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).

[0007] 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).

[0008] 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.

[0009] 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.

[0010] 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

[0011] 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.

[0012] Some compounds of the present invention furthermore possess favorable pharmacological and pharmaceutical properties such as favorable metabolic stability, permeability and / or selectivity.

[0013] Accordingly, in a first aspect the present invention provides a compound of general formula (I) wherein

[0014] X is -O- or -(CRaRb)- or a bond, wherein Raand Rb each independently are selected from the group consisting of hydrogen and (Ci-C4)a I kyl;

[0015] Ri and Riaeach independently are selected from hydrogen and fluoro, or when X is -(CRaRb)- Ri or Riaand Raor Rb together with the carbon atoms to which they are attached may optionally form a fused Cs-cycloalkyl group;

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

[0017] R2 is (Ci-C4)a Ikyl or -NRcRd, wherein Rcand Rd each independently are selected from the group consisting of hydrogen and (Ci-C4)a I kyl;

[0018] Z is phenyl, pyridyl, (Ce-Cyjcycloalkylene or (C2-C4)alkylene, , wherein said phenyl or pyridyl or is optionally substituted with one or more substituents each independently selected from Ari is phenyl, pyridyl, pyrimidyl or thiazolyl, wherein said phenyl, pyridyl, pyrimidyl or thiazolyl is optionally substituted with one or more substituents each independently selected from F ;

[0019] Rs and R4 each independently are halogen or (Ci-C4)a I kyl;

[0020] W is -C(O)-NR5R6, -NH-C(O)-R7, -C(O)-R8, -NH-C(O)-O-R9, -NH-C(O)-NRI0RII, oxopiperidyl, or oxopyrrolidinyl, wherein said oxopiperidyl or oxopyrrolidinyl is optionally substituted with one or more substituents independently selected from R12; with the proviso that when W is selected from -C(O)-R8and -C(O)-NRsR6, and Z is phenyl and X is -CH2-, then Q is -(CH2)2- or R2 is -NRcRd; or when W is selected from -C(O)-R8and -C(O)-NRsR6, and Z is phenyl and X is a bond, then Q is Ci-alkylene;

[0021] Rs and Re each independently are hydrogen, (Ci-C4)a Ikyl or (C3-Ce)cycloalkyl, wherein said (Ci-C4)a Ikyl and (C3-Ce)cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, -OH, (Ci-C4)alkoxy and (Ci-C4)a I kyl;

[0022] R? is (Ci-C4)alkyl, (C3-Ce)cycloalkyl, 4-8-membered heterocycloalkyl or hydroxy(Ci-C4)alkyl;

[0023] R8is a 4-8-membered heterocycloalkyl comprising at least one nitrogen atom and wherein said nitrogen atom is the point of attachment to -C(O)-, wherein said 4-8-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from halogen, -OH, (Ci-C4)alkoxy, (Ci-C4)alkyl and halo(Ci-C4)alkyl;

[0024] R9 is (Ci-C4)alkyl;

[0025] Rioand Rn are each independently selected from hydrogen or (Ci-C4)a Ikyl;

[0026] R12 is (Ci-C4)alkyl;

[0027] Y represents a bond or -O-; or pharmaceutically acceptable salts thereof. 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.

[0028] In a further aspect, the invention provides compounds of formula (I) as disclosed herein or a pharmaceutically acceptable salt thereof for use in therapy.

[0029] DETAILED DESCRIPTION OF THE INVENTION

[0030] DEFINITIONS

[0031] 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, 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.

[0032] 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, or 3-5 carbon atoms or such as 3-4 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. 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).

[0033] 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 (-CHfCHs)-) (C2 alkylene), n- propylene (-CH2CH2CH2-), iso-propylene (-CI-hCHfCHs)-) or (-CH(CH3)CH2-) (C3 alkylene), and the like.

[0034] 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.

[0035] 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.

[0036] The term "halogen" is intended to indicate a substituent from the 7thmain group of the periodic table, such as fluoro, chloro and bromo.

[0037] The term "haloalkyl" is intended to indicate an alkyl group as defined herein substituted with one or more halogen atoms as defined herein, e.g., fluoro or chloro, such as difluoromethyl or trifluoromethyl.

[0038] The term "heteroaryl" is intended to indicate radicals of 5- or 6-membered monocyclic heteroaromatic rings which contains from 1-5 carbon atoms and from 1-4 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. Representative examples of heteroaryl groups include, but are not limited to imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl.

[0039] The term "heterocycloalkyl" is intended to indicate a cycloalkyl radical as described herein, wherein one or more carbon atoms are replaced by heteroatoms, comprising 1-7 carbon atoms, e.g. 2-6, 2-5, 2-4, or 2-3 carbon atoms and further comprising 1-7 heteroatoms, preferably 1, 2, or 3 heteroatoms, each independently 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. In the present context the term 'heterocycloalkyl' comprises both monocyclic, bicyclic and spirocyclic heterocycles. The term '4 - 8 membered heterocycloalkyl' indicates that said heterocycloalkyl comprises from 4 to 8 atoms.

[0040] Representative examples of heterocycloalkyl groups include, but are not limited to azetidinyl, aziridinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetra hydropyranyl, azaspirohexanyl, azaspiro[2.3]hexanyl, oxa-azaspiroheptanyl, oxa- azaspiro[3.3]heptanyl.

[0041] The term "haloalkyl" is intended to indicate an alkyl group as defined herein substituted with one or more halogen atoms as defined herein, e.g. fluoro or chloro, such as difluoromethyl or trifluoromethyl.

[0042] The term "hydroxyalkyl" is intended to indicate an alkyl group as defined above substituted with one or more hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl.

[0043] The term "oxo" is intended to indicate the functional group '=0'; a substituent oxygen atom connected to another atom by a double bond. 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).

[0044] 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).

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] The patient or subject to be treated is preferably a mammal, in particular a human being.

[0050] In the present context the terms 'orexin receptor type 2', 'OX2R', and 'orexin 2 receptor' are used interchangeably.

[0051] Stereochemistry

[0052] 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.

[0053] 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%.

[0054] 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.

[0055] 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).

[0056] Isotopes

[0057] Included in this invention are also isotopica I ly 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,nC,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.

[0058] 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.

[0059] EMBODIMENTS OF THE INVENTION

[0060] In the following, embodiments of the invention are disclosed.

[0061] In a first aspect of the invention, a compound of general formula (I) is provided wherein X is -O- or -(CRaRb)- or a bond, wherein Raand Rb each independently are selected from the group consisting of hydrogen and (Ci-C4)a I kyl;

[0062] Ri and Riaeach independently are selected from hydrogen and fluoro, or when X is -(CRaRb)- Ri or Riaand Raor Rb together with the carbon atoms to which they are attached may optionally form a fused Cs-cycloalkyl group;

[0063] Q is (Ci-C2)alkylene;

[0064] R2 is (Ci-C4)a Ikyl or -NRcRd, wherein Rcand Rd each independently are selected from the group consisting of hydrogen and (Ci-C4)a I kyl;

[0065] Z is phenyl, pyridyl, (Ce-Cyjcycloalkylene or (C2-C4)alkylene, wherein said phenyl or pyridyl is optionally substituted with one or more substituents each independently selected from R3;

[0066] Ari is phenyl, pyridyl, pyrimidyl or thiazolyl, wherein said phenyl, pyridyl, pyrimidyl or thiazolyl is optionally substituted with one or more substituents each independently selected from R4;

[0067] R3 and R4 each independently are halogen or (Ci-C4)a I kyl;

[0068] W is -C(O)-NR5R6, -NH-C(O)-R7, -C(O)-R8, -NH-C(O)-O-R9, -NH-C(O)-NRI0RII, oxopiperidyl, or oxopyrrolidinyl, wherein said oxopiperidyl or oxopyrrolidinyl is optionally substituted with one or more substituents independently selected from R12; with the proviso that when W is selected from -C(O)-R8and -C(O)-NRsR6, and Z is phenyl and X is -CH2-, then Q is -(CH2)2- or R2 is -NRcRd; or when W is selected from -C(O)-R8and -C(O)-NRsR6, and Z is phenyl and X is a bond, then Q is -CH2-;

[0069] Rs and Re each independently are hydrogen, (Ci-C4)a Ikyl or (C3-Ce)cycloalkyl, wherein said (Ci-C4)a Ikyl and (C3-Ce)cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, -OH, (Ci-C4)alkoxy and (Ci-C4)a I kyl;

[0070] R? is (Ci-C4)alkyl, (C3-Ce)cycloalkyl, 4-8-membered heterocycloalkyl or hydroxy(Ci-C4)alkyl;

[0071] R8is a 4-8-membered heterocycloalkyl comprising at least one nitrogen atom and wherein said nitrogen atom is the point of attachment to -C(O)-, wherein said 4-8-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from halogen, -OH, (Ci-C4)alkoxy, (Ci-C4)a Ikyl and ha lo(Ci-C4)a I kyl;

[0072] R9 is (Ci-C4)alkyl;

[0073] Rioand Rn are each independently selected from hydrogen or (Ci-C4)alkyl;

[0074] R12 is (Ci-C4)alkyl;

[0075] Y represents a bond or -O-; or pharmaceutically acceptable salts thereof.

[0076] In a further aspect of the invention, a compound of general formula (la) is provided, or a pharmaceutically acceptable salt thereof, wherein X, Ra, Rb, Ri, Ria, Q , R2, Rc, Rd, Z , Y, R3, Ari, R4, W, Rs, Re , R7 , Rs, R9, Rio, R11, and R12 are as defined above.

[0077] In a further aspect of the invention, a compound of general formula (I) or (la) is provided, wherein said compound is not

[0078] N-((lR,3S)-l-([l,l'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentyl)butyramide,

[0079] N-((lS,3R)-3-([l,l'-biphenyl]-3-ylmethyl)-3-(2-oxopyrrolidin-l- yl)cyclopentyl)methanesulfonamide,

[0080] N-(l-([l,l'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentyl)butyramide, or

[0081] N-(3-([l,l'-biphenyl]-3-ylmethyl)-3-(2-oxopyrrolidin-l-yl)cyclopentyl)methanesulfonamide, or pharmaceutically acceptable salts thereof. In a further aspect of the invention, a compound of general formula (lb) is provided, or a pharmaceutically acceptable salt thereof, wherein R2, Rc, Rd, Z , Y, R3, Ari, R4, W, Rs, Re , R7 , Rs, R9, Rio, R11, and R12 are as defined above.

[0082] In a further aspect of the invention, a compound of general formula (Ic) is provided, or a pharmaceutically acceptable salt thereof, wherein R2, Rc, Rd, Z , Y, R3, Ari, R4, W, Rs, Re , R7 , Rs, R9, Rio, R11, and R12 are as defined above.

[0083] In a further aspect of the invention, a compound of general formula (Id) is provided, or a pharmaceutically acceptable salt thereof, wherein R2, Rc, Rd, Z , Y, R3, Ari, R4, W, Rs, Re , R7 , Rs, R9, Rio, R11, and R12 are as defined above.

[0084] In a further aspect of the invention, a compound of general formula (le) is provided, or a pharmaceutically acceptable salt thereof, wherein R2, Rc, Rd, Z , Y, R3, Ari, R4, W, Rs, Re , R7 , Rs, R9, Rio, R11, and R12 are as defined above.

[0085] 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 Rb each independently are selected from the group consisting of hydrogen and (Ci-C4)a Ikyl;

[0086] Ri and Riaeach independently are selected from hydrogen and fluoro, or when X is -(CRaRb)- Ri or Riaand Raor Rb together with the carbon atoms to which they are attached may optionally form a fused Cs-cycloalkyl group;

[0087] Q is (Ci-C2)alkylene;

[0088] R2 is (Ci-C4)a Ikyl or -NRcRd, wherein Rcand Rd each independently are selected from the group consisting of hydrogen and (Ci-C4)a I kyl;

[0089] Z is phenyl, wherein said phenyl is substituted with one or more substituents each independently selected from R3;

[0090] Ari is phenyl, wherein said phenyl is substituted with one or more substituents each independently selected from R4.

[0091] R3 and R4 each independently are halogen or (Ci-C4)a I kyl;

[0092] W is -C(O)-NR5R6, -NH-C(O)-R7, -C(O)-R8, -NH-C(O)-O-R9, -NH-C(O)-NRI0RII, oxopiperidyl, or oxopyrrolidinyl, wherein said oxopiperidyl or oxopyrrolidinyl is optionally substituted with one or more substituents independently selected from R12; with the proviso that when W is selected from -C(O)-R8and -C(O)-NRsR6, and Z is phenyl and X is -CH2-, then Q is -(CH2)2- or R2 is -NRcRd; or when W is selected from -C(O)-R8and -C(O)-NRsR6, and Z is phenyl and X is a bond, then Q is -CH2-; Rs and Re each independently are hydrogen, (Ci-C4)a Ikyl or (C3-Ce)cycloalkyl, wherein said (Ci-C4)a Ikyl and (C3-Ce)cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, -OH, (Ci-C4)alkoxy and (Ci-C4)a I kyl;

[0093] R? is (Ci-C4)alkyl, (C3-Ce)cycloalkyl, 4-8-membered heterocycloalkyl or hydroxy(Ci-C4)alkyl;

[0094] Rs is a 4-8-membered heterocycloalkyl comprising at least one nitrogen atom and wherein said nitrogen atom is the point of attachment to -C(O)-, wherein said 4-8-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from halogen, -OH, (Ci-C4)alkoxy, (Ci-C4)a Ikyl and ha lo(Ci-C4)a I kyl;

[0095] R9 is (Ci-C4)alkyl;

[0096] Rioand Rn are each independently selected from hydrogen or (Ci-C4)a Ikyl;

[0097] R12 is (Ci-C4)alkyl;

[0098] Y represents a bond or -O-; or pharmaceutically acceptable salts thereof.

[0099] 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.

[0100] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein X is -CH2- or -CHfCHs)-.

[0101] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Q is (Ci)alkylene.

[0102] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein Q is (C2)alkylene.

[0103] 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. In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic),

[0104] (Id) or (le), wherein R2 is methyl, ethyl, NH(CHs) or N(CHs)2.

[0105] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein Y represents a bond.

[0106] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein Y represents -O-.

[0107] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein Z is phenyl, cyclohexylene or bicycloheptanyl, wherein said phenyl is optionally substituted with one or more substituents each independently selected from R3.

[0108] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), 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.

[0109] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), 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.

[0110] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein Ari is phenyl, wherein said phenyl is optionally substituted with one or more substituents each independently selected from F . In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein Ari is phenyl, wherein said phenyl is substituted with one or more substituents each independently selected from F .

[0111] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), 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, and wherein Ari is phenyl, wherein said phenyl is substituted with one or more substituents each independently selected from R4.

[0112] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), 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, and wherein Ari is phenyl, wherein said phenyl is substituted with one or more substituents each independently selected from R4, wherein R4 is the group consisting of fluoro, chloro, methyl and ethyl.

[0113] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein W is -NH-C(O)-R?, -NH-C(O)-O-Rg, -NH-C(0)-NRioRn, oxopiperidyl, or oxopyrrolidinyl, wherein said oxopiperidyl or oxopyrrolidinyl is optionally substituted with one or more substituents independently selected from R12.

[0114] In an embodiment the invention relates to a compound of general formula (I) or (la), wherein W is -NH-C(O)-R?, -NH-C(O)-O-Rg, -NH-C(0)-NRioRn or oxopiperidyl, wherein said oxopiperidyl is optionally substituted with one or more substituents independently selected from R12. In an embodiment the invention relates to a compound of general formula (I) or (la), wherein W is -C(O)-NRsRe or -C(O)-Rs, with the proviso that when Z is phenyl and X is -CH2-, then Q is -(CH2)2- or R2 is -NRcRd; or when Z is phenyl and X is a bond, then Q is -CH2.

[0115] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein R5 and Re each independently are hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl.

[0116] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein R? is methyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxypropyl or oxetanyl.

[0117] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein Rs is azetidinyl, oxa-azaspiro[3.3]heptanyl or azaspiro[2.3]hexanyl, wherein said azetidinyl, oxa-azaspiro[3.3]heptanyl or azaspiro[2.3]hexanyl is optionally substituted with one or more substituents independently selected from methyl, methoxy, fluoro , hydroxy and difluoromethyl.

[0118] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein R9 is methyl or ethyl.

[0119] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein Rwand Rn are each independently selected from hydrogen, methyl and ethyl.

[0120] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein R12 is methyl or ethyl. In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), 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.

[0121] In an embodiment the invention relates to a compound of general formula (I), (la), (lb), (Ic), (Id) or (le), wherein Y represents -O- and Z is (Ce-Cyjcycloalkylene.

