spiro macrocyclic orexin 2 receptor agonist

Abstract

This invention relates to a novel spiro macrocyclic compound of general formula (I) that is an orexin 2 receptor agonist. [Formula 1] JPEG2026518313000385.jpg27170

Description

[Technical Field]

[0001] The present invention relates to a novel spiro macrocyclic compound that is an orexin 2 receptor agonist, the compound for use in therapeutic applications, a pharmaceutical composition containing the compound, and a method for treating a disease using the compound. [Background technology]

[0002] Orexin (hypocretin) is a neuropeptide that exists in two subtypes: orexin A (OXA) and orexin B (OXB). Both OXA and OXB bind to orexin receptors, which are G protein-coupled receptors primarily expressed in the brain. There are two subtypes of orexin receptors: orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R). OX1R is primarily expressed in the lateral hypothalamus and mesolimbic system. OX1R regulates feeding behavior and modulates neurotransmitters such as dopamine and acetylcholine. OX2R is more widely expressed in the brain, including the hypothalamus, brainstem, and cortex. OX2R has been shown to play a crucial role in regulating the sleep-wake cycle and wakefulness (Chemelli et. al., Cell (1999), 98, 437-51; Dale, NC et. al. Front. Cell. Neurosci., (2022), 16, 812359). Therefore, orexin 2 receptor agonists are hypothesized to be useful as therapeutic agents for narcolepsy or other disorders exhibiting excessive daytime sleepiness.

[0003] Narcolepsy is a chronic neurological disorder that affects the control of sleep and wakefulness. The prevalence of narcolepsy is estimated to be between 0.02% and 0.05%. People with narcolepsy experience excessive daytime sleepiness (EDS) and are prone to sudden episodes of sleep symptoms (known as "sleep attacks") that can last from a few seconds to several minutes. In addition to sleep attacks, people with narcolepsy may experience other symptoms such as cataplexy (sudden loss of muscle tone and control), hypnagogic / hypnagogic hallucinations, and sleep paralysis. Narcolepsy is subdivided into narcolepsy type 1 (NT1, narcolepsy with cataplexy) and narcolepsy type 2 (NT2, narcolepsy without cataplexy). Narcolepsy is associated with the loss or dysfunction of orexin neurons that produce orexin; therefore, narcolepsy is associated with a deficiency or imbalance of orexin in the brain (Bassetti, C. et. al., Nat. Rev. Neurol., (2019), 15, 519-539).

[0004] Other indications for orexin deficiency have been reported, including Parkinson's disease, Prader-Willi syndrome, and Lewy body dementia, and orexin deficiency is hypothesized to contribute to dysregulation of arousal or excessive daytime sleepiness in these diseases (Thannickal, TC et al., Brain 130, 1586-1595 (2007); Omokawa, M. et al., Am. J. Med., Genet. Part A 170, 1181-1186 (2016); Kasanuki, K. et al., Neurosci. Lett. 569, 68-73 (2014).

[0005] To study the underlying mechanisms of narcolepsy, an orexin-ataxin 3 mouse model exhibiting orexin level deficiency has been developed; danaborextone (TAK-925), an OX2R selective agonist, has been shown to reverse drowsiness and cataplexy in orexin-ataxin 3 mice (Ishikawa, T.; Pharmacol. Biochem. Behav. (2022), 220, 173464). Furthermore, clinical trials have shown that danaborextone, an OX2R agonist, increases arousal and attention and reduces the frequency of cataplexy in patients with narcolepsy, supporting the therapeutic potential of OX2R selective agonists for the treatment of narcolepsy (Evans, R., Proc. Natl. Acad. Sci. (2022), 119, e2207531119). Danaborexton is also being studied in clinical trials in subjects with obstructive sleep apnea, idiopathic hypersomnia, and post-anesthetic recovery patients. In addition, the OXR2 agonist TAK861 is being studied in clinical trials for its potential treatment of narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia.

[0006] Various compounds possessing orexin-2 receptor agonist activity have been reported. For example, International Publication No. 2021108628 discloses substituted macrocyclic compounds and related therapeutic methods. International Publication No. 2022051583 discloses medium- or macrocyclic benzyl-substituted heterocyclic derivatives and their use as orexin-2 receptor agonists. International Publication No. 2022232025 discloses substituted amide macrocyclic compounds possessing orexin-2 receptor agonist activity. International Publication No. 2022251302 discloses substituted condensed bicyclic macrocyclic compounds and related therapeutic methods. International Publication No. 2022094012 discloses macrocyclic urea orexin receptor agonists. International Publication No. 2022109117 discloses 3-aminopyrrolidine and piperidine macrocyclic orexin receptor agonists. International Publication No. 2024075825 discloses cyclopentane compounds.

[0007] However, there is still a need for compounds that possess orexin-2 receptor agonist activity and desirable pharmacological and pharmaceutical properties. [Overview of the Initiative] [Means for solving the problem]

[0008] To our surprise, the inventors discovered that the novel compound of the present invention is a modulator of the orexin-2 receptor. Therefore, the compound of the present invention exhibits an agonist effect on the orexin-2 receptor.

[0009] Some of the compounds of the present invention further possess desirable pharmacological and pharmaceutical properties, such as favorable metabolic stability, permeability, selectivity, and / or brain distribution.

[0010] Therefore, in the first embodiment, the present invention relates to compounds of general formula (I). [ka] (In the formula, L is selected from (C1-C3)alkylenes, each (C1-C3)alkylene optionally substituted with one or more substituents independently selected from deuterium and (C1-C4)alkyls; Q is an (C1-C2) alkylene; T is -O-, -NH-, and -NR e - Selected from the group consisting of R e This represents (C1~C4) alkyl; X is -(CR a R b )-, -O- or represents a bond, R a and R b Each is independently selected from the group consisting of hydrogen and (C1-C4) alkyl groups; Y represents a bond or -O-; Z is selected from the group consisting of phenyl, pyridyl, (C4-C6) cycloalkyl and (C2-C4) alkylene, and the phenyl and pyridyl are each optionally substituted with one or more substituents independently selected from R3; Ar1 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl, and each of the phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl is optionally substituted with one or more substituents independently selected from R4; Ar2 is selected from the group consisting of oxazolyl, oxadiazolyl, thiazolyl, pyrimidinyl, oxodihydropyrimidinyl, and thiadiazolyl; each of the oxazolyl, oxadiazolyl, thiazolyl, pyrimidinyl, oxodihydropyrimidinyl, and thiadiazolyl is optionally substituted with one or more substituents independently selected from R5; R1 is hydrogen, or R1 and R a Or R b These may form a C3-cycloalkyl group with the carbon atoms to which they are bonded; R2 is (C1-C4) alkyl, (C3-C6) cycloalkyl, halo(C1-C4) alkyl, halo(C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, and -NRc R d selected from the group consisting of, R c and R d are each independently selected from the group consisting of hydrogen and (C1-C4) alkyl; R3 is selected from the group consisting of halogen, (C1-C4) alkyl, and halo(C1-C4) alkyl; R4 is selected from the group consisting of halogen, (C1-C4) alkyl, and halo(C1-C4) alkyl; R5 is (C1-C4) alkyl; R6 and R7 are each independently selected from the group consisting of hydrogen and halogen;) or a pharmaceutically acceptable salt thereof.

[0011] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers.

[0012] In a further aspect, the present invention provides a compound of formula I as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in therapy.

BEST MODE FOR CARRYING OUT THE INVENTION

[0013] Definition The term "alkyl" is intended to denote a monovalent hydrocarbon radical formally obtained by removing one hydrogen atom from a branched or straight-chain saturated hydrocarbon. The alkyl contains 1 to 4, for example 1 to 3, for example 2 to 3, or for example 1 to 2 carbon atoms. This term includes the subclass of normal alkyl (n-alkyl), as well as secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isohexyl.

[0014] In this context, the term "cycloalkyl" is intended to refer to a monovalent or divalent hydrocarbon radical formally obtained by removing one or two hydrogen atoms from a cyclic saturated hydrocarbon. The cycloalkyl includes 3 to 6 carbon atoms, e.g., 3 to 5 carbon atoms, or e.g., 3 to 4 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In this context, the term cycloalkyl may also refer to condensed cyclic saturated hydrocarbons such as condensed cyclopropane.

[0015] The term "alkylene" is intended to refer to a divalent saturated hydrocarbon group formally obtained by removing two hydrogen atoms from a branched or linear saturated hydrocarbon. The alkylene contains 1 to 6, more preferably 1 to 4, linear or branched carbon atoms, for example, 1 to 3 or 1 to 2. The term is exemplified by groups such as methylene (-CH2-)(C1 alkylene), ethylene (-CH2CH2-)(C2 alkylene), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-) or (-CH(CH3)CH2-)(C3 alkylene).

[0016] The number of carbon atoms in a hydrocarbon radical (e.g., alkyl, cycloalkyl, alkylene as described herein) is determined by the prefix "(C a ~C b This can be shown by ) where a is the minimum number of carbon atoms in the hydrocarbon radical and b is the maximum number. Therefore, for example, (C1-C4)alkyl is intended to represent an alkyl radical containing 1-4 carbon atoms, (C3-C5)cycloalkyl is intended to represent a cycloalkyl radical containing 3-5 carbocyclic atoms, and (C1-C2)alkylene is intended to represent an alkylene radical containing 1-2 carbon atoms.

[0017] The term "halogen" is intended to refer to substituents from the seventh group of the periodic table, such as fluoro, chloro, and bromo.

[0018] The term "haloalkyl" is intended to refer to alkyl groups as defined herein that are substituted with one or more halogen atoms as defined herein, for example, fluoro or chloro atoms, such as difluoromethyl or trifluoromethyl.

[0019] The term "heteroaryl" is intended to refer to a five- or six-membered monocyclic aromatic heterocyclic radical containing one to five carbon atoms and one to four heteroatoms selected from oxygen, sulfur, and nitrogen. Heteroaryl radicals can be linked to the parent molecule via carbon or nitrogen atoms located at any point within the heteroaryl group. In this context, the term heteroaryl includes both monovalent and divalent species formally obtained by removing one or two hydrogen atoms from an aromatic heterocyclic ring. Representative examples of heteroaryl groups include, but are not limited to, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolylpyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, and thiazolyl.

[0020] The term “heterocycloalkyl” is intended to refer to a cycloalkyl radical, as described herein, in which one or more carbon atoms are replaced by heteroatoms, comprising 1 to 5 carbon atoms, for example, 2 to 5 or 2 to 4 carbon atoms, and further comprising 1 to 5 heteroatoms selected from O, N, or S, preferably 1, 2, or 3 heteroatoms. A heterocycloalkyl radical may be connected to the parent molecule via a carbon or nitrogen atom contained at any point within the heterocycloalkyl group. Typical examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azilidinyl, morpholinyl, oxetanyl, piperadinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranil, and tetrahydropyranil.

[0021] The term "haloalkyl" is intended to refer to alkyl groups as defined herein that are substituted with one or more halogen atoms as defined herein, such as fluoro or chloro, such as difluoromethyl or trifluoromethyl.

[0022] When it is stated that substituents are selected independently of the group, each substituent is selected independently of the others. Therefore, each substituent can be identical or different from the others.

[0023] The term "optionally substituted" means "unsubstituted or substituted," and therefore, the general formulas described herein include compounds containing certain optional substituents and compounds that do not contain optional substituents.

[0024] As used herein, the term "substituted" means that one or more hydrogen atoms of a given group are replaced by a selection from the group shown.

[0025] In this context, a complete bond line intersecting a wave bond [ka] This indicates a connection that links a specified part to an adjacent part.

[0026] In this context, “excipient” or “pharmaceutically acceptable excipient” refers to pharmaceutical excipients including, but not limited to, fillers, antiadherents, binders, coatings, pigments, tablet disintegrants, flavorings, flow enhancers, lubricants, preservatives, adsorbents, sweeteners, solvents, vehicles, and auxiliaries.

[0027] In this context, “treatment” or “to treat” is intended to refer to the management and care of a patient aimed at reducing, suppressing, partially suppressing, eliminating, or delaying the clinical symptoms of a disease. “Treatment” may also refer to preventive treatment of a disease.

[0028] The patients or subjects being treated are preferably mammals, particularly humans.

[0029] In this context, the terms "orexin receptor type 2," "OX2R," and "orexin 2 receptor" are used interchangeably.

[0030] stereochemistry The compounds of the present invention may have one or more chiral centers, and any separated optical isomers (i.e., enantiomers or diastereomers), pure or partially pure optical isomers, and any mixture thereof, including racemic mixtures, i.e., mixtures of stereoisomers, are intended to be within the scope of the present invention.

[0031] In this context, when specifying an enantiomer form, it is understood that the compound is enantiomerized, for example, particularly in its pure form. Accordingly, one embodiment of the present invention relates to a compound of the present invention having an enantiomer excess (ee) of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.

[0032] Racemates can be divided into optical isomers by known methods, for example, by separating their diastereomer salts using an optically active acid and liberating the optically active amine by treatment with a base; or by separating their diastereomer salts using an optically active base and liberating the optically active acidic compound by treatment with an acid. Another method for dividing racemates into optical isomers is based on chromatography on an optically active matrix. The compounds of the present invention can also be divided by the formation of diastereomer derivatives. Further methods for the division of optical isomers known to those skilled in the art can be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials. Absolute stereochemistry can be determined by methods known to those skilled in the art, such as vibrational circular dichroism (VCD) spectroscopy.

[0033] Some compounds of the present invention can exist as atropisomers. Atropisomers are stereoisomers that arise from hindered rotation around a single bond, for example, due to steric strain, which forms an energy barrier to rotation around the single bond that is high enough to allow the isolation of individual conformosomers. When the substituent on the single bond is achiral, the conformosomer is an enantiomer (atropoenantiomer). When the substituent on the single bond is chiral, the conformosomer is a diastereomer (atropodistereomer).

[0034] Isotopes The present invention includes an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number that is normally found in nature (for example, 2 H, 3 H, 11 C, 13 C, 15 N, 18 This also includes isotope-labeled compounds similar to those claimed by formula (I), represented by F, etc. In particular, 2 Examples include H-substituted compounds, that is, compounds in which one or more H atoms are represented by deuterium.

[0035] In one embodiment of the present invention, one or more hydrogen atoms in the compound of formula [I] are represented by deuterium. The element is present in most synthetic compounds in its natural isotopic abundance, and it is recognized that deuterium is naturally incorporated. However, the natural isotopic abundances of hydrogen isotopes such as deuterium are not significant (about 0.015%) compared to the degree of stable isotopic substitution in the compounds shown in the present invention. Therefore, as used herein, the designation of an atom as deuterium at a certain position indicates that the abundance of deuterium is significantly greater than the natural abundance of deuterium. As will be apparent to those skilled in the art, any atom not designated as a specific isotope is intended to represent any stable isotope of that atom.

[0036] In one embodiment, the designation of a position such as "D" in the compound has a minimum deuterium incorporation of about 60% or more at that position, for example, about 70% or more at that position, for example, about 80% or more at that position, for example, about 85% or more at that position. In a further embodiment, the designation of a position such as "D" in the compound has a minimum deuterium incorporation of about 90% or more at that position, for example, about 95% or more at that position, for example, about 97% or more at that position, for example, about 99% or more at that position.

[0037] Embodiments of the present invention are disclosed below.

[0038] In a first embodiment of the present invention, a compound of general formula (I) [ka] (In the formula, L is selected from (C1-C3)alkylenes, each (C1-C3)alkylene optionally substituted with one or more substituents independently selected from deuterium and (C1-C4)alkyls; Q is an (C1-C2) alkylene; T is -O-, -NH-, and -NR e - Selected from the group consisting of R e This represents (C1~C4) alkyl; X is -(CR a R b )-, -O- or represents a bond, R a and R b Each is independently selected from the group consisting of hydrogen and (C1-C4) alkyl groups; Y represents a bond or -O-; Z is selected from the group consisting of phenyl, pyridyl, (C4-C6) cycloalkyl and (C2-C4) alkylene, and the phenyl and pyridyl are each optionally substituted with one or more substituents independently selected from R3; Ar1 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl, and each of the phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl is optionally substituted with one or more substituents independently selected from R4; Ar2 is selected from the group consisting of oxazolyl, oxadiazolyl, thiazolyl, pyrimidinyl, oxodihydropyrimidinyl, and thiadiazolyl; each of the oxazolyl, oxadiazolyl, thiazolyl, pyrimidinyl, oxodihydropyrimidinyl, and thiadiazolyl is optionally substituted with one or more substituents independently selected from R5; R1 is hydrogen, or R1 and R a Or R b These may form a C3-cycloalkyl group with the carbon atoms to which they are bonded; R2 is (C1-C4) alkyl, (C3-C6) cycloalkyl, halo(C1-C4) alkyl, halo(C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, and -NR c R d Selected from the group consisting of R c and R d Each is independently selected from the group consisting of hydrogen and (C1-C4) alkyl groups; R3 is selected from the group consisting of halogens, (C1-C4) alkyls, and halo(C1-C4)alkyls; R4 is selected from the group consisting of halogens, (C1-C4)alkyls, and halo(C1-C4)alkyls; R5 is an (C1-C4) alkyl group; R6 and R7 are each independently selected from the group consisting of hydrogen and halogens. Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0039] In a further aspect of the present invention, a compound of general formula (I) (wherein L is selected from (C1-C3)alkylenes, and the (C1-C3)alkylenes are optionally substituted with one or more substituents independently selected from deuterium and (C1-C4)alkyls; Q is an (C1-C2) alkylene; T is -O-, -NH-, and -NR e - Selected from the group consisting of R e This represents (C1~C4) alkyl; X is -(CR a R b )- or represents a combination, R a and R b Each is independently selected from the group consisting of hydrogen and (C1-C4) alkyl groups; Y represents a bond or -O-; Z is selected from the group consisting of phenyl, pyridyl, (C4-C6)-cycloalkyl and (C2-C4)alkylene, and the phenyl and pyridyl are each optionally substituted with one or more substituents independently selected from R3; Ar1 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, and pyrimidinyl, and each of the phenyl, pyridyl, pyrazolyl, and pyrimidinyl is optionally substituted with one or more substituents independently selected from R4; Ar2 is selected from the group consisting of oxazolyl, oxadiazolyl, thiazolyl, and pyrimidinyl; the oxazolyl, oxadiazolyl, thiazolyl, and pyrimidinyl are each optionally substituted with one or more substituents independently selected from R5; R1 is hydrogen, or R1 and R a Or R b These may form a C3-cycloalkyl group with the carbon atoms to which they are bonded; R2 is (C1-C4) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, and -NR c R d Selected from the group consisting of R c and R d Each is independently selected from the group consisting of hydrogen and (C1-C4) alkyl groups; R3 is selected from the group consisting of halogens, (C1-C4) alkyls, and halo(C1-C4)alkyls; R4I is selected from the group consisting of halogens, (C1-C4)alkyls, and halo(C1-C4)alkyls; R5 is an (C1-C4) alkyl group; R6 and R7 are each independently selected from the group consisting of hydrogen and halogens. Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0040] In one embodiment, the present invention relates to a compound of general formula (Ia). [ka] (In the formula, Q, X, Y, Z, L, T, Ar1, Ar2, R1, R2, R3, R4, R5, R6, R7, R a , R b , R c , R d and R e This relates to (as defined above) or its pharmaceutically acceptable salts.

[0041] In one embodiment, the present invention relates to a compound of general formula (Ib). [ka] (In the formula, Y, Z, L, T, Ar1, Ar2, R2, R3, R4, R5, R6, R7, R c , R d and R e This relates to (as defined above) or its pharmaceutically acceptable salts.

[0042] In one embodiment, the present invention relates to a compound of general formula (Ic). [ka] (In the formula, Y, Z, L, T, Ar1, R2, R3, R4, R6, R7, R c , R d and R e This relates to (as defined above) or its pharmaceutically acceptable salts.

[0043] In one embodiment, the present invention relates to a compound of general formula (Id-1). [ka] The formula (wherein Z, Ar1, and R2 are as defined above) or relating to its pharmaceutically acceptable salts.

[0044] In one embodiment, the present invention relates to a compound of general formula (Id). [ka] The formula (wherein Z, Ar1, and R2 are as defined above) or relating to its pharmaceutically acceptable salts.

[0045] In one embodiment, the present invention relates to a compound of general formula (Id) or (Id-1) (wherein the formula Z is selected from the group consisting of phenyl, pyridyl, (C4-C6) cycloalkyl and (C2-C4) alkylene, and the phenyl and pyridyl are each optionally substituted with one or more substituents independently selected from R3; Ar1 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl, and each of the phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl is optionally substituted with one or more substituents independently selected from R4; R2 is (C1-C4) alkyl, (C3-C6) cycloalkyl, halo(C1-C4) alkyl, halo(C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, and -NR c R d Selected from the group consisting of R c and R d Each is independently selected from the group consisting of hydrogen and (C1-C4) alkyl groups; R3 is selected from the group consisting of halogens, (C1-C4) alkyls, and halo(C1-C4)alkyls; R4 is selected from the group consisting of halogens, (C1-C4) alkyls, and halo(C1-C4)alkyls. relates to the compound or its pharmaceutically acceptable salt.

[0046] In one embodiment, the present invention relates to a compound of general formula (Ie)

Chemical formula

[0047] In one embodiment, the present invention relates to a compound of general formula (If)

Chemical formula

[0048] In one embodiment, the present invention relates to a compound of general formula (Ig) <[]000903>

Chemical formula

[0049] In one embodiment, the present invention relates to a compound of general formula (Ih)

Chemical formula

[0050] In one embodiment, the present invention relates to a compound of general formula (Ii). [ka] (In the formula, Q, X, L, T, Ar1, Ar2, R1, R2, R4, R5, R6, R7, R a , R b , R c , R d and R e This relates to (as defined above) or its pharmaceutically acceptable salts.

[0051] In one embodiment, the present invention relates to a compound of general formula (Id) or (Id-1), [ka] (In the ceremony Z is phenyl, and the phenyl is optionally substituted with one or more substituents independently selected from R3; Ar1 is phenyl, and each phenyl is optionally substituted with one or more substituents independently selected from R4; R2 is selected from the group consisting of (C1-C4) alkyl and (C3-C6) cycloalkyl groups; R3 is a group consisting of a halogen, (C1-C4)alkyl, and halo(C1-C4)alkyl; R4 is a group consisting of a halogen and (C1-C4) alkyl group. or relating to the pharmaceutically acceptable salt thereof.

[0052] In one embodiment, the present invention relates to a compound of the general formula (Id) or (Id-1). (In the ceremony Z is phenyl, and the phenyl is optionally substituted with one or more substituents independently selected from R3; Ar1 is phenyl, and each phenyl is optionally substituted with one or more substituents independently selected from R4; R2 is selected from the group consisting of (C1-C4) alkyl, halo(C1-C4) alkyl, (C3-C6) heterocycloalkyl, (C3-C6) cycloalkyl, and halo(C3-C6) cycloalkyl; R3 is a group consisting of a halogen, (C1-C4)alkyl, and halo(C1-C4)alkyl; R4 is a group consisting of a halogen and (C1-C4) alkyl group. or relating to the pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the present invention relates to a compound of the general formula (Id) or (Id-1). (In the ceremony Z is phenyl, and the phenyl is optionally substituted with one or more substituents independently selected from R3; Ar1 is phenyl, and each phenyl is optionally substituted with one or more substituents independently selected from R4; R2 is selected from the group consisting of methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, and tetrahydrofuranyl; R3 is a group consisting of fluoromethyl, chloromethyl, fluoromethyl, difluoromethyl, and trifluoromethyl; R4 is a group consisting of fluoro, chloro, and methyl. or relating to the pharmaceutically acceptable salt thereof.

[0054] In one embodiment, the present invention relates to a compound of general formula (Ie). [ka] (In the ceremony Ar2 is oxazolyl; said oxazolyl is optionally substituted with one or more substituents each independently selected from R5; L is (C1) alkylene, said (C1) alkylene is optionally substituted with one or more substituents each independently selected from deuterium and (C1-C4) alkyl, T is -O-, Z is phenyl, said phenyl is optionally substituted with one or more substituents each independently selected from R3; Ar1 is phenyl, said phenyl is optionally substituted with one or more substituents each independently selected from R4; R2 is selected from the group consisting of (C1-C4) alkyl, halo(C1-C4) alkyl, (C3-C6) heterocycloalkyl, (C3-C6) cycloalkyl and halo(C3-C6) cycloalkyl; R3 is a group consisting of halogen, (C1-C4) alkyl and halo(C1-C4) alkyl; R4 is a group consisting of halogen and (C1-C4) alkyl; R5 is (C1-C4) alkyl; R6 and R7 are each independently selected from the group consisting of hydrogen and halogen;) or a pharmaceutically acceptable salt thereof.

[0055] One embodiment of the present invention provides a compound according to any one of the above formulas (I)-(Ii), wherein Ar1 is,

Chemical formula

[0056] One embodiment of the present invention provides a compound according to any one of the above formulas (I)-(Ii), wherein Ar1 is, [ka] Selected from the group consisting of, Furthermore, Ar1 may be optionally substituted with one or more substituents independently selected from R4, where R4 is selected from the group consisting of halogens, (C1-C4)alkyls and halo(C1-C4)alkyls; * indicates a bond site to Z.

[0057] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein Ar1 is [ka] Selected from the group consisting of, * indicates a connection point to Z.

[0058] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein Ar1 is a phenyl compound optionally substituted with one or more substituents independently selected from R4.

[0059] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein Ar1 is phenyl, and the phenyl is optionally substituted with one or more substituents independently selected from R4, where R4 is selected from the group consisting of halogens and (C1 to C4) alkyl groups.

[0060] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein Ar1 is phenyl, and the phenyl is optionally substituted with one or more substituents independently selected from R4, where R4 is selected from the group consisting of fluoro, chloro, methyl, and ethyl.

[0061] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein Ar1 is phenyl, and the phenyl is optionally substituted with one or more substituents independently selected from R4, where R4 is selected from the group consisting of fluoro and methyl.

[0062] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein Ar1 is phenyl, and the phenyl is substituted with one or more fluoro substituents.

[0063] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein Ar1 is pyrazolyl, and the pyrazolyl is optionally substituted with one or more substituents independently selected from R4, where R4 is selected from the group consisting of halogens and (C1 to C4) alkyl groups.

[0064] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein Ar1 is [ka] Selected from the group consisting of, Furthermore, Ar1 may be optionally substituted with one or more substituents independently selected from the group consisting of halogens and (C1-C4) alkyl groups; * indicates a bond site to Z.

[0065] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein Ar1 is [ka] And * indicates a connection point to Z.

[0066] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), where Ar1 is phenyl.

[0067] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ib) and (Ie) to (Ii), wherein Ar2 is [ka] Selected from the group consisting of, * indicates a connection point to L.

[0068] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ib) and (Ie) to (Ii), wherein Ar2 is [ka] Selected from the group consisting of, * indicates a connection point to L.

[0069] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ib) and (Ie) to (Ii), wherein Ar2 is selected from the group consisting of oxazolyl and thiazolyl, and the oxazolyl and thiazolyl are each optionally substituted with one or more substituents independently selected from R5, and R5 is (C1 to C4) alkyl.

[0070] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ib), wherein Ar2 is [ka] Selected from the group consisting of, * indicates a connection point to L.

[0071] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ib) and (Ie) to (Ii), wherein Ar2 is oxazolyl.

[0072] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ib) and (Ie) to (Ii), wherein Ar2 is oxazolyl, and the oxazolyl is optionally substituted with a substituent selected from (C1 to C2) alkyl groups.

[0073] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ib) and (Ie) to (Ii), wherein Ar2 is [ka] Selected from the group consisting of, * indicates a connection point to L.

[0074] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), wherein Z is [ka] Selected from the group consisting of, Phenyl and pyridyl are each optionally substituted with one or more substituents independently selected from R3, where R3 is selected from the group consisting of halogens, (C1-C4)alkyls and halo(C1-C4)alkyls, and * indicates a bond site to Y.

[0075] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (hd), wherein Z is [ka] Selected from the group consisting of, * indicates a connection point to Y.

