (R)-3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide,

[1410] (R)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[1411] (R)-3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[1412] (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,

[1413] (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[1414] (R)-3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide, P6714PC00

[1415] (R)-3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)-3-hydroxybutanamide,

[1416] (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,

[1417] (R)-3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,

[1418] (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)- pyridin-2-yl)cyclopropyl)butanamide, and

[1419] (R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4- trifluoro-3-hydroxy-3-methylbutanamide,

[1420] or a pharmaceutically acceptable salt thereof.

[1421] 251. The compound according to any one of the preceding items, wherein the compound is selected from the group consisting of:

[1422] (S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4- dimethylpentanamide,

[1423] (S)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[1424] (S)-3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[1425] (S)-3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- butanamide,

[1426] (S)-3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)- pentanamide,

[1427] (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)pentanamide,

[1428] (S)-3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)butanamide,

[1429] (S)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3- hydroxybutanamide,

[1430] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3- hydroxybutanamide,

[1431] (S)-3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3- hydroxybutanamide, P6714PC00

[1432] (S)-3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[1433] (S)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[1434] (S)-3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[1435] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide,

[1436] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide,

[1437] (S)-3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[1438] (S)-3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[1439] (S)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,

[1440] (S)-3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[1441] (S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,

[1442] (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[1443] (S)-3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide,

[1444] (S)-3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,

[1445] (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,

[1446] (S)-3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,

[1447] (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide, and

[1448] (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,

[1449] or a pharmaceutically acceptable salt thereof. P6714PC00

[1450] 252. The compound according to any one of the preceding items, wherein the compound is able to modulate the activity of a Kv7 channel.

[1451] 253. The compound according to any one of the preceding items, wherein the compound is an agonist of a Kv7 channel.

[1452] 254. 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.

[1453] 255. 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 EC50of less than 50 µM, such as less than 20 µM, such as less than 10 µM, such as less than 1 µM, such as less than 0.1 µM, such as less than 0.06 µM, such as less than 0.01 µM, such as less than 0.001 µM.

[1454] 256. 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 EC50from about 0.1 nM to about 20 µM, such as from about 0.1 nM to about 10 µM, such as from about 0.1 nM to about 1 µM, such as from about 0.1 nM to about 0.2 µM, such as from 0.1 nM to about 100 nM, such as from about 0.1 nM to about 10 nM.

[1455] 257. The compound according to any one of the preceding items, wherein the compound is able to increase the activity of a Kv7.5 channel.

[1456] 258. The compound according to any one of the preceding items, wherein the Kv7.5 EC50is more than 30 μM.

[1457] 259. 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 EC50from about 0.1 nM to about 20 µM, such as from about 0.1 nM to about 10 µM, such as from about 0.1 nM to about 1 µM, such as from about 0.1 nM to about 0.2 µM, such as from 0.1 nM to about 100 nM, such as from about 0.1 nM to about 10 nM.

[1458] 260. The compound according to any one of the preceding items, wherein the compound is a subtype-selective Kv7 modulator.

[1459] 261. The compound according to any one of the preceding items, wherein the compound is selective for Kv7.2 / Kv7.3.

[1460] 262. The compound according to any one of the preceding items, wherein the compound is selective for Kv7.2 / Kv7.3 over Kv7.5. P6714PC00

[1461] 263. 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.

[1462] 264. The compound according to any one of the preceding items, wherein the compound has an EC50for Kv7.2 / Kv7.3 of less than 10 µM and an EC50for Kv7.5 of more than 20 µM, such as more than 30 µM.

[1463] 265. 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%.

[1464] 266. 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%.

[1465] 267. The compound according to any one of the preceding items, wherein the compound has an efficacy for Kv7.5 of less than 25%.

[1466] 268. 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%, and an efficacy for Kv7.5 of less than 25%.

[1467] 269. The compound according to any one of the preceding items, wherein the compound is efficacy selective.

[1468] 270. The compound according to any one of the preceding items, wherein the EC50is measured in an in vitro cell-based assay of ion flux, such as a Thallium ion (Tl+) assay.

[1469] 271. A pharmaceutical composition comprising the compound according to any one of items 1 to 270.

[1470] 272. A compound according to any one of items 1 to 270, or a pharmaceutical composition according to item 271, for use as a medicament.

[1471] 273. Use of a compound according to any one of items 1 to 270, or a pharmaceutical composition according to item 271, for the manufacture of a medicament for a disease or condition.

[1472] 274. 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 P6714PC00

[1473] one of items 1 to 270, or a pharmaceutical composition according to item 271 to the subject.

[1474] 275. A compound according to any one of items 1 to 270, or a pharmaceutical composition according to item 271, 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.

[1475] 276. The compound or the pharmaceutical composition for use according to item 275, wherein the method is a method of increasing the activity of a Kv7.2 / Kv7.3 heteromeric channel.

[1476] 277. A compound according to any one of items one of items 1 to 270, or a pharmaceutical composition according to item 271, 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.

[1477] 278. Use of a compound according to any one of items 1 to 270, or a pharmaceutical composition according to item 271, for the manufacture of a medicament for the treatment, prevention or alleviation of epilepsy or pain. 279. 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 270, or a pharmaceutical composition according to item 271 to the subject.

[1478] Examples

[1479] General procedure for preparation of compounds according to the present disclosure:

[1480] The compounds of the present disclosure were prepared according to the below synthetic Scheme 1. P6714PC00

[1481] Acid preparation

[1482] Coupling

[1483]

[1484] Scheme 1.

[1485] General procedures for compound-3:

[1486] 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.

[1487] 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 P6714PC00

[1488] 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.

[1489] 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.

[1490] 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.

[1491] 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.

[1492] 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 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-7. Crude compound-7 was purified using combiflash chromatography (20 to 60% EtOAc in hexane) to get pure enough compound-7.

[1493] General procedure for compound-8: To a stirred solution of compound-4 (1 eq) in DMF (10 vol) added HATU (1.5 eq), DIPEA (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.

[1494] Chiral separation: Some of the compounds described in the examples were separated into different stereoisomers using Chiral preparative HPLC. The different compounds obtained after the chiral prep HPLC are annotated based on the order the P6714PC00

[1495] compounds are obtained in, for example Peak-1 and Peak-2 (each peak corresponding to a different stereoisomer). Each peak was isolated, characterized and tested for biological evaluation as described below. For instance, Example 4 peak-1 and Example 4 peak-2 were tested in Example 34, and the two stereoisomers of Example 4 are (R)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (A4a) and (S)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (A4b). Example 4 peak-1 may be A4a or A4b, and Example 4 peak-2 the other stereoisomer. In some of the examples, the assignment of stereochemistry is arbitrary, and thus, it is possible that the stereochemistry is different, for example opposite.

[1496] Example 1a: (S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4-dimethylpentanamide

[1497] Synthesis of 4,4-dimethyl-3-oxopentanoic acid (2):

[1498] o o

[1499]

[1500] 1 M NaOH (21 mL) added to ethyl 4,4-dimethyl-3-oxopentanoate (3 g, 17.419 mmol) and stirred for 6 h. Reaction mixture extracted with Et2O (2 x 10 mL). Aqueous layer acidified and extracted with EtOAc (3x 15 mL). Organic layer further washed with brine and dried over anhydrous Na2SO4. Organic layer removed under vacuo to get compound-2 (2.1 g, 83.63%) as yellow liquid; H-NMR (DMSO-de, 400 MHz): 51.08 (s, 9 H), 2.09 (s, 2 H), 12.42 (bs, 1 H).

[1501] Synthesis of (S)-3-hydroxy-4,4-dimethylpentanoic acid (4a): To a stirred solution of compound-2 (4 g, 27.745 mmol) in dichloromethane (40 mL) added NEt3(3.87 mL, 27.745 mmol) cooled to -20 °C and added (-)-diisopinocamphenyl boranechloride (8.90 g, 27.745 mmol). Resulting reaction mixture stirred at 0 °C for 1 h then at room temperature for 12 h. Reaction was basified using 1N NaOH and extracted with Et20 (2 x 10 mL) to remove impurities. Aq. Layer acidified using 2 N HCI and extracted with EtOAc (3 x 20 mL). Combined organic layer given brine wash, dried over anhydrous Na2SO4. Organic layer removed under vacuo to get compound-4a (2.3 g, 56.70%) as off white solid; H-NMR (DMSO-d6, 400 MHz): 50.80 (s, 9 H), 2.07-2.10 (m, 1 H), 2.18-2.36 (m, 1 H), 3.51-3.57 (m, 1 H), 4.65 (bs, 1 H), 11.97 (bs, 1 H). P6714PC00

[1502] OH O

[1503]

[1504] Synthesis of 1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropan-1 -amine (7a): 4- fluoro-3-(trifluoromethyl)benzonitrile (1 g, 5.287 mmol) converted to compound-7a ( 0.43 g, 37.10%) as off white solid using general procedure used for compound-7, m / z (LC-MS): 220.00 [M+H]+. After acidification and extraction with diethyl ether compound crystalised out HCI salt.

[1505] F

[1506]

[1507] rF

[1508] Synthesis of (S)-N-(1 -(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy- 4,4-dimethylpentanamide (A1a):

[1509] OH O

[1510] N

[1511]

[1512] To a stirred solution of 4a (0.073 g, 0.502 mmol) in anhydrous DMF (2 mL) added EDC. HCI (0.131 g, 0.684 mmol) followed by HOBt (0.0692 g, 0.502 mmol) and DMAP (0.139 mmol, 1.141 mmol) was added at O OC. To this cooled solution added compound-7a (0.1 g, 0.456 mmol). Resulting reaction mixture heated at 800C for 2 h. Reaction mixture cooled to room temperature and diluted with water extracted using EtOAc (2 x 10 mL). Combined organic layer given brine wash, dried over anhydrous Na2SC>4. Organic layer removed under vacuo to get compound-A1a. It was purified further using combi flash chromatography (12 g Silica column, Eluent: 35% EtOAc in Hexane) to get Example 1a (A1a) (118 mg), H-NMR (DMSO-d6, 400 MHz): 50.82 (s, 9 H), 1.14-1.26 (m, 4 H), 2.03-2.10 (m, 1 H), 2.18-2.25 (m, 1 H), 3.49-3.55 (m, 1 H), 4.63-4.65 (d, J = 5.7 Hz, 1 H), 7.34-7.40 (m, 1 H), 7.48-7.55 (m, 2 H), 8.59 (bs, 1 H), HRMS calculated for: [C17H21F4NO2+H]+348.1581; found: 348.1588, Analytical chiral HPLC: REGIS (S, S) WHELK-01 (250X4.6mmX5|jm), Mobile phase: (A) n-HEXANE (B) 0.1% HCOOH IN EtOHL: MeOH (80:20), Isocratic: 95(A):05(B), Flow: 1 ml / min, Diluent: EtOH, Inj. volume: 5.0, (Rt: 11.339, 100% ee). P6714PC00

[1513] Example 1b: (R)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4- dimethylpentanamide

[1514] Synthesis of (R)-3-hydroxy-4,4-dimethylpentanoic acid 4b):

[1515] OH O

[1516]

[1517] To a stirred solution of compound-2 (500 mg, 3.468 mmol) in dichloromethane (5 mL) added NEt3(1.21 mL, 8.67 mL) cooled to -20 °C and added (+)-diisopinocamphenyl boranechloride (1.223 g, 3.815 mmol). Resulting reaction mixture stirred at 0 °C for 1 h then at room temperature for 6 h. Reaction was diluted with water and extracted dichloromethane (2 x 20 mL). Combined organic layer given brine wash and dried over anhydrous NaaSCL. Organic layer removed under vacuo to get compound-3 (0.4 g, 78%) as off white solid; H-NMR (DMSO-d6, 400 MHz): 50.80 (s, 9 H), 2.07 (dd, J = 10 Hz, 14.8 H), 2.36 (dd, J = 12.42 (bs, 1 H), 3.51-3.57 (m, 1 H), 4.65 (bs, 1 H), 11.97 (bs, 1 H).

[1518] Synthesis of (R)-N-(1 -(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy- 4,4-dimethylpentanamide (A1b):

[1519] OH O

[1520] N

[1521]

[1522] Following procedure used for A1a, Compound-4b (0.073 g, 0.502 mmol) converted to compound-A1b (95 mg, 69%, Rt: 11.05) as off white solid. H-NMR (DMSO-de, 300 MHz): 50.80 (s, 9 H), 1.12-1.28 (m, 4 H), 2.03-2.10 (m, 1 H), 2.18-2.25 (m, 1 H), 3.49- 3.55 (m, 1 H), 4.63-4.65 (d, J = 5.7 Hz, 1 H), 7.34-7.40 (m, 1 H), 7.48-7.55 (m, 2 H), 8.59 (bs, 1 H), HRMS calculated for: [C17H21F4NO2+H]+348.1581; found: 348.1590, Analytical Chiral HPLC: REGIS (S, S) WHELK-01 (250X4.6mmX5|jm) Mobile phase: (A) n-HEXANE (B) 0.1% HCOOH IN EtOHL: MeOH (80:20) Flow: 1.0 ml / min Diluent: EtOH, Inj. volume: 5.0, (Rt: 11.05, 100% ee), Rt: 11.05, 100% ee.

