Macrocyclic Orexin Agonists

Abstract

The present invention relates to aryl thiol macrocycles of Formula (I) wherein R1, R2, RA1, X1, X2, X3, X4, L, X5, and Ring A are as described in the description, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of Formula (I), and their use as agonists of the orexin-2 receptor.

Claims

 1. A compound of Formula (I)Formula (I)whereinRing A is a 6-membered aromatic ring, wherein:RA1 represents hydrogen, (C13)alkyl, (C13)alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (C1)fluoroalkyl;X1 represents independently N or CRA3, wherein RA3 represents hydrogen, halogen, (C13)alkyl, or (C13)alkoxy; X2 represents independently N or CRA2, wherein RA2 represents hydrogen or halogen; andX5 represents C;and L represents:linker group L1, wherein the backbone of said linker group L1 is linear and consists of a total of 3 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 6 carbon atoms and 0 to 2 heteroatoms independently selected from O, N or S; wherein said backbone is saturated or partially unsaturated; wherein said backbone is unsubstituted, or mono-, di- or tri-substituted; wherein the substituents are independently selected from the group consisting of:(C1-6)alkyl; (C3-6)cycloalkan-1,1-diyl; (C3-6)cycloalkyl; hydroxy; halogen; and(C1-3)fluoroalkyl;or linker group L2, wherein the backbone of said linker group L2 consists of a total of 4 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 5 carbon atoms and 1 or 2 heteroatoms independently selected from O, N or S; wherein said backbone is saturated or partially unsaturated; wherein 2 or 3 adjacent atoms of said backbone atoms are contained in a 3- to 6-membered saturated, partially unsaturated or aromatic cyclic moiety comprising a total of 0 to 3 heteroatoms independently selected from O, N or S; wherein L2 is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of:(C1-3)alkyl; andhalogen; or the fragment formed by represents: Formula (I-B)whereinRing A represents a 6-membered aromatic ring, wherein:X2 represents CH or N; andRA1 represents independently hydrogen, (C13)alkyl, (C13)alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (C1)fluoroalkyl; and Ring B represents a 5- to 7-membered heterocyclic ring; wherein said Ring B including ring atoms X1 and X5 contains a total of 1 or 2 ring heteroatoms; wherein said heteroatoms are independently selected from N, O, or S; Ring A represents a 6-membered aromatic ring, wherein:X2 represents CH or N; andRA1 represents independently hydrogen, (C13)alkyl, (C13)alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (C1)fluoroalkyl;and Ring B represents a 5-membered heteroaromatic ring; wherein said Ring B including ring atoms X1 and X5 contains a total of 1 to 3 ring heteroatoms; wherein said heteroatoms are independently selected from N, O, or S; orRing A represents a 6-membered aromatic ring, wherein:X2 represents CH or N; andRA1 represents independently hydrogen, (C13)alkyl, (C13)alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (C1)fluoroalkyl;and Ring B represents a 6-membered heteroaromatic ring; wherein said Ring B including ring atoms X1 and X5 contains a total of 1 or 2 ring heteroatoms; wherein said ring heteroatoms are N; and L3 represents:a linear linker group; wherein L3 consists of a total of 3 or 4 backbone atoms; wherein said backbone atoms are independently selected from 3 or 4 carbon atoms and 0 or 1 heteroatom independently selected from O, N or S; wherein said backbone is saturated or mono-unsaturated; wherein said backbone is unsubstituted or mono-substituted with (C1-3)alkyl; or halogen; X3 represents SO2 or S(=O)(=NR3), wherein R3 represents