[0076] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), wherein Z is [ka] Selected from the group consisting of, Phenyl and pyridyl are each optionally substituted with one or more substituents independently selected from R3, where R3 is selected from the group consisting of halogens, (C1-C4)alkyls and halo(C1-C4)alkyls, and * indicates a bond site to Y.

[0077] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), wherein Z is a phenyl compound optionally substituted with one or more substituents independently selected from R3.

[0078] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), wherein Z is phenyl, and the phenyl is optionally substituted with one or more substituents independently selected from R3, where R3 is selected from the group consisting of halogens, (C1-C4)alkyls and halo(C1-C4)alkyls.

[0079] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), wherein Z is phenyl, and the phenyl is optionally substituted with one or more substituents independently selected from R3, where R3 is selected from the group consisting of fluoro, chloro, trifluoromethyl, difluoromethyl, methyl, and ethyl.

[0080] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), wherein Z is phenyl and the phenyl is substituted with one or more fluoro substituents.

[0081] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), wherein Z is [ka] Selected from the options, * indicates a connection point to Y.

[0082] One embodiment of the present invention provides a compound according to any one of the above formulas (I)-(Ih), wherein Z is phenyl optionally substituted with one or more substituents each independently selected from R3, and Ar1 is phenyl optionally substituted with one or more substituents each independently selected from R4.

[0083] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia) or (Ii), wherein X represents -CH2-.

[0084] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia) or (Ii), wherein X is - (CR a R b )-, R a represents CH3, and R b represents hydrogen.

[0085] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia) or (Ii), wherein X represents -CH(CH3)-.

[0086] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia) or (Ii), wherein X represents -O-.

[0087] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia) or (Ii), wherein X represents a bond.

[0088] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia) or (Ii), wherein R1 and R a or R b together with the carbon atom to which they are attached form C3-cycloalkyl;

[0089] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia) or (Ii), wherein Q is (C1) alkylene.

[0090] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia), or (Ii), wherein Q is (C2)alkylene.

[0091] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ih), where Y represents a bond.

[0092] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ih), where Y represents -O-.

[0093] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ii), wherein L is (C1)-alkylene, and the (C1)-alkylene is optionally substituted with one or more substituents independently selected from deuterium and (C1 to C4) alkyl.

[0094] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ii), wherein L is selected from (C1)alkylene, and the (C1)alkylene is optionally substituted with one or more deuterium atoms.

[0095] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ii), where L is -(CH2)-.

[0096] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ii), where T is -O-.

[0097] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ii), where T is -NH-.

[0098] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia), or (Ii), where R1 is hydrogen.

[0099] One embodiment of the present invention provides a compound according to any one of the above formulas (I), (Ia), or (Ii), wherein R1 and R a or R b These, together with the carbon atoms to which they are bonded, form a C3-cycloalkyl group.

[0100] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein R2 is selected from the group consisting of (C1-C4) alkyl, (C3-C6) cycloalkyl, halo(C1-C4) alkyl, and halo(C3-C6) cycloalkyl.

[0101] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein R2 is selected from the group consisting of (C1 to C4) alkyl and (C3 to C6) cycloalkyl.

[0102] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein R2 is selected from the group consisting of methyl, ethyl, cyclopropyl, fluorocyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, -NH(CH3), and -NH(CH3)2.

[0103] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein R2 is selected from the group consisting of methyl, ethyl, cyclopropyl, -NH(CH3), and -NH(CH3)2.

[0104] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein R2 is methyl or ethyl.

[0105] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), wherein R3 is selected from the group consisting of fluoro, chloro, (C1-C2)alkyl and halo(C1-C2)alkyl.

[0106] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), wherein R3 is selected from the group consisting of fluoro, chloro, trifluoromethyl, difluoromethyl, and methyl.

[0107] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ih), where R3 is fluoro.

[0108] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein R4 is selected from the group consisting of halogens and (C1 to C4) alkyl groups.

[0109] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), wherein R4 is selected from the group consisting of fluoro, chloro, and methyl.

[0110] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ii), where R4 is fluorocarbon.

[0111] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ib) or (Ie) to (Ii), wherein R5 is methyl.

[0112] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ih), wherein R6 and R7 are each independently selected from the group consisting of hydrogen and fluoropolymers.

[0113] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ih), where R6 and R7 are hydrogen.

[0114] One embodiment of the present invention provides a compound according to any one of the above formulas (I) to (Ic) or (Ie) to (Ih), wherein R6 or R7 is fluoro.

[0115] In one embodiment, the compound of the present invention is selected from the following list. N-[(1s,1'S,14R,17s)-Spiro[7,12,16-Trioxa-22-Azatetracyclo[15.2.2.12,6.110,13]Tricosa-2,4,6(23),10,13(22)-Pentaen-14,3'-Cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,11,15-trioxa-21,22-diazatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,12(21)-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,9S,14R)-6,19-difluoro-9-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2(7),3,5,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,8R)-spiro[10,15-dioxa-20,21-diazatetracyclo[14.3.1.12,6.19,12]docosa-1(19),2(22),3,5,9(21),11,16(20),17-octaen-8,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-9,9-dijuterio-19-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-9,9-dijuterio-6,19-difluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,21-dioxa-12-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,12,16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-Spiro[8,12-Dioxa-6,21-Diazatetracyclo[14.3.1.110,13.02,7]Henicosa-1(20),2,4,6,10,13(21),16,18-Octaen-14,3'-Cyclopentane]-1'-yl]methanesulfonamide N-[(1'S,14R)-17-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, (1'S,14R)-19-fluoro-N-(methylsulfamoyl)spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaene-14,3'-cyclopentane]-1'-amine, (3'S,14R)-3'-(dimethylsulfamoylamino)-19-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaene-14,1'-cyclopentane], N-[(1'S,14R)-5,6,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-5,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-chloro-6-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,17-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-17,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-fluorospiro[8,12-dioxa-19,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-chloro-19-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, N-[(1'S,14R)-6-fluoro-19-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-fluoro-19-(trifluoromethyl)spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-(trifluoromethyl)spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluoro-11-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-fluoro-11-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-3,6,17-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-5,6,17-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-chloro-17-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-4,6,17,19-tetrafluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-chloro-5,6-difluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-17-chloro-6,19-difluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]cyclopropanesulfonamide, N-[(1'S,14R)-5,6,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]cyclopropanesulfonamide, N-[(1'S,14R)-5,6,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8-oxa-12-thia-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-fluoro-6-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,8S)-Spiro[2,6,10-Trioxa-18-Azatricyclo[11.3.1.14,7]Octadeca-1(17),4,7(18),13,15-Pentaen-8,3'-Cyclopentane]-1'-yl]methanesulfonamide N-[(1s,1'S,14R,17s)-spiro[8,12,16-trioxa-22-azatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,15,21-trioxa-11-azatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,11-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,11,15-trioxa-21-azatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,12(21)-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8-oxa-12-thia-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-spiro[7,11-dioxa-20,21-diazatetracyclo[13.3.1.12,6.19,12]henicosa-1(19),2,4,6(21),9,12(20),15,17-octaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-spiro[7,11-dioxa-20-azatetracyclo[13.3.1.12,6.19,12]henicosa-1(19),2,4,6(21),9,12(20),15,17-octaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14S)-spiro[8,12-dioxa-17,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-20-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-20-Fluorospiro[8,12-Dioxa-6,21-Diazatetracyclo[14.3.1.110,13.02,7]Henicosa-1(20),2,4,6,10,13(21),16,18-Octaen-14,3'-Cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-17,20-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19,20-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19,20-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,4'S,14R)-6,19-difluoro-4'-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'R,4'R,14S)-6,19-difluoro-4'-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'R,4'R,14S)-19-fluoro-4'-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,4'S,14R)-19-fluoro-4'-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,11,15-trioxa-3,21,22-triazatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,12(21)-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,14R,17s)-spiro[8,12,16-trioxa-11,22-diazatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,14R,17s)-Spiro[8,12,16-Trioxa-3,22-Diazatetracyclo[15.2.2.110,13.02,7]Docosa-2,4,6,10,13(22)-Pentaen-14,3'-Cyclopentane]-1'-yl]methanesulfonamide, N-[(1S,8S)-spiro[2,6,10-trioxa-19-azatricyclo[12.3.1.14,7]nonadeca-1(18),4,7(19),14,16-pentaen-8,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-11-methylspiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-4,6,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,14R,17s)-Spiro[8,11,16-Trioxa-12,22-Diazatetracyclo[15.2.2.110,13.02,7]Docosa-2,4,6,10(22),12-Pentaen-14,3'-Cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,21-dioxa-11,12-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2(7),3,5,10,12,16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,10r,12s,15S)-spiro[3,13,17-trioxa-19-azatetracyclo[14.2.1.110,12.04,9]icosa-1(18),4,6,8,16(19)-pentaen-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,14R,17s)-spiro[8,12,16-trioxa-6,22-diazatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-spiro[12-oxa-6,8,21-triazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-(cis)-(6-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,4'-cyclohexane]-1'-yl)methanesulfonamide, N-[(1'S,14R)-19-chloro-4,6-difluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R,15S)-6,15,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R,15R)-6,15,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14S)-spiro[8,12-dioxa-20,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-18-fluoro-4-methyl-spiro[7,11-dioxa-4,5,20-triazatetracyclo[13.3.1.19,12.02,6]icosa-1(18),2,5,9,12(20),15(19),16-heptaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-6,20-difluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2(7),3,5,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-16,18-difluoro-4-methyl-spiro[7,11-dioxa-4,5,20-triazatetracyclo[13.3.1.19,12.02,6]icosa-1(18),2,5,9,12(20),15(19),16-heptaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, N-[(1'S,9R,14R)-6,19-difluoro-9-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2(7),3,5,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-spiro[7-oxa-12,21-diazatetracyclo[14.3.1.12,6.19,13]docosa-1(20),2,4,6(22),9,11,13(21),16,18-nonaene-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-5,6,20-trifluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,9R*,15R)-9-methylspiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaen-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,9S*,15R)-9-methylspiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaen-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-20-fluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-4,6,20-trifluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-5,20-difluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[rel-(1'S,4'S,15R)-6,20-difluoro-4'-methyl-spiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[rel-(1'R,4'R,15S)-6,20-difluoro-4'-methyl-spiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-6,20-difluorospiro[8-oxa-11,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, trans-N-(6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,4'-cyclohexane]-1'-yl)methanesulfonamide, trans-N-(6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,4'-cyclohexane]-1'-yl)methanesulfonamide, trans-N-(6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclobutane]-1'-yl)methanesulfonamide, N-[(1'R,14S)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1R,1'S,14S,17R)-6-fluorospiro[8,12,16-trioxa-22-azatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-6,18,20-trifluoro-12-oxo-spiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2(7),3,5,10,14(22),17(21),18-octaen-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-18-fluoro-4-methyl-spiro[7,11-dioxa-3-thia-5,20-diazatetracyclo[13.3.1.19,12.02,6]icosa-1(18),2(6),4,9,12(20),15(19),16-heptaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-(difluoromethyl)-6-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]cyclopropanesulfonamide, N-[(1'S,14R)-6,17-difluorospiro[8,12-dioxa-19,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14S)-6,19-difluorospiro[8,12-dioxa-17,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'R,14S)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, trans-N-(6,20-difluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaen-15,4'-cyclohexane]-1'-yl)methanesulfonamide, N-[(3'R,14S)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,5'-tetrahydrofuran]-3'-yl]methanesulfonamide, N-[(3'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,5'-tetrahydrofuran]-3'-yl]methanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8-oxa-11-thia-12,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10(21),12,16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-11,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]-1-fluoromethanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2(7),3,5,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]-1,1,1-trifluoromethanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]-1,1-difluoromethanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]-1-fluorocyclopropanesulfonamide, N-[(1'R,2'R,5'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,4'-bicyclo[3.1.0]hexane]-2'-yl]methanesulfonamide, N-[(1'R,2'R,5'S,15R)-6,20-difluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaene-15,4'-bicyclo[3.1.0]hexane]-2'-yl]methanesulfonamide, and N-[(1'R,2'R,5'S,15R)-4,6,20-trifluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaene-15,4'-bicyclo[3.1.0]hexane]-2'-yl]methanesulfonamide, N-[(3'R,14S)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-1',5'-tetrahydrofuran'-3'-yl]methanesulfonamide, N-[(3'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-1',5'-tetrahydrofuran'-3'-yl]methanesulfonamide, N-[(1'S,4'S,15R)-6,20-difluoro-4'-methyl-spiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'R,4'R,15S)-6,20-difluoro-4'-methyl-spiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0116] In one embodiment, the compound of the present invention is selected from the following list. N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-chloro-6-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluoro-11-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-4,6,17,19-tetrafluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8-oxa-12-thia-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,15,21-trioxa-11-azatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,11-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19,20-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,11,15-trioxa-21,22-diazatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,12(21)-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-18-fluoro-4-methyl-spiro[7,11-dioxa-4,5,20-triazatetracyclo[13.3.1.19,12.02,6]icosa-1(18),2,5,9,12(20),15(19),16-heptaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide and N-[(1'S,14R)-6,19,20-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0117] In one embodiment, the compound of the present invention is N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0118] In one embodiment, the compound of the present invention is N-[(1'S,14R)-19-chloro-6-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0119] In one embodiment, the compound of the present invention is N-[(1'S,14R)-6,19-difluoro-11-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0120] In one embodiment, the compound of the present invention is N-[(1'S,14R)-4,6,17,19-tetrafluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0121] In one embodiment, the compound of the present invention is N-[(1'S,14R)-6,17,19-trifluorospiro[8-oxa-12-thia-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0122] In one embodiment, the compound of the present invention is N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0123] In one embodiment, the compound of the present invention is N-[(1s,1'S,13S,16s)-spiro[7,15,21-trioxa-11-azatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,11-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0124] In one embodiment, the compound of the present invention is N-[(1'S,14R)-19,20-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0125] In one embodiment, the compound of the present invention is N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0126] In one embodiment, the compound of the present invention is N-[(1s,1'S,13S,16s)-spiro[7,11,15-trioxa-21,22-diazatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,12(21)-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0127] In one embodiment, the compound of the present invention is N-[(1'S,13R)-18-fluoro-4-methyl-spiro[7,11-dioxa-4,5,20-triazatetracyclo[13.3.1.19,12.02,6]icosa-1(18),2,5,9,12(20),15(19),16-heptaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0128] In one embodiment, the compound of the present invention is N-[(1'S,14R)-6,19,20-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0129] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0130] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-19-chloro-6-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0131] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-6,19-difluoro-11-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0132] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-4,6,17,19-tetrafluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0133] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-6,17,19-trifluorospiro[8-oxa-12-thia-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0134] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0135] In one embodiment, the compound of the present invention is It is N-[(1s,1'S,13S,16s)-spiro[7,15,21-trioxa-11-azatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,11-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0136] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-19,20-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0137] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide.

[0138] In one embodiment, the compound of the present invention is It is N-[(1s,1'S,13S,16s)-spiro[7,11,15-trioxa-21,22-diazatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,12(21)-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0139] In one embodiment, the compound of the present invention is It is N-[(1'S,13R)-18-fluoro-4-methyl-spiro[7,11-dioxa-4,5,20-triazatetracyclo[13.3.1.19,12.02,6]icosa-1(18),2,5,9,12(20),15(19),16-heptaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0140] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-6,19,20-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0141] In one embodiment, the compound of the present invention is It is N-[(1R,1'S,14S,17R)-6-fluorospiro[8,12,16-trioxa-22-azatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide.

[0142] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]cyclopropanesulfonamide.

[0143] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]-1-fluoromethanesulfonamide.

[0144] In one embodiment, the compound of the present invention is It is N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]-1-fluorocyclopropanesulfonamide.

[0145] In one embodiment, the compound of the present invention is It is N-[(1'R,2'R,5'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,4'-bicyclo[3.1.0]hexane]-2'-yl]methanesulfonamide.

[0146] In one embodiment, the compound of the present invention is [ka] That is the case.

[0147] In one embodiment, the compound of the present invention is [ka] That is the case.

[0148] In one embodiment, the compound of the present invention is [ka] That is the case.

[0149] In one embodiment, the compound of the present invention is [ka] That is

[0150] In one embodiment, the compound of the present invention is [ka] That is the case.

[0151] In one embodiment, the compound of the present invention is [ka] That is the case.

[0152] In one embodiment, the compound of the present invention is [ka] That is the case.

[0153] In one embodiment, the compound of the present invention is [ka] That is the case.

[0154] In one embodiment, the compound of the present invention is [ka] That is the case.

[0155] In one embodiment, the compound of the present invention is [ka] That is the case.

[0156] In one embodiment, the compound of the present invention is [ka] That is the case.

[0157] In one embodiment, the compound of the present invention is [ka] That is the case.

[0158] In one embodiment, the compound of the present invention is [ka] That is the case.

[0159] In one embodiment, the compound of the present invention is [ka] That is the case.

[0160] In one embodiment, the compound of the present invention is [ka] That is the case.

[0161] Pharmaceutically acceptable salts The compounds of the present invention are generally used as free substances, i.e., not generally as salts. However, if the compound of formula I contains a free base, the compound may be used as a pharmaceutically acceptable salt thereof. Such salts can be prepared by conventional methods by treating a solution or turbidity of the free base of formula I with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are listed below.

[0162] In this context, pharmaceutically acceptable salts are intended to refer to non-toxic, i.e., physiologically acceptable salts. The term pharmaceutically acceptable salt includes salts formed with inorganic and / or organic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitrite, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, and sulfonic acids, e.g., methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid. Some of the acids listed above are diacids or triacids, i.e., acids containing two or three acidic hydrogens, such as phosphoric acid, sulfuric acid, fumaric acid, and maleic acid. Two or three acids can form 1:1, 1:2, or 1:3 (triacid) salts, i.e., salts formed between two or three molecules of the compound of the present invention and one molecule of the acid.

[0163] If the compound of formula I contains an acidic moiety, the compound may be used as a pharmaceutically acceptable salt thereof. Such salts can be prepared by conventional methods by treating a solution or turbidity of the free acidic moiety of formula I with a molar equivalent of a pharmaceutically acceptable base. Representative examples of suitable organic and inorganic bases are listed below. The term pharmaceutically acceptable salt includes salts formed with inorganic and / or organic bases, e.g., alkali metal bases, e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide; alkaline earth bases, e.g., calcium hydroxide and magnesium hydroxide; and organic bases, e.g., trimethylamine and diethylamine. Some of the bases listed above are dibasic or tribasic bases, i.e., bases capable of accepting two or three acidic hydrogen atoms, such as calcium hydroxide and magnesium hydroxide. Dibasic or tribasic bases can form 1:1 or 2:1 salts, i.e., salts formed between two molecules of the compound of the present invention and one molecule of the base.

[0164] Further examples of acids and bases useful for forming pharmaceutically acceptable salts can be found, for example, in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," 2. nd It can be found in the 2011 edition of Wiley-VCH.

[0165] Pharmaceutical composition The compounds described above, or their pharmaceutically acceptable salts, may be present in the composition as sole active pharmaceutical ingredients or in combination with other pharmaceutically active ingredients. In addition, one or more pharmaceutically acceptable carriers or excipients may be present in the composition.

[0166] Pharmaceutical compositions can be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), perdermal, intracisional, intraperitoneal, vaginal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes, with the oral route being preferred. It will be understood that the preferred route will depend on the overall condition and age of the subject being treated, the nature of the condition being treated, and the active ingredient selected.

[0167] Examples of pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, sugar-coated tablets, pills, lozenges, powders, and granules. Where appropriate, these can be prepared with coatings.

[0168] Liquid dosage forms for oral administration include liquids, emulsions, turbidiants, syrups, and elixirs.

[0169] Examples of pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, turbidities, or emulsions, as well as sterile powders that are reconstituted into sterile injection solutions or dispersions before use.

[0170] Other appropriate forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, transdermal patches, and implants.

[0171] The compounds of the present invention are preferably administered in a unit dosage form containing the compound, in an amount of about 0.1 to 300 mg, for example, 1 to 100 mg. The compounds may be administered as a bolus (i.e., the entire daily dose is administered at once) or in divided doses two or three or more times a day.

[0172] Suitable pharmaceutical carriers include inert solid excipients or fillers, sterile aqueous solutions, and various organic solvents. Pharmaceutical compositions formed by combining the compounds of the present invention with pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed administration routes.

[0173] Formulations of the present invention suitable for oral administration may exist as individual units such as capsules or tablets, each containing a predetermined amount of the active ingredient and appropriate excipients. Furthermore, orally usable formulations may be in the form of powders or granules, aqueous or non-aqueous liquid solutions or turbidities, or liquid emulsions of oil in water or water in oil.

[0174] When a solid carrier is used for oral administration, the formulation may be, for example, a tablet placed in a hard gelatin capsule in the form of a powder or pellet, or a lozenge or troche. The amount of solid carrier may vary, but is usually about 25 mg to 1 g.

[0175] When a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injection solution, such as an aqueous or non-aqueous liquid turbidity or solution.

[0176] Tablets can be prepared by mixing the active ingredient with common auxiliaries and / or excipients, and then compressing the mixture in a conventional tablet press. Auxiliaries or additives commonly used for such purposes, such as colorants, flavorings, and preservatives, may be used, provided they are compatible with the active ingredient.

[0177] Treatment of disease OX2R agonists may be useful in treating diseases related to the orexin type 2 receptor or orexin, such as diseases related to orexin deficiency or orexin imbalance.

[0178] One embodiment of the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, which is useful in the treatment of diseases responsive to modulation of orexin-2 receptor activity.

[0179] One embodiment of the present invention provides a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, which is useful for treating diseases treatable by administration of an orexin-2 receptor agonist.

[0180] In one embodiment, the use of a compound according to the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the treatment of a disease or disorder treatable by administration of an orexin-2 receptor agonist is provided.

[0181] In one embodiment, a method is provided for the treatment of a disease or disorder treatable by the administration of an orexin-2 receptor agonist, the method comprising administering a compound according to the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0182] One embodiment of the present invention provides compounds disclosed herein that are useful for treating orexin-related diseases, such as diseases associated with orexin deficiency or diseases associated with orexin imbalance.

[0183] Orexin-2 receptor agonists can be used to treat narcolepsy, such as narcolepsy type 1 or narcolepsy type 2. Furthermore, orexin-2 receptor agonists may be potentially useful in treating obstructive sleep apnea, such as obstructive sleep apnea with excessive daytime sleepiness, idiopathic hypersomnia, or hypersomnia.

[0184] In one embodiment, a compound according to the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to the present invention, is provided for use in the treatment of narcolepsy, for example, for use in the treatment of narcolepsy type 1 or narcolepsy type 2.

[0185] In one embodiment, a method is provided for the treatment of narcolepsy, such as narcolepsy type 1 or narcolepsy type 2, the method comprising administering a compound according to the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0186] In one embodiment, the use of a compound according to the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the treatment of narcolepsy such as narcolepsy type 1 or narcolepsy type 2 is provided.

[0187] In further embodiments, compounds according to the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds according to the present invention are provided for use in the treatment of obstructive sleep apnea, idiopathic hypersomnia, or hypersomnia.

[0188] In one embodiment, a method is provided for the treatment of obstructive sleep apnea, idiopathic hypersomnia, or hypersomnia, the method comprising administering a compound according to the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0189] In one embodiment, the use of a compound according to the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of obstructive sleep apnea, idiopathic hypersomnia, or hypersomnia is provided.

[0190] Central hypersomnia is a disorder characterized by excessive daytime sleepiness (EDS) that is not caused by nocturnal sleep disturbances or disruptions of the circadian rhythm. Central hypersomnia includes narcolepsy with and without cataplexy, recurrent hypersomnia, idiopathic hypersomnia with and without prolonged sleep, behavior-induced sleep deprivation syndrome, hypersomnia and narcolepsy caused by medical conditions. (Sonka, Ther. Adv. Neurol. Disord. (2012), 5, 297). In related classifications, central hypersomnolence (CDH) is characterized by severe daytime sleepiness that is present despite normal nocturnal sleep quality and timing. CDH includes narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to medical disorders, hypersomnia due to drugs or substances, hypersomnia associated with mental disorders, and sleep deprivation syndrome (Khan, CHEST 2015;148(1):262-273).

[0191] In further embodiments, compounds according to the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds according to the present invention are provided for use in the treatment of one or more central hypersomnolence disorders or one or more central hypersomnolence disorders.

[0192] As mentioned above, OX2R agonists are hypothesized to be useful as medications for treating irregular sleep-wake rhythm disorders or excessive daytime sleepiness in indications such as Parkinson's disease, Alzheimer's disease, Prader-Willi syndrome, or Lewy body dementia.

[0193] In further embodiments, compounds according to the present invention, or pharmaceutically acceptable salts thereof, are provided for use in the treatment of irregular sleep-wake rhythm disorders or excessive daytime sleepiness in indications such as Parkinson's disease, Alzheimer's disease, Prader-Willi syndrome, or Lewy body dementia.

[0194] The compounds of the present invention can be administered as monotherapy or as part of an adjunctive therapy regimen.

[0195] In one embodiment, the compounds of the present invention can be administered as monotherapy in the treatment of orexin-related diseases. Such monotherapy indicates that the compounds of the present invention are the sole active ingredient administered to the patient to treat this particular disease, but such monotherapy does not preclude the patient from being treated with other drugs to treat other conditions.

[0196] In further embodiments, the compounds of the present invention may be administered as part of an adjunctive therapy targeting orexin-related diseases. Such adjunctive therapy involves the compound of the present invention being administered adjunct to an existing treatment regimen targeting orexin-related diseases. Alternatively, the adjunctive therapy may also involve the compound of the present invention being a first drug administered to treat an orexin-related disease, followed by the addition of another drug to the treatment regimen, which also targets an orexin-related disease. Examples of adjunctive therapies for narcolepsy, e.g., narcolepsy type 1 or narcolepsy type 2, include modafinil, almodafinil, sodium oxybate, methylphenidate, dextroamphetamine, and pyrisant.

[0197] In one embodiment, the compound of the present invention can be used in combination with other therapeutically active compounds.

[0198] In one embodiment, the compound of the present invention is administered at a dose of approximately 0.001 mg / kg body weight to approximately 100 mg / kg body weight per day. In particular, the daily dose may range from 0.01 mg / kg body weight to approximately 50 mg / kg body weight per day. The exact dose will depend on the frequency and mode of administration, the sex, age, weight, and overall condition of the person being treated, the nature and severity of the condition being treated, any comorbidities being treated, the desired effect of the treatment, and other factors known to those skilled in the art. The daily dose of the compound may be divided into one, two, or more parts.

[0199] A typical oral dose for adults would be 0.1 to 1000 mg / day of the compound of the present invention, or a pharmaceutically acceptable salt thereof, in the range of 1 to 1000 mg / day, for example, 1 to 1000 mg / day, for example, 1 to 500 mg / day, or for example, 1 to 100 mg / day. This amount may be administered in one, two, three or more portions per day.

[0200] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be administered alone as pure compounds, or in single or multiple doses in a pharmaceutical composition comprising the compound or its pharmaceutical salt and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions according to the present invention, together with pharmaceutically acceptable carriers or excipients, and any other known auxiliaries and excipients, may be administered in Remington: The Science and Practice of Pharmacy, 22 nd It can be prescribed in accordance with prior art, such as that disclosed in Edition, Pharmaceutical Press, 2012.

[0201] Preparation of the compound of the present invention General method The compounds of formula I can be prepared by synthetic methods known in the field of organic chemistry, or by the methods described below with modifications well known to those skilled in the art. For example, the methods describe the use of selective protecting groups in the synthesis of the compounds of the present invention. Those skilled in the art will be able to select protecting groups suitable for specific reactions. Methods for protecting and deprotecting such protecting groups are well known in the art, as seen in Greene's Protective Groups in Organic Synthesis by PGMWuts, 2014, 5 th The starting materials used herein can be found in Edition, Wiley. The starting materials used herein are either commercially available or can be prepared by methods common in the art, such as those described in standard reference books, for example, "Compendium of Organic Synthetic Methods, Vol. I-XII" (published by Wiley Interscience). Preferred methods include, but are not limited to, those described below. The schemes are representative of methods useful for synthesizing the compounds of the present invention. They do not in any way limit the scope of the present invention.