[1523] Synthesis of (R)-N-(1 -(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy- 4,4-dimethylpentanamide: P6714PC00

[1524]

[1525] Following general procedure 8, Compound-3 (0.073 g, 0.502 mmol) converted to compound-A1b (95 mg, 69%, Rt: 11.05) as off white solid. H-NMR (DMSO-de, 300 MHz): 50.80 (s, 9 H), 1.12-1.28 (m, 4 H), 2.03-2.10 (m, 1 H), 2.18-2.25 (m, 1 H), 3.49-3.55 (m, 1 H), 4.63-4.65 (d, J = 5.7 Hz, 1 H), 7.34-7.40 (m, 1 H), 7.48-7.55 (m, 2 H), 8.59 (bs, 1 H), Chiral HPLC Column: REGIS (S, S) WHELK-01 (250X4.6mmX5pm), Mobile phase: (A) n-HEXANE (B)IPA: MeOH (80:20), Isocratic: 95(A):05(B), Flow: 1 ml / min, Diluent: EtOH, Inj. volume: 5.0, Acq. method: REG_9505_8_B_30MIN.amx, HRMS calculated for: [C17H21F4NO2+H]+348.1581; found: 348.1590.

[1526] Example 2: 2-(1-hydroxycyclopentyl)-N-(1-(3-(trifluoromethoxy)phenyl)-cyclopropyl)acetamide

[1527] Synthesis of ethyl 2-(1-hydroxycyclopentyl)acetate (3c): Cyclopentanone (4 g, 23.95 mmol) converted to compound-3c (2 g, crude) as colourless liquid using general procedure A used for compound-3; H-NMR (CDCI3, 400 MHz): 5 1.53 (t, J = 3.2 Hz, 3 H), 1.60-1.62 (m, 2 H), 1.62-1.63 (m, 2 H), 1.77-1.85 (m, 4 H), 2.59 (s, 2 H), 3.37 (s, 1 H), 4.17 (q, J = 6.8 Hz, 2 H).

[1528]

[1529] Synthesis of 2-(1-hydroxycyclopentyl)acetic acid (4c): Compound-3c (1 g, 5.80 mmol) converted to compound-4c (400 mg, Crude) as yellow gummy using general procedure used for compound-4; H-NMR (DMSO-de, 400 MHz): 5 1.49-1.52 (m, 2 H), 1.58-1.62 (m, 4 H), 1.63-1.70 (m, 2 H), 4.03 (bs, 1 H), 12.06 (bs, 1 H).

[1530] L

[1531]

[1532] y^^OH

[1533] Synthesis of 2-(1 -hydroxycyclopentyl)-N-(1 -(3-(trifluoromethoxy)phenyl)-cyclopropyl)acetamide (A2): P6714PC00

[1534]

[1535] Following general procedure for compound-8, compound-4n (50 mg, 0.434 mmol) converted to compound-A2 which was purified by using prep HPLC, Column: (LUNA Phenomenex (250mmx21.2mm), 5. Op), Mobile phase: A= 0.1% HCOOH IN WATER, B= Acetonitrile; Flow: 18ml / min, Gradient program (Time: %B): 0 / 40, 2 / 50, to get compound A2 (15 mg, 12.60%) as colour less gummy; H-NMR (CD3OD, 400 MHz): 5 1.28 (s, 4 H), 1.34-1.38 (m, 4 H), 1.63-1.66 (m, 4 H), 1.70-1.81 (m 2 H), 2.48 (s, 2 H), 7.06-7.09 (m, 1 H), 7.17-7.20 (m, 2 H), 7.36 (t, J = 11.2 Hz, 1 H). HRMS calculated for:

[1536] [C17H20F3NO3+H]+344.1468; found: 344.1508.

[1537] Example 3: N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(3,3-difluoro-1- hydroxycyclobutyl)acetamide

[1538] Synthesis of ethyl 2-(3,3-difluoro-1-hydroxycyclobutyl)acetate (3o): Synthesis of ethyl 2-(3,3-difluoro-1-hydroxycyclobutyl)acetate (3d):

[1539] Cyclopentanone (1 g, 9.42 mmol) converted to compound-3d (500 mg, 27.77%) as colourless liquid using general procedure A used for compound-3; H-NMR (CDCh, 400 MHz):; H-NMR (DMSO, 400 MHz): 51.14 t, J = 4 Hz, 3 H), 2.94-3.31 (m, 6 H), 4.02- 4.06 (q, J = 2.8 Hz, 2 H), 5.84 (s, 1H).

[1540]

[1541] Synthesis of 2-(3,3-difluoro-1-hydroxycyclobutyl)acetic acid: Synthesis of 2-(1- hydroxycyclopentyl)acetic acid (4d):

[1542] Compound-3d (1 g, 5.80 mmol) converted to compounded (400 mg, Crude) as yellow gummy using general procedure used for compound-4; H-NMR (DMSO, 400 MHz): 5 2.50-2.63 (m, 2 H), 2.71-2.86 (m, 2 H), 3.10-3.32 (m, 2 H), 5.56 (s, 1H), 12.52 (bs, 1 H).

[1543] O

[1544] F'X / \r0lX

[1545]

[1546] Synthesis of N-(1 -(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(3,3- difluoro-1 -hydroxycyclobutyl)acetamide (A3): P6714PC00

[1547] F- F

[1548]

[1549] Following general procedure for compound-8, Compounded (45 mg, 0.27 mmol) converted to compound-A3 (6 mg, 5%) as off white solid; H-NMR (CD3OD, 400 MHz): 5 1.16-1.23 (m, 2 H), 1.24-1.26 (m, 3 H), 2.44-2.49 (m, 2 H), 2.49-2.56 (m 2 H), 2.66-2.86 (m, 2 H), 4.77 (q, J = 8.8 Hz, 2 H), 5.70 (s, 1 H), 6.69-6.70 (m, 1 H), 6.90-6.91 (m, 1 H), 6.96-6.97 (m, 1 H), HRMS calculated for: [C17H17ClF5NO3+H]+414.0890; found: 414.0901.

[1550] Example 4: 3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide

[1551] Synthesis of ethyl 3-cyclopropyl-3-hydroxybutanoate (3e): 1-cyclopropylethan-1-one (5 g, 59.44 mmol) converted to compound-3e (9.8 g, crude) using general procedure A used for compound-3, H-NMR (DMSO-de, 400 MHz): 54.18 (s, 1 H), 4.03 (q, J = 6 Hz, 2 H), 2.41 (s, 2 H), 1.18 (s, 3 H), 1.16-1.20 (m, 3 H), 0.92-0.94 (q, 1 H), 0.19-0.37 (m, 4 H).

[1552] OH O

[1553]

[1554] Synthesis of 3-cyclopropyl-3-hydroxybutanoic acid (4e): Compound-3e (9 g, 52.25 mmol) hydrolysed to get 4e (5.2 g, 69.33%) using general procedure used for compound-4, H-NMR (DMSO-d6, 400 MHz): 5 12.00 (bs, 1 H), 4.20 (bs, 1 H), 2.28 (s, 2 H), 1.2 (s, 3 H), 0.98 (m, 1 H), 0.19-0.38 (m, 4 H).

[1555] OH O

[1556]

[1557] Synthesis of 3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 4 peak-1 & Example 4 peak-2. A4a and A4b)): P6714PC00

[1558]

[1559] Following general procedure for compound-8, compound-4e (0.056 g, 0.388) converted to Example-4 (61 mg, 44%) as colourless gum. The enantiomers separated using Chiral prep HPLC, Column: (Chiralpak I H, 250mmX21mm, 5pm), Eluent: n-Hexane(A) EtOH: IPA,1:1(B), Flow: 15 ml / min, Isocratic: 85(A):15(B), Diluents: EtOH: DCM, 3:1, 1.4 mL, Injection volume: 0.2 mL, Run time 14 min, to get Peak-1 (21 mg), Peak-2: (25 mg), H-NMR (DMSO-d6, 400 MHz): 50.19-0.31 (m, 4 H), 0.86-0.88 (m, 1 H), 1.15 (s, 3 H), 1.12-122 (m, 4 H), 2.28-2.50 (m, 2 H), 4.55 (bs, 1 H) 4.70 (q, J = 8.8 Hz, 2 H), 6.79-6.85 (m, 3 H), 7.19-7.23 (m, 1 H), 8.58 (m, 1 H), HRMS calculated for:

[1560] [C18H22F3NO3+H-H2O]+340.1519; found: 340.1525 ( Peak-1), 340.1529 (Peak-2), Analytical chiral HPLC: CHIRALPAK-IH (150X4.6mmX5pm) Mobile Phase: A: n- HEXANE, B: IPA Isocratic: 80:20 Flow: 1.0ml / min Diluent: EtOH, Column Temp: 25°C, Peak-1 (Rt: 4.905, 100% ee) Peak-2: (Rt: 6.017, 100% ee).

[1561] Example 5: 3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide

[1562] Synthesis of Ethyl 3-cyclopentyl-3-hydroxybutanoate (3f): 1-cyclopentylethan-1- one (2.6 g, 23.17 mmol) converted to compound-3f (1.2 g, 25%) as colourless liquid using general procedure A used for compound-3; H-NMR (CDCh, 300 MHz): 51.21 (s, 3 H), 1.28 (t, J = 7.5 Hz, 3 H), 1.46-1.50 (m, 5 H), 1.59-1.68 (m, 3 H), 1.93-1.96 (m, 1H), 2.37-2.56 (m, 2 H), 3.48 (s, 1 H), 4.19 (q, J = 7.2 Hz, 2 H).

[1563]

[1564] Synthesis pf 3-cyclopentyl-3-hydroxybutanoic acid (4f): Compound-3f (1 g, 5.80 mmol) converted to compound-4f (400 mg, Crude) as yellow gummy using general procedure used for compd-4; m / z (LC-MS): 171.0 [M+H.

[1565] HO / O

[1566]

[1567] P6714PC00

[1568] Synthesis of 3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 5 peak-1 & Example 5 peak-2, A 5a and A5b):

[1569]

[1570] Following general procedure 8, Compound-4f (100 mg, 0.58 mmol) converted to Example-5 (100 mg, 44%) using compound-7d. The enantiomers separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x20mm, 5pm), Eluent: n-Hexane(A) and I PA (B), Flow: 15 ml / min, Isocratic: 80(A):20(B), diluent EtOH: DCM (1:1, 4 ML), Injection volume-0.2 mL, run time 20 min, to get Peak-1 (28.7 mg) Peak-2: (38 mg) as white solid. H-NMR (DMSO-d6, 400 MHz): 5 1.19 (s, 3 H), 1.19-1.20 (m, 2 H), 1.20-1.21 (m, 2 H), 1.45-1.58 (m, 7 H), 1.86-1.90 (m, 1 H), 2.17-2.32 (m, 2 H), 4.66 (s, 1 H), 4.71 (q, J = 9.2 Hz, 2 H), 6.79-6.85 (m, 1 H), 6.90-6.91 (m, 3 H), 7.21 (q, J = 8 Hz, 1 H), 8.58 (s, 1 H). HRMS calculated for: [C20H26F3NO3+H]+386.1938; found: 386.1953 (Peak-1 ), 386.1950 (Peak-2). Analytical Chiral HPLC: CHIRAL PAK-IH (150X4.6mmX5pm) Mobile Phase: A: n-HEXANE, B: IPA Isocratic: 80:20 Flow: 1.0ml / min Diluent: EtOH Column Temp: 25°C, Inj. volume: 5.000, Peak-1 (Rt: 5.49, 100% ee) Peak-2: (Rt: 6.88, 100% ee).

[1571] Example 6: 3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide

[1572] Synthesis of ethyl 3-cyclobutyl-3-hydroxybutanoate (3g): 1-cyclopentylethan-1-one (2 g, 8.60 mmol) converted to compound-3g (1.5 g, 93%) as colourless liquid using general procedure A used for compound-3; H-NMR (CDCh, 300 MHz): 5 1.21 (s, 3 H), 1.28 (t, J = 7.5 Hz, 3 H), 1.46-1.50 (m, 5 H), 1.59-1.68 (m, 3 H), 1.93-1.96 (m, 1H), 2.37-2.56 (m, 2 H), 3.48 (s, 1 H), 4.19 (q, J = 7.2 Hz, 2 H).

[1573]

[1574] P6714PC00

[1575] Synthesis of 3-cyclobutyl-3-hydroxybutanoic acid (4g): Compound-3g (500 mg, 2.68 mmol) converted to compound-4g (300 mg, Crude) as colourless gummy using general procedure used for compound-4; m / z (LC-MS): 157.1 [M+H]'.

