Orexin 2 receptor agonists

Abstract

The present invention relates to novel compounds of general formula (I) which are Orexin 2 receptor agonists.

Description

[0001] OREXIN 2 RECEPTOR AGONISTS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel compounds which are Orexin 2 receptor agonists, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds and to methods of treating diseases with said compounds.

[0004] BACKGROUND OF THE INVENTION

[0005] Orexin (hypocretin) is a neuropeptide which exist in two subtypes; Orexin A (OXA) and Orexin B (OXB). OXA and OXB both bind to orexin receptors which are G-protein coupled receptors mainly expressed in the brain. There are two subtypes of orexin receptors; orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R). OX1R is expressed primarily in the lateral hypothalamus and the mesolimbic system. OX1R regulates feeding behavior and modulates neurotransmitters such as dopamine and acetylcholine. OX2R has a wider expression in the brain, including in the hypothalamus, brainstem, and cortex. OX2R has been shown to play a key role in regulating the sleep-wake cycle and arousal (Chemelli et. al., Cell (1999), 98, 437-51; Dale, N. C. et. al. Front. Cell. Neurosci., (2022), 16, 812359). Hence, Orexin 2 receptor agonists are hypothesized to be useful as therapeutic agents for narcolepsy or other disorders displaying excessive daytime sleepiness.

[0006] Narcolepsy is a chronic neurological disorder that affects the control of sleep and wakefulness. The prevalence of narcolepsy is estimated to 0.02% to 0.05%. People with narcolepsy experience excessive daytime sleepiness (EDS) and are prone to sudden episodes of sleep (known as "sleep attacks") which 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 / hypnopompic hallucinations, and sleep paralysis. Narcolepsy is subclassified as narcolepsy type 1 (NT1, narcolepsy with cataplexy) and narcolepsy type 2 (NT2, narcolepsy without cataplexy). Narcolepsy is associated with loss or dysfunction of the orexin neurons which produce orexin; thus, narcolepsy is associated with a lack of or imbalance of orexin in the brain (Bassetti, C. et. al., Nat. Rev. Neurol., (2019), 15, 519-539). Other indications with orexin deficiencies have been reported, like Parkinson's Disease, Prader Willis Syndrome and Lewy Body Dementia and it has been hypothesized that orexin deficiency play a role in dysregulation of wakefulness or excessive daytime sleepiness in said diseases. (Thannickal, T. C. 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).

[0007] The orexin-ataxin 3 mouse model which displays a deficiency in orexin levels has been developed to study the underlying mechanisms of narcolepsy; the OX2R selective agonist Danavorexton (TAK-925) has been shown to reverse the sleepiness and cataplexy in orexin-ataxin 3 mice (Ishikawa, T.; Pharmacol. Biochem. Behav. (2022), 220, 173464). Furthermore, clinical studies indicate that the OX2R agonist Danavorexton increases wakefulness and alertness and reduces the number of cataplexy attacks 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). OXR2 agonist Oveporexton (TAK861) is being studied in two phase III trials (NCT06470828 and NCT06505031) for the treatment of Narcolepsy Type 1. Additionally, Alixorexton (ALKS 2680) is being studied in clinical trials in narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia.

[0008] Various compounds having orexin-2 receptor agonist activity have been reported, for example, W02019027058 discloses heterocyclic compounds and use thereof, W02020167706 discloses 5-alkyl pyrrolidine orexin receptor agonists, W02021026047 discloses heteroaryl pyrrolidine and piperidine orexin receptor agonists, WO2022051596 discloses bicyclic-heterocycle derivatives and their uses as orexin-2 receptor agonists, and WO2024075825 discloses cyclopentane compounds. WO2025211415 discloses substituted sulfonamide compounds.

[0009] However, there is a continued need for compounds which have orexin-2 receptor agonist activity, and which have favorable pharmacological and pharmaceutical properties. SUMMARY OF THE INVENTION

[0010] The inventors have surprisingly found that novel compounds of the present invention are modulators of the orexin-2 receptor. Thus, compounds of the present invention exhibit agonistic effect on the orexin-2 receptor.

[0011] Some compounds of the present invention furthermore possess favorable pharmacological and pharmaceutical properties such as favorable metabolic stability, permeability and / or selectivity.

[0012] Accordingly, in a first aspect the present invention provides a compound of general formula (I)

[0013]

[0014] wherein

[0015] X is -O- or -(CRaRb)- or a bond, wherein Raand Rbeach independently are selected from the group consisting of hydrogen and (C₁-C₄)alkyl;

[0016] Q is (C1-C2)alkylene;

[0017] Ri is hydrogen, or when X is -(CRaRb)- Ri and either Raor Rb together with the carbon atoms to which they are attached may optionally form a fused C3-cycloalkyl group;

[0018] R2is (C1-C4)alkyl, 3-6 membered heterocyclyl, (C3-C6)cycloalkyl or -NRcRd, wherein Rcand Rdeach independently are selected from the group consisting of hydrogen and (C1-C4)alkyl or wherein Rcand Rdtogether with the nitrogen to which they are attached form a 3-6 membered heterocyclyl;

[0019] Y represents a bond or -O-;

[0020] Z is phenyl, pyridyl, piperidinyl, (C6-C7)cycloalkylene, or (C2-C4)alkylene, wherein said phenyl, pyridyl or piperidinyl is optionally substituted with one or more substituents each independently selected from R3; Ar1is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is optionally substituted with one or more substituents each independently selected from R4;

[0021] Ar2is a 5- or 6- membered heteroaryl; wherein said 5- or 6- membered heteroaryl is optionally substituted with one or more substituents each independently selected from R5; R3and R4each independently are halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl or hydroxyl;

[0022] R5is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C3-C5)cycloalkyl or halogen;

[0023] or a pharmaceutically acceptable salt thereof.

[0024] In a further aspect, the 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.

[0025] In a further aspect, the invention provides compounds of formula (I) as disclosed herein or a pharmaceutically acceptable salt thereof for use in therapy.

[0026] DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

[0027] The term "alkyl" is intended to indicate a monovalent hydrocarbon radical formally obtained by the removal of one hydrogen atom from a branched or linear saturated hydrocarbon. Said alkyl comprises 1-4 carbon atoms, such as 1-3, such as 2-3 or such as 1-2 carbon atoms. The term includes the subclasses normal alkyl (n-alkyl), and 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. In the present context the term "cycloalkyl" is intended to indicate a monovalent hydrocarbon radical, formally obtained by the removal of one hydrogen atom from a cyclic saturated hydrocarbon. Said cycloalkyl comprises 3-7 carbon atoms, such as 3-6, such as 3-5 carbon atoms or such as 3-4 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, or cycloheptanyl. In the present context the term cycloalkyl may also indicate a fused cyclic saturated hydrocarbon, such as a fused cyclopropane. In the present context the term cycloalkyl may also indicate a bicyclic saturated hydrocarbon, such as for example bicycloheptane, such as for example bicyclo[4.1.0]heptane (norcarane).

[0028] The term "alkylene" is intended to indicate a divalent saturated hydrocarbon group, formally obtained by the removal of two hydrogen atoms from a branched or linear saturated hydrocarbon. Said alkylene comprises 1 to 6, and more preferably 1 to 4, such as 1 - 3 or 1 - 2 carbon atoms that are either straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-) (Ci alkylene), ethylene (-CH2CH2-) or (-CH(CH3)-) (C2 alkylene), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-) or (-CH(CH3)CH2-) (C3 alkylene), butylene (-CH2CH2CH2CH2-) (C4 alkylene), pentanylene (-CH2CH2CH2CH2CH2-) (C5 alkylene) and hexylene (-CH2CH2CH2CH2CH2CH2-) (C6hexylene).

[0029] The term "alkoxy" is intended to indicate a radical of the formula -OR', wherein R' is alkyl as indicated herein, wherein the alkyl group is appended to the parent molecular moiety through an oxygen atom, e.g. methoxy (-OCH3) or ethoxy (-OCH2CH3), and the like.

[0030] The term "cycloalkylene" is intended to indicate a divalent hydrocarbon radical obtained by the removal of two hydrogen atoms from a cyclic saturated hydrocarbon as defined herein. Said cycloalkylene comprises 5-7 carbon atoms, such as 6-7 carbon atoms, such as 6 carbon atoms or such as 7 carbon atoms. This term is exemplified by groups such as cyclohexylene (Ce-cycloalkylene) or bicycloheptanylene (C7-cycloalkylene), such as for example bicyclo[4.1.0]heptanylene.

[0031] The number of carbon atoms in a hydrocarbon radical (e.g. alkyl, cycloalkyl, alkylene as described herein) may be indicated by the prefix "(Ca-Cb)", wherein a is the minimum number and b is the maximum number of carbons in the hydrocarbon radical. Thus, for example (Ci-C4)alkyl is intended to indicate an alkyl radical comprising from 1 to 4 carbon atoms, (C3-Cs)cycloalkyl is intended to indicate a cycloalkyl radical comprising from 3 to 5 carbon ring atoms and (Ci-C2)alkylene is intended to indicate an alkylene radical comprising from 1 to 2 carbon atoms.

[0032] The term "halogen" is intended to indicate a substituent from the 7thmain group of the periodic table, such as fluoro and chloro.

[0033] The term "haloalkyl" is intended to indicate an alkyl group as defined herein substituted with one or more halogen atoms as defined herein, such as difluoromethyl or trifluoromethyl.

[0034] The term "heteroaryl" is intended to indicate radicals of 5- or 6-membered or 9-membered heteroaromatic mono or bicyclic rings which contains from 1-8 carbon atoms and from 1-8 heteroatoms selected from oxygen, sulfur and nitrogen. The heteroaryl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heteroaryl group. In the present context the term heteroaryl includes both monovalent and divalent species, which are formally obtained by the removal of one or two hydrogen atoms from the heteroaromatic ring.

[0035] The term "5 or 6 membered heteroaryl" is intended to indicate radicals of monocyclic heteroaromatic rings, comprising 5- or 6-membered rings, i.e. having a ring size of 5 or 6 atoms, which contain from 1-5 carbon atoms and from 1-5 heteroatoms selected from oxygen, sulphur and nitrogen, such as I heteroatom, such as 1-2 heteroatoms, such as 1-3 heteroatoms, such as 1-4 heteroatoms selected from oxygen, sulphur and nitrogen. The heteroaryl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heteroaryl group. Representative examples of 5-membered heteroaryl groups include, but are not limited to furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl. Representative examples of 6-membered heteroaryl groups include pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl. The term 9- membered heteroaryl is intended to indicate radicals of fused five and sixmembered heteroaromatic rings, which contain from 3-8 carbon atoms and from 1-6 heteroatoms selected from oxygen, sulphur and nitrogen, such as 1 heteroatom, such as 1-2 heteroatoms, such as 1-3 heteroatoms, such as 1-4 heteroatoms selected from oxygen, sulphur and nitrogen. The heteroaryl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heteroaryl group. Representative examples of 9-membered heteroaryl groups include, but are not limited to benzoimidazolyl, imidazopyrazinyl, pyrazolopyridinyl, imidazopyridinyl and indazolyl.

[0036] The term "heterocycloalkyl" is intended to indicate a cycloalkyl radical as described herein, wherein one or more carbon atoms are replaced by heteroatoms, comprising 1-5 carbon atoms, e.g. 2-5 or 2-4 carbon atoms, further comprising 1-5 heteroatoms, preferably 1, 2, or 3 heteroatoms, selected from O, N, or S. The heterocycloalkyl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heterocycloalkyl group. Representative examples of heterocycloalkyl groups include, but are not limited to azetidinyl, aziridinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetra hydropyranyl.

[0037] The term "hydroxyalkyl" is intended to indicate an alkyl group as defined above substituted with one or more hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl.

[0038] When two or more of the above defined terms are used in combination, such as (Ci-C4)alkoxy(Ci-C4)alkyl, it is to be understood that the first mentioned radical is a substituent on the latter mentioned radical, where the point of attachment to the parent molecular moiety is on the latter radical. If substituents are described as being independently selected from a group, each substituent is selected independent of the other. Each substituent may therefore be identical or different from the other substituent(s).

[0039] The term "optionally substituted" means "unsubstituted or substituted", and therefore the general formulas described herein encompasses compounds containing the specified optional substituent(s) as well as compounds that do not contain the optional substituent(s).

[0040] As used herein, the term 'substituted' means that one or more hydrogen atoms on the designated group is replaced with a selection from the indicated groups.

[0041] In the present context, a full drawn bond which is intersected by a wave-bond indicates a bond which connects the designated moiety to a neighboring moiety.

[0042] In the present context, "excipient" or "pharmaceutically acceptable excipient" refers to pharmaceutical excipients including, but not limited to, fillers, antiadherents, binders, coatings, colours, disintegrants, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, vehicles and adjuvants.

[0043] In the present context, "treatment" or "treating" is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partly arresting, removing or delaying progress of the clinical manifestation of the disease. " Treatment" can also indicate prophylactic treatment of the disease.

[0044] The patient or subject to be treated is preferably a mammal, in particular a human being.

[0045] In the present context the terms 'orexin receptor type 2', 'OX2R', and 'orexin 2 receptor' are used interchangeably. Stereochemistry

[0046] The compounds of the present invention may have one or more asymmetric centers and it is intended that any optical isomers (i.e. enantiomers or diastereomers) as separated, pure or partially purified optical isomers and any mixtures thereof including racemic mixtures, i.e. a mixture of stereoisomers, are included within the scope of the invention.

[0047] In this context is understood that when specifying the enantiomeric form, the compound is in enantiomeric excess, e.g. essentially in a pure form. Accordingly, one embodiment of the invention relates to a compound of the invention having an enantiomeric 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%.

[0048] Racemic forms can be resolved into the optical antipodes by known methods, for example by separation of diastereomeric salts thereof with an optically active acid and liberating the optically active amine compound by treatment with a base; or with an optically active base and liberating the optically active acidic compound by treatment with an acid. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives. Additional methods for the resolution of optical isomers, known to those skilled in the art, may 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 may be determined by methods known to the skilled person, such as vibrational circular dichroism (VCD) Spectroscopic analysis.

[0049] Some compounds of the present invention may exist as atropisomers. Atropisomers are stereoisomers which arise due to hindered rotation about a single bond for example due to steric strain, which creates an energy barrier to rotation around the single bond that is high enough to allow for isolation of individual conformers. When the substituents on the single bond are achiral, the conformers are enantiomers (atropoenantiomers). When the substituents on the single bonds are chiral the conformers are diastereomers (atropodiastereomers). Isotopes

[0050] Included in this invention are also isotopically labelled compounds, which are similar to those claimed in formula (I), wherein one or more atoms are represented by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (e.g.,2H,3H,11C,13C,15N,18F and the like). Particular mention is made of2H substituted compounds i.e., compounds wherein one or more H atoms are represented by deuterium.

[0051] In one embodiment of the invention one or more of the hydrogen atoms of the compound of formula [I] are represented by deuterium. It is recognized that elements are present in natural isotopic abundances in most synthetic compounds, and result in inherent incorporation of deuterium. However, the natural isotopic abundance of hydrogen isotopes such as deuterium is immaterial (about 0.015%) relative to the degree of stable isotopic substitution of compounds indicated herein. Thus, as used herein, designation of an atom as deuterium at a position indicates that the abundance of deuterium is significantly greater than the natural abundance of deuterium. Any atom not designated as a particular isotope is intended to represent any stable isotope of that atom, as will be apparent to the ordinarily skilled artisan. In one embodiment, designation of a position as " D" in a compound has a minimum deuterium incorporation of greater than about 60% at that position such as greater than about 70% at that position such as greater than about 80% at that position such as greater than about 85% at that position. In a further embodiment, designation of a position as " D" in a compound has a minimum deuterium incorporation of greater than about 90% at that position such as greater than about 95% at that position such as greater than about 97% at that position such as greater than about 99% at that position.

[0052] EMBODIMENTS OF THE INVENTION

[0053] In the following, embodiments of the invention are disclosed.

[0054] In a first aspect of the invention, a compound of general formula (I) is provided

[0055]

[0056] wherein

[0057] X is -O- or -(CRaRb)- or a bond, wherein Raand Rbeach independently are selected from the group consisting of hydrogen and (C₁-C₄)alkyl;

[0058] Q is (C1-C2)alkylene;

[0059] Ri is hydrogen, or when X is -(CRaRb)- Ri and either Raor Rb together with the carbon atoms to which they are attached may optionally form a fused C3-cycloalkyl group;

[0060] R2is (C1-C4)alkyl, 3-6 membered heterocyclyl, (C3-C6)cycloalkyl or -NRcRd, wherein Rcand Rdeach independently are selected from the group consisting of hydrogen and (C1-C4)alkyl or wherein Rcand Rdtogether with the nitrogen to which they are attached form a 3-6 membered heterocyclyl;

[0061] Y represents a bond or -O-;

[0062] Z is phenyl, pyridyl, piperidinyl, (C6-C7)cycloalkylene, or (C2-C4)alkylene, wherein said phenyl, pyridyl or piperidinyl is optionally substituted with one or more substituents each independently selected from R3;

[0063] Ari is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is optionally substituted with one or more substituents each independently selected from R4;

[0064] Ar2is a 5- or 6- membered heteroaryl; wherein said 5- or 6- membered heteroaryl is optionally substituted with one or more substituents each independently selected from R5; R3 and R4 each independently are halogen, (C₁-C₄)alkyl, (Ci-C4)alkoxy, halo(C₁-C₄)alkyl or hydroxyl;

[0065] R5is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C3-C5)cycloalkyl or halogen;

[0066] or a pharmaceutically acceptable salt thereof. In a further aspect of the invention, a compound of general formula (la) is provided

[0067]

[0068] (la)

[0069] Wherein X, Ra, Rb, Q, Ri, R2, Rc, Rd, Y, Z, R3, Ari, R4, Ar2 and Rs are as defined above.

[0070] In a further aspect of the invention, the compound of general formula (I) or (la) is not N-((lS,3R)-3-([l,l'-biphenyl]-3-ylmethyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide,

[0071] N-((lS,3R)-3-([l,l'-biphenyl]-3-ylmethyl)-3-(3-methoxypyridin-2-yl)cyclopentyl)methanesulfonamide,

[0072] N-((1S,3R)-3-(1-ethyl-1H-imidazol-2-yl)-3-(3-(pyrimidin-2-yl)benzyl)cyclopentyl)methanesulfonamide,

[0073] N-(3-([l,l'-biphenyl]-3-ylmethyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide, N-(3-([l,l'-biphenyl]-3-ylmethyl)-3-(3-methoxypyridin-2-yl)cyclopentyl)methanesulfonamide, or

[0074] N-(3-(l-ethyl-lH-imidazol-2-yl)-3-(3-(pyrimidin-2-yl)benzyl)cyclopentyl)methanesulfonamide,

[0075] or a pharmaceutically acceptable salt thereof.

[0076] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein X is -O- or -(CRaRb)- or a bond, wherein Raand Rbeach independently are selected from the group consisting of hydrogen and (C₁-C₄)alkyl;

[0077] Q is (C1-C2)alkylene;

[0078] Ri is hydrogen, or when X is -(CRaRb)- Ri and either Raor Rb together with the carbon atoms to which they are attached may optionally form a fused C3-cycloalkyl group;

[0079] R2is (C1-C4)alkyl, 3-6 membered heterocyclyl, (C3-C6)cycloalkyl or -NRcRd, wherein Rcand Rdeach independently are selected from the group consisting of hydrogen and (C1-C4)alkyl or wherein Rcand Rdtogether with the nitrogen to which they are attached form a 3-6 membered heterocyclyl;

[0080] Y represents a bond or -O-;

[0081] Z is phenyl, pyridyl, piperidinyl, (C6-C7)cycloalkylene, or (C2-C4)alkylene, wherein said phenyl, pyridyl or piperidinyl is optionally substituted with one or more substituents each independently selected from R3 and

[0082] Ari is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is substituted with one or more substituents each independently selected from R4; or

[0083] Z is phenyl, pyridyl, piperidinyl, (C6-C7)cycloalkylene, or (C2-C4)alkylene, wherein said phenyl, pyridyl or piperidinyl is substituted with one or more substituents each independently selected from R3 and

[0084] Ari is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is optionally substituted with one or more substituents each independently selected from R4;

[0085] Ar2is a 5- or 6- membered heteroaryl; wherein said 5- or 6- membered heteroaryl is optionally substituted with one or more substituents each independently selected from R5; R3 and R4 each independently are halogen, (C₁-C₄)alkyl, (Ci-C4)alkoxy, halo(C₁-C₄)alkyl or hydroxyl;

[0086] R5is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C3-C5)cycloalkyl or halogen; or a pharmaceutically acceptable salt thereof.

[0087] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein X is -O-, -CH2-, -CH(CH₃)- or a bond.

[0088] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein X is -CH2- or -CH(CH₃)-.

[0089] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Q is (Ci)alkylene.

[0090] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Q is (C2)alkylene.

[0091] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein R₁ is hydrogen.

[0092] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ri and either Raor Rb together with the carbon atoms to which they are attached form a fused Cs-cycloalkyl group.

[0093] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein R2 is (Ci-C4)a Ikyl or (C₃-C₆)cycloalkyl.

[0094] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein R2 is methyl, ethyl, propyl, isopropyl, oxetanyl, cyclopropyl, or-NRcRd, wherein Rcand Rd each independently are selected from the group consisting of hydrogen, methyl and ethyl or wherein Rcand Rd together with the nitrogen to which they are attached form azetidinyl; In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Y represents a bond.

[0095] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Y represents -O-.

[0096] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Z is phenyl, pyridyl, piperidinyl, cyclohexylene or bicycloheptanyl, wherein said phenyl, pyridyl or piperidinyl is optionally substituted with one or more substituents each independently selected from R3; and wherein R3 is the group consisting of halogen and (Ci-C4)alkyl.

[0097] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Z is phenyl, pyridyl, piperidinyl, cyclohexylene or bicycloheptanyl, wherein said phenyl, pyridyl or piperidinyl is substituted with one or more substituents each independently selected from R3; and wherein R3 is the group consisting of halogen and (Ci-C4)alkyl.

[0098] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Z is phenyl, wherein said phenyl is optionally substituted with one or more substituents each independently selected from R3; and wherein R3 is the group consisting of fluoro, chloro, methyl and ethyl.

[0099] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Z is phenyl, wherein said phenyl is substituted with one or more substituents each independently selected from R3; and wherein R3 is the group consisting of fluoro, chloro, methyl and ethyl.

[0100] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ari is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said 5-, 6- or 9-membered heteroaryl is selected from pyridyl, pyrimidyl, imidazolyl, imidazopyrazinyl, pyrazolopyridinyl, imidazopyridinyl, oxadiazolyl, indazolyl, pyrazolyl, furanyl, thiazolyl, isoxazolyl, and wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is optionally substituted with one or more substituents each independently selected from halogen, (Ci-C4)a Ikyl, (Ci-C4)alkoxy, halo(C₁-C₄)alkyl or hydroxyl.

[0101] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ari is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said 5-, 6- or 9-membered heteroaryl is selected from pyridyl, pyrimidyl, imidazolyl, imidazopyrazinyl, pyrazolopyridinyl, imidazopyridinyl, oxadiazolyl, indazolyl, pyrazolyl, furanyl, thiazolyl, isoxazolyl, and wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is substituted with one or more substituents each independently selected from halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkyl or hydroxyl.

[0102] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ari is phenyl, wherein said phenyl is optionally substituted with one or more substituents each independently selected from FU, and wherein R₄ is the group consisting of halogen and (C₁-C₄)alkyl.

[0103] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ari is phenyl, wherein said phenyl is substituted with one or more substituents each independently selected from R₄, and wherein R₄ is the group consisting of halogen and (C₁-C₄)alkyl.

[0104] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ari is a 5-, 6- or 9-membered heteroaryl, wherein said 5-, 6- or 9-membered heteroaryl is optionally substituted with one or more substituents each independently selected from F, and wherein R₄ is the group consisting of halogen and (C₁-C₄)alkyl. In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ari is a 5-, 6- or 9-membered heteroaryl, wherein said 5-, 6- or 9-membered heteroaryl is substituted with one or more substituents each independently selected from R₄, and wherein R₄ is the group consisting of halogen and (C₁-C₄)alkyl.

[0105] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ar2 is a 5- membered heteroaryl; wherein said 5- membered heteroaryl is optionally substituted with one or more substituents each independently selected from Rs, and wherein Rs is (C₁-C₄)alkyl, or (Ci-C4)alkoxy(Ci-C4)alkyl.

[0106] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ar2 is a 6- membered heteroaryl; wherein said 6- membered heteroaryl is optionally substituted with one or more substituents each independently selected from Rs, and wherein Rs is halogen, (C₁-C₄)alkyl or (Ci-C4)alkoxy.

[0107] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ar2 is oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyrazolyl or pyrimidyl; wherein said oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyrazolyl or pyrimidyl is optionally substituted with one or more substituents each independently selected from Rs.

[0108] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ar2 is oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyrazolyl or pyrimidyl; wherein said oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyrazolyl or pyrimidyl is optionally substituted with one or more substituents each independently selected from methyl, ethyl, fluoro, methoxymethyl, hydroxymethyl and methoxy.

[0109] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Ar2 is oxaxolyl or thiazolyl; wherein said oxaxolyl or thiazolyl is optionally substituted with one or more substituents each independently selected from Rs, and wherein Rs is (C₁-C₄)alkyl, or (Ci-C4)alkoxy(Ci-C4)alkyl. In an embodiment the invention relates to a compound of general formula (I) or (la), wherein R3 is halogen or (Ci-C4)a Ikyl.

[0110] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein R3 is fluoro, chloro, methyl or ethyl.

[0111] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein R4 halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkyl or hydroxyl

[0112] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein R4 is fluoro, chloro, methyl, ethyl, difluoromethyl, hydroxy or methoxy.

[0113] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Rs is methyl, ethyl, fluoro, methoxymethyl, hydroxymethyl or methoxy.

[0114] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Y represents a bond, and Z is phenyl, wherein said phenyl is optionally substituted with one or more substituents each independently selected from R3; and wherein R3 is the group consisting of halogen and (C₁-C₄)alkyl.

[0115] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Y represents -O- and Z is (C₆-C₇)cycloalkylene.

[0116] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Y represents -O- and Z is cyclohexylene or bicycloheptanyl.

[0117] In an embodiment the invention relates to a compound selected from the list consisting of N-[(1S,3S)-3-(4-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide, N-[(1S,3S)-3-[[(1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-oxazol-2-yl-cyclopentyl] methanesulfonamide,

[0118] N-[(1S,3S)-3-[[(1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-oxazol-2-yl-cyclopentyl] methanesulfonamide,

[0119] N-[(1S,3S)-3-[[(1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0120] N-[(1S,3S)-3-(5-cyclopropyloxazol-2-yl)-3-[[(1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]cyclopentyl]methanesulfonamide,

[0121] N-[(3R,5S)-5-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl] methanesulfonamide,

[0122] N-[(3S,5R)-5-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl] methanesulfonamide,

[0123] N-[(1S,3S)-3-oxazol-2-yl-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0124] N-[rel-(1S,3R,4S)-4-methyl-3-(5-methyloxazol-2-yl)-3-[(3-phenylphenyl)methyl]cyclopentyl] methanesulfonamide (enantiomer 1),

[0125] N-[(1R,2R,4R,5S)-4-oxazol-2-yl-4-[cis-(4-phenylcyclohexoxy)methyl]-2-bicyclo[3.1.0]hexanyl]methanesulfonamide,

[0126] N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0127] N-[(1S,3S)-3-[[cis-4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-oxazol-2-yl-cyclopentyl] methanesulfonamide,

[0128] N-[(1S,3R)-3-oxazol-2-yl-3-[(3-phenylphenyl)methyl]cyclopentyl]methanesulfonamide, N-[(1S,3S)-3-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0129] N-[(1S,3S)-3-[cis-[4-(3-fluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide, N-[(1R,2R,4R,5S)-4-[[(1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-4-(5-methyloxazol-2-yl)-2-bicyclo[3.1.0]hexanyl]methanesulfonamide,

[0130] N-[trans-4-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-(5-methyloxazol-2-yl)cyclohexyl]methanesulfonamide,

[0131] N-[trans-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclobutyl] methanesulfonamide,

[0132] N-[(1R,3S)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0133] N-[(1S,3R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-[5-(methoxymethyl)oxazol-2-yl]cyclopentyl]methanesulfonamide,

[0134] N-[(1S,3S)-3-(1,3,4-oxadiazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0135] N-[(1S,3R)-3-(1,2,4-oxadiazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0136] N-[(1S,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopentyl] methanesulfonamide,

[0137] N-[(1S,3S)-3-[cis-(4-phenylcyclohexoxy)methyl]-3-thiazol-2-yl-cyclopentyl] methanesulfonamide,

[0138] N-[(1S,3R)-3-(2-methyl-1,2,4-triazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0139] N-[(1S,3R)-3-(1-methyl-1,2,4-triazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0140] N-[(1S,3R)-3-(4-methyl-1,2,4-triazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0141] N-[(1S,3S)-3-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]ethanesulfonamide,

[0142] (1S,3S)-3-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)-N- (methylsulfamoyl)cyclopentanamine, 5-methyl-2-[(1S,3S)-1-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3- (dimethylsulfamoylamino)cyclopentyl]oxazole,

[0143] N-[(1S,3S)-3-(5-ethyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0144] N-[(1S,3S)-3-[5-(methoxymethyl)oxazol-2-yl]-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0145] N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]ethanesulfonamide,

[0146] N-[(lS,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]oxetane- 3-sulfonamide,

[0147] N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]cyclopropanesulfonamide,

[0148] N-[(lS,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]propane- 2-sulfonamide,

[0149] N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]azetidine-1-sulfonamide,

[0150] N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]ethanesulfonamide,

[0151] (1S,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)-N- (methylsulfamoyl)cyclopentanamine,

[0152] 2-[(1R,3S)-1-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3- (dimethylsulfamoylamino)cyclopentyl]-5-methyl-oxazole,

[0153] N-[(1S,3R)-3-[[2,4-difluoro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0154] N-[(1S,3R)-3-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0155] N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopentyl] methanesulfonamide, N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl] methanesulfonamide,

[0156] N-[(1S,3R)-3-[[3-(3-fluorophenyl)phenyl]methyl]-3-[4-(hydroxymethyl)oxazol-2-yl]cyclopentyl]methanesulfonamide,

[0157] N-[rac-(3R,5S)-5-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl] methanesulfonamide,

[0158] N-[(1S,3R)-3-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0159] N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0160] N-[(1S,3R)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0161] N-[(1S,3R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0162] N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0163] N-[(1S,3R)-3-[[3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0164] N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0165] N-[(1S,3R)-3-[(2-fluoro-3-pyrimidin-2-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0166] N-[(lS,3R)-3-[[2-fluoro-3-(2-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0167] N-[(lS,3R)-3-[[2-fluoro-3-(l-methylpyrazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0168] N-[(lS,3R)-3-[[2-fluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide, N-[(lS,3R)-3-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(4-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0169] N-[(lS,3R)-3-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0170] N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(4-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0171] N-[(lS,3R)-3-[(2,4-difluoro-3-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0172] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0173] N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0174] N-[(lS,3R,4S)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0175] N-[(lR,3S,4R)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0176] N-[(lS,3R,4S)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0177] N-[(lR,3S,4R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0178] N-[(lS,3R,4S)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0179] N-[(lR,3S,4R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0180] N-[(lS,3R)-3-[(2,4-difluoro-5-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0181] N-[(lS,3R)-3-[[2,4-difluoro-5-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide, N-[(lS,3R)-3-[[5-(3,5-difluorophenyl)-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0182] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-pyrimidin-2-yl-cyclopentyl] methanesulfonamide,

[0183] N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-pyrimidin-2-yl-cyclopentyl] methanesulfonamide,

[0184] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-fluoropyrimidin-2-yl)cyclopentyl] methanesulfonamide

[0185] N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-(5-fluoropyrimidin-2-yl)cyclopentyl] methanesulfonamide,

[0186] N-[(lS,3R)-3-[[2,4-difluoro-3-(2-oxo-lH-pyridin-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0187] N-[(lS,3R)-3-[[2,4-difluoro-3-(6-oxo-lH-pyridin-3-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0188] N-[(lS,3R)-3-[[2,4-difluoro-3-(4-hydroxyphenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0189] N-[(lS,3R)-3-[[3-(3,5-difluoro-4-hydroxy-phenyl)-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0190] N-[(lS,3R)-3-[[2,4-difluoro-3-(2-furyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0191] N-[(lS,3R)-3-[[3-[4-(difluoromethyl)phenyl]-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2 -yl)cyclopentyl] methanesulfonamide,

[0192] N-[(lS,3R)-3-[[2,4-difluoro-3-(4-hydroxy-3-methyl-phenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0193] N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methyl-6-oxo-lH-pyridin-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0194] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-hydroxyphenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide, N-[(lS,3R)-3-[[2,4-difluoro-3-(6-oxo-lH-pyridin-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0195] N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-indazol-5-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0196] N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-pyrazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0197] N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-pyrazol-3-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0198] N-[(lS,3R)-3-[[2,4-difluoro-3-(5-fluoro-2-oxo-lH-pyridin-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0199] N-[(lS,3R)-3-[[2,4-difluoro-3-(l-methyl-2-oxo-4-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0200] N-[(lS,3R)-3-[[2,4-difluoro-3-(l-methyl-6-oxo-3-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0201] N-[(lS,3R)-3-[[2,4-difluoro-3-(5-fluoro-6-oxo-lH-pyridin-3-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0202] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4-methoxypyrimidin-2-yl)cyclopentyl] methanesulfonamide,

[0203] N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-indazol-6-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0204] N-[(lS,3R)-3-[[3-[3-(difluoromethyl)phenyl]-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2 -yl)cyclopentyl] methanesulfonamide,

[0205] N-[(lS,3R)-3-[[2,4-difluoro-3-(2-fluoro-6-hydroxy-4-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0206] N-[(lS,3R)-3-[[5-fluoro-2-(3-fluorophenyl)-4-pyridyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0207] N-[(lS,3S)-3-[[5-fluoro-4-(3-fluorophenyl)-2-pyridyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide, N-[(lS,3R)-3-[[4-fluoro-3-(8-methoxyimidazo[l,2-a]pyrazin-6-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0208] N-[(lS,3R)-3-[[4-fluoro-3-(8-methoxyimidazo[l,2-a]pyridin-6-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0209] N-[(lS,3R)-3-[[3-(3-chloro-8-methoxy-imidazo[l,2-a]pyridin-6-yl)-4-fluoro-phenyl]methyl]-3- (5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0210] N-[(lS,3R)-3-[(4-fluoro-3-imidazo[l,2-a]pyridin-6-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0211] N-[(lS,3R)-3-[(4-fluoro-3-pyrazolo[l,5-a]pyridin-5-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0212] N-[(lS,3R)-3-[[3-(3-chloroimidazo[l,2-a]pyridin-6-yl)-4-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0213] N-[(lS,3R)-3-[[2-fluoro-3-(5-fluoropyrimidin-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0214] N-[(lS,3R)-3-[[2-fluoro-3-(4-methylthiazol-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0215] N-[(lS,3R)-3-[[2-fluoro-3-(2-methylthiazol-5-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0216] N-[(lS,3R)-3-[[2-fluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0217] N-[(lS,3R)-3-[[2-fluoro-3-(3-furyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0218] N-[(lS,3R)-3-[[2,4-difluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0219] N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0220] N-[(lS,3R)-3-[[2,4-difluoro-3-(5-fluoropyrimidin-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide, N-[(lS,3R)-3-[[2,4-difluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-pyrimidin-2-yl-cyclopentyl] methanesulfonamide,

[0221] N-[(lS,3R)-3-[[2,4-difluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-(5-fluoropyrimidin-2-yl)cyclopentyl] methanesulfonamide,

[0222] N-[(lS,3R)-3-[(4-fluoro-3-imidazo[l,2-a]pyrazin-6-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0223] N-[trans-4-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-pyrimidin-2-yl-cyclohexyl]methanesulfonamide,

[0224] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4-methylpyrimidin-2-yl)cyclopentyl] methanesulfonamide,

[0225] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4,6-dimethylpyrimidin-2-yl)cyclopentyl] methanesulfonamide,

[0226] N-[(lS,3R)-3-[[3-[5-(difluoromethyl)-l,2,4-oxadiazol-3-yl]-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,

[0227] N-[(lS,3R)-3-[(2,4-difluoro-3-imidazol-l-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0228] N-[(lS,3R)-3-[[2,4-difluoro-3-(2-oxo-l-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,

[0229] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(l-methylpyrazol-3-yl)cyclopentyl] methanesulfonamide,

[0230] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(2-methylpyrazol-3-yl)cyclopentyl] methanesulfonamide,

[0231] N-[(lS,3R)-3-[cis-(4-phenylcyclohexoxy)methyl]-3-(lH-pyrazol-3-yl)cyclopentyl] methanesulfonamide,

[0232] N-[(lS,3R)-3-[cis-(4-phenylcyclohexoxy)methyl]-3-pyrimidin-4-yl-cyclopentyl] methanesulfonamide,

[0233] N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-pyrimidin-4-yl-cyclopentyl] methanesulfonamide N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(2-methylpyrimidin-4-yl)cyclopentyl] methanesulfonamide,

[0234] or a pharmaceutically acceptable salt thereof.