hydrogen, (C13)alkyl, monocyclic (C36)cycloalkyl, or phenyl; X4 represents:NRN1; wherein:RN1 represents hydrogen or (C13)alkyl; and R1 represents (C15)alkyl or –(CH2)n-(C3-4)cycloalkyl wherein n independently represents the integer 0 or 1; NRN1; wherein R1 and RN1 together form a ring comprising X4, herein Ring E, wherein said Ring E represents:a 4- to 6-membered saturated monocyclic heterocycloalkan-diyl comprising X4 and zero or one ring oxygen atom; wherein said heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C13)alkyl, halogen, (C13)alkoxy, hydroxy, phenyl, and cyano; ora 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X4; or CHRC1; wherein R1 and RC1 together form a ring comprising X4, herein Ring F, wherein said Ring F represents a monocyclic (C56)cycloalkan-diyl or a monocyclic 5- or 6-membered heterocycloalkan-diyl comprising one ring oxygen atom; andR2 represents:3-cyano-3,3-dimethylpropyl;-(CH2)m-(Ring D), wherein m is the integer 0 or 1, and Ring D represents:a saturated monocyclic (C47)cycloalkyl; wherein said (C47)cycloalkyl is unsubstituted, mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of: (C13)alkyl; wherein said (C13)alkyl independently is unsubstituted or mono-substituted with cyano;halogen; (C13)fluoroalkyl; (C13)alkoxy; (C34)cycloalkyl;carbamoyl; hydroxy; cyano; and(C23)alkynyl;a saturated bicyclic (C58)spirocycloalkyl; wherein said (C58)spirocycloalkyl is unsubstituted, or mono-, di-, tri- or tetra-substituted; wherein the substituents are independently selected from the group consisting of: halogen, cyano, and hydroxy; a saturated fused or bridged bicyclic (C58)cycloalkyl; wherein said bicyclic (C58)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C13)fluoroalkyl, halogen, cyano, and carbamoyl; a 5- or 6-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from O, NRN2, S, or SO2; wherein RN2 represents (C13)alkyl or cyanomethyl; wherein said heterocycle is unsubstituted, or mono-, di-, tri-, or tetra-substituted; wherein the substituents are independently selected from the group consisting of: (C13)alkyl, halogen, (C13)fluoroalkyl, and oxo; a 9-membered saturated spiro bicyclic heterocycle comprising one ring oxygen atom; ora 7-membered saturated fused or bridged bicyclic heterocycle comprising one ring oxygen atom; or a pharmaceutically acceptable salt thereof.   2. A compound according to claim 1, wherein:Ring A is a 6-membered aromatic ring, wherein:RA1 represents hydrogen, (C13)alkyl, (C13)alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (C1)fluoroalkyl; X1 represents independently N or CRA3, wherein RA3 represents hydrogen, halogen, (C13)alkyl, or (C13)alkoxy; X2 represents independently N or CRA2, wherein RA2 represents hydrogen or halogen; andX5 represents C;and L represents:linker group L1, wherein the backbone of said linker group L1 is linear and consists of a total of 3 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 6 carbon atoms and 0 to 2 heteroatoms independently selected from O, N or S; wherein said backbone is saturated or partially unsaturated; wherein said backbone is unsubstituted, or mono-, di- or tri-substituted; wherein the substituents are independently selected from the group consisting of: (C1-6)alkyl; (C3-6)cycloalkan-1,1-diyl; (C3-6)cycloalkyl; hydroxy; halogen, and (C1-3)fluoroalkyl; or linker group L2, wherein the backbone of said linker group L2 consists of a total of 4 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 5 carbon atoms and 1 or 2 heteroatom independently selected from O, N or S; wherein said backbone is saturated or partially unsaturated; wherein 2 or 3 adjacent atoms of said backbone atoms are contained in a 3- to 6-membered saturated, partially unsaturated or aromatic cyclic moiety comprising a total of 0 to 3 heteroatoms independently selected from O, N or S; wherein L2 is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from (C1-3)alkyl or halogen;or a pharmaceutically acceptable salt thereof.   