[1576]

[1577] Synthesis of 3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide: (Example 6 peak-1 & Example 6 peak-2, A6a and A6b):

[1578]

[1579] Following general procedure for compound-8, Compound-4g (100 mg, 0.63 mmol) converted to Example-6 (200 mg, 94.01%) which was separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x20mm, 5pm), Eluent: n-Hexane(A) and IPA (B), Flow: 15 ml / min, Isocratic: 70(A):30(B), diluent EtOH: DCM (3:1, 4 ML), Injection volume-0.4mL, run time 15 min, to get Peak-1 (89.7 mg) Peak-2: (95.4 mg) as white solid; H-NMR (DMSO-d6, 400 MHz): 5 1.19 (s, 3 H), 1.19-1.20 (m, 2 H), 1.20-1.21 (m, 2 H), 1.45-1.58 (m, 8 H), 1.86-1.90 (m, 1 H), 2.17-2.32 (m, 2 H), 4.66 (s, 1 H), 4.71 (q, J = 9.2 Hz, 2 H), 6.79-6.85 (m, 1 H), 6.90-6.91 (m, 3 H), 7.21 (q, J = 8 Hz, 1 H), 8.58 (s, 1 H). HRMS calculated for: [C19H24F3NO3+H]+372.1781; found: 372.1799 (Peak-1), 372.1798 (Peak-2). Analytical Chiral HPLC: CHIRAL PAK-IH (150X4.6mmX5pm), Mobile phase: (A) n-HEXANE (B)IPA, Isocratic: 80(A):20(B), Flow: 1 ml / min, Diluent: EtOH, Inj. volume: 5.0, Peak-1 (Rt: 4.87, 100% ee) Peak-2: (Rt: 6.67, 100% ee).

[1580] Example 7: 3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pentanamide

[1581] Synthesis of ethyl 3-hydroxy-3,4,4-trimethylpentanoate (3h): 3,3-dimethylbutan-2-one (1.164 g, 11.618 mmol) converted to compound-3h (1.8 g, 85%) as colourless liquid using general procedure B used for compound-3; H-NMR (CDCh, 300 MHz): 5 0.90 (s, 9 H), 1.21 (s, 3 H), 1.28 (t, J = 7.5 Hz, 3 H), 2.21-2.34 (m, 2 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.97 (bs, 1 H). P6714PC00

[1582]

[1583] Synthesis of 3-hydroxy-3,4,4-trimethylpentanoic acid (4h): Compound-3h (500 mg, 2.66 mmol) converted to compound-4h (300 mg, Crude) as colourless oil using general procedure used for compound-4; m / z (LC-MS): 161.2 [M+H]'.

[1584]

[1585] Synthesis of 3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)pentanamide (Example 7 peak-1 & Example 7 peak-2, A7a and A7b):

[1586]

[1587] Following general procedure 8, Compound-4h (69 mg, 0.432 mmol) converted to Example 7 (60 mg, 37.26%) which was separated using Chiral prep HPLC, Column: (Lux Amylose-2, 250x21.2mm, 5pm), Eluent: n-Hexane(A) and 0.1% HCOOH in EtOH: MeOH 80:20 (B), Flow: 15 ml / min, Isocratic: 80(A):20(B), diluent EtOH: DCM (3:1, 4 ML), Injection volume-0.25mL, run time 20 min, to get Peak-1 (18 mg) Peak-2: (18 mg) as white solid; H-NMR (DMSO-d6, 300 MHz): 50.88 (s, 9 H), 1.07 (s, 3 H), 1.10-1.20 (m, 4 H), 2.21-2.34 (m, 2 H), 4.72 (q, J = 9 Hz, 2 H), 4.97 (bs, 1 H), 6.79-6.86 (m, 3 H), 7.19-7.24 (m, 1 H), 8.52 (bs, 1 H), 8.79 (bs, 1 H), HRMS calculated for:

[1588] [C19H26F3NO3+H]+374.1938; found: 374.1942 (Peak-1), 374.1943 (Peak-2). Analytical Chiral HPLC: LUX AMYLOSE-2 (150X4.6mmX5pm), Mobile Phase: A: n-HEXANE, B: 0.1 % HCOOH in EtOH: MeOH (80:20), Isocratic: 70:30, Flow: 1.0ml / min, Diluent: EtOH, Column Temp: 25°C, Peak-1 (Rt: 3.64, 100% ee) Peak-2: (Rt: 4.98, 100% ee).

[1589] Example 8: 5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)pentanamide

[1590] Synthesis of ethyl 5,5,5-trifluoro-3-hydroxy-3-methylpentanoate (3i): 4,4,4- trifluorobutan-2-one (2 g, 8.606 mmol) converted to compound-3i (0.8 g, 43%) as P6714PC00

[1591] colourless liquid using general procedure B used for compound-3; m / z (LC-MS):

[1592] 215.05 [M+H]+.

[1593]

[1594] Synthesis of 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid (4i): Compound-3i (0.8 g, 3.735 mmol) converted to compound-4i (0.6 g, 86.33%) as colourless oil using general procedure used for compd-4; m / z (LC-MS): 187.1 [M+H]+.

[1595]

[1596] Synthesis of 5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)pentanamide (Example 8 peak-1 & Example 8 peak-2, A8a and A8b):

[1597]

[1598] Following general procedure 8, Compound-4i (100 mg, 0.537 mmol) converted Example 8 (100 mg, 46.51%). The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IG, 250x21mm, 5pm), Eluent: n-Hexane(A) and IPA: MeOH (1:1) (B), Flow: 13 ml / min, Isocratic: 92(A):08(B), diluent EtOH (3.5 mL), Injection volume-0.05mL, run time 17 min, to get Peak-1 (56 mg) Peak-2: (23.8 mg) as white solid, H-NMR (DMSO-d6, 400 MHz): 5 1.12-1.14 (m, 2 H), 1.19-1.23 (m, 2 H), 1.26 (s, 3 H), 2.37 (s, 2 H), 2.53-2.60 (m, 2 H), 4.69 (q, J = 8.8 Hz, 2 H), 5.19 (s, 1 H), 6.77-6.85 (m, 3 H), 7.19-7.23 (m, 1 H), 8.66 (s, 1 H), HRMS calculated for: [C17H19F6NO3+H]+400.1342; found: 400.1349 (Peak-1), 400.1347 (Peak-2). Analytical chiral HPLC:

[1599] CHIRAL PAK-IG (150X4.6mmX5pm) Mobile Phase: A: n-HEXANE, B: EtOH: MeOH (50:50) Isocratic: 90:10 Flow: 1.0ml / min Diluent: EtOH, Column Temp: 25°C, Inj. volume: 5.000, Peak-1 (Rt: 5.11, 100% ee) Peak-2: (Rt: 5.29, 100% ee).

[1600] Example 9: 2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-methyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)acetamide P6714PC00

[1601] Synthesis of 3-methyl-5-(2,2,2-trifluoroethoxy)benzonitrile (6s): 3-hydroxy-5-methylbenzonitrile (500 mg, 3.75 mmol) converted to 6s (450 mg, 56%) as off white solid using general procedure used for compd-6, H-NMR (DMSO-de, 300 MHz): 52.33 (s, 3 H), 4.85 (q, J = 8.7 Hz, 2 H), 7.27 (s, 1 H), 7.35 (s, 1 H), 7.39 (s, 1 H).

[1602] CN

[1603]

[1604] Synthesis of 1 -(3-methyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1 -amine (7s): 3-methyl-5-(2,2,2-trifluoroethoxy)benzonitrile (450 mg, 4.22 mmol) converted to compound-7s ( 160 mg, 31%) as pale green solid using general procedure used for compound-7, m / z (LC-MS): 246.0 [M+H]+. After acidification and extraction with diethyl ether compound crystalised out HCI salt. H-NMR (DMSO-de, 300 MHz): 5 1.10-1.23 (m, 4 H), 2.28 (s, 3 H), 4.75 (q, J = 9 Hz, 2 H), 6.80 (s, 1 H), 6.84-6.86 (m, 2 H).

[1605]

[1606] Synthesis of 2-(3,3-difluoro-1 -hydroxycyclobutyl)-N-(1 -(3-methyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)acetamide (A9):

[1607]

[1608] Following general procedure 8, Compounded (100 mg, 0.40 mmol) converted to Example 9 (10 mg, 6%) as off white solid; H-NMR (DMSO-d6, 300 MHz): 5 1.11-1.23 (m, 4 H), 2.26 (s, 3 H), 2.43-2.49 (m 2 H), 2.54-2.59 (m, 2 H), 2.82-2.87 (m, 2 H), 4.67 (q, J = 9 Hz, 2 H), 5.66 (s, 1H), 6.56 (s, 1 H), 6.65 (s, 2 H), 8.53 (bs, 1 H). HRMS calculated for: [C18H20F5NO3+H]+394.1436; found: 394.1441.

[1609] Example 10: 2-(2-hydroxyspirof3.31heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)acetamide P6714PC00

[1610] Synthesis of ethyl 2-(2-hydroxyspiro[3.3]heptan-2-yl)acetate (3j): spiro[3.3]heptan-2-one (150 mg, 1.362 mmol) converted to compound-3j (220 g, 80%) as colourless liquid using general procedure A used for compound-3; H-NMR (DMSO-de, 400 MHz): 5 1.18 (t, J = 7.2 Hz, 3 H), 1.72-1.80 (m, 2 H), 1.90-2.02 (m, 6 H), 2.25-2.28 (m, 2 H), 2.38 (s, 2 H), 4.02 (q, J = 7.2 Hz, 2 H), 4.93 (s, 1 H).

[1611]

[1612] Synthesis of 2-(2-hydroxyspiro[3.3]heptan-2-yl)acetic acid (4j): Compound-3j (100 mg, 0.504 mmol) converted to compound-4j (90 mg, crude) as colourless oil using sodium hydroxide and general procedure used for compd-4; H-NMR (DMSO-de, 400 MHz): 5 1.72-1.79 (m, 2 H), 1.90-2.01 (m, 6 H), 2.26-2.28 (m, 2 H), 2.328 (s, 2 H), 4.93 (s, 1 H), 11.90 (bs, 1 H).

[1613]

[1614] Synthesis of 2-(2-hydroxyspiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)acetamide (A10):

[1615]

[1616] Following general procedure 8, compound-4j (90 mg, 0.528 mmol) converted to Example 10 (18 mg, 10%) as off white solid; H-NMR (DMSO-d6, 300 MHz): 5 1.10-1.18 (m, 2 H), 1.19-1.24 (m, 2 H), 1.70-1.85 (m, 2 H), 1.90-2.02 (m, 6 H), 2.19-2.23 (m, 2 H), 2.24-2.28 (m, 2 H), 4.70 (q, J = 8.8 Hz, 2 H), 5.18 (s, 1 H), 6.78-6.83 (m, 3 H), 7.17-7.23 (m, 1 H), 8.44 (s, 1 H), HRMS calculated for: [C20H24F3NO3+H]+384.1781; found: 384.1791.

[1617] Example 11: 3-hydroxy-3-(spirof3.31heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide

[1618] Synthesis of ethyl 3-hydroxy-3-(spiro[3.3]heptan-2-yl)butanoate (3k): 1- (spiro[3.3]heptan-2-yl)ethan-1-one (200 mg, 1.447 mmol) converted to compound-3k P6714PC00

[1619] (330 mg, crude) as yellow liquid using general procedure A used for compound-3; H- NMR (DMSO-d6, 400 MHz): 5 1.03 (s, 3 H), 1.13-1.22 (m, 6 H), 1.74-2.21 (m, 10 H), 4.01 (q, J = 5.8 Hz, 2 H), 4.31 (s, 1 H).

[1620] OH O

[1621]

[1622] 3-hydroxy-3-(spiro[3.3]heptan-2-yl)butanoic acid (4k): Compound-3k (330 mg, 1.458 mmol) converted to compound-4k (100 mg, 34.60%) as yellow gummy using general procedure used for compound-4; H-NMR (DMSO-de, 400 MHz): 5 1.04 (s, 3 H), 1.71-1.80 (m, 6 H), 1.82-1.98 (m, 4 H), 2.1-2.27 (m, 3 H), 4.31 (bs, 1 H), 12.06 (bs, 1 H).