[0235] PHARMACEUTICALLY ACCEPTABLE SALTS

[0236] The compounds of this invention are generally utilized as the free substance, i.e., they are generally not utilized as a salt. However, when a compound of formula I contains a free base, the compound may be used as a pharmaceutically acceptable salt thereof. Such salts may be prepared in a conventional manner by treating a solution or suspension of a free base of formula I with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described below.

[0237] Pharmaceutically acceptable salts in the present context are intended to indicate nontoxic, i.e., physiologically acceptable salts. The term pharmaceutically acceptable salts includes salts formed with inorganic and / or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulphuric 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, salicylic acid and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and benzene-sulfonic acid. Some of the acids listed above are di- or tri-acids, i.e. acids containing two or three acidic hydrogens, such as phosphoric acid, sulphuric acid, fumaric acid and maleic acid. Di- and tri-acids may form 1:1, 1:2 or 1:3 (tri-acids) salts, i.e. a salt formed between two or three molecules of the compound of the present invention and one molecule of the acid.

[0238] If a compound of formula I contains an acidic moiety, the compound may be used as a pharmaceutically acceptable salt thereof. Such salts may be prepared in a conventional manner by treating a solution or suspension of a free acidic moiety of formula I with a molar equivalent of a pharmaceutically acceptable base. Representative examples of suitable organic and inorganic bases are described below. The term pharmaceutically acceptable salts include salts formed with inorganic and / or organic bases, such as alkali metal bases, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, alkaline earth bases, such as calcium hydroxide and magnesium hydroxide, and organic bases, such as trimethylamine, diethylamine. Some of the bases listed above are di- or tri-bases, i.e. bases able to receive two or three acidic hydrogens, such as calcium hydroxide and magnesium hydroxide. Di- and tri-bases may form 1:1 or 1:2 salts, i.e. a salt formed between two molecules of the compound of the present invention and one molecule of the base.

[0239] Additional examples of useful acids and bases to form pharmaceutically acceptable salts can be found e.g. in Stahl and Wermuth (Eds.) " Handbook of Pharmaceutical salts. Properties, selection, and use", 2nded., 2011, Wiley-VCH.

[0240] PHARMACEUTICAL COMPOSITION

[0241] The above-mentioned compounds or pharmaceutically acceptable salts thereof may be in a composition as the sole active pharmaceutical ingredient or in combination with other pharmaceutically active ingredients. Additionally, one or more pharmaceutically acceptable carriers or excipients may be in the composition.

[0242] The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

[0243] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders, and granules. Where appropriate, they can be prepared with coatings.

[0244] Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups, and elixirs.

[0245] Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions, or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, etc.

[0246] Conveniently, the compounds of the invention are administered in a unit dosage form containing said compounds in an amount of about 0.1 to 300 mg, such as 1 to 100 mg of a compound of the present invention. The compound may be administered as a bolus (i.e. the entire daily dosis is administered at once) or in divided doses two or three or more times a day.

[0247] Suitable pharmaceutical carriers include inert solid excipients or fillers, sterile aqueous solutions, and various organic solvents. The pharmaceutical compositions formed by combining the compound of the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.

[0248] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.

[0249] If a solid carrier is used for oral administration, the preparation may be tablet, e.g. placed in a hard gelatine capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

[0250] Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and / or excipients followed by compression of the mixture in a conventional tabletting machine. Adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients. TREATING DISEASES

[0251] OX2R agonists may be useful in the treatment of diseases which are associated with the orexin type 2 receptor, or which are associated with orexin, such as with orexin deficiency or with orexin imbalance.

[0252] An embodiment of the invention provides a compound or a pharmaceutically acceptable salt thereof, as disclosed herein, or a pharmaceutical composition comprising a compound as disclosed herein which is useful in the treatment of a disease which is responsive of the modulation of orexin-2 receptor activity.

[0253] An embodiment of the invention provides a compound or a pharmaceutically acceptable salt thereof, as disclosed herein or a pharmaceutical composition comprising a compound as disclosed herein which is useful in the treatment of a disease which is treatable by the administration of an orexin-2 receptor agonist.

[0254] In an embodiment is provided 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 a disease or disorder that is treatable by administration of an orexin-2 receptor agonist.

[0255] In an embodiment is provided a method for the treatment of a disease or disorder that is treatable by 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.

[0256] An embodiment of the invention provides a compound as disclosed herein which is useful in the treatment of a disease which is associated with orexin, such as a disease which is associated with orexin deficiency or a disease which is associated with orexin imbalance.

[0257] Orexin-2 receptor agonists may be used in the treatment of Narcolepsy, such as Narcolepsy Type 1 or Narcolepsy Type 2. Furthermore, Orexin-2 receptor agonists may potentially be useful in the treatment of obstructive sleep apnea, such as obstructive sleep apnea with excessive daytime sleepiness, idiopathic hypersomnia or hypersomnia. In an embodiment is provided 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, for use in the treatment of narcolepsy, such as for use in the treatment of narcolepsy type 1 or narcolepsy type 2.

[0258] In an embodiment is provided a method 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.

[0259] In an embodiment is provided 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 narcolepsy, such as narcolepsy type 1 or narcolepsy type 2.

[0260] In a further embodiment is provided 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, for use in the treatment of obstructive sleep apnea, idiopathic hypersomnia or hypersomnia.

[0261] In an embodiment is provided a method 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.

[0262] In an embodiment is provided 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.

[0263] Central hypersomnia's are diseases manifested in excessive daytime sleepiness (EDS) not caused by disturbed nocturnal sleep or misaligned circadian rhythms. Central hypersomnias includes narcolepsy with and without cataplexy, recurrent hypersomnia, idiopathic hypersomnia, with and without long sleep time, behaviorally induced insufficient sleep syndrome, hypersomnia and narcolepsy due to medical conditions. (Sonka, Ther. Adv.

[0264] Neurol. Disord. (2012), 5, 297). In a related classification, Central disorders of hypersomnolence (CDH) are characterized by severe daytime sleepiness, which is present despite normal quality and timing of nocturnal sleep. CDH's include Narcolepsy type, 1 Narcolepsy type 2, Idiopathic hypersomnia, Kleine-Levin syndrome, Hypersomnia due to a medical disorder, Hypersomnia due to a medication or substance, Hypersomnia associated with a psychiatric disorder, Insufficient sleep syndrome (Khan, CHEST 2015; 148( 1 ): 262 -273)

[0265] In a further embodiment is provided 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, for use in the treatment of one or more central disorders of hypersomnolence or one or more central hypersomnia's.

[0266] As mentioned above, it has been hypothesized that OX2R agonists may be useful as agents for the treatment of irregular sleep-wake rhythm disorders or excessive daytime sleepiness in indications such as Parkinson's disease, Alzheimer's disease, Prader-Willis syndrome, or Lewis body dementia.

[0267] In a further embodiment is provided a compound according to the present invention, or a pharmaceutically acceptable salt thereof, 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-Willis syndrome, or Lewis body dementia.

[0268] The compounds of the invention may be administered as a monotherapy or as part of an adjunctive treatment regimen.

[0269] In an embodiment, the compounds of the invention may be administered as monotherapy in the treatment of a disease associated with orexin. Such monotherapy indicates that the compound of the invention is the only active ingredient administered to the patient to treat this specific disease, however such monotherapy does not exclude that the patient may be treated with other drugs to treat other conditions.

[0270] In a further embodiment, the compounds of the invention may be administered as part of an adjunctive treatment regimen targeting the disease associated with orexin. Such adjunctive treatment indicates that the compound of the invention is administered adjunctive to an already existing treatment regimen targeting the disease associated with orexin. Alternatively, the adjunctive treatment may also indicate that the compound of the invention is the first drug to be administered to treat the disease associated with orexin and then subsequently another drug is added to the treatment regimen, which additional drug is also targeting the disease associated with orexin. Examples of adjunctive therapeutic treatment for narcolepsy, such as narcolepsy type 1 or narcolepsy type 2, include modafinil, armodafinil, sodium oxybate, methylphenidate, dextroamphetamine, pitolisant.

[0271] In an embodiment, compounds of the invention can be used in combination with other therapeutically active compounds.

[0272] In one embodiment, the compound of the present invention is administered in an amount from about 0.001 mg / kg body weight to about 100 mg / kg body weight per day. In particular, daily dosages may be in the range of 0.01 mg / kg body weight to about 50 mg / kg body weight per day. The exact dosages will depend upon the frequency and mode of administration, the sex, the age, the weight, and the general condition of the subject to be treated, the nature and the severity of the condition to be treated, any concomitant diseases to be treated, the desired effect of the treatment and other factors known to those skilled in the art. The daily dosage of compound may be divided into one, two or more portions.

[0273] A typical oral dosage for adults will be in the range of 0.1 -1000 mg / day of a compound, or pharmaceutically acceptable salt thereof of the present invention, such as 1-1000 mg / day, such as 1-500 mg / day, such a 1 - 100 mg / day. This amount may be administered in one, two, three or more portions daily.

[0274] The compounds, or pharmaceutically acceptable salt thereof of the present invention may be administered alone as a pure compound or in a pharmaceutical composition comprising the compound or a pharmaceutical salt thereof and one or more pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or excipients as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 22ndEdition, Pharmaceutical Press, 2012.

[0275] PREPARATION OF COMPOUNDS OF THE INVENTION GENERAL METHODS

[0276] The compounds of formula (I) may be prepared by methods described below, together with synthetic methods known in the art of organic chemistry, or modifications that are familiar to those of ordinary skill in the art. For example, the methods describe the use of selective protecting groups during the synthesis of the compounds of the invention. One skilled in the art would be able to select the appropriate protecting group for a particular reaction. Methods for protection and deprotection of such groups are well known in the art and may be found in Greene's Protective Groups in Organic Synthesis by P. G. M. Wuts, 2014, 5thEdition, Wiley. The starting materials used herein are available commercially or may be prepared by routine methods known in the art, such as those method described in standard reference books such as " 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 in synthesizing the compounds of the present invention. They are not to constrain the scope of the invention in any way.

[0277] General method-01

[0278]

[0279] Compounds of general formula INT-1 can be prepared by the treatment of compounds of general formula i with a reagent such as benzophenoneimine.

[0280] General method-02

[0281] Lgi %Ag2

[0282] , G Y'Z <'b i

[0283]

[0284] INT-2 where Lgi and Lg2 are leaving groups such as bromide, chloride or methanesulfonate; and G is a halogen such as chloride or bromide.

[0285] Compounds of general formula INT-1 can by reacted with compounds of general formula i to form compounds of general formula ii after treatment with a strong base such as lithium diisopropylamide. After hydrolysis of compounds of general formula ii with an acid such as aqueous hydrochloric acid followed by reaction with compounds of general formula iii compounds of general formula INT-2 can be obtained. General method-03

[0286] INT-2 INT-3

[0287]

[0288] where G is a halogen such as chloride or bromide.

[0289] Compounds of general formula INT-3 can be prepared by reaction of compounds of general formula INT-2 and compounds of general formula i in the presence of a palladium catalyst such as Pd(dppf)Cl2and a base such as Cs2CO3in a solvent mixture such as water and 1,4-dioxane.

[0290]

[0291] INT-4

[0292] INT-1 INT-3

[0293] where Lgi and Lg2 are leaving groups such as bromide, chloride or methanesulfonate.

[0294] Compounds of general formula INT-1 can by reacted with compounds of general formula i to form compounds of general formula INT-4 after treatment with a strong base such as lithium diisopropylamide. After hydrolysis of compounds of general formula INT-4 with an acid such as aqueous hydrochloric acid followed by reaction with compounds of general formula ii compounds of general formula INT-3 can be obtained.

[0295] General method-05 iii V n = 0 or 1 n = 0 or 1 n = 0 or 1

[0296] INT-2

[0297]

[0298] n = 0 or 1 where Pgi is a protection group such as tetrahydro-2H-pyran-2-yl; Lgi is a leaving group such as bromide, chloride or methanesulfonate; and G is a halogen such as chloride or bromide. Compounds of general formula i can be reacted with compounds of general formula ii to form compounds of general formula iii after treatment with a strong base such as lithium diisopropylamide. After removing the protection group (Pgi) from compounds of general formula iii with an acid such as TFA in methanol, compounds of general formula iii can be reacted with compounds of general formula iv using reagents such as diisopropyl azodicarboxylate and triphenyl phosphine in a reaction known as the Mitsunobu reaction to give compounds of general formula v. The Boc group of the compounds of general formula v can be removed by treatment with an acid such as HCI to give compounds of general formula INT-2.

[0299] General method-06

[0300]

[0301] where Pg is a protection group such as tert-butoxy carbonyl.

[0302] Hydrolysis of compounds of general formula INT-4 with an acid such as aqueous hydrochloric acid followed by protection of the amino group gives compounds of general formula i. Compounds of general formula i can be converted to compounds of general formula INT-5 using the methods described in general method-13, general method-14, general method-15, general method-16, general method-17, general method-18, and general method-22.

[0303] General method-07

[0304]

[0305] where Lgi is a leaving group such as bromide, chloride or methanesulfonate; and G is a halogen such as chloride or bromide.

[0306] Compounds of general formula INT-1 can by reacted with compounds of general formula i to form compounds of general formula ii after treatment with a strong base such as lithium diisopropylamide. After hydrolysis of compounds of general formula ii with an acid such as aqueous hydrochloric acid followed by reaction followed by protection of the amino group gives compounds of general formula iii. Compounds of general formula iii can be converted to compounds of general formula INT-9 using the methods described in general method-13, general method-14, general method-15, general method-16, general method-17, general method-18, and general method-22. Compounds of general formula INT-5 can be prepared by reaction of compounds of general formula INT-9 and compounds of general formula v in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3in a solvent mixture such as water and 1,4-dioxane.

[0307] General method-08 INT-5

[0308]

[0309] where G is a halogen such as chloride or bromide, and Pg is a protection group such as tertbutoxy carbonyl.

[0310] Compounds of general formula i can be prepared by the reaction of compounds of general formula INT-9 and Zn(CN)2in the presence of a palladium catalyst such as Pd(dppf)Cl2and zinc. Compounds of general formula ii can be obtained by the treatment of compounds of general formula i with hydroxylamine. Compounds of general formula lnt-5 can be formed by the treatment compounds of general formula ii with compounds of general formula iii using a reagent such as carbonyl diimidazole and MgSO4.

[0311] General method-09

[0312]

[0313] INT-2 INT-6

[0314] where G is a halogen such as chloride or bromide.

[0315] Compounds of general formula INT-2 can be converted to compounds of general formula INT-6 using the methods descried in general method-13, general method-14, general method-15, general method-16, general method-17, general method-18, and general method-22.

[0316] General method-10

[0317]

[0318] where G is a halogen such as chloride or bromide.

[0319] Compounds of general formula i can be prepared by hydrolysis of compounds of general formula INT-3 followed by amide formation by standard procedures such as activation of the carboxylic acid with a reagent such as HATU or thionyl chloride, followed by reaction with ammonia. Reaction of compounds of general formula i with a reagent such as compound ii followed by reaction with ammonia gives compounds of general formula iii, which after reaction with compounds of general formula iv gives compounds of general formula INT-6.

[0320] General method-11

[0321] INT-2

[0322]

[0323] where G is a halogen such as chloride or bromide. Compounds of general formula i can be prepared by ester hydrolysis, or methyl ester demethylation using a reagent such as sodium methanethiolate of compounds of general formula INT-2 followed by amide formation by standard procedures such as HATU and ammonia. Reaction of compounds of general formula i with 1,3 dichloroacteone gives compounds of general formula ii, which after hydrolysis gives compounds of general formula INT-6

[0324] General method-12

[0325] - MgBr ii

[0326]

[0327] INT-8 Compounds of general formula i can be prepared by hydrolysis of compounds of general formula INT-3 followed by amide formation by standard procedures such as activation of the carboxylic acid with a reagent such as HATU or thionyl chloride, followed by reaction with methoxy methyl amine. Reaction of compounds of general formula i with a reagent such as ii gives compounds of general formula INT-8.

[0328] General method-13

[0329]

[0330] Compounds of general formula ii can be prepared by hydrolysis of compounds of general formula INT-3 followed by amide formation by standard procedures such as activation of the carboxylic acid with a reagent such as HATU or thionyl chloride, followed by reaction with an amine of general formula i. Oxidation of the alcohol moiety of compounds of general formula ii with oxidizing conditions known as the Swern reaction or by using the Dess-Martin periodinane gives compounds of general formula vi. Alternatively, after hydrolysis of compounds of general formula INT-3 and activation of the carboxylic acid moiety, reaction with compounds of general formula iii gives compounds of general formula vi, directly. As another alternative, after hydrolysis of compounds of general formula INT-3 and activation of the carboxylic acid moiety, reaction with compounds of general formula iv gives compounds of general formula v, which after deprotection of the carbonyl group, also gives compounds of general formula vi. Compounds of general formula (I) can then be formed by the treatment compounds of general formula vi with a reagent such as Burgess' reagent.

[0331] General method-14

[0332]

[0333] Compounds of general formula ii can be prepared by treatment of compounds of general formula INT-3 with hydrazine. Compounds of general formula (I) can be formed by the treatment of compounds of general formula ii with compounds of general formula iii.

[0334] General method-15 (i)

[0335]

[0336] Compounds of general formula i can be prepared by hydrolysis of compounds of general formula INT-3 followed by amide formation by standard procedures such as activation of the carboxylic acid with a reagent such as HATU or thionyl chloride, followed by reaction with ammonia. Dehydration of compounds of general formula i with a reagent such as cyanuric chloride gives compounds of general formula ii which after treatment with hydroxylamine gives compounds of general formula iii. Compounds of general formula (I) can be formed by the treatment compounds of general formula iii with a compound of general formula iv.

[0337] General method-16

[0338]

[0339] where Lg is a leaving group such as bromide, chloride or methanesulfonate.

[0340] Compounds of general formula i can be prepared by hydrolysis of compounds of general formula INT-3 followed by amide formation by standard procedures such as activation of the carboxylic acid with a reagent such as HATU or thionyl chloride, followed by reaction with ammonia. Treatment of compounds of general formula i with a reagent such as Lawesson's reagent gives compounds of general formula ii. Reaction of compounds of general formula ii with compounds of general formula iii in the presence of a reagent such as Burgess' reagent gives compounds of general formula (I).

[0341] General method-17

[0342]

[0343] Compounds of general formula i can be prepared by hydrolysis of compounds of general formula INT-3 followed by amide formation by standard procedures such as activation of the carboxylic acid with a reagent such as HATU or thionyl chloride, followed by reaction with ammonia. Treatment of compounds of general formula i with compounds of general formula ii gives compounds of general formula iii which after treatment with compounds of general formula iv gives compounds of general formula (I).

[0344] General method-18

[0345]

[0346] Compounds of general formula ii can be prepared by hydrolysis of compounds of general formula INT-3 followed by amide formation by standard procedures such as activation of the carboxylic acid with a reagent such as HATU or thionyl chloride, followed by reaction with compounds of general formula i. Treatment of compounds of general formula ii with a base such as sodium hydroxide gives compounds of general formula iii which after treatment with AcOH and H2O2gives compounds of general formula (I).

[0347] General method-19

[0348] °''eAg

[0349] R? 'b

[0350]

[0351] where Pg is a protection group such as tert-butoxy carbonyl, and Lg is a leaving group such as bromide, chloride or methanesulfonate.

[0352] Removal of the protection group (Pg) from compounds of general formula INT-5 followed by reaction with compounds of general formula iii in the presence of a base such as triethylamine gives compounds of general formula (I).

[0353] General method-20

[0354] INT-6

[0355]

[0356] where G is a halogen such as chloride or bromide.

[0357] Compounds of general formula (I) can be prepared by reaction of compounds of general formula INT-6 with compounds of general formula i in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3in a solvent mixture such as water and 1,4-dioxane.

[0358] General method-21

[0359]

[0360] where G is a halogen such as chloride, bromide, or iodide.

[0361] Compounds of general formula INT-7 can be prepared by reaction of compounds of general formula INT-6 and compounds of general formula i in the presence of a palladium catalyst such as XPhos Pd G3 and a base such as KOAc in a solvent such as 1,4-dioxane. Compounds of general formula (I) can be prepared by reaction of compounds of general formula INT-7 and compounds of general formula ii in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as Cs2CO3in a solvent mixture such as water and 1,4-dioxane.

[0362] General method-22

[0363] F I

[0364] F-B 1’-F F

[0365] R5R5

[0366]

[0367] where G is a halogen such as chloride or bromide.

[0368] Compounds of general formula i can be prepared by hydrolysis of compounds of general formula INT-3 followed by amide formation by standard procedures such as activation of the carboxylic acid with a reagent such as HATU or thionyl chloride, followed by reaction with ammonia. Reaction of compounds of general formula i with a reagent such as compound ii followed by reaction with ammonia gives compounds of general formula iii, which after reaction with compounds of general formula iv gives compounds of general formula (I).

[0369] General method-23

[0370]

[0371] where G is a halogen such as chloride or bromide..

[0372] Compounds of general formula i can be prepared by the reaction of compounds of general formula INT-6 and Zn(CN)2in the presence of a palladium catalyst such as Pd(dppf)Cl2and zinc. Compounds of general formula ii can be obtained by the treatment of compounds of general formula i with hydroxylamine. Compounds of general formula (I) can be formed by the treatment compounds of general formula ii with compounds of general formula iii using a reagent such as carbonyl diimidazole and MgSO4.

[0373] General method-24

[0374] INT-6

[0375]

[0376] where G is a halogen such as iodide or bromide. Compounds of general formula (I) can be prepared by reaction of compounds of general formula INT-6 and compounds of general formula i in the presence of a copper catalyst (Cu(acac)2in combination with L-proline) and a base such as K2CO3in a solvent such as DMF.

[0377] General method-25

[0378]

[0379] Compounds of general formula (I) can be prepared the reaction of compounds of general formula INT-8 with hydrazines of general formula i.

[0380] General method-26

[0381]

[0382] Compounds of general formula (I) can be prepared by the reaction of compounds of general formula INT-8 with amidines of general formula i.

[0383] EXPERIMENTAL SECTION CHEMICAL NAMES

[0384] The chemical names for the Examples of the invention were generated using BIOVIA MDL.Draw.Editor version 20.1.0.2081 from Dassault Systèmes ANALYTICAL METHODS

[0385] LC-MS methods

[0386] Method A:

[0387] LC-MS were run on Waters ACQUITY Premier UPLC-MS consisting of Waters Acquity Premier, including column manager, binary solvent manager, sample organizer, PDA detector, ELS detector, and SQD-2 equipped with Unispray-source or ESI-source operating in positive ion mode.

[0388] LC-conditions: The column was Acquity Premier UPLC BEH C18 1.7 μm; 2.1x50 mm operating at 60 °C with 1.2 mL / min of a binary gradient consisting of water + 0.05% TFA (A) and acetonitrile + 5% water + 0.035% TFA (B).

[0389] Gradient: 0.00 minutes 10% B

[0390] 1.00 minutes 99.9% B

[0391] 1.01 minutes 10% B

[0392] 1.15 minutes 10% B

[0393] Total run time: 1.15 min

[0394] Method B:

[0395] LC-MS were run on Waters Aquity UPLC-MS consisting of Waters Aquity including column manager, binary solvent manager, sample organizer, PDA detector (operating at 254 nm), ELS detector, and SQ-MS equipped with APPI-source operating in positive ion mode.

[0396] LC-conditions: The column was Acquity UPLC BEH C18 1.7 μm; 2.1x50 mm operating at 60 °C with 1.2 ml / min of a binary gradient consisting of water + 0.1% TFA (A) and acetonitrile + 5% water + 0.1% TFA.

[0397] Gradient: 0.00 minutes 10% B

[0398] 1.00 minutes 99.9% B

[0399] 1.01 minutes 10% B

[0400] 1.15 minutes 10% B

[0401] Total run time: 1.15 minutes NMR

[0402] 1H NMR spectra were recorded at 600 MHz on a Bruker 600-Avance-III spectrometer, at 500 MHz on a Bruker 500-Avance DRX spectrometer, at 300 MHz on a Bruker Avance III HD spectrometer, at 400 MHz on a Bruker Avance III HD spectrometer and at 400 MHz on a Bruker Avance NEO spectrometer. Chemical shift values are expressed in ppm-values relative to tetramethylsilane. The following abbreviations or their combinations are used for multiplicity of NMR signals: br = broad, d = doublet, m = multiplet, q = quartet, quint = quintet, s = singlet and t = triplet.

[0403] ABBREVIATIONS

[0404] Abbreviations used in the experimental may include, but are not limited to the following:

[0405] Ac: acetyl; Boc: tert-butyloxycarbonyl; C: Celsius; DCM: dichloromethane; DEAD: diethyl azodicarboxylate; DIAD: diisopropyl azodicarboxylate; DIPEA: N, N-diisopropylethylamine; DMA: N, N-dimethylacetamide; DMAP: N, N-dimethylaminopyridine; DMF: N, N-dimethylformamide; DMSO: dimethylsulfoxide; dppf: 1,1'-bis(diphenylphosphino)ferrocene; Et: ethyl; EtOAc: ethyl acetate; g: gram; h: hour(s); HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HMDS: hexamethyldisilazane; HOAt: 1-hydroxy-7-azabenzotriazole; L: liter; LDA: lithium diisopropylamide; M: molar; Me: methyl; mg: milligram; mL: milliliter; mmol: millimole; Ms: methanesulfonyl; n-Bu: n-butyl; NMI: 1-methylimidazole; NMR: nuclear magnetic resonance; PE: petroleum ether; PG: protecting group; Ph: phenyl; Prep: preperative; SFC: supercritical fluid chromatography; TBS: tert-butyl(dimethyl)si lyl; TCFH: N'-tetramethylformamidinium hexafluorophosphate; TEA: triethylamine; Tf: triflate; TFA: trifluoroacetic acid; THF: tetrahydrofuran; THP: tetrahydropyran; TLC: thin layer chromatography; TMS: trimethylsilyl; Ts: toluenesulfonyl; wt: by weight; XPhos: [2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl]. PREPARATION OF INTERMEDIATES

[0406] Preparation of tert-butyl (lR,4S)-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate

[0407] Boc2O, Et3N, DMAP r.t, 16 h

[0408]

[0409] O To a stirred mixture of (lR,4S)-2-azabicyclo[2.2.1]hept-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) was added BOC2O (44.0 g, 201 mmol) in portions at room temperature under an argon atmosphere. 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 petroleum ether / EtOAc (4:1) to afford the desired product.

[0410] Preparation of tert-butyl (lS,2R,4R,5R)-7-oxo-3-(trimethylsilyl)-6-azatricyclo[3.2.1.02,4]octane-6-carboxylate

[0411] N-Boc

[0412] l Pd(OAC)2, TMSCH2N2

[0413] iVi Et2O, r.t, 2 h O

[0414]

[0415] To a stirred mixture of tert-butyl (lR,4S)-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (3.85 g, 18.4 mmol) and Pd(OAc)2 (206 mg, 0.92 mmol) in Et2O (135 mL) was added TMSCHN2 (10.5 g, 91.9 mmol) dropwise at room temperature over the course of 1 hour under an argon atmosphere. The resulting mixture was stirred for 1 hour at room temperature under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (4:1) to afford the desired product.

[0416] Preparation of methyl (lR,2S,4R,5R)-4-amino-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylate hydrochloride

[0417] cr o

[0418]

[0419] TMS

[0420] To a stirred solution of tert-butyl (lS,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) was added cone. aq. HCI (3.5 mL, 41 mmol) dropwise at room temperature. The resulting mixture was stirred overnight at 55 °C. The resulting mixture was concentrated under reduced pressure and used in the next step directly without further purification.

[0421] Preparation of methyl (lS,2S,4R,5R)-4-aminobicyclo[3.1.0]hexane-2-carboxylate hydrochloride

[0422] cr o Triflic acid, HCI in ether CH2CI2, r.t, 4 h

[0423]

[0424] TMS

[0425] To a stirred solution of methyl (lR,2S,4R,5R)-4-amino-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylate hydrochloride (3.9 g, 17.1 mmol) in DCM (40 mL) was added triflic acid (9.0 mL, 60 mmol,) dropwise at room temperature under an argon atmosphere. The resulting mixture was stirred for 4 hours at room temperature under an argon atmosphere. The mixture was basified to pH 10 with saturated Na2CO3(aq.). The aqueous layer was extracted with CH2Cl2(5 x 50 mL). The combined organic layers were dried over sodium sulfate and filtered. To the filtrate was added cone. aq. HCI (7.2 mL, 85.8 mmol) and the filtrate was concentrated in vacuo to afford the crude product. The crude product was used in the next step directly without further purification.

[0426] Preparation of racemic ethyl (lR,2S,4S)-4-azido-2-methylcyclopentane-l-carboxylate

[0427] PPh3DIAD

[0428]

[0429] DIAD (1.44 mL, 1.25 Eq, 7.40 mmol) was added dropwise to racemic ethyl (lR,2S,4R)-4-hydroxy-2-methylcyclopentane-l-carboxylate (1.02 g, 5.92 mmol) (synthesized as described in US 20180044344 Al), diphenyl phosphorazidate (1.66 mL, 7.40 mmol) and triphenylphosphine (1.71 g, 6.51 mmol) in THF (59.2 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was concentrated. The crude product was purified by flash chromatography on silica gel to obtain the desired product.

[0430] Preparation of racemic ethyl (lR,2S,4S)-4-amino-2-methylcyclopentane-l-carboxylate, HCI

[0431] Pd / C, HCI (aq.)

[0432]

[0433] Racemic

[0434] Racemic ethyl (lR,2S,4S)-4-azido-2-methylcyclopentane-l-carboxylate (0.93 g, 4.7 mmol) was dissolved in EtOH (28 mL). HCI (2.0 mL, 12 M) and Pd-C 10% (50 mg) was added and hydrogenated (1 atm) overnight. The reaction mixture was filtered and concentrated in vacuo. The crude was washed with Et20 to remove diisopropyl hydrazine-1, 2-dicarboxylate. The remaining solid was dried in vacuo to give the desired product

[0435] Preparation of racemic ethyl (lR,2S,4S)-4-((diphenylmethylene)amino)-2-methylcyclopentane-l-carboxylate (general method-01, INT-1)

[0436]

[0437] Racemic

[0438] Racemic

[0439] In a 10 mL microwave vial, diphenylmethanimine (0.43 mL, 2.6 mmol) was dissolved in toluene (2.5 mL) after which racemic ethyl (lR,2S,4S)-4-amino-2-methylcyclopentane-l-carboxylate hydrochloride (0.53 g, 2.6 mmol) was added portion-wise under an argon atmosphere. The reaction mixture was heated to reflux for lh. The reaction mixture was cooled with an ice-water bath and then filtered through a plug of Celite. The filter cake was rinsed with toluene. The organic phases were concentrated in vacuo to give the desired product.

[0440] Preparation of methyl (lR,3S)-3-((diphenylmethylene)amino)cyclopentane-l-carboxylate (general method-01, INT-1)

[0441]

[0442] To a mixture of methyl (lR,3S)-3-aminocyclopentane-l-carboxylate hydrochloride (200.00 g, 1.11 mol) in toluene (1000 mL) was added benzophenone imine (202.00 g, 1.11 mol). The mixture was stirred for 1.5 hours at reflux. The reaction mixture was cooled to ~5 °C and filtered through Arbocell BC200 and concentrated to complete dryness to afford methyl (lR,3S)-3-((diphenylmethylene)amino)cyclopentane-l-carboxylate.

[0443] Preparation of methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate (general method-02, INT-2)

[0444]

[0445] Br To LDA in THF (390 mL, 1.0 molar, 390 mmol) was added dropwise a solution of methyl (lR,3S)-3-((diphenylmethylene)amino)cyclopentane-l-carboxylate (100.00 g, 325.0 mmol) in THF (300 mL) over a period of 15 minutes at -78°C. The mixture was stirred for 45 minutes at -78°C. Then a solution of 2-bromo-4-(bromomethyl)-l-fluorobenzene (109.00 g, 407.0 mmol) in THF (200 mL) was added dropwise at -78°C over a period of 15 minutes. The reaction mixture was stirred for 1 hour at -78°C, and then the flask was placed in an ice-water bath. Sat. NH4Cl solution (100 mL) and water (100 mL) was slowly added. The mixture was concentrated to remove most organic solvents, and the residue was extracted with ethyl acetate. The organic phase was separated, and washed with brine, dried over MgSO4, and concentrated to dryness to yield the desired product.

[0446] The product from above was dissolved in methanol (600 mL) and cone. HCI (104 mL, 37% Wt, 976.0 mmol) was added. The mixture was heated at 50 °C for 20 h.

[0447] The mixture was cooled and evaporated to dryness. The residue was co-evaporated once with toluene and concentrated to dryness. The product from above was dissolved in THF (440 mL) and methanesulfonyl chloride (38.0 mL, 488.0 mmol) was added. The mixture was cooled in ice-water bath, and triethylamine (136 mL, 976.0 mmol) was added dropwise. The reaction mixture was stirred with ice-water bath for additional 1 h.

[0448] Water (200 mL) was added, and the mixture was concentrated to remove most THF, and extracted with ethyl acetate twice. The combined organic phases were washed with brine, dried over MgSO4, and concentrated to dryness to yield the desired product, that was used in the next step without further purification.

[0449] The following intermediates were prepared in a similar manner from the appropriate iminoester (INT-1), alkylation reagent, and sulfonyl chloride or sulfonyl anhydride:

[0450] methyl (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3-(benzhydrylideneamino)cyclopentanecarboxylate and l-bromo-3-(bromomethyl)-2-fluorobenzene,

[0451] methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3-(benzhydrylideneamino)cyclopentanecarboxylate and 2-bromo-4-(bromomethyl)-l-fluorobenzene,

[0452] methyl (lR,3S)-l-(3-bromobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3-(benzhydrylideneamino)cyclopentanecarboxylate and 1-bromo-3-(bromomethyl)benzene,

[0453] methyl (lR,3S)-l-(5-bromo-2,4-difluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3-(benzhydrylideneamino)cyclopentanecarboxylate and l-bromo-5-(bromomethyl)-2,4-difluorobenzene,

[0454] methyl (lS,3R)-l-(3-chloro-2,4-difluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3-(benzhydrylideneamino)cyclopentanecarboxylate and l-(bromomethyl)-3-chloro-2,4-difluorobenzene, methyl (lS,3S)-l-((4-chloro-5-fluoropyridin-2-yl)methyl)-3- (methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3-(benzhydrylideneamino)cyclopentanecarboxylate and 4-bromo-2-(bromomethyl)-5-fluoropyridine.