3. A compound according to claim 2, wherein L represents linker group L1 and the backbone of linker group L1 is selected from the group consisting of: *-O-(CH2)2-, *-O-(CH2)3-, -(CH2)4-, *-S-(CH2)3-, *-O-(CH2)4-, *-(CH2)-O-(CH2)3-, *-(CH2)3-O-(CH2)-, -(CH2)5-, *-NH-(CH2)2-CH=CH-, *-NH-(CH2)4-, *-CH=CH-(CH2)3-, *-O-(CH2)2-CH=CH-, *-O-(CH2)2-O-(CH2)-, *-O-(CH2)5-, and *-O-(CH2)2-NH-(CH2)-, wherein the asterisks indicate the attachment point of linker group L1 to Ring A; wherein said backbone is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C1-6)alkyl, (C3-6)cycloalkan-1,1-diyl, (C3-6)cycloalkyl, hydroxy, halogen, and (C1-3)fluoroalkyl; or L represents linker group L2 and the backbone of linker group L2 is selected from the group consisting of:*-O-(CH2)-(cyclic moiety)-, *-O-(cyclic moiety)-(CH2)-, *-O-(cyclic moiety)-CH=CH-, *-O-(cyclic moiety)-(CH2)2-; wherein independently the cyclic moiety of such linker group L2 represents:(C36)cycloalkan-1,2-diyl;phen-1,2-diyl; or5- or 6-membered heterocycloalkan-diyl; wherein said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in ortho position relative to one another; or*-(cyclic moiety)-(CH2)-, *-(cyclic moiety)-(CH2)2-, *-(cyclic moiety)-CH=CH-, *-(cyclic moiety)-(CH2)3-, *-O-(cyclic moiety)-, *-O-(cyclic moiety)-(CH2)-, and *-O-(CH2)-(cyclic moiety)-; wherein independently the cyclic moiety of such linker group L2 represents:(C36)cycloalkan-1,3-diyl;5- or 6-membered heterocycloalkan-diyl; wherein said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another;5- or 6-membered heteroaryl-diyl; wherein said heteroaryl-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another;wherein the asterisks indicate the attachment point of linker group L2 to Ring A; wherein said L2 is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl and halogen;or a pharmaceutically acceptable salt thereof.   4. A compound according to claim 2, wherein L represents linker group L1; said linker group L1 independently is:**-O-CH(CH3)-CH2-; **-O-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-; **-O-cyclopropan-1,1-diyl-CH2-CH2-; -CH2-CH2-CH2-CH2-; **-S-CH(CH3)-CH2-CH2-; -CH2-CH2-CH2-CH2-CH2-; **-CH=CH-CH2-CH2-CH2-; **-O-CH2-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-CH2-CH2-; **-O-CH(n-propyl)-CH2-CH2-CH2-; **-O-CH(isopropyl)-CH2-CH2-CH2-; **-O-CH(cyclopropyl)-CH2-CH2-CH2-; **-O-CH2-CH(CH3)-CH2-CH2-; **-O-CH2-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-CH(ethyl)-CH2-; **-O-CH2-CF2-CH2-CH2-; **-O-CH2-CH2-C(CH3)2-CH2-; **-O-CH2-CH2-cyclopropan-1,1-diyl-CH2-; **-O-CH2-CH2-C(hydroxy)(cyclopropyl)-CH2-; **-O-CH2-CH2-CH2-CH(CH3)-; **-O-CH(CH3)-CH2-CH=CH-; **-CH2-O-CH2-CH2-CH2-; **-CH2-CH2-CH2-O-CH2-; **-O-CH(CH3)-CH2-O-CH2-; **-NH-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH=CH-; **-NH-CH(CH3)-CH2-CH=CH-; **-NH-CH(CH3)-CH2-CH2-CH2-; or **-O-CH2-CH2-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-O-CH2-; **-O-CH(CH3)-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-N(cyclopropyl)-CH2-; **-O-CH(CH3)-CH2-N(cyclopropyl)-CH2-; **-O-CH(CF3)-CH2-CH2-CH2-; **-O-CH2-CH2-CH(CF3)-CH2-;**-O-CH2-CH2-N(2,2,2-trifluoroethyl)-CH2-; or **-O-CH2-CH2-CH=CH-;L represents linker group L2; said linker group L2 independently