[0202] General method-01 [ka] Compounds of general formula INT-1 can be prepared by treating compounds of general formula i with reagents such as benzophenone imines.

[0203] General method-02 [ka] (In the formula, Lg1 and Lg2 are leaving groups such as bromide, chloride, or methanesulfonate; G is a halogen such as chloride or bromide.) The compound of general formula INT-1 can be treated with a strong base such as lithium diisopropylamide and then reacted with the compound of general formula i to form the compound of general formula ii. After hydrolyzing the compound of general formula ii with an acid such as an aqueous hydrochloric acid solution, the compound of general formula INT-2 can be obtained by reacting it with the compound of general formula iii.

[0204] General method-03 [ka] (In the formula, G is a halogen such as a chloride or bromide.) Compounds of general formula INT-3 can be prepared by hydrolysis or methyl ester demethylation of compounds of general formula INT-2 using reagents such as sodium methanethiolate, followed by amide formation using standard procedures such as subsequent treatment with HATU and ammonia equivalents.

[0205] General method-04 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl; G is a halogen such as chloride or bromide.) Compounds of general formula INT-4 can be prepared by reacting a compound of general formula INT-3 with a compound of general formula i in a mixture of water and a solvent such as 1,4-dioxane, in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3.

[0206] General method-05 [ka] (In the formula, Pg1 is a protecting group such as tetrahydro-2H-pyran-2-yl; Lg1 is a leaving group such as bromide, chloride, or methanesulfonate; and G is a halogen such as chloride or bromide.) Compound i can be reacted with compound ii after treatment with a strong base such as lithium diisopropylamide to form compound iii. After removing the protecting group (Pg1) from compound iii using an acid such as TFA in methanol, compound iii can be reacted with compound iv using reagents such as diisopropylethylamine azodicarboxylate and triphenylphosphine in a reaction known as the Mitsunobu reaction to obtain compound v. The Boc group of compound v can be removed by treatment with an acid such as HCl to obtain compound vi. Compound INT-3 can be prepared by hydrolysis or methyl ester demethylation of compound vi using a reagent such as sodium methanethiolate, followed by amide formation using standard procedures such as treatment with HATU and ammonia equivalents.

[0207] General method-06 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) When a compound of general formula INT-4 is treated with a reagent such as 1,3-dichloroacetone, a compound of general formula INT-5 (wherein Ar2 is an oxazolyl group) can be obtained.

[0208] General method-07 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compounds of general formula i can be prepared by treating compounds of general formula INT-4 with a reagent such as Lawesson's reagent. When compounds of general formula i are treated with a reagent such as 1,3-dichloroacetone, compounds of general formula INT-5 (wherein Ar2 is a thiazolyl group) can be obtained.

[0209] General method - 08 [Chem.] (wherein, Pg is a protecting group such as p - methoxybenzyl, benzyl, or methyl) The compound of general formula i can be obtained by treating the compound of general formula INT - 4 with a reagent such as cyanuric chloride. The compound of general formula ii is obtained by reacting the compound of general formula i with hydroxylamine. The compound of general formula INT - 5 can be formed by treating the compound of general formula ii with the compound of general formula iii and then reacting with a reagent such as Burgess reagent.

[0210] General method - 09 [Chem.] (wherein, G is a halogen such as chloride or bromide) After treating the compound of general formula INT - 3 with the compound of general formula i and then treating with trifluoroacetic anhydride, a compound of general formula INT - 6 (wherein, Ar2 is an oxazolyl group) can be obtained.

[0211] General method - 10 [Chem.] (wherein, Pg is a protecting group such as p - methoxybenzyl, benzyl, or methyl; G is a halogen such as chloride or bromide) The compound of general formula INT - 7 can be prepared by reacting the compound of general formula INT - 6 with the compound of general formula i in a solvent mixture such as water and 1,4 - dioxane in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3. T is - NH - or - NR eIf this is the case, the compound of general formula INT-7 can be protected with a protecting group such as p-methoxybenzyl to obtain the compound of general formula INT-7'. The compounds of general formula INT-7 and INT-7' can be reduced with a reducing agent such as LiAlH4 to obtain the compounds of general formula INT-8 and INT-8', respectively. The compounds of general formula INT-8 and INT-8' can be treated with a reagent such as thionyl chloride to obtain the compound of general formula INT-5.

[0212] General method-11 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl; G is a halogen such as chloride or bromide.) Compounds of general formula ii can be prepared by reacting a compound of general formula INT-6 with a compound of general formula i in a solvent mixture such as water and 1,4-dioxane, in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3. Compounds of general formula ii can be reduced with a reducing agent such as LiAlH4 to obtain a compound of general formula iii. Compounds of general formula iii can be treated with a reagent such as thionyl chloride to obtain a compound of general formula INT-5.

[0213] General method-12 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl; Lg is a leaving group such as chloride or bromide; and E is a bond or a CH2 group.) When a compound of general formula INT-4 is treated with trifluoroacetic anhydride and then with a compound of general formula i, a compound of general formula ii (wherein Ar2 is an oxazolyl group) can be obtained. By reducing the compound of general formula ii with a reducing agent such as LiAlH4, a compound of general formula INT-8' can be obtained.

[0214] General method-13 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl; Lg is a leaving group such as chloride or bromide; and E is a bond or a CH2 group.) When a compound of general formula INT-4 is treated with trifluoroacetic anhydride and then with a compound of general formula i, a compound of general formula ii (wherein Ar2 is an oxazolyl group) can be obtained. The compound of general formula ii can be reduced with a reducing agent such as LiAlH4 to obtain a compound of general formula INT-8.

[0215] General method-14 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compounds of general formula INT-5 can be prepared by treating compounds of general formula INT-8' with reagents such as thionyl chloride.

[0216] General method-15 [ka] (In the formula, Lg1 and Lg2 are leaving groups such as bromide, chloride, or methanesulfonate; Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) A compound of general formula INT-1 can be treated with a strong base such as lithium diisopropylamide and then reacted with a compound of general formula INT-15 to form a compound of general formula i. After hydrolyzing the compound of general formula i with an acid such as an aqueous hydrochloric acid solution, it can be reacted with a compound of general formula ii to obtain a compound of general formula INT-9.

[0217] General method-16 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl; G is a halogen such as chloride or bromide.) Compounds of general formula INT-9 can be prepared by reacting a compound of general formula INT-2 with a compound of general formula i in a mixture of water and a solvent such as 1,4-dioxane, in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3.

[0218] General method-17 [ka] (In the formula, Pg1 is a protecting group such as p-methoxybenzyl or benzyl; Pg2 is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compounds of general formula INT-9 can be formed by reacting compounds of general formula INT-11 with compounds of general formula i using reagents such as trimethylsilyl triflate and triisopropylsilane.

[0219] General method-18 [ka] (In the formula, Pg1 is a protecting group such as p-methoxybenzyl or benzyl; Pg2 is a protecting group such as p-methoxybenzyl, benzyl, or methyl; G is a halogen such as chloride or bromide.) Compounds of general formula ii can be prepared by hydrolysis of the compound of general formula INT-2, followed by amide formation using standard procedures such as treatment with HATU and the amine of general formula i. Compounds of general formula iii can be obtained by oxidizing the alcohol portion of the compound of general formula ii using oxidation conditions known as the Swern reaction. Compounds of general formula iv can be formed by treating the compound of general formula iii with a reagent such as Burgess's reagent. Compounds of general formula vi can be prepared by reacting the compound of general formula iv with the compound of general formula v in a solvent mixture such as water and 1,4-dioxane in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3. Compounds of general formula INT-8 can be obtained by removing the protecting groups (Pg1 and Pg2) of the compound of general formula vi.

[0220] General method-19 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compounds of general formula i can be obtained by hydrolyzing the compound of general formula INT-9 with a base such as an aqueous sodium hydroxide solution, followed by the formation of an acid chloride via a reaction using a reagent such as oxalyl chloride. Compounds of general formula iii can be formed by reacting the compound of general formula i with the compound of general formula ii in the presence of a base such as N,N-diisopropylethylamine. Compounds of general formula INT-5 can be formed by treating the compound of general formula iii with a reagent such as Burgess's reagent.

[0221] General method-20 [ka] (In the formula, G is a halogen such as a chloride or bromide; Pg is a protecting group such as p-methoxybenzyl or benzyl.) When a compound of general formula INT-10 is treated with a compound of general formula i, and then treated with trifluoroacetic anhydride, a compound of general formula INT-17 (wherein Ar2 is an oxazolyl group) can be obtained.

[0222] General method-21 [ka] (In the formula, Pg1 is a protecting group such as p-methoxybenzyl or benzyl; Pg2 is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) The alcohol portion of the compound of general formula INT-11 is oxidized under known oxidation conditions as a Swern reaction to obtain the compound of general formula i. The compound of general formula INT-9 can be formed by reacting the compound of general formula i with the compound of general formula ii using reagents such as trimethylsilyl triflate and triisopropylsilane.

[0223] General method-22 [ka] (In the formula, Pg1 is a protecting group such as p-methoxybenzyl or benzyl; Pg2 is a protecting group such as p-methoxybenzyl, benzyl, or methyl; G is a halogen such as chloride or bromide.) Compounds of general formula INT-12 and INT-12' can be prepared by reacting a compound of general formula INT-17 with a compound of general formula i in a solvent mixture such as water and 1,4-dioxane, in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3. Compounds of general formula INT-12 and INT-12' can be reduced with a reducing agent such as LiAlH4 to obtain compounds of general formula INT-13 and INT-13', respectively. Compounds of general formula INT-13 and INT-13' can be treated with a reagent such as thionyl chloride to obtain compounds of general formula INT-14 and INT-14'.

[0224] General method-23 [ka] (In the formula, G is a halogen such as a chloride or bromide.) Compounds with general formula INT-6 can be reduced with a reducing agent such as LiAlD4 or sodium borohydride to obtain compounds with general formula INT-16.

[0225] General method-24 [ka] (In the formula, G is a halogen such as a chloride or bromide; Pg is a protecting group such as p-methoxybenzyl or benzyl.) Compounds of general formula INT-8 can be prepared by reacting a compound of general formula INT-16 with a compound of general formula i in a solvent mixture such as water and 1,4-dioxane, in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3.

[0226] General method-25 [ka] (In the formula, G is a halogen such as a chloride or bromide.) When the compound of general formula INT-3 is treated with a reagent such as 1,3-dichloroacetone, the compound of general formula ii (wherein Ar2 is an oxazolyl group) can be obtained. By hydrolyzing the compound of general formula ii with a reagent such as NaOH, the compound of general formula INT-16 can be obtained.

[0227] General method-34 [ka] (In the formula, Pg1 is a protecting group such as p-methoxybenzyl or benzyl; Pg2 is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compounds of general formula ii can be prepared by hydrolysis of compounds of general formula INT-9 and subsequent amide formation using standard procedures such as HATU and amines of general formula i. Compounds of general formula iii can be obtained by oxidizing the alcohol portion of compounds of general formula ii with reagents such as Dess-Martin periodinane. Compounds of general formula iv can be formed by treating compounds of general formula iii with reagents such as Burgess' reagent. Compounds of general formula INT-8 can be obtained by removing the protecting group of compounds of general formula iv.

[0228] General method-35 [ka] (In the formula, Lg1 and Lg2 are leaving groups such as bromide, chloride, or methanesulfonate; Pg is a protecting group such as p-methoxybenzyl.) After treatment with a strong base such as lithium diisopropylamide, the compound of general formula INT-1 can be reacted with the compound of general formula i to form the compound of general formula ii. After hydrolyzing the compound of general formula ii with an acid such as aqueous hydrochloric acid, the compound of general formula iv can be obtained by reacting it with the compound of general formula iii. The sulfonamide portion of the compound of general formula iv can be protected using a protecting group such as p-methoxybenzyl using a standard procedure to form the compound of general formula v. The compound of general formula vii can be prepared by hydrolysis or methyl ester demethylation of the compound of general formula v using a reagent such as sodium methanethiolate, followed by amide formation using a standard procedure such as treatment with HATU and ammonia equivalents. After treating the compound of general formula vii with the compound of general formula vii, treatment with trifluoroacetic anhydride can yield the compound of general formula viiii. Compounds of general formula INT-18 (wherein Ar2 is an oxazolyl group) can be obtained by treating compounds of general formula vii by treating benzyl ether with hydrogen in the presence of a catalyst such as palladium-carbon, using a standard procedure to remove the benzyl group, and then oxidizing it under oxidation conditions such as the Swern reaction, which is a known reaction.

[0229] General method-36 [ka] (In the formula, Ar is an aromatic group such as benzene or pyridine with or without substituents, as described for Z in the above embodiments; M is a metal such as Li, MgCl, or MgBr; G is a halogen such as a chloride or bromide; and Pg is a protecting group such as p-methoxybenzyl.) Compounds of general formula ii can be prepared by treating compounds of general formula INT-18 with compounds of general formula i. Compounds of general formula INT-17 can be obtained by treating compounds of general formula ii with reagents such as DAST.

[0230] General method-37 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compound i can be obtained by treating compound INT-4 with trimethyloxonium tetrafluoroborate and then reacting it with an ammonia equivalent such as ammonium chloride. Treating compound i with compound ii yields compound iii (wherein Ar2 is a pyrimidine group). Reducing compound iii with a reducing agent such as NaBH4 yields compound INT-8'. Removing the protecting group, Pg, from compound INT-8' yields compound INT-8.

[0231] General method-26 [ka] Compounds of general formula i can be prepared by reacting compounds of general formula INT-8 with a reagent such as thionyl chloride. Compounds of general formula (I) can be prepared by adding a solution of a compound of general formula i to a diluted suspension or solution of a base such as Cs2CO3.

[0232] General method-27 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compounds of general formula i can be prepared by removing a protecting group (Pg) from compounds of general formula INT-5. Compounds of general formula (I) can be prepared by adding a solution of a compound of general formula i to a diluted suspension or solution of a base such as Cs2CO3.

[0233] General method-28 [ka] (In the formula, Pg1 is a protecting group such as p-methoxybenzyl or benzyl; Pg2 is a protecting group such as p-methoxybenzyl, benzyl, or methyl; Pg3 is a protecting group such as tert-butoxycarbonyl) Compounds of general formula i can be prepared by removing the protecting group (Pg1) from the compound of general formula INT-9. Compounds of general formula iii can be prepared by using the compound of general formula ii, diisopropylethylamine azodicarboxylate, and triphenylphosphine, among other reagents, in a reaction known as the Mitsunobu reaction. Compounds of general formula iv can be formed by removing the protecting group (Pg3) from the compound of general formula iii, hydrolyzing it with a base such as an aqueous lithium hydroxide solution, and forming an amide by an amide coupling procedure such as treatment with HATU. Compounds of general formula v can be formed by removing the protecting group (Pg2) from the compound of general formula iv, and then oxidizing the resulting alcohol portion using a reaction known as the Swern reaction or oxidation conditions such as treatment with Dess-Martin periodinane. Compounds of general formula (I) can be formed by treating the compound of general formula v with a reagent such as Burgess's reagent.

[0234] General method-29 [ka] Compounds of general formula i can be obtained by treating a compound of general formula (I) (R2=Me) with a strong acid such as HBr in acetic acid. Compounds of general formula (I) can also be obtained by treating a compound of general formula i with a compound of general formula ii in the presence of a base such as triethylamine.

[0235] General method-30 [ka] (In the formula, Pg1 is a protecting group such as p-methoxybenzyl or benzyl; Pg2 is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compounds of general formula i can be prepared by adding a solution of a compound of general formula INT-14 to a diluted turbidity or solution of a base such as potassium carbonate. Compounds of general formula (I) can be obtained by removing the protecting group Pg1 from the compound of general formula i.

[0236] General method-31 [ka] Compounds of general formula (I) can be prepared in a reaction known as the Mitsunobu reaction by reacting a compound of general formula INT-8 with reagents such as diisopropylethylamine azodicarboxylate and triphenylphosphine.

[0237] General method-32 [ka] (In the formula, G is a halogen such as a chloride or bromide; Pg is a protecting group such as p-methoxybenzyl or benzyl.) Compounds of general formula i can be prepared by hydrolyzing the compound of general formula INT-2, treating it with oxalyl chloride, and then reacting it with tert-butylhydrazine carboxylate. Compounds of general formula iii can be prepared by reacting the compound of general formula i and the compound of general formula ii in a solvent mixture of water and 1,4-dioxane in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3. Compounds of general formula v can be prepared by removing the Boc protecting group from the compound of general formula iii using an acid such as TFA, and then reacting it with an acid chloride such as the compound of general formula iv. Compounds of general formula vi can be prepared by removing the protecting group (Pg) from the compound of general formula v, and then treating it with a base such as cesium carbonate. Compounds of general formula (I) can be formed by treating the compound of general formula vi with a reagent such as Burgess's reagent.

[0238] General method-33 [ka] Compounds of general formula i can be prepared by reacting a compound of general formula INT-8 (T=NH) with a reagent such as thionyl chloride. Compounds of general formula (I) can be prepared by treating a compound of general formula i with reagents such as CuI and KOtBu.

[0239] General method-38 [ka] (In the formula, Lg1 is a leaving group such as bromide, chloride, or methanesulfonate; G is a halogen such as chloride or bromide; Pg1 is a protecting group such as tetrahydropyran-2-yl; Pg2 is a protecting group such as t-butoxycarbonyl) Compound INT-23 can be reacted with compound i after treatment with a strong base such as lithium diisopropylamide to obtain compound ii. When the protecting group is tetrahydropyran-2-yl, compound iii can be obtained by removing the protecting group of compound ii using an acid such as trifluoroacetic acid. Compound v can be obtained by reacting compound iii with compound iv using conditions known as the Mitsunobu reaction. When the protecting group is t-butoxycarbonyl, compound INT-2 or INT-2' can be obtained by removing the protecting group of compound v using a base such as sodium hydroxide or an acid such as trifluoroacetic acid.

[0240] General method-39 [ka] Compounds of general formula i can be obtained by treating compound INT-3 with a reagent such as trimethyloxonium tetrafluoroborate, and then reacting it with an ammonia equivalent such as ammonium chloride. Treating compound i with compound ii yields compound iii (wherein Ar2 is a pyrimidine group). Reducing compound iii with a reducing agent such as NaBH4 yields compound iv. Compounds of general formula INT-8 can be prepared by reacting compound INT-20 with compound iv in a solvent mixture such as water and 1,4-dioxane in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3.

[0241] General method-40 [ka] Compounds of general formula i can be obtained by treating the compound of general formula INT-20 with an oxidizing agent such as MnO2. Compounds of general formula ii can be obtained by treating the compound of general formula i with a reagent such as methylmagnesium bromide. Compounds of general formula INT-8 can be prepared by reacting the compound of general formula ii and the compound of general formula iii in a solvent mixture such as water and 1,4-dioxane in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3.

[0242] General method-41 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl;) Compounds of general formula i can be prepared by hydrolysis of the compound of general formula INT-9 and subsequent amide formation using standard procedures such as HATU and N,O-dimethylhydroxylamine hydrochloride. Compounds of general formula iii can be obtained by adding a Grignard reagent such as ii to the compound of general formula i. Compounds of general formula INT-21 can be obtained by treating the compound of general formula iii with an amidine such as iv in the presence of a base such as t-BuOK. Compounds of general formula INT-8 can be obtained by treating the compound of general formula INT-21 with a reagent such as boron trichloride.

[0243] General method-42 [ka] (In the formula, Lg1 and Lg2 are leaving groups such as bromide, chloride, or methanesulfonate; G is a halogen such as chloride or bromide; Pg1 is a protecting group such as t-butoxycarbonyl; Pg2 is a protecting group such as p-methoxybenzyl, benzyl, or methyl; E is a bond or a CH2 group) Compound INT-1 can be treated with a strong base such as lithium diisopropylamide and then reacted with compound i to form compound ii. After hydrolyzing compound ii with an acid such as aqueous hydrochloric acid, the amino group can be protected with a protecting group such as t-butoxycarbonyl to obtain compound iii. Compound iv can be prepared by hydrolysis of compound iii and subsequent amide formation using standard procedures such as HATU and ammonia equivalents. Compound vi can be prepared by reacting compound iv with compound v in a solvent mixture such as water and 1,4-dioxane in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3. When compound vi is treated with trifluoroacetic anhydride and then with compound vii, compound viiii (wherein Ar2 is an oxazolyl group) can be obtained. Compounds of general formula viii can be reduced with a reducing agent such as LiAlH4 to obtain compound ix. Compounds of general formula ix can be cyclized by treating them with a reagent such as (tributylphosphoroanilidene)acetonitrile to obtain compound INT-22.

[0244] General method-43 [ka] (In the formula, Lg is a leaving group such as a chloride, methanesulfonate, or trifluoromethanesulfonate; Pg is a protecting group such as t-butoxycarbonyl;) Compounds of general formula i can be obtained by removing the protecting group from compounds of general formula INT-22 using a standard procedure. Compounds of general formula (I) can be obtained by reacting a compound of general formula i with a compound of general formula ii.

[0245] General method-44 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compounds of general formula i can be obtained by treating compound INT-4 with a reagent such as trimethyloxonium tetrafluoroborate. Compounds of general formula ii can be obtained by the reaction of compound i with ammonia. Compounds of general formula INT-5 can be formed by treating compound ii with compound iii in the presence of a base such as potassium phosphate.

[0246] General method-45 [ka] (In the formula, G is a halogen such as a chloride or bromide.) Compounds of general formula ii can be obtained by treating compounds of general formula INT-3 with reagents such as i. Compounds of general formula INT-6 are obtained by the reaction of compounds of general formula ii and compounds of general formula iii.

[0247] General method-46 [ka] (In the formula, G is a halogen such as a chloride or bromide.) Compounds of general formula INT-6 can be obtained by hydrolysis of a compound of general formula INT-2 using reagents such as lithium hydroxide, followed by amide formation with a compound of general formula i using standard procedures such as treatment with coupling reagents such as EDC and heating.

[0248] General method-47 [ka] (In the formula, Pg is a protecting group such as p-methoxybenzyl, benzyl, or methyl.) Compounds of general formula INT-4 can be prepared by hydrolysis of compounds of general formula INT-9, followed by amide formation through standard procedures such as treatment with HATU and ammonia equivalents.

[0249] General method-48 [ka] (In the formula, G is a halogen such as a chloride or bromide.) Compounds of general formula ii can be prepared by hydrolysis of the compound of general formula INT-2 and subsequent amide formation using standard procedures such as treatment with HATU and the amine of general formula i. Compounds of general formula iii can be formed by treating the compound of general formula ii with reagents such as DAST. Compounds of general formula INT-6 can be prepared by treating the compound of general formula iii with reagents such as bromotrichloromethane in the presence of a base such as DBU (2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine). [Examples]

[0250] chemical name The chemical names of the examples of this invention were generated using Dassault Systemes' BIOVIA MDL.Draw.Editor version 20.1.0.2081.

[0251] Analysis method LC-MS method Method A: LC-MS was performed on a Waters Aquity UPLC-MS consisting of a Waters Aquity with a column manager, a two-component solvent manager, a sample organizer, a PDA detector (operating at 254 nm), an ELS detector, and a TQ-MS equipped with an ESI source operating in cation mode.

[0252] LC conditions: The column was an Acquity UPLC BEH C18 1.7 μm; 2.1 x 50 mm, operating at 60°C with a two-component gradient consisting of water + 0.05% trifluoroacetic acid (A) and acetonitrile + 5% water + 0.05% trifluoroacetic acid at 1.2 mL / min.

[0253] [Table 1]

[0254] Method B: LC-MS was performed using a Waters Aquity UPLC-MS, which consists of a Waters Aquity with a column manager, a two-component solvent manager, a sample organizer, a PDA detector (operating at 254 nm), an ELS detector, and an APPI source operating in cation mode.

[0255] LC conditions: The column was an Acquity UPLC BEH C18 1.7 μm; 2.1 x 50 mm, operating at 60°C with a two-component gradient consisting of water + 0.1% TFA(A) and acetonitrile + 5% water + 0.1% TFA at 1.2 mL / min.

[0256] [Table 2]

[0257] Method C: LC-MS was performed using a Waters ACQUITY Premier UPLC-MS, which consists of a Waters Aquity Premier with a column manager, two-component solvent manager, sample organizer, PDA detector, ELS detector, and SQD-2 equipped with a Unispray source operating in cation mode.

[0258] LC conditions: The column was an Acquity Premier UPLC BEH C18 1.7 μm; 2.1 x 50 mm, operating at 60°C with a two-component gradient consisting of water + 0.05% TFA(A) and acetonitrile + 5% water + 0.035% TFA at 1.2 mL / min.

[0259] [Table 3]

[0260] NMR 1 ¹H NMR spectra were recorded at 600 MHz with a Bruker 600-Avance-III spectrometer, 500 MHz with a Bruker 500-Avance DRX spectrometer, 300 MHz with a Bruker Avance III HD spectrometer, 400 MHz with a Bruker Avance III HD spectrometer, and 400 MHz with a Bruker Avance NEO spectrometer. Chemical shift values ​​are expressed in ppm for tetramethylsilane. The following abbreviations or combinations thereof are used for the multiplicity of the NMR signal: br=broad, d=doublet, m=multiplet, q=quartet, quint=quintet, s=singlet, and t=triplet.

[0261] Abbreviation The abbreviations used in the experiment may include, but are not limited to, the following: Ac: Acetyl; Ar: Argon; Bn: Benzyl; Boc: Tert-butyloxycarbonyl; C: Celsius; cPr: Cyclopropyl; DBAD: Di-tert-butylazodicarboxylate; Dichloromethane: Dichloromethane; DIAD: Diisopropylzodicarboxylate; DIPEA: N,N-Diisopropylethylamine; DMA: N,N-Dimethylacetamide; DMF: N,N-Dimethylformamide; D MSO: Dimethyl sulfoxide; DTT: Dithiothreitol; EGTA: Ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid; Et: Ethyl; Ethyl acetate: Ethyl acetate; g: Grams; h: Hours; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HMDS: Hexamethyldisilazane; HOAt: 1-Hydroxy-7 -Azabenzotriazole; HOBt: Hydroxybenzotriazole; L: Liter; LAH: Lithium aluminum hydride; LDA: Lithium diisopropylamide; M: Mole; Me: Methyl; mg: Milligram; mL: Milliliter; mmol: Millimole; Ms: Methanesulfonyl; NBS: N-Bromosuccinimide; n-Bu: N-Butyl; NFSI: N-Fluorobenzenesulfonimide; NMR: Nuclear magnetic resonance; PE: Petroleum ether; PG: Protecting group; Ph: Phenyl; SFC: Supercritical fluid chromatography; TBS: Tert-butyl(dimethyl)silyl; TEA: Triethylamine; Tf: Triflate; TFA: Trifluoroacetic acid; TFAA: Trifluoroacetic anhydride; THF: Tetrahydrofuran; THP: Tetrahydropyran; TLC: Thin-layer chromatography; TMS: Trimethylsilyl; TMS: Trimethylsilyl; Tris: Trisaminomethane; Ts: Toluenesulfonyl; wt: By weight.

[0262] Preparation of intermediates Preparation of methyl 3-(3-(benzyloxy)phenyl)propanoate [ka] A mixture of methyl 3-(3-hydroxyphenyl)propanoate (2.00 g, 11.1 mmol), K2CO3 (2.32 g, 16.6 mmol), and (bromomethyl)benzene (1.90 g, 11.1 mmol) in acetonitrile (50 mL) was stirred at room temperature for 1 hour. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to obtain the desired product.

[0263] Preparation of 3-(3-(benzyloxy)phenyl)propan-1-ol [ka] A mixture of methyl 3-(3-(benzyloxy)phenyl)propanoate (2.80 g, 10.4 mmol) and lithium aluminum hydride (1.0 M in THF) (15.5 mL, 15.5 mmol) in THF (30 mL) was stirred at 0°C for 1 hour. The resulting mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to obtain the desired product.