[0122] In an embodiment the invention relates to a compound selected from the list consisting of

[0123] N-cyclopropyl-l-trans-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-

[0124] (methanesulfonamido)cyclohexanecarboxamide,

[0125] N-[(lS,3R,4S)-3-(azetidine-l-carbonyl)-4-methyl-3-[(3- phenylphenyl)methyl]cyclopentyl]methanesulfonamide,

[0126] N-[(lR,3S,4R)-3-(azetidine-l-carbonyl)-4-methyl-3-[(3- phenylphenyl)methyl]cyclopentyl]methanesulfonamide, l-[(lR,3S)-3-(dimethylsulfamoylamino)-l-[(3- phenylphenyl)methyl]cyclopentanecarbonyl]azetidine,

[0127] N-cis-[4-(azetidine-l-carbonyl)-4-[[3-(3,5-difluorophenyl)-4-fluoro- phenyl]methyl]cyclohexyl] methanesulfonamide,

[0128] N-cyclopropyl-l-trans-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-

[0129] (methanesulfonamido)cyclobutanecarboxamide,

[0130] N-cis-[3-(azetidine-l-carbonyl)-3-[[3-(3,5-difluorophenyl)-4-fluoro- phenyl]methyl]cyclobutyl]methanesulfonamide,

[0131] N-[(lS,3S)-3-cis-(azetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0132] N-[(lS,3S)-3-cis-(3-methoxy-3-methyl-azetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide, azetidin-l-yl-[(lS,3S)-3-(methylsulfamoylamino)-l-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanone, l-[(lS,3S)-3-(dimethylsulfamoylamino)-l-[(4- phenylcyclohexoxy)methyl]cyclopentanecarbonyl]azetidine,

[0133] (15.35)-3-(methanesulfonamido)-N,N-dimethyl-l-[(4- phenylcyclohexoxy)methyl]cyclopentanecarboxamide;

[0134] N-[(lS,3S)-3-cis-(3-hydroxyazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0135] N-[(lS,3S)-3-cis-(3-fluoroazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0136] N-[(lS,3S)-3-cis-(3,3-difluoroazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0137] N-[(lS,3S)-3-[3-cis-(difluoromethyl)azetidine-l-carbonyl]-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0138] N-[(lS,3S)-3-cis-(3-methoxyazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0139] N-[(lS,3S)-3-cis-(l-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0140] N-[(lS,3S)-3-cis-(5-azaspiro[2.3]hexane-5-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0141] N-[(lS,3S)-3-cis-(3-fluoro-3-methyl-azetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0142] N-[(lS,3S)-3-cis-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0143] N-[(lS,3S)-3-(azetidine-l-carbonyl)-3-[[(3R*,6S*)-6-(5-fluoropyrimidin-2-yl)norcaran-3- yl]oxymethyl]cyclopentyl]methanesulfonamide;

[0144] (15.35)-l-[[(lR*,3R*,6S*)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-

[0145] (methanesulfonamido)-N-methyl-cyclopentanecarboxamide, N-[(lS,3S)-3-(azetidine-l-carbonyl)-3-[[(lR*,3R,6S*)-6-(5-fluoropyrimidin-2-yl)norcaran-3- yl]oxymethyl]cyclopentyl]methanesulfonamide,

[0146] N-[(lR,2R,4R,5S)-4-(azetidine-l-carbonyl)-4-[(3-phenylphenyl)methyl]-2- bicyclo[3.1.0]hexanyl]methanesulfonamide,

[0147] (lS,2R,4R,5R)-N-cyclopropyl-4-(methanesulfonamido)-2-[(3- phenylphenyl)methyl]bicyclo[3.1.0]hexane-2-carboxamide,

[0148] (lS,2R,4R,5R)-4-(methanesulfonamido)-N-methyl-2-[(3- phenylphenyl)methyl]bicyclo[3.1.0]hexane-2-carboxamide,

[0149] N-[(lR,2R,4R,5S)-4-(azetidine-l-carbonyl)-4-[(cis-4-phenylcyclohexoxy)methyl]-2- bicyclo[3.1.0]hexanyl]methanesulfonamide,

[0150] (lS,2R,4R,5R)-4-(methanesulfonamido)-2-[(cis-4- phenylcyclohexoxy)methyl]bicyclo[3.1.0]hexane-2-carboxamide,

[0151] (lS,2R,4R,5R)-4-(methanesulfonamido)-N-methyl-2-[(cis-4- phenylcyclohexoxy)methyl]bicyclo[3.1.0]hexane-2-carboxamide,

[0152] N-[rac-(3R,5R)-5-(azetidine-l-carbonyl)-5-[(cis-4- phenylcyclohexoxy)methyl]tetrahydrofuran-3-yl] methanesulfonamide,

[0153] (2S,4S)-4-(methanesulfonamido)-N-methyl-2-[(cis-4- phenylcyclohexoxy)methyl]tetrahydrofuran-2-carboxamide or (2R,4R)-4-

[0154] (methanesulfonamido)-N-methyl-2-[(4-phenylcyclohexoxy)methyl]tetrahydrofuran-2- carboxamide,

[0155] (2R,4R)-4-(methanesulfonamido)-N-methyl-2-[(4- phenylcyclohexoxy)methyl]tetrahydrofuran-2-carboxamide,

[0156] N-[(lS,3S)-3-(methanesulfonamido)-l-[(cis-4- phenylcyclohexoxy)methyl]cyclopentyl]acetamide,

[0157] N-[(lS,3S)-3-(methanesulfonamido)-l-[(cis-4- phenylcyclohexoxy)methyl]cyclopentyl]propenamide,

[0158] N-[(lS,3S)-3-(methanesulfonamido)-l-[(cis-4- phenylcyclohexoxy)methyl]cyclopentyl]cyclopropanecarboxamide, N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(methanesulfonamido)cyclopentyl]-2- hydroxy-2-methyl-propanamide,

[0159] (2R)-N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0160] (methanesulfonamido)cyclopentyl]oxetane-2-carboxamide,

[0161] (2S)-N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0162] (methanesulfonamido)cyclopentyl]oxetane-2-carboxamide, methyl N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0163] (methanesulfonamido)cyclopentyl]carbamate,

[0164] N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0165] (methanesulfonamido)cyclopentyl]acetamide,

[0166] N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0167] (methanesulfonamido)cyclopentyl]cyclopropanecarboxamide,

[0168] N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0169] (methanesulfonamido)cyclopentyl]propenamide,

[0170] N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(methanesulfonamido)cyclopentyl]-2- methyl-propanamide, methyl N-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-

[0171] (methanesulfonamido)cyclopentyl]carbamate, ethyl N-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-

[0172] (methanesulfonamido)cyclopentyl]carbamate, l-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-

[0173] (methanesulfonamido)cyclopentyl]-3-methyl-urea,

[0174] N-[(lS,3S)-3-(2-oxopyrrolidin-l-yl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0175] N-[(lS,3S)-3-(2-oxo-l-piperidyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,

[0176] 3-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-

[0177] (methanesulfonamido)cyclopentyl]-l,l-dimethyl-urea, methyl N-[rac-(lR,2S,4S)-l-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-

[0178] (methanesulfonamido)-2-methyl-cyclopentyl]carbamate, methyl N-[(lS,2R,4R,5R)-2-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-4- (methanesulfonamido)-2-bicyclo[3.1.0]hexanyl]carbamate, methyl N-[(lS,2R,4R,5R)-2-[(2,4-difluoro-3-phenyl-phenyl)methyl]-4-(methanesulfonamido)- 2-bicyclo[3.1.0]hexanyl]carbamate, methyl N-trans-[l-[(2,4-difluoro-3-phenyl-phenyl)methyl]-4- (methanesulfonamido)cyclohexyl]carbamate, methyl N-trans-[l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-4- (methanesulfonamido)cyclohexyl]carbamate, methyl N-trans-[l-[[3-(3,5-difluorophenyl)-2,4-difluoro-phenyl]methyl]-4- (methanesulfonamido)cyclohexyl]carbamate and methyl N-[(lS,2R,4R,5R)-2-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-4- (methanesulfonamido)-2-bicyclo[3.1.0]hexanyl]carbamate.

[0179] PHARMACEUTICALLY ACCEPTABLE SALTS

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] PHARMACEUTICAL COMPOSITION

[0185] 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.

[0186] 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.

[0187] 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.

[0188] Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups, and elixirs.

[0189] 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.

[0190] Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, etc.

[0191] 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.

[0192] Suitable pharmaceutical carriers include inert solid excipients orfillers, 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.

[0193] 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.

[0194] 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 l 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.

[0195] 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.

[0196] TREATING DISEASES

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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. 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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. 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.

[0208] 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. 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)

[0209] 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.

[0210] 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.

[0211] 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.

[0212] The compounds of the invention may be administered as a monotherapy or as part of an adjunctive treatment regimen. 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.

[0213] 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.

[0214] In an embodiment, compounds of the invention can be used in combination with other therapeutically active compounds.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] PREPARATION OF COMPOUNDS OF THE INVENTION

[0219] GENERAL METHODS

[0220] 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.

[0221] General method-01

[0222] Compounds of general formula INT-1 can be prepared by the treatment of compounds of general formula i with a reagent such as benzophenoneimine. General method-02 where Lgi and Lg2 are leaving groups such as bromide, chloride or methanesulfonate.

[0223] 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-3 can be obtained.

[0224] General method-03 where Lgi and Lg2 are leaving groups such as bromide, chloride or methanesulfonate; and G is a halogen such as chloride or bromide.

[0225] Compounds of general formula INT-2 can be synthesized from compounds of general formula INT-1 by the same procedures as described in General method-02. General method-04 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.

[0226] 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.

[0227] General method-05

[0228] Compounds of general formula INT-3 can be prepared by the 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)Cl2 and a base such as CS2CO3 in a solvent mixture such as water and 1,4-dioxane.

[0229] General method-06

[0230] Compounds of general formula INT-3 can be hydrolyzed using a reagent such as sodium hydroxide in water and methanol to form compounds of general formula i. Treatment of compounds of general formula i with a reagent such as DPPA in the presence of a base followed heating, leads to the formation of compounds of general formula INT-6.

[0231] General method-07 where Pgi is hydrogen or a protection group such as p-methoxybenzyl, Pg2 is hydrogen or a protection group such as t-butoxy carbonyl.

[0232] Compounds of general formula INT-2 can be hydrolyzed using a reagent such as sodium hydroxide in water and methanol to form compounds of general formula i. Treatment of compounds of general formula i with a reagent such as DPPA in the presence of a base followed heating leads to the formation of compounds of general formula INT-4. When Pgi and Pg2 are hydrogen, compounds of general formula INT-6 can be prepared by the reaction of compounds of general formula INT-4 and compounds of general formula ii in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as CS2CO3 in a solvent mixture such as water and 1,4-dioxane. When Pgi is a protection group such as p- methoxybenzyl, and / or Pg2 is a protection group such as t-butoxy carbonyl, the reaction will give compounds of general formula iii, which after deprotection will give compounds of general formula INT-6.

[0233] General method-08

[0234] W = -NH-C(O)-NR14R15or -NH-C(O)-O-R9

[0235] Compounds of general formula INT-2 can be hydrolyzed using a reagent such as sodium hydroxide in water and methanol to form compounds of general formula i. Treatment of compounds of general formula i with a reagent such as DPPA in the presence of a base followed by reaction with compounds of general formula ii or compounds of general formula iii, can lead to the formation of compounds of general formula INT-7.

[0236] General method-09

[0237] INT-2 INT-8

[0238] Compounds of general formula INT-2 can be hydrolyzed using a reagent such as sodium hydroxide in water and methanol to form compounds of general formula i. Treatment of compounds of general formula i with a reagent such as DPPA in the presence of a base followed heating, leads to the formation of compounds of general formula INT-8.

[0239] General method-10 where Lg is a leaving group such as chloride.

[0240] Compounds of general formula INT-9 can be synthesized by the reaction of compounds of general formula INT-8 with compounds of general formula i in the using a coupling reagent such as HATU and a base such as diisopropyl ethyl amine, or reaction with compounds of general formula ii or iii in the presence of a base such as diisopropyl ethyl amine.

[0241] General method-11 Compounds of general formula INT-3 can be hydrolyzed using a reagent such as sodium hydroxide in water and methanol followed by removal of the protection group (Pg2) using procedures known to the person skilled in the art, to give compounds of general formula i. Amide formation of between compounds of general formula i and the appropriate amine using a coupling reagent such as HATU and a base such as diisopropyl ethyl amine gives compounds of general formula (I).

[0242] General method-12 where Lg is a leaving group such as chloride.

[0243] Compounds of general formula (I) can be synthesized by the reaction of compounds of general formula INT-6 with compounds of general formula i in the using a coupling reagent such as HATU and a base such as diisopropyl ethyl amine, or reaction with compounds of general formula ii or iii in the presence of a base such as diisopropyl ethyl amine.

[0244] General method-13

[0245]

[0246] Compounds of general formula (I) can be synthesized by the reaction of compounds of general formula INT-6 with compounds of general formula i in the presence of a base such as diisopropyl ethyl amine followed by treatment with a base such as NaOH.

[0247] General method-14

[0248] Compounds of general formula (I) can be prepared by the 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)Cl2 and a base such as CS2CO3 in a solvent mixture such as water and 1,4- dioxane.

[0249] EXPERIMENTAL SECTION

[0250] CHEMICAL NAMES

[0251] The chemical names for the Examples of the invention were generated using or starting from BIOVIA MDL.Draw. Editor version 20.1.0.2081 from Dassault Systemes ANALYTICAL METHODS

[0252] LC-MS methods

[0253] Method A:

[0254] LC-MS were run on Waters ACQUITY Premier UPLC-MS consisting of Waters Aquity Primier, 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.

[0255] LC-conditions: The column was Acquity Premier UPLC BEH C18 1.7 pm; 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.

[0256] Gradient: 0.00 minutes 10% B

[0257] 1.00 minutes 99.9% B

[0258] 1.01 minutes 10% B

[0259] 1.15 minutes 10% B

[0260] Total run time: 1.15 min

[0261] Method B:

[0262] 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.

[0263] LC-conditions: The column was Acquity UPLC BEH C18 1.7 pm; 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.

[0264] Gradient: 0.00 minutes 10% B

[0265] 1.00 minutes 99.9% B

[0266] 1.01 minutes 10% B

[0267] 1.15 minutes 10% B

[0268] Total run time: 1.15 minutes NMR

[0269] 1H NMR spectra were recorded at 600 MHz on a Bruker 600-Avance-lll spectrometer, at 500 MHz on a Bruker 500-Avance DRX spectrometer, on 300 MHz on a Bruker Avance III HD spectrometer, on 400 MHz on a Bruker Avance III HD spectrometer and on 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.

[0270] ABBREVIATIONS

[0271] Abbreviations used in the experimental may include, but are not limited to the following:

[0272] Ac: acetyl; Boc: tert-butyloxycarbonyl; C: Celsius; DCM: dichloromethane; DEAD: diethyl azodicarboxylate; DIAD: diisopropyl azodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMA: / V, / V-dimethylacetamide; DMAP: N,N-dimethylaminopyridine; DMF: N,N- dimethylformamid; DMSO: dimethylsulfoxide; dppf: l,l'-bis(diphenylphosphino)ferrocene; Et: ethyl; EtOAc: ethyl acetate; g: gram; h: hour(s); HATU: l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HMDS: hexamethyldisilazane; HOAt: l-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(di methyl)si lyl; TCFH: N'-tetramethylformamidinium hexafluorophosphate; TEA: triethylamine; Tf: triflate; TFA: trifluoroacetic acid; THF: tetra hydrofuran; THP: tetra hydropyran; TLC: thin layer chromatography; TMS: trimethylsilyl; Ts: toluenesulfonyl; wt: by weight; XPhos: [2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl],

[0273] PREPARATION OF INTERMEDIATES

[0274] Preparation of tert-butyl (lR,4S)-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate

[0275] 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 PE / EtOAc (4:1) to afford the desired product.

[0276] Preparation of tert-butyl (lS,2R,4R,5R)-7-oxo-3-(trimethylsilyl)-6- azatricyclo[3.2.1.02,4]octane-6-carboxylate

[0277] 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 Et20 (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 PE / EtOAc = 4 / 1 to afford the desired product.

[0278] Preparation of methyl (lR,2S,4R,5R)-4-amino-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2- carboxylate

[0279] 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.

[0280] Preparation of methyl (lS,2S,4R,5R)-4-aminobicyclo[3.1.0]hexane-2-carboxylate

[0281] 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 Na2COs (aq . ) . The aqueous layer was extracted with CH2CI2 (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.

[0282] Preparation of methyl 3-((tetrahydro-2H-pyran-2-yl) oxy) cyclobutane-l-carboxylate

[0283] 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 PE / EtOAc (6:1) to afford methyl 3-((tetrahydro-2H-pyran-2-yl) oxy) cyclobutane-l-carboxylate.

[0284] Preparation of methyl l-(3-bromo-4-fluorobenzyl)-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclobutane-l-carboxylate (General method-04)

[0285] 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). The resulting mixture was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2 x 100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford methyl l-[(3-bromo-4- fluorophenyl) methyl]-3-(oxan-2-yloxy) cyclobutane-l-carboxylate.

[0286] Preparation of methyl l-(3-bromo-4-fluorobenzyl)-3-hydroxycyclobutane-l-carboxylate

[0287] 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 PE / EtOAc (1:1) to afford methyl l-[(3-bromo-4-fluorophenyl) methyl]-3-hydroxycyclobutane-l- carboxylate.

[0288] Preparation of methyl (lR,3S)-l-(3-bromo-4-fluorobenzyl)-3-( / V-(tert- butoxycarbonyl)methylsulfonamido)cyclobutane-l-carboxylate (General method-04)

[0289] 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 PPhs (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 (2 x 20 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 (10 mmol / 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.

[0290] Preparation of (lr,3s)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclobutane-l- carboxylic acid (General method-03, INT-2)

[0291] A mixture of methyl (lr,3s)-l-[(3-bromo-4-fluorophenyl)methyl]-3-[ / V-(tert- butoxycarbonyl)methanesulfonamido]cyclobutane-l-carboxylate (400 mg, 0.809 mmol) and NaOH (129 mg, 3.236 mmol) in MeOH (8 mL), THF (8 mL) and H2O (8 mL) was stirred for 2 hours at 70 °C under an argon atmosphere. 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 without further purification.

[0292] Preparation of rac-ethyl (lS,2R,4S)-4-hydroxy-2-methylcyclopentane-l-carboxylate

[0293] A solution of rac-ethyl (lS,2R)-2-methyl-4-oxocyclopentane-l-carboxylate (prepared as described in W02011068881, 11.6 g, 68.2 mmol) in EtOH (350 mL) was cooled to 0 °C. NaBH4 (1.29 g, 34.1 mmol) was added in small portions. The mixture was stirred at 0 °C for 70 min. NH4CI (saturated aqueous solution) was added to quench the reaction. Additional water was added. The mixture was concentrated in vacuo to remove the EtOH. The aqueous solution was extracted with EtOAc. The organic phase was washed with water, dried (MgSO4) and concentrated in vacuo. The crude product was used in the next step without further purification.

[0294] Preparation of rac-ethyl (lR,2S,4S)-4-azido-2-methylcyclopentane-l-carboxylate

[0295] DIAD (1.5 g, 1.4 mL, 7.3 mmol) was added dropwise to rac-ethyl (lR,2S,4R)-4-hydroxy-2- methylcyclopentane-l-carboxylate (1.0 g, 5.8 mmol), diphenyl phosphorazidate (2.0 g, 1.6 mL, 7.3 mmol) and triphenylphosphine (1.7 g, 6.4 mmol) in THF (58 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: heptane / ethyl acetate) to obtain the desired product.

[0296] Preparation of rac-ethyl (lR,2S,4S)-4-amino-2-methylcyclopentane-l-carboxylate hydrochloride

[0297] Rac-ethyl (lR,2S,4S)-4-azido-2-methylcyclopentane-l-carboxylate (2.3 g, 12 mmol) was dissolved in EtOH (68 mL). Concentrated aqueous HCI (4.9 mL, 12 molar, 58 mmol) and Pd / C 10% (0.12 g, 1.2 mmol) were added and hydrogenated overnight at 1 atmosphere of hydrogen. The reaction mixture was filtered and concentrated in vacuo. The crude was washed with Et20 and dried in vacuo to give the desired product which was used in the next step without further purification.

[0298] Preparation of methyl 4-((tetrahydro-2H-pyran-2-yl)oxy)cyclohexane-l-carboxylate

[0299] 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 Dowex C-211 H+ form (1.00 g, 63.2 mmol). The mixture was stirred at room temperature for 18 hours. Further 3,4- dihydro-2H-pyran (2.3 mL, 25.3 mmol) was added along with a further portion of Dowex C- 211 H+ 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. Used without further purification.

[0300] Preparation of methyl (ls,4s)-l-(3-bromo-4-fluorobenzyl)-4-((tetrahydro-2H-pyran-2-yl) oxy)cyclohexane-l-carboxylate (General method-04)

[0301] To a stirred mixture of methyl 4-(oxan-2-yloxy) cyclohexane-l-carboxylate (10 g, 41 mmol) in THF (400 mL) was added LDA (31 mL in THF, 62 mmol) 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 (17.69 g, 66.03 mmol) in THF (10 mL) dropwise over 30 minutes at -78 °C. The resulting mixture was stirred for additional 3 hours at -78 °C. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3:1) to afford methyl (ls,4s)-l- [(3-bromo-4-fluorophenyl) methyl]-4-(oxan-2-yloxy) cyclohexane-l-carboxylate.