[0455] Preparation of methyl (lr,4r)-4-(methylsulfonamido)-l-((3',5',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclohexane-l-carboxylate (general method-03, INT-3)

[0456]

[0457] F A mixture of methyl (lr,4r)-l-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamido)cyclohexane-1-carboxylate (800 mg, 1.90 mmol), 3,5-difluorophenylboronic acid (600 mg, 3.79 mmol), Pd(dppf)Cl2 (139 mg, 0.189 mmol) and Cs2CO3(1.85 g, 5.68 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred for 2 hours at 80 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The residue was dissolved in water (10 mL). The resulting mixture was extracted with EtOAc (5 x 10 mL). The combined organic layers were washed with brine (2x30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford the desired product.

[0458] The following intermediates were prepared in a similar manner:

[0459] ethyl 4-(methylsulfonamido)-2-((3',5',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)tetrahydrofuran-2-carboxylate, prepared from ethyl 2-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamido)tetrahydrofuran-2-carboxylate and (3,5-difluorophenyl)boronic acid, methyl (lr,3s)-3-(N-(tert-butoxycarbonyl) -(methylsulfonamido))-l-((3',5',6-trifluoro-[l,l'-biphenyl]-3-yl) methyl)cyclobutane-l-carboxylate, prepared from methyl (lr,3s)-l-(3-bromo-4-fluorobenzyl)-3-(N-(tert-butoxycarbonyl)-(methylsulfonamido))cyclobutane-l-carboxylate and 3,5-difluorophenylboronic acid,

[0460] methyl (lS,3R)-3-(methylsulfonamido)-l-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentane-l-carboxylate, prepared from methyl (lS,3R)-l-(3-chloro-2,4- difluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and 3-fluorophenylboronic acid,

[0461] Preparation of 2-((lR,4R,6S)-4-(chloromethoxy)bicyclo[4.1.0]heptan-l-yl)-5-fluoropyrimidine

[0462] TMSCI, paraformaldehyde,

[0463] I T DCM, r.t, o / n I T

[0464]

[0465] H0'-O£

[0466] A mixture of (lS,3R,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-ol (prepared as described in patent application WO2022 / 40070) (250 mg, 1.20 mmol), TMSCI (1.95 g, 18.0 mmol) and paraformaldehyde (162 mg, 1.80 mmol) in DCM (5 mL) was stirred overnight at room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification.

[0467] Preparation of methyl (lS,2R,4R,5R)-4-((diphenylmethylene)amino)-2-((((lS,3R,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate (general method-04, INT-4)

[0468]

[0469] A mixture of methyl (lS,2S,4R,5R)-4-((diphenylmethylene)amino)bicyclo[3.1.0]hexane-2-carboxylate (180 mg, 0.564 mmol) and LDA (1.12 mmol) in THF (8 mL) was stirred for 1 hour at -78 °C under an argon atmosphere. To the above mixture was added 2-((lR,4R,6S)-4-(chloromethoxy)bicyclo[4.1.0]heptan-l-yl)-5-fluoropyrimidine (173 mg, 0.68 mmol) in THF (2 mL) at -78 °C. The resulting mixture was stirred for additional 2 hours at -78 °C. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0470] Preparation of methyl (lS,2R,4R,5R)-4-amino-2-((((lS,3R,6R)-6-(5-fluoropyrimidin-2-yl)bicycle [4.1.0]heptan-3-yl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate (general method-04)

[0471] cone. HCI, THF, CH3OH 50 °C, 4 h

[0472]

[0473] A mixture of methyl (lS,2R,4R,5R)-4-((diphenylmethylene)amino)-2-((((lS,3R,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate (220 mg, 0.408 mmol) and cone. HCI (1.70 mL, 20.4 mmol) in THF (4 mL) and CH3OH (2 mL) was stirred for 4 hours at 50 °C. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0474] Preparation of methyl (lS,2R,4R,5R)-2-((((lS,3R,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-4-(methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylate (general method-04, INT-3)

[0475]

[0476] A mixture of methyl (lS,2R,4R,5R)-4-amino-2-((((lS,3R,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate (200 mg, 0.533 mmol), methanesulfonic anhydride (371 mg, 2.13 mmol) and TEA (377 mg, 3.73 mmol) in DCM (10 mL) was stirred for 4 hours at room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (10mmol / L NH4HCO3), 20% to 70% gradient in 25 minutes; detector, UV 220 nm.

[0477] The following intermediates were prepared in a similar manner:

[0478] ethyl (lR,2S,4S)-l-([l,l'-biphenyl]-3-ylmethyl)-2-methyl-4-(methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lS,2S,4S)-4-((diphenylmethylene)amino)-2-methylcyclopentane-l-carboxylate and 3-(bromomethyl)-l,l'-biphenyl,

[0479] methyl (lR,3S)-l-([l,l'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3-(benzhydrylideneamino)cyclopentanecarboxylate and 3-(bromomethyl)-l,l'-biphenyl, methyl (lS,2R,4R,5R)-4-(methylsulfonamido)-2-((((ls,4S)-4-phenylcyclohexyl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate, prepared from methyl (lS,2S,4R,5R)-4-((diphenylmethylene)amino)bicyclo[3.1.0]hexane-2-carboxylate and (cis-4-(chloromethoxy)cyclohexyl)benzene,

[0480] methyl (lS,3S)-l-((((lR,3R,6S)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3-(benzhydrylideneamino)cyclopentanecarboxylate and 2-((lS,4R,6R)-4-(chloromethoxy)bicyclo[4.1.0]heptan-l-yl)-5-fluoropyrimidine,

[0481] methyl (lS,3S)-l-((((lS,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3-(benzhydrylideneamino)cyclopentanecarboxylate and 2-((lR,4S,6S)-4-(chloromethoxy)bicyclo[4.1.0]heptan-l-yl)-5-fluoropyrimidine,

[0482] methyl (lS,3S)-l-((((ls,4r)-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3- (methylsulfonamido)cyclopentane-l-carboxylate, prepared from methyl (lR,3S)-3- (benzhydrylideneamino)cyclopentanecarboxylate and l-(cis-4-(chloromethoxy)cyclohexyl)-3,5-difluorobenzene,

[0483] methyl (lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane- 1-carboxylate, prepared from methyl (lR,3S)-3- (benzhydrylideneamino)cyclopentanecarboxylate and (cis-4-(chloromethoxy)cyclohexyl)benzene.

[0484] Preparation of methyl 4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-l-carboxylate

[0485] o o

[0486]

[0487] To a round bottom flask was added methyl 4-hydroxycyclohexane-l-carboxylate (10.00 g, 63.2 mmol) and anhydrous dichloromethane (50 mL). The atmosphere was exchanged to argon and 3,4-dihydro-2H-pyran (6.1 mL, 66.4 mmol) followed by the addition of Dowex C-211 H+ form (1.00 g, 63.2 mmol). The mixture was stirred at room temperature for 18 hours. Additional 3,4-dihydro-2H-pyran (2.3 mL, 25.3 mmol) was added along with Dowex C-211 H+ form (1.00 g, 63.2 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue obtained was purified via silica gel chromatography to afford the desired product as an approximate 1:2 mixture of isomers, which was used without further purification.

[0488] Preparation of methyl (ls,4s)-l-(3-bromobenzyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-l-carboxylate (general method-05)

[0489]

[0490] To a stirring solution of methyl 4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-l-carboxylate (6.00 g, 24.8 mmol) in anhydrous THF (230 mL) under an argon atmosphere at -78 °C was added a THF / hexane solution of LDA(0.9 M, 44.0 mL, 39.6 mmol) over 5 minutes. The solution was stirred at -78 °C for 1 hour. At this point, a solution of l-bromo-3-(bromomethyl)benzene (9.90 g, 39.6 mmol) in anhydrous THF (15 mL) was added over a period of 60 minutes by a syringe pump after which the solution was stirred for 1 hour at -78 °C. The mixture was quenched by the addition of sat. NH4Cl (150 mL). The phases were separated, and the aqueous phase extracted with ethyl acetate (3 x 100 mL). The combined organics were dried over magnesium sulfate, filtered, and were concentrated in vacuo. The residue obtained was purified via silica gel chromatography to afford the desired product as a single isomer.

[0491] Preparation of methyl (ls,4s)-l-(3-bromobenzyl)-4-hydroxycyclohexane-l-carboxylate (general method-05)

[0492]

[0493] Methyl (ls,4s)-l-(3-bromobenzyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-l- 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 completion. The mixture was then concentrated, and the residue obtained was purified via silica gel chromatography to afford the desired product as a single isomer.

[0494] Preparation of methyl (lr,4r)-l-(3-bromobenzyl)-4-(N-(tert-butoxycarbonyl)- (methylsulfonamido))cyclohexane-l-carboxylate (general method-05)

[0495] PPh3DIAD

[0496]

[0497] In a round bottom flask under an argon atmosphere, triphenylphosphine (3.94 g, 15.0 mmol) was added to DIAD (2.9 mL, 15.0 mmol) in anhydrous THF (150 mL). The mixture was stirred for 10 minutes before tert-butyl (methylsulfonyl)carbamate (2.62 g, 3.4 mmol) and then methyl (ls,4s)-l-(3-bromobenzyl)-4-hydroxycyclohexane-l-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 and dried over MgSO4, and the organics were concentrated in vacuo. Purification via silica gel chromatography afforded the desired product. Preparation of methyl (lr,4r)-l-(3-bromobenzyl)-4-(methylsulfonamido)cyclohexane-l- carboxylate (general method-05, INT-2)

[0498]

[0499] To methyl (lr,4r)-l-(3-bromobenzyl)-4-(N-(tert-butoxycarbonyl)- (methylsulfonamido))cyclohexane-l-carboxylate (955 mg, 1.89 mmol) was added HCI (4M in dioxane) (15 mL, 60 mmol) under an argon atmosphere. The mixture was stirred at 85 °C for 30 minutes and then during stirring allowed to cool down for 2 hours. The mixture was concentrated to dryness to afford the desired product, which was used without further purification.

[0500] The following intermediate was prepared in a similar manner from the appropriate aminoester and benzyl bromide:

[0501] methyl (lr,4r)-l-(3-bromo-4-fluorobenzyl)-4-(N-(tert-butoxycarbonyl)- (methylsulfonamido))cyclohexane-l-carboxylate

[0502] Preparation of methyl 3-((tetrahydro-2H-pyran-2-yl) oxy) cyclobutane-l-carboxylate

[0503]

[0504] A mixture of methyl 3-hydroxycyclobutane-l-carboxylate (30 g, 231 mmol), DHP (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, eluted with petroleum ether / EtOAc (6:1) to afford methyl 3-((tetrahydro-2H-pyran-2-yl) oxy) cyclobutane-l-carboxylate.

[0505] Preparation of methyl l-(3-bromo-4-fluorobenzyl)-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclobutane-l-carboxylate Br

[0506]

[0507] To a stirred mixture of methyl 3-(oxan-2-yloxy) cyclobutane-l-carboxylate (10 g, 46.7 mmol) in THF (400 mL) was added LDA (35.0 mL 2 M in THF, 70.0mmol) dropwise over 30 minutes at -78°C under an argon atmosphere. The resulting mixture was stirred for additional 1 hour at -78°C. To the above mixture was added 2-bromo-4-(bromomethyl)-l-fluorobenzene (20.0 g, 74.7 mmol) dropwise over 1 hour at -78°C. The resulting mixture was stirred for additional 3 hours at-78°C. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2x100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (5:1) to afford methyl l-[(3-bromo-4-fluorophenyl) methyl]-3-(oxan-2-yloxy) cyclobutane-l-carboxylate.

[0508] Preparation of methyl l-(3-bromo-4-fluorobenzyl)-3-hydroxycyclobutane-l-carboxylate

[0509]

[0510] A mixture of methyl l-[(3-bromo-4-fluorophenyl) methyl]-3-(oxan-2-yloxy) cyclobutane-l-carboxylate (4 g, 9.97 mmol) and TFA (1.70 g, 15.0 mmol) in MeOH (60 mL) was stirred for 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (1:1) to afford methyl l-[(3-bromo-4-fluorophenyl) methyl]-3-hydroxycyclobutane-l-carboxylate.

[0511] Preparation of methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(N-(tert-butoxycarbonyl)- (methylsulfonamido))cyclobutane-l-carboxylate (general method-05)

[0512]

[0513] To a stirred mixture of methyl l-[(3-bromo-4-fluorophenyl) methyl]-3-hydroxycyclobutane-1-carboxylate (1.60 g, 5.05 mmol), tert-butyl (methyl sulfonyl) carbamate (1.97 g, 10.1 mmol) and PPh3(3.97 g, 15.1 mmol) in toluene (12 mL) was added DEAD (2.64 g, 15.1 mmol) dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred for additional 15 minutes at 100°C. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2x20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 minutes; detector, UV 254 nm. This resulted in isolation of methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(N-(tert-butoxycarbonyl) methylsulfonamido) cyclobutane-l-carboxylate.

[0514] Preparation of methyl (lS,3S)-3-amino-l-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)cyclopentane-l-carboxylate (general method-06)

[0515]

[0516] A mixture of methyl (lS,3S)-l-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-((diphenylmethylene)amino)cyclopentane-l-carboxylate (2 g, 3.86 mmol) and cone, aqueous HCI (10.5 mL) in THF (35 mL) and H2O (12.5 mL) was stirred for 16 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. Preparation methyl (lS,3S)-3-((tert-butoxycarbonyl)amino)-l-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)cyclopentane-l-carboxylate (general method-06)

[0517] Boc-NH

[0518] (Boc)2O

[0519]

[0520] A mixture of methyl (lS,3S)-3-amino-l-(((cis-4-(3,5-difluorophenyl) cyclohexyl) oxy) methyl) cyclopentane-l-carboxylate (2 g, 5.44 mmol), di-tert-butyl dicarbonate (2.38 g, 10.9 mmol) and TEA (1.65 g, 16.3 mmol) in DCM (100 mL) was stirred for 2 hours at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (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, eluted with CH2Cl2 / MeOH (10:1) to afford the desired product.

[0521] Preparation of (lS,3S)-3-((tert-butoxycarbonyl)amino)-l-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)cyclopentane-l-carboxylic acid (general method-06)

[0522] BOC-NH BOC-NH

[0523]

[0524] F F

[0525] A mixture of methyl (lS,3S)-3-((tert-butoxycarbonyl)amino)-l-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)cyclopentane-l-carboxylate (800 mg, 1.71 mmol) and NaOH (136.87 mg, 3.42 mmol) in MeOH (6 mL) and H2O (2 mL) was stirred for 2 hours at 70 °C. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification.

[0526] Preparation of tert-butyl ((lS,3S)-3-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3- ((2-oxopropyl)carbamoyl)cyclopentyl)carbamate (general method-06)

[0527] Boc-NH

[0528]

[0529] A mixture of (lS,3S)-3-((tert-butoxycarbonyl)amino)-l-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)cyclopentane-l-carboxylic acid (620 mg, 1.36 mmol), 1-aminoacetone (150 mg, 2.05 mmol), HATU (624 mg, 1.64 mmol) and N, N-diisopropylethylamine (530 mg, 4.10 mmol) in DMF (10 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. To obtain the title compound, the residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (15:1).

[0530] Preparation of tert-butyl ((lS,3S)-3-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3- (5-methyloxazol-2-yl)cyclopentyl)carbamate (general method-06, INT-5)

[0531]

[0532] A mixture of tert-butyl ((lS,3S)-3-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-((2-oxopropyl)carbamoyl)cyclopentyl)carbamate (288 mg, 0.55 mmol) and Burgess reagent (662.98 mg, 2.78 mmol) in THF (3 mL) was stirred overnight at 70 °C. The resulting mixture was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 20% to 60% gradient in 20 minutes; detector, UV 254 nm.

[0533] The following intermediates were prepared in a similar manner:

[0534] tert-butyl ((lR,3R)-3-(5-ethyloxazol-2-yl)-3-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate, prepared from methyl (lS,3S)-3-amino-l-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 1-aminobutan-2-ol,

[0535] tert-butyl ((lR,3R)-3-(5-methyloxazol-2-yl)-3-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate, prepared from methyl (lS,3S)-3-amino-l-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 1-aminopropan-2-one,

[0536] tert-butyl ((lS,3S)-3-(5-(methoxymethyl)oxazol-2-yl)-3-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate, prepared from methyl (lS,3S)-3-amino-l-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and l-amino-3-methoxypropan-2-ol,

[0537] N-[(lS,3S)-3-[(4-chloro-5-fluoropyridin-2-yl) methyl]-3-(5-methyl-l,3-oxazol-2-yl) cyclopentyl] methanesulfonamide, prepared from methyl (lS,3S)-l-((4-chloro-5-fluoropyridin-2-yl)methyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and 2-aminoacetone.

[0538] Preparation of (lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(methoxycarbonyl)cyclopentan-l-aminium chloride (general method-07) cr H3+N

[0539] con. HCl. MeOH

[0540] THF, 50°C, 4h

[0541]

[0542] A solution of methyl (lR,3S)-l-[(3-bromo-2-fluorophenyl)methyl]-3-[(diphenylmethylidene) amino]cyclopentane-l-carboxylate (10 g, 20.22 mmol) and cone. HCI (10 mL) in MeOH (12 mL) and THF (35 mL) was stirred for 4 hours at 50 °C. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0543] Preparation of methyl (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-((tert-butoxycarbonyl) amino)cyclo pentane-l-carboxylate (general method-07, INT-9)

[0544] CLH3+N'._^-X J BocHN,. J

[0545] (Boc)2O, TEA,

[0546] DCM, RT,o / n

[0547]

[0548] To a stirred solution of (lS,3R)-3-(3-bromo-2-fluorobenzyl)-3- (methoxycarbonyl)cyclopentan-l-aminium chloride (10 g, 30.2 mmol) and TEA (15.3 g, 151 mmol) in DCM (200 mL) was added (Boc)2O (19.8 g, 90.8 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and extracted with DCM (3 xlOO mL). The combined organic layers were washed with brine (3x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by flash chromatography on silica gel.

[0549] Preparation of (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-((tert-butoxycarbonyl) amino)cyclopentane-l-carboxylic acid (general method-07) LiOH, MeOH, H2O

[0550] 70°C,1h

[0551]

[0552] To a stirred solution of methyl (lR,3S)-l-[(3-bromo-2-fluorophenyl)methyl]-3-[(tert-butoxy carbonyl)amino]cyclopentane-l-carboxylate (9 g, 20.9 mmol) in THF (30 mL), MeOH (30 mL) and H2O (30 mL) was added LiOH (3.51 g, 146 mmol) at room temperature. The resulting mixture was stirred for 1 hour at 70 °C. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0553] Preparation of tert-butyl ((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-((2oxopropyl) carbamoyl)cyclopentyl) carbamate (general method-07)

[0554] O TCFH, NMI,

[0555] ACN, 60°C, 2h

[0556]

[0557] To a stirred solution of (lR,3S)-l-[(3-bromo-2-fluorophenyl)methyl]-3-[(tert-butoxycarbonyl) amino]cyclopentane-l-carboxylic acid (2 g, 4.80 mmol) and a-aminoacetone (3.51 g, 48.0 mmol) in MeCN (20 mL) were added TCFH (2.70 g, 9.60 mmol) and NMI (1.58 g, 19.2 mmol) at room temperature. The resulting mixture was stirred for 2 hours at 60°C. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (3x60 mL) and dried over

[0558] anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm.

[0559] Preparation of tert-butyl ((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)carbamate (general method-07, INT-9) BocHN,

[0560] Burgess reagent,

[0561] THF,60°C,2h

[0562]

[0563] To a stirred solution of tert-butyl N-[(lS,3R)-3-[(3-bromo-2-fluorophenyl)methyl]-3-[(2-oxopropyl) carbamoyl]cyclopentyl]carbamate (415 mg, 0.88 mmol) in THF (20 mL) was added Burgess reagent (2.09 g, 8.80 mmol) at room temperature. The resulting mixture was stirred for 2 hours at 60 °C. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm.

[0564] Preparation of tert-butyl ((1S,3R)-3-(5-methyloxazol-2-yl)-3-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)cyclopentyl)carbamate (general method-07, INT-5)

[0565] Pd(dppf)CI2, dioxane, H2O, 80°C, 2h, Ar

[0566]

[0567] A mixture of tert-butyl ((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclo pentyl)carbamate (165 mg, 0.36 mmol), 3,5-difluorophenylboronic acid (86 mg, 0.54 mmol), Pd(dppf)Cl2 (26 mg, 0.036 mmol), and Cs2CO3(356 mg, 1.09 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred for 2 hours at 80 °C under an argon atmosphere. The residue was dissolved in water (4 mL). The aqueous layer was extracted with EtOAc (3x4 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc 2:1) to afford the desired product. Preparation of tert-butyl N-[(lS,3R)-3-[(5-cyano-2,4-difluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]carbamate (general method-08)

[0568] Zn(CN)2, Zn, Pd(dppf)CI2

[0569] DMSO, Ar, 80 °C

[0570]

[0571] To a stirred solution of tert-butyl N-[(lS,3R)-3-[(5-bromo-2,4-difluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]carbamate (400 mg, 0.84 mmol) and Zn(CN)2 (199 mg, 1.69 mmol) in DMSO (20 mL) were added Pd(dppf)Cl2 (124 mg, 0.17 mmol) and Zn (55 mg, 0.84 mmol) in portions at room temperature under an argon atmosphere. The resulting mixture was stirred at 80 °C for 15 hours. Upon cooling to the room temperature, the reaction was quenched with water and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (2:1) to afford the desired product.

[0572] Preparation of tert-butyl ((lS,3R)-3-(2,4-difluoro-5-((Z)-N'-hydroxycarbamimidoyl)benzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)carbamate (general method-08)

[0573]

[0574] A mixture of tert-butyl N-[(lS,3R)-3-[(5-cyano-2,4-difluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]carbamate (960 mg, 2.30 mmol) and hydroxylamine, 50% in water (2.2 g, 66.6 mmol) was irradiated with microwaves at 100 °C for 30 minutes. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (1:1) to afford the desired product.

[0575] Preparation of tert-butyl ((lS,3R)-3-(2,4-difluoro-5-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl)- 3-(5-methyloxazol-2-yl)cyclopentyl)carbamate (general method-08, INT-5)

[0576]

[0577] To a stirred solution of l-[(lH-imidazol-l-yl)carbonyl]-lH-imidazole (309 mg, 1.90 mmol) and acetic acid (233 mg, 3.89 mmol) in DMF (30 mL) was added tert-butyl N-[(lS,3R)-3-({2,4-difluoro-5-[(Z)-N'-hydroxycarbamimidoyl]phenyl}methyl)-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]carbamate (780 mg, 1.73 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (1:1).

[0578] The following intermediate was prepared in a similar manner:

[0579] N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(3-methyl-l,2,4-oxadiazol-5-yl)cyclopentyl)methanesulfonamide, prepared from methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and (Z)-N'-hydroxyacetimidamide Preparation of (lR,3S)-l-[(3-bromo-2,4-difluorophenyl)methyl]-3-methanesulfonamidocyclopentane-l-carboxylic acid (general method-09)

[0580] NaOH,

[0581] MeOH, H2O,1h,70°C

[0582]

[0583] To a stirred solution of methyl (lR,3S)-l-[(3-bromo-2,4-difluorophenyl)methyl]-3-methanesulfonamidocyclopentane-l-carboxylate (3.4 g, 7.97mmol) in MeOH (30 mL) and H2O (10 mL) was added NaOH (1.60 g, 39.88 mmol) at room temperature. The resulting mixture was stirred for 1 hour at 70 °C. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0584] Preparation of (lR,3S)-l-(3-bromo-2,4-difluorobenzyl)-3-(methylsulfonamido)-N-(2-oxopropyl)cyclopentane-l-carboxamide (general method-09)

[0585] HUTA, TEA,

[0586] DMF,0°C,1h

[0587]

[0588] To a stirred solution of (lR,3S)-l-[(3-bromo-2,4-difluorophenyl)methyl]-3-methanesulfonamidocyclopentane-l-carboxylic acid (3.5 g, 8.49 mmol) and TEA (5.15 g, 50.9 mmol) in DMF (40 mL) were added HATU (16.14 g, 42.45 mmol) and 1-aminoacetone (1.24 g, 17.0 mmol) at 0 °C. The resulting mixture was stirred for 1 hour at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. Preparation of N-((lS,3R)-3-(3-bromo-2,4-difluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide (general method-09, INT-6)

[0589] Burgess reagent

[0590] THF,60°C,2h

[0591]

[0592] To a stirred solution of (lR,3S)-l-[(3-bromo-2,4-difluorophenyl)methyl]-3-methanesulfonamido-N-(2-oxopropyl)cyclopentane-l-carboxamide (2 g, 4.28 mmol) in THF (20 mL) was added Burgess' reagent (5.10 g, 21.4 mmol) at room temperature. The resulting mixture was stirred for 2 hours at 60 °C. The mixture was allowed to cool to room temperature and water was added. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by flash chromatography on silica gel.

[0593] The following intermediates were prepared in a similar manner:

[0594] N-((lS,3R)-3-((2-bromo-5-fluoropyridin-4-yl)methyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide, prepared from (lR,3S)-l-((2-bromo-5-fluoropyridin-4-yl)methyl)-3-(methylsulfonamido)cyclopentane-l-carboxylic acid and l-aminopropan-2-one, N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide, prepared from methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and l-aminopropan-2-one, N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide, prepared from methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and l-aminopropan-2-one, N-((lS,3R)-3-(3-bromobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide, prepared from methyl (lR,3S)-l-(3-bromobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and l-aminopropan-2-one, N-((lS,3R)-3-(5-bromo-2,4-difluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide, prepared from methyl (lR,3S)-l-(5-bromo-2,4-difluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and l-aminopropan-2-one,

[0595] N-((lS,3R,4S)-3-(3-bromo-4-fluorobenzyl)-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide (enantiomer 1), prepared from racemic ethyl (lR,2S,4S)-l-(3-bromo-4-fluorobenzyl)-2-methyl-4-(methylsulfonamido)cyclopentane-l-carboxylate and l-aminopropan-2-one,

[0596] N-((3R,5S)-5-(3-chloro-4-fluorobenzyl)-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl)methanesulfonamide, prepared from (2S,4R)-2-(3-chloro-4-fluorobenzyl)-4-(methylsulfonamido)tetrahydrofuran-2-carboxylic acid and l-aminopropan-2-one, N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl) methanesulfonamide, prepared from methyl (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and l-aminopropan-2-one,

[0597] N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide, prepared from methyl (lR,3S)-l-[(3-chloro-2,4-difluorophenyl)methyl]-3-methanesulfonamidocyclopentane-l-carboxylate and 1-aminopropan-2-one,

[0598] N-[(lS,3S)-3-[(4-chloro-5-fluoropyridin-2-yl) methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl] methanesulfonamide, prepared from (lS,3S)-l-[(4-chloro-5-fluoropyridin-2-yl) methyl]-3-methanesulfonamidocyclopentane-l-carboxylic acid and l-aminopropan-2-one,

[0599] tert-butyl ((lS,3R)-3-(5-methyloxazol-2-yl)-3-((2,3',5'-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentyl)carbamate, prepared from methyl (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-((tert-butoxycarbonyl)amino)cyclopentane-l-carboxylate and 1-aminopropan-2-one, Preparation of methyl (lR,3S)-l-(3-chloro-2,4-difluorobenzyl)-3- (methylsulfonamido)cyclopentane-l-carbimidate (general method-10)

[0600] i

[0601] F-B’-F

[0602] i

[0603] F DCM, 0 °C - r.t, 2 h

[0604]

[0605] To a stirred solution of (lR,3S)-l-(3-chloro-2,4-difluorobenzyl)-3- (methylsulfonamido)cyclopentane-l-carboxamide (1 g, 2.72 mmol) in DCM (11 mL) was added tetrafluoroborate (806 mg, 5.45 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 30% to 60% gradient in 15 min; detector, UV 254 nm

[0606] Preparation of (lR,3S)-l-(3-chloro-2,4-difluorobenzyl)-3- (methylsulfonamido)cyclopentane-l-carboximidamide (general method-10)

[0607] NH4CI, NH3(g) in MeOH,

[0608] 80°C, 4 h

[0609]

[0610] A solution of methyl (lR,3S)-l-(3-chloro-2,4-difluorobenzyl)-3- (methylsulfonamido)cyclopentane-l-carbimidate (360 mg, 0.94 mmol) and NH4Cl (606 mg, 11.3 mmol) in NH3(g) in MeOH (9 mL) was stirred for 4 hours at 80 °C. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0611] Preparation of N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(pyrimidin-2- yl)cyclopentyl)methanesulfonamide (general method-10, INT-6) N K3PO4 dioxane, 120 C, 2 h

[0612]

[0613] F

[0614] To a stirred solution of (lR,3S)-l-(3-chloro-2,4-difluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboximidamide (300 mg, 0.65 mmol) and (E)-3-(dimethylamino)acrylaldehyde (130 mg, 1.31 mmol) in dioxane (5 mL) was added K3PO4 (165 mg, 1.96 mmol) in portions at room temperature. The resulting mixture was stirred for 2 hours at 120 °C. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 10 mL). The filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by flash chromatography on silica gel.

[0615] The following intermediate was prepared in a similar manner:

[0616] N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(4-methoxypyrimidin-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide, prepared from (lR,3S)-l-(3-chloro-2,4-difluorobenzyl)-3-(N-(4-methoxybenzyl)-(methylsulfonamido))cyclopentane-l-carboximidamide and sodium (lE)-3-ethoxy-3-oxoprop-l-en-l-olate, followed by O-methylation using methyl iodide,

[0617] N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(5-fluoropyrimidin-2-yl)cyclopentyl)methanesulfonamide prepared from (lR,3S)-l-(3-chloro-2,4-difluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxamide and (Z)-3-(diethylamino)-2-fluoroacrylaldehyde, Preparation of (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylic acid (general method-11)

[0618]

[0619] To a mixture of methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3- (methylsulfonamido)cyclopentane-l-carboxylate (6.64g, 16.3 mmol) in methanol (80 mL) and water (20 mL) was added sodium hydroxide in water (2.60 g, 6 mL, 10.8 molar, 65.1 mmol). The mixture was heated at 60 °C overnight. The reaction mixture was cooled down and diluted with water (40 mL) and concentrated to remove most of MeOH. The mixture was washed with TBME (3 x 50 mL) and adjusted in pH with cone. HCI to pH ~1. This yielded an emulsion that was extracted with TBME twice. The combined organic phases were dried over MgSO4, filtered and evaporated to dryness to yield the desired product.

[0620] Preparation of (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxamide (general method-11)

[0621]

[0622] Br Br

[0623] Ammonium bicarbonate (8.66 g, 110.0 mmol) was added to (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylic acid (2.88 g, 7.30 mmol), DIPEA (12.7 mL, 73.0 mmol), HATU (6.94 g, 18.3 mmol) and HOAt (IM in DMA) (730 pL, 1 molar, 730 pmol) in dichloromethane (94 mL) and DMF (6 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, redissolved in ethyl acetate, and washed with sat. NH4Cl, and then sat. NaHCCh, and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography on silica gel to yield the desired product. Preparation of N-((lS,3R)-3-(3-bromobenzyl)-3-(4-(chloromethyl)oxazol-2-yl)cyclopentyl)methanesulfonamide (general method-11)

[0624]

[0625] To a dry flask equipped with a stirring bar and containing (lR,3S)-l-(3-bromobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxamide (1.89 g, 5.04 mmol) was added 1,3-dichloropropan-2-one (25 g, 0.20 mol). The mixture was stirred at 125 °C for 1.5 hours. The reaction mixture was cooled to room temperature, diluted by DCM, washed with brine and sat. NaHCO3 (2 x 50 mL). The combined organic phases were dried and concentrated. The crude material was purified via flash chromatography on silica gel to afford the title compound.

[0626] Preparation of N-((lS,3R)-3-(3-bromobenzyl)-3-(4-(hydroxymethyl)oxazol-2-yl)cyclopentyl)methanesulfonamide (general method-11, INT-6)

[0627]

[0628] N-((lS,3R)-3-(3-bromobenzyl)-3-(4-(chloromethyl)oxazol-2-yl)cyclopentyl)methanesulfonamide (1.33 g, 2.97 mmol) was dissolved in 1,4-dioxane (50 mL). NaOH (2M aq.) (15 mL, 30 mmol) was added and the mixture was stirred at 80 °C for 2 hours and at 40 °C overnight. Then the mixture was stirred at 90 °C for 6 hours and at 40 °C overnight. The mixture was cooled and aq., 12 N HCI was carefully added until pH ~1. The mixture was extracted with ethyl acetate and the combined organic phases were dried and concentrated in vacuo. The residue obtained was purified via flash chromatography on silica gel to afford the title compound.

[0629] Preparation of N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(4-methyloxazol-2-yl)cyclopentyl)- N-(4-methoxybenzyl)methanesulfonamide

[0630]

[0631] To a stirred solution of (lR,3S)-l-[(3-bromo-2-fluorophenyl) methyl]-3-{N-[(4-methoxyphenyl) methyl]methanesulfonamido}cyclopentane-l-carboxamide (100 mg, 0.19 mmol) and NaHCCh (98.17 mg, 1.17 mmol) in dioxane (3 mL) was added bromoacetone (133 mg, 0.97mmol) at room temperature. The resulting mixture was stirred overnight at 90°C, then concentrated in vacuo. The crude product was used in the next step directly without further purification. To a stirred solution of the crude product (in THF (4 mL)) was added TFAA (442 mg, 2.10 mmol) at 0°C. The resulting mixture was stirred for 2

[0632] hours at room temperature. The resulting mixture was concentrated under reduced pressure and EtOAc was added. The combined organic layers were washed

[0633] with brine (3x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0634] Preparation of N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(4-methyloxazol-2-yl)cyclopentyl)methane sulfonamide

[0635] TFA, DCE,70°C,30min

[0636]

[0637] To a stirred solution of N-[(lS,3R)-3-[(3-bromo-2-fluorophenyl)methyl]-3-(4-methyl-l,3-oxazol-2-yl)cyclopentyl]-N-[(4-methoxyphenyl)methyl]methanesulfonamide (470 mg, 0.85 mmol) in DCE (5 mL) was added TFA (5 mL, 67 mmol) at room temperature. The resulting mixture was stirred for 1 hour at 70°C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and EtOAc was added. The combined organic layers were washed with brine (3x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0638] Preparation of (lR,3S)-3-(methylsulfonamido)-l-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentane-l-carboxylic acid (general method-12)

[0639] NaOH,CH3OH H2O,80°C,2h

[0640]

[0641] A mixture of methyl (lR,3S)-3-(methylsulfonamido)-l-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentane-l-carboxylate (2.9 g, 6.56 mmol) and NaOH (0.79 g, 19.7 mmol) in CH3OH (20 mL) and H2O (10 mL) was stirred for 2 hours at 70 °C. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0642] Preparation of (lR,3S)-N-methoxy-N-methyl-3-(methylsulfonamido)-l-((2,3',6-trifluoro- [l,l'-biphenyl]-3-yl)methyl)cyclopentane-l-carboxamide (general method-12)

[0643] \XO. HCI N

[0644] n TEA, HATU, DMF,r.t,1h

[0645]

[0646] A mixture of (lR,3S)-3-(methylsulfonamido)-l-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentane-l-carboxylic acid (2 g, 4.67 mmol), N, O-dimethylhydroxylamine hydrochloride (1.43 g, 23.3 mmol), TEA (2.37 g, 23.3 mmol) and HATU (8.90 g, 23.3 mmol) in DMF (20 mL) was stirred for 2 hours at 0 °C. The resulting mixture was extracted with EtOAc (1 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (10mmol / L NH4HCO3), 20% to 80% gradient in 20 minutes; detector, UV 220 nm.

[0647] Preparation of N-((lS,3R)-3-propioloyl-3-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide (general method-12, INT-8)

[0648]

[0649] Bromo(ethynyl)magnesium (31.8 mL, 15.9 mmol) in tetrahydrofuran (10 mL) was added to (lR,3S)-N-methoxy-N-methyl-3-(methylsulfonamido)-l-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentane-l-carboxamide (500 mg, 1.06 mmol) in tetrahydrofuran (10 mL) at - 78 °C under an argon atmosphere. The reaction mixture was stirred overnight while allowing to warm to room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (1:1) to afford the desired product.

