WO2026019302A1 - Novel orexin 2 receptor agonist and use thereof - Google Patents

Abstract

The present invention relates to: a novel compound that acts on an orexin 2 receptor; an optical isomer thereof, a diastereomer thereof, a racemate thereof, a mixture of optical isomers or diastereomers thereof, an isotopically labeled compound thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof; and use thereof for the prevention or treatment of an orexin 2 receptor-mediated disease.

Description

Novel orexin 2 receptor agonists and uses thereof

The present invention relates to a novel compound acting on an orexin 2 receptor, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, and a use thereof for preventing or treating orexin 2 receptor-mediated diseases.

Narcolepsy is a condition that affects approximately 1 in 2,000 people worldwide. Symptoms of narcolepsy often first appear in adolescence and can have a profound impact on quality of life throughout life. Narcolepsy type 1 (NT1) is caused by the loss of orexin-producing neurons in the brain, and currently approved treatments are only symptomatic. Specifically, narcolepsy type 1 is caused by the destruction of neuronal populations that produce orexin A and B (also known as hypocretin 1 and 2, respectively) peptides by an immune mechanism, leading to impaired vigilance during wakefulness. Therefore, developing pharmacological treatments that restore lost orexin signaling is a critical challenge in treating the underlying cause of narcolepsy type 1.

Meanwhile, orexin (hypocretin) is a hormone released from orexin neurons (also called Hcrt neurons) in the hypothalamus, and is a group of neuropeptides that promote arousal through their actions on serotonin, histamine, acetylcholine, and dopamine. Two subtypes of orexin receptors are known: the first subtype OX1 receptor (OX1R) and the second subtype OX2 receptor (OX2R).

Mice with knockout of OX2R neurons exhibited excessive daytime sleepiness and cataplexy, suggesting that OX2R neurons are important for maintaining wakefulness.

Furthermore, intracerebroventricular administration of OX-A to transgenic mice with altered orexin neurons has been shown to improve symptoms of narcolepsy by suppressing cataplexy-like arrest and, for example, increasing alertness. Furthermore, loss of orexin neurons has been shown to contribute to daytime sleepiness in patients with Parkinson's disease, and low plasma OX-A concentrations have been found in patients with obstructive sleep apnea syndrome.

This suggests that orexin receptor agonists may serve as therapeutic agents for narcolepsy or other sleep disorders characterized by excessive sleepiness. Therefore, there is a need in the art to develop novel compounds and pharmaceutical compositions containing them for modulating orexin receptor activity in the brain, including activation of orexin-2 receptors, with improved therapeutic potential.

One object of the present invention is to provide a compound of formula I, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating an orexin 2 receptor (OX2R)-mediated disease, comprising as an active ingredient a compound of formula I, an optical isomer, a diastereoisomer, a racemate, a mixture of optical isomers or diastereoisomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preventing or treating an orexin 2 receptor-mediated disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising, as an active ingredient, a compound of formula I, an optical isomer, a diastereoisomer, a racemate, a mixture of optical isomers or diastereoisomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

The present invention provides a compound of formula I, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmaceutical composition for preventing or treating an orexin 2 receptor (OX2R)-mediated disease, comprising as an active ingredient a compound of formula I, an optical isomer, a diastereoisomer, a racemate, a mixture of optical isomers or diastereoisomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

The present invention provides a method for preventing or treating an orexin 2 receptor-mediated disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising, as an active ingredient, a compound of formula I, an optical isomer, a diastereoisomer, a racemate, a mixture of optical isomers or diastereoisomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

The compound of formula I according to the present invention, its optical isomer, diastereomer, racemate, mixture of optical isomers or diastereomers, isotopically labeled compound, hydrate, solvate or pharmaceutically acceptable salt functions as an orexin 2 receptor agonist and is useful for the prevention or treatment of orexin 2-mediated diseases, specifically hypersomnia disorders such as narcolepsy.

Each description and embodiment disclosed in this invention can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this invention fall within the scope of this invention. Furthermore, the scope of this invention is not limited by the specific descriptions described below.

Furthermore, those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments of the invention described herein. Furthermore, such equivalents are intended to be encompassed by the present invention.

Hereinafter, the present invention will be described in more detail.

The present invention provides a compound of the following formula I, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof:

[Chemical Formula I]

In the above chemical formula I,

n and m are each independently integers from 0 to 2;

p is an integer of 0 or 1;

R ¹ and R ² are each independently C ₁ -C ₃ alkyl or halogen;

R ³ is hydrogen or C ₁ -C ₆ alkyl;

R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, amino, C ₁ -C ₆ alkylamino, di(C ₁ -C ₆ alkyl)amino, or C ₃ -C ₈ cycloalkyl, wherein the C ₁ -C ₆ alkyl contained in R ⁴ may be optionally substituted with one or more deuterium;

R ⁵ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl), 3- to 8-membered heterocycloalkyl containing one heteroatom selected from N, O or S, or NR ^A R ^B ,

R ^A is hydrogen or C ₁ -C ₆ alkyl,

R ^B is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) or (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkylcarbonyl),

When R ⁵ is C ₁ -C ₆ alkyl or NR ^A R ^B , it may be substituted by one or more selected from the group consisting of deuterium, hydroxy, halogen, cyano and amino,

When R ⁵ is C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl), or 3- to 8-membered heterocycloalkyl containing one heteroatom selected from N, O, or S, it may be substituted with one or more selected from the group consisting of deuterium, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkyl;

R ^6a and R ^6b are each independently hydrogen or deuterium.

In the chemical formula I of the present invention, n and m may each independently be an integer from 0 to 2. In one specific example, n and m may each independently be an integer of 1 or 2, or specifically, n may be 2; and m may be 1, but is not limited thereto.

In the present chemical formula I, p can be an integer of 0 or 1. In one specific embodiment, the compound of chemical formula I has an azabicyclo[3.1.0]hexane core when p is 0, and has an azabicyclo[4.1.0]heptane core when p is 1.

In the chemical formula I of this invention, Is It may have the structure of, but is not limited to, this.

In the present chemical formula I, R ¹ and R ² can each independently be C ₁ -C ₃ alkyl or halogen. In one specific embodiment, R ¹ and R ² can each independently be methyl, fluoro or chloro. Specifically, R ¹ and R ² can both be halogen, more specifically, both are fluoro, but are not limited thereto.

In the chemical formula I herein, R ³ may be a compound that is hydrogen or C ₁ -C ₆ alkyl. In one specific example, R ³ may be hydrogen or C ₁ -C ₃ alkyl. Specifically, R ³ may be hydrogen, but is not limited thereto.

In the present general formula I, R ⁴ can be hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, amino, C ₁ -C ₆ alkylamino, di(C ₁ -C ₆ alkyl)amino, or C ₃ -C ₈ cycloalkyl, and the C ₁ -C ₆ alkyl contained in R ⁴ can be optionally substituted with one or more deuterium. In one specific embodiment, R ⁴ can be C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, di(C ₁ -C ₆ alkyl)amino, or C ₃ -C ₈ cycloalkyl. Specifically, R ⁴ can be C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, di(C ₁ -C ₃ alkyl)amino, or C ₃ -C ₈ cycloalkyl. More specifically, R ⁴ can be, but is not limited to, methyl, ethyl, fluoromethyl, difluoromethyl, dimethylamino, di(methyl-d3)amino, or cyclopropyl.

In the present general formula I, R ⁵ can be C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl), a 3- to 8-membered heterocycloalkyl comprising one heteroatom selected from N, O, or S, or NR ^A R ^B. In one specific embodiment, R ⁵ can be C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₃ alkyl), a 3- to 6-membered heterocycloalkyl comprising one heteroatom selected from N, O, or S, or NR ^A R ^B. At this time, when R ⁵ is C ₁ -C ₆ alkyl, R ⁵ may be substituted with deuterium, hydroxy, halogen, cyano and amino, and when R ⁵ is C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)(C ₁ -C ₆ alkyl)- or 3- to 8-membered heterocycloalkyl containing one heteroatom selected from N, O or S, it may be substituted with deuterium, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, specifically, deuterium, hydroxy, halogen, amino, methyl or trifluoromethyl.

In one embodiment, the C ₃ -C ₈ cycloalkyl can be a monocyclic or bicyclic cycloalkyl. When the C ₃ -C ₈ cycloalkyl is a bicyclic group, it can be a fused, bridged, or spiro group. In one embodiment, the bicyclic C ₃ -C ₈ cycloalkyl can be a bridged C ₃ -C ₈ cycloalkyl. The 3- to 8-membered heterocycloalkyl comprising one heteroatom selected from N, O, or S can be a monocyclic or bicyclic heterocycloalkyl. When the 3- to 8-membered heterocycloalkyl is a bicyclic group, it can be a fused, bridged, or spiro group. In one embodiment, the bicyclic 3- to 8-membered heterocycloalkyl can be a bridged heterocycloalkyl. The 3- to 8-membered heterocycloalkyl comprising one heteroatom selected from N, O or S may be, but is not limited to, oxiraneyl, aziridinyl, oxetaneyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, morpholinyl, 2-oxabicyclo[2.1.1]hexanyl, or 5-oxabicyclo[2.1.1]hexanyl.

Alternatively, R ⁵ can be NR ^A R ^B , wherein R ^A is hydrogen or C ₁ -C ₆ alkyl and R ^B can be hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) or (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkylcarbonyl). In one embodiment, R ^A is hydrogen or C ₁ -C ₃ alkyl and R ^B can be hydrogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₃ alkyl) or (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₃ alkylcarbonyl). Specifically, R ^A is hydrogen, and R ^B can be hydrogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, or C ₃ -C ₆ cycloalkylmethylcarbonyl. Here, R ⁵ , specifically R ^B , can be optionally substituted with deuterium, hydroxy, halogen, cyano, and amino.

For example, R ⁵ is ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, 2-bicyclo[1.1.1]pentyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, azetidinyl, oxatanyl, 2-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[2.1.1]hexyl, ethylamino, (cyclopropyl)methylamino, or unsubstituted or substituted with one or more selected from the group consisting of deuterium, hydroxy, methyl, fluoro, amino, cyano, and trifluoromethyl. It could be ethylamino.

Specifically, R ⁵ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or It may include, but is not limited to.

In the present chemical formula I, R ^6a and R ^6b can each independently be hydrogen or deuterium. In one specific embodiment, both R ^6a and R ^6b can be hydrogen or both deuterium.

The compound of formula I can have two cis-isomers and two trans-isomers due to the four chiral carbons of the azabicyclo[3.1.0]hexane or azabicyclo[4.1.0]heptane core. That is, the compound of formula I can have any one of the following stereostructures I-1 to I-4:

[Chemical Formula I-1]

[Chemical Formula I-2]

[Chemical Formula I-3]

[Chemical Formula I-4]

In the above chemical formulas I-1 to I-4, n, m, p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a and R ^6b are each as defined for chemical formula I.

In one embodiment, the compound of formula I herein may be a cis-isomer selected from formulas I-1, I-2, or mixtures thereof. In another embodiment, the compound of formula I herein may be a trans-isomer selected from formulas I-3, I-4, or mixtures thereof.

In one specific embodiment, the compound of the present invention may be any one compound selected from the following, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof:

.

The present invention provides a pharmaceutical composition for preventing or treating an orexin 2 receptor (OX2R)-mediated disease, comprising as an active ingredient a compound of the above-mentioned chemical formula I, an optical isomer, a diastereoisomer, a racemate, a mixture of optical isomers or diastereoisomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

In one specific embodiment, the orexin 2 receptor mediated disorder can be selected from the group consisting of narcolepsy, daytime sleepiness, cataplexy, nocturnal sleep disorder, inappropriately timed rapid eye movement (REM) sleep, sleep paralysis, sleep hallucinations, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome with excessive daytime sleepiness, and coma.

The present invention provides a method for preventing or treating an orexin 2 receptor (OX2R)-mediated disease, comprising administering to a subject in need thereof a pharmaceutical composition for preventing or treating an orexin 2 receptor (OX2R)-mediated disease, the pharmaceutical composition comprising, as an active ingredient, a compound of the above-described chemical formula I, an optical isomer, a diastereoisomer, a racemate, a mixture of optical isomers or diastereoisomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

definition

All technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art, and unless otherwise stated, conventional measuring methods, manufacturing methods, conventional ingredients or materials based on conventional techniques of pharmacology, pharmaceutical manufacturing, mass spectrometry, NMR, HPLC, biochemistry, etc. are used.

The individual features and components of each embodiment described and illustrated in this specification may be combined with the features and components of any other embodiment without departing from the scope or spirit of the present disclosure.

Unless otherwise specified, in this specification and any attached claims, "and" and "or" mean "and/or." The terms "comprises" and "comprised" are open-ended, meaning that the compound, composition, or method may include additional features or components in addition to the specific features or components listed.

In this specification, a numerical range indicated using the term “to” refers to a range that includes the numerical values described before and after the term “to” as the lower and upper limits, respectively.

As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the term "optionally substituted" means that the occurrences include instances where the occurrences are either substituted or unsubstituted with the specified substituent.

compound

The term "alkyl" as used herein, unless otherwise stated, includes instances where it is used alone or as part of a substituent, and means a saturated straight and branched carbon chain having 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkyl may include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like.

The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated non-aromatic monocyclic or bicyclic hydrocarbon group. The cycloalkyl group may contain, for example, 3 to 8, 3 to 6, or 3 to 5 carbon atoms. A monocyclic cycloalkyl group may be, for example, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl. A bicyclic cycloalkyl group may be a fused, bridged, or spiro group. A bicyclic cycloalkyl group may include, for example, bornyl, decahydronaphthyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, or bicyclo[2.2.2]octylyl.

In the present invention, the term "heteroatom" means nitrogen, oxygen or sulfur, and may include any oxidized form of nitrogen, such as N(O) (N ⁺ -O ^- ) and sulfur, such as S(O) and S(O) ₂ and any quaternized form of basic nitrogen.

The terms "heterocycloalkyl", "heterocyclic" or "heterocycle" of the present invention refer to a saturated or partially unsaturated cyclic group containing one or more heteroatoms, the remaining ring atoms being carbon. The heterocycloalkyl group may contain, for example, 1 to 3, 1 or 2, or 1 heteroatom. As used herein, the heterocycloalkyl may be a monocyclic or bicyclic group. A bicyclic heterocycloalkyl may be a fused, bridged or spiro group. A fused heterocycloalkyl may include a structure in which a ring containing a heteroatom is fused with a non-heteroatom containing ring, for example, azabicyclo[3.1.0]hexane and 3-azabicyclo[4.1.0]heptane. Additionally, the bridged heterocycloalkyl may include structures in which two non-adjacent ring atoms of a (hetero)cycloalkyl ring are connected via one or two bridging atoms, such as 2-oxabicyclo[2.1.1]hexanyl and 5-oxabicyclo[2.1.1]hexanyl. The heterocycloalkyl group may include 3 to 10 ring atoms, 3 to 8 ring atoms, 3 to 7 ring atoms, or 3 to 5 ring atoms. The heterocycloalkyl group includes, but is not limited to, aziridinyl, azetidinyl, oxirenyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, morpholinyl, and the like.

The term "halogen" in the present invention refers to an atom belonging to Group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, and iodine, and may be used interchangeably with the term "halo," which refers to a monovalent functional group composed of halogen.

The term "hydroxy" in the present invention refers to an -OH functional group (hydroxyl group).

The term "cyano" of the present invention refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom, as in -CN.

In the present invention, the term "amino" refers to -NH ₂ .

The term "alkylamino" of the present invention refers to a group in which one of the two H groups of an amino group is replaced with an alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and propylamino.

The term "dialkylamino" of the present invention means -N(alkyl) ₂ , wherein the two alkyls may be the same or different. Examples of dialkylamino substituents may include, but are not limited to, dimethylamino, diethylamino, ethylmethylamino, and dipropylamino.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. The halogens may be the same (e.g., CHF ₂ , CF ₃ ) or different (e.g., CF ₂ Cl). Unless otherwise indicated, the haloalkyl group may be optionally substituted with one or more substituents other than the halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

The term "hydroxyalkyl" of the present invention refers to an alkyl group substituted with one or more -OH groups, wherein alkyl is as defined above.

The term "substitution" in the present invention refers to the introduction of a substituted hydrogen atom in the case where one or more hydrogen atoms in an organic compound are replaced with another atomic group to form a derivative, and "substituent" refers to the introduced atomic group. The chemical structure indicated as "substituted" herein is based on the premise that it satisfies the valence of the indicated substituent and the atom substituted by the substitution, and forms a chemically stable structure through substitution.

In this specification, when a combination of substituents is referred to as one group, for example, arylalkyl, cycloalkylalkyl, etc., it generally contains the atom attached to the residue of the compound, as the last mentioned group.

In this specification, "*" or "-" is used to indicate the position at which the substituent is bonded to the remaining residue of the compound. For example, when - is displayed at the end of a substituent, it means that the end is bonded to the remaining residue of the compound. Also, when two or more substituents are connected by "-", it means that the substituent immediately before "-" is bonded to the substitutable atom of the substituent immediately after "-".

At various locations throughout this specification, substituents of a compound are represented by groups or ranges. The description is specifically intended to include each and every individual subcombination of said group and range components. For example, the term "C ₁ -C ₆ alkyl" is specifically intended to _individually represent C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ , C ₁ -C ₃ , C _{1 -C 2} , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₆ , C 4 -C 5 and C ₅ -C ₆ alkyl.

The term "isomer" in "stereoisomer" refers to compounds that have the same molecular formula but different ways of connecting or spatially arranging the constituent atoms within the molecule. Isomers include, for example, structural isomers and stereoisomers. The stereoisomers can be diastereomers or enantiomers. Enantiomers are isomers that are not superimposable with their mirror images, like the relationship between left and right hands, and are also called optical isomers. Enantiomers are distinguished as R (Rectus: clockwise) and S (Sinister: counterclockwise) when they have four or more different substituents at the chiral center carbon. Diastereoisomers refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. The above diastereomers can be divided into cis-trans isomers and conformational isomers (or conformers).