[0264] Preparation of 1-(benzyloxy)-3-(3-(chloromethoxy)propyl)benzene [ka] A solution of 3-(3-(benzyloxy)phenyl)propan-1-ol (1.50 g, 6.2 mmol) in dichloromethane (15 mL) was treated with paraformaldehyde (279 mg, 3.1 mmol) at room temperature for 2 hours, and then TMSCl (12 mL, 92.8 mmol) was added dropwise at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0265] Preparation of 1-(2-methoxypyridine-3-yl)piperidine-4-one [ka] A solution of 1-(2-methoxypyridine-3-yl)piperidine-4-ol (7.30 g, 35.1 mmol) and DMP reagent (22.30 g, 52.57 mmol) in dichloromethane (70 mL) was stirred at 0°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to obtain the desired product.

[0266] Preparation of (2S,3S)-2-amino-3-(benzyloxy)butan-1-ol [ka] 750 mg, 2.5 mmol of tert-butyl-((2S,3S)-3-(benzyloxy)-1-hydroxybutan-2-yl)carbamate was dissolved in 13 mL of dichloromethane, and then 13 mL of TFA was added. This mixture was stirred at room temperature for 90 minutes. The mixture was directly concentrated, co-evaporated with MeOH, and then dried under high vacuum to obtain the desired product.

[0267] Preparation of 1-(benzyloxy)-2-vinylbenzene [ka] Potassium trifluoro(vinyl)borate (10.0 g, 77.0 mmol), PdCl2 (dppf) (4.20 g, 5.7 mmol), and anhydrous DMA (160 mL) were added to a dry flask. Then, 1-(benzyloxy)-2-bromobenzene (15.0 g, 57.0 mmol) and triethylamine (24.0 mL, 0.17 mol) were added. The mixture was degassed by spraying with argon. The mixture was stirred at 130°C for 3 hours. The mixture was cooled to room temperature, then diluted with saturated NH4Cl (100 mL), and extracted with ethyl acetate (3 x 100 mL). The phases were separated, the combined organic matter was washed with water (3 x 50 mL) and brine (50 mL), dried on anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove residual DMA. The resulting residue was purified by silica gel chromatography (ethyl acetate / heptane) to obtain the desired product.

[0268] Preparation of 3-(2-(benzyloxy)phenyl)-2,2-dichlorocyclobutan-1-one [ka] A solution of trichloroacetyl chloride (15.00 g, 9.3 mL, 83.0 mmol) and phosphorus oxychloride (6.7 mL, 72.00 mmol) in anhydrous diethyl ether (35 mL) was added dropwise to a solution of 1-(benzyloxy)-2-vinylbenzene (8.70 g, 41.0 mmol) and Zn-Cu couple (prepared separately) (5.88 g) in anhydrous diethyl ether (75 mL) under argon. The reaction mixture was stirred at 40°C for 1 hour, then at room temperature overnight. The resulting mixture was filtered over Celite while washing with diethyl ether (50 mL). The filtrate was quenched by carefully adding saturated NaHCO3. The organic matter was separated, diluted with diethyl ether, and washed sequentially with water (2 x 50 mL), saturated NaHCO3 (2 x 50 mL), and brine (50 mL), then dried over MgSO4. The organic matter was filtered and concentrated under vacuum to obtain the desired product, which was used without further purification.

[0269] Preparation of Zn-Cu couple: In a round-bottom flask, a solution of copper(II) sulfate pentahydrate (0.76 g, 3.0 mmol) in milliQ water (5 mL) was added in four portions over 60 seconds to a dispersion of zinc (dust) (6.50 g, 99.0 mmol) in milliQ water (10 mL) while stirring. After 5 minutes, the mixture had turned dark. This was filtered, and the solid was washed with milliQ water (2 x 5 mL), acetone (2 x 5 mL), and diethyl ether (5 mL). The resulting dark powder was dried under vacuum at 100°C for 48 hours, then stored under argon, and used without further purification.

[0270] Preparation of 3-(2-(benzyloxy)phenyl)cyclobutan-1-one [ka] 3-(2-(benzyloxy)phenyl)-2,2-dichlorocyclobutan-1-one (7.00 g, 22.0 mmol) and zinc (dust) (4.30 g, 65.0 mmol) were dispersed in glacial acetic acid (150 mL), lightly sonicated, and placed under argon. The mixture was stirred under reflux for 30 minutes. The resulting mixture was filtered and concentrated to a total volume of approximately 15 mL. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 × 75 mL). The organic phase was sequentially washed with saturated NaHCO3 (4 × 50 mL) and brine (30 mL). The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (ethyl acetate / heptane) to obtain the desired product.

[0271] Preparation of (1S,3S)-3-(2-(benzyloxy)phenyl)cyclobutan-1-ol [ka] In a dry round-bottom flask, L-selectlide (1M in THF) (27.0 mL, 27.0 mmol) was added dropwise to a stirring solution of 3-(2-(benzyloxy)phenyl)cyclobutan-1-one (4000 mg, 15.9 mmol) in THF (150 mL) at -78°C over 60 minutes using a syringe pump. The reaction mixture was stirred overnight while returning to room temperature. Then, at 0°C, THF (150 mL) and water (50 mL) were added sequentially, followed by a solution of sodium perborate tetrahydrogen (7.32 g, 47.6 mmol) in water (100 mL). The reaction mixture was stirred at room temperature for 30 minutes. This mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine and dried over MgSO4. The mixture was filtered and concentrated to obtain the residue, which was purified by silica gel chromatography (ethyl acetate / heptane) to obtain the desired product.

[0272] Preparation of methyl 4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1-carboxylate [ka] In a dry round-bottom flask, methyl 4-hydroxycyclohexane-1-carboxylate (10.00 g, 63.2 mmol) and anhydrous dichloromethane (50 mL) were added. The atmosphere was changed to argon, and 3,4-dihydro-2H-pyran (6.1 mL, 66.4 mmol) was added, followed by Dowex C-211 H+ foam (1.00 g, 63.2 mmol). This mixture was stirred at room temperature for 18 hours. Further 3,4-dihydro-2H-pyran (2.3 mL, 25.3 mmol) was added along with a further portion of Dowex C-211 H+ foam (1.00 g, 63.2 mmol). This mixture was stirred at room temperature for 18 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography to obtain the desired product as an approximately 1:2 mixture of isomers. It was used without further purification.

[0273] Preparation of 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene [ka] A mixture of 2-chloro-4-methyl-1-(trifluoromethyl)benzene (10 g, 51 mmol) and NBS (13.7 g, 77.0 mmol) and AIBN (4.22 g, 25.7 mmol) in CHCl3 (200 mL) was stirred overnight at 80°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

[0274] Preparation of methyl 2-(5-bromo-2-fluorophenyl)acetate [ka] To a stirring solution of (5-bromo-2-fluorophenyl)acetic acid (5 g, 21.4 mmol) in MeOH (125 mL), H2SO4 (2 mL, 37.5 mmol) was added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

[0275] Preparation of methyl 2-bromo-2-(5-bromo-2-fluorophenyl)acetate [ka] To a 5g, 20.2 mmol solution of methyl 2-(5-bromo-2-fluorophenyl) acetate in 100 mL of THF, LDA (15.18 mL, 30.3 mmol) was added under an argon atmosphere at -78°C. The resulting mixture was stirred at -78°C for 1 hour. TMSCl (3.30 g, 30.3 mmol) was added dropwise to the above mixture at -78°C. The resulting mixture was stirred for a further 1 hour at -78°C. NBS (5.40 g, 30.3 mmol) was added to the above mixture. The mol of NH4Cl was added dropwise over 5 minutes at -78°C. The resulting mixture was stirred at room temperature for a further 4 hours. The reaction was quenched by adding saturated NH4Cl(aq.)(100 mL) at 0°C. The resulting mixture was extracted with HCl(3 x 100 mL). The combined organic layers were washed with brine(2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

[0276] Preparation of 5-(5-bromo-2-fluorophenyl)-2-methylthiazole-4-ol [ka] To a mixture of methyl 2-bromo-2-(5-bromo-2-fluorophenyl)acetate (500 mg, 1.53 mmol) in dioxane (10 mL) that was being stirred, thioacetamide (575 mg, 7.65 mmol) and TsOH (264 mg, 1.53 mmol) were added in portions at room temperature under an argon atmosphere. The resulting mixture was stirred at 100 °C for 3 hours. The resulting mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the desired product.

[0277] Preparation of 4-(benzyloxy)-5-(5-bromo-2-fluorophenyl)-2-methylthiazole [ka] BnBr (326 mg, 1.90 mmol) was added to a MeCN (10 mL) solution of 5-(5-bromo-2-fluorophenyl)-2-methyl-1,3-thiazole-4-ol (500 mg, 1.73 mmol) and K2CO3 (719.49 mg, 5.20 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 50°C for 1.5 hours. The reaction was quenched with water / ice at 0°C. The resulting mixture was extracted with Â1 (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product.

[0278] Preparation of (3-(4-(benzyloxy)-2-methylthiazole-5-yl)-4-fluorophenyl)methanol [ka] Pd(PPh3)4 (61.1 mg, 0.05 mmol) was added in part to a mixture of 4-(benzyloxy)-5-(5-bromo-2-fluorophenyl)-2-methyl-1,3-thiazole (200 mg, 0.52 mmol) and (tributylstannyl)methanol (339 mg, 1.05 mmol) in toluene (8 mL) under a stirring atmosphere at room temperature. The resulting mixture was stirred at 80 °C for 12 hours. The reaction was quenched with saturated KF (aq.) at room temperature. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (2 x 10 mL). The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried on anhydrous sodium 2 SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

[0279] Preparation of 4-(benzyloxy)-5-(5-(bromomethyl)-2-fluorophenyl)-2-methylthiazole [ka] To a 20 mL solution of {3-[4-(benzyloxy)-2-methyl-1,3-thiazole-5-yl]-4-fluorophenyl}methanol (570 mg, 1.73 mmol) and PPh3 (680 mg, 2.59 mmol) in DCM, CBr4 (860 mg, 2.59 mmol) was added in installments at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

[0280] Preparation of (3-bromo-4-(difluoromethyl)phenyl)methanol. [ka] A solution of 3-bromo-4-(difluoromethyl)benzoic acid (2 g, 7.967 mmol) in THF (40 mL) was treated with BH3.DMS (7.37 mL, 79.670 mmol) under a nitrogen atmosphere at 0°C for 10 minutes. The resulting mixture was stirred overnight at room temperature under an argon atmosphere. The reaction product was quenched with MeOH (20 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 100% gradient over 30 minutes; detector, UV 254 nm, to obtain the desired product.

[0281] Preparation of 2-bromo-4-(bromomethyl)-1-(difluoromethyl)benzene. [ka] A solution of (3-bromo-4-(difluoromethyl)phenyl)methanol (1.8 g, 7.594 mmol) and PPh3 (2.39 g, 9.113 mmol) in DCM (20 mL) was treated with CBr4 (3.02 g, 9.113 mmol) under a nitrogen atmosphere at 0°C for 5 minutes. The resulting mixture was stirred under an argon atmosphere at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 100% gradient over 30 minutes; detector, UV 254 nm, to obtain the desired product.

[0282] Preparation of racemic ethyl (1R,2S,4S)-4-azido-2-methylcyclopentane-1-carboxylate [ka] DIAD (1.44 mL, 1.25 equivalents, 7.40 mmol) was added dropwise at 0°C to racemic ethyl (1R,2S,4R)-4-hydroxy-2-methylcyclopentane-1-carboxylate (1.02 g, 5.92 mmol) (synthesized as described in U.S. Patent No. 20180044344A1), diphenylphosphoradidate (1.66 mL, 7.40 mmol), and triphenylphosphine (1.71 g, 6.51 mmol) in THF (59.2 mL). The reaction mixture was warmed to room temperature overnight with stirring. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0283] Preparation of racemic ethyl (1R,2S,4S)-4-amino-2-methylcyclopentane-1-carboxylate and HCl [ka] Racemic ethyl (1R,2S,4S)-4-azido-2-methylcyclopentane-1-carboxylate (0.93 g, 4.7 mmol) was dissolved in EtOH (28 mL). HCl (2.0 mL, 12 mol) and 10% Pd-C (50 mg) were added, and the mixture was hydrogenated overnight (at 1 atm). The reaction mixture was filtered and concentrated under vacuum. The crude product was washed with Et2O to remove diisopropylethylaminehydrazine-1,2-dicarboxylate. The residual solid was dried under vacuum to obtain the desired product.

[0284] Preparation of racemic ethyl (1R,2S,4S)-4-((diphenylmethylene)amino)-2-methylcyclopentane-1-carboxylate [ka] In a 10 mL microwave vial, diphenylmethanymine (0.43 mL, 2.6 mmol) was dissolved in toluene (2.5 mL), and then racemic ethyl (1R,2S,4S)-4-amino-2-methylcyclopentane-1-carboxylate hydrochloride (0.53 g, 2.6 mmol) was added in installments under argon. The reaction mixture was heated under reflux for 1 hour. The reaction mixture was cooled in an ice bath and then filtered on a Celite plug. The filter cake was rinsed with toluene. The organic matter was concentrated under vacuum to obtain the desired product.

[0285] Preparation of tert-butyl(1R,4S)-3-oxo-2-azabicyclo[2.2.1]hepta-5-ene-2-carboxylate [ka] Boc2O (44.0 g, 201 mmol) was added in part to a mixture of (1R,4S)-2-azabicyclo[2.2.1]hepta-5-en-3-one (20 g, 183 mmol), TEA (55.6 g, 549 mmol), and DMAP (2.24 g, 18.3 mmol) in THF (200 mL) under an argon atmosphere at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (4:1) to obtain the desired product.

[0286] Preparation of tert-butyl(1S,2R,4R,5R)-7-oxo-3-(trimethylsilyl)-6-azatricyclo[3.2.1.02,4]octane-6-carboxylate [ka] To a mixture of tert-butyl(1R,4S)-3-oxo-2-azabicyclo[2.2.1]hepta-5-ene-2-carboxylate (3.85 g, 18.4 mmol) and Pd(OAc)2 (206 mg, 0.92 mmol) in Et2O (135 mL) that was being stirred, trimethylsilyldiazomethane (2 M, 92 mmol in 46 mL hexane) was added dropwise at room temperature over 1 hour under an argon atmosphere. The resulting mixture was stirred at room temperature under an argon atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / siRNA = 4 / 1 elution to obtain the desired product.

[0287] Preparation of methyl(1R,2S,4R,5R)-4-amino-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylate hydrochloride [ka] HCl (3.5 mL, 41.4 mmol) was added dropwise to a stirred solution of tert-butyl(1S,2R,4R,5R)-7-oxo-3-(trimethylsilyl)-6-azatricyclo[3.2.1.02,4]octane-6-carboxylate (4.9 g, 16.5 mmol) in MeOH (50 mL) at room temperature. The resulting mixture was stirred overnight at 55 °C. The resulting mixture was concentrated under reduced pressure and used directly in the next step without further purification.

[0288] Preparation of methyl(1S,2S,4R,5R)-4-aminobicyclo[3.1.0]hexane-2-carboxylate hydrochloride [ka] Triflic acid (9.01 mL, 60.0 mmol) was added dropwise to a 40 mL solution of methyl(1R,2S,4R,5R)-4-amino-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylate hydrochloride (3.9 g, 17.1 mmol) in DCM under an argon atmosphere at room temperature. The resulting mixture was stirred under an argon atmosphere at room temperature for 4 hours. This mixture was basicized to pH 10 with saturated Na₂CO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (5 x 50 mL). The combined organic phases were dried over sodium sulfate and filtered. HCl (7.2 mL, 85.8 mmol) was added to the filtrate, and the filtrate was then concentrated under vacuum to obtain the crude product. This crude product was used directly in the next step without further purification.

[0289] Preparation of methyl(1R,3S)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (General Method-01, INT-1) [ka] To a mixture of methyl(1R,3S)-3-aminocyclopentane-1-carboxylate hydrochloride (200.00 g, 1.11 mol) in toluene (1000 mL), benzophenone imine (202.00 g, 1.11 mol) was added. The mixture was stirred under reflux for 1.5 hours. The reaction mixture was cooled to approximately 5°C, filtered through an Arbocell BC200, and evaporated until completely dry to obtain methyl(1R,3S)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate.

[0290] Methyl(1S,2R,4R,5R)-4-((diphenylmethylene)amino)bicyclo[3.1.0]hexane-2-carboxylate was prepared from methyl(1S,2S,4R,5R)-4-aminobicyclo[3.1.0]hexane-2-carboxylate hydrochloride by the same method.

[0291] Preparation of methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (GM-1 and general method-02, INT-2) [ka] To LDA in THF (390 mL, 1.0 mol, 390 mmol), a solution of methyl (1R,3S)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (100.00 g, 325.0 mmol) in THF (300 mL) was added dropwise over 15 minutes at -78°C. The mixture was stirred at -78°C for 45 minutes. Next, a solution of 2-bromo-4-(bromomethyl)-1-fluorobenzene (109.00 g, 407.0 mmol) in THF (200 mL) was added dropwise over 15 minutes at -78°C. The reaction mixture was stirred at -78°C for 1 hour, and then the flask was placed in an ice bath. A saturated NH4Cl solution (100 mL) and water (100 mL) were slowly added. The mixture was concentrated to remove most of the organic solvent, and the residue was extracted with ethyl acetate. The organic phase was separated, washed with brine, dried on MgSO4, and evaporated until dry to obtain the desired product.

[0292] The above product was dissolved in methanol (600 mL), and concentrated HCl (104 mL, 37% by weight, 976.0 mmol) was added. This mixture was heated at 50°C for 20 hours.

[0293] The mixture was cooled and evaporated until dry. The residue was co-evaporated with toluene until dry. The above product was dissolved in THF (440 mL) and methanesulfonyl chloride (38.0 mL, 488.0 mmol) was added. The mixture was cooled in an ice bath and triethylamine (136 mL, 976.0 mmol) was added dropwise. The reaction mixture was stirred in the ice bath for a further 1 hour.

[0294] Water (200 mL) was added, and the mixture was concentrated to remove most of the THF, which was then extracted twice with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4, and evaporated until dry to obtain the desired product, which was used in the next step without further purification.

[0295] The following intermediates were prepared similarly from suitable amino esters, benzyl bromide, and sulfonyl chlorides: Methyl(1R,3S)-1-((2-bromopyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, Methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-((N,N-dimethylsulfamoyl)amino)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-((N-methylsulfamoyl)amino)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(ethylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(3-bromo-4-methylbenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(3-chloro-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(3-chloro-2,6-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(4-bromo-3-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(5-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-[(5-bromo-2-fluorophenyl)methyl]-3-methanesulfonamidecyclopentane-1-carboxylate, Methyl(1S,3S)-1-((4-bromopyridine-2-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, Methyl(1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(ethylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(3-bromo-4-(difluoromethyl)benzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, Methyl(1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(cyclopropanesulfonamide)cyclopentane-1-carboxylate, Methyl(1S,2R,4R,5R)-2-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamide)bicyclo[3.1.0]hexane-2-carboxylate

[0296] Preparation of (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylic acid (General Method-03 and General Method-47) [ka] A mixture of methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (6.64 g, 16.3 mmol) in methanol (80 mL) and water (20 mL) was mixed with sodium hydroxide (2.60 g, 6.02 mL, 10.8 mol, 65.1 mmol) in water. This mixture was heated overnight at 60°C. The reaction mixture was cooled, diluted with water (40 mL), and concentrated to remove most of the MeOH. This mixture was washed with TBME (3 x 50 mL) and the pH was adjusted to approximately 1 with concentrated HCl. This yielded an emulsion, which was extracted twice with TBME. The combined organic phases were dried over MgSO4, filtered, and evaporated until dry to obtain the desired product.

[0297] Preparation of (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide (General Method-03, INT-3 and General Method-47, INT-9) [ka] Ammonium bicarbonate (8.66 g, 110.0 mmol) was added to (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylic acid (2.88 g, 7.30 mmol), DIPEA (12.7 mL, 73.0 mmol), HATU (6.94 g, 18.3 mmol), and HOAt (1 M in DMA) (730 μL, 1 mol, 730 μmol) in dichloromethane (94 mL) and DMF (6 mL). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated, redissolved in ethyl acetate, and washed with saturated NH4Cl, then saturated NaHCO3, and brine. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0298] The following intermediates were prepared by the same method: Prepared from (1R,3S)-1-(3-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1R,3S)-1-(5-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-(3-chloro-2,6-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1R,3S)-1-(3-chloro-2,6-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-(4-bromo-3-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1R,3S)-1-(4-bromo-3-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-(4-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-(5-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1R,3S)-1-(5-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-[(5-bromo-2,4-difluorophenyl)methyl]-3-methanesulfonamidecyclopentane-1-carboxamide and methyl(1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. (1R,3S)-1-(3-bromo-4-chlorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide, prepared from methyl(1R,3S)-1-(3-bromo-4-chlorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(cyclopropanesulfonamide)cyclopentane-1-carboxamide, prepared from methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(cyclopropanesulfonamide)cyclopentane-1-carboxylate, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(ethylsulfonamide)cyclopentane-1-carboxamide, prepared from methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(ethylsulfonamide)cyclopentane-1-carboxylate, (1R,3S)-1-(3-chloro-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide, prepared from methyl(1R,3S)-1-(3-chloro-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, (1R,3S)-1-(3-chloro-4-(trifluoromethyl)benzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide, prepared from methyl(1R,3S)-1-(3-chloro-4-(trifluoromethyl)benzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, (1R,3S)-1-(5-bromo-2-chloro-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide, prepared from methyl(1R,3S)-1-(5-bromo-2-chloro-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate, rac-(1R,2S,4S)-1-(3-bromo-4-fluorobenzyl)-2-methyl-4-(methylsulfonamide)cyclopentane-1-carboxamide, prepared from rac-ethyl(1R,2S,4S)-1-(3-bromo-4-fluorobenzyl)-2-methyl-4-(methylsulfonamide)cyclopentane-1-carboxamide, (1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(ethylsulfonamide)cyclopentane-1-carboxamide prepared from methyl(1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(ethylsulfonamide)cyclopentane-1-carboxylate Prepared from (1R,3S)-1-(3-bromo-4-(difluoromethyl)benzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1R,3S)-1-(3-bromo-4-(difluoromethyl)benzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1S,3S)-1-(((4-(2-(benzyloxy)-3-fluorophenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1S,3S)-1-(((4-(2-(benzyloxy)-3-fluorophenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(cyclopropanesulfonamide)cyclopentane-1-carboxamide and methyl(1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(cyclopropanesulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-((2-bromo-5-fluoropyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1R,3S)-1-((2-bromo-5-fluoropyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1S,3S)-1-((4-bromo-5-fluoropyridine-2-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1S,3S)-1-((4-bromo-5-fluoropyridine-2-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1R,3S)-1-(3-(4-(benzyloxy)-2-methylthiazole-5-yl)-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, methyl(1R,3S)-1-(3-(4-(benzyloxy)-2-methylthiazole-5-yl)-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, and (1r,3s)-1-[(3-bromo-4-fluorophenyl)methyl]-3-methanesulfonamidecyclobutan-1-carboxylic acid. Prepared from (1r,4r)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide and methyl(1r,4r)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)cyclohexane-1-carboxylate Prepared from (1S,2R,4R,5R)-2-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamide)bicyclo[3.1.0]hexane-2-carboxamide and methyl(1S,2R,4R,5R)-2-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamide)bicyclo[3.1.0]hexane-2-carboxylate.

[0299] The following intermediate (INT-4) was also prepared by the same method: Prepared from (1R,3S)-1-((2-(2-(benzyloxy)-3-fluorophenyl)pyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1R,3S)-1-((2-(2-(benzyloxy)-3-fluorophenyl)pyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1R,3S)-1-((2'-(benzyloxy)-2,6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1R,3S)-1-((2'-(benzyloxy)-2,6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N,N-dimethylsulfamoyl)amino)cyclopentan-1-carboxamide and methyl(1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N,N-dimethylsulfamoyl)amino)cyclopentan-1-carboxylate. Prepared from (1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N-methylsulfamoyl)amino)cyclopentan-1-carboxamide and methyl(1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N-methylsulfamoyl)amino)cyclopentan-1-carboxylate. Prepared from (1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide and methyl(1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1S,3S)-1-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1S,3S)-1-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1S,3S)-1-((((1s,4R)-4-(2-methoxypyridine-3-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1S,3S)-1-((((1s,4R)-4-(2-methoxypyridine-3-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1S,3S)-1-((((1s,4R)-4-(6-methoxypyridine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1S,3S)-1-((((1s,4R)-4-(6-methoxypyridine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1S,3S)-1-(((cis-4-(3-methoxypyridine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1S,3S)-1-(((cis-4-(3-methoxypyridine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1S,3S)-1-(((cis-4-(4-methoxypyrimidine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1S,3S)-1-(hydroxymethyl)-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentan-1-carboxylate. Prepared from (1S,3S)-1-((3-(benzyloxy)phenethoxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1S,3S)-1-((3-(benzyloxy)phenethoxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate. Prepared from (1R,3S)-1-((2'-(benzyloxy)-6-chloro-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1R,3S)-1-((2'-(benzyloxy)-6-chloro-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',4,6'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and methyl(1R,3S)-1-((2'-(benzyloxy)-3',4,6'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide and methyl (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxylate. Prepared from (1S,3S)-1-(((1s,3R)-3-(2-(benzyloxy)phenyl)cyclobutoxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and methyl(1S,3S)-1-(((1s,3R)-3-(2-(benzyloxy)phenyl)cyclobutoxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate.

[0300] Preparation of ethyl 4-hydroxytetrahydrofuran-2-carboxylate [ka] Under argon conditions, ethyl 4-oxotetrahydrofuran-2-carboxylate (20.0 g, 126.5 mmol) was placed in a round-bottom flask, to which THF (350 mL) and water (35.0 mL) were added, and the reaction mixture was cooled to -20°C. Then, sodium borohydride (4.78 g, 126.5 mmol) was added to the reaction mixture in installments, and after 20 minutes, water (150 mL), brine (10 mL), and ethyl 4-hydroxytetrahydrofuran-2-carboxylate were added. The aqueous phase was extracted three times with ethyl 4-hydroxytetrahydrofuran-2-carboxylate, and the combined organic matter was dried over sodium sulfate and concentrated to obtain ethyl 4-hydroxytetrahydrofuran-2-carboxylate.

[0301] Preparation of methyl 3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutan-1-carboxylate [ka] A mixture of methyl 3-hydroxycyclobutane-1-carboxylate (30 g, 231 mmol), dihydropyran (23.27 g, 277 mmol), and TsOH (7.94 g, 46.1 mmol) in DCM (300 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

[0302] The following intermediates were also prepared by the same method: Prepared from ethyl 4-((tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuran-2-carboxylate and ethyl 4-hydroxytetrahydrofuran-2-carboxylate. Prepared from methyl 4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1-carboxylate and 4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1-carboxylic acid.

[0303] Preparation of methyl(1s,4s)-1-(3-bromobenzyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1-carboxylate (General Method-05) [ka] To a stirring solution of methyl 4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1-carboxylate (6.00 g, 24.8 mmol) in anhydrous THF (230 mL), a THF / hexane solution of LDA (0.9 M, 44.0 mL, 39.6 mmol) was added over 5 minutes at -78°C under an argon atmosphere. The solution was stirred at -78°C for 1 hour. At this point, a solution of 1-bromo-3-(bromomethyl)benzene (9.90 g, 39.6 mmol) in anhydrous THF (15 mL) was added by a syringe pump over 60 minutes. At the end of the addition, the solution was stirred for a further 1 hour at -78°C. This mixture was quenched by adding saturated NH4Cl (150 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic matter was dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography to obtain the desired product as a single isomer.

[0304] Preparation of methyl(1s,4s)-1-(3-bromobenzyl)-4-hydroxycyclohexane-1-carboxylate (General Method-05) [ka] Methyl 1-(3-bromobenzyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1-carboxylate (7.985 g, 17.5 mmol) was dissolved in methanol (120 mL), and TFA (1.5 mL, 19.22 mmol) was added. The mixture was stirred at room temperature until complete. The mixture was then concentrated, and the resulting residue was purified by silica gel chromatography to obtain the desired product as a single isomer.