[0650] The following intermediate was prepared in a similar manner:

[0651] N-((lS,3S)-3-((((cis)-4-phenylcyclohexyl)oxy)methyl)-3- propioloylcyclopentyl)methanesulfonamide, prepared from methyl (lS,3S)-3- (methylsulfonamido)-l-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate. COMPOUNDS OF THE INVENTION

[0652] Example 1: N-[(lS,3S)-3-(4-methyloxazol-2-yl)-3-[cis-(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0653] Preparation of (lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylic acid (general method-13)

[0654] NaOH, MeOH,

[0655] H2O, 60°C,4h

[0656]

[0657] A mixture of methyl (lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl)oxy)methyl) cyclopentane-l-carboxylate (500 mg, 1.22 mmol) and NaOH (73 mg, 3.1 mmol) in MeOH (2.7 mL) and H2O (2.3 mL) was stirred for 4 hours at 60 °C. To obtain the title compound, the, residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 30% to 40% gradient in 10 min; detector, UV 220 nm.

[0658] Preparation of (lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carbonyl chloride (general method-13)

[0659]

[0660] A mixture of (lS,3S)-3-(methylsulfonamido)-l-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylic acid (80 mg, 0.20 mmol) and SOCI2 (1 mL, 13.8 mmol) was stirred for 2 hours at 80 °C. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. Preparation of (lS,3S)-N-(l-hydroxypropan-2-yl)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl) oxy)methyl)cyclopentane-l-carboxamide (general method-13)

[0661]

[0662] A mixture of 2-aminopropanol (100 mg, 1.33 mmol) and TEA (555 pL, 3.99 mmol) was stirred for 10 min at room temperature. To the above mixture was added (lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carbonyl chloride (661 mg, 1.59 mmol) at 0 °C. The resulting mixture was stirred for additional 6 hours at room temperature. The resulting mixture was concentrated under vacuum. To obtain the title compound, the residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 30% to 40% gradient in 10 min; detector, UV 254 nm.

[0663] Preparation of (lS,3S)-3-(methylsulfonamido)-N-(l-oxopropan-2-yl)-l-(((cis-4-phenylcyclohexyl) oxy)methyl)cyclopentane-l-carboxamide (general method-13)

[0664] Dess-Martin, DCM, R. T.,6h

[0665]

[0666] A mixture of (lS,3S)-N-(l-hydroxypropan-2-yl)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl) oxy)methyl)cyclopentane-l-carboxamide (45 mg, 0.099 mmol) and Dess-Martin (84 mg, 0.20 mmol) in DCM (1 mL) was stirred for 6 hours at room temperature. The product was precipitated by the addition of water. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 3 mL). The filtrate was concentrated under reduced pressure to give the desired product. Preparation of N-((lS,3S)-3-(4-methyloxazol-2-yl)-3-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentyl) methanesulfonamide (general method-13)

[0667] Burgess reagent, THF, 110°C, overnight

[0668]

[0669]

[0670] A mixture of (lS,3S)-3-(methylsulfonamido)-N-(l-oxopropan-2-yl)-l-(((cis-4-phenylcyclohexyl) oxy) methyl)cyclopentane-l-carboxamide (45 mg, 0.10

[0671] mmol) and Burgess reagent (119 mg, 0.50 mmol) in THF (1 mL) was stirred overnight at 110 °C. The resulting mixture was concentrated under vacuum. To obtain the title compound, the residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 60% to 90% gradient in 20 min; detector, UV 220 nm.

[0672] 1H NMR (400 MHz, Methanol-d4) δ7.54 (d, J = 1.4 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.15 - 7.07 (m, 3H), 3.88 - 3.79 (m, 1H), 3.72 - 3.61 (m, 2H), 3.59 - 3.56 (m, 1H), 2.95 (s, 3H), 2.71 (dd, J = 13.5, 7.4 Hz, 1H), 2.51 - 2.41 (m, 1H), 2.24 - 2.16 (m, 1H), 2.15 (s, 3H), 2.14 - 2.05 (m, 2H), 2.01 - 1.92 (m, 2H), 1.85 (dd, J = 13.5, 8.4 Hz, 1H), 1.79 - 1.68 (m, 1H), 1.66 - 1.51 (m, 3H), 1.51- 1.43 (m, 3H)

[0673] LC-MS (Method B) (m / z) = 433.1 (MH)+tR= 0.84 minutes. [a]20D+16.5° (c = 0.1, MeOH) The following compounds were prepared in a similar manner:

[0674] Example 2: N-[(lS,3S)-3-[[(lR,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-oxazol-2-yl-cyclopentyl]methanesulfonamide

[0675]

[0676] Prepared as Example l from methyl (lS,3S)-l-((((lR,3R,6S)-6-(5-fluoropyrimidin-2- yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and 2,2-dimethoxyethanamine.

[0677] 1H NMR (600 MHz, DMSO-d6) δ8.72 (s, 2H), 8.01 (s, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.10 (s, 1H), 3.68 (dt, J = 17.4, 8.6 Hz, 1H), 3.63 - 3.57 (m, 2H), 3.27 (t, J = 7.3 Hz, 1H), 2.89 (s, 3H), 2.70 (ddd, J = 14.8, 10.3, 5.3 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.30 - 2.17 (m, 1H), 2.07 - 1.86 (m, 5H), 1.69 (dd, J = 13.4, 8.7 Hz, 1H), 1.60 (ddd, J = 14.7, 9.3, 5.3 Hz, 2H), 1.54- 1.42 (m, 3H), 0.91 (dd, J = 6.3, 3.6 Hz, 1H). LC-MS (Method A) (m / z) = 451.3 (MH)+tR= 0.71 minutes.

[0678] Example 3: N-[(lS,3S)-3-[[(lS,3S,6R)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-oxazol-2-yl-cyclopentyl]methanesulfonamide

[0679]

[0680] Prepared as Example l from methyl (lS,3S)-l-((((lS,3S,6R)-6-(5-fluoropyrimidin-2- yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and 2,2-dimethoxyethanamine.

[0681] 1H NMR (600 MHz, Chloroform-d) δ8.47 - 8.42 (m, 2H), 7.58 (s, 1H), 7.01 (s, 1H), 5.73 (d, J = 8.9 Hz, 1H), 4.03 - 3.97 (m, 1H), 3.74 (d, J = 8.7 Hz, 1H), 3.68 (d, J = 9.1 Hz, 1H), 3.20 (q, J = 7.3 Hz, 1H), 2.96 (d, J = 1.3 Hz, 3H), 2.73 - 2.60 (m, 2H), 2.52 (dt, J = 15.0, 8.3 Hz, 1H), 2.30 (dq, J = 13.9, 5.0, 4.0 Hz, 1H), 2.19 - 2.14 (m, 2H), 2.00 - 1.89 (m, 3H), 1.70 - 1.63 (m, 3H), 1.46 (d, J = 4.2 Hz, 1H), 1.40 - 1.32 (m, 1H), 0.98 (t, J = 5.2 Hz, 1H). LC-MS (Method B) (m / z) = 451.1 (MH)+tR= 0.67 minutes.

[0682] Example 4: N-[(lS,3S)-3-[[(lR,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3- (5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0683]

[0684] Prepared as Example 1 from methyl (1S,3S)-1-((((1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate and 2,2-dimethoxypropan-1-amine.

[0685] 1H NMR (600 MHz, Chloroform-d) δ8.43 (d, J = 1.3 Hz, 2H), 6.58 (d, J = 1.7 Hz, 1H), 5.77 (d, J = 8.9 Hz, 1H), 3.99 (tt, J = 6.3, 3.4 Hz, 1H), 3.70 (d, J = 8.7 Hz, 1H), 3.65 (d, J = 8.7 Hz, 1H), 3.43 (tdd, J = 9.9, 6.1, 3.2 Hz, 1H), 2.95 (d, J = 1.3 Hz, 3H), 2.68 (td, J = 13.1, 5.2 Hz, 1H), 2.61 (dd, J = 14.1, 6.8 Hz, 1H), 2.52 (ddd, J = 13.7, 8.9, 6.9 Hz, 1H), 2.33 - 2.26 (m, 4H), 2.20 - 2.10 (m, 2H), 2.03 - 1.86 (m, 4H), 1.70 - 1.63 (m, 2H), 1.45 (dd, J = 9.6, 4.1 Hz, 1H), 1.34 (qd, J = 12.2, 4.4 Hz, 1H), 0.98 (dd, J = 6.2, 4.3 Hz, 1H) ppm. LC-MS (Method B) (m / z) = 465.1 (MH)+tR= 0.70 minutes.

[0686] Example 5: N-[(lS,3S)-3-(5-cyclopropyloxazol-2-yl)-3-[[(lR,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]cyclopentyl]methanesulfonamide

[0687]

[0688] Prepared as Example 1 from methyl (1S,3S)-1-((((1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate and 2-amino-1-cyclopropylethan-1-one hydrochloride.

[0689] 1H NMR (600 MHz, DMSO-d6) δ8.71 (d, J = 7.8 Hz, 2H), 7.12 (dd, J = 25.5, 7.4 Hz, 1H), 6.70-6.58 (m, 1H), 3.70 - 3.46 (m, 3H), 3.28 - 3.18 (m, 1H), 2.98 - 2.88 (m, 1H), 2.89 - 2.84 (m, 3H), 2.76 - 2.67 (m, 1H), 2.47 - 2.35 (m, 1H), 2.20 (dddd, J = 12.5, 8.2, 4.2, 2.5 Hz, 1H), 2.03 - 1.80 (m, 5H), 1.72 (dtd, J = 14.2, 6.0, 2.5 Hz, 1H), 1.66 - 1.54 (m, 2H), 1.54 - 1.37 (m, 2H), 1.33 - 1.22 (m, 2H), 0.88 (ddp, J = 9.7, 6.4, 3.3 Hz, 2H), 0.69 - 0.61 (m, 2H). LC-MS (Method A) (m / z) = 491.5 (MH)+tR= 0.78 minutes.

[0690] Example 6: N-[(3R,5S)-5-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl]methanesulfonamide or N-[(3S,5R)-5-[[3-(3,5- difluorophenyl)-4-fluoro-phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl] methanesulfonamide

[0691]

[0692] Prepared as Example 1 from ethyl 4-(methylsulfonamido)-2-((3',5',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)tetrahydrofuran-2-carboxylate and 2,2-dimethoxypropan-l-amine, followed by separation of the two enantiomers by standard procedures using chiral SFC. 1H NMR (600 MHz, DMSO) 57.31 (tt, J = 9.3, 2.3 Hz, 1H), 7.28 - 7.17 (m, 4H), 7.16 - 7.11 (m, 1H), 6.77 (d, J = 1.3 Hz, 1H), 4.07 - 3.95 (m, 1H), 3.87 (dd, J = 8.7, 6.7 Hz, 1H), 3.59 (dd, J = 8.7, 6.1 Hz, 1H), 3.40 - 3.24 (m, 2H), 2.86 (s, 3H), 2.74 (dd, J = 12.9, 7.6 Hz, 1H), 2.30 (d, J = 1.3 Hz, 3H), 2.07 - 1.95 (m, 1H) LC-MS (Method A) (m / z) = 467.5 (MH)+tR= 0.80 minutes. [a]20D+26.67° (c = 1.2, MeOH)

[0693] Example 7: N-[(3S,5R)-5-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-5-(5- methyloxazol-2-yl)tetrahydrofuran-3-yl]methanesulfonamide or N-[(3R,5S)-5-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl] methanesulfonamide

[0694]

[0695] Prepared as Example 1 from ethyl 4-(methylsulfonamido)-2-((3',5',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)tetrahydrofuran-2-carboxylate and 2,2-dimethoxypropan-l-amine followed by separation of the two enantiomers by standard procedures using chiral SFC. 1H NMR (600 MHz, DMSO) 57.31 (tt, J = 9.4, 2.3 Hz, 1H), 7.26 - 7.16 (m, 4H), 7.14 (ddd, J = 8.5, 4.8, 2.3 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.87 (dd, J = 8.7, 6.7 Hz, 1H), 3.59 (dd, J = 8.7, 6.1 Hz, 1H), 3.43 - 3.17 (m, 2H), 2.86 (s, 3H), 2.74 (dd, J = 12.9, 7.6 Hz, 1H), 2.30 (s, 3H), 2.06 - 1.97 (m, 1H) LC-MS (Method A) (m / z) = 467.4 (MH)+tR= 0.81 minutes.

[0696] [a]20D-20.83° (c = 1.2, MeOH)

[0697] Example 8: N-[(1S,3S)-3-oxazol-2-yl-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0698]

[0699] Prepared as Example 1 from methyl (lS,3S)-3-(methylsulfonamido)-l-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 2,2-dimethoxyethanamine.

[0700] 1H NMR (600 MHz, DMSO) 58.02 (s, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 7.5 Hz, 1H), 7.17 - 7.08 (m, 4H), 3.75 - 3.67(m, 1H), 3.62 (d, J = 8.6 Hz, 1H), 3.58 (d, J = 8.6 Hz, 1H), 3.53 (s, 1H), 2.90 (s, 3H), 2.56 (dd, J = 13.3, 7.4 Hz, 1H), 2.49 - 2.42 (m, 1H), 2.13 - 2.05 (m, 1H), 2.01 - 1.95 (m, 2H), 1.90 - 1.81 (m, 2H), 1.77 (dd, J = 13.3, 8.7 Hz, 1H), 1.69 - 1.60 (m, 1H), 1.56 - 1.39 (m, 6H). LC-MS (Method B) (m / z) = 419.1 (MH)+tR= 0.80 minutes. Example 9: N-[rel-(lS,3R,4S)-4-methyl-3-(5-methyloxazol-2-yl)-3-[(3-phenylphenyl)methyl]cyclopentyl]methanesulfonamide

[0701]

[0702] Prepared as Example 1 from ethyl (lR,2S,4S)-l-([l,l'-biphenyl]-3-ylmethyl)-2-methyl-4-(methylsulfonamido)cyclopentane-l-carboxylate and l-aminopropan-2-one.

[0703] 1H NMR (600 MHz, DMSO) 57.54 - 7.51 (m, 2H), 7.46 - 7.42 (m, 3H), 7.36 - 7.32 (m, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.20 (dd, J = 4.6, 2.8 Hz, 2H), 6.97 (dt, J = 7.6, 1.3 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 4.02 (pd, J = 7.8, 3.7 Hz, 1H), 3.49 (d, J = 13.3 Hz, 1H), 2.87 - 2.82 (m, 4H), 2.46 (dd, J = 13.4, 8.3 Hz, 1H), 2.32 (d, J = 1.2 Hz, 3H), 2.28 - 2.22 (m, 1H), 1.85 (ddd, J = 13.4, 7.6, 4.0 Hz, 1H), 1.77 (dd, J = 13.4, 7.1 Hz, 1H), 1.57 (dt, J = 13.4, 9.4 Hz, 1H), 0.84 (d, J = 6.9 Hz, 3H). LC-MS (Method A) (m / z) = 425.4 (MH)+tR= 0.84 minutes.

[0704] Example 10: N-[(lR,2R,4R,5S)-4-oxazol-2-yl-4-[cis-(4-phenylcyclohexoxy)methyl]-2-bicyclo[3.1.0]hexanyl]methanesulfonamide

[0705]

[0706] Prepared as Example l from methyl (lS,2R,4R,5R)-4-(methylsulfonamido)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate and 2,2-dimethoxyethan- 1-amine.

[0707] 1H NMR (600 MHz, CDCl3) δ7.60 (d, J = 0.8 Hz, 1H), 7.29 (dd, J = 8.1, 7.2 Hz, 2H), 7.23 - 7.20 (m, 2H), 7.18 (ddt, J = 7.9, 6.9, 1.3 Hz, 1H), 7.04 (d, J = 0.8 Hz, 1H), 6.61 (d, J = 10.3 Hz, 1H), 4.05 - 4.00 (m, 2H), 3.84 - 3.81 (m, 1H), 3.61 (d, J = 9.2 Hz, 1H), 2.94 (s, 3H), 2.64 (dd, J = 15.3, 7.6 Hz, 1H), 2.59 (dt, J = 11.7, 3.8 Hz, 1H), 2.24 (dp, J = 14.4, 3.3 Hz, 1H), 2.18 (dp, J = 14.1, 3.1 Hz, 1H), 2.07 (d, J = 15.3 Hz, 1H), 1.89 - 1.83 (m, 1H), 1.82 - 1.76 (m, 2H), 1.75 - 1.71 (m, 2H), 1.71 - 1.66 (m, 2H), 1.63 - 1.55 (m, 1H), 0.64 (td, J = 8.4, 6.0 Hz, 1H), 0.25 (dt, J = 6.1, 4.0 Hz, 1H). LC-MS (Method B) (m / z) =431.1 (MH)+tR= 0.79 minutes.

[0708] Example 11: N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0709]

[0710] Prepared as Example 1 from methyl (1S,3S)-3-(methylsulfonamido)-1-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-1-carboxylate and 1-aminopropan-2-one.

[0711] XH NMR (400 MHz, DMSO-d6): 67.27 (t, J = 7.6 Hz, 2H), 7.20 - 7.13 (m, 2H), 7.10 (d, J = 7.2 Hz, 2H), 6.73 (d, J = 1.2 Hz, 1H), 3.75 - 3.63 (m, 1H), 3.60 - 3.51 (m, 3H), 2.89 (s, 3H), 2.56 - 2.53 (m, 1H), 2.48 - 2.41 (m, 1H), 2.22 (s, 3H), 2.12 - 2.04 (m, 1H), 2.01 - 1.91 (m, 2H), 1.90 - 1.82 (m, 2H), 1.73 (dd, J = 13.2, 8.8 Hz, 1H), 1.67 - 1.58 (m, 1H), 1.53 - 1.37 (m, 6H) LC-MS (Method B) (m / z) =433.1 (MH)+tR= 0.83 minutes. [a]20D+12° (c = 0.1, MeOH)

[0712] Example 12: N-[(1S,3S)-3-[[cis-4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-oxazol-2-yl- cyclopentyl] methanesulfonamide

[0713]

[0714] F Prepared as Example 1 from methyl (1S,3S)-1-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate and 2,2-dimethoxyethanamine.

[0715] TH NMR (400 MHz, CD3OD) 57.86 (d, J = 0.8Hz, 1H), 7.11 (d, J = 0.8Hz, 1H), 6.73-6.69 (m, 3H), 3.89-3.80 (m, 1H), 3.72 (d, J = 4.8Hz, 1H), 3.67 (d, J = 4.8Hz, 1H), 3.59-3.55 (m, 1H), 2.95 (s, 3H), 2.75-2.69 (m, 1H), 2.57-2.49 (m, 1H), 2.22-2.14 (m, 1H), 2.13-2.07 (m, 2H), 1.98-1.94 (m, 2H), 1.90-1.83 (m, 1H), 1.79-1.73 (m, 1H), 1.52-1.47 (m, 6H) LC-MS (Method B) (m / z) = 455.1 (MH)+tR= 0.84 minutes. [a]20D+17° (c = 0.1, MeOH)

[0716] Example 13: N-[(1S,3R)-3-oxazol-2-yl-3-[(3-phenylphenyl)methyl]cyclopentyl]methanesulfonamide

[0717]

[0718] Prepared as Example 1 from methyl (1R,3S)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate and 2,2-dimethoxyethanamine.

[0719] TH NMR (300 MHz, Methanol-d4) δ 7.92 (d, J = 0.9 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.47 - 7.38 (m, 3H), 7.37 - 7.35 (m, 2H), 7.09 (d, J = 0.9 Hz, 1H), 7.00 (t, J = 1.8 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H),3.81 - 3.73 (m, 1H), 2.30 - 2.20 (m, 2H), 2.94 (s, 3H), 2.74 (dd, J = 13.2, 7.3 Hz, 1H), 2.37 - 2.21 (m, 1H), 2.20 - 2.01 (m, 2H), 1.97 - 1.89 (m, 1H), 1.89- 1.69 (m, 1H) LC-MS (Method B) (m / z) = 397.1 (MH)+tR= 0.75 minutes. [a]20D+43° (c = 0.1, MeOH) Example 14: N-[(lS,3S)-3-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0720]

[0721] Prepared as Example 1 from methyl (1S,3S)-1-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate and 1-aminopropan-2-one.

[0722] TH NMR (300 MHz, Methanol-d4) 66.78 - 6.64 (m, 4H), 3.94 - 3.79 (m, 1H), 3.72 - 3.60 (m, 2H), 3.60 - 3.56 (m, 1H), 2.97 (s, 3H), 2.74 - 2.65 (m, 1H), 2.61 - 2.47 (m, 1H), 2.30 (d, J = 1.2 Hz, 3H), 2.24 - 2.16 (m, 1H), 2.15 - 2.04 (m, 2H), 2.00 - 1.91 (m, 2H), 1.87 - 1.77 (m, 1H), 1.77 - 1.66 (m, 1H), 1.60 - 1.42 (m, 6H) LC-MS (Method B) (m / z) =469.1 (MH)+tR= 0.86 minutes. [a]20D+14° (c = 0.1, MeOH)

[0723] Example 15: N-[(1S,3S)-3-[cis-[4-(3-fluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0724]

[0725] Prepared as Example 1 from methyl (1S,3S)-1-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate and 1-aminopropan-2-one.

[0726] TH NMR (300 MHz, Methanol-d4) 67.32 - 7.21 (m, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.92 - 6.80 (m, 2H), 6.75 - 6.71 (m, 1H), 3.86 (p, J = 7.6 Hz, 1H), 3.73 - 3.64 (m, 2H), 3.63 - 3.58 (m, 1H), 2.97 (s, 3H), 2.78 - 2.65 (m, 1H), 2.61 - 2.46 (m, 1H), 2.30 (d, J = 1.2 Hz, 3H), 2.27 - 2.18 (m, 1H), 2.18 - 2.04 (m, 2H), 2.03 - 1.91 (m, 2H), 1.90 - 1.80 (m, 1H), 1.80 - 1.68 (m, 1H), 1.63 - 1.42 (m, 6H) LC-MS (Method B) (m / z) =451.2 (MH)+tR= 0.83 minutes. [a]20D+3° (c = 0.1, MeOH)

[0727] Example 16: N-[(1R,2R,4R,5S)-4-[[(1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-4-(5-methyloxazol-2-yl)-2-bicyclo[3.1.0]hexanyl]methanesulfonamide

[0728]

[0729] Prepared as Example 1 from methyl (1S,2R,4R,5R)-2-((((1S,3R,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-4-(methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylate and 1-aminopropan-2-one.

[0730] XH NMR (400 MHz, Chloroform-d) 68.44 (s, 2H), 6.61 (d, J = 1.5 Hz, 1H), 6.55 (d, J = 10.3 Hz, 1H), 3.98 - 3.85 (m, 2H), 3.65 (d, J = 9.0 Hz, 1H), 3.48 (tdd, J = 9.6, 6.2, 3.2 Hz, 1H), 2.97 (s, 3H), 2.76 - 2.60 (m, 1H), 2.64 - 2.52 (m, 2H), 2.35 (dt, J = 14.2, 4.2 Hz, 1H), 2.29 (d, J = 1.3 Hz, 3H), 2.01 (d, J = 12.7 Hz, 1H), 1.94 (d, J = 15.2 Hz, 1H), 1.77 - 1.64 (m, 2H), 1.67 - 1.60 (m, 2H), 1.46 (dd, J = 9.5, 4.1 Hz, 1H), 1.46 - 1.32 (m, 1H), 1.02 (dd, J = 6.2, 4.2 Hz, 1H), 0.58 (td, J = 8.4, 6.0 Hz, 1H), 0.20 (dt, J = 6.0, 4.0 Hz, 1H) LC-MS (Method B) (m / z) = 477.1 (MH)+tR= 0.71 minutes. [a]20D+94° (c = 0.1, MeOH)

[0731] Example 17: N-[trans-4-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-(5-methyloxazol- 2-yl)cyclohexyl] methanesulfonamide

[0732]

[0733] F Prepared as Example 1 from methyl (1r,4r)-4-(methylsulfonamido)-1-((3',5',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)cyclohexane-1-carboxylate and 1-aminopropan-2-one.

[0734] TH NMR (300 MHz, Chloroform-d) 57.02 - 6.90 (m, 3H), 6.83 - 6.72 (m, 2H), 6.71 - 6.68 (m, 1H), 6.66 - 6.61 (m, 1H), 4.65 - 4.55 (m, 1H), 3.51 - 3.61 (m, 1H), 3.01 (s, 3H), 3.00 - 2.97 (m, 2H), 2.30 - 2.27 (m, 3H), 2.17 - 2.05 (m, 2H), 1.88 - 1.70 (m, 6H) LC-MS (Method A) (m / z) =479.3 (MH)+tR= 0.85 minutes.

[0735] Example 18: N-[trans-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclobutyl]methanesulfonamide

[0736]

[0737] Prepared as Example 1 from methyl (1r,3s)-3-(N-(tert-butoxycarbonyl)-(methylsulfonamido))-1-((3',5',6-trifluoro-[1,1'-biphenyl]-3-yl) methyl)cyclobutane-1-carboxylate and 1-aminopropan-2-one.

[0738] TH NMR (400 MHz, Chloroform-d) 57.07 - 6.85 (m, 5H), 6.84 - 6.77 (m, 1H), 6.65 (d, J = 1.4 Hz, 1H), 4.83 (d, J = 8.7 Hz, 1H), 4.00 (p, J = 8.4 Hz, 1H), 3.17 (s, 2H), 2.99 - 2.94 (m, 2H), 2.93 (s, 3H), 2.31 (s, 3H), 2.25 - 2.17 (m, 2H) LC-MS (Method A) (m / z) = 451.3 (MH)+tR= 0.81 minutes.

[0739] Example 19: N-[(1R,3S)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0740]

[0741] Prepared as Example 1 from methyl (1S,3R)-3-(methylsulfonamido)-1-((2,3',6-trifluoro-[1,1'-biphenyl]-3-yl)methyl)cyclopentane-1-carboxylate and 1-aminopropan-2-one.XH NMR (400 MHz, Chloroform-d) 67.45 - 7.35 (m, 1H), 7.20 - 7.00 (m, 3H), 6.85 - 6.75 (m, 1H), 6.72 - 6.62 (m, 1H), 6.61 - 6.56 (m, 1H), 4.67 - 4.56 (m, 1H), 3.92 - 3.75 (m, 1H), 3.20 -3.01 (m, 2H), 2.99 - 2.72 (m, 4H), 2.39 - 2.20 (m, 4H), 2.20 - 2.08 (m, 1H), 2.03 - 1.87 (m, 1H), 1.74 - 1.59 (m, 2H) LC-MS (Method A) (m / z) =465.4 (MH)+tR= 0.82 minutes. [a]20D+44° (c = 0.1, MeOH)

[0742] Example 20: N-[(1S,3R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-[5-(methoxymethyl)oxazol-2-yl]cyclopentyl]methanesulfonamide

[0743]

[0744] Prepared as Example 1 from methyl (1R,3S)-1-((3',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate and 1-amino-3-methoxypropan-2-ol.

[0745] TH NMR (400 MHz, Chloroform-d) 57.41 - 7.33 (m, 1H), 7.25 - 7.20 (m, 1H), 7.17 - 7.10 (m, 1H), 7.08 - 7.01 (m, 1H), 7.01 - 6.95 (m, 1H), 6.94 - 6.90 (m, 1H), 6.88 - 6.80 (m, 2H), 4.40 (s, 3H), 3.95 - 3.83(m, 1H), 3.30 (s, 3H), 3.22 - 3.08 (m, 2H), 2.95 (s, 3H), 2.88 - 2.79 (m, 1H), 2.40 - 2.30 (m, 1H), 2.25 - 2.12 (m, 1H), 2.07 - 1.96 (m, 1H), 1.77 - 1.62 (m, 2H) LC-MS (Method A) (m / z) = 477.4 (MH)+tR= 0.79 minutes. [a]20D+7° (c = 0.1, MeOH)

[0746] Example 21: N-[(1S,3S)-3-(1,3,4-oxadiazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0747] Preparation of N-[(1S,3S)-3-(1,3,4-oxadiazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide (general method-14)

[0748]

[0749] A mixture of methyl (lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl)oxy) methyl)cyclopentane-l-carboxylate (120 mg, 0.293 mmol) and NH2NH2. H2O (2.40 mL) in EtOH (0.02 mL) was stirred for 1 hour at 70 °C. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification.

[0750] Preparation of N-((1S,3S)-3-(1,3,4-oxadiazol-2-yl)-3-(((cis-4-phenylcyclohexyl)oxy)methyl) cyclopentyl)methanesulfonamide (general method-14)

[0751]

[0752] A mixture of N-((1S,3S)-3-(hydrazinecarbonyl)-3-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentyl) methanesulfonamide (150 mg, 0.366 mmol) and N, N-diisopropylethylamine (191 pL, 1.09 mmol) in trimethyl orthoformate (1 mL) was stirred overnight at 100 °C. The resulting mixture was concentrated under vacuum. To obtain the title compound, the residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 30% to 50% gradient in 10 min; detector, UV 220 nm.

[0753] TH NMR (300 MHz, Chloroform-d) 58.37 (s, 1H), 7.33 - 7.27 (m, 2H), 7.23 - 7.14 (m, 3H), 5.43 (d, J = 8.5 Hz, 1H), 4.13 - 4.02 (m, 1H), 3.80 - 3.75 (m, 1H), 3.74 (s, 2H), 2.94 (s, 3H), 2.71 (dd, J = 14.2, 7.0 Hz, 1H), 2.65 - 2.48 (m, 1H), 2.38 - 2.17 (m, 2H), 2.17 - 1.90 (m, 5H), 1.78 - 1.59 (m, 5H) LC-MS (Method B) (m / z) = 420.1 (MH)+tR= 0.73 minutes. [a]20D-8° (c = 0.1, MeOH) The following intermediate was prepared in a similar manner:

[0754] N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyl-l,3,4-oxadiazol-2-yl)cyclopentyl)methanesulfonamide, prepared from methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclopentane-l-carboxylate and acetic acid anhydride, Example 22: N-[(1S,3R)-3-(1,2,4-oxadiazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0755] Preparation of (1S,3S)-3-(methylsulfonamido)-1-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-1-carboxamide (general method-15)

[0756]

[0757] A mixture of (1S,3S)-3-methanesulfonamido-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)cyclopentane-1-carboxylic acid (120 mg, 0.303 mmol) and NH4Cl (24 mg, 0.46 mmol), HATU (138 mg, 0.364 mmol), N, N-diisopropylethylamine (156 pL, 0.909 mmol) in DMF (1 mL) was stirred for 6 hours at room temperature. The resulting mixture was extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (2 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 30% to 70% gradient in 10 min; detector, UV 254 nm.

[0758] Preparation of N-((1S,3R)-3-cyano-3-(((cis-4-phenylcyclohexyl) oxy) methyl) cyclopentyl) methanesulfonamide (general method-15) Burgess reagent

[0759] DCE;50°C,2h

[0760]

[0761] A mixture of (1S,3S)-3-(methylsulfonamido)-1-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-1-carboxamide (100 mg, 0.253 mmol) and Burgess reagent (91 mg, 0.38 mmol) in DCE (2 mL) was stirred for 2 hours at 50 °C. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / EtOAc 2:1) to afford the desired product.

[0762] Preparation of (1R,3S) -N'-hydroxy-3-(methylsulfonamido)-1-(((cis-4-phenylcyclohexyl)oxy)methyl) cyclopentane-1-carboximidamide (general method-15)

[0763] NH2OH. HCI,

[0764] NaHCO3,60°C,2h

[0765]

[0766] A mixture of N-((lS,3R)-3-cyano-3-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentyl) methane sulfonamide (80 mg, 0.212 mmol), NaHCOs (27 mg, 0.32 mmol) and NH2OH. HCI (22 mg, 0.32 mmol) in EtOH (3 mL) was stirred for 2 hours at 80 °C. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / EtOAc 1:1) to afford the desired product. Preparation of N-((1S,3R)-3-(1,2,4-oxadiazol-3-yl)-3-(((cis-4-phenylcyclohexyl) oxy) methyl) cyclopentyl) methanesulfonamide (general method-15)

[0767]

[0768] A solution of (1R, 3S)-N'-hydroxy-3-(methylsulfonamido)-1-(((cis-4-phenylcyclohexyl) oxy) methyl) cyclopentane-1-carboximidamide (45 mg, 0.11 mmol) and N, N-diisopropylethylamine (28 mg, 0.22 mmol) in trimethyl orthoformate (1 mL) was stirred for 16 hours at 100 °C. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (2:1) to afford the desired product.

[0769] TH NMR (400 MHz, Methanol-d4) δ 9.15 (s, 1H), 7.28 - 7.19 (m, 2H), 7.12 (td, J = 5.9, 3.2 Hz, 3H), 3.95 (q, J = 7.4 Hz, 1H), 3.68 - 3.81 (m, 2H), 3.60 (q, J = 2.8 Hz, 1H), 2.94 (s, 3H), 2.68 (dd, J = 13.5, 7.3 Hz, 1H), 2.54 - 2.43 (m, 1H), 2.32 -2.09 (m, 3H), 2.01 -1.87 (m, 3H), 1.85 - 1.71 (m, 1H), 1.71 - 1.61 (m, 2H), 1.55 - 1.33 (m, 4H) LC-MS (Method B) (m / z) =420.0 (MH)+tR = 0.80 minutes. [a]20D+3° (c = 0.1, MeOH)

[0770] The following compound was prepared in a similar manner:

[0771] Example 23: N-[(1S,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopentyl] methanesulfonamide

[0772]

[0773] Prepared as Example 22 from methyl (lR,3S)-3-(methylsulfonamido)-l-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentane-l-carboxylate and acetic acid anhydride.

[0774] XH NMR (400 MHz, Chloroform-d) δ7.44 - 7.39 (m, 1H), 7.20 - 7.18 (m, 1H), 7.14 - 7.06 (m, 2H), 6.88 - 6.81 (m, 2H), 4.31 - 4.29 (m, 1H), 3.90 - 3.84 (m, 1H), 3.20 - 3.12 (m, 2H), 2.94 (s, 3H), 2.81 - 2.75 (m, 1H), 2.60 (s, 3H), 2.32 - 2.14 (m, 2H), 2.03 - 1.94 (m, 1H), 1.73 - 1.64 (m, 2H) LC-MS (Method A) (m / z) = 466.4 (MH)+tR= 0.80 minutes.

[0775] Example 24: N-[(lS,3S)-3-[cis-(4-phenylcyclohexoxy)methyl]-3-thiazol-2-yl-cyclopentyl] methanesulfonamide

[0776] Preparation of / V-((lS,3S)-3-(((cis-4-phenylcyclohexyl) oxy) methyl) -3-(thiazol-2-yl) cyclopentyl) methanesulfonamide (general method-16)

[0777] Lawesson's reagent THF, r,t, 16 h

[0778]

[0779] A mixture of (lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl) oxy) methyl) cyclopentane-l-carboxamide (45 mg, 0.114 mmol) and Lawesson reagent (92 mg, 0.23 mmol) in THF (1 mL) was stirred for 16 hours at room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2 x 50 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 Prep-TLC (petroleum ether / EtOAc 1:1) to afford the desired product.

[0780] Preparation of N-((lS,3S)-3-(((cis-4-phenylcyclohexyl) oxy) methyl)-3-(thiazol-2-yl)cyclopentyl) methanesulfonamide (general method-16)

[0781]

[0782] A solution of (lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carbothioamide (20 mg, 0.049 mmol) in THF (1 mL) was treated with chloroacetaldehyde (5.74 mg, 0.074 mmol) and Burgess reagent (35 mg, 0.15 mmol) for 2 hours at 60 °C. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (5 x 10 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reverse flash chromatography with the following conditions: (column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 60% gradient in 10 min; detector, UV 254 nm).

[0783] TH NMR (300 MHz, Methanol-4) δ7.74 (d, J = 3.3 Hz, 1H), 7.52 (d, J = 3.4 Hz, 1H), 7.31 - 7.20 (m, 2H), 7.19 - 7.08 (m, 3H), 3.98 - 3.85 (m, 1H), 3.79 - 3.59 (m, 3H), 2.97 (s, 3H), 2.75 (dd, J = 13.6, 7.4 Hz, 1H), 2.51 (t, J = 12.0 Hz, 1H), 2.31 - 2.20 (m, 2H), 2.10 - 1.95 (m, 3H), 1.88 - 1.73 (m, 1H), 1.77 - 1.53 (m, 6H), 1.30 (s, 1H) LC-MS (Method B) (m / z) = 435.1 (MH)+tR = 0.84 minutes.