[0302] Preparation of methyl (ls,4s)-l-(3-bromo-4-fluorobenzyl)-4-hydroxycyclohexane-l- carboxylate (General method-04)

[0303] A mixture of methyl (ls,4s)-l-[(3-bromo-4-fluorophenyl)methyl]-4-(oxan-2-yloxy) cyclohexane-l-carboxylate (9 g, 21 mmol) and TFA (2.87 g, 25.2 mmol) in CH3OH (100 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2:1) to afford methyl (ls,4s)-l-[(3-bromo-4-fluorophenyl) methyl]-4- hydroxycyclohexane-l-carboxylate.

[0304] Preparation of methyl (lr,4r)-l-(3-bromo-4-fluorobenzyl)-4-( / V-(tert-butoxycarbonyl)-

[0305] (methylsulfonamido))cyclohexane-l-carboxylate (General method-04)

[0306] A mixture of methyl (ls,4s)-l-[(3-bromo-4-fluorophenyl) methyl]-4-hydroxycyclohexane-l- carboxylate (4.7 g, 13.6 mmol), tert-butyl / V-methanesulfonylcarbamate (5.32 g, 27.2 mmol), PPh3(10.71 g, 40.8 mmol) and DIAD (8.26 g, 40.8 mmol) in THF (80 mL) was stirred for 4 hours at room temperature under an argon atmosphere. The resulting mixture was diluted with water (80 mL). 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. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3:1) to afford methyl (lr,4r)-l-[(3-bromo-4-fluorophenyl) methyl]-4-[ / V-(tert-butoxycarbonyl) methanesulfonamido] cyclohexane-l-carboxylate.

[0307] Preparation of methyl (lr,4r)-l-(3-bromo-4-fluorobenzyl)-4- (methylsulfonamido)cyclohexane-l-carboxylate (General method-04, INT-2)

[0308] A mixture of methyl (lr,4r)-l-(3-bromo-4-fluorobenzyl)-4-(N-(tert-butoxycarbonyl)methyl sulfonamido)cyclohexane-l-carboxylate (1.3 g, 2.48 mmol) and HCI (gas) in 1,4-dioxane (5 mL) in DCM (10 mL) was stirred for 2 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.

[0309] Preparation of methyl (lr,4r)-4-(methylsulfonamido)-l-((3',5,,6-trifluoro-[l,l,-biphenyl]-3- yl)methyl)cyclohexane-l-carboxylate (General method-05, INT-3).

[0310] A mixture of methyl (lr,4r)-l-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamido)cyclohexane- 1-carboxylate (800 mg, 1.89 mmol), 3,5-difluorophenylboronic acid (598 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. Water (10 mL) was added. The resulting mixture was extracted with EtOAc (5 x 10 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SC>4. 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.

[0311] The following intermediate was prepared in a similar manner:

[0312] (lr,3s)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclobutane-l-carboxylic acid prepared from (lr,3s)-l-(3-bromo-4-fluorobenzyl)-3-(methylsulfonamido)cyclobutane-l- carboxylic acidand 3,5-difluorophenylboronic acid methyl (lr,4r)-4-(methylsulfonamido)-l-((3',5',6-trifluoro-[l,l'-biphenyl]-3- yl)methyl)cyclohexane-l-carboxylate prepared from methyl (lr,4r)-l-(3-bromo-4- fluorobenzyl)-4-(methylsulfonamido)cyclohexane-l-carboxylate and 3,5- difluorophenylboronic acid

[0313] Preparation of methyl (lS,2R,4R,5R)-2-([l,l'-biphenyl]-3-ylmethyl)-4- ((diphenylmethylene)amino)bicyclo[3.1.0]hexane-2-carboxylate (General method-02)

[0314] To a stirring solution of methyl (lS,2S,4R,5R)-4- ((diphenylmethylene)amino)bicyclo[3.1.0]hexane-2-carboxylate (665 mg, 2.08 mmol) in dry THF (8.0 mL), under an argon atmosphere at -78 °C was added a THF / hexane solution of LDA (1.5M in hexane) (1.97 mL, 2.96 mmol) dropwise over 2 minutes. The solution was stirred at -78 °C for 45 minutes. Then a THF solution of l-(bromomethyl)-3-phenylbenzene (566 mg, 2.29 mmol) was added dropwise over 2 minutes. The solution was stirred at -78 °C for 1 hour 30 minutes. The reaction was quenched with water (25 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford methyl (lS,2R,4R,5R)-2-([l,l'-biphenyl]-3- ylmethyl)-4-((diphenylmethylene)amino)bicyclo[3.1.0]hexane-2-carboxylate which was used in the next step without further purification. Preparation of methyl (lS,2R,4R,5R)-2-([l,l'-biphenyl]-3-ylmethyl)-4-

[0315] (methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylate (General method-02, INT-3)

[0316] Methyl (lS,2R,4R,5R)-2-([l,l'-biphenyl]-3-ylmethyl)-4- ((diphenylmethylene)amino)bicyclo[3.1.0]hexane-2-carboxylate (1.441 mmol) was dissolved in THF (20 mL) and methanol (2 mL). The atmosphere was exchanged for argon and HCI (12M aqueous) (720 pL, 8.7 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. Toluene (5 mL) was added, and the mixture was concentrated in vacuo to dryness and on high vacuum overnight. The crude amine hydrochloride salt thus obtained was dissolved in THF (45 mL) under argon. The mixture was cooled to approx. -15 °C. Methanesulfonic anhydride (1.26 g, 7.21 mmol) was added in one portion followed by the addition of TEA (1.21 mL, 8.65 mmol). The mixture was stirred at -15 °C - 0 °C for 30 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and was filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography to afford methyl (1S,2R,4R,5R)- 2-([l,l'-biphenyl]-3-ylmethyl)-4-(methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylate.

[0317] The following intermediates were prepared in a similar manner from the appropriate iminoester (INT-1), alkylation reagent, and sulfonyl chloride or sulfonyl anhydride: methyl (1R,3S)-1-([1, l'-biphenyl]-3-ylmethyl)-3-((N,N- dimethylsulfamoyl)amino)cyclopentane-l-carboxylate methyl (lS,2R,4R,5R)-2-((((lR,3R,6S)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3- yl)oxy)methyl)-4-(methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylate 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 methyl (lS,2R,4R,5R)-4-(methylsulfonamido)-2-((((ls,4S)-4- phenylcyclohexyl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate methyl (lS,3S)-3-((N,N-dimethylsulfamoyl)amino)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate methyl (lS,3S)-3-((N-methylsulfamoyl)amino)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate rac-ethyl (lR,2S,4S)-l-([l,l'-biphenyl]-3-ylmethyl)-2-methyl-4-

[0318] (methylsulfonamido)cyclopentane-l-carboxylate methyl (lS,2R,4R,5R)-2-(3-chloro-2,4-difluorobenzyl)-4-

[0319] (methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylate rac-(lR,2S,4S)-l-(3-bromo-4-fluorobenzyl)-2-methyl-4-(methylsulfonamido)cyclopentane-l- carboxylic acid

[0320] Preparation of 5-fluoro-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrimidine

[0321] K2CO3(2 eq) Pd(dppf)CI2(cat)

[0322] 4,4,5,5-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (1.65 g, 6.22 mmol), 2-bromo-5-fluoropyrimidine (1.00 g, 5.65 mmol), and potassium carbonate (1.72 g, 12.4 mmol) were mixed in 1,4-dioxane (14.5 mL, 170 mmol) and water (5 mL) and the flask evacuated and backfilled with argon 4 times. Then, Pd(dppf)Cl2 (207 mg, 283 pmol) was added and the mixture heated to 80 °C for 2 hours. The contents were poured into water (125 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine and dried with MgSC , the volatiles removed under reduced pressure and the residue purified by flash chromatography giving the desired product.

[0323] Preparation of 5-fluoro-2-(spiro[bicyclo[4.1.0]heptane-3,2'-[l,3]dioxolan]-6-yl)pyrimidine

[0324] Trimethyl(oxo)sulfonium iodide (37.6 g, 171 mmol) was dissolved in dry DMSO (300 mL) and 2-methylpropan-2-olate potassium (19.2 g, 171 mmol) was added in one portion. The mixture was stirred at 30 °C for 90 minutes, before 5-fluoro-2-(l,4-dioxaspiro[4.5]dec-7-en- 8-y I) pyri midine (10.1 g, 42.8 mmol) as a solution in 40 mL dry DMSO was added at 40 °C and stirred at 40 °C for 16 hours and at 80 °C for another 20 hours. Then, the mixture was added dropwise to a stirring aq. sat. NH4CI solution (100 mL) and the resulting mixture extracted into EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the crude purified by flash chromatography providing the desired product.

[0325] Preparation of 6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-one

[0326] 5-fluoro-2-(spiro[bicyclo[4.1.0]heptane-3,2'-[l,3]dioxolan]-6-yl)pyrimidine (5.40 g, 21.6 mmol) was dissolved in tetra hydrofuran (25.4 mL) and aq. hydrogen chloride (43.2 mL, 2 molar, 86.3 mmol) was added. The reaction tube was sealed and heated to 30 °C for 1.5 hours. The mixture was poured into water (50 mL), the pH adjusted to 8 with aq. NaHCCh, and extracted into EtOAc. The combined organic layers were washed with brine and dried with MgSC , the volatiles were removed under reduced pressure giving the desired product.

[0327] Preparation of (+)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-one and (-)-6-(5- fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-one

[0328] The racemic mixture from above was separated by SFC. The following chemistry was carried out on both products. However, for illustrative purposes only one of the enantiomers is depicted in the following schemes. Preparation of (lS,3S,6R)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-ol and

[0329] (lR,3R,6S)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-ol

[0330] (+) or (-)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-one (1.85 g, 8.97 mmol) was dissolved in dry tetra hydrofuran (75 mL) and a LiAl H4 (4.49 mL, 2.0 molar in THF, 8.97 mmol) solution was added dropwise at room temperature. The mixture was stirred for 10 minutes at room temperature, before a sat. aq. solution of Rochelle salt was carefully added. After stirring 15 minutes at room temperature, the contents were partitioned between water and EtOAc, the organic phase washed with brine, dried with MgSC , and the volatiles were removed under reduced pressure. Purification by flash chromatography furnished the desired products.

[0331] Preparation of 2-((lS,4R,6R)-4-(chloromethoxy)bicyclo[4.1.0]heptan-l-yl)-5- fluoropyrimidine and 2-((lR,4S,6S)-4-(chloromethoxy)bicyclo[4.1.0]heptan-l-yl)-5- fluoropyrimidine

[0332] A mixture of (lR,3R,6S)-6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-ol (115 mg, 0.55 mmol), TMSCI (780 mg, 7.2 mmol) and paraformaldehyde (28 mg, 0.93 mmol) in chloroform (5 mL) was stirred 1.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification.

[0333] Preparation of methyl 2-hydroxy-3-(((ls,4s)-4-phenylcyclohexyl)oxy)propanoate Magnesium trifluoromethanesulfonate (2.4 g, 7.3 mmol) was added in one portion to methyl (S)-oxirane-2-carboxylate (2.6 mL, 29 mmol) and (ls,4s)-4-phenylcyclohexan-l-ol (5.2 g, 29 mmol) in ethyl acetate (37 mL, 0.38 mol). The resulting suspension was stirred at 80 °C for 18h. The reaction mixture was cooled to room temperature and additional methyl (S)- oxirane-2-carboxylate (1.5 mL) was added and the reaction mixture was stirred at 80 °C for 96 h. The reaction mixture was cooled to room temperature, filtered through celite and evaporated to dryness. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc to afford the desired product.

[0334] Preparation of methyl 2-oxo-3-(((ls,4s)-4-phenylcyclohexyl)oxy)propanoate

[0335] To a round bottom flask equipped with a stirring bar was added methyl 2-hydroxy-3-(((ls,4s)- 4-phenylcyclohexyl)oxy)propanoate (1.0 g, 3.60 mmol) and DCM (25 mL). DMP (3.0 g, 7.08 mmol) was added and the mixture was stirred at room temperature for 4 hours. Aqueous Na2S20s (100 mL) was then added and the mixture exctracted with DCM (3 x 100 mL). The organic phase was collected and washed with aq. sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc to afford the desired product.

[0336] Preparation of methyl 2-hydroxy-2-((((ls,4s)-4-phenylcyclohexyl)oxy)methyl)pent-4- enoate

[0337] To a cooled (0 °C) solution of methyl 2-oxo-3-(((ls,4s)-4-phenylcyclohexyl)oxy)propanoate (2.6 g, 9.4 mmol) in dry DCM (40 mL) was added allyltrimethylsilane (1.4 g, 12 mmol). Then titanium tetrachloride (1.2 mL, 11 mmol) was added dropwise, and the mixture was stirred at 0 °C for 30 min. The mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) at 0 °C and allowed to warm to room temperature. The mixture was filtered through celite and washed with ethyl acetate. The filtrate was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc to afford the desired product.

[0338] Preparation of 2-((((ls,4s)-4-phenylcyclohexyl)oxy)methyl)pent-4-ene-l,2-diol

[0339] To a stirred solution of methyl 2-hydroxy-2-((((ls,4s)-4-phenylcyclohexyl)oxy)methyl)pent-4- enoate (1.28 g, 4.02 mmol) in dry THF (15 mL) at 0 °C was added a 2M THF solution of LAH (6.0 mL, 12.1 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 hour at room temperature and cooled to 0 °C and then quenched with water dropwise. The mixture was diluted with IM HCI and extracted with ethyl acetate (3 times). The organic phase was collected, dried over sodium sulfate, filtered, and concentrated to afford the desired product, which was used without further purification.

[0340] Preparation of l-((4-methoxybenzyl)oxy)-2-((((ls,4s)-4-phenylcyclohexyl)oxy)methyl)pent- 4-en-2-ol

[0341] 2-((((ls,4s)-4-Phenylcyclohexyl)oxy)methyl)pent-4-ene-l,2-diol (485 mg, 1.67 mmol) was dissolved in THF (10 mL) and DMSO (2.0 mL) and cooled to 0 °C. Sodium hydride (150 mg, 60% Wt, 3.67 mmol) was added and the mixture was stirred for 5 min. Then TBAI (31 mg, 85 pmol) was added followed by addition of l-(chloromethyl)-4-methoxybenzene (340 pL,2.51 mmol). After removal of the ice bath the mixture was stirred at room temperature for 3 h. The mixture was quenched with sat. aqueous ammonium chloride and diluted with water. Extraction was performed with ethyl acetate (3 times) and the combined organic phases were concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc to afford the desired product.

[0342] Preparation of 5-((4-methoxybenzyl)oxy)-4-((((ls,4s)-4- phenylcyclohexyl)oxy)methyl)pentane-l,2,4-triol

[0343] A solution of l-((4-methoxybenzyl)oxy)-2-((((ls,4s)-4-phenylcyclohexyl)oxy)methyl)pent-4- en-2-ol (630 mg, 1.5 mmol) in acetone (2.0 mL) and water (2.0 mL) was treated with 4- methylmorpholine N-oxide (360 mg, 3.1 mmol) and a tert-butanol solution of osmium tetroxide (32 pL, 2.5% Wt, 15 pmol) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with waterand extracted with ethyl acetate (3 times). The combined organic phases were concentrated and the residue was purified by silica gel column chromatography, eluted with PE / EtOAc to afford the desired product.

[0344] Preparation 5-(((4-methoxybenzyl)oxy)methyl)-5-((((ls,4s)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3-ol

[0345] 5-((4-methoxybenzyl)oxy)-4-((((ls,4s)-4-phenylcyclohexyl)oxy)methyl)pentane-l,2,4-triol (762 mg, 1.71 mmol) was dissolved in pyridine (2.77 mL, 34.3 mmol) and then Ts-CI (359 mg, 1.1 Eq, 1.89 mmol) was added at 0 °C and the mixture stirred at room temperature for 48h. The reaction mixture was quenched with 2M aq. HCI and extracted with ethyl acetate (3 times). The combined organic phases were concentrated and the residue was purified by silica gel column chromatography, eluted with PE / EtOAc to afford the desired product.

[0346] Preparation of tert-butyl (5-(((4-methoxybenzyl)oxy)methyl)-5-((((ls,4s)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3-yl)(methylsulfonyl)carbamate

[0347] 5-(((4-Methoxybenzyl)oxy)methyl)-5-((((ls,4s)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3-ol (1.0 g, 2.3 mmol), tert-butyl (methylsulfonyl)carbamate (500 mg, 2.6 mmol) and triphenylphosphine (920 mg, 3.5 mmol) was added to a round-bottom flask, equipped with a stirring bar, capped and put under argon atmosphere. Anhydrous THF (25 mL) was added to the reaction mixture, followed by addition of DIAD (710 mg, 3.5 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel column chromatography, eluted with PE / EtOAc to afford the desired product as a mixture of diastereomers.

[0348] Preparation of ()-N-((rel-3R,5S)-5-(hydroxymethyl)-5-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3-yl)methanesulfonamide and (+)-N-((rel- 3R,5S)-5-(hydroxymethyl)-5-((((ls,4R)-4-phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3- yl)methanesulfonamide

[0349] Tert-butyl (5-(((4-methoxybenzyl)oxy)methyl)-5-((((ls,4s)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3-yl)(methylsulfonyl)carbamate (1.1 g, 1.8 mmol) was dissolved in 1,4-dioxane solution of 4M HCI (16 mL, 64 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel column chromatography, eluted with PE / EtOAc to afford the desired product as a racemic mixture. The enantiomers were separated by SFC to afford the desired product with [a]20D = -14 (c = 0.6, CHCI3) and [a]20D = 13 (c = 0.9, CHCI3), respectively.

[0350] Preparation of (rel-2R,4R)-4-(methylsulfonamido)-2-((((ls,4S)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-2-carboxylic acid (enantiomer 1)

[0351] To a solution of (-)-N-((rel-3R,5S)-5-(hydroxymethyl)-5-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3-yl)methanesulfonamide or (+)-N-((rel- 3R,5S)-5-(hydroxymethyl)-5-((((ls,4R)-4-phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3- yl)methanesulfonamide (100 mg, 0.26 mmol) in dry DMF (2.0 mL) was added PDC (392 mg, 1.04 mmol) and powdered molecular sieves (100 mg). The reaction mixture was stirred at room temperature for 20 hours. A 10% solution of citric acid was added to the reaction mixture and the mixture was further stirred for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc to afford the desired product.

[0352] (rel-2R,4R)-4-(methylsulfonamido)-2-((((ls,4S)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-2-carboxylic acid (enantiomer 2) was prepared in a similar way from (-)-N-((rel-3R,5S)-5-(hydroxymethyl)-5-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3-yl)methanesulfonamide or (+)-N-((rel- 3R,5S)-5-(hydroxymethyl)-5-((((ls,4R)-4-phenylcyclohexyl)oxy)methyl)tetrahydrofuran-3- yl)methanesulfonamide Preparation of tert-butyl (((lS,3S)-3-(methylsulfonamido)-l-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carbonyl)oxy)carbamate

[0353] A mixture of (lS,3S)-3-(methylsulfonamido)-l-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylic acid (600 mg, 1.52 mmol), tertbutyl / V-hydroxycarbamate (303 mg, 2.28 mmol), 2-hydroxy-4H-pyrido[l,2-a]pyrimidin-4- one (369 mg, 2.28 mmol), EDCI (436 mg, 2.28 mmol) and DIEA (980 mg, 7.59 mmol) in MeCN (6 mL) was stirred for 1 hour at 50 °C. The mixture was allowed to cool to 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 (0.1% FA), 10% to 90% gradient in 15 min; detector, UV 220 nm.