[1623] OH O

[1624]

[1625] Synthesis of 3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1 -(3-(2,2,2- trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 11 peak-1 & Example 11 peak-2, A11a and A11b):

[1626]

[1627] Following general procedure 8, Compound-4k (90 mg, 0.454 mmol) converted to Example 11 (80 mg, 43.01%). The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IG, 250x21mm, 5pm), Eluent: n-Hexane(A) and IPA: MeOH 1:1 (B), Flow: 15 ml / min, Isocratic: 90(A):10(B), diluent EtOH: DCM (3:1, 5 ML), Injection volume-0.75 mL, run time 26 min, to get Peak-1 (20 mg) Peak-2: (21.5 mg) as colourless gummy, H-NMR (DMSO-d6, 400 MHz): 50.98 (s, 3 H), 1.1-1.17 (m, 2 H), 1.18-1.21 (m, 2 H), 1.65-1.80 (m, 6 H), 1.70-1.98 (m, 4 H), 2.00-2.15 (m, 3 H), 4.60 (s, 1 H), 6.78-6.79 (m, 1 H), 6.80-6.85 (m, 2 H), 8.52 (s, 1 H), HRMS calculated for:

[1628] [C22H28F3NO3+H]+412.2094; found: 412.2101 (Peak-1), 412.2100 (Peak-2). Analytical chiral HPLC: CHIRALPAK-IG(150X4.6mmX5pm) 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: 5.47, 100% ee) Peak-2: (Rt: 7.42, 100% ee). P6714PC00

[1629] Example 12: N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl- 3-hydroxybutanamide

[1630]

[1631] Synthesis of N-(1 -(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide (Example 12 peak-1 & Example 12 peak-2, A12a and A12b):

[1632] Following general procedure 8, compound-4e (40 mg, 0.32 mmol) converted to Example 12 (30 mg, 21.42%) as pale yellow solid. The enantiomers were separated using chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5pm), Eluent: n-Hexane(A) and IPA (B), Flow: 15 ml / min, Isocratic: 80(A):20(B), diluent EtOH: DCM (1:1, 3.5 ML), Injection volume-0.25mL, run time 27 min, to get Peak-1 (4.4 mg), Peak-2: (3.9 mg) as colourless gummy; H-NMR (DMSO-d6, 400 MHz): 50.21-0.31 (m, 4 H), 0.83-0.88 (m, 2 H), 1.13 (s, 3 H), 1.1-1.14 (m, 2 H), 2.28-2.29 (m, 2 H), 4.49 (s, 1 H), 4.80 (q, J = 8.8 Hz, 2 H), 6.74 (bs, 1 H), 7.05 (s, 1 H), 7.10 (s, 1 H), 8.61 (bs, 1 H), HRMS calculated for: [C18H21BrF3NO3+H-H2O]+418.0624; found: 418.0636 (Peak-1 ), 418.0638 (Peak-2). Analytical chiral HPLC: CHIRALPAK-IH(150X4.6mmX5pm), Mobile phase: (A) n-HEXANE (B)IPA: MeOH(50:50), Isocratic: 93(A):7(B), Flow: 1 ml / min, Diluent: EtOH, Inj. volume: 10.0, Peak-1 (Rt: 4.92, 99% ee) Peak-2: (Rt: 5.71, 98% ee).

[1633] Example 13: N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide

[1634]

[1635] Synthesis of N-(1 -(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide (Example 13 peak-1 & Example 13 peak-2, P6714PC00

[1636] A13a and A13b): Following general procedure for compd-8, compound-4k (0.12 g, 0.832 mmol) was converted to racemic compound-13 (0.17 g, 52.14%) which was separated using Chiral prep HPLC, Column: (Chiralpak I H, 250mmX21mm, 5pm), Eluent: n-Hexane(A) EtOH(B), Flow: 15 ml / min, Isocratic: 93(A):07(B) to get Peak-1 (75 mg, Rt: 4.82, 100% ee); Peak-2: (75.1 mg, Rt: 5.63, 100% ee), Chiral HPLC Column: CHIRALPAK-IH(150X4.6mmX5pm) Mobile Phase: (A) n-HEXANE (B)IPA: MeOH, 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, H-NMR (DMSO-d6, 400 MHz): 50.19-0.34 (m, 4 H), 0.85-0.91 (m, 1 H), 1.13 (s, 3 H), 1.10-1.15 (m, 2 H), 1.23- 1.28 (m, 2 H), 2.25-2.34 (m, 2 H), 4.50 (bs, 1 H), 4.77 (q, J = 8.8 Hz, 2 H), 6.72 (d, J = 1.6 Hz, 1 H), 6.91 (s, 1 H), 6.98-6.99 (m, 1 H), 8.61 (bs, 1 H), HRMS calculated for: [C18H21ClF3NO3+H-H2O]+374.1129; found: 374.1148 (Peak-1 ), 374.1143 (Peak-2).

[1637] Example 14: 3-cvclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cvclopropyl)-3- hydroxybutanamide

[1638] V / O\XCFN v'°\ / CFN if H H ¥

[1639]

[1640] Synthesis of 3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 14 peak-1 & Example 14 peak-2, A14a and A14b):

[1641] Following general procedure for compound-8, compound-4e (0.59 g, 2.367 mmol) converted to Example 14 (550 mg, 62.77%). The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5pm), Eluent: n-Hexane(A) and EtOH (B), Flow: 15 ml / min, Isocratic: 90(A): 10(B), diluent EtOH: DCM (1:1, 7.5 ML), Injection volume-0.35 mL, run time 16 min, to get Peak-1 (218 mg) Peak-2: (227.5 mg)as off white solid, H-NMR (DMSO-d6, 400 MHz): 50.19-0.32 (m, 4 H), 0.86-0.91 (m, 1 H), 1.13 (s, 3 H), 1.14-1.18 (m 2 H), 1.24-1.26 (m, 2 H), 2.32 (q, J = 2 Hz, 2 H), 4.50 (s, 1 H), 4.75 (q, J = 8 Hz, 2 H), 6.60-6.61 (m, 1 H), 6.66-6.70 (m, 1 H), 6.76-6.80 (m, 1 H), 8.58 (s, 1 H), HRMS calculated for: [C18H21F4NO3+H-H2O]+358.1425; found: 358.1434 (Peak-1 ), 358.1436 (Peak-2). Analytical Chiral HPLC: CHIRALPAK- IH(150X4.6mmX5pm) Mobile Phase: (A) n-HEXANE (B) IPA: MeOH (50:50) Isocratic: P6714PC00

[1642] 85:15(A: B) Flow: 1.0ml / min, Diluent: EtOH, Column Temp: 25°C, Inj. volume: 5.000, Peak-1 (Rt: 2.748, 100% ee) Peak-2: (Rt: 3.164, 100% ee).

[1643] Example 15: 3-cvclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide

[1644]

[1645] Synthesis of 3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 15 peak-1 & Example 15 peak-2, A15a and A15b): Following general procedure for compound-8, compound-4e (40 mg, 0.32 mmol) converted to Example 15 (30 mg, 21.42%) as pale yellow solid. The enantiomers were separated using Chiral prep HPLC, Column:

[1646] (Chiralpak I H, 250x21mm, 5pm), Eluent: n-Hexane(A) and IPA (B), Flow: 15 ml / min, Isocratic: 90(A):10(B), diluent EtOH: DCM (1:1, 2 ML), Injection volume-0.4mL, run time 15 min, to get Peak-1 (7 mg) Peak-2: (7 mg) as colourless gummy, H-NMR (DMSO-de, 400 MHz): 50.19-0.31 (m, 4 H), 0.87-0.89 (m, 2 H), 1.13-1.17 (m, 5 H), 1.23-1.26 (m, 2 H), 2.28-2.30 (m, 2 H), 4.50 (s, 1 H), 4.80 (q, J = 8.8 Hz, 2 H), 6.92 (bs, 1 H), 7.04-7.08 (m, 2 H). 8.64 (bs, 1 H), HRMS calculated for: [C19H22F5NO3+H-H2O]+390.1487; found: 390.1492 (Peak-1), 390.1495 (Peak-2). Analytical chiral HPLC: CHIRALPAK-IH(150X4.6mmX5pm), Mobile phase: (A) n-HEXANE (B)IPA: MeOH(50:50), Isocratic: 90(A):10(B), Flow: 1 ml / min, Diluent: EtOH, Inj. volume: 10.0, Peak-1 (Rt: 3.99, 100% ee) Peak-2: (Rt: 5.49, 100% ee).

[1647] Example 16: N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-

[1648]

[1649] Synthesis of N-(1 -(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide (Example 16 peak-1 & Example 16 peak-2, P6714PC00

[1650] A16a and A16b): Following general procedure 8, compound-4e (100 mg, 0.37 mmol) converted to Example 16 (50 mg, 34.01%) as off white solid. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak I H, 250x20mm, 5pm), Eluent: n-Hexane(A) and I PA (B), Flow: 15 ml / min, Isocratic: 85(A): 15(B), diluent EtOH: DCM (3:1, 4 ML), Injection volume-0.2mL, run time 14 min, to get Peak-1 (7 mg) Peak-2: (7 mg) as off white solid; H-NMR (DMSO-d6, 400 MHz): 50.19-0.30 (m, 4 H), 0.87-0.89 (m, 1 H), 1.12 (s, 3 H), 1.15-1.27 (m, 4 H), 2.08-2.32 (m, 2 H), 4.50 (s, 1 H), 4.80 (q, J = 8.8 Hz, 2 H), 6.91-6.92 (m, 2 H), 7.35 (d, J = 8.4 Hz, 1 H), 8.55 (s, 1 H). HRMS calculated for: [C18H21ClF3NO3+H-H2O]+374.1129; found: 374.1134 (Peak-1), 374.1141 (Peak-2). Analytical chiral HPLC: REGIS (S, S) WHELK-01 (250X4.6mmX5pm), Mobile phase: (A) n-HEXANE (B )IPA: MeOH (50:50), Isocratic: 93(A):7(B), Flow: 1 ml / min, Diluent: EtOH, Inj. volume: 5.0, Peak-1 (Rt: 4.41, 100% ee) Peak-2: (Rt: 5.46, 100% ee).

[1651] Example 17: 3-hydroxy-3-(spiro(2.31hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide

[1652] Synthesis of ethyl 3-hydroxy-3-(spiro[2.3]hexan-5-yl)butanoate (3I): 1-(spiro[2.3]hexan-5-yl)ethan-1-one (150 mg, 1.208 mmol) converted to compound-31 (200 mg, 78.12%) as yellow liquid using general procedure A used for compound-3; m / z (LC-MS): 213.05 [M+H]+.

[1653]

[1654] Synthesis of 3-hydroxy-3-(spiro[2.3]hexan-5-yl)butanoic acid (4I): Compound-31 (200 mg, 0.942 mmol) converted to compound-41 (80 mg, 46.24%) as reddish gummy using general procedure used for compd-4; m / z (LC-MS): 185.1 [M+H]+.

[1655] OH O

[1656]

[1657] P6714PC00

[1658] Synthesis of 3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 17 peak-1 & Example 17 peak-2, A17a and A17b):

[1659]

[1660] Following general procedure 8, Compound-41 (80 mg, 0.434 mmol) converted to Example 17 (80 mg, 46.51%) which was separated using Chiral prep HPLC, Column: (Chiralpak I H, 250x20mm, 5pm), Eluent: n-Hexane(A) and EtOH (B), Flow: 15 ml / min, Isocratic: 95(A):05(B), diluent EtOH: DCM (1:1, 4 ML), Injection volume-0.1 mL, run time 23 min, to get Peak-1 (26.5 mg) Peak-2: (26.9 mg) as off white solid, H-NMR (DMSO-d6, 400 MHz): 50.26-0.30 (m, 2 H), 0.37-0.42 (m, 2 H), 1.06 (s, 3 H), 1.17-1.19 (m 2 H), 1.20-1.23 (m, 2 H), 1.72-1.76 (m, 2 H), 2.08-2.22 (m, 4 H), 4.67-4.75 (m, 3 H), 6.80 (s, 1 H), 6.82-6.85 (m, 2 H), 7.19-7.23 (m, 1 H), 8.54 (s, 1 H), HRMS calculated for: [C21H26F3NO3+H]+398.1938; found: 398.1949 (Peak-1), 398.1949 (Peak-2). Analytical chiral HPLC: CHIRALPAK-IH (150X4.6mmX5pm) 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, Peak-1 (Rt: 5.17, 99.40% ee) Peak-2: (Rt: 5.54, 99.74% ee).

[1661] Example 18: N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,3-dimethylbutanamide

[1662]

[1663] Synthesis of N-(1 -(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,3-dimethylbutanamide (A18): Following general procedure for compound-8, 3,3-dimethylbutanoic acid 4m (0.08 g, 0.689 mmol) converted to Example 18 (82 mg, 32.8%) as colourless gum. H-NMR (DMSO-d6, 400 MHz): 50.95 (s, 9 H), 1.09-1.11 (m, 2H), 1.22-1.26 (m, 2 H), 1.99 (s, 2 H), 4.75 (q, J = 8.8 Hz, 2 H), 6.67-6.69 (m, 1 H), 6.89-6.90 (m, 1 H), 6.98-6.99 (m, 1 H), 8.50 (bs, 1 H), HRMS calculated for:

[1664] [C17H21ClF3NO2+H]+364.1286; found: 364.1292. P6714PC00

[1665] Example 19: N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide

[1666]

[1667] Synthesis of N-(1 -(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide (Example 19 peak-1 & Example 19 peak-2, A19a and A19b):

[1668] Following general procedure for compound-8, 3-cyclopropylbutanoic acid 4n (0.1 g, 0.780 mmol) converted to Example 19 (175 mg, 59.72%) as off white solid, which was separated using Chiral prep HPLC, Column: (Regis(S, S) Whelk-01, 250mmX21.1mm, 5pm), Eluent: n-Hexane(A) EtOH(B), Flow: 15 ml / min, Isocratic: 93(A):7(B), Diluents: EtOH : DCM, 1:1, 3.5 mL, Injection volume-0.1 mL, run time 24 min to get Peak-1 (59.2 mg, Rt: 8.938, 95.4% ee), Peak-2: (70.5 mg, Rt: 9.883, 98% ee), H-NMR (DMSO-d6, 400 MHz): 50.02-0.10 (m, 2 H), 0.30-0.38 (m, 2 H), 0.51-0.56 (m, 1 H), 0.91-0.93 (m, 3 H), 1.11-1.20 (m, 3 H), 1.23-1.26 (m, 2 H), 2.01-2.06 (m, 1 H), 2.18-2.24 (m, 1 H), 4.75 (q, J = 8.8 Hz, 2 H), 6.67-6.68 (m, 1 H), 6.87-6.88 (m, 1 H), 6.98-6.99 (m, 1 H), 8.56 (bs, 1 H), HRMS calculated for: [C18H21ClF3NO2+H]+376.1286; found: 376.1293 (Peak-1), 376.1290 (Peak-2). Analytical chiral HPLC: REGIS(S, S) WHELK- 01 (250X4.6mmX5pm), Mobile Phase: (A) n-HEXANE (B) IPA Isocratic: 80:20(A: B), Flow: 1.0ml / min Diluent: EtOH, Column Temp: 25°C, Inj. volume: 5.000, Peak-1 (Rt: 8.938, 95.40% ee) Peak-2: (Rt: 9.883, 98% ee).