The compounds of the present invention may contain one or more asymmetric centers and may be in the form of racemates, single enantiomers, mixtures of enantiomers, single diastereomers, mixtures of diastereomers, etc. Furthermore, due to the nature or restricted rotation of the asymmetric centers, the compounds of the present invention may exist in the form of enantiomers or diastereomers.

Various diastereoisomers and enantiomers of the chemical structures disclosed herein may exist, and all pure isomers, isolated isomers, partially pure isomers, or racemic mixtures are intended to fall within the scope of the present invention. When the stereochemistry of any particular chiral atom in a particular structure depicted herein is not specified, all stereoisomers are included as compounds of the present invention.

In any chemical structure or chemical formula of the present invention, a solid or dotted wedge bond (respectively) attached to the stereocenter of the compound or ) can represent the absolute stereochemistry of a stereocenter as well as the relative stereochemistry of the stereocenter with respect to other stereocenter(s) to which the wedge bond is attached.

The prefix "rac-" as used herein, when used in reference to a chiral compound, refers to a racemic mixture of the compound. In compounds containing the "rac-" prefix, the (R)- and (S)- designators in the compound name reflect the relative stereochemistry of the compound.

The prefix "rel-", as used herein, when used in reference to a chiral compound, refers to a single enantiomer whose absolute configuration is unknown. In compounds containing the "rel-" prefix, the (R)- and (S)- designators in the compound name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound.

As used herein, the term "compound" refers to a collection of molecules having the same chemical structure, except that isotopic variations may exist between the constituent atoms of the molecules, when referring to the compounds of the present invention. The term "compound" includes such a collection of molecules, regardless of the purity of a given sample containing the collection of molecules. Thus, the term "compound" includes a collection of molecules in pure form, in a mixture with one or more other substances (e.g., a solution, suspension, colloid, or pharmaceutical composition, or dosage form), or in the form of a hydrate, solvate, or the like.

The compound of formula I of the present invention has a 2-azabicyclo[3.1.0]hexane or 3-azabicyclo[4.1.0]heptane core. In the N-containing ring portion of formula I of the present invention, in the case of the 2-azabicyclo[3.1.0]hexane core, all four carbon atoms, and in the case of the 3-azabicyclo[4.1.0]heptane core, the remaining four carbon atoms except for the -CH ₂ - adjacent to N, become chiral centers. Therefore, when the compound is arranged on a plane, the four extra-ring bonds connected to the N-containing ring can theoretically be positioned above (up) the plane or below (down) the plane, respectively. However, due to the nature of the chiral center or limited rotation, etc., the compound of the present invention has the biphenylmethyl group and the sulfonamide group each positioned on the same side (up-up or down-down) with respect to the plane on which the compound is located, and the two bonds of the cyclopropyl ring fused to the pyrrolidine ring each positioned on the same side (up-up or down-down).

In the present invention, when the two bonds of the biphenylmethyl group, the sulfonamide group, and the cyclopropyl ring are all located on the same side, it is referred to as "cis-racemic" (i.e., up-up-up-up and down-down-down-down). On the other hand, when the biphenyl group and the sulfonamide group are located on opposite sides of the two bonds of the cyclopropyl ring, it is referred to as "trans-racemic" (i.e., "up-up-down-down" and "down-down-up-up").

Herein, the notation "&" means that the bond at a specific chiral center in the compound exists in a mixed state of an up configuration (wedge bond) and a down configuration (dash bond). The notation "&" may be indicated with an integer, for example, "&1" or "&2". For example, if two chiral centers of the compound are in the cis form and are both indicated as "&1", it means that the compound exists in a mixture state of an up-up compound and a down-down compound at each chiral center (referred to herein as a "cis-racemic form"). On the other hand, if two chiral centers of the compound are in the cis form and are respectively indicated as "&1" and "&2", it means that the compound exists in a mixture state of four isomers, namely, up-up, up-down, down-up, and down-down, at each chiral center. The meaning of the "&" (and) notation with an integer is explained with an example below.

By the notation of "and 1" and "and 2" in Example 1 below, Example 1 represents a mixture of the following four diastereoisomers.

Example 1:

Meanwhile, in the same chemical structure as Example 1, if two chiral centers are identically indicated as “and 1,” it represents a mixture of the two mirror image isomers below.

Example 2:

Purification of the above isomers and separation of the isomer mixture can be achieved by standard techniques known in the art. For example, a diastereomeric mixture can be separated into individual diastereoisomers by chromatographic processes or crystallization, and racemates can be separated into individual enantiomers by chiral phase chromatographic processes or resolution.

The term "isotope" in the present invention refers to an element that is the same element but has a different mass number, that is, an element that has the same number of protons but a different number of neutrons. Examples thereof may include, but are not limited to, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I, etc. In the case of compounds labeled with isotopes, it may be advantageous in that stability in the body is improved and half-life is increased.

The term "solvate" as used herein may refer to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include any solvent that is volatile, non-toxic, and/or suitable for human administration. The solvate is, for example, a hydrate. The compound of the present invention may exist in an unsolvated form, a hydrate solvated with water, a solvate solvated with a pharmaceutically acceptable solvent such as ethanol, and the like, and all such forms are intended to be included within the scope of the present invention.

As used herein, the term "salt" may include inorganic and organic acid addition salts, or base addition salts, of the parent compound. A pharmaceutically acceptable salt herein may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. It may include, but is not limited to, mineral or organic acid salts of basic moieties such as amines, alkali (earth) metal or organic salts of acid moieties such as carboxylic acids, and the like. The inorganic salt may be a hydrochloride, bromate, phosphate, sulfate, or disulfate. The organic acid salt may be formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl, trichloroacetic acid, trifluoroacetate, benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, emboxide, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate. The metal salt may be calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt.

The compound of the present invention can be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid, for example, the salt can be a salt derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, or the like.

A pharmaceutically acceptable salt of the above compound can be prepared by dissolving the compound of formula I in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an excess of an organic acid or an aqueous solution of an inorganic acid, and then precipitating or crystallizing the mixture. Subsequently, the solvent or the excess of acid is evaporated from the mixture, followed by drying to obtain an addition salt, or the precipitated salt can be prepared by suction filtration.

General method for preparing compounds

The compound according to the present invention can be readily prepared from commercially available starting materials, compounds known in the literature, or intermediates readily prepared therefrom, through standard synthetic methods and processes in the relevant field, based on the preparation methods described in the examples herein.

The reaction for preparing the compound of the present invention can be performed in a suitable solvent that can be appropriately selected by those skilled in the art of organic synthesis. Suitable solvents are those that are substantially non-reactive with the starting materials (reactants), intermediates, or target products at the temperature at which the reaction occurs. Those skilled in the art will be able to appropriately select the appropriate solvent for each specific reaction step.

During the synthesis of the compound of the present invention, protection and deprotection of various functional groups can be achieved. Those skilled in the art will readily be able to determine the necessity of protection and deprotection and select appropriate protecting groups.

The methods described herein can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., ¹ H or ¹³ C), infrared spectroscopy, photophotometry (e.g., UV-visible), mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

If necessary, the compounds of the present invention can be purified by, for example, chromatography, crystallization from a solvent or solvent mixture, distillation, extraction, etc. Chromatography can be, but is not limited to, reverse-phase, normal phase, size exclusion, ion exchange, preparative, or flash chromatography. Those skilled in the art will readily be able to select the optimal technique for purifying the target compound.

The compounds of the present invention can be isolated from a mixture of diastereoisomers, or a racemic mixture, if necessary, by any suitable method. For example, formation of ionic diastereomeric salts using chiral compounds and separation by fractional crystallization, formation and separation of diastereoisomers using chiral derivatizing reagents, followed by conversion into pure stereoisomers, and a method of directly separating substantially pure stereoisomers under chiral conditions, etc. can be used.

The compound of the present invention can be synthesized according to the synthetic process described in the examples below, and based on this, the target compound can be manufactured by appropriately changing the reactants and reaction conditions according to the structure of the target compound.

For example, intermediate A can be prepared according to the following reaction scheme I and used to prepare a compound of chemical formula I according to the present invention. In the following reaction scheme I, R ¹ , R ² , R ⁴ , n, m, and p have the same meanings as in chemical formula I.

[Reaction Formula I]

Step 1: Reacting biphenylmethyl bromide with a Boc-protected azabicyclic compound in the presence of NaH;

Step 2: Forming a compound substituted with an (R)-tert-butylsulfinylimino group through condensation of a chiral ligand, (R)-tert-butylsulfinamide, and a ketone;

Step 3: Reduction of (R)-tert-butylsulfinylimino group to (R)-tert-butylsulfinylamino group with NaBH ₄ ;

Step 4: Changing the (R)-tert-butylsulfinylamino group to an amino group using AcCl; and

Step 5: Reacting with R ⁴ -SO ₂ Cl in the presence of triethylamine to obtain intermediate A.

The intermediate A prepared according to the above reaction scheme I can be reacted with an appropriate reactant corresponding to the structure of R ⁵ as shown in the following reaction scheme II to prepare a compound of chemical formula I. In the following reaction scheme II, R ¹ , R ² , R ⁴ , R ⁵ , n, m, and p are as described in chemical formula I.

[Reaction Formula II]

Specifically, when R ⁵ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)(C ₁ -C ₆ alkyl)-, 3- to 8-membered heterocycloalkyl, the compound of formula I can be prepared by reacting intermediate A with R ⁵ -COCl or R ⁵ -COOH.

Alternatively, when R ⁵ is NR ^A R ^B or is an N-containing heterocycloalkyl in which N is bonded to a moiety of formula I, the amine compound of R ⁵ (R ⁵ -H) can be reacted with intermediate A together with triphosgene to prepare the compound of formula I.

The reaction reagents and solvents presented in the above reaction schemes I and II are exemplary, and a person skilled in the art will be able to select appropriate reagents and solvents, and further, will be able to optimize the reaction by appropriately selecting reaction conditions such as reaction time and reaction temperature for each step.

Medicinal uses, pharmaceutical compositions and methods of administration

Another aspect provides a pharmaceutical composition comprising a compound according to one aspect, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers thereof, an isotopically labeled compound, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. The compound, optical isomer, diastereomer, racemate, isotopically labeled compound, hydrate, solvate, and salt are as described above.

A compound according to one aspect of the present invention, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, selectively acts on an orexin 2 receptor (OX2R) and is useful for preventing or treating orexin 2-mediated diseases.

The above orexin-2 mediated diseases may include diseases that can be prevented or treated by acting as an agonist at the orexin-2 receptor. Orexin-2 mediated diseases may include diseases associated with abnormal activity of the orexin-2 receptor. Orexin-2 mediated diseases may include hypersomnia disorder, neurodegenerative disorder, rare genetic disorder, mental health disorder, metabolic syndrome, osteoporosis, cardiac failure, coma, and complications upon awakening from anesthesia.

Orexin 2-mediated disorders may include, for example, hypersomnia. The above hypersomnia disorder may be, for example, narcolepsy, daytime sleepiness, cataplexy, nocturnal sleep disorder, inappropriately timed rapid eye movement (REM) sleep, sleep paralysis, hypnotic hallucinations, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with symptoms such as narcolepsy, hypersomnia syndrome with excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depression with excessive sleepiness, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), or coma.

Orexin 2-mediated disorders may be, for example, neurodegenerative diseases. These neurodegenerative diseases may include Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, traumatic brain injury, sleep apnea, age-related cognitive impairment, and recurrent hypersomnia. In one specific example, the recurrent hypersomnia may be Kleine-Levin syndrome.

Orexin 2-mediated disorders may be, for example, rare genetic disorders. Such rare genetic disorders may be ADCA-DN, Coffin-Lowry syndrome, Möbius syndrome, Norrie disease, Niemann-Pick disease type C, or Prader-Willi syndrome.

An orexin 2-mediated disorder may be, for example, a psychiatric disorder. The psychiatric disorder may be attention deficit hyperactivity disorder or attention deficit disorder.

Orexin 2-mediated disorders may include, for example, metabolic syndrome, which may be obesity.

Orexin 2-mediated diseases may be, for example, osteoporosis.

Orexin 2-mediated diseases may be, for example, heart failure.

Orexin 2-mediated disorders can include, for example, coma.

Orexin 2-mediated disorders may be a complication of awakening from anesthesia, for example.

As used herein, the term "preventing" or "prevention" refers to preventing a disease, condition or disorder, for example, in a subject who may be predisposed to the disease, condition or disorder but does not yet experience or exhibit the pathology or signs of the disease.

As used herein, the term "treating" or "treatment" includes inhibiting a disease, condition or disorder, e.g., inhibiting the disease, condition or disorder in a subject experiencing or exhibiting the pathology or signs of the disease, condition or disorder, i.e., preventing recurrence or further development of the pathology and/or signs after treatment of the pathology and/or signs, or ameliorating a disease, condition or disorder, e.g., ameliorating the disease, condition or disorder in a subject experiencing or exhibiting the pathology or signs of the disease, condition or disorder, i.e., reversing the pathology and/or signs, e.g., reducing disease severity.

As used herein, the term "subject" may refer to any animal, including humans, that has developed or is likely to develop an orexin 2 receptor-mediated disorder. The animal may be, but is not limited to, mammals such as cows, horses, sheep, pigs, goats, camels, antelopes, dogs, and cats that require treatment for symptoms similar to those of humans.

A pharmaceutical composition according to one aspect of the present invention may comprise, in addition to the compound according to one aspect, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, an additional therapeutically active agent. In this case, the compound of the present invention and the additional therapeutically active agent may be a single composition or separate compositions. For example, the compound of the present invention may be provided as a composition in an oral dosage form, and the additional therapeutically active agent may be provided in a parenteral dosage form, or the compound of the present invention may be provided as a parenteral dosage form, and the additional therapeutically active agent may be provided in an oral dosage form.

The above additional therapeutically active agent may be an agent for treating narcolepsy, such as methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine.

The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used to mean an excipient, diluent, or auxiliary. The carrier may be selected from the group consisting of, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, saline, a buffer such as PBS, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include fillers, anticoagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, or combinations thereof.

The pharmaceutical composition described above may be prepared in any dosage form according to conventional methods. For example, the composition may be formulated as an oral dosage form (e.g., powder, tablet, capsule, syrup, pill, or granule) or a parenteral dosage form (e.g., injection). Furthermore, the composition may be prepared as a systemic dosage form or a topical dosage form.

In the pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid preparation may further include an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, the solid preparation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the liquid preparation for oral administration may be a suspension, an oral solution, an emulsion, or a syrup. The liquid preparation may include water or liquid paraffin. The liquid preparation may include an excipient such as a wetting agent, a sweetener, a flavoring agent, or a preservative. In the above pharmaceutical composition, the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solvent, suspension, emulsion, lyophilized product, or suppository. The non-aqueous solvent or suspension may contain a vegetable oil or ester. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The base of the suppository may be witepsol, macrogol, Tween 61, cocoa butter, laurin butter, or glycerogelatin.

The pharmaceutical composition comprises a compound according to one aspect, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, as an active ingredient of the pharmaceutical composition. The term "active ingredient" refers to a physiologically active substance used to achieve pharmacological activity (e.g., narcolepsy).

The pharmaceutical composition may contain an effective amount of a compound according to one aspect, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. The term "effective amount" refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to a subject in need of prevention or treatment. The effective amount can be appropriately selected by a person skilled in the art depending on the cell or subject selected. The preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the subject, the degree of the disease, the drug form, the route and duration of administration, but can be appropriately selected by a person skilled in the art. However, the compound, its optical isomer, diastereomer, racemate, mixture of optical isomers or diastereomers, isotopically labeled compound, hydrate, solvate or pharmaceutically acceptable salt may be administered in an amount of, for example, about 0.0001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 100 mg/kg, once to 24 times a day, once to 7 times every 2 days to 1 week, or once to 24 times every 1 month to 12 months. The compound, its optical isomer, diastereomer, racemate, mixture of optical isomers or diastereomers, isotopically labeled compound, hydrate, solvate or pharmaceutically acceptable salt may be included in an amount of about 0.0001 wt% to about 10 wt%, or about 0.001 wt% to about 1 wt%, based on the total weight of the entire pharmaceutical composition.

Administration may be oral or parenteral. For example, the route of administration may be oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal. The composition may be administered systemically or locally, and may be administered alone or in combination with other therapeutically active agents.

Another aspect provides a method for treating an orexin 2-mediated disorder, comprising administering to a subject a compound according to one aspect, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. The compound, the optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof and the orexin 2-mediated disorder are as described above.

In addition, another aspect provides the use of a compound according to one aspect, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of an orexin-2 mediated disease, or for the manufacture of a medicament for the prevention or treatment of an orexin-2 mediated disease. The compound, the stereoisomer, the isotopically labeled compound, the hydrate, the solvate or the pharmaceutically acceptable salt thereof and the orexin-2 mediated disease are as described above.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are intended to illustrate the present invention more specifically and are not intended to limit the scope of the present invention. Furthermore, technical details not described in this specification can be fully understood and easily implemented by those skilled in the technical field of the present application or similar technical fields.

The meanings of the abbreviations used in the examples below are as follows, and abbreviations not listed below have the meanings commonly used in the relevant fields.