is:**-(pyrrolidin-1*,3-diyl)-CH2-; **-(piperidin-1*,3-diyl)-CH2-; **-O-CH2-(cyclopropan-1,2-diyl)-; **-O-CH2-(cyclobutan-1,2-diyl)-; **-O-(cyclopentan-1,2-diyl)-CH2-; **-O-(cyclohexan-1,2-diyl)-CH2-; **-O-(cyclohexan-1,3-diyl)-; **-O-(cyclohexan-1,3-diyl)-CH2-; **-(pyrrolidin-1*,3-diyl)-CH2-CH2-; **-O-(cyclopentan-1,2-diyl)-CH=CH-; **-O-(cyclopentan-1,3-diyl)-CH2-; **-O-(cyclopentan-1,2-diyl)-CH2-CH2-; **-O-CH2-(cyclobutan-1,3-diyl)-; **-O-(tetrahydrofuran-3,4-diyl)-CH2-CH2-; **-(4-chloro-pyrazol-1,3*-diyl)-CH2-CH2-; **-O-(tetrahydrofuran-2,3*-diyl)-CH2-CH2-; **-O-(cyclobutan-1,2-diyl)-CH2-CH2-; **-O-CH2-CH2-(cyclopropan-1,2-diyl)-; **-O-([1,3,4]oxadiazol-2,5-diyl)-CH2-; **-O-(phen-1,2-diyl)-CH2-CH2-; **-(pyridin-2,6-diyl)-CH2-CH2-; **-([1,2,4]oxadiazol-3*,5-diyl)-CH2-CH2-CH2-; **-O-(cyclobutan-1,3-diyl)-CH2-CH2-; **-O-(tetrahydrofuran-2,4*-diyl)-CH2-; **-O-(tetrahydropyran-2,4*-diyl)-CH2-; **-O-(piperidin-1,3*-diyl)-CH2-; **-O-CH2-(cyclopentan-1,3-diyl)-; **-O-(tetrahydropyran-3,5-diyl)-CH2-; or **-O-(cyclohexan-1,2-diyl)-CH2-CH2-; **-O-CH2-(cyclopropan-1,2-diyl)-CH2-;**-O-CH(CH3)-CH2-(cyclopropan-1,2-diyl)-; **-(pyrazol-1,3*-diyl)-CH2-CH2-; or **-O-(cyclopentan-1,2-diyl)-O-CH2-;wherein the double asterisks indicate the attachment point of the linker group L1, respectively L2 to Ring A; and, where applicable, the single asterisks indicate the attachment point of (i) the linker oxygen atom which is attached to Ring A, or (ii) of Ring A, as the case may be;or a pharmaceutically acceptable salt thereof.   5. A compound according to any of claims 1 to 4, wherein X3 represents SO2 or S(=O)(=NR3), wherein R3 represents hydrogen or (C13)alkyl;or a pharmaceutically acceptable salt thereof.   6. A compound according to any of claims 1 to 5, wherein X4 represents CHRC1, and R1 and RC1 together form a ring comprising X4, herein Ring F, wherein Ring F represents a monocyclic (C56)cycloalkan-diyl;or a pharmaceutically acceptable salt thereof.   7. A compound according to any of claims 1 to 5, wherein X4 represents NRN1, and R1 and RN1 together form a ring comprising X4, herein Ring E; wherein said Ring E represents:a 5- or 6-membered saturated monocyclic heterocycloalkan-diyl comprising X4 and zero or one ring oxygen atom; wherein said heterocycloalkan-diyl is unsubstituted or mono-substituted; wherein the substituents are independently selected from the group consisting of: (C13)alkyl, halogen, and (C13)alkoxy; ora 6- or 7-membered saturated fused or bridged bicyclic heterocycloalkan-diyl comprising X4;or a pharmaceutically acceptable salt thereof.  8. A compound according to any of claims 1 to 7, wherein R2 represents:3-cyano-3,3-dimethylpropyl;-(CH2)m-(Ring D), wherein m is the integer 0 or 1, and Ring D represents:a saturated monocyclic (C47)cycloalkyl; wherein said (C47)cycloalkyl is mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of: (C13)alkyl; wherein said (C13)alkyl is unsubstituted or mono-substituted with cyano;halogen; (C13)alkoxy; (C34)cycloalkyl;hydroxy; and cyano; a saturated bicyclic (C58)spirocycloalkyl; wherein said (C58)spirocycloalkyl is unsubstituted, or mono-, di-, tri- or tetra-substituted; wherein the substituents are independently selected from the group consisting of: halogen, cyano, and hydroxy; a saturated fused or bridged bicyclic (C58)cycloalkyl; wherein said bicyclic (C58)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C13)fluoroalkyl, halogen, and cyano; a 5- or 6-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from O, NRN2, or SO2; wherein RN2 represents (C13)alkyl; wherein said heterocycle is unsubstituted, or mono-, di-, tri-, or tetra-substituted; wherein the substituents are independently selected from the group consisting of: (C13)alkyl and oxo; a 9-membered saturated spiro bicyclic heterocycle comprising one ring oxygen