[1669] Example 20: N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(5-hydroxyspirof2.31hexan-5-yl)acetamide

[1670] Synthesis of ethyl 2-(5-hydroxyspiro[2.3]hexan-5-yl)acetate (3o): spiro[2.3]hexan-5-one (200 mg, 2.081 mmol) converted to compound-3o (180 mg, 46.99%) as off white gum using general procedure A used for compound-3; H-NMR (DMSO-de, 400 MHz): 5 0.37 (s, 4 H), 1.17 (t, J = 7.2 Hz, 3 H), 2.10-2.12 (m, 2 H), 2.23-2.27 (m, 2 H), 2.60 (s, 2 H), 4.04 (q, J = 6.8 Hz, 2 H), 5.17 (bs,1 H). P6714PC00

[1671]

[1672] Synthesis of 2-(5-hydroxyspiro[2.3]hexan-5-yl)acetic acid (4o): Compound-3o (200 mg, 0.942 mmol) converted to compound-4o (80 mg, 46.24%) as reddish gummy using general procedure used for compd-4, H-NMR (DMSO-de, 300 MHz): 50.36 (s, 4 H), 2.06-2.02 (m, 2 H), 2.21-2.26 (m, 2 H), 2.54 (s, 2 H), 5.17 (bs,1 H), 12.0 (bs, 1 H).

[1673]

[1674] Synthesis of N-(1 -(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(5- hydroxyspiro[2.3]hexan-5-yl)acetamide (A20):

[1675]

[1676] Following general procedure 8, compound-4o (120 mg, 0.76 mmol) converted to Example 20 (145.7 mg, 46.95%) as off white solid, H-NMR (DMSO-d6, 400 MHz): 5 0.37-0.39 (m, 4 H), 1.13-1.16 (m, 2 H), 1.23-1.26 (m, 2 H), 2.05-2.08 (m, 2 H), 2.24- 2.27 (m, 2 H), 4.69 (q, J = 8.8 Hz, 2 H), 5.35 (s, 1 H), 6.71 (t, J = 2 Hz, 1 H), 6.91 (t, J = 1.6 Hz, 1 H), 6.96 (t, J = 2 Hz, 1 H), 8.48 (bs, 1 H)), HRMS calculated for:

[1677] [C19H21ClF3NO3+H]+404.1235; found: 404.1242.

[1678] Example 21: N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4- trimethylpentanamide

[1679]

[1680] Synthesis of N-(1 -(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4- trimethylpentanamide (Example 21 peak-1 & Example 21 peak-2, A21a and A21b):

[1681] Following general procedure for compound-8, 3,4,4-trimethylpentanoic acid 4p (65 mg, 0.452 mmol) converted to Example 21 (120 mg, 81.63%) as off white solid. The P6714PC00

[1682] enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x20mm, 5pm), Eluent: n-Hexane(A) and IPA (B), Flow: 15 ml / min, Isocratic:

[1683] 95(A):5(B), diluent EtOH: DCM (1:1, 3.5 ML), Injection volume-0.2mL, run time 25 min, to get Peak-1 (38.6 mg) Peak-2 (37.1 mg), H-NMR (DMSO-d6, 400 MHz): 50.78 (d, J = 6.8 Hz, 3 H), 0.83 (s, 9 H), 1.10 (s, 2 H), 1.12 (s, 2 H), 1.65-1.80 (m, 2 H), 2.24-2.32 (m, 1 H), 4.80 (q, J = 8.8 Hz, 2 H), 6.66 (s, 1 H), 6.87 (s, 1 H), 6.98 (s, 1 H), 8.56 (s, 1 H). HRMS calculated for: [C19H25ClF3NO2+H]+392.1599; found: 392.1601 (Peak-1), 392.1601 (Peak-2). Analytical chiral HPLC: CHIRALPAK-IH(150X4.6mmX5pm), Mobile phase: (A) n-HEXANE (B)IPA, Isocratic: 95(A):5(B), Flow: 1 ml / min, Diluent: EtOH, Inj. volume: 5.0, Peak-1 (Rt: 4.73, 100% ee) Peak-2: (Rt: 5.96: 9.883, 100% ee).

[1684] Example 22: 3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide

[1685]

[1686] Synthesis of 3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 22 peak-1 & Example 22 peak-2, A22a and A22b): Following general procedure for compound-8, compound-4e (0.058 g, 0.0401 mmol) converted to Example 22 (0.075 g, 50%) as off white solid. The enantiomers were separated using Chiral prep HPLC, Column:

[1687] (Chiralpak I H, 250mmX21mm, 5pm), Eluent: n-Hexane(A) and EtOH(B), Flow: 15 ml / min, Isocratic: 90(A):10(B), diluents: EtOH: DCM 1:1, 4 mL, Injection vol- 0.4 mL, run time 16 min, to get Peak-1 (26.5 mg) Peak-2: (26.2 mg), H-NMR (DMSO-de, 400 MHz): 5 0.02-0.18 (m, 4 H), 0.70-0.75 (m, 1 H), 1.00 (s, 3 H), 1.01-1.07 (m, 2 H), 1.10-1.12 (m, 2 H), 2.10-2.21 (m, 2 H), 4.48 (bs, 1 H), 4.79 (q, J = 8.7 Hz, 2 H), 7.02-7.06 (m, 1 H), 7.12-7.20 (m, 2 H), 8.65 (bs, 1 H), HRMS calculated for: [C18H21F4NO3+H-H2O]+358.1425; found: 358.1432 (Peak-1), 358.1431 (Peak-2). Analytical chiral HPLC:

[1688] CHIRALPAK-IH (150X4.6mmX5pm) Mobile Phase: (A) n-HEXANE (B)IPA:

[1689] 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: 2.798, 94% ee) Peak-2: (Rt: 3.227, 98% ee). P6714PC00

[1690] Example 23: 3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide

[1691]

[1692] Synthesis of 3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 23 peak-1 & Example 23 peak-2, A23a and A23b):

[1693] Following general procedure 8, compound-4e (150 mg, 1.04 mmol) converted to Example 23 (100 mg, 30.36%) as off white gummy. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x21mm, 5pm), Eluent: n-Hexane(A) and IPA (B), Flow: 15 ml / min, Isocratic: 92(A):8(B), diluent EtOH: DCM (1:1, 4.5 ML), Injection volume-0.2mL, run time 28 min, to get Peak-1 (48.7 mg, Rt: 4.74, 96% ee); Peak-2: (49.4 mg, Rt: 5.71, 100% ee) as colourless gummy, H-NMR (DMSO-de, 400 MHz): 50.19-0.31 (m, 4 H), 0.64-0.67 (m, 2 H), 0.87-0.92 (m, 3 H), 1.13 (s, 2 H), 1.23 (s, 3 H), 1.23 (s, 2 H), 1.83-1.98 (m, 1 H), 2.49-2.40 (m, 2 H), 4.49 (s, 1H), 4.70 (q, J = 8.8 Hz, 2 H), 6.48 (s, 1 H), 6.54 (s, 1 H), 6.60 (s, 1 H), 8.54 (s, 1 H). HRMS calculated for: [C21H26F3NO3+H-H2O]+380.1832; found: 380.1835 (Peak-1), 380.1837 (Peak-2). Analytical chiral HPLC: CHIRALPAK-IH(150X4.6mmX5pm), Mobile phase: (A) n-HEXANE (B)IPA: MeOH(50:50), Isocratic: 90(A): 10(B), Flow: 1 ml / min, Diluent: EtOH, Inj. volume: 5.0, Peak-1 (Rt: 4.74, 96% ee) Peak-2: (Rt: 5.71, 100% ee).

[1694] Example 24: N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide

[1695] Synthesis of 2-chloro-6-(2,2,2-trifluoroethoxy)isonicotinonitrile (6s): 2,6- Dichloroisonicotinonitrile (200 mg, 1.15 mmol) converted to 6s (100 mg, 50%) as off white solid using general procedure used for compd-6, H-NMR (DMSO-de, 300 MHz): 5 5.04 (q, J = 9 Hz, 2 H), 7.69 (s, 1 H), 7.84 (s, 1 H). P6714PC00

[1696] F

[1697]

[1698] Cl

[1699] Synthesis of 1 -(2-chloro-6-(2,2,2-trifluoroethoxy)cyclopro-4-yl)cyclopropane-1 -amine (7s): 4-chloro-3-(2,2,2-trifluoroethoxy)benzonitrile (1 g, 4.22 mmol) converted to compound-7s ( 350 mg, 31.25%) as off brown solid using general procedure used for compound-7, After acidification and extraction with diethyl ether compound crystalised out HCI salt, m / z (LC-MS): 266.95 [M+H]’.

[1700]

[1701] Cl

[1702] Synthesis of N-(1 -(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide (Example 24 peak-1 & Example 24 peak-2, A24a and A24b):

[1703]

[1704] Cl Cl Following general procedure 8, compound-4e (100 mg, 0.37 mmol) converted to Example 24 (70 mg, 47.61%) as off white solid which was separated using Chiral prep HPLC, Column: (Chiralpak IH, 250x20mm, 5pm), Eluent: n-Hexane(A) and IPA (B), Flow: 15 ml / min, Isocratic: 95(A):5(B), diluent EtOH: DCM (1:1, 3.5 ML), Injection volume-0.2mL, run time 25 min, to get Peak-1 (25 mg) Peak-2: (26 mg) as Off white gummy, H-NMR (DMSO-d6, 400 MHz): 50.27-0.30 (m, 2H), 0.31-0.35 (m, 2 H), 0.88-0.93 (m, 1 H), 1.23 (s, 3 H), 1.25-1.39 (m, 2 H), 1.39-1.41 (m, 2 H), 2.27-2.36 (m, 1 H), 4.45 (bs, 1 H), 4.94 (q, J = 8.8 Hz, 2 H), 6.68 (d, J = 1.2 Hz, 1 H), 6.95 (d, J = 1.2 Hz, 1 H), 8.63 (s, 1 H), HRMS calculated for: [C17H20ClF3N2O3+H-H2O]+375.1082; found: 375.1088 (Peak-1), 375.1088 (Peak-2). Analytical chiral HPLC: CHIRALPAK-IH(150X4.6mmX5pm), Mobile phase: (A) n-HEXANE (B)IPA: MeOH(50:50), Isocratic: 85(A):15(B), Flow: 1 ml / min, Diluent: EtOH, Inj. volume: 5.0, Peak-1 (Rt: 2.97, 95% ee) Peak-2: (Rt: 3.29, 100% ee). P6714PC00

[1705] Example 25: 3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide

[1706]

[1707] Synthesis of 3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 25 peak-1 & Example 25 peak-2, A25a and A25b):

[1708] Following general procedure for compound-8, compound-4e (0.088 g, 0.0401 mmol) converted to Example 25 (0.08 g, 35.24%) as yellowish solid. The enantiomers were separated using Chiral prep HPLC, Column: (Chiralpak IH, 250mmX21mm, 5pm), Eluent: n-Hexane(A) and IPA: MeOH (1:1) (B), Flow: 15 ml / min, Isocratic: 95(A):05(B), diluents: EtOH: DCM 1:1, 4 mL, Injection vol- 0.2 mL, run time 14 min, to get Peak-1 (39.1 mg) Peak-2 (39.1 mg), H-NMR (DMSO-d6, 400 MHz): 50.18-0.20 (m, 2 H), 0.20-0.32 (m, 2 H), 0.85-0.90 (m, 1 H), 1.09 (s, 3 H), 1.08-1.10 (m, 2 H), 1.11-1.23 (m, 2 H), 2.11 (s, 3 H), 2.23-2.32 (m, 2 H), 4.55 (bs, 1 H), 4.68 (q, J = 8.8 Hz, 2 H), 6.76 (s, 1 H), 6.80 (dd, J = 1.6 Hz, 7.6 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 8.52 (bs, 1 H), HRMS calculated for: [Ci9H24F3NO3+H-H2O]+354.1675; found: 354.1683 (Peak-1), 354.1682 (Peak-2). Analytical chiral HPLC: CHIRALPAK-IH(150X4.6mmX5pm) 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: 2.98, 100% ee) Peak-2: (Rt: 3.44, 100% ee).