[0784] Example 25: N-[(lS,3R)-3-(2-methyl-l,2,4-triazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide and Example 26: N-[(lS,3R)-3- (l-methyl-l,2,4-triazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0785] Preparation of (lS,3S)-N-((E)-(dimethylamino)methylene)-3-(methylsulfonamido)-l-(((cis- 4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxamide (general method-17)

[0786]

[0787] A mixture of (lS,3S)-3-(methylsulfonamido)-l-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxamide (50 mg, 0.127 mmol) and N, N- diisopropylethylamine (49 mg, 0.38 mmol) in (dimethoxymethyl)dimethylamine (1 mL) was stirred for 3 hours at 100 °C. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification.

[0788] Preparation of / V-^lS^Rj-S-fl-methyl-lH-l^^-triazol-S-ylJ-S-^cis^- phenylcyclohexylJoxyJmethylJcyclopentylJmethanesulfonamide and / V-((lS,3R)-3-(l- methyl-lH-l,2,4-triazol-3-yl)-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide (general method-17)

[0789] H

[0790] H2N-NH AcOH, 80°C, 3h

[0791]

[0792] To a stirred mixture of (lS,3S)- / V-((E)-(dimethylamino)methylene)-3-(methylsulfonamido)-l- (((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxamide (35 mg, 0.078 mmol) in AcOH (1 mL) was added methyl hydrazine (22 mg, 0.47 mmol) dropwise at 0 °C. The resulting mixture was stirred for 3 hours at 80 °C. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. To obtain the two title compounds, the residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 50% to 80% gradient in 20 min; detector, UV 220 nm.

[0793] Example 25: N-[(lS,3R)-3-(2-methyl-l,2,4-triazol-3-yl)-3-[cis-(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0794]

[0795] TH NMR (400 MHz, Methanol-4) δ7.83 (s, 1H), 7.27 - 7.21 (m, 2H), 7.16 - 7.07 (m, 3H), 4.05 (s, 3H), 3.82 (p, J = 7.9 Hz, 1H), 3.67 - 3.52 (m, 3H), 2.97 (s, 3H), 2.89 (dd, J = 13.8, 8.3 Hz, 1H), 2.53 - 2.43 (m, 1H), 2.41 - 2.33 (m, 1H), 2.31 - 2.22 (m, 1H), 2.20 - 2.11 (m, 1H), 2.02 - 1.91 (m, 3H), 1.82 - 1.69 (m, 1H), 1.60- 1.43 (m, 6H) LC-MS (Method B) (m / z) =433.1 (MH)+tR= 0.68 minutes.

[0796] Example 26: N-[(lS,3R)-3-(l-methyl-l,2,4-triazol-3-yl)-3-[cis-(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0797]

[0798] TH NMR (400 MHz, Methanol-4) δ8.31 (s, 1H), 7.29 - 7.20 (m, 2H), 7.17 - 7.08 (m, 3H), 3.87 (s, 3H), 3.86 - 3.78 (m, 1H), 3.68 - 3.60 (m, 2H), 3.60 - 3.55 (m, 1H), 2.94 (s, 3H), 2.71 (dd, J = 13.2, 7.3 Hz, 1H), 2.48 (tt, J = 11.9, 3.4 Hz, 1H), 2.26 - 2.17 (m, 1H), 2.17 - 2.02 (m, 2H), 2.02 - 1.94 (m, 2H), 1.93 - 1.84 (m, 1H), 1.80 - 1.68 (m, 1H), 1.68 -1.55 (m, 2H), 1.54 - 1.44 (m, 4H) LC-MS (Method B) (m / z) = 433.1 (MH)+tR= 0.68 minutes. Example 27: N-[(lS,3R)-3-(4-methyl-l,2,4-triazol-3-yl)-3-[cis-(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0799] Preparation of / V-methyl-2-((lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl) oxy) methyl) cyclopentane-l-carbonyl) hydrazine-l-carbothioamide (general method-18)

[0800]

[0801] A mixture of (lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl) oxy) methyl) cyclopentane-l-carboxylic acid (100 mg, 0.253 mmol) in SOCI2 (1 mL) was stirred for 2 hours at 80 °C. The resulting mixture was concentrated under reduced pressure. A solution of 1- amino-3-methylthiourea (78 mg, 0.76 mmol) in DCM (5 mL) was treated with TEA (77 mg, 0.76 mmol) for 1 hour at room temperature followed by the addition of the above- mentioned mixture at 0 °C. The resulting mixture was stirred for 1 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0802] Preparation of / V-((lS,3R)-3-(4-methyl-5-thioxo-4,5-dihydro-l / - / -l,2,4-triazol-3-yl)-3-(((cis-4- phenyl cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide (general method-18)

[0803] NaOH, H2O reflux

[0804]

[0805] A mixture of / V-methyl-2-((lS,3S)-3-(methylsulfonamido)-l-((cis-4-phenylcyclohexyl) oxy) methyl) cyclopentane-l-carbonyl) hydrazine-l-carbothioamide (90 mg, 0.186 mmol) and NaOH (3 mg, 0.075 mmol) in H2O (9.7 mL) was stirred for 2 hours at 100 °C. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reverse flash chromatography with the following conditions:

[0806] (column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 20% to 50% gradient in 20 min; detector, UV 254 nm).

[0807] Preparation of / V-((lS,3R)-3-(4-methyl-4H-l,2,4-triazol-3-yl)-3-(((cis-4-phenylcyclohexyl) oxy)methyl)cyclopentyl)methanesulfonamide (general method-18)

[0808] H2O2, ACOH, DCM

[0809]

[0810] A mixture of / V-((lS,3R)-3-(4-methyl-5-thioxo-4,5-dihydro-l / 7-l,2,4-triazol-3-yl)-3-(((cis-4-phenyl cyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide (30 mg, 0.065 mmol), AcOH (0.5 mL) and 32 w% H2O2 in water (0.5 mL) in DCM (1 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. To obtain the title compound, the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 30% B to 54% B in 9 min, 54% B; Wave Length: 254 / 220 nm; RTl(min): 7.88).TH NMR (300 MHz, DMSO-d6) δ8.35 (s, 1H), 7.35 - 7.25 (m, 2H), 7.24 - 7.15 (m, 2H), 7.15 - 7.08 (m, 2H), 3.80 (s, 3H), 3.71 - 3.63 (m, 1H), 3.61 - 3.46 (m, 3H), 2.91 (s, 3H), 2.88 - 2.82 (m, 1H), 2.51 - 2.48 (m, 1H), 2.24 - 2.06 (m, 2H), 2.06 - 1.93 (m, 1H), 1.92 - 1.75 (m, 3H), 1.73 - 1.58 (m, 1H), 1.48 - 1.38 (m, 6H) LC-MS (Method B) (m / z) =433.1 (MH)+tR= 0.57 minutes. [a]20D+8° (c = 0.1, MeOH)

[0811] Example 28: N-[(lS,3S)-3-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]ethanesulfonamide

[0812] Preparation of (lS,3S)-3-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-(5-methyloxazol-2-yl)cyclopentan-l-amine (general method-19)

[0813]

[0814] A mixture of tert-butyl ((lS,3S)-3-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-(5- methyloxazol-2-yl)cyclopentyl)carbamate (150 mg, 0.306 mmol) in HCI (gas) in 1,4-dioxane (3 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification.

[0815] Preparation of / V-((lS,3S)-3-(((cis-4-(3,5-difluorophenyl) cyclohexyl) oxy) methyl)-3-(5- methyloxazol-2-yl) cyclopentyl)ethanesulfonamide (general method-19)

[0816]

[0817] A mixture of (lS,3S)-3-(((cis-4-(3,5-difluorophenyl) cyclohexyl) oxy) methyl) -3-(5- methyloxazol-2-yl) cyclopentan-l-amine (50 mg, 0.128 mmol) and ethanesulfonyl chloride (33 mg, 0.256 mmol) in DCM (2 mL) was stirred for 2 hours at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 30% to 80% gradient in 10 min; detector, UV 220 nm.

[0818] TH NMR (400 MHz, Methanol-d4) δ6.85 - 6.58 (m, 4H), 3.85 - 3.76 (m, 1H), 3.69 - 3.62 (m, 2H), 3.61 - 3.56 (m, 1H), 3.05 (q, J = 7 A Hz, 2H), 2.72 - 2.64 (m, 1H), 2.59 - 2.47 (m, 1H), 2.27 (d, J = 1.3 Hz, 3H), 2.25 - 2.14 (m, 1H), 2.14 - 2.01 (m, 2H), 2.01 - 1.92 (m, 2H), 1.87 - 1.78 (m, 1H), 1.78 - 1.65 (m, 1H), 1.50 (dd, J = 7.0, 2.0 Hz, 6H), 1.32 (t, J = 7 A Hz, 3H) LC-MS (Method A) (m / z) = 483.2 (MH)+tR= 0.88 minutes. [a]20D +3° (c = 0.1, MeOH)

[0819] The following compounds were prepared in a similar manner:

[0820] Example 29: (lS,3S)-3-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)-N-(methylsulfamoyl)cyclopentanamine

[0821]

[0822] Prepared as Example 28 from tert-butyl ((lS,3S)-3-(((cis-4-(3,5-difluorophenyl)cyclohexyl) oxy)methyl)-3-(5-methyloxazol-2-yl)cyclopentyl)carbamate and N-methylsulfamoyl chloride

[0823] TH NMR (300 MHz, Methanol-d4) δ6.78 - 6.62 (m, 4H), 3.78 - 3.52 (m, 4H), 2.72 - 2.62 (m, 1H), 2.60 (s, 3H), 2.58 - 2.48 (m, 1H), 2.27 (d, J = 1.3 Hz, 3H), 2.23 - 2.02 (m, 3H), 2.01 - 1.91 (m, 2H), 1.86 - 1.67 (m, 2H), 1.54 - 1.45 (m, 6H). LC-MS (Method B) (m / z) =484.4 (MH)+tR= 0.86 minutes. [a]20D+3° (c = 0.1, MeOH)

[0824] Example 30: 5-methyl-2-[(lS,3S)-l-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3- (dimethylsulfamoylamino)cyclopentyl]oxazole

[0825] O

[0826]

[0827] Prepared as Example 28 from tert-butyl ((lS,3S)-3-(((cis-4-(3,5-difluorophenyl)cyclohexyl) oxy)methyl)-3-(5-methyloxazol-2-yl)cyclopentyl) carbamate and dimethylsulphamoyl- chloride.

[0828] TH NMR (400 MHz, Methanol-d4) δ6.75 - 6.66 (m, 4H), 3.74 (p, J = 7.5 Hz, 1H), 3.69 - 3.60 (m, 2H), 3.61 - 3.56 (m, 1H), 2.75 (s, 6H), 2.68 - 2.61 (m, 1H), 2.58 - 2.47 (m, 1H), 2.27 (d, J = 1.3 Hz, 3H), 2.25 - 2.14 (m, 1H), 2.11 - 2.01 (m, 2H), 2.01 - 1.92 (m, 2H), 1.85 - 1.78 (m, 1H), 1.77 - 1.66 (m, 1H), 1.56 - 1.42 (m, 6H) LC-MS (Method A) (m / z) = 498.5 (MH)+tR= 0.92 minutes. [a]20D +2° (c = 0.1, MeOH)

[0829] Example 31: N-[(lS,3S)-3-(5-ethyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0830]

[0831] Prepared as Example 28 from tert-butyl ((lR,3R)-3-(5-ethyloxazol-2-yl)-3-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate and methanesulfonic anhydride.

[0832] TH NMR (400 MHz, DMSO-d6) δ7.26 (t, J = 6.0 Hz, 2H), 7.18 - 7.13 (m, 2H), 7.08 (d, J = 7.2 Hz, 2H), 6.73 (s, 1H), 3.70 (t, J = 7.6 Hz, 1H), 3.58 - 3.53 (m, 3H), 2.89 (s, 3H), 2.61 - 2.53 (m, 3H), 2.10 - 2.05 (m, 2H), 1.98 - 1.91 (m, 2H), 1.87 (d, J = 9.2 Hz, 2H), 1.75 - 1.69 (m, 1H), 1.65 - 1.60 (m, 1H), 1.50 - 1.40 (m, 6H), 1.12 (t, J = 7.6 Hz, 3H) LC-MS (Method A) (m / z) = 447.4 (MH)+tR= 0.89 minutes. [a]20D+11° (c = 0.1, MeOH)

[0833] Example 32: N-[(lS,3S)-3-[5-(methoxymethyl)oxazol-2-yl]-3-[cis-(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0834]

[0835] Prepared as Example 28 from tert-butyl ((lS,3S)-3-(5-(methoxymethyl)oxazol-2-yl)-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate and methanesulfonic anhydride.

[0836] TH NMR (400 MHz, DMSO-d6) δ7.26 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 7.3 Hz, 1H), 7.16 - 7.07 (m, 4H), 4.35 (s, 2H), 3.72 - 3.70 (m, 1H), 3.63 - 3.53 (m, 3H), 3.32 - 3.19 (m, 1H), 3.18 (s, 3H), 2.89 (s, 3H), 2.57 - 2.51 (m, 1H), 2.08 - 2.05 (m, 1H), 2.01 - 1.94 (m, 2H), 1.86 (d, J = 10.4Hz, 2H), 1.78 - 1.72 (m, 1H), 1.67 - 1.63 (m, 1H), 1.52 - 1.23 (m, 6H) LC-MS (Method B) (m / z) =463.2 (MH)+tR= 0.80 minutes. [a]20D+3° (c = 0.1, MeOH)

[0837] Example 33: N-[(lS,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4- phenylcyclohexoxy)methyl]cyclopentyl]ethanesulfonamide

[0838]

[0839] Prepared as Example 28 from tert-butyl ((lR,3R)-3-(5-methyloxazol-2-yl)-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate and ethanesulfonyl chloride.

[0840] TH NMR (400 MHz, Methanol-4) δ7.22 (t, J = 7.2 Hz, 2H), 7.13 - 7.08 (m, 3H), 6.71 (s, 1H), 3.80 (t, J = 7.6 Hz, 1H), 3.68 - 3.62 (m, 2H), 3.58 (s, 1H), 3.08 - 3.02 (m, 2H), 2.69 - 2.64 (m, 1H), 2.47 (s, 1H), 2.26 (s, 3H), 2.21 - 2.15 (m, 1H), 2.12 - 2.05 (m, 2H), 1.99 - 1.96 (m, 2H), 1.86 - 1.80 (m, 1H), 1.75 - 1.71 (m, 1H), 1.61 - 1.46 (m, 6H), 1.31 (t, J = 7.2 Hz, 3H) LC-MS (Method B) (m / z) =447.2 (MH)+tR= 0.86 minutes. [a]20D+12° (c = 0.1, MeOH) Ill 1283-WO-PCT

[0841] Example 34: N-[(lS,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4- phenylcyclohexoxy)methyl]cyclopentyl]oxetane-3-sulfonamide

[0842]

[0843] Prepared as Example 28 from tert-butyl ((lR,3R)-3-(5-methyloxazol-2-yl)-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate and oxetane-3-sulfonyl chloride.TH NMR (400 MHz, DMSO-d6) 67.58 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.20 - 7.12 (m, 1H), 7.12 - 7.06 (m, 2H), 6.72 (q, J = 1.2 Hz, 1H), 4.78 (dd, J = 7.8, 6.6 Hz, 2H), 4.68 - 4.53 (m, 3H), 3.69 (p, J = 7.9 Hz, 1H), 3.59 - 3.53 (m, 3H), 2.47 (s, 1H), 2.22 (d, J = 1.2 Hz, 3H), 2.05 (dt, J = 14.6, 8.2 Hz, 1H), 1.95 - 1.86 (m, 4H), 1.70 - 1.68 (m, 1H), 1.67 - 1.40 (m, 8H) LC-MS (Method A) (m / z) = 475.4 (MH)+tR= 0.85 minutes. [a]20D-152° (c = 0.1, MeOH) Example 35: N-[(lS,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]cyclopropanesulfonamide

[0844]

[0845] Prepared as Example 28 from tert-butyl ((lR,3R)-3-(5-methyloxazol-2-yl)-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate and cyclopropanesulfonyl chloride.TH NMR (400 MHz, Methanol-4) δ7.22 (t, J = 8.4 Hz, 2H), 7.11 (t, J = 9.6 Hz, 3H), 6.71 (d, J = 0.8 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.69 - 3.63 (m, 2H), 3.58 (s, 1H), 2.72 - 2.67 (m, 1H), 2.53 - 2.47 (m, 2H), 2.27 (s, 3H), 2.27 - 2.19 (m, 1H), 2.12 - 2.07 (m, 2H), 1.97 (d, J = 10.8 Hz, 2H), 1.89 - 1.83 (m, 1H), 1.81 - 1.72 (m, 1H), 1.61 - 1.46 (m, 6H), 1.04 - 0.98 (m, 4H) LC-MS (Method B) (m / z) =459.2 (MH)+tR= 0.87 minutes. [a]20D+16° (c = 0.1, MeOH) Example 36: N-[(lS,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]propane-2-sulfonamide

[0846]

[0847] Prepared as Example 28 from tert-butyl ((lR,3R)-3-(5-methyloxazol-2-yl)-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate and propane-2-sulfonyl chloride.TH NMR (400 MHz, DMSO-d6) δ7.26 (t, J = 7.6 Hz, 2H), 7.19 - 7.15 (m, 2H), 7.09 (d, J = 6.8 Hz, 2H), 6.72 (d, J = 1.2 Hz, 1H), 3.71 - 3.65 (m, 1H), 3.59 - 3.52 (m, 3H), 3.12 - 3.09 (m, 1H), 2.21 (d, J = 1.2 Hz, 3H), 2.09 - 2.04 (m, 1H), 1.96 - 1.73 (m, 6H), 1.67 - 1.58 (m, 2H), 1.52 - 1.40 (m, 6H), 1.22 - 1.20 (m, 6H) LC-MS (Method B) (m / z) = 461.2 (MH)+tR= 0.90 minutes.

[0848] [a]20D+14° (c = 0.1, MeOH)

[0849] Example 37: N-[(lS,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4- phenylcyclohexoxy)methyl]cyclopentyl]azetidine-l-sulfonamide

[0850]

[0851] Prepared as Example 28 from tert-butyl ((lR,3R)-3-(5-methyloxazol-2-yl)-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)carbamate and azetidine-l-sulfonyl chloride.TH NMR (400 MHz, DMSO-d6) 67.35 - 7.22 (m, 3H), 7.19 - 7.07 (m, 3H), 3.70 - 3.65 (m, 5H), 3.62 - 3.51 (m, 4H), 2.22 (d, J = 1.2 Hz, 3H), 2.15 - 2.02 (m, 4H), 1.99 - 1.84 (m, 4H), 1.86 (s, 1H), 1.78 - 1.68 (m, 1H), 1.64 - 1.59 (m, 1H), 1.49 - 1.39 (m, 6H) LC-MS (Method B) (m / z) = 474.2 (MH)+tR= 0.90 minutes. [a]20D+3° (c = 0.1, MeOH) Example 38: N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]ethanesulfonamide

[0852]

[0853] Prepared as Example 28 from tert-butyl ((lS,3R)-3-(5-methyloxazol-2-yl)-3-((2,3',5'-trifluoro- [l,l'-biphenyl]-3-yl)methyl)cyclopentyl)carbamate and ethanesulfonyl chloride.

[0854] TH NMR (400 MHz, Chloroform-d) 57.22 (d, J = 7.5, 1.7 Hz, 1H), 7.06 - 6.97 (m, 3H), 6.84 - 6.73 (m, 2H), 6.59 (q, J = 1.2 Hz, 1H), 4.17 (d, J = 8.1 Hz, 1H), 3.84 (h, J = 7.9 Hz, 1H), 3.24 - 3.12 (m, 2H), 3.01 (q, J = 7 A Hz, 2H), 2.83 (d, J = 13.1, 7.3 Hz, 1H), 2.38 - 2.30 (m, 1H), 2.29 (d, J = 1.2 Hz, 3H), 2.17 (d, J = 13.0, 7.7 Hz, 1H), 1.99 (d, J = 13.1, 9.2, 7.2 Hz, 1H), 1.74 - 1.63 (m, 2H), 1.34 (t, J = 7 A Hz, 3H) LC-MS (Method A) (m / z) =479.4 (MH)+tR= 0.85 minutes.

[0855] [a]20D+8° (c = 0.1, MeOH)

[0856] Example 39: (lS,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(5-methyloxazol- 2-yl)-N-(methylsulfamoyl)cyclopentanamine

[0857]

[0858] Prepared as Example 28 from tert-butyl ((lS,3R)-3-(5-methyloxazol-2-yl)-3-((2,3',5'-trifluoro- [l,l'-biphenyl]-3-yl)methyl)cyclopentyl)carbamate and N-methylsulfamoyl chloride.TH NMR (400 MHz, Chloroform-d) 57.22 (d, J = 7.4, 1.8 Hz, 1H), 7.08 - 6.96 (m, 3H), 6.85 - 6.74 (m, 2H), 6.60 (q, J = 1.2 Hz, 1H), 4.23 - 4.06 (m, 2H), 3.76 (p, J = 7.5 Hz, 1H), 3.26 - 3.13 (m, 2H), 2.86 (d, J = 13.2, 7.3 Hz, 1H), 2.69 (d, J = 3.1 Hz, 3H), 2.35 (d, J = 13.1, 6.8 Hz, 1H), 2.28 (d, J = 0.8 Hz, 3H), 2.14 (d, J = 15.3, 7.7 Hz, 1H), 1.98 (d, J = 13.1, 8.2 Hz, 1H), 1.78 - 1.70 (m, 2H) LC-MS (Method A) (m / z) = 480.4 (MH)+tR= 0.83 minutes. [a]20D+9° (c = 0.1, MeOH) Example 40: 2-[(lR,3S)-l-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(dimethylsulfamoylamino)cyclopentyl]-5-methyl-oxazole

[0859]

[0860] Prepared as Example 28 from tert-butyl ((lS,3R)-3-(5-methyloxazol-2-yl)-3-((2,3',5'-trifluoro- [l,l'-biphenyl]-3-yl)methyl)cyclopentyl)carbamate and dimethylsulphamoyl-chloride.

[0861] TH NMR (400 MHz, Chloroform-d) 57.23 (td, J = 7.5, 1.8 Hz, 1H), 7.06 - 6.96 (m, 3H), 6.84 - 6.73 (m, 2H), 6.59 (q, J = 1.3 Hz, 1H), 4.25 (d, J = 7.7 Hz, 1H), 3.78 (h, J = 7.7 Hz, 1H), 3.23 - 3.13 (m, 2H), 2.82 (d, J = 13.3, 7.4 Hz, 1H), 2.77 (s, 6H), 2.36 - 2.30 (m, 1H), 2.28 (d, J = 1.2 Hz, 3H), 2.12 (d, J = 13.2, 7.7 Hz, 1H), 1.97 (d, J = 13.1, 8.1 Hz, 1H), 1.72 (d, J = 8.8 Hz, 1H), 1.65 (t, J = 4.4 Hz, 1H) LC-MS (Method A) (m / z) =494.4 (MH)+tR= 0.88 minutes. [a]20D+10° (c = 0.1, MeOH)

[0862] Example 41: N-[(lS,3R)-3-[[2,4-difluoro-5-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl]methyl]-3- (5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0863]

[0864] Prepared as Example 28 from tert-butyl ((lS,3R)-3-(2,4-difluoro-5-(5-methyl-l,2,4-oxadiazol- 3-yl)benzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)carbamate and methanesulfonyl chloride.TH NMR (400 MHz, DMSO-d6) 67.69-7.59 (m, 1H), 7.5-7.37 (m, 1H), 7.23-7.16 (m, 1H), 6.62-6.59 (m, 1H), 3.73 - 3.53 (m, 1H), 3.19 - 3.06 (m, 2H), 2.86 (s, 3H), 2.67 (s, 3H), 2.58 - 2.54 (m, 1H), 2.27-2.23 (m, 3H), 2.18 - 2.10 (m, 1H), 1.96 - 1.87 (m, 2H), 1.79 - 1.58 (m, 2H) LC-MS (Method A) (m / z) = 453.4 (MH)+tR = 0.67 minutes.

[0865] Example 42: N-[(lS,3R)-3-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0866] Preparation of N-((lS,3R)-3-((2-fluoro-[l,l'-biphenyl]-3-yl)methyl)-3-(5-methyloxazol-2-yl)cyclo pentyl)methanesulfonamide (general method-20)

[0867]

[0868] To a stirred solution of N-[(lS,3R)-3-[(3-bromo-2-fluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide (70 mg, 0.16 mmol) and phenyl boronic acid (30 mg, 0.24 mmol) in dioxane (2 mL) and H2O (0.4 mL) were added Pd(dppf)Cl2 (12 mg, 0.01 mmol) and K2CO3(45 mg, 0.32 mmol) at room temperature. The resulting mixture was stirred for 2 hours at 80 °C under an argon atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (3 x 3 mL) and dried over

[0869] anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm.

[0870] TH NMR (300 MHz, Chloroform-d) 67.52 - 7.40 (m, 5H), 7.40 - 7.34 (m, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.69 (t, J = 6.9 Hz, 1H), 6.60 (s, 1H), 4.21-4.18 (d, J = 12 Hz, 1H), 3.91-3.85 (m, 1H), 3.20 (s, 2H), 2.93 (s, 3H), 2.88-2.77 (m, 1H), 2.38-2.31 (m, 4H), 2.22-2.11 (m, 1H), 2.06-1.94 (m, 1H), 1.76 - 1.57 (m, 2H) LC-MS (Method B) (m / z) = 429.3 (MH)+tR= 0.79 minutes. [a]20D+5° (c = 0.1, MeOH)

[0871] The following compounds were prepared in a similar manner:

[0872] Example 43: N-[(lS,3R)-3-(5-methyloxazol-2-yl)-3-[(3-phenylphenyl)methyl]cyclopentyl]methanesulfonamide

[0873]

[0874] Prepared as Example 42 from N-((lS,3R)-3-(3-bromobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and phenyl boronic acid.

[0875] 1H NMR (600 MHz, DMSO) 57.55 - 7.50 (m, 2H), 7.47 - 7.40 (m, 3H), 7.38 - 7.32 (m, 1H), 7.29 - 7.26 (m, 1H), 7.26 - 7.21 (m, 1H), 7.07 - 7.00 (m, 1H), 6.86 - 6.81 (m, 1H), 6.67 (d, J = 1.3 Hz, 1H), 3.72 - 3.56 (m, 1H), 3.19 - 3.01 (m, 2H), 2.87 (s, 3H), 2.53 - 2.48 (m, 1H), 2.28 (d, J = 1.3 Hz, 3H), 2.12 - 2.04 (m, 1H), 1.98 - 1.89 (m, 2H), 1.76 (dd, J = 13.1, 8.5 Hz, 1H), 1.71 - 1.63 (m, 1H) LC-MS (Method A) (m / z) = 411.4 (MH)+tR= 0.81 minutes.

[0876] Example 44: N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(5-methyl- 1, 3, 4-oxadiazol-2-yl)cyclopentyl] methanesulfonamide

[0877]

[0878] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyl-l,3,4- oxadiazol-2-yl)cyclopentyl)methanesulfonamide and 3,5-difluorophenyl)boronic acid.TH NMR (500 MHz, DMSO) 67.35 - 7.25 (m, 2H), 7.23 - 7.12 (m, 3H), 7.07 (dd, J = 7.6, 2.3 Hz, 1H), 7.03 - 6.97 (m, 1H), 3.69 (h, J = 7.4 Hz, 1H), 3.17 - 3.06 (m, 2H), 2.87 (s, 3H), 2.54 -2.51 (m, 1H), 2.48 (s, 3H), 2.12 - 1.92 (m, 3H), 1.82 (dd, J = 13.3, 8.4 Hz, 1H), 1.74 - 1.64 (m, 1H). LC-MS (Method A) (m / z) = 466.4 (MH)+tR= 0.76 minutes.

[0879] Example 45: N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(3-methyl- 1, 2, 4-oxadiazol-5-yl)cyclopentyl] methanesulfonamide

[0880]

[0881] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(3-methyl-l,2,4-oxadiazol-5-yl)cyclopentyl)methanesulfonamide and (3,5-difluorophenyl)boronic acid.XH NMR (600 MHz, DMSO) 67.34 - 7.26 (m, 2H), 7.21 (dd, J = 10.8, 8.5 Hz, 1H), 7.17 - 7.13 (m, 2H), 7.06 (dd, J = 7.6, 2.3 Hz, 1H), 7.00 (ddd, J = 8.5, 4.7, 2.3 Hz, 1H), 3.69 (h, J = 7.6 Hz, 1H), 3.24 - 3.12 (m, 2H), 2.89 (s, 3H), 2.53 (dd, J = 13.5, 7.5 Hz, 1H), 2.29 (s, 3H), 2.14 - 2.03 (m, 2H), 2.02 - 1.93 (m, 1H), 1.88 (dd, J = 13.4, 8.3 Hz, 1H), 1.75 - 1.66 (m, 1H). LC-MS (Method A) (m / z) = 466.4 (MH)+tR= 0.84 minutes.

[0882] Example 46: N-[rac-(lS,3R)-3-[[3-(3-fluorophenyl)phenyl]methyl]-3-[4-(hydroxymethyl)oxazol-2-yl]cyclopentyl] methanesulfonamide

[0883]

[0884] Prepared as Example 42 from N-((lS,3R)-3-(3-bromobenzyl)-3-(4-(hydroxymethyl)oxazol-2- yl)cyclopentyl)methanesulfonamide and (3-fluorophenyl)boronic acid. 1H NMR (600 MHz, CDCI3) 57.55 (s, 1H), 7.41 - 7.35 (m, 2H), 7.30 - 7.25 (m, 2H), 7.14 (dt, J = 10.3, 2.1 Hz, 1H), 7.02 (td, J = 8.4, 2.7 Hz, 1H), 6.97 (t, J = 1.9 Hz, 1H), 6.86 (dt, J = 7.6, 1.4 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H), 4.38 (d, J = 7.8 Hz, 1H), 3.87 (h, J = 7.7 Hz, 1H), 3.21 (d, J = 13.5 Hz, 1H), 3.14 (d, J = 13.6 Hz, 1H), 2.93 (s, 3H), 2.82 (dd, J = 13.2, 7.2 Hz, 1H), 2.35 - 2.29 (m, 1H), 2.15 (ddd, J = 15.6, 7.8, 5.8 Hz, 2H), 2.02 (ddd, J = 13.3, 9.2, 7.2 Hz, 1H), 1.73 (dd, J = 13.2, 8.8 Hz, 1H), 1.69 - 1.63 (m, 1H). LC-MS (Method A) (m / z) = 445.4 (MH)+tR= 0.69 minutes.

[0885] Example 47: N-[rac-(3R,5S)-5-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl] methanesulfonamide

[0886]

[0887] Prepared as Example 42 from N-((3R,5S)-5-(3-chloro-4-fluorobenzyl)-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl)methanesulfonamide and (3-fluorophenyl)boronic acid.

[0888] 1H NMR (600 MHz, DMSO) 57.56 - 7.50 (m, 1H), 7.43 - 7.38 (m, 1H), 7.33 - 7.30 (m, 1H), 7.29 - 7.25 (m, 2H), 7.22 - 7.18 (m, 1H), 7.13 - 7.01 (m, 1H), 6.81 - 6.71 (m, 1H), 4.11 - 3.99 (m, 1H), 3.91 - 3.80 (m, 1H), 3.65 - 3.53 (m, 1H), 3.39 - 3.23 (m, 2H), 2.92 (s, 3H), 2.80 - 2.67 (m, 1H), 2.30 (s, 3H), 2.10 - 1.94 (m, 1H) LC-MS (Method A) (m / z) = 449.4 (MH)+tR= 0.77 minutes.

[0889] Example 48: N-[(lS,3R)-3-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0890]

[0891] Prepared as Example 42 from N-[(lS,3R)-3-[(3-bromo-2-fluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 3-fluorophenylboronic acid.

[0892] TH NMR (400 MHz, Chloroform-d) 57.43-7.36 (m, 1H), 7.24 (s, 1H), 7.20 - 7.17 (d, J = 12 Hz, 1H), 7.10 - 7.00 (m, 2H), 6.73(s, 1H), 6.61 (s, 1H), 4.26-4.23 (d, J = 12 Hz,1H), 3.93-3.83 (m, 1H), 3.20 (t, 2H), 2.94 (s, 3H), 2.90-2.80 (m, 1H), 2.40-2.31 (m, 1H), 2.29 (s, 3H), 2.23-2.10 (m, 1H), 2.06-1.93 (m, 1H), 1.75 - 1.63 (m, 3H) LC-MS (Method B) (m / z) = 447.3 (MH)+tR= 0.80 minutes. [a]20D+8° (c = 0.1, MeOH)

[0893] Example 49: N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0894]

[0895] Prepared as Example 42 from N-[(lS,3R)-3-[(3-bromo-2-fluorophenyl)methyl]-3-(5-methyl- l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 3,5-difluorophenylboronic acid.TH NMR (400 MHz, Chloroform-d) 57.24-7.22 (d, J = 8 Hz, 1H), 7.06 - 6.96 (m, 3H), 6.85 - 6.72 (m, 2H), 6.60 (s, 1H), 4.25-4.23 (d, J = 8 Hz,1H), 3.93-3.82 (m, 1H), 3.19 (t, 2H), 2.94 (s, 3H), 2.88-2.81 (m, 1H), 2.40-2.31(m, 1H), 2.28 (s, 3H), 2.21-2.09 (m, 1H), 2.04-1.94 (m, 1H), 1.72-1.64 (m, 2H) LC-MS (Method B) (m / z) = 465.4 (MH)+tR= 0.82 minutes. [a]20D+10° (c = 0.1, MeOH)

[0896] Example 50: N-[(lS,3R)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-3-(5-methyloxazol-2- yl)cyclopentyl] methanesulfonamide

[0897]

[0898] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methane sulfonamide and phenyl boronic acid.

[0899] TH NMR (300 MHz, Chloroform-d) 57.49 - 7.34 (m, 5H), 7.00 (dd, J = 10.4, 8.3 Hz, 1H), 6.90 (dd, J = 7.5, 2.2 Hz, 1H), 6.85 - 6.76 (m, 1H), 6.68 - 6.60 (m, 1H), 4.31 (d, J = 7.6 Hz, 1H), 3.90 (q, J = 7.7 Hz, 1H), 3.24 - 3.02 (m, 2H), 2.97 (s, 3H), 2.83 (dd, J = 12.9, 7.1 Hz, 1H), 2.43 - 2.31 (m, 1H), 2.30 (s, 3H), 2.19 (dt, J = 14.8, 7.2 Hz, 1H), 1.99 (dt, J = 12.8, 8.2 Hz, 1H), 1.72 - 1.60 (m, 2H) LC-MS (Method A) (m / z) = 429.4 (MH)+tR= 0.80 minutes. [a]20D+5° (c = 0.1, MeOH) Example 51: N-[(lS,3R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0900]

[0901] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2- yl)cyclopentyl)methane sulfonamide and 3-fluorophenyl boronic acid.

[0902] TH NMR (300 MHz, Chloroform-d) 57.39 (td, J = 8.0, 6.0 Hz, 1H), 7.24 (dq, J = 7.8, 1.4 Hz, 1H), 7.18 - 6.96 (m, 3H), 6.84 (ddd, J = 7.0, 4.7, 2.3 Hz, 2H), 6.63 (q, J = 1.2 Hz, 1H), 4.43 (d, J = 7.7 Hz, 1H), 3.90 (h, J = 7.7 Hz, 1H), 3.13 (d, J = 5.4 Hz, 2H), 2.97 (s, 3H), 2.82 (dd, J = 13.1, 7.2 Hz, 1H), 2.41 - 2.31 (m, 1H), 2.30 (s, 3H), 2.31 - 2.21 (m, 1H), 2.20 - 1.78 (m, 1H), 1.77 - 1.68 (m, 2H) LC-MS (Method B) (m / z) = 447.4 (MH)+tR= 0.81 minutes. [a]20D+7° (c = 0.1, MeOH) Example 52: N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0903]

[0904] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methane sulfonamide and 3,5-difluorophenylboronic acid.