DCM: dichloromethane

DIPEA: N,N-diisopropylethylamine

DMF: N,N-dimethylformamide

DMSO: dimethylsulfoxide

EtOAc: ethyl acetate

EtOH: ethanol

HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate

Hep: n-heptane

Hex: n-hexane

IPA: isopropanol

LDA: lithium diisopropylamide

MeOH: methanol

TEA: triethylamine

THF: tetrahydrofuran

TLC: thin-layer chromatography

TMSI: trimethylsilyl iodide

Manufacturing Example 1: tert-Butyl 4-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-1)

Step 1: tert-Butyl 3-hydroxy-2,3-dihydro-1H-pyrrole-1-carboxylate (Compound I-1b)

At -75°C, LDA (135 mL, 270 mmol, 2 M THF solution) was slowly added to a THF (250 mL) solution of potassium tert-butoxide (KOtBu, 30.3 g, 270 mmol) and stirred for 1 hour while maintaining the temperature. To the mixture, a THF (25 mL) solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (compound I-1a, 25 g, 135 mmol) was added dropwise at -75°C and stirred at room temperature for 1 hour. The mixture was monitored by TLC. After completion of the reaction, the reaction was quenched with ammonium chloride (NH ₄ Cl) aqueous solution (50 mL) and extracted with EtOAc (100 mL × 2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-10% EtOAc/Hex) to obtain compound I-1b (25 g, yield 90%) as a racemic mixture.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.89-6.70 (m, 1H), 5.22-5.17 (m, 1H), 4.92-4.88 (m, 1H), 3.74-3.66 (m, 2H), 1.67 (d, J = 7.6 Hz, 1H), 1.44 (s, 9H).

Step 2: tert-Butyl 3-(benzyloxy)-2,3-dihydro-1H-pyrrole-1-carboxylate (Compound I-1c)

Potassium tert-butoxide (KOtBu, 10.8 g, 96.4 mmol) was added to a THF (226 mL) solution of compound I-1b (11.9 g, 64.2 mmol) at 0℃, and the mixture was stirred at room temperature for 1 h. A THF (25 mL) solution of benzyl bromide (11.4 mL, 96.4 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 h. The mixture was monitored using TLC. After completion of the reaction, the reaction was quenched with cold water (50 mL) and extracted with EtOAc (100 mL × 2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-10% EtOAc/Hex) to obtain compound I-1c (10.5 g, yield 59%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.37-7.22 (m, 5H), 6.91-6.75 (m, 1H), 5.25-5.18 (m, 1H), 4.51 (s, 2H), 3.85-3.68 (m, 2H), 1.47 (s, 9H).

Step 3: tert-Butyl 4-(benzyloxy)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Compound I-1d)

At 0℃, a solution of compound I-1c (4.0 g, 16.3 mmol) in DCM (5.0 mL) was added to a solution of diethylzinc (87.1 mL, 27.2 mmol, 1.0 M hexane solution) in DCM (163 mL), and the mixture was stirred at room temperature for 1 h. A solution of diiodomethane (6.59 mL, 81.7 mmol) in DCM (16.0 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 h. The mixture was monitored by TLC. After completion of the reaction, the reaction was quenched with an aqueous solution of ammonium chloride (NH ₄ Cl) (50 mL), and the filtrate, filtered through a Celite filter, was extracted with DCM (50 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄₎ , filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 10-20% EtOAc/Hep) to obtain compound I-1d (3.3 g, yield 70%).

^1H NMR (400 MHz, DMSO-d6): δ 7.37-7.34 (m, 5H), 4.55 (d, J = 11.6 Hz, 1H), 4.54 (d, J = 11.6 Hz, 2H), 3.78-3.73 (m, 1H), 3.47-3.42 (m, 1H), 2.79-2.75 (m, 1H), 1.83-1.85 (m, 1H), 1.39 (s, 9H), 0.85-0.82 (m, 1H), 0.76-0.71 (m, 1H).

Step 4: tert-Butyl 4-hydroxy-2-azabicyclo[3.1.0]hexane-2-carboxylate (Compound I-1e)

Palladium hydroxide (PdOH ₂ , 1.21 g, 0.864 mmol) was added to a solution of compound I-1d (2.5 g, 8.64 mmol) in MeOH (125 mL), and the mixture was hydrogenated at 60°C under 100 Psi hydrogen pressure for 16 h in a Parr shaker apparatus. The reaction was monitored by TLC. After completion of the reaction, the mixture was cooled. The solid was filtered through a Celite filter, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) to obtain compound I-1e (1.0 g, yield 58%).

^1H NMR (400 MHz, DMSO-d6): δ 4.92 (d, J = 5.2 Hz, 1H), 4.51-4.48 (m, 1H), 3.64-3.59 (m, 1H), 3.40-3.35 (m, 1H), 2.57-2.54 (m, 1H), 1.70-1.63 (m, 1H), 1.39 (s, 9H), 0.84-0.82 (m, 1H), 0.63-0.58 (m, 1H).

Step 5: tert-Butyl 4-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-1)

At -78°C, a solution of oxalyl chloride ((ClCO) ₂ , 2.61 mL, 33.1 mmol) in DCM (66 mL) was added a solution of DMSO (4.71 mL, 66.2 mmol) in DCM (10.0 mL) and stirred for 15 min. To the mixture was added a solution of compound I-1e (3.3 g, 16.6 mmol) in DCM (10.0 mL) and stirred at -78°C for 2 h. While maintaining the temperature, triethylamine ( _Et3N , 14 mL, 99.4 mmol) was added and stirred for 1 h, then cooled to room temperature and stirred for 1 h. The mixture was monitored by TLC. After completion of the reaction, the reaction was quenched with cold aqueous sodium bicarbonate ( _NaHCO3 ) solution (25 mL) and extracted with DCM (50 mL). The organic layer was washed with water (50 mL) and sodium chloride (NaCl) aqueous solution (50 mL), dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was washed with n-pentane (10 mL × 2) and dried under reduced pressure to obtain intermediate I-1 (2.4 g, yield 73%) as a racemic mixture.

^1H NMR (400 MHz, DMSO-d6): δ 4.02-3.97 (m, 1H), 3.66 (s, 2H), 2.13-2.08 (m, 1H), 1.43-1.42 (m, 11H).

Manufacturing Example 2: 3-(Bromomethyl)-2,3',5'-trifluoro-1,1'-biphenyl (Intermediate I-2)

Step 1: 2,3',5'-Trifluoro-[1,1'-biphenyl]-3-carbaldehyde (Compound I-2b)

To a solution of 3-bromo-2-fluorobenzaldehyde (compound I-2a, 4 g, 19.7 mmol) in toluene (21.3 mL), ethanol (2.67 mL), and water (2.67 mL) was added sodium carbonate (Na ₂ CO ₃ , 6.26 g, 59.1 mmol) and (3,5-difluorophenyl)boronic acid (6.22 g, 39.4 mmol), and the mixture was filled with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ₃ ) ₄ , 2.28 g, 1.97 mmol) was added, and the mixture was stirred at 100 °C for 16 h. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled, diluted with water (50 mL), and extracted with EtOAc (50 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-10% EtOAc/Hep) to obtain compound I-2b (4.5 g, yield 96%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.45 (s, 1H), 7.94-7.90 (m, 1H), 7.69-7.65 (m, 1H), 7.38-7.28 (m, 1H), 7.10-7.08 (m, 2H), 6.91-6.85 (m, 1H).

Step 2: (2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methanol (Compound I-2c)

Sodium borohydride (NaBH ₄ , 0.08 g, 2.12 mmol) was slowly added to a THF (15 mL) solution of compound I-2b (1 g, 4.23 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction was quenched with aqueous ammonium chloride (NH ₄ Cl) solution (20 mL) and extracted with EtOAc (15 mL × 2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated to obtain compound I-2c (1.0 g, yield 99%).

^1H NMR (400 MHz, CDCl ₃ ): δ 7.51-7.46 (m, 1H), 7.37-7.33 (m, 1H), 7.22 (m, 1H), 7.07 (d, J = 5.2 Hz, 2H), 6.82 (m, 1H), 4.83 (s, 2H).

Step 3: 3-(Bromomethyl)-2,3',5'-trifluoro-1,1'-biphenyl (Intermediate I-2)

To a DCM (40 mL) solution of compound I-2c (2.0 g, 8.4 mmol) were sequentially added triphenylphosphine (PPh ₃ , 4.18 g, 16 mmol) and tetrabromomethane (CBr ₄ , 5.29 g, 16 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-5% EtOAc/Hep) to obtain intermediate I-2 (1.5 g, yield 59%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.45-7.41 (m, 1H), 7.39-7.35 (m, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.09-7.07 (m, 2H), 6.86-6.81 (m, 1H), 4.57 (s, 2H).

Preparation Example 3: tert-Butyl 4-(methylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-3)

Step 1: tert-Butyl 4-oxo-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Compound I-3a)

At 0℃, sodium hydride (NaH, 0.16 g, 4.06 mmol, 60% in mineral oil) was slowly added to a THF (40 mL) solution of intermediate I-1 (1.0 g, 5.07 mmol), which was a racemic mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0℃, and a THF (10 mL) solution of intermediate I-2 (1.22 g, 4.06 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was monitored by TLC. After the reaction was completed, the reaction was quenched with cold water (20 mL) and extracted with EtOAc (20 mL×2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 15-20% EtOAc/Hep) to obtain compound I-3a (0.48 g, yield 23%).

LCMS (ES): m/z 318.16 (M-Boc).

Step 2: tert-Butyl 4-(((R)-tert-butylsulfinyl)imino)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Compound I-3b)

To a toluene (5.0 mL) solution of compound I-3a (0.2 g, 0.47 mmol) were added titanium tetraethoxide (Ti(OEt) ₄ , 0.55 mL, 2.39 mmol) and (R)-2-methyl-2-propanesulfinamide (0.134 g, 1.1 mmol), and the mixture was stirred at 115°C for 16 h under nitrogen. The mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction was quenched with cold water (10 mL), and the solid was filtered. The filtrate was extracted with EtOAc (20 mL × 2), and the organic layer was washed with aqueous sodium chloride (NaCl) solution (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-35% EtOAc/Hep) to obtain compound I-3b (0.11 g, yield 44%) as a mixture of four diastereoisomers.

LCMS (ES): m/z 421.23 (M-Boc).

Step 3: tert-Butyl 4-((R)-1,1-dimethylethylsulfinamino)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Compound I-3c)

-Sodium borohydride (NaBH ₄ , 0.012 g, 0.317 mmol) was added to a solution of compound I-3b (0.11 g, 0.211 mmol) in THF (3.0 mL) and water (0.1 mL) at -50°C, and the mixture was stirred at room temperature for 2 h. The reaction was monitored using LCMS. After completion of the reaction, MeOH (2 mL) was added, and the mixture was stirred at room temperature for 3 h to terminate the reaction. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-50% EtOAc/Hep) to obtain compound I-3c (0.09 g, yield 81%).

LCMS (ES): m/z 523.23 (M+H).

Step 4: tert-Butyl 4-amino-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Compound I-3d)

At 0℃, acetyl chloride (AcCl, 0.013 mL, 0.189 mmol) was added to a solution of compound I-3c (0.09 g, 0.172 mmol) in MeOH (3 mL), and the mixture was stirred at room temperature for 16 hours. Acetyl chloride (0.013 mL, 0.189 mmol) was additionally added to the mixture, and the mixture was stirred for 12 hours. After completion of the reaction, the reaction was quenched with an aqueous solution of sodium bicarbonate (NaHCO ₃ ) (10 mL) and extracted with EtOAc (10 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated to obtain compound I-3d (0.05 g, yield 69%) as a brown liquid. Through repeated experiments, compound I-3d (0.2 g) was finally secured.

LCMS (ES): m/z 419.19 (M+H).

Step 5: tert-Butyl 4-(methylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-3)

At 0℃, a solution of compound I-3d (0.2 g, 4.7 mmol) in DCM (5 mL) was added triethylamine (Et ₃ N, 0.2 mL, 1.43 mmol) and methanesulfonyl chloride (MsCl, 0.044 mL, 5.74 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was monitored by TLC. After completion of the reaction, the mixture was diluted with DCM (25 mL) and extracted with aqueous sodium bicarbonate (NaHCO ₃ ) solution (10 mL) and water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated to obtain intermediate I-3 (0.15 g). Intermediate I-3 was a mixture of cis-racemic ("up-up-up-up" and "down-down-down-down") and trans-racemic ("up-up-down-down" and "down-down-up-up").

LCMS (ES): m/z 495.19 (M-H).

Preparation Examples 4 and 5: cis-rac-tert-butyl 4-(methylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate and trans-rac-tert-butyl 4-(methylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediates I-4 and I-5)

Intermediate I-3, a mixture of diastereoisomers, was separated by column chromatography (Combiflash purifier, mobile phase: 0-70% EtOAc/Hep) to obtain cis-racemic intermediate I-4 (0.06 g, yield 25%, non-polar peak) and trans-racemic intermediate I-5 (0.09 g, yield 38%, polar peak).

Intermediate I-4: LCMS (ES): m/z 495.19 (M-H),

Intermediate I-5: LCMS (ES): m/z 495.19 (M-H).

Manufacturing Example 6: tert-Butyl 5-oxo-3-azabicyclo[4.1.0]heptane-3-carboxylate (Intermediate I-6)

Step 1: tert-Butyl 3-hydroxy-4-iodopiperidine-1-carboxylate (Compound I-6b)

TMSI (9.4 mL, 66.2 mmol) was slowly added to a DMF (120 mL) solution of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (compound I-6a, 12 g, 60.2 mmol) at 0℃, and the mixture was stirred at room temperature for 16 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtOAc (100 mL) and extracted sequentially with 1 M aqueous HCl solution (50 mL × 2) - sodium bicarbonate (NaHCO ₃ , 50 mL × 2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-15% EtOAc/Hep) to obtain compound I-6b (18.7 g, yield 94%) as a trans-racemic mixture.

LCMS (ES): m/z 227.0 (M-Boc).

Step 2: tert-Butyl 4-iodo-3-((tetrahydro-2H-pyran-2-yl)oxy)piperidine-1-carboxylate (Compound I-6c)

To a DCM (235 mL) solution of compound I-6b (18.7 g, 57.5 mmol), 3,4-dihydropyran (DHP, 15.7 mL, 172 mmol) and pyridinium para-toluenesulfonic acid (PPTS, 1.44 g, 5.75 mmol) were added, and the mixture was stirred at room temperature for 16 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 5-7% EtOAc/Hep) to obtain compound I-6c (23.0 g, yield 97%).

LCMS (ES): m/z 312.0 (M-Boc).

Step 3: tert-Butyl 5-((tetrahydro-2H-pyran-2-yl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (Compound I-6d)

A mixture of compound I-6c (23.0 g, 55.9 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 15 mL) was stirred at 80°C for 16 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtOAc (100 mL) and extracted sequentially with 1 M aqueous HCl solution (50 mL × 2) - sodium bicarbonate (NaHCO ₃ , 100 mL × 2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-15% EtOAc/Hep) to obtain compound I-6d (15 g, yield 94%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.93-5.90 (m, 2H), 4.83-4.78 (m, 1H), 4.28-4.20 (m, 1H), 4.06-3.80 (m, 4H), 3.57-3.51 (m, 2H), 1.86-1.82 (m, 1H), 1.75-1.70 (m, 1H), 1.61-1.57 (m, 4H), 1.47 (s, 9H).

Step 4: tert-Butyl 5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Compound I-6e)

At 0℃, a solution of compound I-6d (15 g, 52.9 mmol) in DCM (129 mL) and MeOH (51.7 mL) was added hydrochloric acid (HCl) solution (50 mL, 4 M 1,4-indioxane solution), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in THF (300 mL) and water (75 mL), and then adjusted to pH 10 with aqueous sodium carbonate (Na ₂ CO ₃ ) solution. Di-tert-butyl dicarbonate (Boc ₂ O, 18.2 mL, 79.4 mmol) was added, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with EtOAc (100 mL) and extracted with water (100 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 20-30% EtOAc/Hep) to obtain compound I-6e (7.52 g, yield 71%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.93-5.84 (m, 2H), 4.20 (bs, 1H), 4.29-4.07-3.96 (m, 1H), 3.82-3.77 (m, 1H), 3.57-3.54 (m, 2H), 1.87-1.83 (m, 1H), 1.47 (s, 9H).

Step 5: tert-Butyl 5-hydroxy-3-azabicyclo[4.1.0]heptane-3-carboxylate (Compound I-6f)

Compound I-6e (2.0 g, 10 mmol) was added to a solution of diethylzinc (50.2 mL, 50.2 mmol, 1 M hexane solution) in DCM (100 mL) at 0°C, and the mixture was stirred for 30 minutes while maintaining the temperature. After that, diiodomethane (CH ₂ I ₂ , 4.05 mL, 50.2 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was monitored by TLC. After completion of the reaction, the reaction was quenched with aqueous ammonium chloride (NH ₄ Cl) solution (50 mL) and extracted with DCM (100 mL × 2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 40-45% EtOAc/Hep) to obtain compound I-6f (1.4 g, yield 65%) as a cis-racemic and trans-racemic mixture.

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.13-4.11 (m, 1H), 3.63-3.55 (m, 2H), 3.33-3.28 (m, 1H), 3.09 (bs, 1H), 1.47 (s, 9H), 1.43-1.41 (m, 1H), 1.29-1.25 (m, 2H) 0.66-0.61 (m, 1H), 0.52-0.48 (m, 1H).

Step 6: tert-Butyl 5-oxo-3-azabicyclo[4.1.0]heptane-3-carboxylate (Intermediate I-6)

At 0℃, a solution of compound I-6f (2.95 g, 13.8 mmol) in DCM (70 mL) was stirred, and Dess-Martin periodinane (DMP, 10.6 g, 24.9 mmol) was added, followed by stirring at room temperature for 2 h. After completion of the reaction, the solid of the mixture was filtered and washed with an aqueous sodium bicarbonate (NaHCO ₃ ) solution (50 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 15-20% EtOAc/Hep) to obtain intermediate I-6 (1.9 g, yield 65%) as a racemic mixture.