[1709] Example 26: 3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide

[1710] Synthesis of Ethyl 3-(3,3-difluorocyclobutyl)-3-hydroxybutanoate(3q):

[1711] 1-(3,3-difluorocyclobutyl)ethan-1-one (0.3 g, 2.2367 mmol) converted to compound-3q (0.4 g, 80.48%) using general procedure A used for compound-3, H-NMR (DMSO-de, 400 MHz): 54.82 (s, 1 H), 4.11 (q, 2 H), 2.48-2.59 (m, 6 H), 1.7 (m, 1 H), 1.18 (s, 3 H), 1.16-1.20 (m, 3 H) P6714PC00

[1712]

[1713] Synthesis of 3-(3,3-difluorocyclobutyl)-3-hydroxybutanoic acid (4q):

[1714] Compound-3q (0.4 g, 1.7999 mmol) hydrolysed to get 4q (0.22 g, 62.85%) using general procedure used for compound-4, H-NMR (DMSO-de, 400 MHz): 5 12.00 (bs, 1 H), 4.20 (bs, 1 H), 2.48-2.59 (m, 6 H), 1.7 (m, 1 H), 1.1 (s, 3 H).

[1715] \ OH O

[1716]

[1717] F

[1718] Synthesis of 3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1 -(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide (Example 26 peak-1 & Example 26 peak-2, A26a and A26b):

[1719]

[1720] Following general procedure for compound-8, compound-4q (0.1 g, 0.515 mmol) converted to Example 26 (0.12 g, HPLC: 96.68%) which was separated using Chiral prep HPLC, Column: (Chiralpak IG, 250mmX21mm, 5pm), Eluent: n-Hexane(A) EtOH(B), Flow: 15 ml / min, Isocratic: 93(A):07(B) to get Peak-1 (50 mg) Peak-2: (50 mg), H-NMR (DMSO-d6, 400 MHz): 5 1.10-1.21 (m, 4 H), 1.23 (s, 3 H), 2.12-2.23 (m, 4 H), 2.53 (m, 1 H), 2.49-2.50 (m, 2 H), 4.67-4.73 (q, J = 8 Hz, 2 H), 4.95 (bs, 1 H), 6.78-6.84 (m, 3 H), 7.19-7.23 (m, 1 H), 8.59 (s, 1 H), HRMS calculated for:

[1721] [Ci9H22F5NO3+H]+408.1593; found: 408.1601 (Peak-1), 408.1605 (Peak-2). Analytical chiral HPLC: CHIRALPAK-IG(150X4.6mmX5pm) Mobile Phase: (A) n-HEXANE (B)EtOH Isocratic: 93:07 (A: B) Flow: 1.0ml / min, Diluent: EtOH Column Temp: 25°C, Inj. volume: 5.000, Peak-1 (Rt: 9.28, 100% ee) Peak-2: (Rt: 12.04, 98.90% ee).

[1722] Example 27: N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro- 3-hydroxy-3-methylbutanamide: P6714PC00

[1723] Synthesis of (S)-1 -phenylethyl (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutanoate (3r) and (S)-1 -phenylethyl (S)-4,4,4-trifluoro-3-hydroxy-3-methylbutanoate (3s):

[1724]

[1725] 3r 3s

[1726] To a stirred solution of 4,4,4-trifluoro-3-hydroxy-3-methylbutanoic acid (6 g, 34.8632 mmol) in N, N-Dimethylformamide cooled to 0 °C and added EDC. HCI (10.02 g, 52.29 mmol), HOBt (5.28 g, 38.3495 mmol) DMAP (10.64 g, 87.15 mmol). To this reaction mixture added (S)-1-phenylethan-1-ol (4.68 g, 38.3495 mmol) and stirred for 6 h at room temperature. The reaction mixture was diluted with cold water and extracted with EtOAc (2 x 100 mLI). Combined organic layer given brine wash, dried over anhydrous Na2SC>4 and concentrated under vacuo to get crude compound which was purified using combi flash chromatography 20 to 30% EtoAc in Hexane) to get pure mixture of diasteromers (1.9 g) which are further separated using Chiral prep HPLC, Column: CHIRALPAK IH, 250mmX20mm, 5pm, Eluent: n-Hexane(A) and EtOH: MeOH (80:20) (B), Flow: 15 ml / min, Isocratic: 93(A): 07(B), diluent EtOH: DCM, 1:1, 10 mL, Injection vol, 0.2 mL, run time 8 min, to get Peak-1 (3r): (0.9 g, Rt: 2.677):1H NMR (400 MHz, DMSO-cfe) 6 ppm 1.41 (s, 3 H), 1.49 (s, 3 H), 2.64 (s, 2 H), 5.84 (q, J = 6.8 Hz, 1 H), ), 6.24 (s, 1 H), 7.27-7.40 (m, 5 H) and Peak-2 (3s): (0.730 g, Rt: 3.309).1H NMR (400 MHz, DMSO-cfe) 6 ppm 1.41 (s, 3 H), 1.49 (d, J = 6.6 Hz, 3 H), 2.66 (dd, J = 14 Hz, 2 H), 5.84 (q, J = 6.8 Hz, 1 H), ), 6.24 (s, 1 H), 7.27-7.40 (m, 5 H).

[1727] Synthesis of (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutanoic acid (4r):

[1728] To a stirred solution of compound 3r (0.9 g, 3.2579 mmol) in ethanol (10 mL) was added palladium on carbon (10%) (0.345 g) and the reaction mixture was stirred under H2 bladder for 4 hours. The reaction mixture was filtered through celite and washed with ethanol. Filtrate obtained was concentrated to get 4r (480 mg).1H NMR (400 MHz, CDCh) 6 ppm 1.42 (s, 3 H), 2.64 (d, J = 16 Hz 1 H). 2.86 (d, J = 16 Hz, 1 H), 4.84 (bs, 1 H). Stereochemistry arbitrarily assigned.

[1729]

[1730] Synthesis of (S)-4,4,4-trifluoro-3-hydroxy-3-methylbutanoic acid (4s): P6714PC00

[1731] To a stirred solution of compound 3s (0.73 g, 2.642 mmol) in ethanol (10 mL) was added palladium on carbon (10%) (0.28 g) and the reaction mixture was stirred under H2 bladder for 4 hours. The reaction mixture was filtered through celite and washed with ethanol. Filtrate obtained was concentrated to get 4s (380 mg).1H NMR (400 MHz, CDCh) 6 ppm 1.42 (s, 3 H), 2.64 (d, J = 16 Hz 1 H). 2.86 (d, J = 16 Hz, 1 H), 4.84 (bs, 1 H). Stereochemistry arbitrarily assigned.

[1732] HO '''?

[1733] FgC^^^OH

[1734] Example 27 a: (R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide:

[1735] CF3

[1736]

[1737] Following general procedure for compound-8, compound-4r (0.13 g, 0.755 mmol) converted to Example 27a (A27a) (95.5 mg, 30.12%) using compound-7a as brownish solid.1H NMR (400 MHz, CDCh) 6 ppm 1.14-1.17 (m, 2 H), 1.25-1.31 (m, 2 H), 1.37 (s, 3 H), 2.40 (d, J = 14 Hz, 1 H), 2.55 (d, J = 14 Hz, 1 H), 4.76 (q, J = 8.8 Hz, 2 H), 6.25 (s, 1 H), 6.69 (t, J = 2 Hz, 1 H), 6.91 (t, J = 3.2 Hz, 1 H), 6.98 (t, J=, 8.36 Hz, H), 8.73 (s, 1 H). HRMS calculated for: [Ci6Hi6CIF6NO3+H]+420.0796; found: 420.0804, Analytical Chiral HPLC: CHIRALPAK-IH (250X4.6mmX5pm) 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: 5.000, (Rt: 2.989).

[1738] Example 27b: (S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide:

[1739]

[1740] Following general procedure for compound-8, compound-4s (0.1 g, 0.581 mmol) converted to Example 27b (A27b) (59.1 mg, 24.23%) using compound-7c as brownish solid.1H NMR (400 MHz, CDCh) 6 ppm 1.14-1.17 (m, 2 H), 1.25-1.31 (m, 2 H), 1.37 P6714PC00

[1741] (s, 3 H), 2.40 (d, J = 14 Hz, 1 H), 2.55 (d, J = 14 Hz, 1 H), 4.76 (q, J = 8.8 Hz, 2 H), 6.25 (s, 1 H), 6.69 (t, J = 2 Hz, 1 H), 6.91 (t, J = 3.2 Hz, 1 H), 6.98 (t, J=, 8.36 Hz, H), 8.73 (s, 1 H). HRMS calculated for: [Ci6Hi6CIF6NO3+H]+420.0796; found: 420.0806. Analytical Chiral HPLC: CHIRALPAK-IH (250X4.6mmX5|jm) 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: 5.000, (Rt: 3.031).

[1742] Example 28: 3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2- vDcyclopropyDbutanamide:

[1743] Synthesis of 1-(6-chloropyridin-2-yl)cyclopropan-1 -amine (2):

[1744] 6-chloropicolinonitrile 1 (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): 169.05 [M+H]+. H NMR (400 MHz, DMSO-cfe) 6 ppm 0.99-1.01 (m, 2 H), 1.16-1.17 (m, 2 H), 7.19-7.21 (m, 1 H), 7.72-7.80 (m, 2 H).

[1745]

[1746] Synthesis of N-(1 -(6-chloropyridin-2-yl)cyclopropyl)-3-cyclopropyl-3- hydroxybutanamide (3):

[1747] Following general procedure for compound-8, compound-2 (150 mg, 0.889 mmol) converted to compound-3 (130 mg, 49.61%), m / z (LC-MS): 295.05 [M+H]+. H NMR (400 MHz, DMSO-cfe) 6 ppm 0.30-0.33 (m, 4 H), 0.89-0.96 (m, 1 H), 1.15-1.19 (m, 2 H), 1.23 (s, 3 H), 1.40-1.42 (m, 2 H), 2.31-2.38 (m, 2 H), 4.49 (s, 1 H), 7.25 (d, J = 7.6 Hz, 1 H), 7.42 (d, J = 7.6 Hz, 1 H), 7.74 (t, J = 8 Hz, 1 H), 8.68 (s, 1 H).

[1748]

[1749] Synthesis of 3-cyclopropyl-3-hydroxy-N-(1 -(6-((2,2,2-trifluoroethyl)amino)pyridin- 2-yl)cyclopropyl)butanamide (Example 28 peak-1 & Example 28 peak-2, A28a and A28b):

[1750]

[1751] P6714PC00

[1752] To a sealed tube containing stirred solution of compound-3 (0.05 g, 0.169 mmol) in Dioxane: 1,2-Dimethoxyethane (1:1, 0.5 mL) added 2,2,2-trifluoroethan-1-amine hydrogen chloride (0.023, 0.169 mmol) followed by Cesium carbonate (0.13 g, 0.424 mmol). Resulting reaction mixture purged with Argon for 10 min added XPhos-Pd-G2 (0.013 g, 0.017 mmol) and heated at 110 °C for 1 h. Progress of the reaction was monitored by TLC and LCMS. Crude compound was purified using prep HPLC, Column: X SELECT (250mmx20.0mm), 5.0p, Eluent: A= 0.02% NH4OH IN WATER, B = Acetonitrile, Flow: 15 ml / min, Gradient time / %B 0 / 20, 2 / 30, 8 / 60 to get 16 mg of Example 28. The enantiomers were separated using Chiral prep HPLC, Column:

[1753] CHIRALPAK IH, 250mmX21mm, 5pm, Eluent: (A) n-HEXANE (B) IPA IN MeOH (1:1), Flow: 15 mL / min, Isocratic: 85(A):15(B), diluent: EtOH: DCM,1:1, 3 ml, Injection vol, 0.65 mL, run time 18 mL / min, to get Peak-1 (5 mg), Peak-2: (6 mg); H NMR (400 MHz, DMSO-cfe) 6 ppm 0.32-0.34 (m, 4 H), 0.88-0.92 (m, 1 H), 1.00-1.15 (m, 2 H), 1.23 (s, 3 H), 1.41-1.42 (m, 2 H), 2.23-2.27 (m, 2 H), 4.24 (q, J = 6.8 Hz, 2 H), 4.59 (s, 1 H), 6.36 (d, J = 8 Hz, 1 H), 6.68 (d, J = 7.2 Hz, 1H), 7.00-7.03 (m, 1 H), 7.30-7.34 (m, 1 H), 8.54 (bs, 1 H), HRMS calculated for: [CI7H22F3N3O2+H]+358.1737; found: 358.1750 (Peak- I), 358.1751 (Peak-2). Analytical Chiral HPLC: Chiralpak IH, 150mmX4.6 mm, 5pm), Eluent: (A) n-HEXANE (B)0.1% HCOOH IN EtOH: MeOH (80:20), Flow: 1 mL / min, Isocratic: 90(A):10(B), diluent: EtOH, Injection vol, 10 mL, run time 20 min, Column Temp: 25°C, Peak-1 (Rt: 9.297, 100% ee) Peak-2: (Rt: 13.873, 100% ee)

[1754] Example 29: 3-(bicyclof2.2.21octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide:

[1755] Synthesis of tert-butyl 3-(bicyclo[2.2.2]octan-1-yl)-3-hydroxybutanoate (3t):

[1756] 1-(bicyclo[2.2.2]octan-1-yl)ethan-1-one (30 mg, 0.197 mmol) converted to compound-3t (60 mg, crude) using general procedure B used for compound-3, H-NMR (DMSO-de, 400 MHz): 51.23 (s, 3 H), 1.37-1.58, m, 21 H), 2.25 (d, J = 14 Hz, 1 H), 2.49 (d, J = 14 Hz, 1 H), 3.95 (s, 1 H).