[0305] Preparation of methyl(1r,4r)-1-(3-bromobenzyl)-4-(N-(tert-butoxycarbonyl)methylsulfonamide)cyclohexane-1-carboxylate (General Method-05) [ka] In a dry round-bottom flask under argon, DIAD (2.9 mL, 15.0 mmol) was added to triphenylphosphine (3.94 g, 15.0 mmol) in anhydrous THF (150 mL). After stirring the mixture for 10 minutes, tert-butyl(methylsulfonyl)carbamate (2.62 g, 3.4 mmol) and then methyl(1s,4s)-1-(3-bromobenzyl)-4-hydroxycyclohexane-1-carboxylate (3.90 g, 10.7 mmol) in anhydrous THF (10 mL) were added. The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine, dried over MgSO4, and the organic matter was concentrated under vacuum. The desired product was obtained by purification by silica gel chromatography.

[0306] Preparation of methyl(1r,4r)-1-(3-bromobenzyl)-4-(methylsulfonamide)cyclohexane-1-carboxylate (General Method-05, INT-2) [ka] Methyl(1r,4r)-1-(3-bromobenzyl)-4-(N-(tert-butoxycarbonyl)methylsulfonamide)cyclohexane-1-carboxylate (955 mg, 1.89 mmol) was mixed with HCl (4 M in dioxane) (15 mL, 60 mmol) under argon. The mixture was stirred at 85°C for 30 minutes, then cooled under stirring for 2 hours. The mixture was concentrated until dry to obtain the desired product, which was used without further purification.

[0307] Ethyl 2-(5-chloro-2,4-difluorobenzyl)-4-(methylsulfonamide)tetrahydrofuran-2-carboxylate was prepared from 1-(bromomethyl)-5-chloro-2,4-difluorobenzene and ethyl 4-((tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuran-2-carboxylate using the same method.

[0308] Preparation of (1r,4r)-1-(3-bromobenzyl)-4-(methylsulfonamide)cyclohexane-1-carboxylic acid (General Method-05) [ka] Methyl(1r,4r)-1-(3-bromobenzyl)-4-(methylsulfonamide)cyclohexane-1-carboxylate (730 mg, 1.8 mmol) and sodium methanethiolate (506 mg, 7.2 mmol) were added to a dry microwave vial. The atmosphere was changed to argon, and anhydrous DMF (15 mL) was added. The vial was sealed with a crimp cap, and the reaction mixture was heated at 110°C for 60 minutes by microwave irradiation using a Biotage Initiator instrument. 2N HCl (3 mL) was added to this mixture, and it was extracted with ethyl acetate. The organic matter was dried on magnesium sulfate and concentrated under vacuum. This yielded the desired product with sufficient purity, which was used without further purification.

[0309] Preparation of (1r,4r)-1-(3-bromobenzyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide (General Method-05, INT-3) [ka] Equipped with a stirring bar, a flask containing (1r,4r)-1-(3-bromobenzyl)-4-(methylsulfonamide)cyclohexane-1-carboxylic acid (672 mg, 1.7 mmol) in dichloromethane (40 mL) and anhydrous DMF (1 mL) was placed under argon conditions. Ammonium bicarbonate (681 mg, 8.6 mmol) and DIPEA (900 μL, 5.2 mmol) were added. Then, HATU (1.11 g, 2.9 mmol) was added under stirring. The mixture was stirred at room temperature for 2 hours. The mixture was washed with 0.5 N HCl (4 x 15 mL) and water (2 x 10 mL). The organic matter was collected, washed with brine (10 mL), and dried on sodium sulfate. The mixture was filtered and concentrated to obtain the residue, which was purified by silica gel chromatography to obtain the desired product with sufficient purity.

[0310] The following intermediates were prepared by the same method: Prepared from (1r,4r)-1-[(5-bromo-2,4-difluorophenyl)methyl]-4-methanesulfonamide cyclohexane-1-carboxamide, 1-bromo-5-(bromomethyl)-2,4-difluorobenzene, and methyl 4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1-carboxylate. Prepared from (1r,4r)-1-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide, 2-bromo-4-(bromomethyl)-1-fluorobenzene, and methyl 4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-1-carboxylate.

[0311] Preparation of (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (General Method-04, INT-4) [ka] In a 1000 mL three-necked flask, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide (10.34 g, 26.3 mmol) was dissolved in 1,4-dioxane (237 mL) and water (26 mL). (2-(benzyloxy)-3-fluorophenyl)boronic acid (10.35 g, 42.1 mmol) and K2CO3 (9.99 g, 72.3 mmol) were added, and nitrogen was sprayed over the solution for 5 minutes. Pd(dppf)Cl2 (1.92 g, 2.63 mmol) was added, and argon was sprayed over the solution for 5 minutes. The reaction mixture was heated at 95 °C for 90 minutes. The mixture was cooled, and water (50 mL) and ethyl acetate (200 mL) were added. The phases were separated, and the organic phase was washed with saturated NaHCO3 (50 mL) and brine (50 mL). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel using a CombiFlash Rf instrument (ethyl acetate / heptane) to obtain the desired product.

[0312] The following intermediates were prepared by the same method: Prepared from (1R,3S)-1-((2'-(benzyloxy)-4-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(5-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 2-(2-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from (1R,3S)-1-((2-fluoro-2'-methoxy-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 2-(2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from (1R,3S)-1-(2-fluoro-3-(2-methoxypyridine-3-yl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-methoxypyridine-3-yl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3'-chloro-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-chlorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-4',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-4-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-{[2'-(benzyloxy)-3',4',6-trifluoro-[1,1'-biphenyl]-3-yl]methyl}-3-methanesulfonamidecyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3,4-difluorophenyl)boronic acid. Prepared from (1R,3S)-1-{[2'-(benzyloxy)-6-fluoro-3'-methyl-[1,1'-biphenyl]-3-yl]methyl}-3-methanesulfonamidecyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 2-(benzyloxy)-3-methylphenylboronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)phenyl)boronic acid. Prepared from (1R,3S)-1-((3'-(benzyloxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 2-(3-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from (1R,3S)-1-(3-(2-methoxypyridine-3-yl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. Prepared from (1R,3S)-1-(3-(6-methoxypyridine-2-yl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. Prepared from (1R,3S)-1-((2'-(benzyloxy)-2,4-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-chloro-2,6-difluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 2-(2-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from (1R,3S)-1-((2'-(benzyloxy)-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(4-bromo-3-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)phenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(4-bromobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',4,4'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(5-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3,4-difluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',4-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(5-bromo-2-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-{[2'-(benzyloxy)-3'-fluoro-6-methyl-[1,1'-biphenyl]-3-yl]methyl}-3-methanesulfonamidecyclopentan-1-carboxamide, (1R,3S)-1-[(3-bromo-4-methylphenyl)methyl]-3-methanesulfonamidecyclopentan-1-carboxamide and 2-(benzyloxy)-3-fluorophenylboronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-4,6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-[(5-bromo-2,4-difluorophenyl)methyl]-3-methanesulfonamidecyclopentan-1-carboxamide and 2-(benzyloxy)phenylboronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3'-chloro-4-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-[(5-bromo-2-fluorophenyl)methyl]-3-methanesulfonamidecyclopentan-1-carboxylic acid and 2-(benzyloxy)-3-chlorophenylboronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-6-chloro-3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-chlorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3,4-difluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-6-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-chlorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3,5-difluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(cyclopropanesulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(cyclopropanesulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',4',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(cyclopropanesulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(cyclopropanesulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3,4-difluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',4',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3,4-difluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-2,3',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-chloro-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3'-fluoro-6-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-chloro-4-(trifluoromethyl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-6-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-chloro-4-(trifluoromethyl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)phenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',4,5',6-tetrafluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3,5-difluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-4-chloro-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(5-bromo-2-chloro-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from rac-(1R,2S,4S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-2-methyl-4-(methylsulfonamide)cyclopentan-1-carboxamide, rac-(1R,2S,4S)-1-(3-bromo-4-fluorobenzyl)-2-methyl-4-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from rac-(1R,2S,4S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-2-methyl-4-(methylsulfonamide)cyclopentan-1-carboxamide, rac-(1R,2S,4S)-1-(3-bromo-4-fluorobenzyl)-2-methyl-4-(methylsulfonamide)cyclopentan-1-carboxamide and 2-(2-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from (1r,4r)-1-((2'-(benzyloxy)-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide, (1r,4r)-1-(3-bromobenzyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-((2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1R,3S)-1-(3-(3-(benzyloxy)-1-methyl-1H-pyrazole-4-yl)-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 3-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Prepared from (1R,3S)-1-(5-(3-(benzyloxy)-1-methyl-1H-pyrazole-4-yl)-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 3-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Prepared from (1R,3S)-1-((2'-(benzyloxy)-6-(difluoromethyl)-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-(3-bromo-4-(difluoromethyl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 2-(benzyloxy)-3-fluorophenylboronic acid. Prepared from (1R,3S)-1-{[2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl]methyl}-3-cyclopropanesulfonamide cyclopentan-1-carboxamide, (1R,3S)-1-(5-bromo-2,4-difluorobenzyl)-3-(cyclopropanesulfonamide)cyclopentan-1-carboxamide and 2-(benzyloxy)-3-fluorophenylboronic acid. Prepared from (1R,3S)-1-((2-(2-(benzyloxy)-3-fluorophenyl)-5-fluoropyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide, (1R,3S)-1-((2-bromo-5-fluoropyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1S,3S)-1-({4-[2-(benzyloxy)-3-fluorophenyl]-5-fluoropyridine-2-yl}methyl)-3-methanesulfonamidecyclopentan-1-carboxamide, (1S,3S)-1-((4-bromo-5-fluoropyridine-2-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1r,4r)-1-{[2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl]methyl}-4-methanesulfonamidecyclohexane-1-carboxamide, (1r,4r)-1-[(5-bromo-2,4-difluorophenyl)methyl]-4-methanesulfonamidecyclohexane-1-carboxamide, and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1r,4r)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide, (1r,4r)-1-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1r,3s)-1-{[2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl]methyl}-3-methanesulfonamidecyclobutan-1-carboxamide, (1r,3s)-1-[(3-bromo-4-fluorophenyl)methyl]-3-methanesulfonamidecyclobutan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from (1S,2R,4R,5R)-2-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)bicyclo[3.1.0]hexane-2-carboxamide, (1S,2R,4R,5R)-2-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamide)bicyclo[3.1.0]hexane-2-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid.

[0313] Preparation of N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide (General Method-06, INT-5) [ka] 1,3-Dichloropropan-2-one (19.60 g, 154.0 mmol) was added to (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (7.94 g, 15.4 mmol). This mixture was heated at 140°C for 1 hour. Then, another portion of 1,3-Dichloropropan-2-one (19.6 g, 154.0 mmol) was added, and this mixture was heated at 140°C for a further 0.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (12 mL), and purified by flash chromatography on silica gel using a CombiFlash Rf instrument with heptane / EA, after being passed directly to a column, to obtain the desired product.

[0314] The following intermediates were prepared by the same method: Prepared from 4-chloromethyl-2-((1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N,N-dimethylsulfamoyl)amino)cyclopentan-n-1-yl)-oxazole, (1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N,N-dimethylsulfamoyl)amino)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from 4-chloromethyl-2-((1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N-methylsulfamoyl)amino)cyclopentan-n-1-yl)-oxazole, (1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N-methylsulfamoyl)amino)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2-(2-(benzyloxy)-3-fluorophenyl)pyridine-4-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2-(2-(benzyloxy)-3-fluorophenyl)pyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-2,4-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-2,4-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-2,6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-2,6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',4,4'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',4,4'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',4',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-{[2'-(benzyloxy)-3',4',6-trifluoro-[1,1'-biphenyl]-3-yl]methyl}3-methanesulfonamide, cyclopentan-1-carboxamide, and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',4-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',4-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)thiazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3'-chloro-4-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3'-chloro-4-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3'-chloro-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3'-chloro-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3'-fluoro-6-methyl-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-{[2'-(benzyloxy)-3'-fluoro-6-methyl-[1,1'-biphenyl]-3-yl]methyl}3-methanesulfonamide, cyclopentan-1-carboxamide, and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-4,6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2-fluoro-2'-methoxy-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-4-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-4-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)ethanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-2-fluoro-[1,1'-biphenyl]-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-6-fluoro-3'-methyl-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-{[2'-(benzyloxy)-6-fluoro-3'-methyl-[1,1'-biphenyl]-3-yl]methyl}3-methanesulfonamide, cyclopentan-1-carboxamide, and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((3'-(benzyloxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((3'-(benzyloxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-(4-(chloromethyl)oxazole-2-yl)-3-(2-fluoro-3-(2-methoxypyridine-3-yl)benzyl)cyclopentyl)methanesulfonamide, (1R,3S)-1-(2-fluoro-3-(2-methoxypyridine-3-yl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-(4-(chloromethyl)oxazol-2-yl)-3-(3-(6-methoxypyridine-2-yl)benzyl)cyclopentyl)methanesulfonamide, (1R,3S)-1-(3-(6-methoxypyridine-2-yl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3S)-3-((3-(3-(benzyloxy)phenyl)propoxy)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1S,3S)-1-((3-(3-(benzyloxy)phenyl)propoxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3S)-3-((3-(benzyloxy)phenethoxy)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1S,3S)-1-((3-(benzyloxy)phenethoxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3S)-3-((4-(2-(benzyloxy)phenyl)pyridine-2-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1S,3S)-1-((4-(2-(benzyloxy)phenyl)pyridine-2-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3S)-3-(4-(chloromethyl)oxazole-2-yl)-3-((((1s,4R)-4-(2-methoxypyridine-3-yl)cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide, (1S,3S)-1-((((1s,4R)-4-(2-methoxypyridine-3-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3S)-3-(4-(chloromethyl)oxazole-2-yl)-3-((((1s,4R)-4-(3-hydroxyphenyl)cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide, (1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3S)-3-(4-(chloromethyl)oxazole-2-yl)-3-((((1s,4R)-4-(6-hydroxypyridine-2-yl)cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide, (1S,3S)-1-((((1s,4R)-4-(6-methoxypyridine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3S)-3-(4-(chloromethyl)oxazole-2-yl)-3-(((cis-4-(3-methoxypyridine-2-yl)cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide, (1S,3S)-1-(((cis-4-(3-methoxypyridine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-[(1S,3R)-3-{[2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl]methyl}-3-[4-(chloromethyl)-1,3-oxazole-2-yl]cyclopentyl]methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-[(1S,3R)-3-{[2'-(benzyloxy)-4'-fluoro-[1,1'-biphenyl]-3-yl]methyl}-3-[4-(chloromethyl)-1,3-oxazole-2-yl]cyclopentyl]methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-4',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-2,3',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-2,3',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',4,5',6-tetrafluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',4,5',6-tetrafluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',4',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)cyclopropanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',4',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(cyclopropanesulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',4',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)ethanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',4',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',4,6'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',4,6'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)thiazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)cyclopropanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(cyclopropanesulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3'-fluoro-6-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3'-fluoro-6-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-4-chloro-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-4-chloro-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-6-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-6-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-6-chloro-3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-6-chloro-3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-6-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-6-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-6-chloro-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-6-chloro-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from rac-N-((1R,3S,4R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)-4-methylcyclopentyl)methanesulfonamide, rac-(1R,2S,4S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-2-methyl-4-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from rac-N-((1R,3S,4R)-3-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)-4-methylcyclopentyl)methanesulfonamide, rac-(1R,2S,4S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-2-methyl-4-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-(4-(chloromethyl)oxazol-2-yl)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)ethanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3S)-3-(((1s,3R)-3-(2-(benzyloxy)phenyl)cyclobutoxy)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1S,3S)-1-(((1s,3R)-3-(2-(benzyloxy)phenyl)cyclobutoxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1r,4r)-4-((2'-(benzyloxy)-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(4-(chloromethyl)oxazole-2-yl)cyclohexyl)methanesulfonamide, (1r,4r)-1-((2'-(benzyloxy)-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-((2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)ethanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-(3-(3-(benzyloxy)-1-methyl-1H-pyrazole-4-yl)-4-fluorobenzyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-(3-(3-(benzyloxy)-1-methyl-1H-pyrazole-4-yl)-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. Prepared from N-((1S,3R)-3-(5-(3-(benzyloxy)-1-methyl-1H-pyrazole-4-yl)-2,4-difluorobenzyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-(5-(3-(benzyloxy)-1-methyl-1H-pyrazole-4-yl)-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 1,3-dichloroacetone. (1S,3S)-1-[[4-(2-benzyloxy-3-fluorophenyl)cyclohexoxy]methyl]-3-(methanesulfonamide)cyclopentanecarboxamide and N-((1S,3S)-3-((((1s,4R)-4-(2-(benzyloxy)-3-fluorophenyl)cyclohexyl)oxy)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide prepared from 1,3-dichloroacetone (1R,3S)-1-(3-(4-(benzyloxy)-2-methylthiazole-5-yl)-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and N-((1S,3R)-3-(3-(4-(benzyloxy)-2-methylthiazole-5-yl)-4-fluorobenzyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide prepared from 1,3-dichloroacetone, (1R,3S)-1-((2'-(benzyloxy)-6-(difluoromethyl)-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and N-((1S,3R)-3-((2'-(benzyloxy)-6-(difluoromethyl)-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide prepared from 1,3-dichloroacetone, (1R,3S)-1-{[2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl]methyl}-3-cyclopropanesulfonamide, prepared from cyclopentan-1-carboxamide and 1,3-dichloroacetone, N-((1S,3R)-3-((2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)cyclopropanesulfonamide, (1R,3S)-1-((2-(2-(benzyloxy)-3-fluorophenyl)-5-fluoropyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and N-[(1S,3R)-3-[4-(chloromethyl)-1,3-oxazole-2-yl]-3-{[5-fluoro-2-(3-fluoro-2-hydroxyphenyl)pyridine-4-yl]methyl}cyclopentyl]methanesulfonamide prepared from 1,3-dichloroacetone, (1S,3S)-1-({4-[2-(benzyloxy)-3-fluorophenyl]-5-fluoropyridine-2-yl}methyl)-3-methanesulfonamide, N-[(1S,3S)-3-({4-[2-(benzyloxy)-3-fluorophenyl]-5-fluoropyridine-2-yl}methyl)-3-[4-(chloromethyl)-1,3-oxazole-2-yl]cyclopentyl]methanesulfonamide prepared from cyclopentan-1-carboxamide and 1,3-dichloroacetone, Prepared from N-((1r,4r)-4-((2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(4-(chloromethyl)oxazole-2-yl)cyclohexyl)methanesulfonamide, (1r,4r)-1-{[2'-(benzyloxy)-3',4,6-trifluoro-[1,1'-biphenyl]-3-yl]methyl}4-methanesulfonamide, cyclohexane-1-carboxamide, and 1,3-dichloroacetone. Prepared from N-((1r,4r)-4-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(4-(chloromethyl)oxazole-2-yl)cyclohexyl)methanesulfonamide, (1r,4r)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide and 1,3-dichloroacetone. Prepared from N-[(1s,3r)-3-{[2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl]methyl}-3-[4-(chloromethyl)-1,3-oxazole-2-yl]cyclobutyl]methanesulfonamide, (1r,3s)-1-{[2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl]methyl}-3-methanesulfonamidecyclobutan-1-carboxamide and 1,3-dichloroacetone. Prepared from (N-((1R,2R,4R,5S)-4-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(4-(chloromethyl)oxazol-2-yl)bicyclo[3.1.0]hexane-2-yl)methanesulfonamide, (1S,2R,4R,5R)-2-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)bicyclo[3.1.0]hexane-2-carboxamide and 1,3-dichloroacetone.

[0315] Preparation of (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carbothioamide (General Method-07) [ka] (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (1.44 g, 2.5 mmol) was dissolved in anhydrous THF (76 mL) under argon. Lawesson's reagent (604 mg, 1.5 mmol) was added to this solution, and the mixture was stirred at room temperature for 2.5 hours. The mixture was concentrated directly, and the resulting slurry was divided between water and ethyl acetate. The organic phase was washed with saturated NH4Cl, then with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated.

[0316] The crude substance was purified by silica gel chromatography (heptane / ethyl acetate) to obtain the desired product.

[0317] Preparation of N-((1S,3R)-3-((((1s,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-cyanocyclopentyl)methanesulfonamide (General Method-08) [ka] (1S,3S)-1-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide (368 mg, 0.6 mmol) was dissolved in anhydrous DMF (6 mL) under argon. 2,4,6-trichloro-1,3,5-triazine (58 mg, 316 μmol) was added all at once to this mixture and stirred for 5 hours. A further portion of 2,4,6-trichloro-1,3,5-triazine (58 mg, 316 μmol) was added and the mixture was stirred overnight.

[0318] This mixture was separated into water and ethyl acetate, the organic phase was washed with a 5% aqueous NaHCO3 solution, then brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate / heptane) to obtain the desired product.

[0319] Preparation of (1R,3S,Z)-1-((((1s,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-N'-hydroxy-3-(methylsulfonamide)cyclopentan-1-carboximamide (General Method-08) [ka] N-((1S,3R)-3-((((1s,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-cyanocyclopentyl)methanesulfonamide (248 mg, 509 μmol) was dissolved in ethanol (3 mL) and cooled to 0°C. Hydroxylamine in water (35.0 μL, 50 wt%, 560 μmol) was added to this mixture and stirred overnight under reflux. Volatile substances were removed under vacuum, and the mixture was left to stand under vacuum for 1 hour to obtain the desired product, which was used without further purification.

[0320] Preparation of (1R,3S,Z)-1-((((1s,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-N'-(2-chloroacetoxy)-3-(methylsulfonamide)cyclopentane-1-carboximidoamide (General Method-08) [ka] (1R,3S,Z)-1-((((1s,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-N'-hydroxy-3-(methylsulfonamide)cyclopentane-1-carboximidoamide (262 mg, 509 μmol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to 0°C. 2-chloroacetyl chloride (65 μL, 814 μmol) was added to this mixture, followed by the slow addition of DIPEA (532 μL, 3.1 mmol). The mixture was stirred at room temperature for 1 hour.

[0321] This mixture was separated into two parts: the aqueous phase and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried over Na2SO4, filtered, and concentrated to obtain the desired product, which was used without further purification.

[0322] Preparation of N-((1S,3R)-3-((((1s,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(5-(chloromethyl)-1,2,4-oxadiazole-3-yl)cyclopentyl)methanesulfonamide (General Method-08, INT-5) [ka] (1R,3S,Z)-1-((((1s,4S)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-N'-(2-chloroacetoxy)-3-(methylsulfonamide)cyclopentane-1-carboximidoamide (318 mg, 440 μmol) was dissolved in acetic acid (3 mL) and heated in a microwave reactor at 150°C for 30 minutes.

[0323] This mixture was concentrated, the resulting residue was dissolved in ethyl acetate, washed three times with saturated NaHCO3, then brined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate / heptane) to obtain the desired product.

[0324] Preparation of ethyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentyl)-4-hydroxy-5-methyl-4,5-dihydroxazole-4-carboxylate (General Method-09) [ka] A solution of (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide (700 mg, 1.8 mmol), ethyl 3-bromo-2-oxobutanoate (1.86 g, 8.9 mmol), and NaHCO3 (897 mg, 10.7 mmol) in dioxane (10 mL) was stirred at 90°C for 2 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with THF (3 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0325] Preparation of ethyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentyl)-5-methyloxazole-4-carboxylate (General Method-09, INT-6) [ka] To a 10 mL THF solution of ethyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentyl)-4-hydroxy-5-methyl-4,5-dihydroxazole-4-carboxylate (700 mg, 1.3 mmol), TFAA (1.13 g, 5.4 mmol) was added in installments at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated NaHCO3 (30 mL) at 0°C. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (1 x 10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient over 10 minutes; detector, UV 220 nm. This yielded the desired product.

[0326] The following intermediates were prepared by the same method: Prepared from ethyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentyl)oxazole-4-carboxylate, (1R,3S)-1-(4-bromo-3-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and ethyl 3-bromo-2-oxopropanoate. Prepared from ethyl 2-((1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentyl)-5-methyloxazole-4-carboxylate, (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide and ethyl 3-bromo-2-oxobutanoate. Prepared from ethyl 2-((1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentyl)oxazole-4-carboxylate, (1R,3S)-1-(4-bromo-3-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide, and ethyl 3-bromo-2-oxopropanoate.

[0327] Preparation of ethyl 2-((1S,3S)-1-(((cis-4-(4-methoxypyrimidine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (General Method-09, INT-7') [ka] A mixture of (1S,3S)-1-(((cis-4-(4-methoxypyrimidine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (320 mg, 0.8 mmol) and ethyl 3-bromo-2-oxopropanoate (731 mg, 3.8 mmol) in 1,4-dioxane (2 mL) was stirred overnight at 90°C. The resulting mixture was filtered, and the filter cake was washed with 1,4-dioxane (3 x 4 mL). The filtrate was concentrated under reduced pressure. TFAA (630 mg, 3.0 mmol) was added dropwise to the above mixture at 0°C. The resulting mixture was stirred for a further 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 45% to 65% gradient over 20 minutes; detector, UV 220 nm, to obtain the desired product.

[0328] Preparation of N-((1S,3S)-3-(4-(hydroxymethyl)oxazol-2-yl)-3-(((cis-4-(4-methoxypyrimidine-2-yl)cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide (General Method-09, INT-8') [ka] A mixture of ethyl 2-[(1S,3S)-3-methanesulfonamide-1-({[cis-4-(4-methoxypyrimidine-2-yl)cyclohexyl]oxy}methyl)cyclopentyl]-1,3-oxazole-4-carboxylate (200 mg, 0.4 mmol) and LiAlH4 (29 mg, 0.8 mmol) in THF (4 mL) was stirred at 0°C for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (1 mL). The residue was purified by Prep-TLC (dichloromethane / MeOH = 10:1) to obtain the desired product.

[0329] Preparation of ethyl 2-((1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentyl)-5-methyloxazole-4-carboxylate (General Method-11) [ka] A solution of ethyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentyl)-5-methyloxazole-4-carboxylate (320 mg, 0.6 mmol), 2-(benzyloxy)-3-fluorophenylboronic acid (188 mg, 0.8 mmol), Pd(dppf)Cl2 (47 mg, 0.06 mmol), and Cs2CO3 (621 mg, 1.9 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 80°C for 2 hours under an argon atmosphere. This mixture was cooled to room temperature and diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to obtain the desired product.

[0330] Preparation of N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)-5-methyloxazole-2-yl)cyclopentyl)methanesulfonamide (General Method-11) [ka] To a stirring solution of ethyl 2-((1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentyl)-5-methyloxazole-4-carboxylate (200 mg, 0.3 mmol) in THF (8 mL), LiAlH4 (1 M in THF, 1.3 mL, 1.3 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction was quenched with Na2SO4·10H2O at 0°C. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (dichloromethane / MeOH = 10:1) to obtain the desired product.

[0331] Preparation of N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(chloromethyl)-5-methyloxazole-2-yl)cyclopentyl)methanesulfonamide (General Method-11, INT-5) [ka] SOCl2 (80 mg, 0.7 mmol) was added in part at 0°C to a stirring solution of N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)-5-methyloxazole-2-yl)cyclopentyl)methanesulfonamide (130 mg, 0.2 mmol) in dichloromethane (3 mL). The resulting mixture was stirred at 0°C for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (dichloromethane / MeOH = 10:1) to obtain the desired product.

[0332] The following intermediates were prepared by the same method: Prepared from N-((1S,3R)-3-(4-(chloromethyl)-5-methyloxazol-2-yl)-3-((6-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide, ethyl 2-((1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentyl)-5-methyloxazol-4-carboxylate, and (2-hydroxyphenyl)boronic acid.

[0333] Preparation of ethyl 4-hydroxy-2-((1R,3S)-1-(3-(2-methoxypyridine-3-yl)benzyl)-3-(methylsulfonamide)cyclopentyl)-4,5-dihydroxazole-4-carboxylate (General Method-12) [ka] A solution of (1R,3S)-1-(3-(2-methoxypyridine-3-yl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (280 mg, 0.7 mmol), ethyl 3-bromo-2-oxopropanoate (676 mg, 3.5 mmol), and NaHCO3 (349 mg, 4.2 mmol) in dioxane (5 mL) was stirred overnight at 90 °C. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with THF (3 x 20 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0334] Preparation of ethyl 2-((1R,3S)-1-(3-(2-methoxypyridine-3-yl)benzyl)-3-(methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (General method-12) [ka] To a stirring solution of ethyl 4-hydroxy-2-((1R,3S)-1-(3-(2-methoxypyridine-3-yl)benzyl)-3-(methylsulfonamide)cyclopentyl)-4,5-dihydroxazole-4-carboxylate (280 mg, 0.5 mmol) in THF (5 mL), TFAA (454 mg, 2.2 mmol) was added in installments at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated NaHCO3 (15 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (1 x 5 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to obtain the desired product.