[0354] Preparation of / V-((lS,3S)-3-amino-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide

[0355] A mixture of tert-butyl (((lS,3S)-3-(methylsulfonamido)-l-(((cis-4- phenylcyclohexyl)oxy)methyl) cyclopentane-l-carbonyl)oxy)carbamate (600 mg, 1.18 mmol) and CS2CO3 (750 mg, 2.30 mmol) in MeCN (15 mL) was stirred for 5 hours at 100 °C. The mixture was allowed to cool to 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 (0.1% FA), 10% to 90 gradient in 15 min; detector, UV 220m.

[0356] Preparation of (lS,2R,4R,5R)-2-(3-chloro-2,4-difluorobenzyl)-4-

[0357] (methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylic acid (General method-09)

[0358] A solution of methyl (lR,2R,4R,5S)-2-[(3-chloro-2,4-difluorophenyl)methyl]-4-methane- sulfonamidobicyclo[3.1.0]hexane-2-carboxylate (800 mg, 2.03 mmol) and LiOHmonohydrate (852 mg, 20.3 mmol) in MeOH (8 mL) and THF (8 mL) and H2O (8 mL) was stirred overnight at 70 °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.

[0359] Preparation of (lS,2R,4R,5R)-2-(3-chloro-2,4-difluorobenzyl)-4-

[0360] (methylsulfonamido)bicyclo[3.1.0]hexane-2-carbonyl azide (General method-09)

[0361] To a stirred solution of (lS,2R,4R,5R)-2-[(3-chloro-2,4-difluorophenyl)methyl]-4- methanesulfonamidobicyclo[3.1.0]hexane-2-carboxylic acid (1.43 g, 3.76 mmol) and TEA (1.91 g, 18.8 mmol) in DCM (15 mL) was added DPPA (5.18 g, 18.8 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The mixture was extracted with CH2CI2 (3 x 30 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 crude product was used in the next step without further purification.

[0362] Preparation of N-((lR,2R,4R,5S)-4-amino-4-(3-chloro-2,4- difluorobenzyl)bicyclo[3.1.0]hexan-2-yl)methanesulfonamide (General method-09, INT-8)

[0363] A solution of (lS,2R,4R,5R)-2-[(3-chloro-2,4-difluorophenyl)methyl]-4- methanesulfonamidobicyclo[3.1.0]hexane-2-carbonyl azide (4.5 g, 11.1 mmol) in dioxane (45 mL) was stirred for 1 hour at 80 °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.

[0364] Preparation of methyl ((lS,2R,4R,5R)-2-(3-chloro-2,4-difluorobenzyl)-4-

[0365] (methylsulfonamido)bicyclo[3.1.0]hexan-2-yl)carbamate (General method-10, INT-9)

[0366] To a stirred solution of N-[(lR,2R,4R,5S)-4-amino-4-[(3-chloro-2,4- difluorophenyl)methyl]bicyclo[3.1.0]hexan-2-yl]methanesulfonamide (4.1 g, 11.68 mmol) and TEA (3.55 g, 35.1 mmol) in DCM (40 mL) was added dimethyl dicarbonate (7.84 g, 58.4 mmol) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0 °C. The resulting mixture was extracted with CH2CI2 (3 x 40 mL). The combined organic layers were washed with brine (1 x 60 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 (10 mmol / L NH4HCO3), 20% to 70% gradient in 10 min; detector, UV 220 nm.

[0367] Preparation of (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-(N-(4- methoxybenzyl)methylsulfonamido)cyclo pentane-l-carboxylic acid (General method-07)

[0368] A solution of methyl (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-(N-(4- methoxybenzyl)methylsulfon amido)cyclopentane-l-carboxylate (4 g, 7.57 mmol) and NaOH (605 mg, 15.1 mmol) in MeOH (21 mL) and H2O (7 mL) was stirred for 2 hours at 70 °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.

[0369] Preparation of (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-(N-(4- methoxybenzyl)methylsulfonamido)cyclo pentane-l-carbonyl azide (General method-07)

[0370] A solution of (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonami do)cyclo pentane-l-carboxylic acid (3.8 g, 7.38 mmol) in DCM (50 mL) was treated with TEA (3.08 mL, 22.1 mmol) for 5 minutes at 0 °C followed by the addition of DPPA (6.10 g, 22.1 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 hours 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), 70% to 90% gradient in 10 minutes; detector, UV 254 nm.

[0371] Preparation of N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-isocyanatocyclopentyl)-N-(4- methoxybenzyl)methanesulfonamide (General method-07)

[0372] A solution of (lR,3S)-l-(3-bromo-2-fluorobenzyl)-3-(N-(4- methoxybenzyl)methylsulfonamido)cyclo pentane-l-carbonyl azide (l g, 1.85 mmol) in 1,4- dioxane (10 mL) was stirred for 2 hours at 100 °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.

[0373] Preparation of N-((lS,3R)-3-amino-3-(3-bromo-2-fluorobenzyl)cyclopentyl)-N-(4- methoxybenzyl)methanesulfonamide (General method-07, INT-4)

[0374] A solution of N-((lS,3R)-3-(3-bromo-2-fluorobenzyl)-3-isocyanatocyclopentyl)-N-(4- methoxybenzyl)methanesulfonamide (900 mg, 1.76 mmol), t-BuOH (195 mg, 2.64 mmol) and cone. HCI (aq.) (32.0 mg, 0.88 mmol) in DCM (8 mL) was stirred for 2 hours 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, silica gel; mobile phase, DCM in PE, 40% to 60% gradient in 10 min; detector, UV 220 nm.

[0375] Preparation of / V-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3-yl)methyl)cyclopentyl)- / V- (4-methoxybenzyl)methanesulfonamide (General method-07)

[0376] A mixture of / V-[(lS,3R)-3-amino-3-[(3-bromo-2-fluorophenyl)methyl]cyclopentyl]- / \ / -[(4- methoxyphenyl)methyl]methanesulfonamide (1 g, 2.06 mmol) and phenyl boronic acid (502 mg, 4.12 mmol), CS2CO3 (1.34 g, 4.12 mmol), and Pd(dppf)Cl2 (151 mg, 0.206 mmol) in 1,4- dioxane (40 mL) and H2O (10 mL) was stirred overnight at 80 °C under argon atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 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 PE / EtOAc (6:1) to afford desired product.

[0377] Preparation of / V-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide (General method-07, INT-6)

[0378] A mixture of / V-[(lS,3R)-3-amino-3-({2-fluoro-[l,l'-biphenyl]-3-yl}methyl)cyclopentyl]- / \ / -[(4- methoxyphenyl)methyl]methanesulfonamide (667 mg, 1.382 mmol) and DCE (26.68 mL) was stirred for 5 minutes at 0 °C. To the above mixture was added TFA (13.34 mL) at 0 °C. The resulting mixture was stirred for additional 2 hours at 60°C. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification.

[0379] The following intermediate was prepared in a similar manner: N-((lS,3R)-3-amino-3-((2,3',6-trifluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide, prepared from tert-butyl ((lR,3S)-l-(3-chloro- 2,4-difluorobenzyl)-3-(methylsulfonamido)cyclopentyl)carbamate and (3- fluorophenyl)boronic acid

[0380] Preparation of (lR,3S)-l-(3-chloro-2,4-difluorobenzyl)-3- (methylsulfonamido)cyclopentane-l-carboxylic acid (General method-08)

[0381] A solution of methyl (lR,3S)-l-[(3-chloro-2,4-difluorophenyl)methyl]-3- methanesulfonamidocyclo pentane-l-carboxylate (1.35 g, 3.54 mmol) and LiOHmonohydrate (1.48 g, 35.4 mmol) in THF (5 mL), MeOH (5 mL) and H2O (5 mL) was stirred for 1 hour at 70°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.

[0382] Preparation of (lR,3S)-l-[(3-chloro-2,4-difluorophenyl)methyl]-3- methanesulfonamidocyclopentane-l-carbonyl azide (General method-08)

[0383] To a stirred solution of (lR,3S)-l-[(3-chloro-2,4-difluorophenyl)methyl]-3- methanesulfonamidocy clopentane-l-carboxylic acid (2.9 g, 7.89 mmol) and TEA (3.29 mL, 23.7 mmol) in DCM (30 mL) and DMF (10 mL) was added DPPA (6.51 g, 237 mmol) dropwise at 0°C. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 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. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford the desired product.

[0384] Preparation of / V-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(3,3- dimethylureido)cyclopentyl)methane-sulfonamide (General method-08, INT-7)

[0385] A solution of (lR,3S)-l-[(3-chloro-2,4-difluorophenyl)methyl]-3- methanesulfonamidocyclopentane-l-carbonyl azide (1.2 g, 3.06 mmol) in dioxane (10 mL) was stirred for 2 hours at 80°C. The resulting mixture was concentrated under reduced pressure. The crude product (N-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3- isocyanatocyclopentyl)methanesulfonamide) was used in the next step directly without further purification. A mixture of / V-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3- isocyanatocyclopentyl)methanesulfonamide (500 mg, 1.37 mmol) in dimethylamine (2 M in THF) (5 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. 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 95% gradient in 25 minutes; detector, UV 254 nm to afford the desired product.

[0386] The following intermediates were prepared in a similar manner: methyl ((lr,4r)-l-(3-chloro-2,4-difluorobenzyl)-4-(methylsulfonamido)cyclohexyl)carbamate, prepared from methyl (lr,4r)-4-(N-(tert-butoxycarbonyl)-(methylsulfonamido))-l-(3-chloro- 2,4-difluorobenzyl)cyclohexane-l-carboxylate and methanol rac-methyl ((lR,2S,4S)-l-(3-bromo-4-fluorobenzyl)-2-methyl-4-

[0387] (methylsulfonamido)cyclopentyl)carbamate, prepared from rac-(lR,2S,4S)-l-(3-bromo-4- fluorobenzyl)-2-methyl-4-(methylsulfonamido)cyclopentane-l-carboxylic acid and methanol COMPOUNDS OF THE INVENTION

[0388] Example 1: N-cyclopropyl-l-trans-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4-

[0389] (methanesulfonamido)cyclohexanecarboxamide

[0390] Preparation of (lr,4r)-4-(methylsulfonamido)-l-((3',5',6-trifluoro-[l,T-biphenyl]-3- yl)methyl) cyclohexane-l-carboxylic acid (General method-11).

[0391] A mixture of methyl (lr,4r)-4-(methylsulfonamido)-l-((3',5',6-trifluoro-[l,l'-biphenyl]-3- yl)methyl)cyclohexane-l-carboxylate (720 mg, 1.58 mmol) and NaOH (632 mg, 15.8 mmol) in MeOH (10 mL) and H2O (3 mL) was stirred for 16 hours at 80 °C. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0392] Preparation of (lr,4r)-N-cyclopropyl-4-(methylsulfonamido)-l-((3,,5,,6-trifluoro-[l,l>- biphenyl]-3-yl)methyl)cyclohexane-l-carboxamide (General method-11).

[0393] To a stirred mixture of (lr,4r)-4-(methylsulfonamido)-l-((3',5',6-trifluoro-[l,l'-biphenyl]-3- yl)methyl)cyclohexane-l-carboxylic acid (80 mg, 0.181 mmol), HATU (139 mg, 0.362 mmol), HOAt (24.7 mg, 0.181 mmol) and aminocyclopropane (21 mg, 0.36 mmol) in DMF (5 mL) was added TEA (92 mg, 0.91 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine (2x20 mL) and dried over anhydrous Na2SC>4. 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 C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 50% B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 9.46)

[0394] XH NMR (300 MHz, Chloroform-d) 6 7.17 - 7.03 (m, 5H), 6.88 - 6.80 (m, 1H), 5.39 - 5.32 (m, 1H), 4.38 - 4.30 (m, 1H), 3.56 - 3.44 (m, 1H), 3.02 (s, 3H), 2.93 - 2.88 (m, 2H), 2.97- 2.60 (m, 1H), 1.97 - 1.83 (m, 2H), 1.80 - 1.66 (m, 6H), 0.77 - 0.68 (m, 2H), 0.32 - 0.24 (m, 2H). LC-MS (Method A) (m / z) = 481.6 (MH)+tR= 0.75 minutes. [a]20D-10(c=0.1 g / 100 mL, MeOH).

[0395] The following compounds were prepared in a similar manner:

[0396] Example 2: N-[(lS,3R,4S)-3-(azetidine-l-carbonyl)-4-methyl-3-[(3- phenylphenyl)methyl]cyclopentyl]methanesulfonamide or N-[(lR,3S,4R)-3-(azetidine-l- carbonyl)-4-methyl-3-[(3-phenylphenyl)methyl]cyclopentyl] methanesulfonamide

[0397] Prepared as Example 1 from rac-ethyl (lR,2S,4S)-l-([l,l'-biphenyl]-3-ylmethyl)-2-methyl-4- (methylsulfonamido)cyclopentane-l-carboxylate and azetidine followed by separation of the two enantiomers by standard procedures using chiral SFC.TH NMR (600 MHz, DMSO) 6 7.67 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.36 (dd, J = 12.9, 7.2 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 4.10 (q, J = 7.8 Hz, 1H), 3.95 (ddt, J = 13.6, 8.7, 4.5 Hz, 1H), 3.73 (dq, J = 41.6, 8.7 Hz, 2H), 3.04 (d, J = 13.4 Hz, 1H), 2.93 - 2.84 (m, 5H), 2.36 (dd, J = 14.4, 10.1 Hz, 1H), 2.21 (p, J = 7.0 Hz, 1H), 2.08 - 2.01 (m, 1H), 2.01 - 1.94 (m, 1H), 1.90 - 1.79 (m, 2H), 1.57 (dd, J = 14.4, 4.2 Hz, 1H), 0.85 (d, J = 7.0 Hz, 3H). LC-MS (Method A) (m / z) =427.4 (MH)+tR= 0.70 minutes.

[0398] Example 3: N-[(lS,3R,4S)-3-(azetidine-l-carbonyl)-4-methyl-3-[(3- phenylphenyl)methyl]cyclopentyl] methanesulfonamide or N-[(lR,3S,4R)-3-(azetidine-l- carbonyl)-4-methyl-3-[(3-phenylphenyl)methyl]cyclopentyl] methanesulfonamide

[0399] Prepared as Example 1 from rac-ethyl (lR,2S,4S)-l-([l,l'-biphenyl]-3-ylmethyl)-2-methyl-4- (methylsulfonamido)cyclopentane-l-carboxylate and azetidine followed by separation of the two enantiomers by standard procedures using chiral SFC.1H NMR (600 MHz, DMSO) 6 7.69 - 7.65 (m, 2H), 7.55 (dt, J = 7.7, 1.4 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.23 (dt, J = 7.6, 1.4 Hz, 1H), 4.14 - 4.07 (m, 1H), 3.95 (ddt, J = 16.3, 12.5, 6.4 Hz, 1H), 3.80 - 3.66 (m, 2H), 3.43 (d, J = 8.7 Hz, 1H), 3.04 (d, J = 13.4 Hz, 1H), 2.89 (s, 3H), 2.87 (d, J = 13.4 Hz, 1H), 2.40 - 2.33 (m, 1H), 2.21 (p, J = 7.0 Hz, 1H), 2.14 - 2.01 (m, 1H), 1.97 (ddd, J = 12.9, 8.5, 6.7 Hz, 1H), 1.90 - 1.80 (m, 2H), 1.58 (dd, J = 14.4, 4.2 Hz, 1H), 0.85 (d, J = 7.1 Hz, 3H). LC-MS (Method A) (m / z) = 427.4 (MH)+tR= 0.70 minutes.

[0400] Example 4: l-[(lR,3S)-3-(dimethylsulfamoylamino)-l-[(3- phenylphenyl)methyl]cyclopentanecarbonyl]azetidine

[0401] Prepared as Example 1 from methyl (lR,3S)-l-([l,l'-biphenyl]-3-ylmethyl)-3-((N,N- dimethylsulfamoyl)amino)cyclopentane-l-carboxylate and azetidine.TH NMR (600 MHz, DMSO) 5 7.66 - 7.63 (m, 2H), 7.55 - 7.51 (m, 1H), 7.50 - 7.45 (m, 2H), 7.43 - 7.35 (m, 3H), 7.31 (d, J = 7.5 Hz, 1H), 7.16 - 7.12 (m, 1H), 3.96 - 3.85 (m, 2H), 3.80 - 3.73 (m, 2H), 3.50 - 3.45 (m, 1H), 2.98 (d, J = 13.5 Hz, 1H), 2.87 (d, J = 13.5 Hz, 1H), 2.63 (s, 6H), 2.36 (dd, J = 13.3, 8.0 Hz, 1H), 2.00 (p, J = 7.7 Hz, 2H), 1.91 - 1.83 (m, 2H), 1.74 - 1.67 (m, 1H), 1.65 - 1.57 (m, 1H), 1.50 (dd, J = 13.3, 8.1 Hz, 1H). LC-MS (Method A) (m / z) =442.1 (MH)+tR= 0.73 minutes.

[0402] Example 5: N-cis-[4-(azetidine-l-carbonyl)-4-[[3-(3,5-difluorophenyl)-4-fluoro- phenyl]methyl]cyclohexyl] methanesulfonamide

[0403] Prepared as Example 1 from methyl (lr,4r)-l-(3-bromo-4-fluorobenzyl)-4- (methylsulfonamido)cyclohexane-l-carboxylate and azetidine.TH NMR (300 MHz, Chloroform-d) 6 7.23 - 7.18 (m, 1H), 7.17 - 7.05 (m, 4H), 6.90 - 6.81 (m, 1H), 4.41 - 4.30 (m, 1H), 4.02 -3.49 (m, 5H), 3.02 (s, 3H), 2.89 - 2.82 (m, 2H), 2.07- 1.90 (m, 4H), 1.87 - 1.72 (m, 4H), 1.70- 1.67 (m, 1H), 1.66 - 1.63 (m, 1H). LC-MS (Method A) (m / z) =481.6 (MH)+tR= 0.75 minutes. [a]20D -2 ° (c=0.1 g / 100 mL, MeOH).

[0404] Example 6: N-cyclopropyl-l-trans-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3- (methanesulfonamido)cyclobutanecarboxamide

[0405] Prepared as Example l from (lr,3s)-l-(3-bromo-4-fluorobenzyl)-3-

[0406] (methylsulfonamido)cyclobutane-l-carboxylic acid and aminocyclopropane.TH NMR (400

[0407] MHz, DMSO-de) 6 7.85 - 7.73 (m, 1H), 7.38 - 7.05 (m, 7H), 3.54 (q, J = 8.3 Hz, 1H), 3.01 (s,

[0408] 2H), 2.84 (s, 3H), 2.71 - 2.56 (m, 3H), 1.99 - 1.91 (m, 2H), 0.58 - 0.50 (m, 2H), 0.34 - 0.32

[0409] (m, 2H). LC-MS (Method A) (m / z) = 453.4 (MH)+tR= 0.73 minutes. [a]20D-4 ° (c=0.1 g / 100 mL, MeOH).