[0905] 1H NMR (300 MHz, Chloroform-d) δ7.06 - 6.93 (m, 3H), 6.92 - 6.74 (m, 3H), 6.64 (q, J = 1.2 Hz, 1H), 4.40 (d, J = 7.7 Hz, 1H), 3.90 (h, J = 7.7 Hz, 1H), 3.19 - 3.05 (m, 2H), 2.98 (s, 3H), 2.82 (dd, J = 13.0, 7.1 Hz, 1H), 2.40 - 2.31 (m, 1H), 2.30 (s, 3H), 2.31 - 2.21 (m, 1H), 2.20 - 1.78 (m, 1H), 1.78 - 1.67 (m, 2H) LC-MS (Method B) (m / z) = 465.3 (MH)+tR= 0.84 minutes. [a]20D+3° (c = 0.1, MeOH)

[0906] Example 53: N-[(lS,3R)-3-[[3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0907]

[0908] Prepared as Example 42 from N-((lS,3R)-3-(3-bromobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 3-fluorophenylboronic acid.

[0909] 1H NMR (400 MHz, Chloroform-d) δ7.42 - 7.33 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.15 (dt, J = 10.3, 2.1 Hz, 1H), 7.06 - 6.96 (m, 2H), 6.89 (d, J = 7.5 Hz, 1H), 6.62 (s, 1H), 4.20 (s, 1H), 3.88 (s, 1H), 3.16 (q, J = 13.4 Hz, 2H), 2.93 (s, 3H), 2.81 (dd, J = 12.8, 6.2 Hz, 1H), 2.38 - 2.30 (m, 1H), 2.29 (s, 3H), 2.18 (s, 1H), 2.01 (s, 1H), 1.73 - 1.65(m, 2H) LC-MS (Method B) (m / z) = 429.4 (MH)+tR= 0.80 minutes. [a]20D+9° (c = 0.1, MeOH)

[0910] Example 54: N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0911]

[0912] Prepared as Example 42 from N-((lS,3R)-3-(3-bromobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 3,5-difluorophenylboronic acid.

[0913] 1H NMR (400 MHz, Chloroform-d) δ7.37 (d, J = 7.7 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.00 - 6.90 (m, 4H), 6.77 (tt, J = 8.9, 2.3 Hz, 1H), 6.67 (s, 1H), 4.34 (s, 1H), 3.88 (s, 1H), 3.17 (q, J = 13.4 Hz, 2H), 2.95 (s, 3H), 2.88 - 2.80 (m, 1H),2.4O - 2.34 (m, 1H), 2.31 (s, 3H), 2.19 (d, J = 6.6 Hz, 1H), 2.08 - 1.96 (m, 1H), 1.77 - 1.62 (m, 2H) LC-MS (Method B) (m / z) = 447.4 (MH)+tR= 0.82 minutes. [a]20D+7° (c = 0.1, MeOH)

[0914] Example 55: N-[(lS,3R)-3-[(2-fluoro-3-pyrimidin-2-yl-phenyl)methyl]-3-(5-methyloxazol-2- yl)cyclopentyl] methanesulfonamide

[0915]

[0916] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2- yl)cyclopentyl) methanesulfonamide and 2-(tributylstannyl)pyrimidine.1H NMR (300 MHz, Chloroform-d) δ8.88 (d, J = 4.9 Hz, 2H), 7.86 (td, J = 7.5, 1.8 Hz, 1H), 7.28 (s, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.81 (t, J = 6.8 Hz, 1H), 6.60 (d, J = 1.3 Hz, 1H), 4.38 (d, J = 8.2 Hz, 1H), 3.92 (p, J = 7.8 Hz, 1H), 3.35 - 3.14 (m, 2H), 2.94 (s, 3H), 2.84 (dd, J = 13.3, 7.6 Hz, 1H), 2.36 - 2.28 (m, 4H), 2.16 (dq, J = 14.2, 7.4 Hz, 1H), 2.08 - 1.96 (m, 1H), 1.74 (dd, J = 13.4, 8.6 Hz, 1H), 1.66 - 1.62 (m, 1H) LC-MS (Method A) (m / z) = 431.4 (MH)+tR= 0.58 minutes. [a]20D+5° (c = 0.1, MeOH)

[0917] Example 56: N-[(lS,3R)-3-[[2-fluoro-3-(2-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0918]

[0919] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl) methanesulfonamide and 2-(tributylstannyl)pyridine.

[0920] 1H NMR (400 MHz, Chloroform-d) δ8.74 (d, J = 5.0 Hz, 1H), 7.86 - 7.62 (m, 3H), 7.35 - 7.27 (m, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.80 (t, J = 7.1 Hz, 1H), 6.60 (d, J = 1.3 Hz, 1H), 4.38 (s, 1H), 3.89 (h, J = 7.8 Hz, 1H), 3.30 - 3.14 (m, 2H), 2.93 (s, 3H), 2.84 (dd, J = 13.2, 7.4 Hz, 1H), 2.39 - 2.27 (m, 4H), 2.21 - 2.09 (m, 1H), 2.01 (dt, J = 13.1, 8.2 Hz, 1H), 1.77 - 1.71 (m, 1H), 1.69 (d, J = 6.0 Hz, 1H) LC-MS (Method A) (m / z) = 430.4 (MH)+tR= 0.50 minutes. [a]20D+7° (c = 0.1, MeOH)

[0921] Example 57: N-[(lS,3R)-3-[[2-fluoro-3-(l-methylpyrazol-4-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0922]

[0923] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl) methanesulfonamide and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole.

[0924] 1H NMR (400 MHz, Chloroform-d) δ7.79 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.38 (td, J = 7.5, 1.7 Hz, 1H), 6.96 (td, J = 7.6, 1.4 Hz, 1H), 6.62 - 6.53 (m, 2H), 4.34 (d, J = 8.0 Hz, 1H), 3.95 (d, J = 1.4 Hz, 3H), 3.86 (p, J = 7.7 Hz, 1H), 3.23 - 3.11 (m, 2H), 2.92 (d, J = 1.3 Hz, 3H), 2.83 (dd, J = 13.2, 7.3 Hz, 1H), 2.33 (ddd, J = 13.1, 5.3, 1.5 Hz, 1H), 2.27 (d, J = 1.4 Hz, 3H), 2.16 (dq, J = 13.7, 7.8 Hz, 1H), 1.99 (dt, J = 13.4, 8.4 Hz, 1H), 1.74 - 1.61 (m, 2H) LC-MS (Method A) (m / z) = 433.4 (MH)+tR= 0.61 minutes. [a]20D+3° (c = 0.1, MeOH)

[0925] Example 58: N-[(lS,3R)-3-[[2-fluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0926]

[0927] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl) methanesulfonamide and 5-methyl-2-(tributylstannyl)thiazole.

[0928] 1H NMR (400 MHz, Chloroform-d) δ8.09 - 8.00 (m, 1H), 7.56 (dd, J = 2.4, 1.2 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.75 (td, J = 7.3, 1.8 Hz, 1H), 6.58 (q, J = 1.3 Hz, 1H), 4.34 (d, J = 7.9 Hz, 1H), 3.88 (h, J = 7.9 Hz, 1H), 3.27 - 3.14 (m, 2H), 2.94 (s, 3H), 2.85 (dd, J = 13.1, 7.3 Hz, 1H), 2.53 (d, J = 1.2 Hz, 3H), 2.41 - 2.30 (m, 1H), 2.27 (d, J = 1.2 Hz, 3H), 2.17 (dq, J = 13.2, 7.8 Hz, 1H), 2.06 - 1.94 (m, 1H), 1.75 - 1.63 (m, 2H) LC-MS (Method A) (m / z) = 450.5 (MH)+tR= 0.72 minutes. [a]20D+8° (c = 0.1, MeOH)

[0929] Example 59: N-[(lS,3R)-3-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(4-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0930]

[0931] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(4-methyloxazol-2-yl)cyclopentyl)methane sulfonamide and phenyl boronic acid.

[0932] 1H NMR (400 MHz, Chloroform-d) δ7.52-7.32 (m, 6H), 7.31-7.27 (m, 1H), 7.04 (t, J = 20 Hz, 1H), 6.71 (m, 1H), 4.23-4.21 (d, J = 8 Hz, 1H), 3.90 (m, 1H), 3.31-3.16 (m, 2H), 2.97-2.88 (m, 4H), 2.38 (m, 1H), 2.20-2.06 (m, 4H), 1.79-1.70 (m, 2H) LC-MS (Method A) (m / z) = 429.4 (MH)+tR= 0.80 minutes. [a]20D+24° (c = 0.1, MeOH)

[0933] Example 60: N-[(lS,3R)-3-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4-methyloxazol-2- yl)cyclopentyl] methanesulfonamide

[0934]

[0935] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(4-methyloxazol-2- yl)cyclopentyl)methane sulfonamide and 3-fluorophenyl boronic acid.

[0936] 1H NMR (300 MHz, Chloroform-d) δ7.41 (td, J = 8.0, 6.0 Hz, 1H), 7.34 (q, J = 1.2 Hz, 1H), 7.32-7.28 (m, 1H), 7.27-7.17 (m, 2H), 7.12-7.01 (m, 2H), 6.77-6.64 (m, 1H), 4.37 (d, J = 7.9 Hz, 1H), 3.90 (d, J = 7.5 Hz, 1H), 3.22 (t, J = 2.0 Hz, 2H), 2.96 (s, 3H), 2.87 (dd, J = 13.2, 7.3 Hz, 1H), 2.44-2.31 (m, 1H), 2.26-2.11 (m, 4H), 2.10-1.98 (m, 1H), 1.80-1.62 (m, 2H) LC-MS (Method B) (m / z) = 447.3 (MH)+tR= 0.80 minutes. [a]20D+13° (c = 0.1, MeOH) Example 61: N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(4-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0937]

[0938] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(4-methyloxazol-2- yl)cyclopentyl)methane sulfonamide and 3,5-difluorophenylboronic acid.

[0939] 1H NMR (400 MHz, Chloroform-d) δ7.32 (d, J = 1.4 Hz, 1H), 7.24-7.21(d, J = 12 Hz, 1H), 7.07-6.95 (m, 3H), 6.81 (m, 1H), 6.73 (m, 1H), 4.27-4.25 (d, J = 8 Hz, 1H), 3.87 (m, 1H), 3.19 (m, 2H), 2.94 (s, 3H), 2.85 (m, 1H), 2.34 (m, 1H), 2.25 - 2.08 (m, 4H), 2.01 (m, 1H), 1.77-1.65 (m, 2H) LC-MS (Method A) (m / z) = 465.4 (MH)+tR= 0.83 minutes. [a]20D+35° (c = 0.1, MeOH) Example 62: N-[(lS,3R)-3-[(2,4-difluoro-3-phenyl-phenyl)methyl]-3-(5-methyloxazol-2- yl)cyclopentyl] methanesulfonamide

[0940]

[0941] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and phenyl boronic acid.

[0942] 1H NMR (400 MHz, Chloroform-d) δ7.49 - 7.32 (m, 5H), 6.85-6.74 (m, 1H), 6.68 - 6.55 (m, 2H), 4.35-4.25 (m, 1H), 3.94-3.80 (m, 1H), 3.20 - 3.07 (m, 2H), 2.94 (s, 3H), 2.88-2.78 (m, 1H), 2.39 - 2.31 (m, 1H), 2.29 (d, J = 1.3 Hz, 3H), 2.22-2.11 (m, 1H), 2.04-1.92 (m, 1H), 1.74 - 1.64 (m, 2H) LC-MS (Method A) (m / z) = 447.5 (MH)+tR= 0.80 minutes. [a]20D+8° (c = 0.1, MeOH)

[0943] Example 63: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0944]

[0945] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 3-fluorophenylboronic acid.1H NMR (400 MHz, Chloroform-d) δ7.45-7.36 (m, 1H), 7.21-7.15 (m, 1H), 7.14 - 7.06 (m, 2H), 6.85-6.77 (m, 1H), 6.73-6.64 (m, 1H), 6.62-6.57 (m, 1H), 4.40 (d, J = 7.9 Hz, 1H), 3.93- 3.80 (m, 1H), 3.20 - 3.08 (m, 2H), 2.94 (s, 3H), 2.84 (dd, J = 13.0, 7.5 Hz, 1H), 2.39 - 2.27 (m, 4H), 2.23-2.11 (m, 1H), 2.02-1.93 (m, 1H), 1.74- 1.67 (m, 2H) LC-MS (Method A) (m / z) = 465.4 (MH)+tR= 0.81 minutes. [a]20D+10° (c = 0.1, MeOH)

[0946] Example 64: N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-2,4-difluoro-phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0947]

[0948] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl] methanesulfonamide and 3,5-difluorophenylboronic acid.1H NMR (400 MHz, Chloroform-d) δ6.98-6.90 (m, 2H), 6.89 - 6.79 (m, 2H), 6.78 - 6.68 (m, 1H), 6.65 - 6.59 (m, 1H), 4.48-4.33 (m, 1H), 3.97-3.82 (m, 1H), 3.19 - 3.11 (m, 2H), 2.96 (s, 3H), 2.89-2.81 (m, 1H), 2.37 - 2.27 (m, 4H), 2.24 - 2.13 (m, 1H), 2.04 - 1.93 (m, 1H), 1.74 - 1.67 (m, 2H) LC-MS (Method A) (m / z) = 483.4 (MH)+tR= 0.83 minutes. [a]20D+13° (c = 0.1, MeOH)

[0949] Example 65: N-[(lS,3R,4S)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide or N-[(lR,3S,4R)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0950]

[0951] Prepared as Example 42 from rac-N-((lS,3R,4S)-3-(3-bromo-4-fluorobenzyl)-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and phenyl boronic acid followed by separation of the two enantiomers by standard procedures using chiral SFC.

[0952] 1H NMR (400 MHz, Chloroform-d) δ7.47 - 7.39 (m, 4H), 7.38 - 7.33 (m, 1H), 7.05 - 6.97 (m, 2H), 6.93 - 6.89 (m, 1H), 6.65 - 6.63 (m, 1H), 4.31 - 4.17 (m, 2H), 3.52 (d, J = 13.7 Hz, 1H), 2.93 (s, 3H), 2.83 (d, J = 13.7 Hz, 1H), 2.78 - 2.71 (m, 1H), 2.32 (d, J = 1.3 Hz, 3H), 2.25 - 2.16 (m, 1H), 1.90 - 1.75 (m, 2H), 1.67- 1.63 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H) LC-MS (Method A) (m / z) = 443.5 (MH)+tR= 0.85 minutes. [a]20D-9° (c = 0.1, MeOH)

[0953] Example 66: N-[(lR,3S,4R)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide or N-[(lS,3R,4S)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0954]

[0955] Prepared as Example 42 from rac-N-((lS,3R,4S)-3-(3-bromo-4-fluorobenzyl)-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and phenyl boronic acid followed by separation of the two enantiomers by standard procedures using chiral SFC.

[0956] 1H NMR (400 MHz, Chloroform-d) δ7.48 - 7.40 (m, 4H), 7.38 - 7.33 (m, 1H), 7.05 - 6.96 (m, 2H), 6.94 - 6.89 (m, 1H), 6.64 (d, J = 1.5 Hz, 1H), 4.31- 4.20 (m, 2H), 3.52 (d, J = 13.7 Hz, 1H), 2.93 (s, 3H), 2.86 - 2.80 (m, 1H), 2.79 - 2.69 (m, 1H), 2.33- 2.30 (m, 3H), 2.26 - 2.15 (m, 1H), 1.90 - 1.77 (m, 2H), 1.65 - 1.60 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H) LC-MS (Method A) (m / z) = 443.5 (MH)+tR= 0.85 minutes. [a]20D+9° (c = 0.1, MeOH)

[0957] Example 67: N-[(lS,3R,4S)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide or N-[(lR,3S,4R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0958]

[0959] Prepared as Example 42 from rac-N-((lS,3R,4S)-3-(3-bromo-4-fluorobenzyl)-4-methyl-3-(5- methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 3-fluorophenylboronic acid followed by separation of the two enantiomers by standard procedures using chiral SFC.1H NMR (300 MHz, Chloroform-d) δ7.38 - 7.33 (m, 1H), 7.25 - 7.21 (m, 1H), 7.17- 7.10 (m, 1H), 7.08 - 6.94 (m, 3H), 6.66 - 6.64 (m, 1H), 4.33 - 4.18 (m, 2H), 3.58 - 3.50 (m, 1H), 2.94 (s, 3H), 2.83 - 2.71 (m, 2H), 2.32 (d, J = 1.2 Hz, 3H), 2.26 - 2.15 (m, 1H), 1.91 - 1.77 (m, 2H), 1.69 - 1.61 (m, 1H), 0.94 (d, J = 6.9 Hz, 3H) LC-MS (Method A) (m / z) = 461.5 (MH)+tR= 0.86 minutes. [a]20D-9° (c = 0.1, MeOH)

[0960] Example 68: N-[(lR,3S,4R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-methyl-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide or N-[(lS,3R,4S)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0961]

[0962] Prepared as Example 42 from rac-N-((lS,3R,4S)-3-(3-bromo-4-fluorobenzyl)-4-methyl-3-(5- methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 3-fluorophenylboronic acid followed by separation of the two enantiomers by standard procedures using chiral SFC.1H NMR (300 MHz, Chloroform-d) δ7.41 - 7.33 (m, 1H), 7.25 - 7.20 (m, 1H), 7.16 - 7.11 (m, 1H), 7.08 - 6.90 (m, 3H), 6.66 - 6.64 (m, 1H), 4.31 - 4.23 (m, 2H), 3.59 - 3.51 (m, 1H), 2.94 (s, 3H), 2.85 - 2.71 (m, 2H), 2.34 - 2.31 (m, 3H), 2.27 - 2.18 (m, 1H), 1.90 - 1.80 (m, 2H), 1.69 - 1.66 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H) LC-MS (Method A) (m / z) = 461.5 (MH)+tR= 0.86 minutes. [a]20D+13° (c = 0.1, MeOH)

[0963] Example 69: N-[(lS,3R,4S)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-methyl-3- (5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide or N-[(lR,3S,4R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0964]

[0965] Prepared as Example 42 from rac-N-((lS,3R,4S)-3-(3-bromo-4-fluorobenzyl)-4-methyl-3-(5- methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 3,5-difluorophenylboronic acid followed by separation of the two enantiomers by standard procedures using chiral SFC.1H NMR (300 MHz, Chloroform-d) δ7.03 - 6.92 (m, 5H), 6.84 - 6.76 (m, 1H), 6.68 - 6.66 (m, 1H), 4.31 - 4.24 (m, 2H), 3.57 (d, J = 13.7 Hz, 1H), 2.95 (s, 3H), 2.83 - 2.69 (m, 2H), 2.35 - 2.33 (m, 3H), 2.28 - 2.19 (m, 1H), 1.89 - 1.79 (m, 2H), 1.70 - 1.62 (m, 1H), 0.95 (d, J = 6.8 Hz, 3H) LC-MS (Method A) (m / z) = 479.5 (MH)+tR= 0.89 minutes. [a]20D-5° (c = 0.1, MeOH) Example 70: N-[(lR,3S,4R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide or N-[(lS,3R,4S)-3-[[3-(3,5- difluorophenyl)-4-fluoro-phenyl]methyl]-4-methyl-3-(5-methyloxazol-2- yl)cyclopentyl] methanesulfonamide

[0966]

[0967] Prepared as Example 42 from rac-N-((lS,3R,4S)-3-(3-bromo-4-fluorobenzyl)-4-methyl-3-(5- methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 3,5-difluorophenylboronic acid followed by separation of the two enantiomers by standard procedures using chiral SFC.1H NMR (300 MHz, Chloroform-d) δ7.04 - 6.93 (m, 5H), 6.85 - 6.74 (m, 2H), 4.39 - 4.18 (m, 2H), 3.59 (d, J = 13.7 Hz, 1H), 2.97 (s, 3H), 2.88 - 2.75 (m, 2H), 2.38 - 2.24 (m, 4H), 1.97 - 1.68 (m, 3H), 0.96 (d, J = 6.8 Hz, 3H) LC-MS (Method A) (m / z) = 479.5 (MH)+tR= 0.89 minutes. [α]20D+7° (c = 0.1, MeOH)

[0968] Example 71: N-[(lS,3R)-3-[(2,4-difluoro-5-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[0969]

[0970] Prepared as Example 42 from N-((lS,3R)-3-(5-bromo-2,4-difluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and phenyl boronic acid.

[0971] 1H NMR (400 MHz, Chloroform-d) δ7.42 - 7.31 (m, 5H), 6.84 - 6.75 (m, 2H), 6.67 - 6.64 (m, 1H), 4.33 - 4.28 (m, 1H), 3.93 - 3.84 (m, 1H), 3.20 - 3.10 (m, 2H), 2.96 (s, 3H), 2.91 -2.84 (m, 1H), 2.40 -2.32 (m, 1H), 2.27 (d, J = 1.1 Hz, 3H), 2.24 -2.14 (m, 1H), 2.06 - 1.98 (m, 1H), 1.75 - 1.67 (m, 2H) LC-MS (Method A) (m / z) = 447.4 (MH)+tR= 0.82 minutes. [a]20D+7° (c = 0.1, MeOH)

[0972] Example 72: N-[(lS,3R)-3-[[2,4-difluoro-5-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0973]

[0974] Prepared as Example 42 from N-((lS,3R)-3-(5-bromo-2,4-difluorobenzyl)-3-(5-methyloxazol- 2-yl)cyclopentyl)methanesulfonamide and 3-fluorophenylboronic acid.

[0975] 1H NMR (400 MHz, Chloroform-d) δ7.40 - 7.33 (m, 1H), 7.17 - 7.13 (m, 1H), 7.08 - 7.01 (m, 2H), 6.89 - 6.82 (m, 1H), 6.74 - 6.65 (m, 2H), 4.36 - 4.27 (m, 1H), 3.96 - 3.84 (m, 1H), 3.21 - 3.10 (m, 2H), 2.97 (s, 3H), 2.91 - 2.83 (m, 1H), 2.41 - 2.32 (m, 1H), 2.29 (s, 3H), 2.25 - 2.15 (m, 1H), 2.06 - 1.97 (m, 1H), 1.77 - 1.67 (m, 2H) LC-MS (Method A) (m / z) = 465.5 (MH)+tR= 0.83 minutes. [α]20D+9° (c = 0.1, MeOH)

[0976] Example 73: N-[(lS,3R)-3-[[5-(3,5-difluorophenyl)-2,4-difluoro-phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0977]

[0978] Prepared as Example 42 from N-((lS,3R)-3-(5-bromo-2,4-difluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 3,5-difluorophenylboronic acid.

[0979] 1H NMR (400 MHz, Chloroform-d) δ6.89 - 6.76 (m, 4H), 6.69 - 6.64 (m, 2H), 4.36 - 4.29 (m, 1H), 3.94 - 3.82 (m, 1H), 3.22 - 3.10 (m, 2H), 2.97 (s, 3H), 2.90 - 2.82 (m, 1H), 2.41 - 2.30 (m, 4H), 2.26 - 2.16 (m, 1H), 2.06 - 1.97 (m, 1H), 1.78 - 1.68 (m, 2H) LC-MS (Method A) (m / z) = 483.4 (MH)+tR= 0.85 minutes. [a]20D+13° (c = 0.1, MeOH)

[0980] Example 74: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-pyrimidin-2-yl- cyclopentyl] methanesulfonamide

[0981]

[0982] Prepared as Example 42 from N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(pyrimidin-2-yl)cyclopentyl)methanesulfonamide and 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane.

[0983] 1H NMR (400 MHz, Chloroform-d) δ8.70 (d, J = 4.8 Hz, 2H), 7.44 - 7.35 (m, 1H), 7.18 - 7.13 (m, 2H), 7.12 - 7.05 (m, 2H), 6.75 - 6.69 (m, 1H), 6.59 - 6.52 (m, 1H), 4.29 (d, J = 8.0 Hz, 1H), 3.88 - 3.76 (m, 1H), 3.32 - 3.16 (m, 2H), 3.14 - 3.06 (m, 1H), 2.95 (s, 3H), 2.57 - 2.45 (m, 1H), 2.15 - 1.99 (m, 2H), 1.73 - 1.67 (m, 2H) LC-MS (Method A) (m / z) = 462.4 (MH)+tR= 0.79 minutes. [α]20D+7° (c = 0.1, MeOH)

[0984] Example 75: N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-pyrimidin- 2-yl-cyclopentyl] methanesulfonamide

[0985]

[0986] Prepared as Example 42 from N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(pyrimidin-2-yl)cyclopentyl)methanesulfonamide and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiazole.

[0987] 1H NMR (400 MHz, Chloroform-d) δ8.68 (d, J = 4.9 Hz, 2H), 7.30 - 7.28 (m, 1H), 7.14 (t, J = 4.9 Hz, 1H), 6.73 - 6.66 (m, 1H), 6.53 - 6.45 (m, 1H), 4.34 (d, J = 8.2 Hz, 1H), 3.89 - 3.77 (m, 1H), 3.33 - 3.27 (m, 1H), 3.24 - 3.17 (m, 1H), 3.12 - 3.04 (m, 1H), 2.95 (s, 3H), 2.79 (s, 3H), 2.48 - 2.41 (m, 1H), 2.13 - 1.98 (m, 2H), 1.71 - 1.60 (m, 2H) LC-MS (Method A) (m / z) = 465.4 (MH)+tR= 0.65 minutes. [a]20D+5° (c = 0.1, MeOH)

[0988] Example 76: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-fluoropyrimidin-2-yl)cyclopentyl]methanesulfonamide

[0989]

[0990] Prepared as Example 42 from N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(5-fluoropyrimidin-2-yl)cyclopentyl)methanesulfonamide and 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane.1H NMR (400 MHz, Chloroform-d) δ8.54 (s, 2H), 7.45 - 7.36 (m, 1H), 7.17 - 7.05 (m, 3H), 6.78 - 6.70 (m, 1H), 6.61 - 6.53 (m, 1H), 4.33 - 4.21 (m, 1H), 3.85 - 3.71 (m, 1H), 3.30 - 3.15 (m, 2H), 3.10 - 3.02 (m, 1H), 2.95 (s, 3H), 2.53 - 2.43 (m, 1H), 2.13 - 1.97 (m, 2H), 1.74 - 1.63 (m, 2H) LC-MS (Method A) (m / z) = 480.4 (MH)+tR= 0.84 minutes. [a]20D+5° (c = 0.1, MeOH)

[0991] Example 77: N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-(5-fluoropyrimidin-2-yl)cyclopentyl]methanesulfonamide

[0992]

[0993] Prepared as Example 42 from N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(5-fluoropyrimidin-2-yl)cyclopentyl)methanesulfonamide and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiazole.

[0994] 1H NMR (400 MHz, Chloroform-d) δ8.52 (s, 2H), 7.30 - 7.28 (m, 1H), 6.76 - 6.70 (m, 1H), 6.59 - 6.52 (m, 1H), 4.34 (d, J = 8.1 Hz, 1H), 3.87 - 3.75 (m, 1H), 3.30 - 3.14 (m, 2H), 3.08 - 3.00 (m, 1H), 2.95 (s, 3H), 2.79 (s, 3H), 2.48 - 2.38 (m, 1H), 2.12 - 1.98 (m, 2H), 1.74 - 1.62 (m, 2H) LC-MS (Method A) (m / z) = 483.4 (MH)+tR= 0.72 minutes. [a]20D+2° (c = 0.1, MeOH) Example 78: N-[(lS,3R)-3-[[2,4-difluoro-3-(2-oxo-lH-pyridin-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0995]

[0996] O Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and (2-oxo-l,2-dihydropyridin-4-yl)boronic acid.

[0997] 1H NMR (400 MHz, Chloroform-d) δ7.63-7.47 (m, 1H), 6.87 - 6.70 (m, 3H), 6.63 (s, 1H), 6.48 (s, 1H), 5.29 (s, 1H), 3.94-3.80 (m, 1H), 3.21 - 3.07 (m, 2H), 2.96 (s, 3H), 2.87-2.76 (m, 1H), 2.38-2.28 (m, 4H), 2.18-2.12 (m, 1H), 2.03-1.95 (m, 1H), 1.81-1.68 (m, 2H) LC-MS (Method A) (m / z) = 464.4 (MH)+tR= 0.53 minutes. [a]20D+3° (c = 0.1, MeOH)

[0998] Example 79: N-[(lS,3R)-3-[[2,4-difluoro-3-(6-oxo-lH-pyridin-3-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[0999]

[1000] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 6-oxo-lH-pyridin-3-ylboronic acid.

[1001] 1H NMR (400 MHz, Chloroform-d) δ7.50 - 7.43 (m, 1H), 6.84-6.80 (m, 1H), 6.75-6.68 (m, 2H), 6.61 (s, 1H), 6.49-6.35 (m, 1H), 5.29 (s, 1H), 3.90-3.85 (m, 1H), 3.26 - 3.10 (m, 2H), 2.96 (s, 3H), 2.84-2.79 (m, 1H), 2.34 - 2.28 (m, 4H), 2.19 - 2.11 (m, 1H), 2.03-1.95 (m, 1H), 1.78 - 1.69 (m, 2H) LC-MS (Method A) (m / z) = 464.4 (MH)+tR= 0.53 minutes. [a]20D+2° (c = 0.1, MeOH)

[1002] Example 80: N-[(lS,3R)-3-[[2,4-difluoro-3-(4-hydroxyphenyl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1003]

[1004] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 4-hydroxyphenylboronic acid.1H NMR (400 MHz, Chloroform-d) δ7.27 - 7.22 (m, 2H), 6.85 - 6.76 (m, 3H), 6.65 (s, 1H), 6.60 - 6.53 (m, 1H), 4.38-4.30 (m, 1H), 3.91-3.85 (m, 1H), 3.21 - 3.11 (m, 2H), 2.93 (s, 3H), 2.84 - 2.78 (m, 1H), 2.34-2.29 (m, 4H), 2.20-2.13 (m, 1H), 2.05-2.00 (m, 1H), 1.73 - 1.67 (m, 2H) LC-MS (Method A) (m / z) = 463.4 (MH)+tR= 0.67 minutes. [a]20D+5° (c = 0.1, MeOH) Example 81: N-[(lS,3R)-3-[[3-(3,5-difluoro-4-hydroxy-phenyl)-2,4-difluoro-phenyl]methyl]-3- (5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[1005]

[1006] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl] methanesulfonamide and 3,5-difluoro-4- hydroxyphenylboronic acid.

[1007] 1H NMR (400 MHz, Chloroform-d) δ6.97-6.91 (m, 2H), 6.82-6.77 (m, 1H), 6.69 - 6.61 (m, 2H), 4.41-4.32 (m, 1H), 3.92-3.82 (m, 1H), 3.18 - 3.07 (m, 2H), 2.96 (s, 3H), 2.86-2.81 (m, 1H), 2.37 - 2.30 (m, 4H), 2.18 - 2.13 (m, 1H), 2.01 - 1.96 (m, 1H), 1.74-1.65 (m, 2H) LC-MS (Method A) (m / z) = 499.4 (MH)+tR= 0.71 minutes. [a]20D+5° (c = 0.1, MeOH)

[1008] Example 82: N-[(lS,3R)-3-[[2,4-difluoro-3-(2-furyl)phenyl]methyl]-3-(5-methyloxazol-2- yl)cyclopentyl] methanesulfonamide

[1009]

[1010] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and furan-2-ylboronic acid.

[1011] 1H NMR (400 MHz, Chloroform-d) δ7.58-7.57 (m, 1H), 6.83 - 6.75 (m, 2H), 6.63 - 6.51 (m, 3H), 4.25-4.22 (m, 1H), 3.93-3.83 (m, 1H), 3.18-3.10 (m, 2H), 2.95 (s, 3H), 2.86-2.80 (m, 1H), 2.37-2.30 (m, 1H), 2.28 (s, 3H), 2.20 - 2.07 (m, 1H), 2.01-1.94 (m, 1H), 1.75 - 1.64 (m, 2H) LC-MS (Method A) (m / z) = 437.4 (MH)+tR= 0.76 minutes. [a]20D+1° (c = 0.1, MeOH) Example 83: N-[(lS,3R)-3-[[3-[4-(difluoromethyl)phenyl]-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1012]

[1013] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 4-(difluoromethyl)phenylboronic acid.

[1014] 1H NMR (400 MHz, Chloroform-d) δ7.61-7.59 (m, 2H), 7.52-7.48 (m, 2H), 6.87 - 6.66 (m, 4H), 4.30-4.26 (m, 1H), 3.90-3.85 (m, 1H), 3.22-3.13 (m, 2H), 2.96 (s, 3H), 2.90 - 2.84 (m, 1H), 2.42 - 2.33 (m, 1H), 2.32-2.29 (m, 3H), 2.23-2.14 (m, 1H), 2.05-1.98 (m, 1H), 1.72 - 1.68 (m, 2H) LC-MS (Method A) (m / z) = 497.4 (MH)+tR= 0.81 minutes. [a]20D+6° (c = 0.1, MeOH) Example 84: N-[(lS,3R)-3-[[2,4-difluoro-3-(4-hydroxy-3-methyl-phenyl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1015]

[1016] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and (4-hydroxy-3- methylphenyl)boronic acid.

[1017] 1H NMR (400 MHz, Chloroform-d) δ7.19 - 7.15 (m, 1H), 7.08 - 7.03 (m, 1H), 6.81 - 6.75 (m, 1H), 6.70 (d, J = 8.2 Hz, 1H), 6.65 - 6.62 (m, 1H), 6.59 - 6.52 (m, 1H), 4.50 - 4.41 (m, 1H), 3.92 - 3.81 (m, 1H), 3.20 - 3.08 (m, 2H), 2.91 (s, 3H), 2.85 - 2.79 (m, 1H), 2.36 - 2.29 (m, 4H), 2.25 (s, 3H), 2.20 - 2.10 (m, 1H), 2.06 - 1.95 (m, 1H), 1.91 - 1.63 (m, 3H) LC-MS (Method A) (m / z) = 477.4 (MH)+tR= 0.72 minutes. [a]20D+8° (c = 0.1, MeOH)

[1018] Example 85: N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methyl-6-oxo-lH-pyridin-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[1019]

[1020] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine, followed by demethylation using LiCI.TH NMR (400 MHz, Chloroform-d) 6 12.39 - 11.8 (m, 1H), 6.84 - 6.77 (m, 1H), 6.72 - 6.66 (m, 1H), 6.61 - 6.59 (m, 1H), 6.51 (s, 1H), 6.16 (s, 1H), 5.15 (s, 1H), 3.92 - 3.83 (m, 1H), 3.20 - 3.09 (m, 2H), 2.96 (s, 3H), 2.85 - 2.78 (m, 1H), 2.40 (s, 3H), 2.36 - 2.32 (m, 1H), 2.30 - 2.28 (m, 3H), 2.20 - 2.11 (m, 1H), 2.02 - 1.97 (m, 1H), 1.75 - 1.69 (m, 2H) LC-MS (Method A) (m / z) = 478.4 (MH)+tR= 0.56 minutes. [a]20D+7° (c = 0.1, MeOH)

[1021] Example 86: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-hydroxyphenyl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1022]

[1023] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 3-hydroxyphenylboronic acid.1H NMR (400 MHz, Chloroform-d) δ7.31 (d, J = 7.9 Hz, 1H), 6.96 - 6.84 (m, 3H), 6.78 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 10.1 Hz, 2H), 4.56 (d, J = 7.7 Hz, 1H), 3.90-3.84 (m, 1H), 3.19-3.09 (m, 2H), 2.94 (s, 3H), 2.86 - 2.79 (m, 1H), 2.35 - 2.30 (m, 4H), 2.20-2.12 (m, 1H), 2.03-1.97 (m, 1H), 1.71 - 1.53 (m, 3H) LC-MS (Method A) (m / z) = 463.4 (MH)+tR= 0.69 minutes. [a]20D+6° (c = 0.1, MeOH)

[1024] Example 87: N-[(lS,3R)-3-[[2,4-difluoro-3-(6-oxo-lH-pyridin-2-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1025]

[1026] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 6-oxo-lH-pyridin-2-ylboronic acid.