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.44-4.35 (m, 2H), 3.47-3.19 (m, 2H), 1.93-1.85 (m, 2H), 1.46 (s, 9H), 1.33-1.29 (m, 1H), 1.25-1.20 (m, 1H).

Manufacturing Examples 7 and 8: cis-rac-tert-butyl 4-(ethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate and trans-rac-tert-butyl 4-(ethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-7 and Intermediate I-8)

At 0°C, triethylamine (TEA, 403 μL, 3 eq., 2.87 mmol) was added to a solution of compound I-3d (0.4 g, 956 μmol) in DCM (5.71 mL), followed by ethanesulfonyl chloride (108 μL, 1.2 eq., 1.15 mmol). The mixture was stirred at room temperature for 12 h and monitored by TLC. After completion of the reaction, the mixture was diluted with DCM (50 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 25 mL) - water (25 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 30-50% EtOAc/Hep) to obtain cis-racemic form of intermediate I-7 (70 mg, yield 14%) and trans-racemic form of intermediate I-8 (0.2 g, yield 40%).

Intermediate I-7: LCMS (ES): m/z 455.1 [M-tert-butyl]; ¹ H NMR (400 MHz, DMSO-d6): δ 7.48-7.23 (m, 7H), 4.45 (s, 1H), 3.99 (bs, 1H), 3.72 (bs, 1H), 3.20-3.02 (m, 4H), 2.81-2.66 (m, 2H), 2.28 (s, 1H), 1.88 (bs, 1H), 1.49 (s, 9H), 1.38-1.03 (m, 6H), 0.89-0.72 (m, 3H),

Intermediate I-8: LCMS (ES): m/z 455.1 [M-tert-butyl]; ^1H NMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 10.0 Hz, 1H), 7.45-7.20 (m, 6H), 4.20 (bs, 1H), 3,73-3.70 (m, 1H), 3.18-3.03 (m, 4H), 2.80-2.67 (m, 1H), 1.68-1.67 (m, 1H), 1.47-1.24 (m, 4H), 1.11-0.80 (m, 11H), 0.64 (bs, 1H).

Preparation Examples 9 and 10: cis-rac-tert-butyl 4-(fluoromethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate and trans-rac-tert-butyl 4-(fluoromethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-9 and Intermediate I-10)

At 0℃, triethylamine (TEA, 403 μL, 3 eq., 2.87 mmol) was added to a solution of compound I-3d (0.4 g, 956 μmol) in DCM (5.71 mL), followed by fluoromethanesulfonyl chloride (152 mg, 1.2 eq., 1.15 mmol). The mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC. After completion of the reaction, the mixture was diluted with DCM (50 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 25 mL) - water (25 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 30-50% EtOAc/Hep) to obtain cis-racemic form of intermediate I-9 (40 mg, yield 8%) and trans-racemic form of intermediate I-10 (0.1 g, yield 20%).

Intermediate I-9: LCMS (ES): m/z 415.1 [M-Boc]; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.12-8.10 (d, J = 10.0 Hz, 1H), 7.48-7.24 (m, 8H), 5.76 (s, 1H), 5.30-4.93 (m, 2H), 4.04 (br, 1H), 3.75 (br, 1H), 3.16-3.01 (m, 3H), 2.01-1.80 (m, 1H), 1.34-0.70 (m, 16H),

Intermediate I-10 : LCMS (ES): m/z 458.9 [M-tert-butyl]; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.57-8.56 (d, J = 5.0 Hz, 1H), 7.45-7.20 (m, 7H), 5.60-5.34 (m, 2H), 4.22 (br, 1H), 3.82-3.79 (m, 1H), 3.10-2.80 (m, 3H), 1.68 (br, 1H), 1.24-0.63 (m, 13H).

Manufacturing Example 11: trans-rac-tert-butyl 4-((N,N-dimethylsulfamoyl)amino)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-11)

At 0°C, triethylamine (TEA, 846 μL, 3 eq., 2.87 mmol) was added to a THF (5.0 mL) solution of compound I-3d (0.4 g, 956 μmol), followed by dimethylsulfamoyl chloride (122 μL, 1.2 eq., 1.15 mmol). The mixture was stirred at 55°C for 5 h and monitored by TLC. After completion of the reaction, the mixture was diluted with DCM (50 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 25 mL) - water (25 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 2-5% MeOH/DCM) to obtain intermediate I-11 (110 mg, yield 21%) in trans-racemic form.

LCMS (ES): m/z 426.10 [M-Boc].

Manufacturing Example 12: trans-rac-tert-butyl-4-(cyclopropanesulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-12)

At 0℃, triethylamine (TEA, 1.0 mL, 3 eq., 7.17 mmol) was added to a solution of compound I-3d (1.0 g, 2.39 mmol) in DCM (100 mL), followed by cyclopropanesulfonyl chloride (336 mg, 1.0 eq., 2.39 mmol). The mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC. After completion of the reaction, the mixture was diluted with DCM (50 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 100 mL) - water (100 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 30-50% EtOAc/Hep) to obtain intermediate I-12 (0.63 g, yield 50%) in trans-racemic form.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.84-7.82 (d, J = 10.5 Hz, 1H), 7.45-7.16 (m, 6H), 4.22 (br, 1H), 3.76-3.72 (m, 1H), 3.10-3.00 (m, 2H), 2.83-2.62 (m, 2 H), 1.99 (br, 1H), 1.30-0.65 (m, 14H).

Manufacturing Examples 13 and 14: cis-rac-tert-butyl 4-(difluoromethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate and trans-rac-tert-butyl 4-(difluoromethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-13 and Intermediate I-14)

At 0°C, pyridine (482 μL, 5 eq., 5.97 mmol) was added to a solution of compound I-3d (0.5 g, 1.19 mmol) in acetonitrile (10 mL), followed by difluoromethanesulfonyl chloride (234 mg, 1.3 eq., 1.55 mmol). The mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC. After completion of the reaction, the mixture was diluted with DCM (50 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 25 mL) - water (25 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 30-50% EtOAc/Hep) to obtain cis-racemic form of intermediate I-13 (70 mg, yield 11%) and trans-racemic form of intermediate I-14 (0.23 g, yield 36%).

Intermediate I-13: LCMS (ES): m/z 477.1 [M-tert-butyl]; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.72-8.70 (m, 1H), 7.46-7.25 (m, 6H), 4.10 (br, 1H), 3.78 (br, 1H), 3.15-3.02 (m, 5H), 1.99-1.81 (m, 3H), 1.34-0.73 (m, 17H).

Intermediate I-14: LCMS (ES): m/z 433.1 [M-Boc]; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.47-6.96 (m, 7H), 4.21 (br, 1H), 3.85 (br, 1H), 3.14-2.83 (m, 3H), 1.73 (br, 1H), 1.53-0.72 (m, 20H).

Manufacturing Examples 15 to 19: (S)-3-chloro-1,1,1-trifluoro-2-methyl-3-oxopropan-2-yl acetate and others (intermediates I-15 to I-19)

Step 1: (S)-2-Acetoxy-3,3,3-trifluoro-2-methylpropanoic acid (I-15b)

Acetyl chloride (9.93 mL, 1.39 mmol) was added dropwise to a stirred solution of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (I-15a, 1 g, 0.63 mmol) dissolved in DCM (16 mL) at 0°C, and the reaction mixture was stirred at 50°C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain (S)-2-acetoxy-3,3,3-trifluoro-2-methylpropanoic acid (I- 15 b, 1.2 g, 94%) as a colorless liquid.

^1H NMR (400 MHz, DMSO-d6): δ 14.50-13.50 (bs, 1H), 2.13 (s, 3H), 1.71 (s, 3H).

Step 2: (S)-3-chloro-1,1,1-trifluoro-2-methyl-3-oxopropan-2-yl acetate (I-15)

To a stirred solution of (S)-2-acetoxy-3,3,3-trifluoro-2-methylpropanoic acid (I-15b, 0.08 g, 0.4 mmol) in THF (5.33 mL) at 0°C under a nitrogen stream, oxalyl chloride (0.0054 mL, 0.6 mmol) and 2 drops of DMF were added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure to obtain the title compound as a colorless oil. The obtained product was used directly in the next step.

I-17 to I-19 were synthesized in a similar manner to steps 1 and 2 above.

Example 1: trans-rac-N-(2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide

Step 1: trans-rac-N-(3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide (Compound E-1a)

To a 1,4-indioxane solution of intermediate I-5 (0.13 g, 0.262 mmol) was added hydrochloric acid (HCl, 2.5 mL, 4 M 1,4-indioxane solution), and the mixture was stirred at room temperature for 4 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain compound E-1a (0.11 g, yield 97%).

LCMS (ES): m/z 397.11 (M+H).

Step 2: trans-rac-2-methyl-1-(4-(methylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-2-yl)-1-oxopropan-2-yl acetate (Compound E-1b)

DIPEA (0.24 mL, 1.4 mmol) was added to a THF (8 mL) solution of compound E-1a (0.11 g, 0.25 mmol) and stirred for 30 minutes. The mixture was cooled to 0°C, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.055 mL, 0.38 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored using LCMS. After completion of the reaction, the reaction was quenched with cold water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-10% MeOH/DCM) to obtain compound E-1b (0.1 g, yield 75%).

LCMS (ES): m/z 525.0 (M+H).

Step 3: trans-rac-N-(2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide (Example 1)

Lithium hydroxide monohydrate (LiOH-H ₂ O, 0.024 g, 0.572 mmol) was added to a solution of compound E-1b (0.1 g, 0.191 mmol) in THF (2 mL) and water (2 mL), and the mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was acidified to pH 4 by adding 1 M aqueous hydrochloric acid (HCl) solution and extracted with EtOAc (10 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-40% EtOAc/Hep) to obtain the trans-racemic form of the compound of Example 1 (0.05 g, yield 54%).

LCMS (ES): m/z 483.4 (M+H); ^1H NMR (400 MHz, DMSO-d6): δ 7.73 (d, J = 7.2 Hz, 1H), 7.37-7.34 (m, 2H), 7.29-7.25 (m, 3H), 7.14 (t, J = 7.6 Hz, 1H), 4.85-4.78 (m, 2H), 3.70-3.62 (m, 2H), 3.12-3.05 (m, 1H), 2.94 (s, 3H), 2.89-2.80 (m, 1H), 1.82-1.75 (m, 1H), 1.21-1.1.6 (m, 4H), 1.10 (m, 3H), 0.86-0.76 (m, 1H).

Examples 2 and 3: N-((1S,3S,4S,5R)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide and N-((1R,3R,4R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide

The compound of Example 1, which is a mixture of diastereoisomers, was separated by Prep HPLC (Column: Chiralpak IA (250 mm×20 mm×5 mic), Mobile phase: n-hexane: IPA (50:50), Flow rate: 18 mL/min) to obtain 0.025 g (yield 27%) and 0.008 g (yield 9%) of the two enantiomers, respectively. The two enantiomers were separated at Rt-5.06 min (Peak-1) and Rt-11.67 min (Peak-2).

Example 2: LCMS (ES): m/z 483.40 (M+H); ^1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J = 7.2 Hz, 1H), 7.37-7.25 (m, 5H), 7.14 (t, J = 7.6 Hz, 1H), 4.85-4.80 (m, 2H), 3.69-3.66 (m, 2H), 3.10-3.05 (m, 1H), 2.94 (s, 3H), 2.85-2.80 (m, 1H), 1.82-1.78 (m, 1H), 1.23-1.02 (m, 7H), 0.82-0.79 (m, 1H).

Example 3: LCMS (ES): m/z 483.40 (M+H); ^1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J = 7.2 Hz, 1H), 7.37-7.25 (m, 5H), 7.14 (t, J = 7.6 Hz, 1H), 4.85-4.80 (m, 2H), 3.69-3.66 (m, 2H), 3.10-3.05 (m, 1H), 2.94 (s, 3H), 2.85-2.80 (m, 1H), 1.82-1.78 (m, 1H), 1.23-1.02 (m, 7H), 0.82-0.79 (m, 1H).

Example 4: cis-rac-N-(2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide

The compound of Example 4 was obtained by the experimental method used in Example 1 using I-4 instead of I-5.

LCMS (ES): m/z 483.40 (M+H); ¹ H NMR (400 MHz, DMSO-d6): δ 7.48-7.39 (m, 2H), 7.35-7.28 (m, 5H), 5.20 (bs, 1H), 4.10-4.06 (m, 1H), 3.99-3.90 (m, 2H), 3.10-3.06 (m, 1H), 2.98-2.92 (m, 1H), 2.65 (s, 3H), 2.06-2.02 (m, 1H), 1.36 (d, J = 6.4 Hz, 6H), 0.98-0.95 (m, 1H), 0.88-0.83 (m, 1H).

Examples 5 and 6: trans-rac-N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide and cis-rac-N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide

Step 1: N-(3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide (Compound E-5a)

Compound E-5a (0.11 g) was obtained in the same manner as step 1 of Example 1 using intermediate I-3 (0.13 g, 0.262 mmol) as a starting material.

LCMS (ES): m/z 397.11 (M+H).

Step 2: N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide (Compound E-5b)

At 0℃, DIPEA (0.06 mL, 0.347 mmol) and HATU (0.065 g, 0.173 mmol) were added to a solution of compound E-5a (0.05 g, 0.116 mmol) and cyclobutanecarboxylic acid (0.011 g, 0.116 mmol) in DMF (5 mL, 64.6 mmol). The mixture was stirred at room temperature for 1 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was diluted with EtOAc (10 mL) and extracted with water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) to obtain compound E-5b (diastereomeric mixture).

Step 3: trans-rac-N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide and cis-rac-N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide (Examples 5 and 6)

A mixture of diastereoisomers was separated by Prep HPLC to obtain the compound of Example 5 in trans-racemic form (0.008 g, yield 14%) and the compound of Example 6 in cis-racemic form (0.005 g, yield 9%).

Prep HPLC conditions: Column: Kinetex EVO C18 (150 mm×4.6 mm×2.6 μm); Mobile phase (A): 0.1% ammonia aqueous solution; Mobile phase (B): Acetonitrile; Gradient% B: 0/20 5/90 8/98, 8.1/20 15/20; Flow rate: 0.8 mL/min.

Example 5: LCMS (ES): m/z 479.4 (M+H); ¹ H NMR (400 MHz, DMSO-d6): δ 7.78 (bs, 1H), 7.37 (t, J = 12.0 Hz, 1H), 7.30-7.25 (m, 4H), 7.15 (t, J = 7.6 Hz, 1H), 4.oxetane-4.65 (m, 1H), 3.65 (bs, 1H), 3.18-3.12 (m, 1H), 3.03-3.02 (m, 2H), 2.97 (s, 3H), 2.83-2.81 (m, 1H), 2.02-1.97 (m, 2H), 1.83-1.73 (m, 4H), 1.56-1.53 (m, 1H), 1.15-1.10 (m, 1H), 0.75 (s, 1H),

Example 6: LCMS (ES): m/z 479.4 (M+H); ¹ H NMR (400 MHz, DMSO-d6): δ 7.46-7.42 (m, 1H), 7.37-7.33 (m, 6H), 4.01 (d, J = 8.0 Hz, 2H), 3.48-3.41 (m, 1H), 3.25-3.23 (m, 2H), 3.06 (d, J = 8.0 Hz, 1H), 2.97-2.90 (m, 2H), 2.oxetane (s, 3H), 2.32-2.11 (m, 5H), 1.95-1.74 (m, 1H), 0.93 (s, 1H).

Examples 7 and 8: N-((1S,3S,4S,5R)-2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide and N-((1R,3R,4R,5S)-2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide

The compound of Example 5 in trans-racemic form was separated by Chiral Prep HPLC (column: CHIRALPAK IA (100 mm×4.6 mm×3 μm), mobile phase: n-hexane: IPA containing 0.1% DEA (50:50), flow rate: 1.0 mL/min) to obtain 0.022 g (yield 29%) and 0.022 g (yield 29%) of the two enantiomers, respectively. These compounds were separated at Rt-2.03 min (peak-1) and Rt-3.98 min (peak-2), respectively.

Example 7: LCMS (ES): m/z 479.4 (M+H); ^1H NMR (400 MHz, DMSO-d6): 7.78 (d, J = 8.0 Hz, 1H), 7.40-7.35 (m, 1H), 7.28-7.25 (m, 4H), 7.14 (t, J = 7.6 Hz, 1H), 4.68-4.63 (m, 1H), 3.67-3.64 (m, 1H), 3.30 (bs, 1H), 3.15-3.12 (bs, 1H), 3.04-3.02 (m, 1H), 2.97 (s, 3H), 2.83-2.77 (m, 1H), 2.12-2.08 (m, 1H), 1.89-1.70 (m, 5H), 1.56-1.53 (m, 1H), 1.14-1.12 (m, 1H), 0.79- 0.75 (m, 1H),

Example 8: LCMS (ES): m/z 479.4 (M+H); ^1H NMR (400 MHz, DMSO-d6): 7.78 (d, J = 8.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.31-7.25 (m, 4H), 7.14 (t, J = 8.0 Hz, 1H), 4.68-4.63 (m, 1H), 3.67-3.64 (m, 1H), 3.31-3.26 (m, 1H), 3.17-3.11 (m, 1H), 3.05-3.01 (m, 1H), 2.97 (s, 3H), 2.84-2.67 (m, 1H), 2.21-2.17 (m, 2H), 2.02-1.85 (m, 4H), 1.58-1.53 (m, 1H), 1.27-1.23 (m, 1H), 0.79-0.75 (bs, 1H).

Examples 9 to 36

In Step 2 of Examples 5 and 6, the appropriate carboxylic acid corresponding to the structure of the target compound was used, and, if necessary, the isomer separation method of Examples 5 to 8 was used to obtain the compounds of Examples 9 to 36. The structural formulas and names of these compounds, as well as the LCMS and/or NMR data identifying these compounds, are shown in Table 1 below.