[1757]

[1758] Synthesis of 3-(bicyclo[2.2.2]octan-1-yl)-3-hydroxybutanoic acid (4t): To a solution of compound-3t (40 mg, 0.149 mmol) in DCM (1 mL) at 0 °C added dioxane HCI (0.12 mL, 0.447 mmol). Resulting reaction mixture stirred at room temperature for 2 h and P6714PC00

[1759] concentrated under vacuo to get crude compound-4t (20 mg, crude%), H-NMR (DMSO-d6, 400 MHz): 5 1.23 (s, 3 H), 1.38-1.5 (13 H, 2 H), 2.33 (d, J = 14 Hz, 1 H), 2.49 (d, J = 14 Hz, 1 H), 3.71 (s, 1 H).

[1760]

[1761] Synthesis of 3-(bicyclo[2.2.2]octan-1 -y I )-N -( 1 -(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide (Example 29 peak-1 & Example 29 peak-2, A29a and A29b):

[1762]

[1763] Following general procedure 8, Compound-4t (20 mg, 0.0942 mmol) converted to crude Example 29 which was purified using prep HPLC, Column: Gemini NX (250mmx21.2mm), 5. Op, Eluent: A = 0.1% HCOOH in water, B = Acetonitrile, Flow: 18 mL / min, to get target-56. (13 mg, 80.19%) which was separated using Chiral prep HPLC, Column: CHIRALPAK IH, 250mmX20mm, 5pm; Mobile Phase:n-Hexane(A) and IPA (B), Flow:15ml; Isocratic:75(A):25 (B); Diluents: EtOH: DCM, 1: 1, 2.5 ml, Injection: Volume-0.3ml; Run Time-15 min; Instrument Make and Model: Agilent-1200 series, to get Peak-1 (3.1 mg), Peak-2: (3.3 mg), 1H NMR (400 MHz, CDCh) 6 ppm 1.35 (s, 3 H), 1.37-1.41 (m, 2 H), 1.42-1.50 (m, 5 H), 1.51-1.62 (m, 9 H), 2.09 (d, J = 14.8 Hz, 1 H), 2.45 (d, J = 14.8 Hz, 1 H), 4.31 (q, J = 8 Hz, 2 H), 6.73-6.77 (m, 2 H), 6.80-6.82 (m, 1 H), 6.90-6.92 (m, 1 H) HRMS calculated for: [C23H29CIF3NO3+H]+460.1861; found: 460.1871 (Peak-1), 460.1868 (Peak-2). Analytical Chiral HPLC: CHIRALPAK-IG (150X4.6mmX5pm), Mobile Phase: (A) n-HEXANE (B) 0.1% HCOOH IN EtOH: MeOH (80: 20), Isocratic: 85: 15 (A: B), Flow: 1.0ml / min, Diluent: EtOH, Column Temp: 25°C, Inj. volume: 5.000, Acq. method: IG_8515_1_B_12MIN.amx, Peak-1 (Rt: 3.77, 100% ee), Peak-2: (Rt: 4.41, 98.80% ee).

[1764] Example 30: 4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2- yl) cyclopropyl) butanamide

[1765] Synthesis of 2-(2,2,2-trifluoroethoxy)isonicotinonitrile (2): P6714PC00

[1766]

[1767] To a stirred solution of 6-chloropicolinonitrile (2.0 g, 14.4315 mmol) in anhydrous DMF (20 mL) was added potassium carbonate (4.98 g, 36.0863 mmol) and 2,2,2-trifluoroethan-1-ol (3.61g, 36.086 mmol) at RT. Resulting reaction mixture stirred at 60 °C for 16h. Reaction was quenched using ice cold water 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-2 (1.6 g, 51.7%) as off white solid; m / z (LC-MS): 202.90 [M+H]+.

[1768] Synthesis of 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropan-1-amine (3):

[1769]

[1770] Compound-2 (1 g, 4.9472 mmol) converted to compound-3 (710 mg, 62.28%) using general procedure used for compound-7. After basification using NaHCCh, compound extracted as free base, m / z (LC-MS): 233.15 [M+H]+.

[1771] Example 30a: (R)-4,4,4-trifluoro-3-hvdroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide:

[1772]

[1773] Following general procedure for compound-8, compound-4r (66 mg, 0.2615 mmol) converted to Example 30a (A30a) (52 mg, 51.48%). It was purified using prep TLC. 1H NMR (400 MHz, CDCI3) 5 ppm 1.26-1.29 (m, 2 H), 1.45 (s, 3 H), 1.64-1.67 (m, 2 H), 2.5 (d, J = 15.26 Hz, 1 H), 2.64 (d, J = 15.26 Hz, 1 H), 4.65 (q, J = 8.8 Hz, 2 H), 5.77 (s, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 6.95 (d, J = 7.48 Hz, 1 H), 7.54-7.58 (m, 1 H). HRMS calculated for: [Ci5Hi6FeN2O3+H]+387.1138; found: 387.1148, Analytical Chiral HPLC: REGIS(S, S) WHELK-01 (250X4.6mmX5|jm); Mobile Phase: (A) n-HEXANE (B) 0.1% HCOOH IN EtOH: MeOH (80:20) Isocratic: 50:50 (A: B) Flow: 1.0ml / min Diluent: EtOH, Column Temp: 25°C, Inj. volume: 5.000, (Rt: 3.235, 100% ee). P6714PC00

[1774] Example 30b: (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide:

[1775]

[1776] Following general procedure for compound-8, compound-4s (100 mg, 0.581 mmol) converted to Example 30b (A30b) (110 mg, 49.10%). It was purified using prep TLC.

[1777] 1H NMR (400 MHz, CDCI3) 5 ppm 1.26-1.29 (m, 2 H), 1.45 (s, 3 H), 1.64-1.67 (m, 2 H), 2.5 (d, J = 15.26 Hz, 1 H), 2.64 (d, J = 15.26 Hz, 1 H), 4.65 (q, J = 8.8 Hz, 2 H), 5.77 (s, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 6.95 (d, J = 7.48 Hz, 1 H), 7.54-7.58 (m, 1 H). HRMS calculated for: [Ci5Hi6FeN2O3+H]+387.1138; found: 387.1148, Analytical Chiral HPLC: REGIS(S, S) WHELK-01 (250X4.6mmX5|jm); Mobile Phase: (A) n-HEXANE (B) 0.1% HCOOH IN EtOH: MeOH (80:20) Isocratic: 50:50 (A: B) Flow: 1.0ml / min Diluent: EtOH, Column Temp: 25°C, Inj. volume: 5.000, (Rt: 3.221, 100% ee).

[1778] Example 31: 3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide:

[1779]

[1780] Synthesis of 3-cyclopropyl-3-hydroxy-N-(1 -(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide (Example 31 peak-1 & Example 31 peak-2, A31a and A31b)

[1781] Following general procedure for compd-8, compound-4e (0.1 g, 0.694 mmol) converted to Example 31 (0.120 g, 48.38%) as brown gummy, which was separated using Chiral prep HPLC, Column: Chiralpak IH, 150mmX4.6mm X 5pm, Mobile Phase: CO2 (A) and 100% IPA (B), Flow:60 ml, Isocratic:85(A):15(B) to get Peak-1 (41.3 mg) Peak-2: (40 mg). 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.21-0.35 (m, 4 H), 0.90-0.94 (m, 1 H), 1.09-1.11 (m, 2 H), 1.19 (s, 3 H), 1.49-1.52 (m, 2 H), 2.30-2.39 (m,2 H), 4.53 (s, 1 H), 4.89 (q, J = 9.24 Hz, 2 H), 6.71 (d, J = 8.07 Hz, 1 H), 7.11 (d, J=7.48 Hz, 1 H), 7.65-7.69 (m, 1 H), 8.63 (s, 1 H). HRMS calculated for: [Ci7H2iF3N2O3+H]+359.1577; found: 359.1592 (Peak-1), 359.1594 (Peak-2). Analytical Chiral HPLC: CHIRALPAK-IH, 4.6 MM x150MM x 5pm; Co-Solvent Name: 10mM Ammonia in IPA; Flow: 3 ml / min; P6714PC00

[1782] Column Temp: 40 °C, Inj. volume: 15 pl, Acq. method: C:\Pic Solution\Methode\Analytical\3-20-20MIN.met. Peak-1 (Rt: 2.23, 100% ee), Peak-2: (3.99, 100% ee).

[1783] Example 32: (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide:

[1784] HO CH3O ^—7H

[1785] N N

[1786] H

[1787]

[1788] i Y

[1789] Following general procedure for compound-8, compound-4r (0.07 g, 0.302 mmol) converted to Example 32 (A32). Crude compound purified using prep TLC (70% EtOAc in hexane in pet ether as an eluent) to get pure enough Example 32 (16 mg, 14%).1H NMR (400 MHz, DMSO-d6) 5 = 8.70 (s, 1

[1790] H), 7.32 (t, J = 7.8 Hz, 1 H), 7.03 (t, J = 6.4 Hz, 1 H), 6.69 (d, J = 7.2 Hz, 1 H), 6.37 - 6.32 (m, 2 H), 4.10 - 4.01 (m, 2 H), 2.57 (d, J = 14 Hz, 1 H), 2.39 (d, J = 14 Hz, 1 H), 1.46 - 1.34 (m, 5 H), 1.01 (dd, J = 14.1, 10.6 Hz, 2H). HRMS calculated for:

[1791] [Ci5Hi7F6N3O2+H]+386.1298; found: 386.1286. Analytical Chiral HPLC: CHIRALPAK- IK (250X4.6mmX5pm); Mobile Phase: 0.1% DEA IN n-Hexane: ETHNAOL:

[1792] DCM(60:20:20), Isocratic: 100 Flow: 1.0ml / min, Column Temp: 25°C, Inj. volume: 5.000, (Rt: 3.801).

[1793] 33: N-

[1794]

[1795] -chloro-6-(2,2,2-tri

[1796]

[1797] in-2-yl)cyclopropyl)-4,4,4-trifluoro-3-l

[1798] 33a: (R)-N-(1 -(4-chloro-6-(2,2,2-- in-2-yl)cyclopropyl)-4,4,4-trifluoro-3-l '-3-I OH O N

[1799] H

[1800]

[1801] Following general procedure 8, Compound-4r (0.15 g, 0.871 mmol) converted to Example 35a (A33a) (155 mg, 42.35%) which was purified by flash chromatography (EtOAc: Hexane 50:50). H-NMR (DMSO-d6, 400 MHz): 5 ppm 1.13-1.23 (m, 2 H), 1.41 (s, 3 H), 1.49-1.59 (m, 2 H), 2.42 (d, J = 14 Hz, 1 H), 2.61 (d, J = 14 Hz, 1 H), 4.93 (q, P6714PC00

[1802] J = 9.05 Hz, 2 H), 6.29 (s, 1 H), 6.93 (d, J = 1.47 Hz, 1 H), 7.17 (d, J = 1.47 Hz, 1 H), 8.8 (bs, 1 H), HRMS calculated for: [Ci5Hi5CIF6N2O3+H]+421.0755; found: 421.0759, Analytical Chiral HPLC: CHIRALPAK-IK (250X4.6mmX5|jm); Mobile Phase: 0.1% DEA IN n-Hexane: ETHNAOL: DCM(60:20:20), Isocratic: 100% Flow: 1.0ml / min, Column Temp: 25°C, Inj. volume: 3.000, (Rt: 3.46).

[1803] Example 33b: (S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide (33b):

[1804]

[1805] Cl

[1806] Following general procedure 8, compound-4s (0.1 g, 0.581 mmol) converted to Example 33b (59 mg, 24.18%). It was purified using prep TLC (EtOAc: Hexane 20:80). H-NMR (DMSO-d6, 400 MHz): 5 ppm 1.13-1.23 (m, 2 H), 1.41 (s, 3 H), 1.49-1.59 (m, 2 H), 2.42 (d, J = 14 Hz, 1 H), 2.61 (d, J = 14 Hz, 1 H), 4.93 (q, J = 9.05 Hz, 2 H), 6.29 (s, 1 H), 6.93 (d, J = 1.47 Hz, 1 H), 7.17 (d, J = 1.47 Hz, 1 H), 8.8 (bs, 1 H), HRMS calculated for: [C15H15ClF6N2O3+H]+421.0755; found: 421.0754, Analytical Chiral HPLC: CHIRALPAK-IG (250X4.6mmX5|jm); Mobile Phase: (A) n-Hexane, (B) 0.1% NH4OH in (EtOH:: DCM) (50:50), Isocratic: (A: B) (50:50), Flow: 1.0ml / min, Column Temp: 25°C, Inj. volume: 10.000, (Rt: 3.201).