[0335] Preparation of N-((1S,3R)-3-(4-(hydroxymethyl)oxazol-2-yl)-3-(3-(2-methoxypyridine-3-yl)benzyl)cyclopentyl)methanesulfonamide (General Method-12) [ka] To a stirring solution of ethyl 2-((1R,3S)-1-(3-(2-methoxypyridine-3-yl)benzyl)-3-(methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (300 mg, 0.6 mmol) in THF (5 mL), LiAlH4 (1 M in THF, 88 μL, 0.88 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction was quenched with MeOH at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 60% to 80% gradient over 10 minutes; detector, UV 220 nm, to obtain the desired product.

[0336] The following intermediates were prepared by the same method: Prepared from N-((1S,3S)-3-(4-(hydroxymethyl)oxazol-2-yl)-3-((((1s,4R)-4-(4-methoxypyrimidine-2-yl)cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide, (1S,3S)-1-((((1s,4R)-4-(4-methoxypyrimidine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and ethyl 3-bromo-2-oxopropanoate.

[0337] Preparation of ethyl 2-(2-((1R,3S)-1-(3-(6-hydroxypyridine-2-yl)benzyl)-3-(methylsulfonamide)cyclopentyl)oxazole-4-yl)acetate (General Method-13) [ka] A mixture of (1R,3S)-3-methanesulfonamide-1-{[3-(6-methoxypyridine-2-yl)phenyl]methyl}cyclopentan-1-carboxamide (160 mg, 0.4 mmol) and ethyl 4-chloro-3-oxobutanoate (978 mg, 5.9 mmol) in phenoxybenzene (4 mL) was stirred overnight at 120 °C under an argon atmosphere. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 20% to 40% gradient over 15 minutes; detector, UV 200 nm, to obtain the desired product.

[0338] Preparation of N-((1S,3R)-3-(4-(2-hydroxyethyl)oxazol-2-yl)-3-(3-(6-hydroxypyridine-2-yl)benzyl)cyclopentyl)methanesulfonamide (General Method-13, INT-8) [ka] A mixture of ethyl 2-(2-((1R,3S)-1-(3-(6-hydroxypyridine-2-yl)benzyl)-3-(methylsulfonamide)cyclopentyl)oxazole-4-yl) acetate (125 mg, 0.3 mmol) and LiAlH4 (38 mg, 1.0 mmol) in THF (5 mL) was stirred at 0°C for 4 hours. The reaction mixture was quenched at 0°C with Na2SO4.10H2O. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 80% gradient over 20 minutes; detector, UV 254 nm, to obtain the desired product.

[0339] Preparation of N-((1S,3R)-3-(4-(chloromethyl)oxazol-2-yl)-3-(3-(2-methoxypyridine-3-yl)benzyl)cyclopentyl)methanesulfonamide (General Method-14) [ka] To a stirring solution of N-((1S,3R)-3-(4-(hydroxymethyl)oxazole-2-yl)-3-(3-(2-methoxypyridine-3-yl)benzyl)cyclopentyl)methanesulfonamide (250 mg, 0.5 mmol), thionyl chloride (195 mg, 1.6 mmol) was added in portions at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (pentane / ethyl acetate = 1:1) to obtain the desired product.

[0340] The following intermediates were prepared by the same method: Prepared from N-((1r,4r)-4-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(4-(chloromethyl)pyrimidine-2-yl)cyclohexyl)methanesulfonamide and N-((1r,4r)-4-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(4-(hydroxymethyl)pyrimidine-2-yl)cyclohexyl)methanesulfonamide

[0341] Preparation of methyl(1S,3S)-1-((3-(3-(benzyloxy)phenyl)propoxy)methyl)-((diphenylmethylene)amino)cyclopentane-1-carboxylate (General Method-15) [ka] A solution of methyl(1R,3S)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (1.90 g, 6.2 mmol) in THF (20 mL) was treated with LDA (2 M in THF / hexane, 5 mL, 10 mmol) at -78°C for 1 hour under an argon atmosphere, and then 1-(benzyloxy)-3-[3-(chloromethoxy)propyl]benzene (1.70 g, 5.8 mmol) was added dropwise at -78°C. The resulting mixture was stirred at room temperature under an argon atmosphere for 2 hours. The reaction product was quenched with brine at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (2 x 10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0342] Preparation of methyl(1S,3S)-3-amino-1-((3-(3-(benzyloxy)phenyl)propoxy)methyl)cyclopentane-1-carboxylate (General Method-15) [ka] A solution of methyl(1S,3S)-1-((3-(3-(benzyloxy)phenyl)propoxy)methyl)-((diphenylmethylene)amino)cyclopentane-1-carboxylate (2.00 g, 3.6 mmol) and concentrated HCl (3 mL) in MeOH (15 mL) and THF (5 mL) was stirred at 50°C for 2 hours. This mixture was cooled to room temperature. The crude product was concentrated and co-evaporated with toluene. The crude product was used directly in the next step without further purification.

[0343] Preparation of methyl(1S,3S)-1-((3-(3-(benzyloxy)phenyl)propoxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (General Method-15, INT-9) [ka] A solution of methyl(1S,3S)-3-amino-1-((3-(3-(benzyloxy)phenyl)propoxy)methyl)cyclopentane-1-carboxylate (2.00 g, 5.0 mmol) in dichloromethane (40 mL) was treated with TEA (3.18 g, 31.5 mmol) at -10°C for 15 minutes, and then methanesulfonic anhydride (2.20 g, 12.6 mmol) was added in portions at -10°C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with dichloromethane (3 x 40 mL). The combined organic phase was washed with brine (2 x 20 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 50% to 80% gradient over 20 minutes; detector, UV 220 nm, to obtain the desired product.

[0344] The following intermediates were prepared by the same method: Prepared from methyl(1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate and 1-(benzyloxy)-2-((1s,4s)-4-(chloromethoxy)cyclohexyl)benzene. Prepared from methyl(1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate and 1-(benzyloxy)-3-((1s,4s)-4-(chloromethoxy)cyclohexyl)benzene. Prepared from methyl(1S,3S)-1-((3-(benzyloxy)phenethoxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate and 1-(benzyloxy)-3-(2-(chloromethoxy)ethyl)benzene. Prepared from methyl(1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate and 1-(benzyloxy)-3-((1s,4s)-4-(chloromethoxy)cyclohexyl)benzene. Prepared from methyl(1R,3S)-1-(3-(4-(benzyloxy)-2-methylthiazole-5-yl)-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate and 4-(benzyloxy)-5-(5-(bromomethyl)-2-fluorophenyl)-2-methylthiazole.

[0345] Preparation of methyl(1S,3S)-1-((4-(2-(benzyloxy)phenyl)pyridine-2-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate (General Method-16, INT-9) [ka] A mixture of methyl(1S,3S)-1-((4-bromopyridine-2-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate (2.50 g, 6.4 mmol), 2-[2-(benzyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.97 g, 9.6 mmol), Pd(dppf)Cl2 (0.47 g, 0.6 mmol), and K2CO3 (2.65 g, 19.1 mmol) in dioxane (20 mL) and water (4 mL) was stirred at 80°C for 2 hours under an argon atmosphere. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (1 x 100 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using dichloromethane / MeOH (10:1) to obtain the desired product.

[0346] The following intermediates were prepared by the same method: Prepared from methyl(1S,3S)-1-((4-(2-(benzyloxy)phenyl)pyridine-2-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1S,3S)-1-((4-bromopyridine-2-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, and 2-(2-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from methyl(1R,3S)-1-((2'-(benzyloxy)-2,6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1R,3S)-1-(3-chloro-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, and 2-(2-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from methyl(1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxylate, methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(ethylsulfonamide)cyclopentan-1-carboxylate, and 2-(2-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from methyl(1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N-methylsulfamoyl)amino)cyclopentan-1-carboxylate, methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-((N-methylsulfamoyl)amino)cyclopentan-1-carboxylate, and 2-(2-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from methyl(1R,3S)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-((N,N-dimethylsulfamoyl)amino)cyclopentan-1-carboxylate, methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-((N,N-dimethylsulfamoyl)amino)cyclopentan-1-carboxylate, and 2-(2-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Prepared from methyl(1R,3S)-1-((2-(2-(benzyloxy)-3-fluorophenyl)pyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1R,3S)-1-((2-bromopyridine-4-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from methyl(1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from methyl(1R,3S)-1-((2'-(benzyloxy)-6-chloro-3'-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1R,3S)-1-(3-bromo-4-chlorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from methyl(1R,3S)-1-((2'-(benzyloxy)-3',4,6'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1R,3S)-1-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate and 2-(benzyloxy)-3-bromo-1,4-difluorobenzene. Prepared from methyl(1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxylate, (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(ethylsulfonamide)cyclopentan-1-carboxamide and (2-(benzyloxy)-3-fluorophenyl)boronic acid. Prepared from methyl(1r,4r)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)cyclohexane-1-carboxylate, methyl(1r,4r)-1-[(3-bromo-4-fluorophenyl)methyl]-4-methanesulfonamidecyclohexane-1-carboxylate, and 2-(benzyloxy)-3-fluorophenylboronic acid.

[0347] Preparation of methyl(1S,3S)-1-(((1-(2-methoxypyridine-3-yl)piperidine-4-yl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate (General Method-17) [ka] A mixture of 1-(2-methoxypyridine-3-yl)piperidine-4-one (500 mg, 2.42 mmol) and methyl(1S,3S)-1-(hydroxymethyl)-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentane-1-carboxylate (692.7 mg, 1.865 mmol) in acetonitrile (10 mL) was stirred at 0°C under an argon atmosphere. Triisopropylsilane (590.6 mg, 3.729 mmol) and TMSOTf (1.66 g, 7.45 mmol) in dichloromethane (10 mL) were added dropwise to this mixture at 0°C. The resulting mixture was stirred overnight at room temperature. The residue was neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 20% to 60% gradient over 15 minutes; detector, UV 254 nm. This yielded the desired product.

[0348] The following intermediates were prepared by the same method: Prepared from methyl(1S,3S)-1-(((cis-4-(3-methoxypyridine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1S,3S)-1-(hydroxymethyl)-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentan-1-carboxylate and 4-(3-methoxypyridine-2-yl)cyclohexane-1-one. Prepared from methyl(1S,3S)-1-((((1s,4R)-4-(6-methoxypyridine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1S,3S)-1-(hydroxymethyl)-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentan-1-carboxylate and 4-(6-methoxypyridine-2-yl)cyclohexane-1-one. Prepared from methyl(1S,3S)-1-((((1s,4R)-4-(2-methoxypyridine-3-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1S,3S)-1-(hydroxymethyl)-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentan-1-carboxylate and 4-(2-methoxypyridine-3-yl)cyclohexane-1-one. Prepared from methyl(1S,3S)-1-(((cis-4-(4-methoxypyrimidine-2-yl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1S,3S)-1-(hydroxymethyl)-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentan-1-carboxylate and 4-(4-methoxypyrimidine-2-yl)cyclohexane-1-one. Prepared from methyl(1S,3S)-1-(((4-(2-(benzyloxy)-3-fluorophenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, methyl(1S,3S)-1-(hydroxymethyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate, and 4-(2-(benzyloxy)-3-fluorophenyl)cyclohexane-1-one.

[0349] Preparation of (1R,3S)-N-((2S,3S)-3-(benzyloxy)-1-hydroxybutan-2-yl)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (General Method-18) [ka] (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxylic acid (1.15 g, 2.45 mmol) and (2S,3S)-2-amino-3-(benzyloxy)butan-1-ol (478 mg, 2.45 mmol) were dissolved in DMF (1.3 mL) and dichloromethane (10 mL). DIPEA (2.56 mL, 14.7 mmol) was added, followed by HATU (1.12 g, 2.94 mmol). The mixture was stirred for 90 minutes. The mixture was separated into water and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated NH4Cl aqueous solution, saturated NaHCO3 aqueous solution, and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The desired product was obtained by purification by silica gel chromatography (heptane / ethyl acetate).

[0350] Preparation of (1R,3S)-N-((2R,3S)-3-(benzyloxy)-1-oxobutan-2-yl)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (General Method-18) [ka] Oxalyl dichloride (0.17 mL, 1.95 mmol) was dissolved in anhydrous dichloromethane (3.52 mL, 54.7 mmol) under argon, and the solution was cooled to -78°C. (Methylsulfinyl)methane (0.27 mL, 3.75 mmol) dissolved in anhydrous dichloromethane (1.81 mL) was added to the reaction mixture, and the mixture was stirred for 15 minutes. (1R,3S)-N-((2S,3S)-3-(benzyloxy)-1-hydroxybutan-2-yl)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (930 mg, 1.56 mmol) dissolved in anhydrous dichloromethane (3.52 mL) was slowly added, and the reaction mixture was stirred for 15 minutes. Triethylamine (523 μL, 3.75 mmol) was added, and the reaction mixture was stirred at -78°C for 15 minutes. Then it was heated to 0°C, triethylamine (523 μL, 3.75 mmol) was added, and the mixture was stirred for 15 minutes. Water (10 mL) was added, and the mixture was allowed to reach room temperature. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated NH4Cl aqueous solution, saturated NaHCO3 aqueous solution, and brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain the desired product, which was used without further purification.

[0351] Preparation of N-((1S,3R)-3-(4-((S)-1-(benzyloxy)ethyl)oxazol-2-yl)-3-(3-bromo-4-fluorobenzyl)cyclopentyl)methanesulfonamide (General Method-18) [ka] (1R,3S)-N-((2R,3S)-3-(benzyloxy)-1-oxobutan-2-yl)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (766 mg, 1.35 mmol) was dissolved in anhydrous THF (19.1 mL) under argon. Then, Burgess' reagent (1.92 g, 8.07 mmol) was added, and the reaction mixture was heated under reflux for 15 minutes.

[0352] The reaction mixture was cooled to room temperature, concentrated under vacuum, and separated into water and ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (heptane / ethyl acetate) to obtain the desired product.

[0353] The following intermediates were prepared by the same method: Prepared from N-((1S,3R)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(5-(hydroxymethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (S)-1-amino-3-(benzyloxy)propane-2-ol and methyl(1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate.

[0354] Preparation of N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4((S)-1-(benzyloxy)ethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide (General Method-18) [ka] N-((1S,3R)-3-(4-((S)-1-(benzyloxy)ethyl)oxazole-2-yl)-3-(3-bromo-4-fluorobenzyl)cyclopentyl)methanesulfonamide (461 mg, 761 μmol) was dissolved in 1,4-dioxane (6.85 mL) and water (761 μL) under argon. (2-(benzyloxy)-3-fluorophenyl)boronic acid (318 mg, 1.29 mmol) and K2CO3 (289 mg, 2.09 mmol) were added, and nitrogen was sprayed over the solution for 5 minutes. PdCl2 (dppf) (55.7 mg, 76.1 μmol) was added, and nitrogen was sprayed over the solution for 5 minutes. The reaction mixture was heated at 95°C for 90 minutes.

[0355] The mixture was cooled to room temperature, and water (10 mL) and ethyl acetate (30 mL) were added. The phases were separated, and the organic phase was washed with NaHCO3 (30 mL) and brine (30 mL). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (heptane / ethyl acetate) to obtain the desired product.

[0356] Preparation of N-((1S,3R)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-((S)-1-hydroxyethyl)oxazol-2-yl)cyclopentyl)methanesulfonamide (General Method-18, INT-8) [ka] N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-((S)-1-(benzyloxy)ethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide (473 mg, 612 μmol) and Pd / C (130 mg, 10 wt%) were suspended in ethyl acetate (11.9 mL) and MeOH (4.95 mL). Two balloons of H2 gas were bubbling through the mixture, and the mixture was then maintained under an H2 atmosphere for 2 days. The reaction mixture was filtered on Celite and concentrated under vacuum. The crude product was purified by silica gel chromatography (heptane / ethyl acetate) to obtain the desired product.

[0357] Preparation of (1S,3S)-1-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylic acid (General method-19) [ka] Lithium hydroxide hydrate (1.16 g, 27.7 mmol) in water (12 mL) was added to methyl(1S,3S)-1-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (1.93 g, 2.77 mmol) in THF (22.5 mL) and MeOH (11.2 mL). The mixture was stirred at 70°C for 90 minutes.

[0358] The reaction mixture was concentrated under vacuum and then separated into dichloromethane and water. The aqueous phase was acidified with 2M aqueous HCl solution and extracted with dichloromethane. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the desired product, which was used without further purification.

[0359] Preparation of (1S,3S)-1-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carbonyl chloride (General method-19) [ka] (1S,3S)-1-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylic acid (1.75 g, 2.34 mmol) was dissolved in anhydrous dichloromethane (23 mL) and cooled to 0°C. Oxalyl chloride (409 μL, 4.68 mmol) was added to this mixture, followed by 2 drops of DMF. This mixture was heated to room temperature overnight with stirring. This mixture was concentrated under vacuum to obtain the desired product, which was used without further purification.

[0360] Preparation of (1S,3S)-1-((((1S,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-N-((E / Z)-2-chloro-1-(hydroxyimino)ethyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (General Method-19) [ka] (1S,3S)-1-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carbonyl chloride (630 mg, 0.74 mmol) was dissolved in dichloromethane (15 mL) and cooled to 0°C. (E / Z)-2-chloro-N'-hydroxyacetimidoamide (112 mg, 1.03 mmol) was added to this mixture, followed by the slow addition of DIPEA (772 μL, 4.43 mmol). The mixture was stirred for 2 hours while being heated to room temperature. The mixture was separated into water and ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4, filtered, and concentrated to obtain the desired product, which was used without further purification.

[0361] Preparation of N-((1S,3S)-3-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(3-(chloromethyl)-1,2,4-oxadiazole-5-yl)cyclopentyl)methanesulfonamide (General Method-19, INT-5) [ka] (1S,3S)-1-((((1s,4R)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-N-((E / Z)-2-chloro-1-(hydroxyimino)ethyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide (633 mg, 609 μmol) was dissolved in acetic acid (4 mL) and heated in a microwave reactor at 150°C for 30 minutes.

[0362] This mixture was concentrated and then dissolved in ethyl acetate. The organic phase was washed three times with saturated aqueous NaHCO3 solution, followed by brine, dried over Na2SO4, filtered, and concentrated under vacuum.

[0363] The desired product was obtained by purification using silica gel chromatography (ethyl acetate / heptane).

[0364] Preparation of (1R,3S)-1-(3-bromobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentane-1-carboxylic acid (General method-20) [ka] A mixture of methyl(1R,3S)-1-[(3-bromophenyl)methyl]-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentane-1-carboxylate (90 mg, 0.176 mmol) and NaOH (1.32 g, 32.913 mmol) in MeOH (30 mL) and water (10 mL) was stirred at 70°C for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The crude product was used directly in the next step without further purification.

[0365] Preparation of (1R,3S)-1-(3-bromobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentane-1-carboxamide (General Method-20) [ka] (1R,3S)-1-[(3-bromophenyl)methyl]-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentane-1-carboxylic acid (2 g, 4.029 mmol), NH4HCO3 (4.78 g, 60.435 mmol), and HoAt (548.4 mg, 4.029 mmol) were mixed in dichloromethane (80 mL) and DMF (20 mL) and stirred at 0°C for 10 minutes. HATU (1532 mg, 4.029 mmol) was added to the mixture in installments over 2 minutes at 0°C. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction was quenched by adding water / ice (60 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient over 10 minutes; detector, UV 254 nm. This yielded the desired product.

[0366] Preparation of ethyl 2-((1R,3S)-1-(3-bromobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)-5-methyloxazole-4-carboxylate (General Method-20, INT-17) [ka] A mixture of (1R,3S)-1-[(3-bromophenyl)methyl]-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentane-1-carboxamide (360 mg, 0.727 mmol) and ethyl 3-bromo-2-oxobutanoate (759.4 mg, 3.635 mmol) in dioxane (18 mL) was stirred at 90°C for 4 hours. The mixture was cooled to room temperature. The resulting mixture was filtered. The filter cake was washed with THF (3 x 10 mL). The filtrate was concentrated under reduced pressure. TFAA (610.4 mg, 2.908 mmol) was added to the above mixture at 0°C. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction was quenched by adding saturated NaHCO3 aqueous solution (30 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The desired product was obtained by purification using silica gel chromatography (ethyl acetate / heptane).

[0367] The following intermediates were prepared by the same method: Prepared from ethyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate and (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentane-1-carboxamide.

[0368] Preparation of methyl(1S,3S)-1-formyl-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentane-1-carboxylate (General Method-21) [ka] In a dry flask, a solution of oxalyl dichloride (554 μL, 6.461 mmol) in anhydrous dichloromethane (25 mL) was added to (methylsulfinyl)methane (0.92 mL, 12.92 mmol) at -78°C. After stirring for 1 hour, methyl(1S)-1-(hydroxymethyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentane-1-carboxylate (2500 mg, 80 wt%, 5.384 mmol) in anhydrous dichloromethane (25 mL) was added over 2 minutes, and the reaction mixture was heated at -78°C for a further 1 hour. At this point, triethylamine (2.63 mL, 18.85 mmol) was added to the mixture, and the reaction mixture was allowed to reach room temperature over 16 hours. The reaction mixture was then quenched with water (20 mL) and extracted with dichloromethane (2 x 100 mL). The dichloromethane phase was washed with ammonium chloride and brine, dried on sodium sulfate, and concentrated. The desired product was obtained by purification using silica gel chromatography (ethyl acetate / heptane).

[0369] Preparation of methyl(1S,3S)-1-(((1s,3R)-3-(2-(benzyloxy)phenyl)cyclobutoxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (General Method-21, INT-9) [ka] To a solution of methyl(1S,3S)-1-formyl-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentan-1-carboxylate (899 mg, 80% by weight, 1.95 mmol), (1s,3s)-3-(2-(benzyloxy)phenyl)cyclobutan-1-ol (450 mg, 1.77 mmol), and 1,2,3,4,5-pentamethylbenzene (1.57 g, 10.6 mmol) in anhydrous acetonitrile (30 mL), tris(propan-2-yl)silane (726 μL, 3.54 mmol) was added at 0°C. Then, a solution of trimethylsilyltrifluoromethanesulfonate (2 M in dichloromethane) (2.21 mL, 4.42 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour under an argon atmosphere. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO3 and brine. The organic phase was concentrated under vacuum. The crude substance was purified by silica gel chromatography to obtain the desired product.

[0370] Preparation of ethyl 2-((1R,3S)-1-((2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)-5-methyloxazole-4-carboxylate (General Method-22) [ka] A solution of ethyl 2-[(1R,3S)-1-[(3-bromophenyl)methyl]-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentyl]-5-methyl-1,3-oxazole-4-carboxylate (200 mg, 0.330 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (109.0 mg, 0.495 mmol), Cs2CO3 (322.8 mg, 0.990 mmol), and Pd(dppf)Cl2 (24.1 mg, 0.033 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 80°C for 2 hours under an argon atmosphere. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to obtain the desired compound.

[0371] Preparation of N-((1S,3R)-3-((2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)-5-methyloxazol-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (General Method-22) [ka] LiAlH4 (20.8 mg, 0.55 mmol) was added at 0°C to a THF (5 mL) solution of ethyl 2-[(1R,3S)-1-({2'-hydroxy-[1,1'-biphenyl]-3-yl}methyl)-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamide}cyclopentyl]-5-methyl-1,3-oxazole-4-carboxylate (170 mg, 0.28 mmol). The resulting mixture was stirred at 0°C for 30 minutes. The reaction was quenched with Na2SO4·10H2O at 0°C. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (pentane / ethyl acetate 1:1) to obtain the desired product.

[0372] Preparation of N-((1S,3R)-3-(4-(chloromethyl)-5-methyloxazol-2-yl)-3-((2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (General Method-22, INT-14) [ka] A mixture of N-[(1S,3R)-3-({2'-hydroxy-[1,1'-biphenyl]-3-yl}methyl)-3-[4-(hydroxymethyl)-5-methyl-1,3-oxazole-2-yl]cyclopentyl]-N-[(4-methoxyphenyl)methyl]methanesulfonamide (50 mg, 0.087 mmol) and dichloromethane (5 mL) was stirred at 0°C for 5 minutes. SOCl2 (30.9 mg, 0.26 mmol) was added to the mixture at 0°C. The resulting mixture was stirred at room temperature for a further 0.5 hours. The reaction product was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0373] The following intermediates were prepared by the same method: Prepared from N-((1S,3R)-3-(4-(chloromethyl)oxazol-2-yl)-3-((3',5',6-trifluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide, ethyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazol-4-carboxylate and (3,5-difluoro-2-hydroxyphenyl)boronic acid. Prepared from N-((1S,3R)-3-(4-(chloromethyl)oxazol-2-yl)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)fluoromethyl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide, ethyl 2-((1R,3S)-1-((3-chloro-4-fluorophenyl)fluoromethyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazol-4-carboxylate and (2-(benzyloxy)-3-fluorophenyl)boronic acid.

[0374] Preparation of N-((1S,3R)-3-(3-bromo-4-fluorobenzyl)-3-(4-(hydroxymethyl-d2)oxazole-2-yl)cyclopentyl)methanesulfonamide (General Method-23) [ka] A solution of ethyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (1.20 g, 2.21 mmol) in anhydrous THF (60 mL) was stirred at 0°C under an argon atmosphere. Then, LiAlD4 (139 mg, 3.31 mmol) was slowly added. The mixture was stirred at 0°C for 0.5 hours. The mixture was filtered through a Celite plug and washed with THF. This liquid was diluted with saturated NH4Cl and extracted with ethyl acetate. The organic phase was washed with brine and dried over MgSO4. The mixture was filtered and concentrated under vacuum to obtain the desired product with sufficient purity.

[0375] The following intermediates were prepared by the same method: Prepared from N-((1S,3R)-3-(5-chloro-2,4-difluorobenzyl)-3-(5-(hydroxymethyl)-1,2,4-thiadiazole-3-yl)cyclopentyl)methanesulfonamide, methyl 3-((1R,3S)-1-(5-chloro-2,4-difluorobenzyl)-3-(methylsulfonamide)cyclopentyl)-1,2,4-thiadiazole-5-carboxylate and sodium borohydride. Prepared from N-((1S,3R)-3-(3-bromo-4-fluorobenzyl)-3-(3-(hydroxymethyl)-1,2,4-oxadiazole-5-yl)cyclopentyl)methanesulfonamide, ethyl 5-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentyl)-1,2,4-oxadiazole-3-carboxylate and sodium borohydride.

[0376] Preparation of N-((1S,3R)-3-((6-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl-d2)oxazole-2-yl)cyclopentyl)methanesulfonamide (General Method-24) [ka] In a microwave vial, N-((1S,3R)-3-(3-bromo-4-fluorobenzyl)-3-(4-(hydroxymethyl-d2)oxazole-2-yl)cyclopentyl)methanesulfonamide (80 mg, 0.15 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). (2-hydroxyphenyl)boronic acid (42 mg, 0.30 mmol) and K2CO3 (52 mg, 0.38 mmol) were added. Argon was sprayed over this mixture for 5 minutes. Then, PdCl2 (dppf) (11 mg, 15 μmol) was added, and argon was sprayed over this mixture for 10 minutes. The reaction mixture was then stirred under argon at 100°C for 90 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with brine. The organic phase was concentrated under vacuum. The crude product was purified by silica gel chromatography to obtain the desired product.