atom;or a 7-membered saturated fused or bridged bicyclic heterocycle comprising one ring oxygen atom; or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 1 which is a compound of Formula (IV)Formula (IV)wherein the fragment represents , , or whereinRA1 independently represents hydrogen, (C13)alkyl, (C13)alkoxy, or halogen; and RA3, if present, independently represents hydrogen, halogen, or (C13)alkyl; L represents:linker group L1 wherein such linker group L1 independently is:**-O-CH(CH3)-CH2-; **-O-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-; **-O-cyclopropan-1,1-diyl-CH2-CH2-; -CH2-CH2-CH2-CH2-; **-S-CH(CH3)-CH2-CH2-; -CH2-CH2-CH2-CH2-CH2-; **-CH=CH-CH2-CH2-CH2-; **-O-CH2-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-CH2-CH2-; **-O-CH(n-propyl)-CH2-CH2-CH2-; **-O-CH(isopropyl)-CH2-CH2-CH2-; **-O-CH(cyclopropyl)-CH2-CH2-CH2-; **-O-CH2-CH(CH3)-CH2-CH2-; **-O-CH2-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-CH(ethyl)-CH2-; **-O-CH2-CF2-CH2-CH2-; **-O-CH2-CH2-C(CH3)2-CH2-; **-O-CH2-CH2-cyclopropan-1,1-diyl-CH2-; **-O-CH2-CH2-C(hydroxy)(cyclopropyl)-CH2-; **-O-CH2-CH2-CH2-CH(CH3)-; **-O-CH(CH3)-CH2-CH=CH-; **-CH2-O-CH2-CH2-CH2-; **-CH2-CH2-CH2-O-CH2-; **-O-CH(CH3)-CH2-O-CH2-; **-NH-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH=CH-; **-NH-CH(CH3)-CH2-CH2-CH2-; or **-O-CH2-CH2-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-O-CH2-; **-O-CH2-CF2-CH2-CH2-; **-O-CH(CH3)-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-N(cyclopropyl)-CH2-; **-O-CH(CH3)-CH2-N(cyclopropyl)-CH2-; **-O-CH(CF3)-CH2-CH2- CH2-; **-O-CH2-CH2-CH(CF3)-CH2-; or **-O-CH2-CH2-N(2,2,2-trifluoroethyl)-CH2-; wherein the double asterisks indicate the attachment point of said linker group L1 to Ring A;or linker group L2; wherein such linker group L2 independently is:**-(pyrrolidin-1*,3-diyl)-CH2-; **-(piperidin-1*,3-diyl)-CH2-; **-O-CH2-(cyclopropan-1,2-diyl)-; **-O-CH2-(cyclobutan-1,2-diyl)-; **-O-(cyclopentan-1,2-diyl)-CH2-; **-O-(cyclohexan-1,2-diyl)-CH2-; **-O-(cyclohexan-1,3-diyl)-; **-O-(cyclohexan-1,3-diyl)-CH2-; **-(pyrrolidin-1*,3-diyl)-CH2-CH2-; **-O-(cyclopentan-1,2-diyl)-CH=CH-; **-O-(cyclopentan-1,3-diyl)-CH2-; **-O-(cyclopentan-1,2-diyl)-CH2-CH2-; **-O-CH2-(cyclobutan-1,3-diyl)-; **-O-(tetrahydrofuran-3,4-diyl)-CH2-CH2-; **-(4-chloro-pyrazol-1,3*-diyl)-CH2-CH2-; **-O-(tetrahydrofuran-2,3*-diyl)-CH2-CH2-; **-O-(cyclobutan-1,2-diyl)-CH2-CH2-; **-O-CH2-CH2-(cyclopropan-1,2-diyl)-; **-O-([1,3,4]oxadiazol-2,5-diyl)-CH2-; **-O-(phen-1,2-diyl)-CH2-CH2-; **-(pyridin-2,6-diyl)-CH2-CH2-; **-([1,2,4]oxadiazol-3*,5-diyl)-CH2-CH2-CH2-; **-O-(cyclobutan-1,3-diyl)-CH2-CH2-; **-O-(tetrahydrofuran-2,4*-diyl)-CH2-; **-O-(tetrahydropyran-2,4*-diyl)-CH2-; **-O-(piperidin-1,3*-diyl)-CH2-; **-O-CH2-(cyclopentan-1,3-diyl)-; **-O-(tetrahydropyran-3,5-diyl)-CH2-; **-O-(cyclohexan-1,2-diyl)-CH2-CH2-; **-O-CH2-(cyclopropan-1,2-diyl)-CH2-; **-O-CH(CH3)-CH2-(cyclopropan-1,2-diyl)-; **-(pyrazol-1,3*-diyl)-CH2-CH2-; or **-O-(cyclopentan-1,2-diyl)-O-CH2-; wherein the double asterisks indicate the attachment point of linker group L2 to Ring A; and, where applicable, the single asterisks indicate the attachment point of (i) the linker oxygen atom which is attached to Ring A, or (ii) of Ring A, as the case may be;X3 represents SO2 or S(=O)(=NR3), wherein R3 represents hydrogen or methyl;X4 represents N or CH; and R2 represents:cyclopentyl or cyclohexyl; wherein said cyclopentyl or cyclohexyl independently is mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C13)alkyl, halogen, and cyano; or a saturated bicyclic (C68)spirocycloalkyl; wherein said (C68)spirocycloalkyl is unsubstituted, or di-substituted with fluoro;or a pharmaceutically acceptable salt thereof.  