[0410] Example 7: N-cis-[3-(azetidine-l-carbonyl)-3-[[3-(3,5-difluorophenyl)-4-fluoro- phenyl]methyl]cyclobutyl]methanesulfonamide

[0411] Prepared as Example l from methyl (lR,3S)-3-(N-(tert-butoxycarbonyl) methylsulfonamido)- l-((3',5',6-trifluoro-[l, l'-biphenyl]-3-yl) methyl) cyclobutane-l-carboxylate and azetidine.1H NMR (400 MHz, Chloroform-d) 6 7.23 - 7.00 (m, 5H), 6.89 - 6.80 (m, 1H), 4.55 - 4.49 (m, 1H), 4.09 -3.90 (m, 4H), 3.82 (p, J = 7.9 Hz, 1H), 3.02 (s, 2H), 2.99 - 2.85 (m, 5H), 2.18 (p, J =

[0412] 7.7 Hz, 2H), 2.10 - 1.94 (m, 2H). LC-MS (Method A) (m / z) =453.4 (MH)+tR= 0.73 minutes. [a]20D+6 ° (c=0.1 g / 100 mL, MeOH).

[0413] Example 8: N-[(lS,3S)-3-cis-(azetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0414] Prepared as Example 1 from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and azetidine.TH NMR (600 MHz, DMSO) 6 7.31 - 7.26 (m, 2H), 7.22 - 7.18 (m, 2H), 7.18 - 7.14 (m, 1H), 7.09 (d, J = 7.2 Hz, 1H), 4.46 - 4.22 (m, 2H), 3.84 (bs, 2H), 3.60 - 3.51 (m, 2H), 3.42 - 3.35 (m, 2H), 2.89 (s, 3H), 2.57 - 2.51 (m, 1H), 2.50 - 2.45 (m, 1H), 2.17 - 2.07 (m, 2H), 1.97 - 1.86 (m, 4H), 1.80 - 1.74

[0415] (m, 1H), 1.74 - 1.64 (m, 2H), 1.58 - 1.46 (m, 5H), 1.42 (dd, J = 13.5, 8.2 Hz, 1H). LC-MS (Method A) (m / z) = 435.2 (MH)+tR= 0.73 minutes.

[0416] Example 9: N-[(lS,3S)-3-cis-(3-methoxy-3-methyl-azetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0417] Prepared as Example l from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 3-methoxy-3-methyl- azetidine hydrochloride.TH NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.6 Hz, 2H), 7.21 - 7.14 (m, 3H), 7.13 - 7.08 (m, 1H), 4.37 - 4.00 (m, 2H), 3.85 - 3.51 (m, 4H), 3.45 - 3.35 (m, 2H), 3.10 (s, 3H), 2.89 (s, 3H), 2.57 - 2.45 (m, 2H), 1.97 - 1.85 (m, 4H), 1.81 - 1.62 (m, 3H), 1.57 - 1.47 (m, 5H), 1.47 - 1.39 (m, 1H), 1.35 (s, 3H). LC-MS (Method A) (m / z) =479.2 (MH)+tR= 0.76 minutes.

[0418] Example 10: azetidin-l-yl-[(lS,3S)-3-(methylsulfamoylamino)-l-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanone

[0419] Prepared as Example l from methyl (lS,3S)-3-((N-methylsulfamoyl)amino)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and azetidine.1H NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.5 Hz, 2H), 7.21 - 7.14 (m, 3H), 6.91 (d, J = 7.2 Hz, 1H), 6.63 (q, J = 5.1 Hz, 1H), 4.47 - 4.23 (m, 2H), 3.84 (bs, 2H), 3.57 (s, 1H), 3.44 - 3.35 (m, 3H), 2.58 - 2.51 (m, 1H), 2.48 - 2.40 (m, 4H), 2.16 - 2.07 (m, 2H), 1.97 - 1.92 (m, 2H), 1.92 - 1.84 (m, 2H), 1.77 - 1.64 (m, 3H), 1.58 - 1.46 (m, 5H), 1.42 (dd, J = 13.6, 8.2 Hz, 1H). LC-MS (Method A) (m / z) = 450.2 (MH)+tR = 0.74 minutes.

[0420] Example 11: l-[(lS,3S)-3-(dimethylsulfamoylamino)-l-[(4- phenylcyclohexoxy)methyl]cyclopentanecarbonyl]azetidine

[0421] Prepared as Example 1 from methyl (lS,3S)-3-((N,N-dimethylsulfamoyl)amino)-l-((((ls,4R)- 4-phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and azetidine.1H NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.6 Hz, 2H), 7.22 - 7.14 (m, 4H) 4.43 - 4.24 (m, 2H), 3.84 (bs, 2H), 3.57 (s, 1H), 3.51 - 3.43 (m, 1H), 3.42 - 3.35 (m, 2H), 2.66 - 2.62 (m, 6H), 2.58 - 2.51 (m, 1H),

[0422] 2.45 (dd, J = 13.5, 7.9 Hz, 1H), 2.16 - 2.06 (m, 2H), 1.97 - 1.91 (m, 2H), 1.90 - 1.82 (m, 2H), 1.78 - 1.64 (m, 3H), 1.58 - 1.46 (m, 5H), 1.43 (dd, J = 13.5, 8.3 Hz, 1H). LC-MS (Method A) (m / z) =464.2 (MH)+tR = 0.79 minutes.

[0423] Example 12: (lS,3S)-3-(methanesulfonamido)-N,N-dimethyl-l-[(4- phenylcyclohexoxy)methyl]cyclopentanecarboxamide

[0424] Prepared as Example 1 from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and dimethylammonium chloride.

[0425] TH NMR (600 MHz, DMSO) 5 7.31 - 7.25 (m, 2H), 7.21 - 7.13 (m,3H), 7.10 (d, J = 7.2 Hz, 1H), 3.55 (bs, 1H), 3.51 - 3.45 (m, 3H), 3.00 - 2.82 (m, 9H), 2.65 (dd, J = 13.2, 7.7 Hz, 1H), 2.56 -

[0426] 2.51 (m, 1H), 2.05 - 1.97 (m, 1H), 1.94 - 1.83 (m, 4H), 1.69 - 1.59 (m, 2H), 1.59 - 1.42 (m, 6H).

[0427] LC-MS (Method A) (m / z) = 423.2 (MH)+tR= 0.75 minutes.

[0428] Example 13: N-[(lS,3S)-3-cis-(3-hydroxyazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0429] Prepared as Example l from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and azetidin-3-ol hydrochloride.XH NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.7 Hz, 2H), 7.23 - 7.14 (m, 2H), 7.13 - 7.07 (m, 1H), 5.65 (bs, 1H), 4.62 - 4.32 (m, 2H), 4.16 - 3.91 (m, 2H), 3.71 - 3.49 (m, 3H), 3.43 - 3.26 (m,

[0430] 3H), 2.89 (s, 3H), 2.57 - 2.44 (m, 2H), 2.00 - 1.85 (m, 4H), 1.82 - 1.61 (m, 3H), 1.58 - 1.32 (m, 6H). LC-MS (Method A) (m / z) = 451.6 (MH)+tR= 0.63 minutes.

[0431] Example 14: N-[(lS,3S)-3-cis-(3-fluoroazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0432] Prepared as Example l from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 3-fluoroazetidine hydrochloride.TH NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.6 Hz, 2H), 7.24 - 7.14 (m, 3H), 7.13 - 7.05 (m, 1H), 5.44 - 5.21 (m, 1H), 4.81 - 3.77 (m, 3H), 3.62 - 3.52 (m, 2H), 3.46 - 3.35 (m, 2H), 2.89 (s, 3H), 2.57 - 2.41 (m, 3H), 2.02 - 1.60 (m, 7H), 1.58 - 1.38 (m, 6H). LC-MS

[0433] (Method A) (m / z) = 453.6 (MH)+tR= 0.74 minutes.

[0434] Example 15: N-[(lS,3S)-3-cis-(3,3-difluoroazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0435] Prepared as Example 1 from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 3,3-difluoroazetidine.TH NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.6 Hz, 2H), 7.20 - 7.11 (m, 4H), 5.09 - 4.09 (m, 4H), 3.64 - 3.55 (m, 2H), 3.47 - 3.36 (m, 2H), 2.89 (s, 3H), 2.57 - 2.50 (m, 1H), 2.50 - 2.44 (m, 1H), 1.97

[0436] - 1.85 (m, 4H), 1.83 - 1.76 (m, 1H), 1.70 - 1.59 (m, 2H), 1.59 - 1.42 (m, 6H). LC-MS (Method A) (m / z) =471.6 (MH)+tR = 0.78 minutes.

[0437] Example 16: N-[(lS,3S)-3-[3-cis-(difluoromethyl)azetidine-l-carbonyl]-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0438] Prepared as Example l from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 3-(difluoromethyl)azetidine hydrochloride.XH NMR (600 MHz, DMSO) 6 7.31 - 7.25 (m, 2H), 7.21 - 7.13 (m, 3H), 7.11 (d, J = 7.1 Hz, 1H), 6.39 - 6.10 (m, 1H), 4.57 - 4.16 (m, 2H), 3.97 - 3.70 (m, 2H), 3.64 - 3.50 (m, 2H), 3.48 - 3.31 (m, 2H), 3.04 (s, 1H), 2.89 (s, 3H), 2.57 - 2.50 (m, 1H), 2.50 - 2.44 (m, 1H),

[0439] 2.04 - 1.84 (m, 4H), 1.83 - 1.75 (m, 1H), 1.74 - 1.61 (m, 2H), 1.59 - 1.39 (m, 6H). LC-MS (Method A) (m / z) = 485.6 (MH)+tR = 0.76 minutes.

[0440] Example 17: N-[(lS,3S)-3-cis-(3-methoxyazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0441] Prepared as Example 1 from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 3-methoxyazetidine hydrochloride.XH NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.6 Hz, 2H), 7.23 - 7.18 (m, 2H), 7.18 - 7.14 (m, 1H), 7.10 (d, J = 7.1 Hz, 1H), 4.63 - 4.40 (m, 1H), 4.29 - 3.90 (m, 3H), 3.74 - 3.50 (m, 3H), 3.46 - 3.33 (m, 2H), 3.15 (s, 3H), 2.89 (s, 3H), 2.59 - 2.43 (m, 2H), 2.02 - 1.83 (m, 4H), 1.82 - 1.61 (m, 3H), 1.60 - 1.37 (m, 6H). LC-MS (Method A) (m / z) =465.6 (MH)+tR= 0.73 minutes.

[0442] Example 18: N-[(lS,3S)-3-cis-(l-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0443] Prepared as Example 1 from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and l-oxa-6-azaspiro[3.3]heptane oxalic acid salt.TH NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.5 Hz, 2H), 7.22 - 7.18 (m, 2H), 7.18 - 7.14 (m, 1H), 7.09 (d, J = 7.1 Hz, 1H), 4.66 - 4.26 (m, 4H), 4.19 - 3.81 (m, 2H), 3.60 - 3.51 (m, 2H), 3.42 - 3.32 (m, 2H), 2.88 (s, 3H), 2.79 - 2.65 (m, 2H), 2.55 - 2.50 (m, 1H), 2.48 - 2.42 (m, 1H), 1.96 - 1.82 (m, 4H), 1.80 - 1.72 (m, 1H), 1.72 - 1.59 (m, 2H), 1.56 - 1.45 (m, 5H), 1.41 (dd, J = 13.6, 8.1 Hz, 1H). LC-MS (Method A) (m / z) = 477.6 (MH)+tR= 0.72 minutes.

[0444] Example 19: N-[(lS,3S)-3-cis-(5-azaspiro[2.3]hexane-5-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0445] Prepared as Example l from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 5-azaspiro[2.3]hexane hydrochloride.XH NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.5 Hz, 2H), 7.22 - 7.13 (m, 3H), 7.10 (d, J = 7.1 Hz, 1H), 4.54 - 4.28 (m, 2H), 3.97 - 3.81 (m, 2H), 3.63 - 3.53 (m, 2H), 3.44 - 3.37

[0446] (m, 2H), 2.89 (s, 3H), 2.60 - 2.45 (m, 2H), 2.01 - 1.87 (m, 4H), 1.82 - 1.64 (m, 3H), 1.58 - 1.47 (m, 5H), 1.42 (dd, J = 13.6, 8.1 Hz, 1H), 0.59 - 0.45 (m, 4H). LC-MS (Method A) (m / z) = 461.6 (MH)+tR = 0.80 minutes.

[0447] Example 20: N-[(lS,3S)-3-cis-(3-fluoro-3-methyl-azetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0448] Prepared as Example l from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 3-fluoro-3-methyl-azetidine hydrochloride.TH NMR (600 MHz, DMSO) 6 7.28 (t, J = 7.6 Hz, 2H), 7.21 - 7.13 (m, 3H), 7.11 (d, J = 7.1 Hz, 1H), 4.42 (bs, 2H), 4.10 - 3.78 (m, 2H), 3.63 - 3.52 (m, 2H), 3.44 - 3.35 (m, 2H),

[0449] 2.89 (s, 3H), 2.60 - 2.40 (m, 2H), 2.01 - 1.84 (m, 4H), 1.82 - 1.62 (m, 3H), 1.59 - 1.36 (m, 9H). LC-MS (Method A) (m / z) = 467.2 (MH)+tR= 0.78 minutes.

[0450] Example 21: N-[(lS,3S)-3-cis-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0451] Prepared as Example l from methyl (lS,3S)-3-(methylsulfonamido)-l-((((ls,4R)-4- phenylcyclohexyl)oxy)methyl)cyclopentane-l-carboxylate and 2-oxa-6-azaspiro[3.3]heptane oxalic acid salt.TH NMR (600 MHz, DMSO) 6 7.33 - 7.27 (m, 2H), 7.18 (d, J = 7.5 Hz, 3H), 7.09 (d, J = 7.2 Hz, 1H), 4.66 - 4.39 (m, 6H), 4.06 - 3.96 (m, 2H), 3.60 - 3.50 (m, 2H), 3.40 - 3.34 (m, 2H), 2.88 (s, 3H), 2.59 - 2.40 (m, 2H), 1.96 - 1.84 (m, 4H), 1.80 - 1.72 (m, 1H), 1.68 - 1.45 (m, 7H), 1.41 (dd, J = 13.6, 8.1 Hz, 1H). LC-MS (Method A) (m / z) =477.6 (MH)+tR= 0.67 minutes.

[0452] Example 22: N-[(lS,3S)-3-(azetidine-l-carbonyl)-3-[[(3R*,6S*)-6-(5-fluoropyrimidin-2- yl)norcaran-3-yl]oxymethyl]cyclopentyl]methanesulfonamide

[0453] Prepared as Example 1 from N-((lS,3S)-3-(azetidine-l-carbonyl)-3-((((lR*,3R*,6S*)-6-(5- fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)cyclopentyl)methanesulfonamide and azetidine.XH NMR (600 MHz, DMSO-d6) 6 8.74 (s, 2H), 7.06 (d, J = 6.3 Hz, 1H), 4.29 (d, J = 29.0 Hz, 2H), 3.82 (s, 2H), 3.59 - 3.49 (m, 1H), 3.42 (d, J = 9.2 Hz, 1H), 3.37 (d, J = 9.2 Hz, 1H), 3.31 (qd, J = 5.9, 2.8 Hz, 1H), 2.88 (s, 3H), 2.75 (ddd, J = 14.0, 10.6, 5.3 Hz, 1H), 2.43 (dd, J = 13.4, 7.9 Hz, 1H), 2.38 - 2.29 (m, 1H), 2.19 - 2.07 (m, 3H), 1.92 - 1.81 (m, 2H), 1.69 (tdd, J = 16.3, 8.8, 4.2 Hz, 2H), 1.56 (ddd, J = 14.1, 8.5, 1.8 Hz, 2H), 1.52 - 1.41 (m, 1H), 1.38 - 1.29 (m, 3H), 1.03 (dd, J = 6.3, 3.6 Hz, 1H). LC-MS (Method A) (m / z) = 467.4 (MH)+tR= 0.64 minutes.

[0454] Example 23: (lS,3S)-l-[[(lR*,3R*,6S*)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3- (methanesulfonamido)-N-methyl-cyclopentanecarboxamide

[0455] Prepared as Example 1 from N-((lS,3S)-3-(azetidine-l-carbonyl)-3-((((lR*,3R*,6S*)-6-(5- fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)cyclopentyl)methanesulfonamide and methylamine.XH NMR (600 MHz, DMSO-d6) 6 8.73 (s, 2H), 7.44 (q, J = 4.5 Hz, 1H), 7.05 (d, J = 5.7 Hz, 1H), 3.58 (q, J = 6.9 Hz, 1H), 3.45 (d, J = 9.2 Hz, 1H), 3.40 (d, J = 9.1 Hz, 1H), 3.28 (tdd, J = 8.8, 5.9, 2.9 Hz, 1H), 2.88 (s, 3H), 2.73 (ddd, J = 14.1, 10.5, 5.2 Hz, 1H), 2.58 (d, J = 4.4 Hz, 3H), 2.31 (ddd, J = 28.1, 13.8, 7.5 Hz, 2H), 2.08 (dt, J = 14.1, 5.1 Hz, 1H), 1.86 (dddd, J = 20.6, 16.0, 12.4, 7.4 Hz, 2H), 1.65 (dddd, J = 31.1, 12.8, 8.6, 4.6 Hz, 2H), 1.58 - 1.43 (m, 3H), 1.41 - 1.27 (m, 3H), 1.01 (dd, J = 6.3, 3.6 Hz, 1H). LC-MS (Method A) (m / z) =463.4 (MH)+tR = 0.60 minutes.