Example 37: N-(3-(2-hydroxy-2-methylpropanoyl)-4-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-azabicyclo[4.1.0]heptan-5-yl)methanesulfonamide

Step 1: tert-Butyl 5-oxo-4-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (Compound E-37a)

At 0℃, sodium hydride (NaH, 51 mg, 1.28 mmol, 60% in mineral oil) was slowly added to a THF (8.1 mL) solution of intermediate I-6 (270 mg, 1.28 mmol), which was a racemic mixture, and the mixture was stirred at room temperature for 30 min. The mixture was cooled to 0℃, and a THF (0.5 mL) solution of intermediate I-2 (0.38 g, 1.28 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was monitored by TLC. After the reaction was completed, the reaction was quenched with cold water (20 mL) and extracted with EtOAc (10 mL×2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 20% EtOAc/Hep) to obtain compound E-37a (0.2 g, yield 36%).

LCMS (ES): m/z 432.10 (M+H).

Step 2: tert-Butyl (E)-5-(((S)-tert-butylsulfinyl)imino)-4-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (Compound E-37b)

To a solution of compound E-37a (0.25 g, 0.58 mmol) in toluene (10.0 mL) were added titanium tetraethoxide (Ti(OEt) ₄ , 0.62 mL, 2.9 mmol) and (R)-2-methyl-2-propanesulfinamide (0.16 g, 1.33 mmol), and the mixture was stirred at 110°C for 12 h under nitrogen. The mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction was quenched with cold water (10 mL) and the solid was filtered. The filtrate was extracted with EtOAc (30 mL × 2), and the organic layer was washed with aqueous sodium chloride (NaCl) solution (20 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 50% EtOAc/Hep) to obtain compound E-37b (0.07 g, yield 22%).

LCMS (ES): m/z 435.20 (M-Boc).

Step 3: tert-Butyl 5-(((S)-tert-butylsulfinyl)amino)-4-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (Compound E-37c)

-Sodium borohydride (NaBH ₄ , 0.017 g, 0.449 mmol) was added to a solution of compound E-37b (0.16 g, 0.299 mmol) in THF (5.0 mL) and water (0.2 mL) at -50°C, and the mixture was stirred at room temperature for 2 h. The reaction was monitored using LCMS. After completion of the reaction, MeOH (2 mL) was added, and the mixture was stirred at room temperature for 3 h to terminate the reaction. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (Combiflash purifier, mobile phase: 5% MeOH/DCM) to obtain compound E-37c (0.12 g, yield 74%).

LCMS (ES): m/z 537.10 (M+H).

Step 4: tert-Butyl 5-amino-4-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (Compound E-37d)

Acetyl chloride (AcCl, 0.021 mL, 0.298 mmol) was added to a solution of compound E-37c (0.08 g, 0.149 mmol) in MeOH (2 mL) at 0℃, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction was quenched with aqueous sodium bicarbonate (NaHCO ₃ ) solution (10 mL) and extracted with EtOAc (10 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated to obtain compound E-37d (0.065 g, yield 101%) as a brown liquid.

LCMS (ES): m/z 433.20 (M+H).

Step 5: tert-Butyl 5-(methylsulfonamido)-4-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (E-37e)

At 0℃, a solution of compound E-37d (0.09 g, 0.208 mmol) in DCM (6.5 mL) was added triethylamine (Et ₃ N, 0.087 mL, 0.624 mmol) and methanesulfonyl chloride (MsCl, 0.019 mL, 0.25 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was monitored by TLC. After the reaction was completed, the mixture was diluted with DCM (10 mL) and extracted with aqueous sodium bicarbonate (NaHCO ₃ ) solution (5 mL) and water (5 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated to obtain compound E-37e (0.1 g, yield 94%).

LCMS (ES): m/z 455.10 (M-tert-butyl).

Step 6: N-(4-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-aza bicyclo [4.1.0] heptane-5-yl)methanesulfonamide (Compound E-37f)

Compound E-37e (0.035 g, 0.068 mmol) was added to a 1,4-indioxane solution of hydrochloric acid (HCl, 1.5 mL, 4 M 1,4-indioxane solution) and stirred at room temperature for 4 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain compound E-37f (0.20 g, yield 65%).

LCMS (ES): m/z 411.10 (M+H).

Step 7: 2-Methyl-1-(5-(methylsulfonamido)-4-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-1-oxopropan-2-yl acetate (Compound E-37g)

DIPEA (0.021 mL, 0.123 mmol) was added to a THF (1 mL) solution of compound E-37f (0.10 g, 0.022 mmol) and stirred for 30 minutes. The mixture was cooled to 0°C, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.004 mL, 0.26 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored using LCMS. After the reaction was completed, the reaction was quenched with cold water (5 mL) and extracted with EtOAc (5 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-10% MeOH/DCM) to obtain compound E-37g (0.05 g, yield 41%).

LCMS (ES): m/z 539.20 (M+H).

Step 8: N-(3-(2-hydroxy-2-methylpropanoyl)-4-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-azabicyclo[4.1.0]heptan-5-yl)methanesulfonamide (Example 37)

Lithium hydroxide monohydrate (LiOH-H ₂ O, 0.035 g, 0.836 mmol) was added to a solution of compound E-37 (0.15 g, 0.279 mmol) in THF (2 mL) and water (2 mL), and the mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was acidified to pH 4 by adding 1 M aqueous hydrochloric acid (HCl) solution and extracted with EtOAc (100 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was separated by Prep HPLC to obtain the compound of Example 37 (0.08 g, yield 3%).

Prep HPLC conditions: Column: X-Select CSH C18 (250 mm×20 mm×5 μm), mobile phase A: 0.1% ammonia aqueous solution; mobile phase B: acetonitrile; Flow rate: 17 mL/min.

LCMS (ES): m/z 496.55 (M+H); ¹ H NMR (400 MHz, DMSO-d6): δ 7.48-7.36 (m, 2H), 7.35-7.18 (m, 4H), 6.80 (d, J=8.8Hz, 1H), 5.15-4.65 (m, 3H), 3.75 (t, J=8.4Hz, 1H), 3.16-3.0 (m, 1H), 2.88 (br s, 4H), 1.46-1.38 (m, 1H), ), 3.30-1.18 (m, 5H), 1.02 (br s, 2 H), 0.51 (br s, 2H) .

Examples 38 and 39: trans-rac-N-(2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide and cis-rac-N-(2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide

At 0°C, a solution of compound E-5a (0.06 g, 0.139 mmol) in DCM (2.0 mL) was added a solution of DIPEA (0.12 mL, 0.693 mmol) and triphosgene (0.02 g, 0.693 mmol) in DCM (0.5 mL), and the mixture was stirred at room temperature for 1 h. After cooling the mixture to 0°C, a solution of azetidine hydrochloride (0.039 g, 0.693 mmol) and DIPEA (0.12 mL, 0.693 mmol) in DCM (0.5 mL) was added, and the mixture was stirred at room temperature for 3 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with DCM (25 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 10 mL) - water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM). The diastereoisomers were separated by preparative HPLC to obtain the trans-racemic form of Example 38 (0.02 g, yield 30%) and the cis-racemic form of Example 39 (0.015 g, yield 15%).

Prep HPLC conditions: Column: X-Select CSH C18 (250 mm×20 mm×5 μm), mobile phase A: 0.1% ammonia aqueous solution; mobile phase B: acetonitrile; Flow rate: 17 mL/min.

Example 38: LCMS (ES): m/z 480.4 (M+H); ^1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J = 7.2 Hz, 1H), 7.40-7.34 (m, 2H), 7.31-7.26 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 4.52-4.47 (m, 1H), 3.87-3.81 (m, 2H), 3.70-3.62 (m, 3H), 3.11-2.96 (m, 2H), 2.94 (s, 3H), 2.80 (t, J = 13.2 Hz, 1H), 2.07-1.99 (m, 2H), 1.73-1.72 (m, 1H), 1.03-.98 (m, 1H), 0.69-0.68 (m, 1H),

Example 39: LCMS (ES): m/z, 480.4 (M+H); ¹ H NMR (400 MHz, DMSO-d6): δ 7.45-7.42 (m, 1H), 7.38-7.23 (m, 6H), 4.04-3.98 (m, 2H), 3.94-3.79 (m, 4H), 3.09-3.06 (m, 1H), 2.98-2.94 (m, 2H), 2.73 (s, 3H), 2.16-2.07 (m, 2H), 1.95-1.88 (m, 1H), 0.9-0.87 (m, 1H), 0.69-0.64 (m, 1H).

Examples 40 and 41: N-((1R,3R,4R,5S)-2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide and N-((1S,3S,4S,5R)-2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide

The compound of Example 38 in trans-racemic form was separated by Chiral Prep HPLC (column: Chiralpak IC (250 mm×20 mm×5 mic), mobile phase: 100% ethanol, flow rate: 16 mL/min) to obtain 0.003 g and 0.005 g of two enantiomers, respectively. These enantiomers were separated at Rt-4.41 min (Peak-1) and Rt-6.05 min (Peak-2), respectively.

Example 40: LCMS (ES): m/z 480.2 (M+H); ^1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J = 8.0 Hz, 1H), 7.40-7.34 (m, 2H), 7.32-7.26 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 4.51-4.47 (m, 1H), 3.87-3.81 (m, 2H), 3.70-3.62 (m, 3H), 3.04-2.96 (m, 2H), 2.94 (s, 3H), 2.80 (t, J = 13.2 Hz, 1H), 2.07-1.99 (m, 2H), 1.73-1.72 (m, 1H), 1.03-.98 (m, 1H), 0.69 (bs, 1H),

Example 41: LCMS (ES): m/z 480.2 (M+H); ^1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J = 8.0 Hz, 1H), 7.40-7.34 (m, 2H), 7.32-7.26 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 4.51-4.47 (m, 1H), 3.87-3.81 (m, 2H), 3.70-3.62 (m, 3H), 3.04-2.96 (m, 2H), 2.94 (s, 3H), 2.80 (t, J = 13.2 Hz, 1H), 2.07-1.99 (m, 2H), 1.73-1.72 (m, 1H), 1.03-0.98 (m, 1H), 0.69 (bs, 1H).

Examples 42 to 55

Similar to Examples 38 and 39, compounds of Examples 42 to 55 were obtained by using appropriate amine compounds corresponding to the structures of the target compounds as reactants and, if necessary, by using the isomer separation method of Examples 40 and 41. The structural formulas and names of these compounds and the LCMS and/or NMR data identifying these compounds are shown in Table 2 below.

Example 56: trans-rac-N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide

Step 1: trans-rac-N-(3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide (Compound E-56a)

To a 1,4-indioxane solution of intermediate I-8 (220 mg, 431 μmol) in trans-racemic form, hydrochloric acid (HCl) solution (1.5 mL, 4 M 1,4-indioxane solution) was added, and the mixture was stirred at room temperature for 4 h. The mixture was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain compound E-56a (170 mg, yield 88%) in solid form.

LCMS (ES): m/z 411.1 [M+H]; ^1H NMR (400 MHz, DMSO-d6); δ 9.61-9.42 (m, 2H), 7.53-7.27 (m, 7H), 4.10 (q, J = 7.0 Hz, 1H), 3.76-3.75 (m, 1H), 3.22-3.10 (m, 4H), 1.80 (p, J = 6.0 Hz, 1H), 1.26-1.07 (m, 4H), 0.83-0.78 (m, 1H).

Step 2: trans-rac-N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide (Example 56)

At 0℃, DIPEA (60.5 μL, 3 eq., 347 μmol) and HATU (38.3 mg, 1.5 eq., 101 μmol) were added to a solution of compound E-56a (30 mg, 67.1 μmol) and cyclobutanecarboxylic acid (11.6 mg, 116 μmol) in DMF (2.91 mL), and the mixture was stirred at room temperature for 1 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtOAc (25 mL) and extracted with water (10 mL × 2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified first through column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) and then second through Prep HPLC to obtain the compound of Example 56 (10 mg, yield 30%) in the form of a white solid.

Prep HPLC conditions: Column: X-Select CSH C18 (19 mm × 250 mm × 5 mic), Mobile phase (A): 0.1% ammonia aqueous solution, Mobile phase (B): Acetonitrile, Flow rate: 19 mL/min

LCMS (ES): m/z 493.2 [M+H]; ^1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6Hz, 1H), 7.31-7.25 (m, 4H), 7.14 (t, J = 7.6 Hz, 1H), 4.66-4.60 (m, 1H), 3.66-3.60 (m, 1H), 3.33-3.20 (m, 1H), 3.15-3.05(m, 4H), 2.83-2.80 (m, 1H), 2.01-1.96 (m, 2H), 1.88-1.67 (m, 4H), 1.55-1.53 (m, 1H), 1.24 (t, J=7.6Hz, 3H), 1.14-1.12 (m, 1H), 0.78-0.75 (m, 1H).

Examples 57 to 128

In Step 2 of Examples 5 and 6, appropriate carboxylic acid and deuterium compounds corresponding to the structures of the target compounds were used, and, if necessary, the isomer separation method of Examples 5 to 8 was used to obtain compounds of Examples 57 to 128. The structural formulas and names of these compounds, as well as the LCMS and/or NMR data identifying these compounds, are shown in Table 3 below.

Example 129: trans-rac-N-(2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide

At 0℃, DIPEA (57.8 μL, 5 eq., 336 μmol) was added to a DCM solution (1.04 mL) of compound E-56a (30 mg, 67.1 μmol) and stirred for 15 min. Then, a DCM solution (0.5 mL) of triphosgene (9.96 mg, 0.5 eq., 33.6 μmol) was slowly added and stirred at room temperature for 1 h. To the mixture, azetidine hydrochloride (31.4 mg, 5 eq., 336 μmol) and a DCM solution (0.5 mL) of DIPEA (57.8 μL, 5 eq., 336 μmol) were added and stirred at room temperature for 16 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was diluted with DCM (25 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 10 mL) - water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified first by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) and second by Prep HPLC to obtain the compound of Example 129 (20 mg, yield 60%).

Prep HPLC conditions: Column: X-select CSH C18 (250 mm × 20 mm × 5 μm), Mobile phase A: 0.1% ammonia aqueous solution, Mobile phase B: acetonitrile, Flow rate: 17 mL/min

LCMS (ES): m/z 494.2 [M+H]; ^1H NMR (400 MHz, DMSO-d6); δ 7.73 (d, J = 1.0 Hz, 1H), 7.41-7.18 (m, 6H), 4.488 (p, J = 6.5 Hz, 1H), 3.87-3.60 (m, 5H), 3.10-2.80 (m, 4H), 2.07-1.99 (m, 2H), 1.73 (bs, 1H), 1.22 (t, J = 9.0 Hz, 3H), 1.04-0.99 (m, 1H), 0.69 (bs, 1H).

Examples 130 and 131: N-((1R,3R,4R,5S)-2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide and N-((1S,3S,4S,5R)-2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide

The compound of Example 129 in trans-racemic form was separated by Chiral Prep HPLC (column: CHIRALPAK IA (100 mmХ4.6 mmХ3 μm), mobile phase: n-hexane: IPA + 0.1% DEA (50:50), flow rate: 1.0 mL/min), and the isomers of Example 130 and Example 131 were separated from the trans-racemic mixture of Example 129, respectively.

Example 130: LCMS (ES): m/z 494.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.74 (d, J = 8.4 Hz, 1H), 7.41-7.26 (m, 5H), 7.19 (t, J = 7.6 Hz, 1H), 4.51-4.46 (m, 1H), 3.86-3.80 (m, 2H), 3.69-3.59 (m, 3H), 3.09-2.94 (m, 4H), 2.86-2.80 (m, 1H), 2.06-1.98 (m, 2H), 1.75-1.70 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.06-0.99 (m, 1H), 0.69-0.66 (m, 1H),

Example 131: LCMS (ES): m/z 494.2 (M+H); 1H NMR (400MHz, DMSO-d6): δ 7.74 (d, J = 8.4 Hz, 1H), 7.41-7.26 (m, 5H), 7.19 (t, J = 7.6 Hz, 1H), 4.51-4.46 (m, 1H), 3.86-3.80 (m, 2H), 3.69-3.59 (m, 3H), 3.09-2.96 (m, 4H), 2.86-2.80 (m, 1H), 2.06-1.98 (m, 2H), 1.75-1.70 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.06-0.99 (m, 1H), 0.69-0.66 (m, 1H).

Example 132: trans-rac-4-(ethylsulfonamido)-N-((1-fluorocyclopropyl)methyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxamide

The compound of Example 132 was obtained in the same manner as in Example 61, using (1-fluorocyclopropyl)methaneamine instead of azetidine hydrochloride in Example 129.

LCMS (ES): m/z 579.4 (M+Na); ^1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J = 10.5 Hz, 1H), 7.38-7.13 (m, 6H), 6.52 (t, J = 7.5 Hz, 1H), 4.48 (p, J = 6.5 Hz, 1H), 3.66 (t, J = 7.5 Hz, 1H), 3.26-2.85 (m, 6H), 1.76 (bs, 1H), 1.22 (t, J = 4.0 Hz, 1H), 1.05-1.00 (m, 1H), 0.80-0.47 (m, 6H).

Example 133: trans-rac-N-ethyl-4-(ethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxamide

The compound of Example 133 was obtained in the same manner as in Example 129, using ethylamine instead of azetidine hydrochloride in Example 129.