10. A compound according to claim 1, which is selected from the following compounds:(6R,12aS,15aR)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10,11,13,14,15,15a-decahydrocyclopenta[e]pyrido[2,3-b][1]oxa[4]thia[8]azacyclotridecin-12(12aH)-one 16,16-dioxide;(6R,12aS,17S)-11-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-17-imino-3,6-dimethyl-6,7,8,9,10,11,12a,13,14,15-decahydro-12H,17H-17l4-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17-oxide;(6R,12aS,17S)-11-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-17-(methylimino)-6,7,8,9,10,11,12a,13,14,15-decahydro-12H,17H-17l4-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17-oxide;(6R,11aS)-10-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14-octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide;(6R,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10,11,12a,13,14,15-decahydro-12H-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide;(6R,12aS)-11-((3R,5s)-1,1-Difluorospiro[2.3]hexan-5-yl)-3,6-dimethyl-6,7,8,9,10,11,12a,13,14,15-decahydro-12H-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide; (1R,4s)-4-((6R,12aS)-3,6-Dimethyl-17,17-dioxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)-1-methylcyclohexane-1-carbonitrile; or (1R,4s)-4-((6R,12aS)-4-Fluoro-3,6-dimethyl-17,17-dioxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H-benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)-1-methylcyclohexane-1-carbonitrile; (6R,12aS,17S)-11-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-17-(methylimino)-6,7,8,9,10,11,12a,13,14,15-decahydro-12H,17H-17l4-benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17-oxide; (6R,12aS,17S)-11-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-17-((methyl-d3)imino)-6,7,8,9,10,11,12a,13,14,15-decahydro-12H,17H-17l4-benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17-oxide;(12S,51S,53S,2R)-8-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-2-imino-36-methyl-2l6-4-oxa-2l6-thia-8-aza-3(3,2)-pyridina-1(1,2)-pyrrolidina-5(1,3)-cyclohexanacyclononaphan-9-one 2-oxide; (12S,51R,53R,2S)-8-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-2-imino-36-methyl-2l6-4-oxa-2l6-thia-8-aza-3(3,2)-pyridina-1(1,2)-pyrrolidina-5(1,3)-cyclohexanacyclononaphan-9-one 2-oxide(1R,4s)-1-Methyl-4-((12S,51R,53R,2S)-36-methyl-2-(methylimino)-2-oxido-9-oxo-2l6-4-oxa-2l6-thia-8-aza-3(3,2)-pyridina-1(1,2)-pyrrolidina-5(1,3)-cyclohexanacyclononaphane-8-yl)cyclohexane-1-carbonitrile;(1R,4s)-4-((6R,12aS,17S)-3,6-Dimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H,17H-17l4-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)-1-methylcyclohexane-1-carbonitrile;(1R,4s)-4-((6R,12aS,17S)-3,6-Dimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H,17H-17l4-benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)-1-methylcyclohexane-1-carbonitrile;(1R,4s)-4-((8R,12aS,17S)-3,8-Dimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H,17H-17l4-benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)-1-methylcyclohexane-1-carbonitrile;(1R,4s)-1-Methyl-4-((12S,51R,53R,2S)-34-methyl-2-(methylimino)-2-oxido-9-oxo-2l6-4-oxa-2l6-thia-8-aza-1(1,2)-pyrrolidina-3(1,2)-benzena-5(1,3)-cyclohexanacyclononaphane-8-yl)cyclohexane-1-carbonitrile;(1R,4s)-1-Methyl-4-((6R,8R,12aS,17S)-3,6,8-trimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H,17H-17l4-benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)cyclohexane-1-carbonitrile; (6R,12aS,17S)-11-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-17-((methyl-d3)imino)-6,7,8,9,10,11,12a,13,14,15-decahydro-12H,17H-17l4-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17-oxide;(1R,4s)-4-((6