[1027] 1H NMR (400 MHz, Chloroform-d) δ7.62 - 7.55 (m, 1H), 6.92 - 6.82 (m, 2H), 6.72 - 6.66 (m, 1H), 6.64 - 6.60 (m, 1H), 6.52 - 6.44 (m, 1H), 5.40 - 5.22 (m, 1H), 3.93 - 3.79 (m, 1H), 3.25 - 3.08 (m, 2H), 2.95 - 2.92 (m, 4H), 2.84 - 2.75 (m, 1H), 2.45 - 2.23 (m, 4H), 2.19 - 2.08 (m, 1H), 2.05 - 1.95 (m, 1H), 1.84 - 1.66 (m, 2H) LC-MS (Method A) (m / z) = 464.4 (MH)+tR= 0.55 minutes. [a]20D+8° (c = 0.1, MeOH)

[1028] Example 88: N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-indazol-5-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1029]

[1030] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and lH-indazol-5-ylboronic acid.1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.88-7.82 (m, 1H), 7.60-7.55 (m, 1H), 7.46- 7.42 (m, 1H), 6.86-6.82 (m, 1H), 6.70 - 6.62 (m, 2H), 4.58-4.42 (m, 1H), 3.91 - 3.89 (m, 1H), 3.21-3.16 (m, 2H), 2.97-2.91 (m, 4H), 2.33 - 2.29 (m, 4H), 2.21-2.16 (m, 1H), 2.04 - 1.99 (m, 1H), 1.75 - 1.71 (m, 2H), indazole-NH proton not observed LC-MS (Method A) (m / z) = 487.5 (MH)+tR= 0.66 minutes. [a]20D+4° (c = 0.1, MeOH)

[1031] Example 89: N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-pyrazol-4-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1032]

[1033] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and lH-pyrazol-4-ylboronic acid.1H NMR (400 MHz, Chloroform-d) δ 8.03 (t, J = 2.0 Hz, 2H), 6.83 (s, 1H), 6.60-6.58 (m, 1H), 6.55 - 6.48 (m, 1H), 4.73 (d, J = 7.9 Hz, 1H), 3.91-3.83 (m, 1H), 3.22 - 3.08 (m, 2H), 2.95 (d, J = 2.1 Hz, 3H), 2.87-2.81 (m, 1H), 2.42 - 2.28 (m, 4H), 2.22 - 2.11 (m, 1H), 2.03 - 1.94 (m, 1H), 1.73-1.66 (m, 3H) LC-MS (Method A) (m / z) = 437.4 (MH)+tR= 0.59 minutes. [a]20D+4° (c = 0.1, MeOH)

[1034] Example 90: N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-pyrazol-3-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1035]

[1036] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and lH-pyrazol-3-ylboronic acid.1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 2.1 Hz, 1H), 6.87-6.83 (m, 1H), 6.76-6.74 (m, 1H), 6.69-6.63 (m, 1H), 6.60-6.58 (m, 1H), 4.73 (d, J = 7.9 Hz, 1H), 3.92-3.82 (m, 1H), 3.22 - 3.11 (m, 2H), 2.95 (s, 3H), 2.86-2.80 (m, 1H), 2.35 - 2.26 (m, 4H), 2.20-2.12 (m, 1H), 2.02- 1.94 (m, 1H), 1.74 - 1.67 (m, 3H) LC-MS (Method A) (m / z) = 437.4 (MH)+tR= 0.60 minutes.

[1037] [a]20D+4° (c = 0.1, MeOH)

[1038] Example 91: N-[(lS,3R)-3-[[2,4-difluoro-3-(5-fluoro-2-oxo-lH-pyridin-4-yl)phenyl]methyl]-3- (5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[1039]

[1040] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and (5-fluoro-2-oxo-l,2-dihydropyridin-4-yl)boronic acid.1H NMR (400 MHz, Chloroform-d) δ 7.42 – 7.40 (m, 1H), 6.87 - 6.77 (m, 2H), 6.62 - 6.59 (m, 2H), 4.77 (s, 1H), 3.91 - 3.85 (m, 1H), 3.16 - 3.11 (m, 3H), 2.96 (s, 3H), 2.85 - 2.80 (m, 1H), 2.35 - 2.28 (m, 4H), 2.20 - 2.15 (m, 1H), 2.01 - 1.95 (m, 1H), 1.71 - 1.68 (m, 2H) LC-MS (Method A) (m / z) = 482.4 (MH)+tR= 0.55 minutes.

[1041] Example 92: N-[(lS,3R)-3-[[2,4-difluoro-3-(l-methyl-2-oxo-4-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1042]

[1043] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and l-methyl-2-oxopyridin-4- ylboronic acid.

[1044] 1H NMR (400 MHz, Chloroform-d) δ 7.33 (d, J = 7.0 Hz, 1H), 6.84 - 6.76 (m, 1H), 6.75 - 6.64 (m, 2H), 6.50 - 6.56 (m, 1H), 6.22 - 6.18 (m, 1H), 4.60 - 4.52 (m, 1H), 3.92 - 3.81 (m, 1H), 3.59 (s, 3H), 3.19 - 3.07 (m, 2H), 2.95 (s, 3H), 2.86 - 2.76 (m, 1H), 2.39 - 2.26 (m, 4H), 2.24 -2.1 (m, 1H), 2.02 - 1.90 (m, 1H), 1.76- 1.72 (m, 1H), 1.72- 1.71 (m, 1H) LC-MS (Method A) (m / z) = 478.5 (MH)+tR= 0.57 minutes. [a]20D+7° (c = 0.1, MeOH)

[1045] Example 93: N-[(lS,3R)-3-[[2,4-difluoro-3-(l-methyl-6-oxo-3-pyridyl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1046] N' " O

[1047]

[1048] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and l-methyl-6-oxopyridin-3- ylboronic acid.

[1049] XH NMR (400 MHz, Chloroform-d) δ7.44 - 7.37 (m, 2H), 6.86 - 6.76 (m, 1H), 6.69 - 6.58 (m, 3H), 4.44 - 4.44 (m, 1H), 3.92 - 3.80 (m, 1H), 3.61 (s, 3H), 3.19 - 3.06 (m, 2H), 2.95 (s, 3H), 2.89 - 2.79 (m, 1H), 2.39 - 2.26 (m, 4H), 2.24 - 2.11 (m, 1H), 2.02 - 1.90 (m, 1H), 1.76 - 1.72 (m, 1H), 1.72 - 1.70 (m, 1H) LC-MS (Method A) (m / z) = 478.4 (MH)+tR= 0.58 minutes. [a]20D+3° (c = 0.1, MeOH)

[1050] Example 94: N-[(lS,3R)-3-[[2,4-difluoro-3-(5-fluoro-6-oxo-lH-pyridin-3-yl)phenyl]methyl]-3- (5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[1051]

[1052] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 3-fluoro-2-methoxy-5-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine, followed by demethylation using LiCI.

[1053] 1H NMR (400 MHz, Chloroform-d) δ 7.49 – 7.44 (m, 1H), 7.38 - 7.34 (m, 1H), 6.96 - 6.75 (m, 2H), 6.66 - 6.64 (m, 1H), 5.94 - 5.37(m, 1H), 3.89 (s, 1H), 3.22 - 3.04 (m, 2H), 2.95 - 2.93 (m, 3H), 2.85 - 2.75 (m, 1H), 2.31 (s, 3H), 2.26 - 2.12 (m, 2H), 2.04 - 1.95 (m, 2H), 1.90 - 1.73 (m, 2H) LC-MS (Method A) (m / z) = 482.4 (MH)+tR= 0.59 minutes.

[1054] Example 95: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4- methoxypyrimidin-2-yl)cyclopentyl] methanesulfonamide

[1055]

[1056] Prepared as Example 42 from N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(4- methoxypyrimidin-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide and 3- fluorophenylboronic acid.

[1057] 1H NMR (400 MHz, Chloroform-d) δ 8.43 – 8.37 (m, 1H), 7.45 - 7.35 (m, 1H), 7.18 - 7.11 (m, 1H), 7.14 - 7.04 (m, 2H), 6.81 - 6.73 (m, 1H), 6.73 - 6.63 (m, 1H), 6.63 - 6.57 (m, 1H), 4.36 - 4.30 (m, 1H), 3.91 (s, 3H), 3.89 - 3.77 (m, 1H), 3.33 - 3.25 (m, 1H), 3.24 - 3.16 (m, 1H), 3.15 - 3.05 (m, 1H), 2.95 (s, 3H), 2.57 - 2.46 (m, 1H), 2.17 - 1.96 (m, 2H), 1.70 - 1.61 (m, 2H) LC- MS (Method A) (m / z) = 492.4 (MH)+tR= 0.81 minutes.

[1058] Example 96: N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-indazol-6-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1059]

[1060] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2,4-difluorobenzyl)-3-(5-methyloxazol- 2-yl)cyclopentyl)methanesulfonamide and (lH-indazol-6-yl)boronic acid.

[1061] 1H NMR (400 MHz, Chloroform-d) δ 8.20-8.10 (m, 1H), 7.84-7.80 (m, 1H), 7.60 (s, 1H), 7.24- 7.19 (m, 1H), 6.87-6.80 (m, 1H), 6.73 - 6.63 (m, 2H), 4.70-4.57 (m, 1H), 3.94-3.84 (m, 1H), 3.23 - 3.13 (m, 2H), 2.95 (s, 3H), 2.90-2.82 (m, 1H), 2.39-2.32 (m, 1H), 2.32-2.27 (m, 3H), 2.23-2.13 (m, 1H), 2.06-1.98 (m, 1H), 1.79-1.65 (m, 2H), indazole-NH proton not observed LC-MS (Method A) (m / z) = 487.4 (MH)+tR= 0.68 minutes. [a]20D+2° (c = 0.1, MeOH) Example 97: N-[(lS,3R)-3-[[3-[3-(difluoromethyl)phenyl]-2,4-difluoro-phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1062]

[1063] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2,4-difluorobenzyl)-3-(5-methyloxazol- 2-yl)cyclopentyl)methanesulfonamide and 3-(difluoromethyl)phenylboronic acid.

[1064] 1H NMR (400 MHz, Chloroform-d) δ 7.58-7.50 (m, 4H), 6.86-6.81 (m, 1H), 6.73 - 6.71 (m, 1H), 6.71 - 6.68 (m, 1H), 6.66 - 6.62 (m, 1H), 4.37-4.30 (m, 1H), 3.93-3.80 (m, 1H), 3.21 - 3.10 (m, 2H), 2.95 (s, 3H), 2.89-2.83 (m, 1H), 2.40-2.28 (m, 4H), 2.23-2.13 (m, 1H), 2.04-1.95 (m, 1H), 1.75 - 1.64 (m, 2H) LC-MS (Method A) (m / z) = 497.5 (MH)+tR= 0.81 minutes. [a]20D-124° (c = 0.1, MeOH)

[1065] Example 98: N-[(lS,3R)-3-[[2,4-difluoro-3-(2-fluoro-6-hydroxy-4-pyridyl)phenyl]methyl]-3- (5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[1066]

[1067] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-2,4-difluorobenzyl)-3-(5-methyloxazol- 2-yl)cyclopentyl)methanesulfonamide and 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine, followed by demethylation using LiCI.

[1068] 1H NMR (400 MHz, Chloroform-d) 59.18-9.03 (m, 1H), 6.86-6.80 (m, 1H), 6.76-6.70 (m, 1H), 6.6-6.67 (m, 1H), 6.63 - 6.53 (m, 2H), 4.66-4.58 (m, 1H), 3.94-3.83 (m, 1H), 3.20 - 3.11 (m, 2H), 3.00-2.95 (m, 3H), 2.88-2.81 (m, 1H), 2.40-2.33 (m, 1H), 2.32-2.29 (m, 3H), 2.24-2.14 (m, 1H), 2.03-1.94 (m, 1H), 1.76-1.67 (m, 2H) LC-MS (Method A) (m / z) = 482.4 (MH)+tR= 0.66 minutes. [α]20D+11° (c = 0.1, MeOH)

[1069] Example 99: N-[(lS,3R)-3-[[5-fluoro-2-(3-fluorophenyl)-4-pyridyl]methyl]-3-(5-methyloxazol- 2-yl)cyclopentyl] methanesulfonamide

[1070] ° H

[1071] -S-N

[1072] II

[1073] O

[1074]

[1075] Prepared as Example 42 from N-((lS,3R)-3-((2-bromo-5-fluoropyridin-4-yl)methyl)-3-(5- methyloxazol-2-yl)cyclopentyl)methanesulfonamide and (3-fluorophenyl)boronic acid.1H NMR (400 MHz, Chloroform-d) δ 8.44 – 8.42 (m, 1H), 7.56 - 7.53 (m, 1H), 7.50 - 7.46 (m, 1H), 7.41 - 7.36 (m, 1H), 7.11 - 7.04 (m, 1H), 6.99 - 6.97 (d, 1H), 6.66 - 6.64 (m, 1H), 4.45 - 4.37 (m, 1H), 3.95 - 3.85 (m, 1H), 3.27 - 3.17 (m, 2H), 2.96 (s, 3H), 2.90 - 2.85 (m, 1H), 2.43 - 2.36 (m, 1H), 2.29 - 2.27 (m, 3H), 2.24 - 2.16 (m, 1H), 2.06 - 1.98 (m, 1H), 1.76 - 1.70 (m, 2H) LC-MS (Method A) (m / z) = 448.4 (MH)+tR= 0.75 minutes. [a]20D+13° (c = 0.1, MeOH) Example 100: N-[(lS,3S)-3-[[5-fluoro-4-(3-fluorophenyl)-2-pyridyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1076] ° H

[1077] -S'N

[1078] it

[1079] O

[1080]

[1081] Prepared as Example 42 from N-[(lS,3S)-3-[(4-chloro-5-fluoropyridin-2-yl)methyl]-3-(5- methyl-l,3-oxazol-2-yl) cyclopentyl]methanesulfonamide and (3-fluorophenyl)boronic acid.1H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 7.46 - 7.37 (m, 1H), 7.27 (m, 1H), 7.20 - 7.10 (m, 2H), 6.93-6.90 (m, 1H), 6.65 - 6.61 (m, 1H), 5.89-5.85 (m, 1H), 4.11 - 3.95 (m, 1H), 3.49-3.42 (m, 1H), 3.27-3.21 (m, 1H), 2.97 (s, 3H), 2.73 - 2.61 (m, 1H), 2.31 - 2.23 (m, 4H), 2.22 - 2.11 (m, 2H), 1.98 - 1.85 (m, 2H) LC-MS (Method A) (m / z) = 448.4 (MH)+tR= 0.72 minutes. [α]20D+6° (c = 0.1, MeOH) Example 101: N-[(lS,3R)-3-[[4-fluoro-3-(8-methoxyimidazo[l,2-a]pyrazin-6-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1082]

[1083] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and (8-methoxyimidazo[l,2-a]pyrazin-6-yl)boronic acid.1H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 7.75 (dd, J = 7.7, 2.4 Hz, 1H), 7.66 (dd, J = 9.0, 1.2 Hz, 2H), 7.03 - 6.98 (m, 1H), 6.83 - 6.79 (m, 1H), 6.57 - 6.55 (m, 1H), 4.42 - 4.40 (m, 1H), 4.22 (s, 3H), 3.92 - 3.83 (m, 1H), 3.22 - 3.11 (m, 2H), 2.93 (s, 3H), 2.84 - 2.79 (m, 1H), 2.36 - 2.29 (m, 1H), 2.25 (s, 3H), 2.21 - 2.14 (m, 1H), 2.03 - 1.96 (m, 1H), 1.74 - 1.61 (m, 2H) LC-MS (Method A) (m / z) = 500.4 (MH)+tR= 0.56 minutes. [a]20D+2° (c = 0.1, MeOH) Example 102: N-[(lS,3R)-3-[[4-fluoro-3-(8-methoxyimidazo[l,2-a]pyridin-6-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1084]

[1085] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 8-methoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine.

[1086] 1H NMR (400 MHz, Chloroform-d) 58.11 (s, 1H), 7.78 - 7.64 (m, 2H), 7.13 (d, J = 7.2 Hz, 1H), 7.05 - 6.96 (m, 1H), 6.82 - 6.73 (m, 2H), 6.64 - 6.57 (m, 1H), 5.20 (br s, 1H), 4.04 (s, 3H), 3.96 - 3.84 (m, 1H), 3.28 - 3.09 (m, 2H), 2.98 (s, 3H), 2.81 - 2.71 (m, 1H), 2.33 - 2.21 (m, 4H), 2.21 - 2.14 (m, 1H), 2.07 - 1.98 (m, 1H), 1.91 - 1.75 (m, 2H) LC-MS (Method A) (m / z) = 499.4 (MH)+tR= 0.50 minutes. [a]20D-3° (c = 0.1, MeOH)

[1087] Example 103: N-[(lS,3R)-3-[[3-(3-chloro-8-methoxy-imidazo[l,2-a]pyridin-6-yl)-4-fluoro- phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[1088]

[1089] Cl

[1090] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 3-chloro-8-methoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine.

[1091] 1H NMR (400 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.60 (s, 1H), 7.08 - 7.01 (m, 1H), 6.93 - 6.84 (m, 2H), 6.72 (s, 1H), 6.65 - 6.61 (m, 1H), 4.54 - 4.41 (m, 1H), 4.07 (s, 3H), 3.94 - 3.82 (m, 1H), 3.22 - 3.09 (m, 2H), 2.95 (s, 3H), 2.84 - 2.75 (m, 1H), 2.36 - 2.27 (m, 4H), 2.24 - 2.13 (m, 1H), 2.03 - 1.94 (m, 1H), 1.80 - 1.65 (m, 2H) LC-MS (Method A) (m / z) = 533.4 (MH)+tR= 0.60 minutes. [a]20D+2° (c = 0.1, MeOH)

[1092] Example 104: N-[(lS,3R)-3-[(4-fluoro-3-imidazo[l,2-a]pyridin-6-yl-phenyl)methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1093]

[1094] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2- yl)cyclopentyl)methanesulfonamide and 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)imidazo[l,2-a]pyridine.1H NMR (400 MHz, Chloroform-d) δ 8.29 (s, 1H), 7.76 - 7.61 (m, 3H), 7.30 (d, J = 9.4 Hz, 1H), 7.06 - 6.99 (m, 1H), 6.92 - 6.86 (m, 1H), 6.85 - 6.80 (m, 1H), 6.61 (s, 1H), 4.58 (br s, 1H), 3.93 - 3.85 (m, 1H), 3.21 - 3.06 (m, 2H), 2.96 (s, 3H), 2.84 - 2.75 (m, 1H), 2.37 - 2.26 (m, 1H), 2.30 (s, 3H), 2.24 - 2.13 (m, 1H), 2.05 - 1.93 (m, 1H), 1.75 - 1.64 (m, 2H) LC-MS (Method A) (m / z) = 469.4 (MH)+tR= 0.48 minutes. [a]20D+3° (c = 0.1, MeOH)

[1095] Example 105: N-[(lS,3R)-3-[(4-fluoro-3-pyrazolo[l,5-a]pyridin-5-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1096]

[1097] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridine.

[1098] 1H NMR (400 MHz, Chloroform-d) δ 8.49 (d, J = 7.3 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.05 - 6.98 (m, 1H), 6.92 - 6.81 (m, 3H), 6.63 - 6.54 (m, 2H), 4.32 (d, J = 7.6 Hz, 1H), 3.95 - 3.82 (m, 1H), 3.19 - 3.07 (m, 2H), 2.95 (s, 3H), 2.86 - 2.76 (m, 1H), 2.39 - 2.31 (m, 1H), 2.29 (s, 3H), 2.25 - 2.12 (m, 1H), 2.02 - 1.93 (m, 1H), 1.73 - 1.60 (m, 2H) LC-MS (Method A) (m / z) = 469.4 (MH)+tR= 0.72 minutes. [a]20D+8° (c = 0.1, MeOH)

[1099] Example 106: N-[(lS,3R)-3-[[3-(3-chloroimidazo[l,2-a]pyridin-6-yl)-4-fluoro-phenyl]methyl]- 3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[1100]

[1101] Prepared as Example 42 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and 3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine.

[1102] TH NMR (400 MHz, Chloroform-d) 58.17 (s, 1H), 7.81 - 7.73 (m, 1H), 7.66 (s, 1H), 7.52 - 7.41 (m, 1H), 7.09 - 7.01 (m, 1H), 6.93 - 6.83 (m, 2H), 6.66 - 6.61 (m, 1H), 4.67 - 4.51 (m, 1H), 3.95 - 3.82 (m, 1H), 3.24 - 3.05 (m, 2H), 2.96 (s, 3H), 2.86 - 2.73 (m, 1H), 2.40 - 2.27 (m, 4H), 2.26 - 2.11 (m, 1H), 2.06 -1.92 (m, 1H), 1.81 - 1.64 (m, 2H) LC-MS (Method A) (m / z) = 503.4 (MH)+tR= 0.56 minutes. [a]20D+15° (c = 0.1, MeOH)

[1103] Example 113: N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1104]

[1105] Prepared as Example 42 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-thiazole.

[1106] TH NMR (300 MHz, Chloroform-d) 57.35 (s, 1H), 6.87 - 6.77 (m, 1H), 6.76-6.66 (m, 1H), 6.65-6.58 (m, 1H), 4.65-4.54 (m, 1H), 3.96-3.79 (m, 1H), 3.27 - 3.07 (m, 2H), 2.95 (s, 3H), 2.89-2.74 (m, 4H), 2.34-2.24 (m, 4H), 2.22-2.08 (m, 1H), 2.05-1.92 (m, 1H), 1.79- 1.61 (m, 2H) LC- MS (Method A) (m / z) = 468.4 (MH)+tR= 0.69 minutes. [a]20D+4° (c = 0.1, MeOH) Example 107: N-[(lS,3R)-3-[[2-fluoro-3-(5-fluoropyrimidin-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1107] Preparation of / V-((lS,3R)-3-(2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide (general method-21) X Phos Pd G3, AcOK

[1108] dioxane, 90°C, 12 h

[1109]

[1110] A mixture of / V-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl) methanesulfonamide (500 mg, 1.15 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.18 g, 4.63 mmol), XPhos Pd G3 (0.10 g, 0.116 mmol) and AcOK (0.34 g, 3.47 mmol) in dioxane (10 mL) was stirred overnight at 90 °C under an argon atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the desired product.

[1111] Preparation of / V-((lS,3R)-3-(2-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-(5-methyloxazol- 2-yl)cyclo pentyl)methanesulfonamide (general method-21)

[1112] Pd(dppf)CI2, Cs2CO3, dioxane: H20=5:1, 80 °C, 2 h, Ar

[1113]

[1114] A mixture of / V-((lS,3R)-3-(2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide (50 mg, 0.105 mmol), 2-bromo-5-fluoropyrimidine (27.7 mg, 0.158 mmol), Pd(dppf)Cl2 (7.7 mg, 0.011 mmol) and Cs2CO3(102 mg, 0.315 mmol) in dioxane (2 mL) and H2O (0.4 mL) was stirred for 2 hours at 80 °C under an argon atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD RP18 Column, 30*150 mm, 5pm; Mobile Phase A:

[1115] Water(10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 30% B to 43% B in 8 min; Wave Length: 254nm / 220nm; RTl(min): 9.37).

[1116] TH NMR (400 MHz, Chloroform-d) 58.73 (s, 2H), 7.83 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.81 (t, J = 7.1 Hz, 1H), 6.61 (s, 1H), 4.41 (d, J = 7.5 Hz, 1H), 3.90 (s, 1H), 3.25 (t, J = 10.7 Hz, 2H), 2.94 (d, J = 1.3 Hz, 3H), 2.86 (s, 1H), 2.38 - 2.25 (m, 4H), 2.22 - 2.12 (m, 1H), 2.03 (s, 1H), 1.71 - 1.65 (m, 2H) LC-MS (Method B) (m / z) = 449.3 (MH)+tR= 0.64 minutes. [a]20D+5° (c = 0.1, MeOH)

[1117] The following compounds were prepared in a similar manner:

[1118] Example 108: N-[(lS,3R)-3-[[2-fluoro-3-(4-methylthiazol-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1119]

[1120] Prepared as Example 107 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl) methanesulfonamide and 2-bromo-4-methyl-l,3-thiazole.

[1121] TH NMR (400 MHz, Chloroform-d) 58.15 (t, J = 7 A Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 1.0 Hz, 1H), 6.79 (t, J = 7.3 Hz, 1H), 6.59 (q, J = 1.2 Hz, 1H), 4.25 (d, J = 7.9 Hz, 1H), 3.88 (q, J = 7.7 Hz, 1H), 3.27 - 3.14 (m, 2H), 2.94 (s, 3H), 2.86 (dd, J = 13.1, 7.3 Hz, 1H), 2.55 (d, J = 1.0 Hz, 3H), 2.36 (dt, J = 13.2, 7.1 Hz, 1H), 2.27 (d, J = 1.2 Hz, 3H), 2.17 (dt, J = 15.4, 7.6 Hz, 1H), 2.00 (dt, J = 13.2, 8.3 Hz, 1H), 1.70 (dd, J = 12.9, 9.0 Hz, 2H) LC-MS (Method B) (m / z) = 450.3 (MH)+tR= 0.72 minutes. [a]20D+8° (c = 0.1, MeOH)

[1122] Example 109: N-[(lS,3R)-3-[[2-fluoro-3-(2-methylthiazol-5-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1123]

[1124] Prepared as Example 107 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl) methanesulfonamide and 5-bromo-2-methylthiazole.

[1125] TH NMR (400 MHz, Chloroform-d) 57.89 (s, 1H), 7.42 - 7.34 (m, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.73 - 6.64 (m, 1H), 6.58 (d, J = 1.5 Hz, 1H), 4.43 (d, J = 7.8 Hz, 1H), 3.87 (h, J = 7.8 Hz, 1H), 3.24 - 3.12 (m, 2H), 2.94 (s, 3H), 2.85 (dd, J = 13.1, 7.3 Hz, 1H), 2.74 (s, 3H), 2.35 (dt, J = 13.2, 6.7 Hz, 1H), 2.28 (d, J = 1.2 Hz, 3H), 2.17 (dq, J = 13.2, 7.8 Hz, 1H), 1.99 (dt, J = 13.1, 8.0 Hz, 1H), 1.69 (dt, J = 13.4, 8.1 Hz, 2H) LC-MS (Method A) (m / z) = 450.4 (MH)+tR= 0.66 minutes.

[1126] [a]20D+15° (c = 0.1, MeOH)

[1127] Example 110: N-[(lS,3R)-3-[[2-fluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1128]

[1129] Prepared as Example 107 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2- yl)cyclopentyl) methanesulfonamide and 4-bromo-2-methylthiazole.

[1130] TH NMR (400 MHz, Chloroform-d) 58.01 (td, J = 7.6, 1.8 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.68 (td, J = 7.3, 1.8 Hz, 1H), 6.59 (d, J = 1.5 Hz, 1H), 4.27 (d, J = 7.9 Hz, 1H), 3.86 (p, J = 7.8 Hz, 1H), 3.26 - 3.13 (m, 2H), 2.93 (s, 3H), 2.84 (dd, J = 13.2, 7.3 Hz, 1H), 2.77 (s, 3H), 2.34 (dt, J = 13.5, 6.8 Hz, 1H), 2.26 (s, 3H), 2.16 (dq, J = 13.1, 7.8 Hz, 1H), 2.00 (ddd, J = 13.1, 9.1, 7.2 Hz, 1H), 1.74 - 1.58 (m, 2H) LC-MS (Method A) (m / z) = 450.4 (MH)+tR= 0.72 minutes. [α]20D+6° (c = 0.1, MeOH) Example 111: N-[(lS,3R)-3-[[2-fluoro-3-(3-furyl)phenyl]methyl]-3-(5-methyloxazol-2- yl)cyclopentyl] methanesulfonamide

[1131]

[1132] Prepared as Example 107 from N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-(5-methyloxazol-2- yl)cyclopentyl) methanesulfonamide and 2-(furan-3-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane.

[1133] TH NMR (300 MHz, Methanol-cU) 67.83 (s, 1H), 7.56 (t, J = 1.8 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.82 - 6.74 (m, 2H), 6.63 (d, J = 1.4 Hz, 1H), 3.72 (p, J = 7.7 Hz, 1H), 3.19 (dd, J = 7.0, 1.7 Hz, 2H), 2.91 (s, 3H), 2.73 (dd, J = 13.1, 7.3 Hz, 1H), 2.27 (d, J = 1.2 Hz, 4H), 2.10 - 2.00 (m, 2H), 1.84 (dd, J = 13.2, 9.1 Hz, 1H), 1.77 - 1.70 (m, 1H) LC-MS (Method A) (m / z) = 419.3 (MH)+tR= 0.73 minutes. [a]20D+2° (c = 0.1, MeOH)

[1134] Example 112: N-[(lS,3R)-3-[[2,4-difluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1135]

[1136] Prepared as Example 107 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 2-bromo-5-methyl-l,3- thiazole.

[1137] TH NMR (400 MHz, Chloroform-d) 57.66 (s, 1H), 6.89-6.80 (m, 1H), 6.76 - 6.64 (m, 1H), 6.63- 6.54 (m, 1H), 4.45 (d, J = 7.9 Hz, 1H), 3.97-3.81 (m, 1H), 3.24 - 3.10 (m, 2H), 2.93 (s, 3H), 2.88-2.78 (m, 1H), 2.56 (s, 3H), 2.37-2.31 (m, 1H), 2.29 (s, 3H), 2.21-2.11 (m, 1H), 2.04-1.93 (m, 1H), 1.70 - 1.62 (m, 2H) LC-MS (Method A) (m / z) = 468.5 (MH)+tR= 0.71 minutes. [a]20D+8° (c = 0.1, MeOH)

[1138] Example 114: N-[(lS,3R)-3-[[2,4-difluoro-3-(5-fluoropyrimidin-2-yl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1139]

[1140] Prepared as Example 107 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 2-bromo-5-fluoropyrimidine.TH NMR (400 MHz, Chloroform-d) 58.77 (s, 2H), 6.89-6.81 (m, 1H), 6.81-6.74 (m, 1H), 6.61 (s, 1H), 4.40-4.26 (m, 1H), 3.98-3.80 (m, 1H), 3.22 - 3.18 (m, 2H), 2.94 (s, 3H), 2.88-2.79 (m, 1H), 2.39 - 2.24 (m, 4H), 2.23-2.11 (m, 1H), 2.04 - 1.91 (m, 1H), 1.74-1.64 (m, 2H) LC-MS (Method A) (m / z) = 467.4 (MH)+tR= 0.64 minutes. [α]20D+5° (c = 0.1, MeOH)

[1141] Example 115: N-[(lS,3R)-3-[[2,4-difluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3- pyrimidin-2-yl-cyclopentyl]methanesulfonamide

[1142]

[1143] Prepared as Example 107 from N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(pyrimidin-2- yl)cyclopentyl)methanesulfonamide and 2-bromo-5-methyl-l,3-thiazole.

[1144] TH NMR (400 MHz, Chloroform-d) 58.70-8.65 (m, 2H), 7.65 (s, 1H), 7.16-7.11 (m, 1H), 6.79 - 6.69 (m, 1H), 6.61 - 6.51 (m, 1H), 4.34-4.29 (m, 1H), 3.87-3.76 (m, 1H), 3.35 - 3.26 (m, 1H), 3.25-3.18 (m, 1H), 3.13-3.03 (m, 1H), 2.95 (s, 3H), 2.57-2.52 (m, 3H), 2.52-2.43 (m, 1H), 2.16 - 1.98 (m, 2H), 1.73-1.65 (m, 2H) LC-MS (Method A) (m / z) = 465.4 (MH)+tR= 0.67 minutes. Example 116: N-[(lS,3R)-3-[[2,4-difluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-(5-fluoropyrimidin-2-yl)cyclopentyl]methanesulfonamide

[1145]

[1146] Prepared as Example 107 from N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(5-fluoropyrimidin-2-yl)cyclopentyl)methanesulfonamide and 2-bromo-5-methyl-l,3-thiazole.TH NMR (400 MHz, Chloroform-d) 58.55-8.51 (m, 2H), 7.68-7.64 (m, 1H), 6.81 - 6.74 (m, 1H), 6.68 - 6.58 (m, 1H), 4.39-4.35 (m, 1H), 3.82-3.76 (m, 1H), 3.32 - 3.14 (m, 2H), 3.10-3.04 (m, 1H), 2.95 (s, 3H), 2.57-2.53 (m, 3H), 2.50-2.42 (m, 1H), 2.10-2.02 (m, 2H), 1.75 - 1.63 (m, 2H) LC-MS (Method A) (m / z) = 483.4 (MH)+tR= 0.74 minutes. [a]20D+8° (c = 0.1, MeOH) Example 117: N-[(lS,3R)-3-[(4-fluoro-3-imidazo[l,2-a]pyrazin-6-yl-phenyl)methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1147]

[1148] Prepared as Example 107 from N-((lS,3R)-3-(3-bromo-4-fluorobenzyl)-3-(5-methyloxazol-2- yl)cyclopentyl)methanesulfonamide and 6-bromoimidazo[l,2-a]pyrazine.

[1149] TH NMR (400 MHz, Chloroform-d) 69.20 (br s, 1H), 8.70 (br s, 1H), 7.94 - 7.69 (m, 2H), 7.07 - 6.96 (m, 1H), 6.83 - 6.74 (m, 1H), 6.55 (s, 1H), 4.40 - 4.32 (m, 1H), 3.95 - 3.81 (m, 1H), 3.23 - 3.10 (m, 2H), 2.94 (s, 3H), 2.84 - 2.75 (m, 1H), 2.38 - 2.23 (m, 4H), 2.20 - 2.12 (m, 1H), 2.04 - 1.94 (m, 1H), 1.74 - 1.69 (m, 1H), 1.63 - 1.58 (m, 1H), 1.52 - 1.42 (m, 1H) LC-MS (Method A) (m / z) = 470.4 (MH)+tR= 0.53 minutes. [a]20D+7° (c = 0.1, MeOH) Example 118: N-[trans-4-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-pyrimidin-2-yl- cyclohexyl]methanesulfonamide

[1150]

[1151] Prepared as described in general method-22 and general method-10 from methyl (lr,4r)-4-(methylsulfonamido)-l-((3',5',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclohexane-l-carboxylate and (2E)-3-(dimethylamino)prop-2-enal.

[1152] TH NMR (300 MHz, Chloroform-d) 58.75 (d, J = 4.9 Hz, 2H), 7.24 - 7.19 (m, 1H), 6.95 - 6.75 (m, 4H), 6.67- 6.54 (m, 1H), 6.59- 6.54 (m, 1H), 4.53- 4.45 (m, 1H), 3.61 - 3.50 (m, 1H), 3.15 - 3.07 (m, 2H), 3.03 (s, 3H), 2.42 - 2.27 (m, 2H), 2.00 - 1.87 (m, 3H), 1.86 - 1.59 (m, 3H) LC-MS (Method A) (m / z) = 476.6 (MH)+tR= 0.83 minutes.

[1153] Example 119: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4-methylpyrimidin-2-yl)cyclopentyl] methanesulfonamide

[1154]

[1155] Prepared as described in general method-22 and general method-10 from methyl (lR,3S)-3-(methylsulfonamido)-l-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentane-l- carboxylate and (3E)-4-(dimethylamino)but-3-en-2-one.