[0456] Example 24: N-[(lS,3S)-3-(azetidine-l-carbonyl)-3-[[(lR*,3R,6S*)-6-(5-fluoropyrimidin-2- yl)norcaran-3-yl]oxymethyl]cyclopentyl]methanesulfonamide

[0457] Prepared as Example 1 from N-((lS,3S)-3-(azetidine-l-carbonyl)-3-((((lR*,3R*,6S*)-6-(5- fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3- yl)oxy)methyl)cyclopentyl)methanesulfonamideand azetidine.TH NMR (600 MHz, DMSO-de) 6 8.74 (d, J = 0.9 Hz, 2H), 7.06 (d, J = 7.3 Hz, 1H), 4.29 (s, 2H), 3.82 (s, 2H), 3.54 (h, J = 7.8 Hz, 1H), 3.44 (d, J = 9.2 Hz, 1H), 3.34 - 3.26 (m, 2H), 2.88 (s, 3H), 2.75 (ddd, J = 14.0, 10.7, 5.2 Hz, 1H), 2.43 (dd, J = 13.5, 7.9 Hz, 1H), 2.32 (ddd, J = 14.0, 8.5, 6.5 Hz, 1H), 2.15 (td, J = 14.2, 13.0, 6.4 Hz, 3H), 1.92 - 1.78 (m, 2H), 1.75 - 1.63 (m, 2H), 1.60 - 1.53 (m, 3H), 1.52 - 1.41 (m, 1H), 1.36 (td, J = 8.4, 8.0, 4.3 Hz, 2H), 1.03 (dd, J = 6.3, 3.5 Hz, 1H). LC-MS (Method A) (m / z) =467.1 (MH)+tR = 0.61 minutes. Example 25: N-[(lR,2R,4R,5S)-4-(azetidine-l-carbonyl)-4-[(3-phenylphenyl)methyl]-2- bicyclo[3.1.0]hexanyl]methanesulfonamide

[0458] Prepared as Example 1 from methyl (lS,2R,4R,5R)-2-([l,l'-biphenyl]-3-ylmethyl)-4- (methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylate and azetidine.1H NMR (600 MHz, CDCI3) 6 7.63 (d, J = 8.2, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.52 (br s, 1H), 7.47 - 7.41 (m, 3H), 7.39 - 7.33 (m, 1H), 7.28 - 7.24 (m, 1H), 4.28 (d, J = 7.0 Hz, 1H), 3.92 - 3.81 (m, 3H), 3.83 - 3.77 (m, 1H), 3.25 - 3.17 (m, 2H), 3.04 (d, J = 13.0 Hz, 1H), 2.96 (d, J = 0.9 Hz, 3H), 2.12 (dd, J = 15.5, 7.1 Hz, 1H), 2.00 (d, J = 15.5 Hz, 1H), 1.96 - 1.87 (m, 1H), 1.83 - 1.75 (m, 1H), 1.66 (dd, j = 8.4, 4.0 Hz, 2H), 0.67 (td, J = 8.4, 5.8 Hz, 1H), 0.29 - 0.23 (m, 1H). LC-MS (Method A) (m / z) = 425.3 (MH)+tR = 0.68 minutes.

[0459] Example 26: (lS,2R,4R,5R)-N-cyclopropyl-4-(methanesulfonamido)-2-[(3- phenylphenyl)methyl]bicyclo[3.1.0]hexane-2-carboxamide

[0460] Prepared as Example 1 from methyl (lS,2R,4R,5R)-2-([l,l'-biphenyl]-3-ylmethyl)-4- (methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylate and cyclopropylamine.TH NMR (600 MHz, Chloroform-d) 6 7.61 - 7.57 (m, 2H), 7.49 (dd, J = 7.8 Hz, 1H), 7.46 - 7.41 (m, 3H), 7.37 - 7.31 (m, 2H), 7.20 (dd, J = 7.5, 1.6 Hz, 1H), 5.77 (s, 1H), 4.64 (d, J = 6.9 Hz, 1H), 3.93 (dt, J = 7.5, 4.0 Hz, 1H), 3.35 (d, J = 13.0 Hz, 1H), 3.02 (d, J = 13.1 Hz, 1H), 2.92 (s, 3H), 2.62 (tq, J = 7.2, 3.7 Hz, 1H), 2.02 - 1.98 (m, 2H), 1.72 - 1.66 (m, 1H), 1.57 - 1.52 (m, 1H), 0.74 - 0.62 (m, 3H), 0.31 - 0.23 (m, 2H), 0.23 - 0.18 (m, 1H). LC-MS (Method A) (m / z) = 424.9 (MH)+tR= 0.65 minutes.

[0461] Example 27: (lS,2R,4R,5R)-4-(methanesulfonamido)-N-methyl-2-[(3- phenylphenyl)methyl]bicyclo[3.1.0]hexane-2-carboxamide

[0462] Prepared as Example l from methyl (lS,2R,4R,5R)-2-([l,l'-biphenyl]-3-ylmethyl)-4- (methylsulfonamido)bicyclo[3.1.0]hexane-2-carboxylate and methylamine.1H NMR (600 MHz, CDCI3) 6 7.61 - 7.56 (m, 2H), 7.51 (d, J = 7.7 Hz, 1H), 7.47 - 7.32 (m, 5H), 7.19 (d, J = 7.7 Hz, 1H), 5.75 - 5.70 (m, 1H), 4.50 (d, J = 7.3 Hz, 1H), 3.95 (t, J = 7.2 Hz, 1H), 3.37 (d, J = 13.1 Hz, 1H), 3.00 (d, J = 13.1 Hz, 1H), 2.93 (s, 3H), 2.72 (d, J = 4.9, 3H), 2.09 - 1.98 (m, 2H), 1.69 (dt, J = 9.1, 4.7 Hz, 1H), 1.59 (dt, J = 8.0, 4.8 Hz, 1H), 0.74 (td, J = 8.4, 5.7 Hz, 1H), 0.25 (q, j = 4.4 Hz, 1H). LC-MS (Method A) (m / z) = 399.4 (MH)+tR= 0.63 minutes.

[0463] Example 28: N-[(lR,2R,4R,5S)-4-(azetidine-l-carbonyl)-4-[(cis-4-phenylcyclohexoxy)methyl]- 2-bicyclo[3.1.0]hexanyl]methanesulfonamide

[0464] Prepared as Example 1 from methyl (lS,2R,4R,5R)-4-(methylsulfonamido)-2-((((ls,4S)-4- phenylcyclohexyl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate and azetidine.TH NMR (600 MHz, Chloroform-d) 6 7.29 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.1 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 6.17 (d, J = 9.8 Hz, 1H), 4.48 (q, J = 8.2 Hz, 1H), 4.37 (q, J = 8.0 Hz, 1H), 4.03 (h, J = 9.7 Hz, 2H), 3.87 (dd, J = 9.8, 7.4 Hz, 1H), 3.77 (p, J = 3.0 Hz, 1H), 3.70 (d, J = 8.8 Hz, 1H), 3.50 (d, J = 8.8 Hz, 1H), 2.92 (s, 3H), 2.60 (tt, J = 11.2, 4.2 Hz, 1H), 2.34 (dd, J = 15.6, 7.5 Hz, 1H), 2.26 (pd, J = 7.6, 1.3 Hz, 2H), 2.20 - 2.12 (m, 2H), 1.88 (d, J = 15.6 Hz, 1H), 1.85 - 1.63 (m, 6H), 1.62 - 1.53 (m, 2H), 0.70 (td, J = 8.6, 5.8 Hz, 1H), 0.19 (dt, J = 5.8, 4.1 Hz, 1H). LC-MS (Method A) (m / z) = 447.2 (MH)+tR = 0.72 minutes.

[0465] Example 29: (lS,2R,4R,5R)-4-(methanesulfonamido)-2-[(cis-4- phenylcyclohexoxy)methyl]bicyclo[3.1.0]hexane-2-carboxamide

[0466] Prepared as Example 1 from methyl (lS,2R,4R,5R)-4-(methylsulfonamido)-2-((((ls,4S)-4- phenylcyclohexyl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate and ammonium hydrogen carbonate.TH NMR (500 MHz, CDCI3) 6 7.31 - 7.25 (m, 2H), 7.22 - 7.16 (m, 3H), 6.34 (br s, 1H), 6.08 (d, J = 9.1 Hz, 1H), 5.65 (br s, 1H), 3.94 (dd, J = 9.1, 7.3 Hz, 1H), 3.80 - 3.76 (m, 1H), 3.73 - 3.64 (m, 2H), 2.93 (s, 3H), 2.64 - 2.54 (m, 1H), 2.26 (dd, J = 15.5, 7.4 Hz, 1H), 2.20 - 2.10 (m, 2H), 1.88 (d, J = 15.5 Hz, 1H), 1.85 - 1.53 (m, 8H), 0.77 (td, J = 8.3, 5.8 Hz, 1H), 0.34 (dt, J = 5.8, 4.1 Hz, 1H). LC-MS (Method A) (m / z) = 407.1 (MH)+tR= 0.64 minutes.

[0467] Example 30: (lS,2R,4R,5R)-4-(methanesulfonamido)-N-methyl-2-[(cis-4- phenylcyclohexoxy)methyl]bicyclo[3.1.0]hexane-2-carboxamide

[0468] Prepared as Example l from methyl (lS,2R,4R,5R)-4-(methylsulfonamido)-2-((((ls,4S)-4- phenylcyclohexyl)oxy)methyl)bicyclo[3.1.0]hexane-2-carboxylate and methylamine.TH NMR (600 MHz, DMSO) 6 7.39 - 7.35 (m, 1H), 7.14 (t, J = 7.6 Hz, 2H), 7.09 - 7.05 (m, 2H), 7.02 (t, J = 7.1, 1H), 6.87 (d, J = 5.4 Hz, 1H), 3.62 - 3.57 (m, 1H), 3.50 (d, J = 8.7 Hz, 1H), 3.47 - 3.42 (m, 2H), 2.78 (s, 3H), 2.47 (d, J = 4.6 Hz, 3H), 1.86 - 1.74 (m, 3H), 1.64 - 1.52 (m, 4H), 1.42 - 1.30 (m, 6H), 0.44 (td, J = 8.4, 5.4 Hz, 1H), 0.01 - -0.02 (m, 1H). LC-MS (Method A) (m / z) =421.1 (MH)+tR = 0.68 minutes.

[0469] Example 31: N-[rac-(3R,5R)-5-(azetidine-l-carbonyl)-5-[(cis-4- phenylcyclohexoxy)methyl]tetrahydrofuran-3-yl] methanesulfonamide

[0470] Prepared as Example l from rel-2R,4R)-4-(methylsulfonamido)-2-((((ls,4S)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-2-carboxylic acid and azetidine.1H NMR (600 MHz, DMSO) 6 7.32 - 7.25 (m, 3H), 7.24 - 7.19 (m, 2H), 7.19 - 7.13 (m, 1H), 4.60 - 4.52 (m, 1H), 4.29 - 4.20 (m, 1H), 3.93 - 3.79 (m, 4H), 3.69 (dd, J = 8.7, 5.1 Hz, 1H), 3.64 - 3.57 (m, 2H), 3.46 (d, J = 9.8 Hz, 1H), 2.93 (s, 3H), 2.60 - 2.51 (m, 2H), 2.23 - 2.13 (m, 1H), 2.09 - 2.00 (m, 1H), 1.97 - 1.89(m, 6.6, 2H), 1.79 - 1.62 (m, 3H), 1.61 - 1.42 (m, 4H). LC-MS (Method A) (m / z) =437.1 (MH)+tR = 0.71 minutes.

[0471] Example 32: (2S,4S)-4-(methanesulfonamido)-N-methyl-2-[(cis-4- phenylcyclohexoxy)methyl]tetrahydrofuran-2-carboxamide or (2R,4R)-4- (methanesulfonamido)-N-methyl-2-[(4-phenylcyclohexoxy)methyl]tetrahydrofuran-2- carboxamide

[0472] Prepared as Example l from rel-2R,4R)-4-(methylsulfonamido)-2-((((ls,4S)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-2-carboxylic acid (enantiomer 1) and methylamine followed by separation of the two enantiomers by standard procedures using chiral SFC.TH NMR (500 MHz, CDCI3) 6 7.33 - 7.26 (m, 2H), 7.25 - 7.21 (m, 2H), 7.20 - 7.15 (m, 1H), 6.92 - 6.84 (m, 1H), 6.36 (d, J = 9.6 Hz, 1H), 4.15 (ddd, J = 9.4, 1.9, 1.1 Hz, 1H), 4.09 - 4.02 (m, 1H), 3.82 - 3.73 (m, 2H), 3.51 (d, J = 10.1 Hz, 1H), 2.91 (s, 3H), 2.83 (d, J = 5.0 Hz, 3H), 2.63 - 2.50 (m, 2H), 2.32 (dt, J = 14.3, 1.6 Hz, 1H), 2.16 - 2.06 (m, 2H), 1.84 - 1.71 (m, 4H), 1.67 - 1.55 (m, 3H). LC-MS (Method A) (m / z) =411.1 (MH)+tR= 0.65 minutes. [a]20D- 14.6 ° (c=1.0 g / 100 mL, CHCI3).

[0473] Example 33: (2S,4S)-4-(methanesulfonamido)-N-methyl-2-[(cis-4- phenylcyclohexoxy)methyl]tetrahydrofuran-2-carboxamide or (2R,4R)-4- (methanesulfonamido)-N-methyl-2-[(4-phenylcyclohexoxy)methyl]tetrahydrofuran-2- carboxamide

[0474] Prepared as Example l from rel-2R,4R)-4-(methylsulfonamido)-2-((((ls,4S)-4- phenylcyclohexyl)oxy)methyl)tetrahydrofuran-2-carboxylic acid (enantiomer 2) and methylamine followed by separation of the two enantiomers by standard procedures using chiral SFC.XH NMR (500 MHz, CDCI3) 6 7.33 - 7.26 (m, 2H), 7.25 - 7.21 (m, 2H), 7.20 - 7.15 (m, 1H), 6.92 - 6.84 (m, 1H), 6.36 (d, J = 9.6 Hz, 1H), 4.15 (ddd, J = 9.4, 1.9, 1.1 Hz, 1H), 4.09 - 4.02 (m, 1H), 3.82 - 3.73 (m, 2H), 3.51 (d, J = 10.1 Hz, 1H), 2.91 (s, 3H), 2.83 (d, J = 5.0 Hz, 3H), 2.63 - 2.50 (m, 2H), 2.32 (dt, J = 14.3, 1.6 Hz, 1H), 2.16 - 2.06 (m, 2H), 1.84 - 1.71 (m, 4H), 1.67 - 1.55 (m, 3H). LC-MS (Method A) (m / z) =411.1 (MH)+tR= 0.65 minutes. [a]20D+13 ° (c=0.9 g / 100 mL, CHCI3).

[0475] Example 34: N-[(lS,3S)-3-(methanesulfonamido)-l-[(cis-4- phenylcyclohexoxy)methyl]cyclopentyl]acetamide

[0476] Preparation of / V-((lS,3S)-3-(methylsulfonamido)-l-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl) acetamide (General method-12)

[0477]

[0478] A mixture of / V-((lS,3S)-3-amino-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)methane sulfonamide (50 mg, 0.14 mmol), HATU (77 mg, 0.20 mmol), DIPEA (88 mg, 0.68 mmol) and acetic acid (10 mg, 0.16 mmol) in MeCN (1.5 mL) was stirred for 2 hours at room temperature. 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 (0.1% FA), 30% to 60% gradient in 30 min; detector, UV 220 nm.

[0479] XH NMR (300 MHz, Methanol-d4) 67.29 - 7.19 (m, 4H), 7.18 - 7.09 (m, 1H), 3.95 - 3.87(m, 1H), 3.65 - 3.62 (m, 3H), 2.96 (s, 3H), 2.64 - 2.42 (m, 2H), 2.21 - 1.96 (m, 5H), 1.93 (s, 3H),

[0480] 1.89 - 1.76 (m, 3H), 1.73 - 1.53 (m, 5H). LC-MS (Method A) (m / z) = 431.4 (MH)+tR= 0.72 minutes. [a]20D -6 ° (c=0.1 g / 100 mL, MeOH).

[0481] The following compounds were prepared in a similar manner:

[0482] Example 35: N-[(lS,3S)-3-(methanesulfonamido)-l-[(cis-4- phenylcyclohexoxy)methyl]cyclopentyl]propanamide

[0483] Prepared as Example 34 from N-((lS,3S)-3-amino-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)methane sulfonamide and propanoic acid.TH NMR (300 MHz, Methanol-d4) 6 7.30 - 7.20 (m, 5H), 3.97 - 9.93 (m, 1H), 3.69 - 3.56 (m, 3H), 2.96 (s, 3H), 2.64 - 2.42 (m, 2H), 2.24 - 1.99 (m, 7H), 1.97- 1.76 (m, 3H), 1.73 - 1.51 (m, 5H), 1.58 (s, 1H), 1.14 - 1.09 (m, 3H). LC-MS (Method A) (m / z) =445.4 (MH)+tR= 0.76 minutes. [a]20D-4 ° (c=0.1 g / 100 mL, MeOH).

[0484] Example 36: N-[(lS,3S)-3-(methanesulfonamido)-l-[(cis-4- phenylcyclohexoxy)methyl]cyclopentyl]cyclopropanecarboxamide

[0485] Prepared as Example 34 from N-((lS,3S)-3-amino-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)methane sulfonamide and cyclopropanecarboxylic acid.XH NMR (300 MHz, Methanol-d4) 6 7.3 - 7.19 (m, 4H), 7.18 - 7.08 (m, 1H), 4.02 - 3.89 (m, 1H), 3.67 -3.57 (m, 3H), 2.96 (s, 3H), 2.62 - 2.45 (m, 2H), 2.23 - 2.01 (m, 5H), 1.91 - 1.75 (m, 3H), 1.70 - 1.54 (m, 6H), 0.87 - 0.75 (m, 2H), 0.74 - 0.65 (m, 2H). LC-MS (Method A) (m / z) =457.5 (MH)+tR= 0.79 minutes. [a]20D-3 ° (c=0.1 g / 100 mL, MeOH).

[0486] Example 37: N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3- (methanesulfonamido)cyclopentyl]-2-hydroxy-2-methyl-propanamide

[0487] Prepared as Example 34 from N-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and 2-hydroxy-2-methylpropanoic acid.TH NMR (400 MHz, Chloroform-d) 6 7.54 - 7.50 (m, 2H), 7.48 - 7.43 (m, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.18 - 7.07 (m, 2H), 6.52 (s, 1H), 4.19 (d, J = 7.8 Hz, 1H), 4.01 (q, J = 7.8 Hz, 1H), 3.33 - 3.23 (m, 2H), 2.96 (d, J = 0.8 Hz, 3H), 2.64 (dd, J = 13.8, 7.5 Hz, 1H), 2.26 (dq, J = 14.6, 7.6 Hz, 1H), 2.06 - 1.99 (m, 2H), 1.77 - 1.47 (m, 3H), 1.44 (s, 6H). LC-MS (Method A) (m / z) =449.4 (MH)+tR= 0.69 minutes. [a]20D+13 ° (c=0.1 g / 100 mL, MeOH).

[0488] Example 38: (2R)-N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0489] (methanesulfonamido)cyclopentyl]oxetane-2-carboxamide

[0490] Prepared as Example 34 from N-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and (2R)-oxetane-2-carboxylic acid.1H NMR (400 MHz, Chloroform-d) 6 7.52 (dt, J = 8.1, 1.6 Hz, 2H), 7.47 - 7.41 (m, 2H), 7.40 - 7.30 (m, 2H), 7.18 - 7.09 (m, 2H), 6.63 (s, 1H), 4.94 (dd, J = 9.2, 6.5 Hz, 1H), 4.65 (dt, J = 8.7, 6.6 Hz, 1H), 4.40 (dt, J = 9.0, 6.4 Hz, 1H), 4.32 (d, J = 7.8 Hz, 1H), 4.04 (h, J = 7.8 Hz, 1H), 3.39 (dd, J = 13.7, 1.6 Hz, 1H), 3.23 (dd, J = 13.6, 1.6 Hz, 1H), 3.06 - 2.94 (m, 4H), 2.62 (ddt, J = 11.8, 9.0, 6.6 Hz, 2H), 2.34 - 2.15 (m, 2H), 2.05 (ddd, J = 14.2, 9.4, 6.7 Hz, 1H), 1.79 (dd, J = 13.8, 8.9 Hz, 1H), 1.73 - 1.54 (m, 1H). LC-MS (Method A) (m / z) =447.4 (MH)+tR= 0.69 minutes. [a]20D+67 ° (c=0.1 g / 100 mL, MeOH).