R,12aS,17S)-3,6-Dimethyl-17-((methyl-d3)imino)-17-oxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H,17H-17l4-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)-1-methylcyclohexane-1-carbonitrile;(1R,4s)-4-((6R,12aS,17S)-3,6-Dimethyl-17-((methyl-d3)imino)-17-oxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H,17H-17l4-benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)-1-methylcyclohexane-1-carbonitrile;(1R,4s)-4-((8R,12aS,17S)-3,8-Dimethyl-17-((methyl-d3)imino)-17-oxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H,17H-17l4-benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)-1-methylcyclohexane-1-carbonitrile;(1R,4s)-1-Methyl-4-((6R,8R,12aS,17S)-3,6,8-trimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9,10,12a,13,14,15-octahydro-6H,17H-17l4-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11(12H)-yl)cyclohexane-1-carbonitrile; or (1R,4s)-4-((6R,12aS)-6-Ethyl-3-methyl-17,17-dioxido-12-oxo-6,7,9,10,12a,13,14,15-octahydropyrido[2,3-e]pyrrolo[1,2-h][1,4]dioxa[7]thia[8,11]diazacyclotridecin-11(12H)-yl)-1-methylcyclohexane-1-carbonitrile;or a pharmaceutically acceptable salt thereof.  11. A compound according to claim 1, which is;or a pharmaceutically acceptable salt thereof.  12. A pharmaceutical composition comprising, as active principle, one or more compounds according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.  13. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use as a medicament.  14. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in improving wakefulness.  15. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof:for use in the treatment of hypersomnia including narcolepsy, narcolepsy associated with inherited disorders; narcolepsy associated with tumors, narcolepsy associated with head trauma, idiopathic hypersomnia, or Kleine-Levin syndrome;for use in improving symptoms of excessive daytime sleepiness (EDS) including:improving symptoms of EDS in subjects having a circadian rhythm sleep-wake disorder;improving symptoms of EDS due to or associated with a medical disorder, wherein said medical disorder is especially an objective sleep disturbance, obesity, diabetes, a neurodegenerative disorder, an auto-immune disorder, a psychiatric disorder, or insufficient sleep syndrome;improving symptoms of EDS due to a medication or substance; for use in the treatment of eating disorders, obesity, neuropsychiatric disorders, pain, inflammation, or cognitive impairments associated with diminished wakefulness; orfor the use in treatment of fatigue including:improving symptoms of fatigue accompanied by poor concentration and memory;improving symptoms of chronic fatigue associated with cancer or chemotherapy;improving symproms of chronic fatigue associated with infections, (chronic) inflammatory diseases, autoimmune diseases or neurological diseases;treatment of chronic fatigue associated with myalgic encephalomyelitis / chronic fatigue syndrome;for use in improving symptoms of cognitive impairment including age-related cognitive disorders;for use in the treatment of attention deficit including attention-deficit hyperactivity disorder; orfor use in the treatment of mood disorders associated with reduced hedonic drive including depression, schizophrenia, or addiction.   16. Use of a compound of Formula (I) as defined in any one of claims 1 to 11, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for improving wakefulness.   17. A method for improving wakefulness comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) as defined in any one of claims 1 to 11, or of a pharmaceutically acceptable salt thereof.

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