LCMS (ES): m/z 482.2 (M+H); ^1H NMR (400MHz, DMSO-d6): δ 7.72 (d, J=8.4 Hz, 1H), 7.37-7.25 (m, 5H), 7.14 (t, J=7.6 Hz, 1H), 6.15 (t, J=5.6 Hz, 1H), 4.45-4.38 (m, 1H), 3.68-3.62 (m,1H), 3.07-2.83 (m, 6H), 1.74-1.72 (m, 1H), 1.01-0.96 (m, 1H), 1.22 (t, J=7.2 Hz, 3H), 1.00-0.98 (m, 1H), 0.79 (t, J=7.2Hz, 3H), 0.63-0.61 (m, 1H).

Examples 134 to 143

In Example 129, appropriate amine compounds corresponding to the structures of the target compounds were used as reactants, and, if necessary, the isomer separation methods of Examples 130 and 131 were used to obtain compounds of Examples 134 to 143. The structural formulas and names of these compounds, as well as the LCMS and/or NMR data identifying these compounds, are shown in Table 4 below.

Examples 144 and 145: N-((1S,3S,4S,5R)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide and N-((1R,3R,4R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide

Step 1: trans-1-(4-(ethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-methyl-1-oxopropan-2-yl acetate (Compound E-56b)

DIPEA (0.1 mL, 0.6 mmol) was added to a THF (2 mL) solution of compound E-56a (0.05 g, 0.11 mmol) and stirred for 30 minutes. The mixture was cooled to 0°C, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.023 mL, 0.16 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored via LCMS. After completion of the reaction, the reaction was quenched with cold water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated to obtain compound E-56b.

Step 2: N-((1S,3S,4S,5R)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'- trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide and N-((1R,3R,4R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)ethanesulfonamide (Examples 144 and 145)

Lithium hydroxide monohydrate (LiOH-H ₂ O, 0.011 g, 0.279 mmol) was added to a solution of compound E-56b (0.05 g, 0.093 mmol) in THF (2 mL) and water (2 mL), and the mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was acidified to pH 4 with 1 M aqueous hydrochloric acid (HCl) and extracted with EtOAc (10 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by Prep HPLC (Column: X-Bridge C18 (150 mm × 4.6 mm × 5 μm), Mobile phase A: 0.1% aqueous ammonia solution; Mobile phase B: acetonitrile; Flow rate: 1.0 mL/min). The compound in the form of a mixture of optical isomers was separated by Prep HPLC (Column: Chiralpak IG (250 mm×4.6 mm×5 mic), Mobile phase: EtOH (0.1% TFA), Flow rate: 0.5 mL/min) to obtain 0.008 g (yield 36%) and 0.013 g (yield 50%) of the two optical isomers, respectively. The two optical isomers were separated at Rt-7.90 min (Peak-1) and Rt-12.5 min (Peak-2).

Example 144: LCMS (ES): m/z 497.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.75-7.73 (m, 1H), 7.37-7.25 (m, 5H), 7.16-7.12 (m, 1H), 4.89-4.77 (m, 2H), 3.71-3.62 (m, 2H), 3.11-3.01 (m, 3H), 2.85-2.79 (m, 1H), 1.80-1.75 (m, 1H), 1.25-1.21 (m, 4H), 1.17-1.11 (m, 3H), 1.09 (s, 3H), 0.88-0.80 (m, 1H),

Example 145: LCMS (ES): m/z 497.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.75-7.74 (m, 1H), 7.37-7.25 (m, 5H), 7.16-7.12 (m, 1H), 4.82-4.77 (m, 2H), 3.71-3.62 (m, 2H), 3.12-2.99 (m, 3H), 2.85-2.79 (m, 1H), 1.80-1.75 (m, 1H), 1.25-1.21 (m, 3H), 1.17-1.09 (m, 4H), 1.05 (s, 3H), 0.88-0.80 (m, 1H).

Examples 146 to 169

In Example 144, appropriate acyl chloride compounds and deuterium compounds corresponding to the structures of the target compounds were used as reactants to obtain compounds of Examples 146 to 169. The structural formulas and names of these compounds, as well as the LCMS and/or NMR data identifying these compounds, are shown in Table 5 below.

Example 170: trans-rac-N-ethyl-4-(fluoromethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxamide

Step 1: trans-rac-1-fluoro-N-(3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide (Compound E-170a)

To a 1,4-indioxane solution (3.5 mL) of intermediate I-10 (0.1 g, 194 μmol) was added hydrochloric acid (HCl) solution (1.5 mL, 4 M 1,4-indioxane solution), and the mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain compound E-170a (80 mg, yield 91%).

LCMS (ES): m/z 415.10 [M+H]; ^1H NMR (400 MHz, DMSO-d6); δ 9.70-9.68 (m, 1H), 9.32-9.30 (m, 1H), 8.18-8.15 (d, J = 15.0 Hz, 1H), 7.53-7.27 (m, 7H), 4.16-4.12 (m, 1H), 3.81-3.79 (m, 1H), 3.23-3.10 (m, 2H), 1.80-1.78 (m, 1H), 1.16-0.82 (m, 2H).

Step 2: trans-rac-N-ethyl-4-(fluoromethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxamide (Example 170)

At 0℃, DIPEA (49.8 μL, 5 eq., 277 μmol) was added to a DCM (3.0 mL) solution of compound E-170a (25 mg, 55.4 μmol) and stirred for 15 min. Then, a DCM (1.0 mL) solution of triphosgene (8.23 mg, 0.5 eq., 27.7 μmol) was slowly added and stirred at room temperature for 1 h. To the mixture, a DCM (0.5 mL) solution of ethylamine hydrochloride (22.6 mg, 5 eq., 277 μmol) and DIPEA (49.8 μL, 5 eq., 277 μmol) were added and stirred at room temperature for 16 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was diluted with DCM (25 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 10 mL) - water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) to obtain the compound of Example 170 (26.9 mg, yield 52%).

LCMS (ES): m/z 468.4 (M+H); ^1H NMR (400MHz, DMSO-d6): δ 7.71 (d, J=7.2 Hz, 1H), 7.37-7.26 (m, 5H), 7.15 (t, J=7.2 Hz, 1H), 6.19 (t, J=5.2 Hz, 1H), 4.44-4.42 (m, 1H), 3.68-3.64 (m,1H), 3.10-3.05 (m, 1H), 2.93 (s, 3H), 2.86-2.83 (m, 4H), 1.74-1.72 (m, 1H), 1.01-0.96 (m, 1H), 0.81 (t, J=7.2Hz, 3H), 0.63-0.61 (m, 1H).

Example 171: trans-rac-N-(2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)-1-fluoromethanesulfonamide

In Example 170, azetidine hydrochloride was used instead of ethylamine hydrochloride to obtain the compound of Example 171 .

LCMS (ES): m/z 498.2 (M+H); ^1H NMR (400MHz, DMSO-d6): δ: 8.46 (d, J=8.4Hz, 1H), 7.41-7.26 (m, 5H), 7.19 (t, J=7.6 Hz, 1H), 5.50-5.28 (m, 2H), 4.52-4.44 (m, 1H), 3.90-3.75 (m, 3H), 3.72-3.62 (m, 3H), 3.11-3.02 (m, 1H), 3.00-2.92 (m, 1H), 2.97-2.87 (m, 1H), 2.17-1.99 (m, 3H), 1.78-1.69 (m, 1H), 1.03-0.96 (m, 1H), 0.67 (br s, 1H).

Example 172: trans-rac-N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)-1-fluoromethanesulfonamide

At 0℃, DIPEA (34.4 μL, 0.2 mmol) and HATU (37.9 mg, 99.8 μmol) were added to a solution of compound E-170a (37 mg, 66.5 μmol) and cyclobutanecarboxylic acid (9.9 mg, 99.8 μmol) in DMF (2.88 mL). The mixture was stirred at room temperature for 3 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was diluted with EtOAc (10 mL) and extracted with water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) to obtain the compound of Example 172 (mixture of enantiomers).

LCMS (ES): m/z 497.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.54 (br s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.35-7.21 (m, 5H), 7.15 (t, J = 7.6 Hz, 1H), 5.55-5.32 (m, 2H), 4.73-4.60 (m, 1H), 3.80-3.70 (m, 1H), 3.30-3.10 (m, 2H), 3.09-3.02 (m, 1H), 2.86-2.80 (m, 1H), 2.01-1.94 (m, 2H), 1.88-1.66 (m, 5H), 1.56-1.52 (m, 1H),1.18-1.11 (m, 1H), 0.73 (br s, 1H).

Examples 173 and 174: N-((1S,3S,4S,5R)-2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)-1-fluoromethanesulfonamide and N-((1R,3R,4R,5S)-2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)-1-fluoromethanesulfonamide

The compound of Example 172, which is a mixture of optical isomers, was separated by Prep HPLC (Column: Chiralpak IA (250 mm×20 mm×5 mic), Mobile phase: n-Hexane: EtOH + 0.1% DEA (80:20), Flow rate: 40 mL/min) to obtain 5 mg (Peak-1, yield 33%) and 8 mg (Peak-2, yield 53%) of the two optical isomers, respectively. The two optical isomers were separated at Rt-1.91 min (Peak-1) and Rt-3.59 min (Peak-2).

Example 173: LCMS (ES): m/z 497.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.53 (br s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.31-7.25 (m, 4H), 7.15 (t, J = 7.6 Hz, 1H), 5.55-5.32 (m, 2H), 4.68-4.60 (m, 1H), 3.76-3.67 (m, 1H), 3.30-3.21 (m, 1H), 3.20-3.10 (m, 1H), 3.09-3.02 (m, 1H), 2.88-2.80 (m, 1H), 2.05-1.92 (m, 2H), 1.88-1.66 (m, 4H), 1.58-1.52 (m, 1H), 1.15-1.08 (m, 1H), 0.73 (br s, 1H),

Example 174: LCMS (ES): m/z 497.2 (M+H); ^1H NMR (400 MHz, DMSO-d ₆ ): δ 8.52 (br s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.31-7.25 (m, 5H), 7.15 (t, J = 7.6 Hz, 1H), 5.56-5.32 (m, 2H), 4.68-4.60 (m, 1H), 3.76-3.68 (m, 1H), 3.30-3.22 (m, 2H), 3.20-3.10 (m, 1H), 3.09-3.02 (m, 1H), 2.88-2.80 (m, 1H), 2.05-1.92 (m, 2H), 1.90-1.56 (m, 4H), 1.60-1.51 (m, 1H), 1.18-1.09 (m, 1H), 0.73 (br s, 1H).

Examples 175 to 180

In Example 170, appropriate carboxylic acid compounds and deuterium compounds corresponding to the structures of the target compounds were used as reactants, and, if necessary, the isomer separation methods of Examples 173 and 174 were used to obtain compounds of Examples 175 to 180. The structural formulas and names of these compounds and the LCMS and/or NMR data identifying these compounds are shown in Table 6 below.

Examples 181 and 182: 1-Fluoro-N-((1S,3S,4S,5R)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide and 1-Fluoro-N-((1R,3R,4R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide

Step 1: trans-1-(4-(fluoromethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-methyl-1-oxopropan-2-yl acetate (Compound E-170b)

DIPEA (0.11 mL, 0.66 mmol) was added to a THF (3 mL) solution of compound E-170a (0.05 g, 0.12 mmol) and stirred for 30 minutes. The mixture was cooled to 0°C, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.026 mL, 0.18 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored using LCMS. After completion of the reaction, the reaction was quenched with cold water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) to obtain compound E-170b (50 mg, 76%).

LCMS (ES): m/z 543.2 (M+H).

Step 2: 1-Fluoro-N-((1S,3S,4S,5R)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0] hexan -4-yl)methanesulfonamide and 1-Fluoro-N-((1R,3R,4R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide (Examples 181 and 182)

Lithium hydroxide monohydrate (LiOH-H ₂ O, 0.011 g, 0.276 mmol) was added to a solution of compound E-170b (0.05 g, 0.092 mmol) in THF (2 mL), water (2 mL), and MeOH (0.86 mL), and the mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was acidified to pH 4 with 1 M aqueous hydrochloric acid (HCl) solution and extracted with EtOAc (20 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM). The compound in the form of a mixture of optical isomers was separated by Prep HPLC (Column: Chiralpak IG (250 mm×4.6 mm×5 μm), Mobile phase: Hex:EtOH (0.1% DEA)=50:50, Flow rate: 1.0 mL/min) to obtain 0.005 g (yield 10%) and 0.009 g (yield 20%) of the two optical isomers, respectively. The two optical isomers were separated at Rt-1.99 min (Peak-1) and Rt-3.38 min (Peak-2).

Example 181: LCMS (ES): m/z 501.2 (M+H); ^1H NMR (400 MHz, DMSO-d ₆ ): δ 8.62-8.46 (m,1H), 7.37-7.25 (m, 5H), 7.16-7.12 (m, 1H), 5.54-5.40 (m, 2H), 5.32-5.29 (m, 2H), 4.85-4.79 (m, 2H), 3.74-3.68 (m, 1H), 3.17-3.07 (m, 1H), 2.88-2.67 (m, 1H), 1.82-1.79 (m, 1H), 1.17-1.09 (m, 6H), 0.81-0.79 (m, 1H),

Example 182: LCMS (ES): m/z 501.2 (M+H); ^1H NMR (400 MHz, DMSO-d ₆ ): δ 8.40-8.33 (m,1H), 7.37-7.25 (m, 5H), 7.16-7.12 (m, 1H), 5.54-5.29 (m, 2H), 5.32-5.29 (m, 2H), 4.90-4.81 (m, 2H), 3.74-3.72 (m, 1H), 3.10-3.06 (m, 1H), 2.88-2.85 (m, 1H), 1.82-1.79 (m, 1H), 1.17-1.06 (m, 6H), 0.81-0.79 (m, 1H).

Examples 183 to 186

Compounds of Examples 183 to 186 were obtained using appropriate acyl chloride compounds and deuterium compounds corresponding to the structures of the target compounds in Step 1 of Examples 181 and 181 as reactants, and, if necessary, using the isomer separation method of Step 2 of Examples 181 and 182. The structural formulas and names of these compounds and the LCMS and/or NMR data identifying these compounds are shown in Table 7 below.

187: trans-rac-4-((N,N-dimethylsulfamoyl)amino)-N-ethyl-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxamide

Step 1: Synthesis of trans-rac-4-((N,N-dimethylsulfamoyl)amino)-N-ethyl-3-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-azabicyclo[3.1.0]hexan-2-yl)carboxamide (Compound E-187a)

To a 1,4-indioxane solution (3.5 mL) of intermediate I-11 (0.1 g, 194 μmol) was added hydrochloric acid (HCl) solution (1.5 mL, 4 M 1,4-indioxane solution), and the mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain compound E-187a (90 mg, yield 93%).

LCMS (ES): m/z 426.10 [M+H]; ^1H NMR (400 MHz, DMSO-d6); δ 9.57-9.55 (m, 1H), 8.90-8.87 (m, 1H), 7.54-7.28 (m, 7H), 4.04-4.00 (m, 1H), 3.79-3.77 (m, 1H), 3.56 (s, 2H), 3.39-3.13 (m, 3H), 2,70 (s, 6H), 2.58-2.55 (m, 1H), 1.86-1.84 (m, 1H), 1.11-0.81 (m, 2H).

Step 2: trans-rac-4-((N,N-dimethylsulfamoyl)amino)-N-ethyl-3-((2,3',5'- trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxamide (Example 187)

At 0℃, DIPEA (56 μL, 5 eq., 325 μmol) was added to a solution of compound E-187a (30 mg, 64.9 μmol) in DCM (2.8 mL) and stirred for 15 min. Then, a solution of triphosgene (9.64 mg, 0.5 eq., 32.5 μmol) in DCM (1.0 mL) was slowly added and stirred at room temperature for 1 h. To the mixture, a solution of ethylamine hydrochloride (26.5 mg, 5 eq., 325 μmol) and DIPEA (56 μL, 5 eq., 325 μmol) in DCM (0.5 mL) were added and stirred at room temperature for 16 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was diluted with DCM (25 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 10 mL) - water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified first by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) and second by Prep HPLC to obtain the compound of Example 187 (32.2 mg, yield 27%).

LCMS (ES): m/z 497.2 (M+H); ^1H NMR (400MHz, DMSO-d6): δ 7.78 (d, J=8.4 Hz, 1H), 7.37-7.25 (m, 5H), 7.14 (t, J=7.6 Hz, 1H), 6.15 (t, J=5.6 Hz, 1H), 4.42-4.40 (m, 1H), 3.59-3.56 (m,1H), 3.09-3.06 (m, 1H), 2.96-2.81 (m, 4H), 2.69 (s, 6H), 1.74-1.72 (m, 1H), 1.02-1.00 (m, 1H), 0.79 (t, J=7.2Hz, 3H), 0.63-0.56 (m, 1H),

Prep HPLC conditions: Column: X-Bridge C18 (19 mm × 250 mm × 5 mic), mobile phase (A): 0.1% ammonia aqueous solution, mobile phase (B): acetonitrile, flow rate: 19 mL/min, target compound RT 12.16 min.

Example 188: trans-rac-{4-(dimethylaminosulfonylamino)-3-[(2,3',5'-trifluoro-3-biphenylyl)methyl]-2-azabicyclo[3.1.0]hexan-2-yl}azetidinylmethanone

The compound of Example 188 was obtained in the same manner as in Example 187, using azetidine hydrochloride as a reactant instead of ethylamine hydrochloride in Example 187.

LCMS (ES): m/z 509.2 (M+H); ^1H NMR (400MHz, DMSO-d6): δ 7.79 (d, J=8.4 Hz, 1H), 7.41-7.26 (m, 5H), 7.19 (t, J=7.6 Hz, 1H), 4.51-4.46 (m, 1H), 3.86-3.80 (m, 2H), 3.69-3.63 (m, 2H), 3.55-3.52 (m, 1H), 3.06-2.98 (m, 2H), 2.86-2.79 (m, 1H), 2.69 (s, 6H), 2.04-1.96 (m, 2H), 1.74-1.72 (m, 1H), 1.05-1.00 (m, 1H), 0.65-0.62 (m, 1H).