[0491] Example 39: (2S)-N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3- (methanesulfonamido)cyclopentyl]oxetane-2-carboxamide

[0492] Prepared as Example 34 from N-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and (2S)-oxetane-2-carboxylic acid.TH NMR (400 MHz, Chloroform-d) 6 7.52 (dt, J = 8.1, 1.6 Hz, 2H), 7.47 - 7.41 (m, 2H), 7.40 - 7.30 (m, 2H), 7.18 - 7.09 (m, 2H), 6.63 (s, 1H), 4.94 (dd, J = 9.2, 6.5 Hz, 1H), 4.65 (dt, J = 8.7, 6.6 Hz, 1H), 4.40 (dt, J = 9.0, 6.4 Hz, 1H), 4.32 (d, J = 7.8 Hz, 1H), 4.04 (h, J = 7.8 Hz, 1H), 3.39 (dd, J = 13.7, 1.6 Hz, 1H), 3.23 (dd, J = 13.6, 1.6 Hz, 1H), 3.06 - 2.94 (m, 4H), 2.90 - 2.82 (m, 1H), 2.62

[0493] (ddt, J = 11.8, 9.0, 6.6 Hz, 1H), 2.34 - 2.15 (m, 1H), 2.05 (ddd, J = 14.2, 9.4, 6.7 Hz, 1H), 1.79 (dd, J = 13.8, 8.9 Hz, 1H), 1.73 - 1.54 (m, 2H). LC-MS (Method A) (m / z) = 447.4 (MH)+tR= 0.69 minutes. [a]20D-32 ° (c=0.1 g / 100 mL, MeOH).

[0494] Example 40: methyl N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3- (methanesulfonamido)cyclopentyl]carbamate

[0495] Preparation of methyl N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3- (methanesulfonamido)cyclopentyl]carbamate

[0496] To a stirred mixture of N-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide (50 mg, 0.14 mmol) and TEA (56 mg, 0.55 mmol) in DCM (3 mL) was added dimethyl dicarbonate (20 mg, 0.21 mmol) at 0 °C. The resulting mixture was stirred for 0.5 hour at 0 °C. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with DCM (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 (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm..

[0497] XH NMR (400 MHz, Chloroform-d) 6 7.54 - 7.49 (m, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.41 - 7.30 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 4.52 (s, 1H), 4.18 (d, J = 8.1 Hz, 1H), 4.02 (q, J = 7.9 Hz, 1H), 3.69 (s, 3H), 3.27 - 3.16 (m, 2H), 2.95 (s, 3H), 2.63 - 2.54 (m, 1H), 2.28 (dq, J = 15.5, 7.7 Hz, 1H), 1.98 (dd, J = 16.3, 8.1 Hz, 2H), 1.72 - 1.45 (m, 2H). LC-MS (Method A) (m / z) = 443.1 (MH)+tR= 0.73 minutes. [a]20D+4 ° (c=0.1 g / 100 mL, MeOH).

[0498] Example 41: N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0499] (methanesulfonamido)cyclopentyl]acetamide

[0500] Prepared as Example 40 from N-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and acetic anhydride.1H NMR (400 MHz, Chloroform-d) 6 7.54 - 7.49 (m, 2H), 7.48 - 7.42 (m, 2H), 7.41 - 7.35 (m, 1H), 7.32 (td, J = 7 A, 1.9 Hz, 1H), 7.18 - 7.07 (m, 2H), 5.18 (s, 1H), 4.26 (d, J = 7.9 Hz, 1H), 4.00 (h, J = 7.9 Hz, 1H), 3.33 - 3.21 (m, 2H), 2.96 (d, J = 0.8 Hz, 3H), 2.63 - 2.54 (m, 1H), 2.25 (dq, J = 14.5, 7.5 Hz, 1H), 2.07 - 1.94 (m, 2H), 1.93 (s, 3H) 1.75 - 1.46 (m, 2H). LC-MS (Method A) (m / z) = 405.4 (MH)+tR= 0.66 minutes. [a]20D+42 ° (c=0.1 g / 100 mL, MeOH).

[0501] Example 42: N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0502] (methanesulfonamido)cyclopentyl]cyclopropanecarboxamide

[0503] Prepared as Example 40 from N-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and cyclopropanecarbonyl chloride.TH NMR (400 MHz, Chloroform-d) 6 7.55 - 7.49 (m, 2H), 7.49 - 7.42 (m, 2H), 7.41 - 7.30 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.11 - 7.05 (m, 1H), 5.35 (s, 1H), 4.19 (d, J = 7.9 Hz, 1H), 4.04 (h, J = 7.9 Hz, 1H), 3.26 (t, J = 2.5 Hz, 2H), 2.96 (s, 3H), 2.61 (dd, J = 13.7, 7.4 Hz, 1H), 2.28 (dq, J = 14.5, 7.5 Hz, 1H), 2.02 (t, J = 7.6 Hz, 2H), 1.75 - 1.48 (m, 2H), 1.31 - 1.18 (m, 1H), 0.99 (dt, J = 6.3, 3.4 Hz, 2H), 0.74 (dq, J = 7.1, 3.9 Hz, 2H). LC-MS (Method A) (m / z) = 431.4 (MH)+tR= 0.73 minutes. [a]20D +13 ° (c=0.1 g / 100 mL, MeOH).

[0504] Example 43: N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-

[0505] (methanesulfonamido)cyclopentyl]propanamide

[0506] Prepared as Example 40 from N-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and propanoyl chloride.TH NMR (400 MHz, Chloroform-d) 6 7.51 (dt, J = 8.2, 1.5 Hz, 2H), 7.47 - 7.42 (m, 2H), 7.39 (d, J = 7.1 Hz, 1H), 7.32 (td, J = 7 A, 1.9 Hz, 1H), 7.16 - 7.05 (m, 2H), 5.15 (s, 1H), 4.23 (d, J = 7.9 Hz, 1H), 4.01 (h, J = 7.9 Hz, 1H), 3.32 - 3.22 (m, 2H), 2.96 (s, 3H), 2.65 - 2.60 (m, 1H), 2.25 (dq, J = 14.4, 7.5 Hz, 1H), 2.15 (q, J = 7.5 Hz, 2H), 2.07 - 1.94 (m, 2H), 1.77 - 1.60 (m, 2H), 1.55 (t, J = 7.5 Hz, 3H). LC-MS (Method A) (m / z) = 419.4 (MH)+tR= 0.71 minutes. [a]20D+80 ° (c=0.1 g / 100 mL, MeOH).

[0507] Example 44: N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3- (methanesulfonamido)cyclopentyl]-2-methyl-propanamide

[0508] Prepared as Example 40 from N-((lS,3R)-3-amino-3-((2-fluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and isobutyryl chloride.TH NMR (400 MHz, Chloroform-d) 6 7.51 (dt, J = 8.1, 1.5 Hz, 2H), 7.48 - 7.41 (m, 2H), 7.41 - 7.35 (m, 2H), 7.32 (td, J = 7.3, 2.0 Hz, 1H), 7.17 - 7.05 (m, 1H), 5.20 (s, 1H), 4.32 (d, J = 7.8 Hz, 1H), 4.00 (q, J = 7.9 Hz, 1H), 3.27 (t, J = 2.0 Hz, 2H), 2.95 (d, J = 1.3 Hz, 3H), 2.59 (dd, J = 13.8, 7.5 Hz, 1H), 2.24 (dq, J = 14.0, 7.0 Hz, 2H), 2.07 - 1.94 (m, 2H), 1.78 - 1.52 (m, 2H), 1.13 (dd, J = 6.9, 1.3 Hz, 6H). LC-MS (Method A) (m / z) = 455.6 (MH)+tR= 0.75 minutes. [a]20D+20 ° (c=0.1 g / 100 mL, MeOH).

[0509] Example 45: methyl N-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3- (methanesulfonamido)cyclopentyl]carbamate

[0510] Prepared as Example 40 from N-((lS,3R)-3-amino-3-((2,3',6-trifluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and dimethyl dicarbonate.TH NMR (300 MHz, Chloroform-d) 6 7.49 - 7.41 (m, 1H), 7.28- 7.05 (m, 4H), 7.01 - 6.92 (m, 1H), 4.50 - 4.48 (m, 1H), 4.24 - 4.19 (m, 1H), 4.07 - 3.99 (m, 1H), 3.71 (s, 3H), 3.19 (d, J = 7.4 Hz, 2H), 2.98 (s,

[0511] 3H), 2.65 - 2.56 (m, 1H), 2.35 - 2.24 (m, 1H), 2.03 - 1.93 (m, 2H), 1.73 - 1.61 (m, 2H). LC-MS (Method A) (m / z) = 457.3 (MH)+tR= 0.75 minutes. [a]20D+8 ° (c=0.1 g / 100 mL, MeOH).

[0512] Example 46: ethyl N-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3- (methanesulfonamido)cyclopentyl]carbamate

[0513] Prepared as Example 40 from N-((lS,3R)-3-amino-3-((2,3',6-trifluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and diethyl dicarbonate.TH NMR (400 MHz, Chloroform-d) 6 7.45 - 7.39 (m, 1H), 7.24 - 7.20 (m, 1H), 7.19 - 7.05 (m, 3H), 6.97 - 6.89 (m, 1H), 4.44 (s, 1H), 4.30- 3.98 (m, 4H), 3.17 (q, J = 13.8 Hz, 2H), 2.96 (s, 3H), 2.62 - 2.54 (m,

[0514] 1H), 2.34 - 2.23 (m, 1H), 1.95 - 1.90 (m, 2H), 1.69 - 1.59 (m, 2H), 1.29 - 1.24 (m, 3H). LC-MS

[0515] (Method A) (m / z) = 471.3 (MH)+tR= 0.78 minutes. [a]20D+5 ° (c=0.1 g / 100 mL, MeOH).

[0516] Example 47: l-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-

[0517] (methanesulfonamido)cyclopentyl]-3-methyl-urea

[0518] Prepared as Example 40 from N-((lS,3R)-3-amino-3-((2,3',6-trifluoro-[l,l'-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide and methylcarbamic chloride.1H NMR (300

[0519] MHz, Chloroform-d) 6 7.47 - 7.38 (m, 1H), 7.25 - 7.08 (m, 4H), 6.94 (t, J = 8.5 Hz, 1H), 4.08 -

[0520] 3.95 (m, 1H), 3.29 - 3.16 (m, 2H), 2.96 (s, 3H), 2.76 (s, 3H), 2.63 - 2.51 (m, 1H), 2.34 - 2.19

[0521] (m, 1H), 2.01- 1.89 (m, 2H), 1.77 - 1.57 (m, 2H). LC-MS (Method A) (m / z) = 456.4 (MH)+tR=

[0522] 0.67 minutes. [a]20D+3 ° (c=0.1 g / 100 mL, MeOH).

[0523] Example 48: N-[(lS,3S)-3-(2-oxopyrrolidi n-l-yl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0524] Preparation of 4-chloro- / V-((lS,3S)-3-(methylsulfonamido)-l-(((cis-4-phenylcyclohexyl)oxy) methyl) cyclopentyl)butanamide (General method-13)

[0525] A / -((lS,3S)-3-amino-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide (70 mg) in DCM (1 mL) was treated with TEA (96 mg) for 1 hour at room temperature followed by the addition of 4- chlorobutanoyl chloride (40 mg, 0.29 mmol) dropwise at 0 °C. The resulting mixture was concentrated under reduced pressure and used in the next step directly without further purification.

[0526] Preparation of / V-((lS,3S)-3-(2-oxopyrrolidin-l-yl)-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)-(methanesulfonamide) (General method-13)

[0527] A mixture of 4-chloro- / V-((lS,3S)-3-(methylsulfonamido)-l-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)butanamide (50 mg, 0.106 mmol) and NaOH (12 mg, 0.318 mmol) in MeCN (2 mL) was stirred for 1 hour at 70 °C. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 x5 mL). The combined organic layers were washed with brine (2 x5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To obtain the title compound, the crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5pm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 44% B to 65% B in 9 min, 65% B; Wave Length: 254 / 220 nm; RTl(min): 7.75).

[0528] XH NMR (400 MHz, Methanol-c ) 6 7.27 - 7.10 (m, 5H), 3.95 - 3.83 (m, 1H), 3.78 - 3.69 (m, 2H), 3.65 - 3.57 (m, 2H), 2.94 (s, 3H), 2.72 (dd, J = 14.4, 8.2 Hz, 1H), 2.61 - 2.49 (m, 1H), 2.45 - 2.41 (m, 2H), 2.24 - 2.07 (m, 3H), 2.07 - 1.94 (m, 4H), 1.89 - 1.70 (m, 3H), 1.67 - 1.47 (m, 5H), 1.29 - 1.26 (m, 1H). LC-MS (Method A) (m / z) = 435.7 (MH)+tR= 0.78 minutes. [a]20D-2 ° (c=0.1 g / 100 mL, MeOH).

[0529] The following compound was prepared in a similar manner:

[0530] Example 49: N-[(lS,3S)-3-(2-oxo-l-piperidyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide

[0531] Prepared as Example 48 from N-((lS,3S)-3-amino-3-(((cis-4- phenylcyclohexyl)oxy)methyl)cyclopentyl)methanesulfonamide and 5-chloropentanoyl chloride.XH NMR (400 MHz, Methanol-c ) 6 7.34 - 7.07 (m, 5H), 3.95 - 3.76 (m, 2H), 3.66 - 3.42 (m, 4H), 2.93 (s, 3H), 2.65 - 2.52 (m, 2H), 2.43 - 2.25(m, 3H), 2.18 - 1.88 (m, 5H), 1.88 - 1.67(m, 6H), 1.66 - 1.51 (m, 5H). LC-MS (Method A) (m / z) = 449.2 (MH)+tR= 0.82 minutes. [a]20D+12 ° (c=0.1 g / 100 mL, MeOH).

[0532] Example 50: 3-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3- (methanesulfonamido)cyclopentyl]-l,l-dimethyl-urea

[0533] Preparation of / V-((lS,3R)-3-(3,3-dimethylureido)-3-((2,3',6-trifluoro-[l,r-biphenyl]-3- yl)methyl)cyclopentyl)methanesulfonamide (General method-14)

[0534] A mixture of / V-((lS,3R)-3-(3-chloro-2,4-difluorobenzyl)-3-(3,3- dimethylureido)cyclopentyl)methanesulfonamide (91 mg, 0.222 mmol), (3- fluorophenyl)boronic acid (109 mg, 0.777 mmol), CS2CO3 (362 mg, 1.110 mmol) and RuPhos Pd G3 (39 mg, 0.084 mmol) in H2O (1 mL) and dioxane (5 mL) was stirred for 2 hours at 80 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. 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 (lOmmol / L NH4HCO3, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 47% B in 10 min; Wave Length: 254nm / 220nm;

[0535] RTl(min): 9.77) to afford the desired product.TH NMR (300 MHz, Chloroform-d) 6 7.49 - 7.41 (m, 1H), 7.27 - 7.04 (m, 4H), 6.99 - 6.92 (m, 1H), 4.33 (d, J = 7.9 Hz, 1H), 4.10 - 4.02 (m, 2H), 3.34 - 3.28 (m, 1H), 3.23 - 3.17 (m, 1H), 2.98 (s, 3H), 2.89 (s, 6H), 2.71 - 2.62 (m, 1H), 2.33 - 2.25 (m, 1H), 2.03 - 1.92 (m, 2H), 1.72 - 1.63 (m, 2H). LC-MS (Method A) (m / z) = 470.4 (MH)+tR= 0.72 minutes. [a]20D+1 ° (c=0.1 g / 100 mL, MeOH).

[0536] The following compounds were prepared in a similar manner:

[0537] Example 51: methyl N-[rac-(lR,2S,4S)-l-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4- (methanesulfonamido)-2-methyl-cyclopentyl]carbamate

[0538] Prepared as Example 50 from rac-methyl ((lR,2S,4S)-l-(3-bromo-4-fluorobenzyl)-2-methyl- 4-(methylsulfonamido)cyclopentyl)carbamate and (3-fluorophenyl)boronic acid.1H NMR (600 MHz, DMSO) 6 7.54 (td, J = 8.0, 6.2 Hz, 1H), 7.39 (dq, J = 7.7, 1.3 Hz, 1H), 7.34 (ddt, J = 10.4, 3.0, 1.4 Hz, 1H), 7.30 (dd, J = 7.8, 2.2 Hz, 1H), 7.29 - 7.21 (m, 3H), 7.18 - 7.15 (m, 1H), 6.74 (s, 1H), 3.84 (h, J = 7.5 Hz, 1H), 3.54 (s, 3H), 3.45 - 3.39 (m, 1H), 2.86 (s, 3H), 2.77 (d, J = 13.4 Hz, 1H), 2.21 - 2.12 (m, 2H), 1.88 - 1.75 (m, 2H), 1.67 (dd, J = 14.0, 6.3 Hz, 1H), 0.86 (d, J = 7.0 Hz, 3H). LC-MS (Method A) (m / z) = 453.4 (MH)+tR= 0.80 minutes.

[0539] Example 52: methyl N-[(lS,2R,4R,5R)-2-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-4-

[0540] (methanesulfonamido)-2-bicyclo[3.1.0]hexanyl]carbamate Prepared as Example 50 from methyl ((lS,2R,4R,5R)-2-(3-chloro-2,4-difluorobenzyl)-4- (methylsulfonamido)bicyclo[3.1.0]hexan-2-yl)carbamate and 3-fluorophenylboronic acid.1H NMR (400 MHz, Chloroform-d) 6 7.46 - 7.39 (m, 1H), 7.25 - 7.21 (m, 1H), 7.20 - 7.07 (m, 3H), 7.02 - 6.96 (m, 1H), 4.96 - 4.85 (m, 1H), 4.43 - 4.32 (m, 1H), 4.04 (t, J = 6.7 Hz, 1H), 3.69 (s, 3H), 3.46 - 3.33 (m, 1H), 3.29 - 3.19 (m, 1H), 2.99 (s, 3H), 2.40 - 2.27 (m, 1H), 1.83 - 1.69 (m, 2H), 1.63 - 1.59 (m, 1H), 0.69 - 0.55 (m, 1H), 0.45 - 0.35 (m, 1H). LC-MS (Method A) (m / z) = 469.4 (MH)+tR= 0.74 minutes. [a]20D+3 ° (c=0.1 g / 100 mL, MeOH).

[0541] Example 53: methyl N-[(lS,2R,4R,5R)-2-[(2,4-difluoro-3-phenyl-phenyl)methyl]-4- (methanesulfonamido)-2-bicyclo[3.1.0]hexanyl]carbamate

[0542] Prepared as Example 50 from methyl ((lS,2R,4R,5R)-2-(3-chloro-2,4-difluorobenzyl)-4- (methylsulfonamido)bicyclo[3.1.0]hexan-2-yl)carbamate and phenyl boronic acid.TH NMR (400 MHz, Chloroform-d) 6 7.48 - 7.39 (m, 5H), 7.17 - 7.06 (m, 1H), 7.02 - 6.94 (m, 1H), 4.96 - 4.88 (m, 1H), 4.38 - 4.30 (m, 1H), 4.08 - 4.00 (m, 1H), 3.69 (s, 3H), 3.44 - 3.34 (m, 1H), 3.28 - 3.19 (m, 1H), 2.97 (s, 3H), 2.36 - 2.26 (m, 1H), 1.83 - 1.69 (m, 2H), 1.62 - 1.58 (m, 1H), 0.66 - 0.57 (m, 1H), 0.42 - 0.35 (m, 1H). LC-MS (Method A) (m / z) = 451.4 (MH)+tR= 0.73 minutes. [a]20D+3 ° (c=0.1 g / 100 mL, MeOH).