[0377] The following intermediates were prepared by the same method: Prepared from N-((1S,3R)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl-d2)oxazole-2-yl)cyclopentyl)methanesulfonamide, N-((1S,3R)-3-(3-bromo-4-fluorobenzyl)-3-(4-(hydroxymethyl-d2)oxazole-2-yl)cyclopentyl)methanesulfonamide and (3-fluoro-2-hydroxyphenyl)boronic acid. Prepared from N-((1S,3R)-3-(3-(2-aminopyridine-3-yl)benzyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, N-((1S,3R)-3-(3-bromobenzyl)-3-(4-(hydroxymethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine. Prepared from N-((1S,3R)-3-(5-(hydroxymethyl)-1,2,4-thiadiazole-3-yl)-3-((3',4,6-trifluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide, N-((1S,3R)-3-(5-chloro-2,4-difluorobenzyl)-3-(5-(hydroxymethyl)-1,2,4-thiadiazole-3-yl)cyclopentyl)methanesulfonamide and (3-fluoro-2-hydroxyphenyl)boronic acid. Prepared from N-((1S,3R)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(3-(hydroxymethyl)-1,2,4-oxadiazole-5-yl)cyclopentyl)methanesulfonamide, N-((1S,3R)-3-(3-bromo-4-fluorobenzyl)-3-(3-(hydroxymethyl)-1,2,4-oxadiazole-5-yl)cyclopentyl)methanesulfonamide and (3-fluoro-2-hydroxyphenyl)boronic acid.

[0378] Preparation of N-((1S,3R)-3-(3-bromobenzyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide (General Method-25) [ka] A dry flask equipped with a stirring bar, containing (1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (3.50 g, 54 wt%, 5.04 mmol), was mixed with 1,3-dichloropropan-2-one (25 g, 0.20 mol). The mixture was stirred at 125°C for 90 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane (150 mL), and washed with brine (50 mL) and saturated NaHCO3 (2 x 50 mL). The organic matter was dried and concentrated to the minimum volume. The desired product was obtained with sufficient purity by purification of the residue by silica gel chromatography.

[0379] Preparation of N-((1S,3R)-3-(3-bromobenzyl)-3-(4-(hydroxymethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide (General Method-25, INT-16) [ka] N-((1S,3R)-3-(3-bromobenzyl)-3-(4-(chloromethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide (1775 mg, 75 wt%, 2.97 mmol) was dissolved in 1,4-dioxane (50 mL). 2 M NaOH (aq.) (14.87 mL, 29.73 mmol) was added, and the mixture was stirred at 90°C for 8 hours, then at 40°C overnight. The mixture was cooled, and 12N HCl (aq.) was carefully added until the pH reached approximately 1. The mixture was extracted with ethyl acetate (3 x 100 mL), the combined organic matter was washed with brine (50 mL), and concentrated under vacuum. The desired product was obtained by purification by silica gel chromatography.

[0380] Preparation of methyl(1S,3S)-1-((((1s,4R)-4-(3-hydroxyphenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (General Method-28) [ka] Methyl(1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (700 mg, 1.02 mmol) and pentamethylbenzene (528 mg, 3.56 mmol) were dissolved in anhydrous dichloromethane (65.5 mL) under argon and cooled to -78°C. Boron trichloride (1 M in dichloromethane) (3.10 mL, 3.05 mmol) was added dropwise, and the mixture was stirred at -78°C for 15 minutes.

[0381] The reaction mixture was quenched by adding 140 mL of 1:10 dichloromethane:MeOH and allowed to reach room temperature. This mixture was concentrated on Celite and purified by silica gel chromatography to obtain the desired product.

[0382] Preparation of methyl(1S,3S)-1-((((1R,4R)-4-(3-((S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)butoxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (General Method-28) [ka] Methyl(1S,3S)-1-((((1s,4R)-4-(3-hydroxyphenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylate (367 mg, 0.62 mmol), tert-butyl(S)-(1-(benzyloxy)-4-hydroxybutan-2-yl)carbamate (468 mg, 1.58 mmol), and tri-n-butylphosphine (460 μL, 1.86 mmol) were dissolved in anhydrous THF (28 mL), to which 1,1-(azodicarbonyl)-dipiperidine (470 mg, 1.86 mmol) was added all at once under argon. The reaction mixture was stirred for 2 hours. The mixture was filtered, the filtrate was concentrated, and the desired product was purified by silica gel chromatography.

[0383] Preparation of N-((1S,1'R,3S,4'R,8'S)-8'-((benzyloxy)methyl)-6'-oxospiro[cyclopentan-1,5'-3,11-dioxa-7-aza-1(1,3)-benzena-2(1,4)-cyclohexanacycloundecaphan]-3-yl)methanesulfonamide (General Method-28) [ka] A solution of lithium hydroxide hydrate (157 mg, 3.75 mmol) in water (2.7 mL) was added to methyl (1S,3S)-1-((((1R,4R)-4-(3-((S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)butoxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (303 mg, 375 μmol) in a mixture of THF (12 mL) and MeOH (6.1 mL). The reaction mixture was stirred overnight at 50°C.

[0384] The reaction mixture was concentrated under vacuum, and the resulting slurry was suspended in dichloromethane (19 mL). Hydrogen chloride (4 M in dioxane) (6.60 mL, 26.3 mmol) was then added. The mixture was stirred at room temperature for 90 minutes.

[0385] The reaction mixture was concentrated under vacuum, co-evaporated with toluene, and then dried under vacuum.

[0386] The residue was dissolved in a mixture of dichloromethane (145 mL) and DMF (2.90 mL), and then triethylamine (1.05 mL, 7.50 mmol) was added. To this solution, 2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (164 mg, 0.43 mmol) in DMF (2 mL) was added, and the mixture was stirred for 2 hours.

[0387] The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed twice with saturated NH4Cl and brine, dried on Na2SO4, and then filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography to obtain the desired product.

[0388] Preparation of N-((1S,1'R,3S,4'R,8'S)-8'-(hydroxymethyl)-6'-oxospiro[cyclopentan-1,5'-3,11-dioxa-7-aza-1(1,3)-benzena-2(1,4)-cyclohexanacycloundekaphan]-3-yl)methanesulfonamide (General Method-28) [ka] N-((1S,1'R,3S,4'R,8'S)-8'-((benzyloxy)methyl)-6'-oxospiro[cyclopentan-1,5'-3,11-dioxa-7-aza-1(1,3)-benzena-2(1,4)-cyclohexanacycloundecaphan]-3-yl)methanesulfonamide (75 mg, 0.13 mmol) and Pd / C (10 wt%) (28 mg, 26 μmol) were suspended in ethyl acetate (2.6 mL) and MeOH (1.1 mL). Two H2 gas balloons were bubbling through the turbidity, and the mixture was then kept overnight under an H2 atmosphere. The reaction mixture was filtered on Celite and concentrated under vacuum to obtain the desired product, which was used without further purification.

[0389] Preparation of N-((1S,1'R,3S,4'R,8'S)-8'-formyl-6'-oxospiro[cyclopentan-1,5'-3,11-dioxa-7-aza-1(1,3)-benzena-2(1,4)-cyclohexanacycloundekaphan]-3-yl)methanesulfonamide (General Method-28) [ka] Oxalyl dichloride (12 μL, 0.14 mmol) was dissolved in anhydrous dichloromethane (0.25 mL), and the solution was cooled to -78°C. To this reaction mixture, DMSO (19 μL, 0.27 mmol) dissolved in anhydrous dichloromethane (0.13 mL) was added, and the mixture was stirred for 15 minutes. N-((1S,1'R,3S,4'R,8'S)-8'-(hydroxymethyl)-6'-oxospiro[cyclopentan-1,5'-3,11-dioxa-7-aza-1(1,3)-benzena-2(1,4)-cyclohexanacycloundecaphan]-3-yl)methanesulfonamide (69 mg, 0.11 mmol) dissolved in dichloromethane (0.25 mL) was slowly added, and the reaction mixture was stirred for 15 minutes. Triethylamine (37 μL, 0.27 mmol) was added, and the reaction mixture was stirred at -78°C for 15 minutes. The reaction mixture was heated to 0°C, triethylamine (37 μL, 0.27 mmol) was added, and the mixture was stirred for 15 minutes. Then, water (1 mL) was added, and the mixture was allowed to reach room temperature. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with 1 M aqueous HCl, saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered under vacuum, and concentrated to obtain the desired product.

[0390] Preparation of (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylic acid (General Method - 32) [ka] Lithium hydroxide (2.16 g, 90.3 mmol) in water (25 mL) was added to methyl (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (7.84 g, 18.1 mmol) in anhydrous THF (125 mL) and methanol (25 mL). This mixture was stirred at 60 °C for 3 hours, then at room temperature overnight. The mixture was concentrated under vacuum, and the resulting residue was co-evaporated with toluene (3 x 50 mL) and then dried. This yielded the desired product with sufficient purity.

[0391] Preparation of (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carbonyl chloride (General method - 32) [ka] (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxylic acid (1.15 g, 2.45 mmol) was dissolved in anhydrous dichloromethane (24.5 mL) under argon and cooled to 0°C. Oxalyl chloride (429 μL, 4.90 mmol) was added to this mixture, followed by 2 drops of DMF. This mixture was heated to room temperature overnight with stirring. The mixture was concentrated until dry to obtain the desired product, which was used without further purification.

[0392] Preparation of tert-butyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carbonyl)hydrazine-1-carboxylate (General Method-32) [ka] (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carbonyl chloride (1.01 g, 2.45 mmol) was dissolved in anhydrous dichloromethane (49 mL) under argon and cooled to 0°C. Tert-butylhydrazine carboxylate (334 mg, 2.45 mmol) was added to this mixture, followed by the slow addition of DIPEA (2.56 mL, 14.7 mmol). The mixture was allowed to return to room temperature with stirring for 2 hours. The mixture was separated into water and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried over Na2SO4, filtered, and concentrated.

[0393] The desired product was obtained by purification using silica gel chromatography.

[0394] Preparation of tert-butyl 2-((1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carbonyl)hydrazine-1-carboxylate (General Method-32) [ka] 843 mg, 1.33 mmol of tert-butyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentane-1-carbonyl)hydrazine-1-carboxylate was dissolved in 12 mL of 1,4-dioxane and 1.35 mL of water under argon. 555 mg, 2.26 mmol of (2-(benzyloxy)-3-fluorophenyl)boronic acid and 504 mg, 3.65 mmol of K2CO3 were added, and the solution was sprayed with nitrogen for 5 minutes. 97.1 mg, 133 μmol of PdCl2 (dppf) was added, and the solution was sprayed with nitrogen for 5 minutes. The reaction mixture was heated at 95°C for 2 hours. After the mixture cooled, 10 mL of water and 50 mL of ethyl acetate were added. The phases were separated, and the organic phase was washed with saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography to obtain the desired product.

[0395] Preparation of N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(hydrazinecarbonyl)cyclopentyl)methanesulfonamide (General Method-32) [ka] tert-butyl 2-((1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carbonyl)hydrazine-1-carboxylate (770 mg, 1.11 mmol) was dissolved in dichloromethane (5.5 mL) and TFA (5.5 mL) and stirred for 1 hour. This mixture was concentrated under vacuum, co-evaporated with MeOH, and then dried under vacuum to obtain the desired product, which was used without further purification.

[0396] Preparation of N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)cyclopentyl)methanesulfonamide (General Method-32) [ka] N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(hydrazinecarbonyl)cyclopentyl)methanesulfonamide (589 mg, 1.11 mmol) was dissolved in anhydrous dichloromethane (22.2 mL) under argon and cooled to 0°C. 2-chloroacetyl chloride (115 μL, 1.45 mmol) was added to this mixture, followed by the slow addition of DIPEA (1.16 mL, 6.67 mmol). The mixture was allowed to return to room temperature with stirring for 1 hour. The mixture was separated into water and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The desired product was obtained by purification by silica gel chromatography.

[0397] Preparation of N-((1S,3R)-3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide (General Method-32) [ka] A solution of N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)cyclopentyl)methanesulfonamide (307 mg, 365 μmol) and pentamethylbenzene (189 mg, 1.28 mmol) in anhydrous dichloromethane (19 mL) was placed under argon and cooled to -78°C. Boron trichloride (1 M in heptane) (1.09 mL, 1.09 mmol) was slowly added, and the mixture was stirred at -78°C for 15 minutes.

[0398] This mixture was quenched with MeOH, allowed to reach room temperature, and then concentrated under vacuum to obtain the desired product, which was not further purified.

[0399] Preparation of N-((1R,3S)-3',6'-difluoro-5',8'-dioxospiro[cyclopentan-1,9'-3-oxa-6,7-diaza-1(1,3),2(1,2)-dibenzenacyclodecafane]-3-yl)methanesulfonamide (General Method-32) [ka] N-((1S,3R)-3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide (92.0 mg, 178 μmol) was dissolved in anhydrous acetonitrile (14 mL) under argon. This solution was then added dropwise at 60°C under argon via a syringe pump to a mixture of Cs2CO3 (174 mg, 535 μmol) in anhydrous acetonitrile (60.5 mL) which was stirred over 10 hours. The mixture was stirred overnight at 60°C. The reaction mixture was concentrated to remove most of the solvent, and then separated into dichloromethane and water. The phases were separated, and the aqueous phase was neutralized with 2 M HCl(aq) and extracted with dichloromethane and 2-Me-THF. The combined organic phases were dried over Na2SO4, filtered, and concentrated to obtain the desired product with sufficient purity.

[0400] Preparation of methyl 1-(3-bromo-4-fluorobenzyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutan-1-carboxylate (General Method-38) [ka] To a mixture of methyl 3-(oxan-2-yloxy)cyclobutane-1-carboxylate (10 g, 46.6 mmol) in THF (400 mL) being stirred, LDA (2 M in THF, 35 mL, 70 mmol) was added dropwise over 30 minutes at -78°C under an argon atmosphere. The resulting mixture was stirred for a further 1 hour at -78°C. To the above mixture, 2-bromo-4-(bromomethyl)-1-fluorobenzene (20 g, 74.7 mmol) was added dropwise over 1 hour at -78°C. The resulting mixture was stirred for a further 3 hours at -78°C. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with siRNA (3 x 400 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

[0401] Preparation of methyl 1-(3-bromo-4-fluorobenzyl)-3-hydroxycyclobutane-1-carboxylate (General Method - 38) [ka] A mixture of methyl 1-[(3-bromo-4-fluorophenyl)methyl]-3-(oxan-2-yloxy)cyclobutane-1-carboxylate (4 g, 10 mmol) and TFA (1.70 g, 15 mmol) in MeOH (60 mL) was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

[0402] Preparation of methyl(1r,3s)-1-[(3-bromo-4-fluorophenyl)methyl]-3-[N-(tert-butoxycarbonyl)methanesulfonamide]cyclobutane-1-carboxylate (General Method-38) [ka] To a mixture of methyl 1-[(3-bromo-4-fluorophenyl)methyl]-3-hydroxycyclobutane-1-carboxylate (1.6 g, 5.0 mmol), tert-butyl(methylsulfonyl)carbamate (1.97 g, 10.1 mmol), and PPh3 (3.97 g, 15.1 mmol) in toluene (12 mL) while stirring, diethyl azodicarboxylate (DEAD) (2.64 g, 15.1 mmol) was added dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred further at 100°C for 15 minutes under an argon atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with SiO (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient over 10 minutes; detector, UV 254 nm, to obtain the desired product.

[0403] Preparation of (1r,3s)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclobutane-1-carboxylic acid (General Method - 38) [ka] A mixture of methyl(1r,3s)-1-[(3-bromo-4-fluorophenyl)methyl]-3-[N-(tert-butoxycarbonyl)methanesulfonamide]cyclobutane-1-carboxylate (400 mg, 0.809 mmol) and NaOH (129.45 mg, 3.236 mmol) in MeOH (8 mL), THF (8 mL), and H2O (8 mL) was stirred at 70°C for 2 hours under an argon atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0404] Preparation of methyl(2-(5-chloro-2,4-difluorobenzyl)-4-(methylsulfonamide)tetrahydrofuran-2-carbonyl) serinate (General Method-48) [ka] In a 250 mL round-bottom flask containing 2-(5-chloro-2,4-difluorobenzyl)-4-(methylsulfonamide)tetrahydrofuran-2-carboxylic acid (2.51 g, 6.79 mmol) in DMF (50 mL), methyl serinet hydrochloride (1.37 g, 8.82 mmol) and 1H-benzo[d][1,2,3]triazole-1-ol (1.01 g, 7.47 mmol) were added sequentially. After dissolution, N-ethyl-N-isopropylpropan-2-amine (2.01 mL, 11.5 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (1.56 g, 8.15 mmol) were added, the flask was evacuated, argon was packed in, and the mixture was stirred at room temperature. The reaction mixture was diluted with SiO2 and washed with water, saturated sodium bicarbonate aqueous solution, and brine. The aqueous phase was back-extracted once, the combined organic matter was washed with brine, dried on sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain the desired product.

[0405] Preparation of rac-methyl 2-((2S,4R)-2-(5-chloro-2,4-difluorobenzyl)-4-(methylsulfonamide)tetrahydrofuran-2-yl)-4,5-dihydroxazole-4-carboxylate (General Method-48) [ka] In a 500 mL round-bottom flask containing methyl (2-(5-chloro-2,4-difluorobenzyl)-4-(methylsulfonamide)tetrahydrofuran-2-carbonyl) selinate (2.60 g, 5.52 mmol) in anhydrous DCM (100 mL) at -78°C, N,N-diethyl-1,1,1-trifluoro-14-sulfanamine (875 μL, 6.63 mmol) was added, and the reaction mixture was stirred at -78°C for 90 minutes. Potassium carbonate (1.15 g, 8.28 mmol) was added to the reaction mixture, and the mixture was stirred at -78°C for 5 minutes. After that, the cooling bath was removed, and the reaction mixture was allowed to reach room temperature. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate aqueous solution. The combined organic matter was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain the desired product.

[0406] Preparation of rac-methyl 2-((2S,4R)-2-(5-chloro-2,4-difluorobenzyl)-4-(methylsulfonamide)tetrahydrofuran-2-yl)oxazole-4-carboxylate (General Method-48) [ka] In a round-bottom flask containing rac-methyl-2-((2S,4R)-2-(5-chloro-2,4-difluorobenzyl)-4-(methylsulfonamide)tetrahydrofuran-2-yl)-4,5-dihydroxazole-4-carboxylate (1.03 g, 2.27 mmol) in 34 mL of DCM, 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (1.36 mL, 9.10 mmol) was added under argon at 0°C, followed by the addition of bromotrichloromethane (897 μL, 9.10 mmol). The flask was evacuated, filled with argon, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was allowed to reach room temperature and stirred for another hour. The reaction mixture was diluted with DCM, and saturated ammonium chloride aqueous solution was added. The aqueous phase was extracted twice with DCM, and the combined organic matter was dried over sodium sulfate, then filtered and concentrated. The resulting residue was purified by silica gel column chromatography to obtain the desired product.

[0407] Preparation of rac-N-((3R,5S)-5-(5-chloro-2,4-difluorobenzyl)-5-(4-(hydroxymethyl)oxazole-2-yl)tetrahydrofuran-3-yl)methanesulfonamide (General Method-23) [ka] In a round-bottom flask containing rac-methyl 2-((2S,4R)-2-(5-chloro-2,4-difluorobenzyl)-4-(methylsulfonamide)tetrahydrofuran-2-yl)oxazole-4-carboxylate (890 mg, 1.97 mmol) in THF (44 mL) and MeOH (0.44 mL), sodium borohydride (299 mg, 7.90 mmol) was added under argon, and the reaction mixture was heated to 55°C. Water and ethyl acetate were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate. The combined organic compounds were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain the desired product.

[0408] Preparation of rac-N-((3R,5S)-5-(4-(hydroxymethyl)oxazol-2-yl)-5-((3',4,6-trifluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)tetrahydrofuran-3-yl)methanesulfonamide (General Method-24) [ka] In a round-bottom flask under argon, rac-N-((3R,5S)-5-(5-chloro-2,4-difluorobenzyl)-5-(4-(hydroxymethyl)oxazole-2-yl)tetrahydrofuran-3-yl)methanesulfonamide (685 mg, 1.62 mmol), (3-fluoro-2-hydroxyphenyl)boronic acid (467 mg, 3.00 mmol), and potassium triphosphate (774 mg, 3.65 mmol) were dissolved in degassed dioxane (26 mL) and water (1.4 mL). The reaction mixture was degassed for 5 minutes, XPhos Pd G2 (127 mg, 162 μmol) was added, and the solution was degassed further under argon for 5 minutes. The reaction mixture was fitted with a condenser and stirred at 80°C. The reaction mixture was dissolved in ethyl acetate, water was added, and the aqueous phase was extracted three times. The combined organic was washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain the desired product.

[0409] Preparation of (1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylic acid (General method - 34) [ka] LiOH (418 mg, 17.5 mmol) in water (7.6 mL) was added to methyl(1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxylate (1.2 g, 1.8 mmol) in THF (11 mL) and MeOH (11 mL). This mixture was stirred at 60°C for 16 hours. After concentrating the reaction mixture under vacuum, the desired product was obtained by removing residual water by azeotropic distillation with toluene.

[0410] Preparation of (1S,3S)-N-((S)-3-(benzyloxy)-2-hydroxypropyl)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (General Method-34) [ka] 1-hydroxy-7-azabenzotriazole (72 μL, 1 mol, 71.8 μmol) as a 1 M solution in DMA was added to (1S,3S)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylic acid (200 mg, 360 μmol), (S)-1-amino-3-(benzyloxy)propan-2-ol (130 mg, 718 μmol), HATU (205 mg, 538 μmol), and Et3N (250 μL, 1.79 mmol) in dichloromethane (7 mL) and DMF (0.3 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane and washed with saturated NH4Cl. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was purified by flash chromatography on silica gel to obtain the desired product.

[0411] Preparation of (1S,3S)-N-(3-(benzyloxy)-2-oxopropyl)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (General Method-34) [ka] (1S,3S)-N-((S)-3-(benzyloxy)-2-hydroxypropyl)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide (195 mg, 264 μmol) was dissolved in dichloromethane (6 mL) and THF (6 mL). This mixture was cooled in an ice bath, and then Dess-Martin periodinane (336 mg, 792 μmol) was slowly added in part. This mixture was warmed and stirred at 40°C for 16 hours. The reaction was quenched by adding 10% Na2S2O3 and saturated NaHCO3 (7:1). This mixture was stirred vigorously for 10 minutes. This mixture was extracted with EtOAC (3 times). The combined organic phases were washed with brine, dried on MgSO4, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to obtain the desired compound.

[0412] Preparation of N-((1S,3S)-3-(5-((benzyloxy)methyl)oxazole-2-yl)-3-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide (General Method-34) [ka] (1S,3S)-N-(3-(benzyloxy)-2-oxopropyl)-1-((((1s,4R)-4-(3-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide (109 mg, 0.14 mmol) was dissolved in THF (15 mL). Burgess reagent (0.25 g, 1.06 mmol) was added, and the reaction mixture was heated at 110°C for 15 minutes under an argon atmosphere. Burgess reagent (0.50 g, 2.1 mmol) was added, and the reaction mixture was heated at 110°C for 10 minutes under an argon atmosphere. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to obtain the desired compound.

[0413] Preparation of N-((1S,3S)-3-(5-(hydroxymethyl)oxazol-2-yl)-3-((((1s,4R)-4-(3-hydroxyphenyl)cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide (General Method-34, INT-8) [ka] Pd / C (59 mg, 10 wt%, 55 μmol) was added to N-((1S,3S)-3-(5-((benzyloxymethyl)oxazole-2-yl)-3-((((1s,4R)-4-(3-(benzyloxyphenyl)cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide (89 mg, 92 μmol) in ethyl acetate (9 mL) and MeOH (7.5 mL) under an argon atmosphere. Hydrogen was bubbling through the reaction mixture for 30 minutes. The reaction mixture was then stirred at room temperature under a hydrogen atmosphere for 90 minutes. The reaction mixture was filtered through a Celite plug and concentrated under vacuum to obtain the desired compound.

[0414] The following intermediates were prepared by the same method: Prepared from N-((1S,3R)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-((R)-1-hydroxyethyl)oxazole-2-yl)cyclopentyl)methanesulfonamide, (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxylic acid and (2S,3R)-2-amino-3-(benzyloxy)butan-1-ol

[0415] Preparation of (1S,3S)-1-((benzyloxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentane-1-carboxamide (General Method-35) [ka] A solution of LiOH (2.30 g, 96.2 mmol) in water (42 mL) was added to methyl (1S,3S)-1-((benzyloxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentane-1-carboxylate (4.5 g, 9.62 mmol) in THF (62 mL) and MeOH (58 mL). This mixture was stirred at 60°C for 4 hours.

[0416] The reaction mixture was cooled, concentrated directly under vacuum, co-evaporated with anhydrous toluene, and then dried under vacuum. It was used directly in the next step.

[0417] The product obtained above, along with ammonium bicarbonate (15.2 g, 193 mmol), was added at 0°C to a dry flask containing dichloromethane (248 mL) and DMF (4 mL). Then, Et3N (6.7 mL, 48.2 mmol), HOAt (1.93 mL, 1.93 mmol) as a 1 M solution in DMA, and HATU (14.6 g, 38.5 mmol) were added. This mixture was warmed and stirred at room temperature for 16 hours.

[0418] The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0419] Preparation of ethyl 2-((1S,3S)-1-((benzyloxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (General Method-35) [ka] Sodium bicarbonate (3.54 g, 42.1 mmol) was added to (1S,3S)-1-((benzyloxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentane-1-carboxamide (3.60 g, 7.01 mmol) and ethyl bromopirubate (4.40 mL, 35.1 mmol) in anhydrous THF (63 mL). The mixture was stirred at 90°C for 16 hours.

[0420] The reaction mixture was cooled, filtered through a Celite plug, and washed with THF. The filtrate was collected and concentrated. The residue was dissolved in anhydrous THF (63 mL) and cooled to 0°C. Anhydrous trifluoroacetic acid (4 mL, 28.1 mmol) was added dropwise. The mixture was stirred at 0°C for 2 hours.

[0421] The reaction mixture was quenched by adding saturated NaHCO3 and extracted with ethyl acetate. The organic phase was washed with brine and concentrated. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0422] Preparation of ethyl 2-((1S,3S)-1-(hydroxymethyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (General Method-35) [ka] Ethyl 2-((1S,3S)-1-((benzyloxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (3.7 g, 6.5 mmol) was dissolved in dichloromethane (42 mL) and MeOH (26 mL) under argon. Then, palladium carbon (0.34 g, 10 wt%) was added. The atmosphere was switched to H2. The reaction mixture was stirred at room temperature under an H2 balloon for 2 hours.

[0423] Next, the reaction mixture was filtered through a Celite plug. The filtrate was concentrated until dry, and then dried under high vacuum to obtain the product.

[0424] Preparation of ethyl 2-((1R,3S)-1-formyl-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (General Method-35, INT-18) [ka] In a pre-dried flask, a solution of oxalyl dichloride (330 μL, 3.85 mmol) in anhydrous dichloromethane (10 mL) was slowly added to anhydrous DMSO (0.55 mL, 7.69 mmol) at -78°C. After stirring for 1 hour, ethyl 2-((1S,3S)-1-(hydroxymethyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (1450 mg, 3.20 mmol) in anhydrous dichloromethane (20 mL) was added over 2 minutes, and the reaction mixture was stirred for a further 1 hour at -78°C. The mixture was then added to anhydrous triethylamine (2.1 mL, 15.06 mmol), and the reaction mixture was allowed to reach room temperature over 16 hours.

[0425] Next, the reaction mixture was quenched with water and extracted with dichloromethane. The dichloromethane phase was washed with saturated NH4Cl, and then with brine. The organic phase was concentrated. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0426] Preparation of ethyl 2-((1S,3S)-1-((R)-(3-chloro-4-fluorophenyl)(hydroxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (General Method-36) [ka] In a dry flask containing ethyl 2-((1R,3S)-1-formyl-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (940 mg, 1.98 mmol), anhydrous THF (16 mL) was added under argon. Then, a solution of (3-chloro-4-fluorophenyl)magnesium chloride (488 mg, 2.58 mmol) in anhydrous THF (5 mL) was added over 2 minutes at -10°C. The mixture was left to stir at -10°C for 1 hour.