Examples 189 and 190

In Examples 187 and 188, appropriate amine compounds corresponding to the structures of the target compounds were used as reactants, and compounds in the form of a mixture of optical isomers were separated through Prep HPLC (Column: Chiralpak IA (250 mm×21 mm×5 mic), Mobile phase: Hex:IPA (60:40), Flow rate: 18 mL/min) to obtain compounds of Examples 189 to 190. The structural formulas and names of these compounds and the LCMS and/or NMR data identifying these compounds are shown in Table 8 below.

Example 191: trans-rac-{4-(dimethylaminosulfonylamino)-3-[(2,3',5'-trifluoro-3-biphenylyl)methyl]-2-azabicyclo[3.1.0]hexan-2-yl}cyclobutylmethanone

At 0℃, DIPEA (36 μL, 3 eq., 195 μmol) and HATU (37 mg, 1.5 eq., 97.4 μmol) were added to a solution of compound E-187a (30 mg, 64.9 μmol) and cyclobutanecarboxylic acid (6.5 mg, 64.9 μmol) in DMF (1.12 mL). The mixture was stirred at room temperature for 1 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtOAc (25 mL) and extracted with water (10 mL × 2). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified first through column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) and then second through prep HPLC to obtain the compound of Example 191 (33 mg, yield 45%).

LCMS (ES): m/z 508.2 (M+H); ^1H NMR (400MHz, DMSO-d6): δ 7.84 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.2Hz, 1H), 7.30-7.25 (m, 4H), 7.14 (t, J=7.6 Hz, 1H), 4.64-4.61 (m, 1H), 3.55-3.49 (m, 1H), 3.28-3.26 (m, 1H), 3.12-3.03 (m, 2H), 2.89-2.74 (m, 2H), 2.71 (s, 6H), 2.07-1.97 (m, 1H), 1.87-1.66 (m, 4H), 1.55-1.52 (m, 1H), 1.14-1.26 (m, 1H), 0.75-0.73 (m, 1H),

Prep HPLC conditions: Column: X-Bridge C18 (19 mm × 250 mm × 5 mic), mobile phase (A): 0.1% ammonia aqueous solution, mobile phase (B): acetonitrile, flow rate: 19 mL/min, target compound RT 17.32 min.

Examples 192 to 201

In Example 191, appropriate carboxylic acid compounds and deuterium compounds corresponding to the structures of the target compounds were used as reactants, and if necessary, the isomer separation method of Example 191 or Prep HPLC (Column: Chiralpak IG (250 mm×21 mm×5 mic), Mobile phase: MTBE:ethanol (55:45), Flow rate: 18 mL/min) was used to separate the optical isomers, thereby obtaining the compounds of Examples 192 to 201. The structural formulas and names of these compounds and the LCMS and/or NMR data identifying these compounds are shown in Table 9 below.

Examples 202 and 203: 1-{(1S,3S,4S,5R)-4-(dimethylaminosulfonylamino)-3-[(2,3',5'-trifluoro-3-biphenyl)methyl]-2-azabicyclo[3.1.0]hexan-2-yl}-2-hydroxy-2-methyl-1-propanone and 1-{(1R,3R,4R,5S)-4-(dimethylaminosulfonylamino)-3-[(2,3',5'-trifluoro-3-biphenyl)methyl]-2-azabicyclo[3.1.0]hexan-2-yl}-2-hydroxy-2-methyl-1-propanone

Step 1: trans-rac-2-{4-(dimethylaminosulfonylamino)-3-[(2,3',5'-trifluoro-3-biphenylyl)methyl]-2-azabicyclo[3.1.0]hexan-2-yl}-1,1-dimethyl-2-oxoethyl acetate (Compound E-187b)

DIPEA (0.1 mL, 0.6 mmol) was added to a THF (2 mL) solution of compound E-187a (0.05 g, 0.11 mmol) and stirred for 30 minutes. The mixture was cooled to 0°C, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.023 mL, 0.16 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored using LCMS. After completion of the reaction, the reaction was quenched with cold water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated to obtain compound E-187b (0.05 g, yield 82%).

LCMS (ES): m/z 554.2 (M+H).

Step 2: 1-{(1S,3S,4S,5R)-4-(dimethylaminosulfonylamino)-3-[(2,3',5'-trifluoro-3-biphenyl)methyl]-2-azabicyclo[3.1.0]hexan-2-yl}-2-hydroxy-2-methyl-1-propanone and 1-{(1R,3R,4R,5S)-4-(dimethylaminosulfonylamino)-3-[(2,3',5'-trifluoro-3-biphenyl)methyl]-2-azabicyclo[3.1.0]hexan-2-yl}-2-hydroxy-2-methyl-1-propanone (Examples 202 and 203)

Lithium hydroxide monohydrate (LiOH-H ₂ O, 0.011 g, 0.271 mmol) was added to a solution of compound E-187b (0.05 g, 0.09 mmol) in THF (2 mL), water (1 mL), and MeOH (1 mL), and the mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was acidified to pH 4 with 1 M aqueous hydrochloric acid (HCl) and extracted with EtOAc (10 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-40% EtOAc/Hep) to obtain the trans-racemic compound. The compound in the form of a mixture of optical isomers was separated by Prep HPLC (Column: Chiralpak IA (250 mm×20 mm×5 mic), Mobile phase: MeOH, Flow rate: 12 mL/min) to obtain 0.01 g (Peak-1, yield 21%) and 0.013 g (Peak-2, yield 28%) of the two optical isomers, respectively. The two optical isomers were separated at Rt-3.74 min (Peak-1) and Rt-4.78 min (Peak-2).

Example 202: LCMS (ES): m/z 512.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.81 (d, J = 8.4 Hz, 1H), 7.37-7.25 (m, 5H), 7.14 (t, J = 8.4 Hz, 1H), 4.79 (br s, 2H), 3.66-3.56 (m, 2H), 3.12-3.07 (m, 1H), 2.82 (t, J = 10 Hz, 1H), 2.71 (s, 6H), 1.82-1.78 (m, 1H), 1.16-1.12 (m, 3H), 1.08 (s, 3H), 0.80-0.78 (m, 1H),

Example 203: LCMS (ES): m/z 512.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.81 (d, J = 8.4 Hz, 1H), 7.37-7.27 (m, 5H), 7.14 (t, J = 8.4 Hz, 1H), 4.79 (br s, 2H), 3.65-3.56 (m, 2H), 3.11-3.07 (m, 1H), 2.82 (t, J = 10 Hz, 1H), 2.71 (s, 6H), 1.82-1.78 (m, 1H), 1.16-1.14 (m, 3H), 1.08 (s, 3H), 0.80-0.78 (m, 1H).

Examples 204 to 208

In step 1 of Examples 202 and 203, appropriate acyl chloride compounds corresponding to the structures of the target compounds were used as reactants, and the optical isomers were separated by Prep HPLC (column: Chiralpak IC (100 mm×4.6 mm×3 mic), mobile phase: MTBE:ethanol + 0.1% DEA (70:30), flow rate: 1.0 mL/min) to obtain compounds of Examples 204 to 208. The structural formulas and names of these compounds and the LCMS and/or NMR data identifying these compounds are shown in Table 10 below.

Examples 209 and 210: N-((1S,3S,4S,5R)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)cyclopropanesulfonamide and N-((1R,3R,4R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)cyclopropanesulfonamide

Step 1: trans-rac-N-(3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)cyclopropanesulfonamide (Compound E-209a)

To a 1,4-indioxane solution of intermediate I-12 (0.63 g, 1.21 mmol) was added hydrochloric acid (HCl, 8 mL, 4 M 1,4-indioxane solution), and the mixture was stirred at room temperature for 4 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain compound E-209a (0.5 g, yield 97%).

LCMS (ES): m/z 423.2 (M+H).

Step 2: trans-rac-1-(4-(cyclopropanesulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-methyl-1-oxopropan-2-yl acetate (Compound E-209b)

DIPEA (0.1 mL, 0.6 mmol) was added to a THF (3 mL) solution of compound E-209a (0.05 g, 0.11 mmol) and stirred for 30 minutes. The mixture was cooled to 0°C, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.023 mL, 0.16 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored using LCMS. After completion of the reaction, the reaction was quenched with cold water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated to obtain compound E-209b (0.055 g, yield 91%).

LCMS (ES): m/z 551.5 (M+H).

Step 3: N-((1S,3S,4S,5R)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'- trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)cyclopropanesulfonamide and N-((1R,3R,4R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)cyclopropanesulfonamide (Examples 209 and 210)

Lithium hydroxide monohydrate (LiOH-H ₂ O, 0.012 g, 0.3 mmol) was added to a solution of compound E-209b (0.055 g, 0.099 mmol) in THF (2 mL), water (1 mL), and MeOH (1 mL), and the mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was acidified to pH 4 with 1 M aqueous hydrochloric acid (HCl) solution and extracted with EtOAc (10 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The residue was first purified by column chromatography (Combiflash purifier, mobile phase: 0-40% EtOAc/Hex) and secondly purified by Prep HPLC (Column: X-Select CSH C18 (250 mm×19 mm×5 μm.), Mobile phase A: 0.1% ammonia aqueous solution; Mobile phase B: acetonitrile; Flow rate: 19.0 mL/min). The compound in the form of a mixture of optical isomers was separated by Prep HPLC (Column: Chiralpak IG (250 mm×20 mm×5 mic), Mobile phase: Hex:IPA (80:20), Flow rate: 20 mL/min) to obtain 0.004 g (Peak-1, yield 7%) and 0.007 g (Peak-2, yield 13%) of the two optical isomers, respectively. Two optical isomers were separated at Rt-3.32 min (Peak-1) and Rt-4.02 min (Peak-2).

Example 209: LCMS (ES): m/z 509.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.76 (d, J = 8.8 Hz, 1H), 7.35-7.27 (m, 5H), 7.13 (t, J = 8.0 Hz, 1H), 4.85-4.80 (m, 2H), 3.69-3.66 (m, 2H), 3.19-3.08 (m, 3H), 2.88-2.82 (m, 2H), 1.87-1.85 (m, 1H), 1.23-0.95 (m, 6H), 0.88-0.81 (m, 4H),

Example 210: LCMS (ES): m/z 509.2: (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.76 (d, J = 8.8 Hz, 1H), 7.37-7.25 (m, 5H), 7.14 (t, J = 7.6 Hz, 1H), 4.83-4.80 (m, 2H), 3.68-3.65 (m, 2H), 3.17-3.08 (m, 1H), 2.88-2.82 (m, 1H), 1.86-1.83 (m, 1H), 1.23-1.09 (m, 7H), 1.00-0.81 (m, 6H).

Examples 211 to 223

In step 2 of Examples 209 and 210, appropriate acyl chloride compounds and deuterium compounds corresponding to the structures of the target compounds were used as reactants, and the optical isomers were separated by Prep HPLC (column: Chiralpak IC (100 mm×4.6 mm×3 mic), mobile phase: MTBE:ethanol + 0.1% DEA (70:30), flow rate: 1.0 mL/min) to obtain compounds of Examples 211 to 223. The structural formulas and names of these compounds and the LCMS and/or NMR data identifying these compounds are shown in Table 11 below.

Example 224: trans-rac-N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)cyclopropanesulfonamide

At 0°C, DIPEA (57.1 μL, 0.327 mmol) and HATU (62.1 mg, 163 μmol) were added to a DMF (2 mL) solution of compound E-209a (50 mg, 109 μmol), and the mixture was stirred at 0°C for 3 h. Cyclobutanecarboxylic acid (10.9 mg, 99.8 μmol) was added to the mixture, and the mixture was stirred at room temperature for 1 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was diluted with EtOAc (10 mL) and extracted with water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was first purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) and second purified by Prep HPLC (column: Kinetex EVO C18 (150 mm×4.6 mm×2.6 μm) mobile phase A: 0.1% ammonia aqueous solution; mobile phase B: acetonitrile; flow rate: 0.8 mL/min) to obtain the compound of Example 224 (17 mg, yield 30%) in trans-racemic form.

LCMS (ES): m/z 505.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.81 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.30-7.24 (m, 4H), 7.14 (t, J = 7.2 Hz, 1H), 4.65-4.61 (m, 1H), 3.65 (s, 1H), 3.32-3.27 (m, 1H), 3.25-3.13 (m, 1H), 3.06-3.02 (m, 1H), 2.89-2.80 (m, 1H), 2.60-2.57 (m, 1H), 2.02-1.97 (m, 2H), 1.87-1.69 (m, 4H), 1.66-1.53 (m, 1H), 1.23-1.10 (m, 1H), 1.00-0.91 (m, 4H), 0.86-0.76 (m, 1H).

Examples 225 to 251

In Example 224, appropriate carboxylic acid compounds corresponding to the structures of the target compounds were used as reactants, and the optical isomers were separated by Prep HPLC (Column: Chiralpak IC (100 mm×4.6 mm×3 mic), Mobile phase: MTBE:ethanol + 0.1% DEA (70:30), Flow rate: 1.0 mL/min) to obtain compounds of Examples 225 to 251. The structural formulas and names of these compounds and the LCMS and/or NMR data identifying these compounds are shown in Table 12 below.

Example 252: trans - rac-N-(2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)cyclopropanesulfonamide

At 0℃, a solution of compound E-209a (0.05 g, 0.109 mmol) in DCM (10.0 mL) was added to a solution of DIPEA (0.09 mL, 0.545 mmol) and triphosgene (0.016 g, 0.054 mmol) in DCM (0.5 mL), and the mixture was stirred at room temperature for 1 h. After cooling the mixture to 0℃, azetidine hydrochloride (0.051 g, 0.545 mmol) was added, and the mixture was stirred at room temperature for 3 h. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with DCM (25 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 10 mL) - water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was first purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) and second purified by Prep HPLC (column: X-Bridge C18 (150 mm×4.6 mm×3.5 μm), mobile phase A: 0.1% ammonia aqueous solution; mobile phase B: acetonitrile; flow rate: 0.8 mL/min) to obtain the compound of Example 252 (20 mg, yield 36%) in trans-racemic form.

LCMS (ES): m/z 506.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.75 (d, J = 12 Hz, 1H), 7.40-7.36 (m, 2H), 7.31-7.26 (m, 3H), 7.19 (t, J = 7.8 Hz, 1H), 4.50-4.45 (m, 1H), 3.87-3.81 (m, 2H), 3.70-3.61 (m, 3H), 3.07-2.97 (m, 2H), 2.89-2.73 (m, 1H), 2.58-2.50 (m, 1H), 2.07-1.99 (m, 2H), 1.78-1.77 (m, 1H), 1.04-0.88 (m, 5H), 0.68-0.67 (m, 1H).

Examples 253 and 254: N-((1R,3R,4R,5S)-2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)cyclopropanesulfonamide and N-((1S,3S,4S,5R)-2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)cyclopropanesulfonamide

The compound of Example 252 in trans-racemic form was separated by Chiral Prep HPLC (Column: CHIRALPAK IA (100 mm×4.6 mm×3 μm), Mobile phase: Hex:IPA+0.1 DEA (50:50), Flow rate: 1.0 mL/min) to obtain 0.002 g (Peak-1, yield 14%) and 0.002 g (Peak-2, yield 14%) of the two enantiomers, respectively. The enantiomers were separated at Rt-4.48 min (Peak-1) and Rt-2.71 mi (Peak-2), respectively.

Example 253: LCMS (ES): m/z 506.2 (M+H); ^1H NMR (400MHz, DMSO-d ₆ ): δ 7.80-7.76 (m, 1H), 7.38-7.17 (m, 6H), 6.52-6.28 (m, 1H), 4.48-4.40 (m, 1H), 3.85-3.81 (m, 2H), 3.70-3.64 (m, 3H), 3.06-2.98 (m, 3H), 2.86-2.81 (m, 2H), 2.04-2.01 (m, 4H), 1.33-1.23 (m, 1H), 1.13-0.99 (m, 2H),

Example 254: LCMS (ES): m/z 506.3 (M+H); ^1H NMR (400MHz, DMSO-d ₆ ): δ 7.76-7.74 (m, 1H), 7.40-7.35 (m, 2H), 7.31-7.26 (m, 3H), 7.21-7.17 (m, 1H), 6.52-6.28 (m, 1H), 4.50-4.45 (m, 1H), 3.87-3.81 (m, 2H), 3.70-3.64 (m, 3H), 3.07-2.97 (m, 2H), 2.89-2.81 (m, 2H), 2.60-2.57 (m, 2H), 2.06-1.99 (m, 2H), 1.78-1.75 (m, 1H), 1.04-0.96 (m, 3H).

Examples 255 to 261

In Example 252, appropriate amine compounds corresponding to the structures of the target compounds were used as reactants, and, if necessary, the isomer separation methods of Examples 253 and 254 were used to obtain compounds of Examples 255 to 261. The structural formulas and names of these compounds, as well as the LCMS and/or NMR data identifying these compounds, are shown in Table 13 below.

Examples 262 and 263: 1,1-Difluoro-N-((1S,3S,4S,5R)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide and 1,1-Difluoro-N-((1R,3R,4R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide

Step 1: trans-rac-1,1-difluoro-N-(3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide (Compound E-262a)

Intermediate I-13 (0.15 g, 0.28 mmol) was stirred at room temperature for 4 h in a 1,4-indioxane solution (3 mL) containing hydrochloric acid (HCl, 1.5 mL, 4 M 1,4-indioxane solution). The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain compound E-262a (0.5 g, yield 97%).

LCMS (ES): m/z 433.1 (M+H).