[1156] TH NMR (400 MHz, Chloroform-d) 58.59-8.56 (m, 1H), 7.45 - 7.35 (m, 1H), 7.25 - 7.22 (m, 1H), 7.15-7.12 (m, 1H), 7.13 - 7.04 (m, 3H), 6.75-6.71 (m, 1H), 6.68-6.64 (m, 1H), 4.35-4.32 (m, 1H), 3.85-3.80 (m, 1H), 3.38-3.25 (m, 2H), 3.13-3.09 (m, 1H), 2.96 (s, 3H), 2.57-2.53 (m, 4H), 2.10-2.06 (m, 3H) LC-MS (Method A) (m / z) = 476.4 (MH)+tR= 0.82 minutes. Example 120: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4,6- dimethylpyrimidin-2-yl)cyclopentyl]methanesulfonamide

[1157]

[1158] Prepared as described in general method-22 and general method-10 from methyl (lR,3S)-3-(methylsulfonamido)-l-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentane-l-carboxylate and acetylacetone.

[1159] TH NMR (400 MHz, Chloroform-d) 57.45 - 7.35 (m, 1H), 7.18-7.15 (m, 1H), 7.12-7.06 (m, 2H), 6.90-6.87 (m, 1H), 6.74-6.70 (m, 1H), 6.67-6.64 (m, 1H), 4.29-4.24 (m, 1H), 3.83-3.81 (m, 1H), 3.34-3.32 (m, 1H), 3.24-3.19 (m, 1H), 3.12-3.08 (m, 1H), 2.95 (s, 3H), 2.46 (s, 6H), 2.11-2.07 (m, 2H), 2.00-1.97 (m, 3H) LC-MS (Method A) (m / z) = 490.5 (MH)+tR= 0.84 minutes. Example 121: N-[(lS,3R)-3-[[3-[5-(difluoromethyl)-l,2,4-oxadiazol-3-yl]-2,4-difluoro- phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[1160]

[1161] Prepared as described in general method-23 and general method-08 from N-((lS,3R)-3-(3-bromo-2,4-difluorobenzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide and difluoroacetic acid.

[1162] 1H NMR (600 MHz, DMSO) 57.58 (t, J = 51.5 Hz, 1H), 7.29 - 7.22 (m, 3H), 6.66 (d, J = 1.2 Hz, 1H), 3.62 (h, J = 7.5 Hz, 1H), 3.17 - 3.08 (m, 2H), 2.86 (s, 3H), 2.59 (dd, J = 12.9, 7.4 Hz, 1H), 2.24 (d, J = 1.3 Hz, 3H), 2.15 (tq, J = 10.1, 5.3 Hz, 1H), 1.95 - 1.87 (m, 2H), 1.73 (dd, J = 13.0, 8.7 Hz, 1H), 1.68 - 1.61 (m, 1H). LC-MS (Method A) (m / z) = 489.4 (MH)+tR= 0.72 minutes. Example 122: N-[(lS,3R)-3-[(2,4-difluoro-3-imidazol-l-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide

[1163] Preparation of / V-((lS,3R)-3-(2,4-difluoro-3-(lH-imidazol-l-yl)benzyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide (general method-24)

[1164]

[1165] A solution of N-[(lS,3R)-3-[(3-bromo-2,4-difluorophenyl)methyl]-3-(5-methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide (30 mg, 0.067 mmol) and imidazole (23 mg, 0.34 mmol), L-Proline (7.7 mg, 0.067 mmol), Cu(acac)2(17 mg, 0.067 mmol), K2CO3(28 mg, 0.20 mmol) in DMF (2 mL) was stirred overnight at 100 °C under an argon atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.

[1166] TH NMR (400 MHz, Chloroform-d) 57.59 (s, 1H), 7.19 - 6.98 (m, 2H), 6.99-6.94 (m, 1H), 6.65 - 6.58 (m, 2H), 4.28-4.26 (m, 1H), 3.94-3.85 (m, 1H), 3.15 (s, 2H), 2.96 (s, 3H), 2.86-2.80 (m, 1H), 2.38 - 2.28 (m, 4H), 2.25-2.15 (m, 1H), 2.02 - 1.95 (m, 1H), 1.77-1.68 (m, 2H) LC-MS (Method A) (m / z) = 437.4 (MH)+tR= 0.44 minutes.

[1167] The following compounds were prepared in a similar manner:

[1168] Example 123: N-[(lS,3R)-3-[[2,4-difluoro-3-(2-oxo-l-pyridyl)phenyl]methyl]-3-(5- methyloxazol-2-yl)cyclopentyl]methanesulfonamide

[1169]

[1170] Prepared as Example 122 from N-[(lS,3R)-3-[(3-chloro-2,4-difluorophenyl)methyl]-3-(5- methyl-l,3-oxazol-2-yl)cyclopentyl]methanesulfonamide and 2(lH)-pyridinone.

[1171] TH NMR (400 MHz, Chloroform-d) 58.12-8.10 (m, 1H), 7.78 - 7.72 (m, 1H), 7.08-7.02 (m, 2H), 6.89-6.84 (m, 1H), 6.70 - 6.61 (m, 2H), 4.35 (s, 1H), 3.91-3.89 (m, 1H), 3.24 - 3.12 (m, 2H), 2.94 (s, 3H), 2.89 - 2.83 (m, 1H), 2.37 - 2.27 (m, 4H), 2.18 - 2.11 (m, 1H), 2.05 - 1.99 (m, 1H), 1.73-1.62 (m, 2H) LC-MS (Method A) (m / z) = 464.4 (MH)+tR= 0.72 minutes.

[1172] Example 124: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(l- methylpyrazol-3-yl)cyclopentyl]methanesulfonamide and Example 125: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(2-methylpyrazol-3-yl)cyclopentyl] methanesulfonamide

[1173] Preparation of / V-((lS,3R)-3-(l-methyl-lH-pyrazol-3-yl)-3-((2,3',6-trifluoro-[l,l,-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide and / V-((lS,3R)-3-(l-methyl-lH-pyrazol-5-yl)-3-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide (general method-25)

[1174]

[1175] A mixture of / V-((lS,3R)-3-propioloy l-3-((2,3', 6-trif luo ro-[l, l'-bi phenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide (250 mg, 0.574 mmol), methyl hydrazine sulfuric acid salt (124 mg, 0.861 mmol) and K2CO3 (238 mg, 1.72 mmol) in EtOH (5 mL) was stirred overnight at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. To obtain the two title compounds, the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 33% B to 48 % B in 10 minutes; Wave Length: 254nm / 220nm; RTl(min): 12.03+13.49).

[1176] Example 124: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(l- methylpyrazol-3-yl)cyclopentyl]methanesulfonamide

[1177]

[1178] XH NMR (400 MHz, Chloroform-d) 67.46 - 7.37 (m, 1H), 7.25 - 7.23 (m, 1H), 7.22 - 7.17 (m, 1H), 7.16 - 7.04 (m, 2H), 6.80 - 6.72 (m, 1H), 6.70 - 6.61 (m, 1H), 5.93 (d, J = 2.2 Hz, 1H), 4.26 (d, J = 8.2 Hz, 1H), 3.88 - 3.79 (m, 4H), 3.05 - 3.00 (m, 2H), 2.92 (s, 3H), 2.77 - 2.67 (m, 1H), 2.25 - 2.08 (m, 2H), 1.98 - 1.85 (m, 1H), 1.64 - 1.59 (m, 2H) LC-MS (Method A) (m / z) = 464.4 (MH)+tR= 0.79 minutes. [a]20D+6° (c = 0.1, MeOH)

[1179] Example 125: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(2- methylpyrazol-3-yl)cyclopentyl]methanesulfonamide

[1180]

[1181] TH NMR (400 MHz, Chloroform-d) 67.46 - 7.37 (m, 1H), 7.36 - 7.32 (m, 1H), 7.17 - 7.06 (m, 3H), 6.84 - 6.76 (m, 1H), 6.52 - 6.43 (m, 1H), 5.83 (d, J = 1.9 Hz, 1H), 4.50 (d, J = 7.6 Hz, 1H), 3.95 (s, 3H), 3.92 - 3.82 (m, 1H), 3.14 - 2.99 (m, 2H), 2.96 (s, 3H), 2.70 - 2.60 (m, 1H), 2.30 - 2.17 (m, 1H), 2.12 - 2.01 (m, 2H), 1.97 - 1.87 (m, 1H), 1.80 - 1.70 (m, 1H) LC-MS (Method A) (m / z) = 464.4 (MH)+tR= 0.75 minutes. [a]20D+5° (c = 0.1, MeOH)

[1182] The following compounds were prepared in a similar manner: Example 126: N-[(lS,3R)-3-[cis-(4-phenylcyclohexoxy)methyl]-3-(lH-pyrazol-3-yl)cyclopentyl] methanesulfonamide

[1183]

[1184] Prepared as Example 124 from N-((lS,3S)-3-((((cis)-4-phenylcyclohexyl)oxy)methyl)-3-propioloylcyclopentyl)methanesulfonamide and hydrazine.

[1185] 1H NMR (600 MHz, DMSO) 512.44 (s, 1H), 7.56 (s, 1H), 7.27 (t, J = 7.6 Hz, 2H), 7.19 - 7.11 (m, 4H), 6.16 (s, 1H), 3.66 (h, J = 7.8 Hz, 1H), 3.53 (s, 1H), 3.44 (d, J = 8.7 Hz, 1H), 3.40 (d, J = 8.7 Hz, 1H), 2.88 (s, 3H), 2.50 - 2.45 (m, 1H), 2.44 - 2.36 (m, 1H), 2.06 - 1.87 (m, 5H), 1.81 (dd, J = 12.8, 9.1 Hz, 1H), 1.69 - 1.58 (m, 3H), 1.50 - 1.40 (m, 4H). LC-MS (Method B) (m / z) = 418.6 (MH)+tR = 0.71 minutes.

[1186] Example 128: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-pyrimidin-4-yl-cyclopentyl] methanesulfonamide

[1187] Preparation of N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-pyrimidin- 4-yl-cyclopentyl]methanesulfonamide (general method-26)

[1188] f-BuOK, MeOH, EtOH, r.t, o / n

[1189]

[1190] A mixture of formamidine acetic acid salt (66.9 mg, 0.644 mmol) and t-BuOK (72.1 mg, 0.644 mmol) in MeOH (2 mL) was stirred for 15 minutes at room temperature. To the above mixture was added A / -((lS,3R)-3-propioloyl-3-((2,3',6-trif luoro-[l, l'-bi phenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide (70 mg, 0.161 mmol) in EtOH (2 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. To obtain the title compound, the crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5pm; Mobile Phase A: water(10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 37% B to 57% B in 10 minutes; Wave Length: 254nm / 220nm; RTl(min): 8.68).

[1191] XH NMR (400 MHz, Chloroform-d) 69.31 - 9.21 (m, 1H), 8.74 - 8.65 (m, 1H), 7.47 - 7.37 (m, 1H), 7.34 - 7.27 (m, 1H), 7.15 - 7.04 (m, 3H), 6.83 - 6.75 (m, 1H), 6.63 - 6.55 (m, 1H), 4.50 - 4.34 (m, 1H), 3.82 - 3.70 (m, 1H), 3.25 - 3.10 (m, 2H), 2.96 (s, 3H), 2.92 - 2.85 (m, 1H), 2.35 - 2.03 (m, 3H), 1.78 - 1.62 (m, 2H) LC-MS (Method A) (m / z) = 462.4 (MH)+tR= 0.74 minutes.

[1192] [a]20D+13° (c = 0.1, MeOH)

[1193] The following compound was prepared in a similar manner:

[1194] Example 127: N-[(lS,3R)-3-[cis-(4-phenylcyclohexoxy)methyl]-3-pyrimidin-4-yl- cyclopentyl] methanesulfonamide

[1195]

[1196] Prepared as Example 128 from N-((lS,3S)-3-((((cis)-4-phenylcyclohexyl)oxy)methyl)-3- propioloylcyclopentyl)methanesulfonamide and formamidine acetic acid salt.

[1197] 1H NMR (600 MHz, DMSO) 59.13 (s, 1H), 8.72 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 5.4 Hz, 1H), 7.25 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 2H), 3.68 (h, J = 7.9 Hz, 1H), 3.61 (d, J = 8.7 Hz, 1H), 3.53 (d, J = 8.7 Hz, 1H), 3.50 (s, 1H), 2.90 (s, 3H), 2.62 (dd, J = 13.5, 7.9 Hz, 1H), 2.46 - 2.39 (m, 1H), 2.09 - 1.95 (m, 3H), 1.88 - 1.79 (m, 2H), 1.74 (dd, J = 13.5, 8.5 Hz, 1H), 1.70 - 1.61 (m, 1H), 1.46 - 1.31 (m, 6H). LC-MS (Method B) (m / z) = 430.0 (MH)+tR= 0.76 minutes.

[1198] Example 129: N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(2- methylpyrimidin-4-yl)cyclopentyl] methanesulfonamide

[1199]

[1200] Prepared as Example 128 from N-((lS,3R)-3-propioloyl-3-((2,3',6-trifluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentyl)methanesulfonamide and acetamidine acetic acid salt.

[1201] XH NMR (400 MHz, Chloroform-d) 68.56 - 8.51 (m, 1H), 7.46 - 7.37 (m, 1H), 7.17 - 7.05 (m, 3H), 6.99 - 6.93 (m, 1H), 6.82 - 6.72 (m, 1H), 6.60 - 6.50 (m, 1H), 4.33 (d, J = 7.7 Hz, 1H), 3.80 - 3.69 (m, 1H), 3.19 - 3.06 (m, 2H), 2.95 (s, 3H), 2.96 - 2.88 (m, 1H), 2.76 (s, 3H), 2.31 -2.21 (m, 1H), 2.16 - 1.98 (m, 2H), 1.78 - 1.76 (m, 1H), 1.75 - 1.71 (m, 1H) LC-MS (Method A) (m / z) = 476.4 (MH)+tR= 0.74 minutes. [a]20D+11° (c = 0.1, MeOH)

[1202] MEASUREMENT OF OX2R AGONIST ACTIVITY

[1203] The Ox2R has a broad signaling profile and couple to a range of different Ga-proteins. The cell-based calcium release assay is primarily assessing signaling through the Gaq signaling pathway, which promotes calcium mobilization via inositol triphosphate production upon activation of Ox2R.

[1204] A CHO Flp-In cell-line stably expressing the human Ox2R (hOx2R-CHO Flp-In) was established as follows: The gene encoding hOx2R was subcloned into the expression plasmid pcDNA5 / FRT / TO and then transfected into CHO Flp-ln cells together with the Flp recombinase vector, pOG44. Cells were cultured in growth medium: Ham's F12 (Gibco), 10% fetal bovine serum (Gibco) and 100 U / mL penicillin-streptomycin (Gibco) supplemented with hygromycin B (Thermo Fisher Scientific) as selection marker at 37°C in the presence of 5% CO2.

[1205] To prepare the hOx2R-CHO FlpIn cells for calcium release assay, the cells were suspended in growth medium and seeded in black, clear-bottomed 384-well plates (Corning) at 10,000 cells / well. The plated cells were grown overnight at 37°C and 5% CO2. The following day, the media was removed, and the cells were incubated with assay buffer (HBSS with 20mM HEPES, pH 7.4) containing 2.5mM probenecid (Thermo Fisher Scientific), 10mM CaCl2, 0.1% pluronic F68 (Gibco) and IX calcium-4 dye (Molecular Devices) for 1h at 37°C and 5% CO2. After incubation, cells were allowed to equilibrate at room temperature for 15 minutes and then loaded into FDSS7000Ex system (Hamamatsu Photonics) together with a plate containing test compounds serially diluted in assay buffer. Cells were stimulated with test compounds (online injection) and the agonist activity was determined as an increase in intracellular calcium concentration measured from the ratio of fluorescence emission at 542nm by excitation at 480nm. The agonist response for each applied concentration was assessed as the ratio: maximum fluorescence / average pre-stimulated fluorescence and was normalized to responses from assay buffer alone (0% response) and lOpM Danavorexton (100% response). EC50 and Emax values were calculated from concentration-response curves by using Genedata Screener software.

[1206] Table 1 below shows the EC50 values in nM and Emax values in % obtained as described above for the exemplified compounds, data is based on n > 2 tests.

[1207] Table 1: measurement of Ox2R agonist activity

[1208] Example EC50 (nM) Emax (%)

[1209] 1 77 98

[1210] 2 >20000

[1211] 3 480 99

[1212] 4 52 95

[1213] 5 520 95

[1214] 6 2.8 98

[1215] 7 2.3 99

[1216] 8 13 98

[1217] 9 9.8 96

[1218] 10 5.2 98

[1219] 11 3.4 100

[1220] 12 4.7 98

[1221] 13 120 96

[1222] 14 1.2 100

[1223] 15 1.8 94

[1224] 16 100 98

[1225] 17 0.59 94

[1226] 18 2.4 97

[1227] 19 0.7 100

[1228]

[1229] 4.5 100 100 100 210 94 7.9 100 210 99 560 90 120 99 280 100 0.8 98 0.25 100 0.32 98 1.4 98 2.8 100 4.5 100 36 100 14 99 16 100 14 98 6.9 100 1.3 100 1.7 100 7.5 99 1.5 100 6.4 110 1.6 100 490 89 210 79 3.1 100 0.7 98 3.9 98 0.23 100 0.17 99 0.63 110

[1230]

[1231] 2.5 100 12 99 32 100 6.4 96 170 100 15 96 43 97 49 96 240 97 0.099 96 0.076 96 0.21 96 7.3 100 430 84 2.9 98 320 95 12 99 >10000

[1232] 0.13 99 0.087 100 0.17 96 1.6 98 30 100 2.6 99 8.7 96 0.71 99 0.63 99 0.94 98 1.6 100 0.2 97 15 100 1 95 0.36 95

[1233]

[1234] 0.061 92 35 99 0.14 98 6.1 100 2.7 100 0.68 96 4.6 99 130 100 250 100 45 96 3.7 100 0.51 98 1.8 100 9.3 98 13 96 >10000

[1235] 310 110 >10000

[1236] 25 100 9.1 98 63 80 9.1 100 180 98 110 95 45 96 2.4 99 1.9 100 0.47 100 2.1 100 32 99 29 100 190 97 9.7 98

[1237]

[1238] 119 3.1 96

[1239] 120 8.9 95

[1240] 121 11 110

[1241] 122 110 99

[1242] 123 0.91 100

[1243] 124 35 99

[1244] 125 96 89

[1245] 126 290 97

[1246] 127 290 96

[1247] 128 10 99

[1248] 129 60 97

[1249]

[1250] Table 1 disclose that the compounds of the invention were shown to have orexin 2 receptor agonist activity.

[1251] Hepatic microsomal intrinsic clearance assay:

[1252] Test compounds (final concentration 1 pM, 1% organic) were incubated for 1 hour at 37°C, with shaking, in phosphate buffer (pH7.4) containing commercially sourced pooled liver microsomes (final concentration 0.5 mg / mL). The intrinsic clearance (CLint) reactions were initiated by addition of cofactor solution (final concentration 1 mM NADPH and 1 mM MgCl2, final incubation volume 100 pL). At designated time points (0, 5, 10, 20, 30 and 60 minutes) ice-cold acetonitrile containing internal standard (300 pL) was added to an incubation well to stop the reaction then mixed and centrifuged (3220 g for 20 minutes at 4°C). Supernatant was diluted (1:4) with deionized water then analyzed by liquid chromatography (LC)-tandem mass spectrometry (MS / MS). The intrinsic clearances were calculated from the slope (k) of the linear regressions of percentages of compound remaining in incubation against incubation time, according to equations 1 and 2.

[1253] Equation 1:

[1254]

[1255] =ln (2) / k(1)

[1256] Equation 2: CLint (L / h / kg body weight) = ln(2) × V (L / mg) / t1 / 2 (h) × microsomal protein concentration (mg protein / g liver) × liver weight (g liver / kg body weight)(2)

[1257] V = incubation volume = 0.002 L / mg (0.5 mg / mL protein concentration)

[1258] Microsomal protein concentration = 45 mg / g liver

[1259] Rat liver weight = 45 g / kg body weight

[1260] Human liver weight = 25 g / kg body weight

[1261] Some of the compounds of the present invention were tested in the hepatic microsomal intrinsic clearance assay.

[1262] MDR1-MDCKII assay

[1263] Bidirectional transport in MDCKII cells transfected with human MDR1 were assessed according to previously published methodology (Langthaler, K. et al. (2024). Fluids Barriers CNS, 21 (11): 1-15).. In brief, cells obtained from the Netherlands Cancer Institute were maintained at 37°C in a-MEM containing 10% FBS, 100 pg / mL penicillin-G, 100 pg / mL streptomycin, 1% non-essential amino acid under culture conditions of 5% CO2 and 95% relative humidity. Transport of test compound (0.5 pM, 0.4% DMSO final concentrations) across the cell monolayer was determined in triplicate on a single test occasion along with controls for low and high permeability (fenoterol and metoprolol, 2 pM) and P-gp efflux (digoxin, 10 pM). Each compound was loaded onto either the apical side (75 pL) or basolateral side (275 pL) with transport buffer (1% BSA in HBSS with 10 mM HEPES (pH 7.4)) on the opposing side of the cells (e.g. 50 pL or 250 pL on the apical or basolateral side). A sample (25 pL) from the donor compartment was taken 30 s after test compound is loaded onto the plate, resulting in a final incubation volume of 50 pL and 250 pL on apical and basolateral sides respectively. At the end of the incubation period, samples (75 pL) were taken from both sides. The donor samples (25 pL) were firstly diluted with transport buffer (50 pL) and then all samples were quenched in acetonitrile (125 pL) containing internal analytical standards. After centrifugation (20 min, 3220 g, 4°C) the supernatants were analysed by LC–MS / MS. The apparent permeability coefficient (Papp) and efflux ratio (ER) were calculated using the equations below; where dCr / dt is the compound concentration in the receiver chamber as a function of time (pM / s); Vris the solution volume in the receiver chamber; A is the surface area of the cell monolayer; C0 is the initial concentration in the donor compartment; and PappA-B and PappB-A refer to the apparent permeabilities in the respective directions. Compound permeability is classified as low, moderate, or high according to Pappvalue binning classifications: <1, 1 to 6 or >6 x 10-6cm / s, respectively. The ER is employed to classify compounds as unlikely, possible, or likely P-gp substrates when ER was: <1.5, 1.5 to <2 or >2, respectively.

[1264] Equations:

[1265] Papp = (dCr / dt) × Vr / (A × C0)

[1266] Efflux Ratio (ER) = Papp B-A / Papp A-B

[1267] Some of the compounds of the present invention were tested in the MDR1-MDCKII assay.

[1268] Based on the MDR1-MDCKII assay, some compounds of the present invention were classified as displaying high permeability.

[1269] Based on the MDR1-MDCKII assay, some compounds of the present invention were classified as displaying moderate permeability.

[1270] Based on the MDR1-MDCKII assay, some compounds of the present invention were classified as being unlikely to be P-gp substrates and thus more likely to have favourable brain disposition.

[1271] Based on the MDR1-MDCKII assay, some compounds of the present invention were classified as possibly being P-gp substrates.

[1272] In vitro Selectivity

[1273] Some compounds of the present invention have been tested in vitro against the Orexin-1 receptor. Said compounds displayed favourable selectivity for OX2R over OX1R.

Claims

CLAIMS1. A compound of general formula (I)whereinX is -O- or -(CRaRb)- or a bond, wherein Raand Rbeach independently are selected from the group consisting of hydrogen and (C₁-C₄)alkyl;Q is (C1-C2)alkylene;Ri is hydrogen, or when X is -(CRaRb)- Ri and either Raor Rb together with the carbon atoms to which they are attached may optionally form a fused C3-cycloalkyl group;R2 is (Ci-C4)alkyl, 3-6 membered heterocyclyl, (C₃-C₆)cycloalkyl or-NRcRd, wherein Rcand Rd each independently are selected from the group consisting of hydrogen and (Ci-C4)a Ikyl or wherein Rcand Rd together with the nitrogen to which they are attached form a 3-6 membered heterocyclyl;Y represents a bond or -O-;Z is phenyl, pyridyl, piperidinyl, (C6-C7)cycloalkylene, or (C2-C4)alkylene, wherein said phenyl, pyridyl or piperidinyl is optionally substituted with one or more substituents each independently selected from R3;Ari is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is optionally substituted with one or more substituents each independently selected from R4;Ar2is a 5- or 6- membered heteroaryl; wherein said 5- or 6- membered heteroaryl is optionally substituted with one or more substituents each independently selected from R5;R3and R4each independently are halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl or hydroxyl;R5is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C3-C5)cycloalkyl or halogen;or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, with the proviso that said compound is notN-((1S,3R)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide,N-((1S,3R)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(3-methoxypyridin-2-yl)cyclopentyl)methanesulfonamide, orN-((1S,3R)-3-(1-ethyl-1H-imidazol-2-yl)-3-(3-(pyrimidin-2-yl)benzyl)cyclopentyl)methanesulfonamide,or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1,wherein X is -O- or -(CRaRb)- or a bond, wherein Raand Rbeach independently are selected from the group consisting of hydrogen and (Ci-C4)a Ikyl;Q is (C1-C2)alkylene;Ri is hydrogen, or when X is -(CRaRb)- Ri and either Raor Rb together with the carbon atoms to which they are attached may optionally form a fused C3-cycloalkyl group;R2is (C1-C4)alkyl, 3-6 membered heterocyclyl, (C3-C6)cycloalkyl or -NRcRd, wherein Rcand Rdeach independently are selected from the group consisting of hydrogen and (C1-C4)alkyl or wherein Rcand Rdtogether with the nitrogen to which they are attached form a 3-6 membered heterocyclyl;Y represents a bond or -O-;Z is phenyl, pyridyl, piperidinyl, (C6-C7)cycloalkylene, or (C2-C4)alkylene, wherein said phenyl, pyridyl or piperidinyl is optionally substituted with one or more substituents each independently selected from R3, andAri is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is substituted with one or more substituents each independently selected from R4; orZ is phenyl, pyridyl, piperidinyl, (C6-C7)cycloalkylene, or (C2-C4)alkylene, wherein said phenyl, pyridyl or piperidinyl is substituted with one or more substituents each independently selected from R3, andAri is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is optionally substituted with one or more substituents each independently selected from R4;Ar2is a 5- or 6- membered heteroaryl; wherein said 5- or 6- membered heteroaryl is optionally substituted with one or more substituents each independently selected from R5; R3 and R4 each independently are halogen, (C₁-C₄)alkyl, (Ci-C4)alkoxy, halo(C₁-C₄)alkyl or hydroxyl;R5is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C3-C5)cycloalkyl or halogen;or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3, wherein X is -CH2- or -CH(CH₃)-.

5. The compound according to any one of claims 1-4, wherein Q is (Ci)alkylene.

6. The compound according to any one of claims 1-5, wherein Ri is hydrogen.

7. The compound according to any one of claims 1-6, wherein R2 is methyl, ethyl, propyl, isopropyl, oxetanyl, cyclopropyl, or -NRcRd, wherein Rc and Rd each independently are selected from the group consisting of hydrogen, methyl and ethyl or wherein Rc and Rd together with the nitrogen to which they are attached form azetidinyl.

8. The compound according to any one of claims 1-7, wherein Z is phenyl, pyridyl, cyclohexylene or bicycloheptanyl, wherein said phenyl, pyridyl is optionally substituted with one or more substituents each independently selected from R3.

9. The compound according to any one of claims 1-8, wherein Ari is phenyl, oxopyridinyl, or a 5-, 6- or 9-membered heteroaryl, wherein said 5-, 6- or 9-membered heteroaryl is selected from pyridyl, pyrimidyl, imidazolyl, imidazopyrazinyl, pyrazolopyridinyl, imidazopyridinyl, oxadiazolyl, indazolyl, pyrazolyl, furanyl, thiazolyl, isoxazolyl, and wherein said phenyl, oxopyridinyl or 5-, 6- or 9-membered heteroaryl is optionally substituted with one or more substituents each independently selected from R4.

10. The compound according to any one of claims 1-9, wherein Ar2 is oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyrazolyl or pyrimidyl; wherein said oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyrazolyl or pyrimidyl is optionally substituted with one or more substituents each independently selected from R5.

11. The compound according to any one of claims 1-10, wherein R3 is fluoro, chloro, methyl or ethyl.

12. The compound according to any one of claims 1-10, wherein R4 is fluoro, chloro, methyl, ethyl, difluoromethyl, hydroxy or methoxy.

13. The compound according to any one of claims 1-11, wherein Rs is methyl, ethyl, fluoro, methoxymethyl, hydroxymethyl or methoxy.

14. The compound according to any one of claims 1 - 12, wherein the compound is selected from the list consisting of N-[(1S,3S)-3-(4-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(1S,3S)-3-[[(1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-oxazol-2-yl-cyclopentyl] methanesulfonamide,N-[(1S,3S)-3-[[(1S,3S,6R)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-oxazol-2-yl-cyclopentyl] methanesulfonamide,N-[(1S,3S)-3-[[(1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(1S,3S)-3-(5-cyclopropyloxazol-2-yl)-3-[[(1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]cyclopentyl]methanesulfonamide,N-[(3R,5S)-5-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl] methanesulfonamide,N-[(3S,5R)-5-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl] methanesulfonamide,N-[(1S,3S)-3-oxazol-2-yl-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[rel-(1S,3R,4S)-4-methyl-3-(5-methyloxazol-2-yl)-3-[(3-phenylphenyl)methyl]cyclopentyl] methanesulfonamide (enantiomer 1),N-[(1R,2R,4R,5S)-4-oxazol-2-yl-4-[cis-(4-phenylcyclohexoxy)methyl]-2-bicyclo[3.1.0]hexanyl]methanesulfonamide,N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(1S,3S)-3-[[cis-4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-oxazol-2-yl-cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-oxazol-2-yl-3-[(3-phenylphenyl)methyl]cyclopentyl]methanesulfonamide, N-[(1S,3S)-3-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3S)-3-[cis-[4-(3-fluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1R,2R,4R,5S)-4-[[(1R,3R,6S)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-4-(5-methyloxazol-2-yl)-2-bicyclo[3.1.0]hexanyl]methanesulfonamide,N-[trans-4-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-(5-methyloxazol-2-yl)cyclohexyl]methanesulfonamide,N-[trans-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclobutyl] methanesulfonamide,N-[(1R,3S)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-[5-(methoxymethyl)oxazol-2-yl]cyclopentyl]methanesulfonamide,N-[(1S,3S)-3-(1,3,4-oxadiazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(1S,3R)-3-(1,2,4-oxadiazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(1S,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopentyl] methanesulfonamide,N-[(1S,3S)-3-[cis-(4-phenylcyclohexoxy)methyl]-3-thiazol-2-yl-cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-(2-methyl-1,2,4-triazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(1S,3R)-3-(1-methyl-1,2,4-triazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(1S,3R)-3-(4-methyl-1,2,4-triazol-3-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(1S,3S)-3-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]ethanesulfonamide,(1S,3S)-3-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3-(5-methyloxazol-2-yl)-N- (methylsulfamoyl)cyclopentanamine,5-methyl-2-[(1S,3S)-1-[cis-[4-(3,5-difluorophenyl)cyclohexoxy]methyl]-3- (dimethylsulfamoylamino)cyclopentyl]oxazole,N-[(1S,3S)-3-(5-ethyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(1S,3S)-3-[5-(methoxymethyl)oxazol-2-yl]-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]ethanesulfonamide,N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]oxetane-3-sulfonamide,N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]cyclopropanesulfonamide,N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]propane-2-sulfonamide,N-[(1S,3S)-3-(5-methyloxazol-2-yl)-3-[cis-(4-phenylcyclohexoxy)methyl]cyclopentyl]azetidine-1-sulfonamide,N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]ethanesulfonamide,(1S,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)-N- (methylsulfamoyl)cyclopentanamine,2-[(1R,3S)-1-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3- (dimethylsulfamoylamino)cyclopentyl]-5-methyl-oxazole,N-[(1S,3R)-3-[[2,4-difluoro-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(1S,3R)-3-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[[3-(3-fluorophenyl)phenyl]methyl]-3-[4-(hydroxymethyl)oxazol-2-yl]cyclopentyl]methanesulfonamide,N-[rac-(3R,5S)-5-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-5-(5-methyloxazol-2-yl)tetrahydrofuran-3-yl] methanesulfonamide,N-[(1S,3R)-3-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[[3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[[3-(3,5-difluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(1S,3R)-3-[(2-fluoro-3-pyrimidin-2-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2-fluoro-3-(2-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2-fluoro-3-(l-methylpyrazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2-fluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(4-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-3-(4-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[(2,4-difluoro-3-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[3-(3,5-difluorophenyl)-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R,4S)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lR,3S,4R)-3-[(4-fluoro-3-phenyl-phenyl)methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R,4S)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lR,3S,4R)-3-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R,4S)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lR,3S,4R)-3-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-methyl-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[(2,4-difluoro-5-phenyl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-5-(3-fluorophenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[5-(3,5-difluorophenyl)-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-pyrimidin-2-yl-cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-pyrimidin-2-yl-cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(5-fluoropyrimidin-2-yl)cyclopentyl] methanesulfonamideN-[(lS,3R)-3-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-(5-fluoropyrimidin-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(2-oxo-lH-pyridin-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(6-oxo-lH-pyridin-3-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(4-hydroxyphenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[3-(3,5-difluoro-4-hydroxy-phenyl)-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(2-furyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[3-[4-(difluoromethyl)phenyl]-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol- 2 -yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(4-hydroxy-3-methyl-phenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methyl-6-oxo-lH-pyridin-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-hydroxyphenyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(6-oxo-lH-pyridin-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-indazol-5-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-pyrazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-pyrazol-3-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(5-fluoro-2-oxo-lH-pyridin-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(l-methyl-2-oxo-4-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(l-methyl-6-oxo-3-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(5-fluoro-6-oxo-lH-pyridin-3-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4-methoxypyrimidin-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(lH-indazol-6-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[3-[3-(difluoromethyl)phenyl]-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol- 2 -yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(2-fluoro-6-hydroxy-4-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[[5-fluoro-2-(3-fluorophenyl)-4-pyridyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3S)-3-[[5-fluoro-4-(3-fluorophenyl)-2-pyridyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[4-fluoro-3-(8-methoxyimidazo[l,2-a]pyrazin-6-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[[4-fluoro-3-(8-methoxyimidazo[l,2-a]pyridin-6-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[[3-(3-chloro-8-methoxy-imidazo[l,2-a]pyridin-6-yl)-4-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[(4-fluoro-3-imidazo[l,2-a]pyridin-6-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[(4-fluoro-3-pyrazolo[l,5-a]pyridin-5-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[3-(3-chloroimidazo[l,2-a]pyridin-6-yl)-4-fluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[[2-fluoro-3-(5-fluoropyrimidin-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2-fluoro-3-(4-methylthiazol-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2-fluoro-3-(2-methylthiazol-5-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2-fluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2-fluoro-3-(3-furyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(5-fluoropyrimidin-2-yl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-pyrimidin-2-yl-cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(5-methylthiazol-2-yl)phenyl]methyl]-3-(5-fluoropyrimidin-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[(4-fluoro-3-imidazo[l,2-a]pyrazin-6-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[trans-4-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-pyrimidin-2-yl-cyclohexyl]methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4-methylpyrimidin-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(4,6-dimethylpyrimidin-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[3-[5-(difluoromethyl)-l,2,4-oxadiazol-3-yl]-2,4-difluoro-phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl]methanesulfonamide,N-[(lS,3R)-3-[(2,4-difluoro-3-imidazol-l-yl-phenyl)methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(2-oxo-l-pyridyl)phenyl]methyl]-3-(5-methyloxazol-2-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(l-methylpyrazol-3-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(2-methylpyrazol-3-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[cis-(4-phenylcyclohexoxy)methyl]-3-(lH-pyrazol-3-yl)cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[cis-(4-phenylcyclohexoxy)methyl]-3-pyrimidin-4-yl-cyclopentyl] methanesulfonamide,N-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-pyrimidin-4-yl-cyclopentyl] methanesulfonamideN-[(lS,3R)-3-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(2-methylpyrimidin-4-yl)cyclopentyl] methanesulfonamide,or a pharmaceutically acceptable salt thereof.

15. A compound according to any one of claims 1 – 14 for use in therapy.

16. A compound according to any one of claims 1 – 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 1-14 together with one or more pharmaceutically acceptable excipients or carriers.

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

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