[0427] The reaction mixture was quenched with ammonium chloride, and the aqueous phase was extracted with dichloromethane. The organic phase was washed with brine and concentrated. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0428] Preparation of ethyl 2-((1R,3S)-1-((R)-(3-chloro-4-fluorophenyl)fluoromethyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (General Method-36, INT-17) [ka] DAST (203 μL, 1.53 mmol) was added to ethyl 2-((1S,3S)-1-((R)-(3-chloro-4-fluorophenyl)(hydroxy)methyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (330 mg, 511 μmol) in anhydrous dichloromethane (16 mL). The mixture was stirred under argon at 25°C for 1 hour.

[0429] The reaction mixture was quenched by adding saturated NaHCO3. The mixture was vigorously stirred for 10 minutes. This mixture was extracted with dichloromethane. The organic phase was collected, washed with brine, and concentrated. The crude product was purified by flash chromatography on silica gel chromatography to obtain the desired product.

[0430] Preparation of ethyl 2-((1R,3S)-1-((R)-(2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)fluoromethyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (General Method-22) [ka] In a microwave vial, ethyl 2-((1R,3S)-1-((R)-(3-chloro-4-fluorophenyl)fluoromethyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (266 mg, 415 μmol) was added to water (3 mL) and 1,4-dioxane (21 mL). (2-(benzyloxy)-3-fluorophenyl)boronic acid (153 mg, 623 μmol) and potassium phosphate (176 mg, 830 μmol) were added. Argon was sprayed over this solution for 10 minutes. XPhos Pd G2 (32.7 mg, 41.5 μmol) was added, and argon was sprayed over the solution for 5 minutes. The reaction mixture was heated under argon at 80°C for 15 minutes.

[0431] The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0432] Preparation of N-((1S,3R)-3-((R)-(2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)fluoromethyl)-3-(4-(hydroxymethyl)oxazole-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (General Method-36, INT-13') [ka] A solution of ethyl 2-((1R,3S)-1-((R)-(2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)fluoromethyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (222 mg, 270 μmol) in anhydrous THF (15 mL) was stirred at 0°C under an argon atmosphere. Then, lithium aluminum hydride (1 M in THF) (1.08 mL, 1.08 mmol) was added. The mixture was warmed and stirred at room temperature for 1 hour.

[0433] This mixture was filtered through a Celite plug and washed with ethyl acetate. The filtrate was then diluted with saturated NH4Cl. This mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated under vacuum. The crude product was used directly in the next step.

[0434] Preparation of N-((1S,3R)-3-((R)-(3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)fluoromethyl)-3-(4-(hydroxymethyl)oxazole-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (INT-13) [ka] Palladium carbon (20 mg, 10 wt%) was added to N-((1S,3R)-3-((R)-(2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)fluoromethyl)-3-(4-(hydroxymethyl)oxazole-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (198 mg, 190 μmol) in ethyl acetate (19 mL) and MeOH (4 mL) under an argon atmosphere. The reaction mixture was bubbling with H2 for 10 minutes, and then stirred with an H2 balloon at room temperature for 2 hours.

[0435] This mixture was filtered through a Celite plug, washed with ethyl acetate, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0436] Preparation of N-(4-methoxybenzyl)-N-((1R,3S,Z)-3',6',7'-trifluorospiro[cyclopentan-1,6'-3-oxa-5(4,2)-oxazole a-1(1,3),2(1,2)-dibenzenacycloheptaphan]-3-yl)methanesulfonamide [ka] A dry flask containing a solution of N-((1S,3R)-3-((R)-(3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)fluoromethyl)-3-(4-(hydroxymethyl)oxazole-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (111 mg, 169 μmol) in dichloromethane (11 mL) was mixed with thionyl chloride (185 μL, 2.54 mmol) at 0°C. The mixture was heated at 40°C for 10 hours. The reaction mixture was cooled, quenched with saturated NaHCO3, and extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. The product was further dried under high vacuum to obtain the product, which was used directly in the next step without further purification. The product obtained above was dissolved in anhydrous acetonitrile (18 mL). Next, this solution was slowly added dropwise over 15 hours at 80°C to a mixture of Cs2CO3 (165 mg, 505 μmol) in anhydrous acetonitrile (70 mL) via a syringe pump. The mixture was then stirred at 80°C for a further 1 hour. The reaction mixture was cooled and concentrated. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0437] Preparation of methyl(1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboimidate (General Method-37) [ka] (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide (2.11 g, 3.85 mmol) was dissolved in anhydrous dichloromethane (15.4 mL) and cooled to 0°C. Trimethyloxonium tetrafluoroborate (1.14 g, 7.71 mmol) was added to this mixture, and the mixture was stirred at room temperature for 90 minutes.

[0438] The reaction products were quenched with saturated NaHCO3 aqueous solution and extracted with dichloromethane. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0439] Preparation of (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboximidoamide hydrochloride (General method - 37) [ka] Methyl(1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboimidate (867 mg, 1.43 mmol) and ammonium chloride (916 mg, 17.1 mmol) were suspended in MeOH (14.3 mL) in a capped microwave vial and stirred overnight at 80°C. This mixture was concentrated under vacuum, resuspended in dichloromethane, and filtered. The filter cake was washed with MeOH, and the filtrate was concentrated to obtain the desired product.

[0440] Preparation of ethyl 2-((1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentyl)pyrimidine-4-carboxylate (General Method-37) [ka] (1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentan-1-carboximidoamide hydrochloride (1.00 g, 1.40 mmol) and K2CO3 (484 mg, 3.50 mmol) were suspended in acetonitrile (9.35 mL). To this solution, ethyl(E)-4-(dimethylamino)-2-oxobuta-3-enoate (200 mg, 1.17 mmol) in acetonitrile (2.34 mL) was added, and the mixture was heated at 120°C for 3.5 hours.

[0441] This mixture was concentrated, and the resulting residue was separated into ethyl acetate and water. The phases were separated, the organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was purified by flash chromatography (ethyl acetate / heptane) to obtain the desired product.

[0442] Preparation of N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)pyrimidine-2-yl)cyclopentyl)methanesulfonamide (General Method-37) [ka] Ethyl 2-((1R,3S)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamide)cyclopentyl)pyrimidine-4-carboxylate (363 mg, 520 μmol) was dissolved in anhydrous THF (7.4 mL) and cooled to 0°C under an argon atmosphere. Sodium borohydride (79.0 mg, 2.10 mmol) and MeOH (126 μL) were added, and the mixture was stirred at 0°C for 2 hours, then slowly warmed to room temperature overnight.

[0443] The mixture was cooled to 0°C and quenched with water. Volatile substances were removed under vacuum, and the aqueous turbidity was extracted with dichloromethane. The combined organic phase was dried over MgSO4, filtered, and concentrated under vacuum to obtain the desired product, which was used without further purification.

[0444] Preparation of N-((1S,3R)-3-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)pyrimidine-2-yl)cyclopentyl)methanesulfonamide (General Method-37, INT-8) [ka] N-((1S,3R)-3-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)pyrimidine-2-yl)cyclopentyl)methanesulfonamide (323 mg, 513 μmol) and Pd / C (109 mg, 103 μmol) were suspended in MeOH (12.8 mL). H2 gas was bubbling through the turbidity, and the mixture was stirred under an H2 atmosphere for 90 minutes. The turbidity was filtered on Celite and concentrated under vacuum to obtain the desired product, which was used without further purification.

[0445] The following intermediates were prepared by the same method: Prepared from N-((1r,4r)-4-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(4-(hydroxymethyl)pyrimidine-2-yl)cyclohexyl)methanesulfonamide and (1r,4r)-1-((2'-(benzyloxy)-3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamide)cyclohexane-1-carboxamide

[0446] Preparation of (1'S,14R)-6-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaene-14,3'-cyclopentane]-1'-amine (General Method - 29) [ka] In a microwave vial, HBr (33 wt% in AcOH) (1 mL, 5.65 mmol) was added to N-[(1'S,14R)-6-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide (100 mg, 226 μmol) in AcOH (5 mL). The vial was sealed and the mixture was stirred at 80°C for 20 hours. The reaction mixture was concentrated directly under vacuum. The residue was diluted with saturated NaHCO3 and then extracted with dichloromethane. The combined organic phase was washed with brine and concentrated under vacuum. The crude product was purified by silica gel chromatography to obtain the desired product.

[0447] Preparation of N-((1S,3R)-3-(3-bromo-4-fluorobenzyl)-3-(4-(hydroxymethyl)oxazole-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide. [ka] To a mixture of ethyl 2-((1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonamide)cyclopentyl)oxazole-4-carboxylate (2.4 g, 3.938 mmol) in THF (20 mL) being stirred, NaBH4 (1489 mg, 39.380 mmol) was added in installments at 0°C. The resulting mixture was stirred at 50°C for 16 hours. The desired product was detected by LC-MS. The reaction mixture was quenched by slowly adding it in installments to a saturated NH4Cl (aq.) (500 mL) solution at 0°C. The resulting mixture was extracted with ELISA (3 x 50 mL). The combined organic layers were washed with brine (3 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 20-90 gradient over 10 minutes; detector, UV 220 nm. This yielded the desired product.

[0448] Preparation of methyl(1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboimidate (General Method - 39) [ka] A solution of (1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboxamide (1 g, 2.089 mmol) and trimethyloxonium tetrafluoroborate (618 mg, 4.178 mmol) in DCE (20 mL) was stirred overnight at 50°C. The reaction mixture was quenched at 0°C by adding water (100 mL). The aqueous layer was extracted with DCM (3 x 100 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 100% gradient over 30 minutes; detector, UV 254 nm. The desired product was obtained.

[0449] Preparation of (1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboximamide (General Method - 39) [ka] A solution of methyl(1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboimidate (500 mg, 1.284 mmol) and NH4Cl (824 mg, 15.408 mmol) in MeOH with NH3 (10 mL) was sealed and stirred at 80°C for 3 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (2 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product (500 mg) was used directly in the next step without further purification.

[0450] Preparation of ethyl 2-((1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentyl)pyrimidine-4-carboxylate (General Method-39) [ka] A solution of (1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentane-1-carboximidoamide (500 mg, 1.336 mmol) and K2CO3 (554 mg, 4.008 mmol) in MeCN (5 mL) was treated with ethyl (3E)-4-(dimethylamino)-2-oxobuta-3-enoate (274 mg, 1.603 mmol) at room temperature for 2 minutes. The resulting mixture was stirred at 120 °C for 3 hours. The resulting mixture was dissolved in ELISA (200 mL). The organic layer was extracted with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 100% gradient over 30 minutes; detector, UV 254 nm. This resulted in obtaining the desired product.

[0451] Preparation of N-((1S,3R)-3-(3-bromobenzyl)-3-(4-(hydroxymethyl)pyrimidine-2-yl)cyclopentyl)methanesulfonamide (General Method-39) [ka] A solution of ethyl 2-((1R,3S)-1-(3-bromobenzyl)-3-(methylsulfonamide)cyclopentyl)pyrimidine-4-carboxylate (300 mg, 0.622 mmol) in THF (10 mL) was treated with MeOH (119 mg, 3.732 mmol) under a nitrogen atmosphere at 0°C for 2 minutes, and then NaBH4 (94 mg, 2.488 mmol) was added in installments at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The reaction product was quenched with water (10 mL) at 0°C. The resulting mixture was extracted with CH2Cl2 (100 mL). The organic layer was extracted with water (2 x 100 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / siRNA (1:1) to obtain the desired product.

[0452] Preparation of methyl N-((1S,3R)-3-((3'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)pyrimidine-2-yl)cyclopentyl)methanesulfonamide (General Method-39) [ka] A solution of N-((1S,3R)-3-(3-bromobenzyl)-3-(4-(hydroxymethyl)pyrimidine-2-yl)cyclopentyl)methanesulfonamide (100 mg, 0.227 mmol), XPhos Pd G3 (19 mg, 0.023 mmol), Cs2CO3 (222 mg, 0.681 mmol), and 3-hydroxyphenylboronic acid (47 mg, 0.341 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 80°C for 2 hours under an argon atmosphere. The resulting mixture was extracted with  (2 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 100% gradient over 10 minutes; detector, UV 254 nm. The desired product was obtained.

[0453] The following intermediates were prepared by the same method: N-((1S,3R)-3-(4-(hydroxymethyl)pyrimidine-2-yl)-3-((3',4',6-trifluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide prepared from (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and (3,4-difluoro-2-hydroxyphenyl)boronic acid, N-((1S,3R)-3-((6-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)pyrimidine-2-yl)cyclopentyl)methanesulfonamide prepared from (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 2-hydroxyphenylboronic acid, N-((1S,3R)-3-(4-(hydroxymethyl)pyrimidine-2-yl)-3-((3',5',6-trifluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide, prepared from (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide)cyclopentan-1-carboxamide and 3,5-difluoro-2-hydroxyphenylboronic acid, N-((1S,3R)-3-((4',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)pyrimidine-2-yl)cyclopentyl)methanesulfonamide prepared from (1R,3S)-1-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamide) and 4-fluoro-2-hydroxyphenylboronic acid, Prepared from N-[(1S,3R,4S)-3-({3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl}methyl)-3-[4-(hydroxymethyl)pyrimidine-2-yl]-4-methylcyclopentyl]methanesulfonamide, rac-(1R,2S,4S)-1-(3-bromo-4-fluorobenzyl)-2-methyl-4-(methylsulfonamide)cyclopentan-1-carboxamide and 3-fluoro-2-hydroxyphenylboronic acid. Prepared from N-((1R,2R,4R,5S)-4-((3',6-difluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-4-(4-(hydroxymethyl)pyrimidine-2-yl)bicyclo[3.1.0]hexane-2-yl)methanesulfonamide, (1S,2R,4R,5R)-2-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamide)bicyclo[3.1.0]hexane-2-carboxamide and 3-fluoro-2-hydroxyphenylboronic acid. Prepared from N-((1R,2R,4R,5S)-4-(4-(hydroxymethyl)pyrimidine-2-yl)-4-((3',5',6-trifluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)bicyclo[3.1.0]hexane-2-yl)methanesulfonamide, (1S,2R,4R,5R)-2-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamide)bicyclo[3.1.0]hexane-2-carboxamide and (3,5-difluoro-2-hydroxyphenyl)boronic acid.

[0454] Preparation of N-((1S,3R)-3-(4-(chloromethyl)pyrimidine-2-yl)-3-((3'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide (General Method-39) [ka] A solution of N-((1S,3R)-3-((3'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(4-(hydroxymethyl)pyrimidine-2-yl)cyclopentyl)methanesulfonamide (110 mg, 0.243 m...

Claims

1. Compounds of general formula (I) 【Chemistry 1】 (In the formula, L is (C １ ~C ３ ) Selected from alkylenes, and the above (C １ ~C ３ ) Alkylenes each independently contain deuterium and (C １ ~C ４ ) optionally substituted with one or more substituents selected from alkyl groups; Q is (C １ ~C ２ ) is alkylene; T is selected from the group consisting of -O-, -NH- and -NR ｅ -, and R ｅ represents (C １ ~C ４ ) alkyl; X is -(CR ａ R ｂ )-, -O- or represents a bond, R ａ and R ｂ These are, independently, hydrogen and (C) １ ~C ４ ) Selected from the group consisting of alkyl groups; Y represents a combination or -O-; Z is phenyl, pyridyl, (C ４ ~C ６ ) Cycloalkyl and (C ２ ~C ４ ) Selected from the group consisting of alkylenes, wherein phenyl and pyridyl are each independently R ３ Optionally substituted with one or more substituents selected from; Ar １ R is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl, and each of the phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl is independently R ４ Optionally substituted with one or more substituents selected from; Ar ２ is selected from the group consisting of oxazolyl, oxadiazolyl, thiazolyl, pyrimidinil, oxodihydropyrimidinil and thiadiazolyl; and each of the oxazolyl, oxadiazolyl, thiazolyl, pyrimidinil, oxodihydropyrimidinil and thiadiazolyl is independently R ５ Optionally substituted with one or more substituents selected from; R １ is hydrogen, or R １ and R ａ Or R ｂ C ３ - May form a cycloalkyl group; R ２ is, (C １ ~C ４ ) alkyl, (C ３ ~C ６ ) Cycloalkyl, Halo(C １ ~C ４ ) alkyl, halo(C ３ ~C ６ ) Cycloalkyl, (C ３ ~C ６ ) Heterocycloalkyl and -NR ｃ R ｄ Selected from the group consisting of R ｃ and R ｄ These are, independently, hydrogen and (C) １ ~C ４ ) Selected from the group consisting of alkyl groups; R ３ is halogen, (C １ ~C ４ ) alkyl and halo(C １ ~C ４ ) Selected from the group consisting of alkyl groups; R ４ is halogen, (C １ ~C ４ ) alkyl and halo(C １ ~C ４ ) Selected from the group consisting of alkyl groups; R ５ is, (C １ ~C ４ ) is alkyl; R ６ and R ７ (Each of these is independently selected from the group consisting of hydrogen and halogens.) or a pharmaceutically acceptable salt thereof.

2. General formula (Ia) 【Chemistry 2】 The compound according to claim 1.

3. Ar ２ The compound according to claim 1 or 2, wherein is oxazolyl.

4. Ar １ Each of them is R independently ４ The compound according to any one of claims 1 to 3, wherein the compound is a phenyl optionally substituted with one or more substituents selected from the following.

5. Q is C １ - A compound according to any one of claims 1 to 4, which is an alkylene.

6. x is - (CH ２ The compound according to any one of claims 1 to 5, wherein the compound is:

7. The compound according to any one of claims 1 to 6, wherein T is -O-.

8. Z is R, each independently ３ The compound according to any one of claims 1 to 7, wherein the compound is a phenyl optionally substituted with one or more substituents selected from the following.

9. The compound according to any one of claims 1 to 8, wherein Y is a bond.

10. L is C １ - A compound according to any one of claims 1 to 9, which is an alkylene.

11. R １ The compound according to any one of claims 1 to 10, wherein is hydrogen.

12. Compound according to claim 1 or 2 of general formula (Id) 【Transformation 3】 (In the formula, Z is phenyl, pyridyl, (C ４ ~C ６ ) Cycloalkyl and (C ２ ~C ４ ) Selected from the group consisting of alkylenes, wherein phenyl and pyridyl are each independently R ３ Optionally substituted with one or more substituents selected from; Ar １ R is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl, and each of the phenyl, pyridyl, pyrazolyl, pyrimidinyl, and thiazolyl is independently R ４ Optionally substituted with one or more substituents selected from; R ２ is selected from the group consisting of (C １ -C ４ )alkyl, (C ３ -C ６ )cycloalkyl, halo(C １ -C ４ )alkyl, halo(C ３ -C ６ )cycloalkyl, (C ３ -C ６ )heterocycloalkyl and -NR ｃ R ｄ , and R ｃ and R ｄ are each independently selected from the group consisting of hydrogen and (C １ -C ４ )alkyl; R ３ is selected from the group consisting of halogen, (C １ -C ４ )alkyl, and halo(C １ -C ４ )alkyl; R ４ is halogen, (C １ ~C ４ ) alkyl and halo(C １ ~C ４ (Selected from the group consisting of alkyl groups) or a pharmaceutically acceptable salt thereof.

13. Z is phenyl, and each of the phenyl molecules is independently R ３ Optionally substituted with one or more substituents selected from; Ar １ is phenyl, and each of the phenyl molecules independently is R ４ Optionally substituted with one or more substituents selected from; R ２ is, (C １ ~C ４ ) alkyl and (C ３ ~C ６ ) Selected from the group consisting of cycloalkyl groups; R ３ is halogen, (C １ ~C ４ ) alkyl and halo(C １ ~C ４ ) A group consisting of alkyl; R ４ is halogen and (C １ ~C ４ ) A group consisting of alkyl; The compound according to claim 12, or a pharmaceutically acceptable salt thereof.

14. The aforementioned compound, N-[(1s,1'S,14R,17s)-spiro[7,12,16-trioxa-22-azatetracyclo[15.2.2.12,6.110,13]tricosa-2,4,6(23),10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,11,15-trioxa-21,22-diazatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,12(21)-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,9S,14R)-6,19-difluoro-9-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2(7),3,5,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,8R)-spiro[10,15-dioxa-20,21-diazatetracyclo[14.3.1.12,6.19,12]docosa-1(19),2(22),3,5,9(21),11,16(20),17-octaen-8,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-9,9-dijuterio-19-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-9,9-dijuterio-6,19-difluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,21-dioxa-12-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,12,16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-spiro[8,12-dioxa-6,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide N-[(1'S,14R)-17-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, (1'S,14R)-19-fluoro-N-(methylsulfamoyl)spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaene-14,3'-cyclopentane]-1'-amine, (3'S,14R)-3'-(dimethylsulfamoylamino)-19-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaene-14,1'-cyclopentane], N-[(1'S,14R)-5,6,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-5,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-chloro-6-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,17-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-17,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-fluorospiro[8,12-dioxa-19,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-chloro-19-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, N-[(1'S,14R)-6-fluoro-19-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-fluoro-19-(trifluoromethyl)spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-(trifluoromethyl)spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluoro-11-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-fluoro-11-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-3,6,17-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-5,6,17-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-chloro-17-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-4,6,17,19-tetrafluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-chloro-5,6-difluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-17-chloro-6,19-difluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]cyclopropanesulfonamide, N-[(1'S,14R)-5,6,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]cyclopropanesulfonamide, N-[(1'S,14R)-5,6,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8-oxa-12-thia-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-fluoro-6-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,8S)-Spiro[2,6,10-Trioxa-18-Azatricyclo[11.3.1.14,7]Octadeca-1(17),4,7(18),13,15-Pentaen-8,3'-Cyclopentane]-1'-Il]Methanesulfonamide N-[(1s,1'S,14R,17s)-spiro[8,12,16-trioxa-22-azatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,15,21-trioxa-11-azatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,11-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,11,15-trioxa-21-azatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,12(21)-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8-oxa-12-thia-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-spiro[7,11-dioxa-20,21-diazatetracyclo[13.3.1.12,6.19,12]henicosa-1(19),2,4,6(21),9,12(20),15,17-octaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-spiro[7,11-dioxa-20-azatetracyclo[13.3.1.12,6.19,12]henicosa-1(19),2,4,6(21),9,12(20),15,17-octaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14S)-spiro[8,12-dioxa-17,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-20-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-20-fluorospiro[8,12-dioxa-6,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-17,20-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19,20-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19,20-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,4'S,14R)-6,19-difluoro-4'-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'R,4'R,14S)-6,19-difluoro-4'-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'R,4'R,14S)-19-fluoro-4'-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,4'S,14R)-19-fluoro-4'-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,13S,16s)-spiro[7,11,15-trioxa-3,21,22-triazatetracyclo[14.2.2.12,6.19,12]docosa-2,4,6(22),9,12(21)-pentaen-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,14R,17s)-spiro[8,12,16-trioxa-11,22-diazatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,14R,17s)-spiro[8,12,16-trioxa-3,22-diazatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1S,8S)-spiro[2,6,10-trioxa-19-azatricyclo[12.3.1.14,7]nonadeca-1(18),4,7(19),14,16-pentaen-8,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-11-methylspiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-4,6,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,14R,17s)-spiro[8,11,16-trioxa-12,22-diazatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10(22),12-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,21-dioxa-11,12-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2(7),3,5,10,12,16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,10r,12s,15S)-spiro[3,13,17-trioxa-19-azatetracyclo[14.2.1.110,12.04,9]icosa-1(18),4,6,8,16(19)-pentaen-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1s,1'S,14R,17s)-spiro[8,12,16-trioxa-6,22-diazatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-spiro[12-oxa-6,8,21-triazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-(cis)-(6-fluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,4'-cyclohexane]-1'-yl)methanesulfonamide N-[(1'S,14R)-19-chloro-4,6-difluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R,15S)-6,15,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R,15R)-6,15,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14S)-spiro[8,12-dioxa-20,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-18-fluoro-4-methyl-spiro[7,11-dioxa-4,5,20-triazatetracyclo[13.3.1.19,12.02,6]icosa-1(18),2,5,9,12(20),15(19),16-heptaene-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-6,20-difluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2(7),3,5,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-16,18-difluoro-4-methyl-spiro[7,11-dioxa-4,5,20-triazatetracyclo[13.3.1.19,12.02,6]icosa-1(18),2,5,9,12(20),15(19),16-heptaene-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]ethanesulfonamide, N-[(1'S,9R,14R)-6,19-difluoro-9-methyl-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2(7),3,5,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-spiro[7-oxa-12,21-diazatetracyclo[14.3.1.12,6.19,13]docosa-1(20),2,4,6(22),9,11,13(21),16,18-nonaene-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-5,6,20-trifluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,9R*,15R)-9-methylspiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,9S*,15R)-9-methylspiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-20-fluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-4,6,20-trifluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-5,20-difluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,4'S,15R)-6,20-difluoro-4'-methyl-spiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'R,4'R,15S)-6,20-difluoro-4'-methyl-spiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-6,20-difluorospiro[8-oxa-11,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2,4,6,10,12,14(22),17(21),18-nonaene-15,3'-cyclopentane]-1'-yl]methanesulfonamide, trans-N-(6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,4'-cyclohexane]-1'-yl)methanesulfonamide, trans-N-(6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,4'-cyclohexane]-1'-yl)methanesulfonamide, trans-N-(6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclobutane]-1'-yl)methanesulfonamide, N-[(1'R,14S)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1R,1'S,14S,17R)-6-fluorospiro[8,12,16-trioxa-22-azatetracyclo[15.2.2.110,13.02,7]docosa-2,4,6,10,13(22)-pentaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,15R)-6,18,20-trifluoro-12-oxo-spiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(20),2(7),3,5,10,14(22),17(21),18-octaen-15,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,13R)-18-fluoro-4-methyl-spiro[7,11-dioxa-3-thia-5,20-diazatetracyclo[13.3.1.19,12.02,6]icosa-1(18),2(6),4,9,12(20),15(19),16-heptaene-13,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-19-(difluoromethyl)-6-fluoro-spiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]cyclopropanesulfonamide, N-[(1'S,14R)-6,17-difluorospiro[8,12-dioxa-19,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14S)-6,19-difluorospiro[8,12-dioxa-17,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'R,14S)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, trans-N-(6,20-difluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaene-15,4'-cyclohexane]-1'-yl)methanesulfonamide, N-[(3'R,14S)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-1',5'-tetrahydrofuran'-3'-yl]methanesulfonamide, N-[(3'S,14R)-6,17,19-trifluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10,13(21),16(20),17-octaen-1',5'-tetrahydrofuran'-3'-yl]methanesulfonamide, N-[(1'S,14R)-6,17,19-trifluorospiro[8-oxa-11-thia-12,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2,4,6,10(21),12,16(20),17-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-11,21-diazatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]methanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]-1-fluoromethanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(19),2(7),3,5,10,13(21),16(20),17-octaen-14,3'-cyclopentane]-1'-yl]-1,1,1-trifluoromethanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]-1,1-difluoromethanesulfonamide, N-[(1'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,3'-cyclopentane]-1'-yl]-1-fluorocyclopropanesulfonamide, N-[(1'R,2'R,5'S,14R)-6,19-difluorospiro[8,12-dioxa-21-azatetracyclo[14.3.1.110,13.02,7]henicosa-1(20),2,4,6,10,13(21),16,18-octaen-14,4'-bicyclo[3.1.0]hexane]-2'-yl]methanesulfonamide, N-[(1'R,2'R,5'S,15R)-6,20-difluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaene-15,4'-bicyclo[3.1.0]hexane]-2'-yl]methanesulfonamide, and N-[(1'R,2'R,5'S,15R)-4,6,20-trifluorospiro[8-oxa-13,22-diazatetracyclo[15.3.1.110,14.02,7]docosa-1(21),2,4,6,10,12,14(22),17,19-nonaene-15,4'-bicyclo[3.1.0]hexane]-2'-yl]methanesulfonamide, A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from the list comprising the above.

15. A compound according to any one of claims 1 to 14 for use in therapeutic applications.

16. A compound according to any one of claims 1 to 14 for use in the treatment of narcolepsy, such as narcolepsy type 1 or narcolepsy type 2.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 together with one or more pharmaceutically acceptable excipients or carriers.

18. The pharmaceutical composition according to claim 17, comprising one or more other therapeutically active compounds.

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