[0543] Example 54: methyl N-trans-[l-[(2,4-difluoro-3-phenyl-phenyl)methyl]-4-

[0544] (methanesulfonamido)cyclohexyl]carbamate Prepared as Example 50 from methyl ((lr,4r)-l-(3-chloro-2,4-difluorobenzyl)-4- (methylsulfonamido)cyclohexyl)carbamate and phenyl boronic acid.TH NMR (400 MHz, Chloroform-d) 6 7.48 - 7.38 (m, 5H), 7.07 - 7.01 (m, 1H), 6.95 - 6.91 (m, 1H), 4.32 - 4.26 (m, 2H), 3.67 (s, 3H), 3.59-3.57 (m, 1H), 3.10 (s, 2H), 2.98 (s, 3H), 1.86 - 1.74 (m, 6H), 1.69 - 1.64 (m, 2H). LC-MS (Method A) (m / z) = 453.4 (MH)+tR= 0.76 minutes. [a]20D-3 ° (c=0.1 g / 100 mL, MeOH).

[0545] Example 55: methyl N-trans-[l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-4-

[0546] (methanesulfonamido)cyclohexyl]carbamate

[0547] Prepared as Example 50 from methyl ((lr,4r)-l-(3-chloro-2,4-difluorobenzyl)-4- (methylsulfonamido)cyclohexyl) carbamate and 3-fluorophenylboronic acid.1H NMR (400 MHz, Chloroform-d) 6 7.44 - 7.39 (td, J = 8.0, 5.9 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.16 - 7.03 (m, 3H), 6.99 - 6.91 (m, 1H), 4.40 (d, J = 6.8 Hz, 1H), 4.32 (s, 1H), 3.67 (s, 3H), 3.62 - 3.55 (m, 1H), 3.15 - 3.08 (m, 2H), 2.98 (s, 3H), 1.86 - 1.74 (m, 6H), 1.71 - 1.66 (m, 2H). LC-MS (Method A) (m / z) = 471.3 (MH)+tR= 0.75 minutes. [a]20D-1 ° (c=0.1 g / 100 mL, MeOH).

[0548] Example 56: methyl N-trans-[l-[[3-(3,5-difluorophenyl)-2,4-difluoro-phenyl]methyl]-4-

[0549] (methanesulfonamido)cyclohexyl]carbamate

[0550] Prepared as Example 50 from methyl ((lr,4r)-l-(3-chloro-2,4-difluorobenzyl)-4- (methylsulfonamido)cyclohexyl)carbamate and 3,5-difluorophenylboronic acid.TH NMR (400 MHz, Chloroform-d) 6 7.12 - 7.06 (m, 1H), 6.98 - 6.93 (m, 3H), 6.89 - 6.84 (m, 1H), 4.29 (d, J = 6.4 Hz, 2H), 3.68 (s, 3H), 3.59-3.57 (m, 1H), 3.12 - 3.08 (m, 2H), 2.98 (s, 3H), 1.86 - 1.76 (m, 6H), 1.70 - 1.66 (m, 2H). LC-MS (Method A) (m / z) = 489.4 (MH)+tR= 0.79 minutes. [a]20D-3 ° (c=0.1 g / 100 mL, MeOH).

[0551] Example 57: methyl N-[(lS,2R,4R,5R)-2-[[2,4-difluoro-3-(2-methylthiazol-4- yl)phenyl]methyl]-4-(methanesulfonamido)-2-bicyclo[3.1.0]hexanyl]carbamate

[0552] Prepared as Example 50 from methyl ((lS,2R,4R,5R)-2-(3-chloro-2,4-difluorobenzyl)-4- (methylsulfonamido)bicyclo[3.1.0]hexan-2-yl)carbamate and 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-thiazole.1H NMR (400 MHz, Chloroform-d) 6 7.47

[0553] - 7.38 (m, 1H), 7.21 - 7.12 (m, 1H), 7.04 - 6.94 (m, 1H), 4.95 - 4.84 (m, 1H), 4.70 - 4.59 (m, 1H), 4.09 - 3.96 (m, 1H), 3.70 (s, 3H), 3.42 - 3.24 (m, 2H), 3.03 (s, 3H), 2.89 (s, 3H), 2.38 - 2.25 (m, 1H), 1.87 - 1.81 (m, 1H), 1.75 - 1.66 (m, 2H), 0.68 - 0.57 (m, 1H), 0.42 - 0.31 (m, 1H). LC-MS (Method A) (m / z) = 472.4 (MH)+tR= 0.60 minutes. [a]20D+4 ° (c=0.1 g / 100 mL, MeOH).

[0554] MEASUREMENT OF OX2R AGONIST ACTIVITY

[0555] 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.

[0556] A CHO Fl p-l n cell-line stably expressing the human Ox2R (hOx2R-CHO Fl p-l n) 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. To prepare the hOx2R-CHO Fl pl n 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), lOmM CaCh, 0.1% pluronic

[0557] F68 (Gibco) and IX calcium-4 dye (Molecular Devices) for lh 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

[0558] Scree ner software.

[0559] 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.

[0560] Table 1: measurement of Ox2R agonist activity

[0561] Hepatic microsomal intrinsic clearance assay:

[0562] 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 waterthen 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. Equation 1:

[0563] Equation 2: CLint (L / h / kg body weight) = ln(2) x V (L / mg) / ti / 2 (h) x microsomal protein concentration (mg protein / g liver) x liver weight (g liver / kg body weight)(2)

[0564] V = incubation volume = 0.002 L / mg (0.5 mg / mL protein concentration) Microsomal protein concentration = 45 mg / g liver Rat liver weight = 45 g / kg body weight Human liver weight = 25 g / kg body weight

[0565] Some of the compounds of the present invention were tested in the hepatic microsomal intrinsic clearance assay.

[0566] MDR1-MDCKII assay

[0567] 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; Co 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.

[0568] Equations:

[0569] Papp = (dCr / dt) x Vr / (A x CO)

[0570] Efflux Ratio (ER) = Papp B-A / Papp A-B

[0571] Some of the compounds of the present invention were tested in the MDR1-MDCKII assay.

[0572] Based on the MDR1-MDCKII assay, some compounds of the present invention were classified as displaying high permeability.

[0573] Based on the MDR1-MDCKII assay, some compounds of the present invention were classified as displaying moderate permeability.

[0574] 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 favorable brain disposition.

[0575] Based on the MDR1-MDCKII assay, some compounds of the present invention were classified as possibly being P-gp substrates.

[0576] In vitro Selectivity

[0577] 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

1. CLAIMS1. A compound of general formula (I)whereinX is -O- or -(CRaRb)- or a bond, wherein Raand Rb each independently are selected from the group consisting of hydrogen and (Ci-C4)a I kyl;Ri and Riaeach independently are selected from hydrogen and fluoro, or when X is -(CRaRb)- Ri or Riaand Raor Rb together with the carbon atoms to which they are attached may optionally form a fused Cs-cycloalkyl group;Q is (Ci-C2)alkylene;R2 is (Ci-C4)a Ikyl or -NRcRd, wherein Rcand Rd each independently are selected from the group consisting of hydrogen and (Ci-C4)a I kyl;Z is phenyl, pyridyl, (Ce-Czjcycloalkylene or (C2-C4)alkylene, wherein said phenyl or pyridyl is optionally substituted with one or more substituents each independently selected from R3;Ari is phenyl, pyridyl, pyrimidyl or thiazolyl, wherein said phenyl, pyridyl, pyrimidyl or thiazolyl is optionally substituted with one or more substituents each independently selected from R4;R3 and R4 each independently are halogen or (Ci-C4)a I kyl;W is -C(O)-NR5R6, -NH-C(O)-R7, -C(O)-R8, -NH-C(O)-O-R9, -NH-C(O)-NRI0RII, oxopiperidyl, or oxopyrrolidinyl, wherein said oxopiperidyl or oxopyrrolidinyl is optionally substituted with one or more substituents independently selected from R12; with the proviso that when W is selected from -C(O)-R8and -C(O)-NRsR6, and Z is phenyl and X is -CH2-, then Q is -(CH2)2- or R2 is -NRcRd; or when W is selected from -C(O)-R8and -C(O)-NRsR6, and Z is phenyl and X is a bond, then Q is -CH2- ;Rs and Re each independently are hydrogen, (Ci-C4)a Ikyl or (C3-Ce)cycloalkyl, wherein said (Ci-C4)a I ky I and (C3-Ce)cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, -OH, (Ci-C4)alkoxy and (Ci-C4)a I kyl;R? is (Ci-C4)a Ikyl, (C3-Ce)cycloalkyl, 4-8-membered heterocycloalkyl or hydroxy(Ci-C4)alkyl;Rs is a 4-8-membered heterocycloalkyl comprising at least one nitrogen atom and wherein said nitrogen atom is the point of attachment to -C(O)-, wherein said 4-8-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from halogen, -OH, (Ci-C4)alkoxy, (Ci-C4)a Ikyl and ha lo(Ci-C4)a I kyl;R9 is (Ci-C4)alkyl;Rioand Rn are each independently selected from hydrogen or (Ci-C4)a Ikyl;R12 is (Ci-C4)alkyl;Y represents a bond or -O-; or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, with the proviso that said compound is notN-((lR,3S)-l-([l,l'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentyl)butyramide, orN-((lS,3R)-3-([l,l'-biphenyl]-3-ylmethyl)-3-(2-oxopyrrolidin-l- yl)cyclopentyl)methanesulfonamide, or pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 wherein Z is phenyl, wherein said phenyl is substituted with one or more substituents each independently selected from R3; and Ari is phenyl, wherein said phenyl is substituted with one or more substituents each independently selected from R4.

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 and Riaare hydrogen.

7. The compound according to any one of claims 1-6, wherein R2 is methyl, ethyl, NH(CH3) orN(CH3)2.

8. The compound according to any one of claims 1-7, wherein Z is phenyl, cyclohexylene or bicycloheptanyl, wherein said phenyl 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, wherein said phenyl 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 W is -NH-C(O)-R?, -NH-C(O)- O-R9, -NH-C(0)-NRioRn, oxopiperidyl, or oxopyrrolidinyl, wherein said oxopiperidyl or oxopyrrolidinyl is optionally substituted with one or more substituents independently selected from R12.

11. The compound according to any one of claims 1-9, wherein W is -C(O)-NRsR6 or -C(O)-Rs, with the proviso that when Z is phenyl and X is -CH2-, then Q is -(0-12)2- or R2 is -NRcRd; or when Z is phenyl and X is a bond, then Q is -CH2-.

12. The compound according to any one of claims 1 - 11, wherein the compound is selected from the list consisting ofN-cyclopropyl-l-trans-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-4- (methanesulfonamido)cyclohexanecarboxamide,N-[(lS,3R,4S)-3-(azetidine-l-carbonyl)-4-methyl-3-[(3- phenylphenyl)methyl]cyclopentyl]methanesulfonamide,N-[(lR,3S,4R)-3-(azetidine-l-carbonyl)-4-methyl-3-[(3- phenylphenyl)methyl]cyclopentyl]methanesulfonamide, l-[(lR,3S)-3-(dimethylsulfamoylamino)-l-[(3- phenylphenyl)methyl]cyclopentanecarbonyl]azetidine,N-cis-[4-(azetidine-l-carbonyl)-4-[[3-(3,5-difluorophenyl)-4-fluoro- phenyl]methyl]cyclohexyl] methanesulfonamide,N-cyclopropyl-l-trans-[[3-(3,5-difluorophenyl)-4-fluoro-phenyl]methyl]-3-(methanesulfonamido)cyclobutanecarboxamide,N-cis-[3-(azetidine-l-carbonyl)-3-[[3-(3,5-difluorophenyl)-4-fluoro- phenyl]methyl]cyclobutyl]methanesulfonamide,N-[(lS,3S)-3-cis-(azetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-cis-(3-methoxy-3-methyl-azetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide, azetidin-l-yl-[(lS,3S)-3-(methylsulfamoylamino)-l-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanone, l-[(lS,3S)-3-(dimethylsulfamoylamino)-l-[(4- phenylcyclohexoxy)methyl]cyclopentanecarbonyl]azetidine,(lS,3S)-3-(methanesulfonamido)-N,N-dimethyl-l-[(4- phenylcyclohexoxy)methyl]cyclopentanecarboxamide;N-[(lS,3S)-3-cis-(3-hydroxyazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-cis-(3-fluoroazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-cis-(3,3-difluoroazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-[3-cis-(difluoromethyl)azetidine-l-carbonyl]-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-cis-(3-methoxyazetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-cis-(l-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-cis-(5-azaspiro[2.3]hexane-5-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-cis-(3-fluoro-3-methyl-azetidine-l-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-cis-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-(azetidine-l-carbonyl)-3-[[(3R*,6S*)-6-(5-fluoropyrimidin-2-yl)norcaran-3- yl]oxymethyl]cyclopentyl]methanesulfonamide;(lS,3S)-l-[[(lR*,3R*,6S*)-6-(5-fluoropyrimidin-2-yl)norcaran-3-yl]oxymethyl]-3-(methanesulfonamido)-N-methyl-cyclopentanecarboxamide,N-[(lS,3S)-3-(azetidine-l-carbonyl)-3-[[(lR*,3R,6S*)-6-(5-fluoropyrimidin-2-yl)norcaran-3- yl]oxymethyl]cyclopentyl]methanesulfonamide,N-[(lR,2R,4R,5S)-4-(azetidine-l-carbonyl)-4-[(3-phenylphenyl)methyl]-2- bicyclo[3.1.0]hexanyl]methanesulfonamide,(lS,2R,4R,5R)-N-cyclopropyl-4-(methanesulfonamido)-2-[(3- phenylphenyl)methyl]bicyclo[3.1.0]hexane-2-carboxamide,(lS,2R,4R,5R)-4-(methanesulfonamido)-N-methyl-2-[(3- phenylphenyl)methyl]bicyclo[3.1.0]hexane-2-carboxamide,N-[(lR,2R,4R,5S)-4-(azetidine-l-carbonyl)-4-[(cis-4-phenylcyclohexoxy)methyl]-2- bicyclo[3.1.0]hexanyl]methanesulfonamide,(lS,2R,4R,5R)-4-(methanesulfonamido)-2-[(cis-4- phenylcyclohexoxy)methyl]bicyclo[3.1.0]hexane-2-carboxamide,(lS,2R,4R,5R)-4-(methanesulfonamido)-N-methyl-2-[(cis-4- phenylcyclohexoxy)methyl]bicyclo[3.1.0]hexane-2-carboxamide,N-[rac-(3R,5R)-5-(azetidine-l-carbonyl)-5-[(cis-4- phenylcyclohexoxy)methyl]tetrahydrofuran-3-yl] methanesulfonamide,(2S,4S)-4-(methanesulfonamido)-N-methyl-2-[(cis-4- phenylcyclohexoxy)methyl]tetrahydrofuran-2-carboxamide or (2R,4R)-4-(methanesulfonamido)-N-methyl-2-[(4-phenylcyclohexoxy)methyl]tetrahydrofuran-2- carboxamide,(2R,4R)-4-(methanesulfonamido)-N-methyl-2-[(4- phenylcyclohexoxy)methyl]tetrahydrofuran-2-carboxamide,N-[(lS,3S)-3-(methanesulfonamido)-l-[(cis-4- phenylcyclohexoxy)methyl]cyclopentyl]acetamide,N-[(lS,3S)-3-(methanesulfonamido)-l-[(cis-4- phenylcyclohexoxy)methyl]cyclopentyl]propenamide,N-[(lS,3S)-3-(methanesulfonamido)-l-[(cis-4- phenylcyclohexoxy)methyl]cyclopentyl]cyclopropanecarboxamide,N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(methanesulfonamido)cyclopentyl]-2- hydroxy-2-methyl-propanamide,(2R)-N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(methanesulfonamido)cyclopentyl]oxetane-2-carboxamide,(2S)-N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(methanesulfonamido)cyclopentyl]oxetane-2-carboxamide, methyl N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(methanesulfonamido)cyclopentyl]carbamate,N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(methanesulfonamido)cyclopentyl]acetamide,N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3- (methanesulfonamido)cyclopentyl]cyclopropanecarboxamide,N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(methanesulfonamido)cyclopentyl]propenamide,N-[(lR,3S)-l-[(2-fluoro-3-phenyl-phenyl)methyl]-3-(methanesulfonamido)cyclopentyl]-2- methyl-propanamide, methyl N-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(methanesulfonamido)cyclopentyl]carbamate, ethyl N-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(methanesulfonamido)cyclopentyl]carbamate,1-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(methanesulfonamido)cyclopentyl]-3-methyl-urea,N-[(lS,3S)-3-(2-oxopyrrolidin-l-yl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,N-[(lS,3S)-3-(2-oxo-l-piperidyl)-3-[(4- phenylcyclohexoxy)methyl]cyclopentyl]methanesulfonamide,3-[(lR,3S)-l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-3-(methanesulfonamido)cyclopentyl]-l,l-dimethyl-urea, methyl N-[rac-(lR,2S,4S)-l-[[4-fluoro-3-(3-fluorophenyl)phenyl]methyl]-4-(methanesulfonamido)-2-methyl-cyclopentyl]carbamate, methyl N-[(lS,2R,4R,5R)-2-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-4-(methanesulfonamido)-2-bicyclo[3.1.0]hexanyl]carbamate, methyl N-[(lS,2R,4R,5R)-2-[(2,4-difluoro-3-phenyl-phenyl)methyl]-4-(methanesulfonamido)-2-bicyclo[3.1.0]hexanyl]carbamate, methyl N-trans-[l-[(2,4-difluoro-3-phenyl-phenyl)methyl]-4-(methanesulfonamido)cyclohexyl]carbamate,methyl N-trans-[l-[[2,4-difluoro-3-(3-fluorophenyl)phenyl]methyl]-4-(methanesulfonamido)cyclohexyl]carbamate, methyl N-trans-[l-[[3-(3,5-difluorophenyl)-2,4-difluoro-phenyl]methyl]-4-(methanesulfonamido)cyclohexyl]carbamate and methyl N-[(lS,2R,4R,5R)-2-[[2,4-difluoro-3-(2-methylthiazol-4-yl)phenyl]methyl]-4- (methanesulfonamido)-2-bicyclo[3.1.0]hexanyl]carbamate.

13. A compound according to any one of claims 1 -12 for use in therapy.

14. A compound according to any one of claims 1 - 12 for use in the treatment of narcolepsy, such as Narcolepsy Type 1 or Narcolepsy Type 2.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 - 12 together with one or more pharmaceutically acceptable excipients or carriers.

16. The pharmaceutical composition according to claim 15 together with one or more other therapeutically active compounds.

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