[1807] Example 34: Kv7 modulating activity

[1808] Aim

[1809] To demonstrate the ability of the compounds according to the present disclosure to modulate the activity of Kv7 potassium channels.

[1810] Materials and Methods

[1811] Cell seeding. HEK293 cells stably expressing concatenated hKv7.3-hKv7.2 were seeded on poly-D-lysine (10 pg / ml) coated 384-well, clear bottomed, black-walled Corning Optiplates. The cells were seeded at a density of approximately 3x106cells / ml P6714PC00

[1812] in 20 µl DMEM containing 10% FCS per well and left overnight at 37 °C in a 5% CO2 incubator.

[1813] 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 pl Cl"-free loading buffer (assay buffer containing an additional 2 pM 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 1 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 Tl2SO4(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 K2SO4concentration 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).

[1814] 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. EC50and efficacy (% of positive control) values are reported, where positive control is defined as response to 30 pM retigabine.

[1815] Results

[1816] 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. P6714PC00

[1817] Table 1:

[1818] FLIPR: Kv7.2 / Kv7.3 FLIPR: Kv7.5 Test example EC50 (pM) Efficacy EC50 Efficacy (%) (pM) (%) Examplela 2 98 1.81 102 Examplelb 16 81 15.8 105 Example 2 9.4 109 13.6 113 Example 3 1.2 106 21 76 Example 4 peak-1 2.8 91 >30 0 Example 4 peak-2 2.9 81 >30 0 Example 5 peak-1 0.52 100 2.8 34 Example 5 peak-2 0.9 94 2.3 31 Example 6 peak-1 1.1 83 >30 0 Example 6 peak-2 1.7 103 >30 0 Example 7 peak-1 0.5 119 0.5 156 Example 7 peak-2 2.0 119 8.9 99 Example 8 peak-1 4.5 90 >30 0 Example 8 peak-2 1.9 92 >30 0 Example 9 3.2 101 11 80 Example 10 3.0 107 >30 0 Example 11 peak-1 0.3 99 >30 0 Example 11 peak-2 0.46 108 >30 0 Example 12 peak-1 11 110 >30 0 Example 12 peak-2 19 100 >30 0 Example 13 peak-1 1.2 100 >30 0 Example 13 peak-2 4.7 97 >30 0 Example 14 peak-1 2.2 107 >30 0 Example 14 peak-2 3.5 98 >30 0 Example 15 peak-1 12 83 >30 0 Example 15 peak-2 21 103 >30 0 Example 16 peak-1 12 69 >30 0 Example 16 peak-2 16 107 >30 0 Example 17 peak-1 0.3 100 3.5 71

[1819]

[1820] P6714PC00

[1821] Example 17 peak-2 0.6 96 >30 0

[1822] Example 18 0.1 110 >30 0

[1823] Example 19 peak-1 0.1 91 >30 0

[1824] Example 19 peak-2 0.1 96 >30 0

[1825] Example 20 0.7 88 >30 0

[1826] Example 21 peak-1 0.1 91 >30 0

[1827] Example 21 peak-2 0.3 97 1.1 92

[1828] Example 22 peak-1 4.9 92 23 86

[1829] Example 22 peak-2 6.5 94 2.7 100

[1830] Example 23 peak-1 3.1 60 >30 0

[1831] Example 23 peak-2 12 110 >30 0

[1832] Example 24 peak-1 5.8 92 24 11

[1833] Example 24 peak-2 13 85 >30 0

[1834] Example 25 peak-1 4.3 70 >30 0

[1835] Example 25 peak-2 4.9 99 >30 0

[1836] Example 26 peak-1 2.4 67 >30 0

[1837] Example 26 peak-2 3.6 87 >30 0

[1838] Example 27a 0.7 87 >30 0

[1839] Example 27b 0.3 96 1 59

[1840] Example 28 peak-1 1.1 99 >30 0

[1841] Example 28 peak-2 0.8 101 >30 0

[1842] Example 29 peak-1 0.8 94 1.2 54

[1843] Example 29 peak-2 1.1 92 >30 0

[1844] Example 30a 1.0 86 >30 0

[1845] Example 30b 2.0 99 6.1 85

[1846] Example 31 peak-1 3.7 66 >30 0

[1847] Example 31 peak-2 3.8 100 >30 0

[1848] Example 32 0.6 82 >30 0

[1849] Example 33a 0.6 64 >30 0

[1850] Example 33b 2.1 75 16 14

[1851]

[1852] Conclusion

[1853] The compounds according to the present disclosure are able to modulate the activity of Kv7 channels. P6714PC00

[1854] 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

P6714PC00Claims1. 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; whereinB is of formula (II):R1formula (II)R1is selected from the group consisting of –OH and -CH3;R2is C1-10 alkyl optionally substituted with one or more, identical or different, substituents R4; or C3-6 cycloalkyl optionally substituted with one or more R4and / or with two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s);R4is C1-5 alkyl, halogen or C1-5 haloalkyl;G1is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R4; andR3is -H or-CH3;or R2and R3are linked together to form a 3- to 6-membered ring, and R2and R3are individually C1-3 alkanediyl, optionally substituted with one or more, identical or different substituents R11, and / or with two substituents G2together forming a 3- to 6-membered ring together with the intervening atom(s);R11is halogen, C1-5 alkyl, or C1-5 haloalkyl;G2is individually C1-3 alkanediyl optionally substituted with one or more, identical of different, substituents R11;A is of formula (III):P6714PC00formula (III)whereinA1is C-R5or N;R5is selected from -H, or halogen;A2is C-R6;R6is selected from the group consisting of C1-5 alkoxy optionally substituted with one or more halogen; C1-5 alkyl optionally substituted with one or more halogen; and N(R10)(H);R10is C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;R12is halogen, C3-5 cycloalkyl or C1-3 alkyl;A3is C-R7or N;R7is -H, halogen, or C1-5 alkyl;A4is C-R8or N;R8is -H, halogen, C3-5 cycloalkyl, C1-5 alkyl optionally substituted with one or more halogen, C1-5 alkoxy, or-CN;A5is C-R9or N; andR9is -H or halogen;with the proviso that the compound is not3-Hydroxy--[1-(3-methoxyphenyl)cyclopropyl]-3-methylbutanamide.

2. The compound according to claim 1, wherein R1is -OH and R3is -CH3.

3. The compound according to claim 1 or 2, wherein R2is C1-4 alkyl optionally substituted with one or more R4.

4. The compound according to claim 1 or 2, wherein R2is C3-6 cycloalkyl optionally substituted with one or more R4, or two substituents G1together forming a 3- to 6- membered ring together with the intervening atom(s).P6714PC005. The compound according to claim 1 or 2, wherein R2is -CF3, CH2CF3, -CH3,tert-butyl, cyclopropyl, cyclobutyl,, cyclopentyl,FOH6. The compound according to claim 1 or 2, wherein B isF^ x / ”^7. The compound according to any one of the preceding claims, wherein R6is - CF3, -OCF3, -OCH2CF3,or -NHCH2CF3.

8. The compound according to any one of the preceding claims, wherein A is of formula (III),formula (III)whereinA1is C-R5; A2is C-R6; A3is C-R7; A4is C-R8; and A5is C-R9,R5is -H or-F,R6is -CF3, -OCF3, -OCH2CF3,or -NHCH2CF3,R7is -H, -F, -Cl or-CH3,R8is -H, -F, -Cl, -Br, -CH3, -CF2H, or cyclopropyl, andR9is H.

9. The compound according to any one of claims 1 to 6, wherein A is of formula (III),P6714PC00formula (III)whereina) A1is N; A2is C-R6; A3is C-R7; A4is C-R8; and A5is C-R9, orb) A1is C-R5; A2is C-R6; A3is N; A4is C-R8; and A5is C-R9,R5is -H or-F,R6is -CF3, -OCF3, -OCH2CF3,or -NHCH2CF3,R7is -H, -F, -Cl or-CH3,R8is -H, -F, -Cl, -Br, -CH3, -CF2H, or cyclopropyl, andR9is H.

10. The compound according to any one of the preceding claims, wherein at least one of A1, A3, A4, and A5is not C(H).

11. The compound according to any one of claims 1 to 6, wherein A isP6714PC0012. The compound according to claim 1, whereinR1is -OH or-CH3;R2is -CH3, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CF₃,-CH₂CF₃;ciP6714PC0013. The compound according to claim 1, whereinR1is -OH,R2is -CH3, tert-butyl, -CF3, or -CH2CF3,R3is -CH3, andor14. The compound according to claim 1, whereinR1is -OH,R2is cyclopropyl, cyclobutyl, cyclopentyl,R3is -CH3, and15. The compound according to claim 1, wherein the compound is2-(1-hydroxycyclopentyl)-N-(1-(3-(trifluoromethoxy)phenyl)cyclopropyl)- acetamide,N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(3,3-difluoro-1- hydroxycyclobutyl)acetamide,2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-methyl-5-(2,2,2-trifluoroethoxy)- phenyl)cyclopropyl)acetamide,2-(2-hydroxyspiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)- cyclopropyl)acetamide,N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,3-dimethyl- butanamide,P6714PC00N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-2-(5-hydroxyspiro- [2,3]hexan-5-yl)acetamide,(R)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4-dimethylpentanamide,(R)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,(R)-3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,(R)-3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,(R)-3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-pentanamide,(R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)pentanamide,(R)-3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,(R)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,(R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,(R)-3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,(R)-3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)-3-hydroxybutanamide,(R)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,(R)-3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)-phenyl)cyclopropyl)butanamide,(R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide,(R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide,(R)-3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,P6714PC00(R)-3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide,(R)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,(R)-3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,(R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,(R)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,(R)-3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide,(R)-3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)-3-hydroxybutanamide,(R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,(R)-3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,(R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2-trifluoroethyl)amino)-pyridin-2-yl)cyclopropyl)butanamide,(R)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,(S)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-3-hydroxy-4,4-dimethylpentanamide,(S)-3-cyclopropyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,(S)-3-cyclopentyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,(S)-3-cyclobutyl-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-butanamide,(S)-3-hydroxy-3,4,4-trimethyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-pentanamide,(S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)pentanamide,P6714PC00(S)-3-hydroxy-3-(spiro[3.3]heptan-2-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-cyclopropyl)butanamide,(S)-N-(1-(3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,(S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,(S)-3-cyclopropyl-N-(1-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,(S)-3-cyclopropyl-N-(1-(3-(difluoromethyl)-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,(S)-N-(1-(4-chloro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,(S)-3-hydroxy-3-(spiro[2.3]hexan-5-yl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,(S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-cyclopropylbutanamide,(S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3,4,4-trimethylpentanamide,(S)-3-cyclopropyl-N-(1-(2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,(S)-3-cyclopropyl-N-(1-(3-cyclopropyl-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,(S)-N-(1-(2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)cyclopropyl)-3-cyclopropyl-3-hydroxybutanamide,(S)-3-cyclopropyl-3-hydroxy-N-(1-(4-methyl-3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,(S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)butanamide,(S)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide,(S)-3-cyclopropyl-3-hydroxy-N-(1-(6-((2,2,2-trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide,(S)-3-(bicyclo[2.2.2]octan-1-yl)-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-3-hydroxybutanamide,P6714PC00(S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl) butanamide,(S)-3-cyclopropyl-3-hydroxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl) cyclopropyl)butanamide,(S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-(1-(6-((2,2,2- trifluoroethyl)amino)pyridin-2-yl)cyclopropyl)butanamide, or(S)-N-(1-(4-chloro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-4,4,4- trifluoro-3-hydroxy-3-methylbutanamide,or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of the preceding claims, wherein the compound is an agonist of a Kv7 channel.

17. The compound according to any one of the preceding claims, wherein the compound is selective for Kv7.2 / Kv7.3 over Kv7.5.

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17.

19. A compound according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18, for use as a medicament.

20. A compound according to any one of claims one of claims 1 to 17, or a pharmaceutical composition according to claim 18, for use in the treatment, prevention or alleviation of epilepsy or pain.

21. 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 claims 1 to 17, or a pharmaceutical composition according to claim 18 to the subject.

22. A method of modulating the activity of a Kv7 channel in a subject, the method comprising administering an effective amount of the a compound according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18.

23. The method according to claim 22, wherein the method is a method of increasing the activity of a Kv7.2 / Kv7.3 heteromeric channel.

24. 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 claims 1 to 17, or a pharmaceutical composition according to claim 18 to the subject.P6714PC0025. Use of a compound according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18, for the manufacture of a medicament for the treatment, prevention or alleviation of epilepsy or pain.

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