Step 2: trans-rac-1-(4-(difluoromethylsulfonamido)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-methyl-1-oxopropan-2-yl acetate (Compound E-262b)

DIPEA (0.1 mL, 0.6 mmol) was added to a THF (3 mL) solution of compound E-262a (0.05 g, 0.11 mmol) and stirred for 30 minutes. The mixture was cooled to 0°C, 1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.023 mL, 0.16 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored via LCMS. After completion of the reaction, the reaction was quenched with cold water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated to obtain compound E-109b.

Step 3: 1,1-Difluoro-N-((1S,3S,4S,5R)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide and 1,1-difluoro-N-((1R,3R,4R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)methanesulfonamide (Examples 262 and 263)

Lithium hydroxide monohydrate (LiOH-H ₂ O, 0.012 g, 0.29 mmol) was added to a solution of compound E-262b (0.055 g, 0.098 mmol) in THF (2 mL), water (1 mL), and MeOH (0.9 mL), and the mixture was stirred at room temperature for 12 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was acidified to pH 4 with 1 M aqueous hydrochloric acid (HCl) solution and extracted with EtOAc (10 mL × 3). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The residue was first purified by column chromatography (Combiflash purifier, mobile phase: 0-10% MeOH/DCM) and secondly purified by Prep HPLC (Column: X-Select CSH C18 (250 mm×20 mm×5 μm.), Mobile phase A: 0.1% aqueous ammonia solution; Mobile phase B: acetonitrile; Flow rate: 17.0 mL/min). The trans-racemic form of the compound was separated by Chiral Prep HPLC (Column: CHIRALPAK IA (250 mm×20 mm×5 μm), Mobile phase: Hex: IPA+0.1% formic acid (50:50), Flow rate: 18.0 mL/min) to obtain 0.009 g (yield 18%) and 0.014 g (yield 27%) of the two enantiomers, respectively. The optical isomers were separated at Rt-4.04 min (Peak-1) and Rt-6.3 min (Peak-2), respectively.

Example 262: LCMS (ES): m/z 519.2 (M+H); 1H NMR (400 MHz, DMSO-d6): δ 7.37-6.84 (m, 7H), 4.86-4.76 (m, 2H), 3.78-3.71 (m, 2H), 3.10-2.85 (m, 2H), 1.79 (br, 1H), 1.26-0.77 (m, 7H),

Example 263: LCMS (ES): m/z 519.2 (M+H); 1H NMR (400 MHz, DMSO-d6): δ 7.38-6.87 (m, 7H), 4.87-4.77 (m, 2H), 3.79-3.72 (m, 2H), 3.09-2.85 (m, 2H), 1.80 (br, 1H), 1.23-0.78 (m, 7H).

Example 264: trans-rac-N-(2-(cyclobutanecarbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)-1,1-difluoromethanesulfonamide

At 0℃, DIPEA (33.1 μL, 0.192 mmol) and HATU (36.5 mg, 96 μmol) were added to a solution of compound E-262a (30 mg, 64 μmol) and cyclobutanecarboxylic acid (9.6 mg, 96 μmol) in DMF (2.77 mL). The mixture was stirred at room temperature for 3 h. The mixture was monitored by TLC and LCMS. After the reaction was completed, the mixture was diluted with EtOAc (10 mL) and extracted with water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) to obtain the trans-racemic form of compound 264 (23 mg, yield 69%).

LCMS (ES): m/z 515.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.20 (br s, 1H), 7.45-7.25 (m, 5H), 7.15 (t, J = 7.6 Hz, 1H), 7.04-6.94 (m, 1H), 4.64-4.61 (m, 1H), 3.81-3.70 (m, 1H), 3.18 (br s, 2H), 3.03-2.99 (m, 1H), 2.89-2.83 (m, 1H), 2.01-1.95 (m, 2H), 1.87-1.69 (m, 5H), 1.61-1.49 (m, 1H), 1.19-1.10 (m, 1H), 0.77 (br s, 1H).

Examples 265 to 274

In Example 264, appropriate carboxylic acid compounds and deuterium compounds corresponding to the structures of the target compounds were used as reactants, and, if necessary, the isomer separation method of Example 252 was used to obtain compounds of Examples 265 to 274. The structural formulas and names of these compounds, as well as the LCMS and/or NMR data identifying these compounds, are shown in Table 14 below.

Example 275: trans - rac-N-(2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)-1,1-difluoromethanesulfonamide

At 0℃, DIPEA (0.09 mL, 0.533 mmol) was added to a solution of compound E-262a (0.05 g, 0.107 mmol) in DCM (5.0 mL) and stirred for 15 minutes. Triphosgene (0.016 g, 0.053 mmol) was added to the mixture and stirred at room temperature for 1 hour. After the mixture was cooled to 0℃, azetidine hydrochloride (0.050 g, 0.533 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with DCM (25 mL) and extracted sequentially with sodium bicarbonate (NaHCO ₃ , 10 mL) - water (10 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered under reduced pressure, and concentrated. The residue was first purified by column chromatography (Combiflash purifier, mobile phase: 0-5% MeOH/DCM) and second purified by Prep HPLC (column: X-Bridge C18 (150 mm×4.6 mm×5 μm), mobile phase A: 0.1% ammonia aqueous solution; mobile phase B: acetonitrile; flow rate: 0.8 mL/min) to obtain the compound of Example 275 (17 mg, yield 30%) in trans-racemic form.

LCMS (ES): m/z 516.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.15 (s, 1H), 7.41-7.27 (m, 5H), 7.22-7.16 (m, 1H), 7.02-6.89 (m, 1H), 4.48-4.43 (m, 1H), 3.89-3.83 (m, 2H), 3.78-3.66 (m, 3H), 3.12-3.09 (m, 1H), 2.99-2.86 (m, 2H), 2.08-2.01 (m, 2H), 1.72-1.71 (m, 1H), 1.02-0.97 (m, 1H), 0.67-0.73 (m, 1H).

Examples 276 and 277: N-((1S,3S,4S,5R)-2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)-1,1-difluoromethanesulfonamide and N-((1R,3R,4R,5S)-2-(azetidine-1-carbonyl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-4-yl)-1,1-difluoromethanesulfonamide

The compound of Example 275 in trans-racemic form was separated by Chiral Prep HPLC (Column: CHIRALPAK IA (100 mm×4.6 mm×3 μm), Mobile phase: Hex:IPA+0.1 DEA (50:50), Flow rate: 1.0 mL/min) to obtain 0.005 g (Peak-1, yield 35%) and 0.007 g (Peak-2, yield 48%) of the two enantiomers, respectively. The enantiomers were separated at Rt-1.80 min (Peak-1) and Rt-2.96 min (Peak-2), respectively.

Example 276: LCMS (ES): m/z 516.2 (M+H); ^1H NMR (400MHz, DMSO-d ₆ ): δ 9.15-9.23 (m, 1H), 7.41-7.15 (m, 6H), 7.06-6.68 (m, 1H), 4.48-4.43 (m, 1H), 3.89-3.83 (m, 2H), 3.75-3.66 (m, 3H), 3.18-3.10 (m, 1H), 3.00-2.86 (m, 2H), 2.08-2.02 (m, 2H), 1.80-1.70 (m, 1H), 1.02-0.97 (m, 1H), 0.71-0.67 (m, 1H),

Example 277: LCMS (ES): m/z 516.2 (M+H); ^1H NMR (400MHz, DMSO-d ₆ ): δ 9.15-9.23 (m, 1H), 7.41-7.16 (m, 6H), 7.02-6.89 (m, 1H), 4.48-4.43 (m, 1H), 3.89-3.83 (m, 2H), 3.75-3.66 (m, 3H), 3.18-3.10 (m, 1H), 2.99-2.86 (m, 2H), 2.06-2.03 (m, 2H), 1.80-1.70 (m, 1H), 1.02-0.99 (m, 1H), 0.71-0.67 (m, 1H).

Examples 278 to 280

In Example 275, compounds of Examples 278 to 280 were obtained using appropriate amine compounds corresponding to the structures of the target compounds as reactants, and, if necessary, using the isomer separation method of Example 276 and 277. The structural formulas and names of these compounds, as well as the LCMS and/or NMR data identifying these compounds, are shown in Table 15 below.

Experimental Example 1: Measurement of Orexin 2 Receptor Agonist Activity

For plate preparation, 50 μg/mL of poly-L-lysine hydrobromide was added to 20 μL per well of a 384-well black clear-bottom plate (Greiner) and incubated at 37°C for 2 hours or overnight. After removing poly-L-lysine hydrobromide, the plate was washed with sterile water and prepared for cell seeding.

For cell preparation, the medium was aspirated from a flask in which CHO cells (Woosi Aptec) artificially expressing the human OX2 receptor were cultured. 3 mL of Trypsin-EDTA was added and incubated at 37°C for 1 to 2 minutes. The progress of the enzyme treatment was confirmed under an inverted phase-contrast microscope, and the cells were detached by tapping the bottom of the flask. The cells were suspended by adding medium using a pipette, and any remaining cells at the bottom of the flask were washed away. The collected cells were centrifuged at 1,000 rpm for 5 minutes. The supernatant was gently discarded, being careful not to aspirate the cells. The cell pellet was resuspended in 5 to 10 mL of medium, and 1 mL was taken for counting. Cells were counted using ViCell. The cells were resuspended in medium to a concentration of 10 × 10 ⁵ . Cell suspension was injected into a 384-well plate (20 K/well) at 20 μL per well. Cells were incubated overnight at 37°C under O ₂ conditions.

A 250 mM assay buffer was prepared by adding 1 mL of FLIPR assay buffer to 77 mg of probenecid. To prepare 10 mL of 2× (8 μM) Fluo-4 Direct™ loading buffer, first thaw one vial of Fluo-4 Direct™ crystals (F10471) and add 10 mL of FLIPR assay buffer to the vial. 0.2 mL of probenecid was added to each 10 mL Fluo-Direct vial (final assay concentration 2.5 mM). Vortex and incubate at room temperature for at least 5 minutes, protected from light. The dye was prepared fresh for each test.

The experimental compounds were diluted threefold from a starting concentration of 100 μM.

Using Echo, 1500 nL of compound solution was transferred to the compound plate, followed by the addition of 30 μL of compound plate assay buffer. The cell plate was removed from the incubator and 20 μL of 2× (8 μM) Fluo-4 Direct™ NO-wash loading buffer was gently pipetted into each 384-well plate (final volume of the cell plate was 40 μL). The plate was incubated at 37°C O ₂ for 50 minutes and at room temperature for 10 minutes, and the cell plate was removed from the incubator and placed into the FLIPR. The protocol was run on the FLIPR TETRA to transfer 10 μL of compound from the compound plate to the cell plate and measure the fluorescence values. The measurement interval was read from 1 to the maximum allowable range and the “max-min” was calculated and the data was analyzed using Prism software.

All of the example compounds measured by the above method showed activity as orexin type 2 receptor agonists, and the activity was classified into the following grades, and the results are shown in Table 16:

Class A - EC ₅₀ < 100 nM; Class B - 100 nM ≤ EC ₅₀ < 1,000 nM; Class C - 1,000 nM ≤ EC ₅₀ < 3,000 nM; Class D - EC ₅₀ ≥ 3,000 nM

Example EC ₅₀ Example EC ₅₀ Example EC ₅₀ Example EC ₅₀ 1 B 2 A 3 D 4 D 5 A 6 B 7 A 8 C 9 B 10 B 11 D 12 A 13 A 14 D 15 B 16 A 17 A 18 C 19 A 20 D 21 D 22 A 23 A 24 D 25 A 26 D 27 A 28 D 29 B 30 D 31 A 32 D 33 B 34 D 35 D 36 B 37 C 38 A 39 B 40 C 41 A 42 A 43 B 44 C 45 A 46 A 47 B 48 C 49 A 50 A 51 B 52 A 53 D 54 C 55 A 56 A 57 A 58 C 59 A 60 C 61 D 62 A 63 D 64 A 65 A 66 D 67 A 68 C 69 B 70 D 71 D 72 A 73 B 74 D 75 B 75 D 77 D 78 D 79 B 80 D 81 A 82 D 83 D 84 A 85 A 86 B 87 B 88 D 89 A 90 B 91 B 92 D 93 A 94 A 95 C 96 D 97 B 98 D 99 B 100 A 101 D 102 A 103 D 104 A 105 B 106 B 107 D 108 A 109 A 110 D 111 B 112 A 113 B 114 D 115 B 116 D 117 B 118 A 119 B 120 B 121 D 122 D 123 A 124 C 125 A 126 D 127 B 128 A 129 A 130 D 131 A 132 A 133 A 134 A 135 D 136 A 137 D 138 A 139 C 140 A 141 B 142 B 143 D 144 A 145 D 146 A 147 D 148 D 149 A 150 A 151 A 152 B 153 D 154 A 155 B 156 A 157 B 158 D 159 A 160 D 161 D 162 A 163 A 164 D 165 A 166 A 167 B 168 D 169 A 170 A 171 A 172 A 173 A 174 C 175 D 176 A 177 B 178 A 179 D 180 A 181 A 182 B 183 A 184 D 185 D 186 A 187 A 188 A 189 A 190 B 191 A 192 A 193 D 194 A 195 D 196 A 197 C 198 A 199 B 200 A 201 D 202 A 203 B 204 A 205 B 206 D 207 A 208 C 209 A 210 D 211 A 212 D 213 D 214 A 215 A 216 B 217 D 218 A 219 D 220 A 221 D 222 D 223 A 224 A 225 A 226 D 227 A 228 C 229 A 230 C 231 B 232 D 233 A 234 D 235 D 236 A 237 A 238 D 239 B 240 D 241 A 242 D 243 A 244 A 245 D 246 A 247 D 248 A 249 D 250 A 251 D 252 A 253 B 254 A 255 A 256 A 257 A 258 D 259 A 260 A 261 C 262 A 263 D 264 A 265 A 266 B 267 D 268 A 269 D 270 A 271 A 272 B 273 D 274 B 275 A 276 A 277 B 278 A 279 A 280 A

As shown in Table 17 above, it was confirmed that the compounds of the present invention exhibited excellent agonistic activity against the orexin 2 receptor.

From the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without altering its technical spirit or essential characteristics. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as encompassing all changes or modifications derived from the meaning and scope of the following claims and their equivalent concepts, rather than the detailed description above.

Claims (14)

A compound of the following formula I, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof: [Chemical Formula I] In the above chemical formula I, n and m are each independently integers from 0 to 2; p is an integer of 0 or 1; R ¹ and R ² are each independently C ₁ -C ₃ alkyl or halogen; R ³ is hydrogen or C ₁ -C ₆ alkyl; R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, amino, C ₁ -C ₆ alkylamino, di(C ₁ -C ₆ alkyl)amino, or C ₃ -C ₈ cycloalkyl, wherein the C ₁ -C ₆ alkyl contained in R ⁴ may be optionally substituted with one or more deuterium; R ⁵ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl), 3- to 8-membered heterocycloalkyl containing one heteroatom selected from N, O or S, or NR ^A R ^B , R ^A is hydrogen or C ₁ -C ₆ alkyl, R ^B is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) or (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkylcarbonyl), When R ⁵ is C ₁ -C ₆ alkyl or NR ^A R ^B , it may be substituted by one or more selected from the group consisting of deuterium, hydroxy, halogen, cyano and amino, When R ⁵ is C ₃ -C ₈ cycloalkyl, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl), or 3- to 8-membered heterocycloalkyl containing one heteroatom selected from N, O, or S, it may be substituted with one or more selected from the group consisting of deuterium, hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkyl; R ^6a and R ^6b are each independently hydrogen or deuterium. In the first paragraph, n is 2; m is 1; A compound, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein p is an integer of 0 or 1. In the first paragraph, Is A compound having the structure of, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. In the first paragraph, A compound, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein both R ¹ and R ² are fluoro. In the first paragraph, A compound, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen. In the first paragraph, A compound, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein R ⁴ is methyl, ethyl, fluoromethyl, difluoromethyl, dimethylamino, di(methyl-d3)amino, or cyclopropyl. In the first paragraph, R ⁵ is ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, 2-bicyclo[1.1.1]pentyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, azetidinyl, oxatanyl, 2-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[2.1.1]hexyl, ethylamino, (cyclopropyl)methylamino, or ethylamino, which is unsubstituted or substituted with one or more selected from the group consisting of deuterium, hydroxy, methyl, fluoro, amino, cyano, and trifluoromethyl. A compound, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. In the first paragraph, R ⁵ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or A compound, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. In the first paragraph, A compound, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein R ^6a and R ^6b are both hydrogen or both deuterium. In the first paragraph, The compound of the above formula I is a compound having any one of the stereostructures I-1 to I-4 below, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof: [Chemical Formula I-1] [Chemical Formula I-2] [Chemical Formula I-3] [Chemical Formula I-4] In the above chemical formulas I-1 to I-4, n, m, p, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a and R ^6b are each as defined in claim 1. In the first paragraph, The compound is selected from the following compounds, an optical isomer, a diastereomer, a racemate, a mixture of optical isomers or diastereomers, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof: . A pharmaceutical composition for preventing or treating an orexin 2 receptor (OX2R)-mediated disease, comprising as an active ingredient a compound of any one of claims 1 to 11, an optical isomer, a diastereoisomer, a racemate, a mixture of optical isomers or diastereoisomers thereof, an isotopically labeled compound, a hydrate, a solvate or a pharmaceutically acceptable salt thereof. In Article 12, A pharmaceutical composition, wherein the above orexin 2 receptor-mediated disease is selected from the group consisting of narcolepsy, daytime sleepiness, cataplexy, nocturnal sleep disorder, inappropriately timed rapid eye movement (REM) sleep, sleep paralysis, sleep hallucinations, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome with excessive daytime sleepiness, and coma. A method for preventing or treating an orexin 2 receptor-mediated disease, comprising administering the pharmaceutical composition of claim 12 to a subject in need thereof, other than a human.