Emopamil binding protein inhibitors and uses thereof

Abstract

Compounds of formula (I): JPEG2025504889000177.jpg4267, or a pharma- ceutically acceptable salt thereof, is provided, which is useful for inhibiting EBP and for treating various EBP-mediated conditions or diseases, such as multiple sclerosis.

Description

[Technical field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 63 / 302,195, filed January 24, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to inhibitors of emopamil binding protein (EBP) and pharma- ceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, their use in the treatment of disease, their use optionally in combination with a pharma- ceutically acceptable carrier for the manufacture of a pharmaceutical preparation, the use of the pharmaceutical preparation in the treatment of disease, and methods of treating disease comprising administering an EBP inhibitor to a warm-blooded animal, particularly a human. [Background technology]

[0003] Emopamil-binding protein (EBP) is a Δ8-Δ7 sterol isomerase enzyme that isomerizes the double bond in the sterol molecule, moving it from position 8-9 to position 7-8. Specifically, EBP converts either zymostenol to lathosterol or zymosterol to dehydrolatosterol during cholesterol biosynthesis (Silve et al., 1996, J Biol Chem. 271(37), 22434-22440). Accumulation of 8-9 unsaturated sterols has been shown to activate oligodendrocyte formation and remyelination (Hubler et al., 2019, Nature 560(7718), 372-376).

[0004] Myelin is a lipid-based molecule that forms a protective layer (myelin sheath) around nerve cell axons, insulating them. Demyelinating, or myelin-related, diseases are the result of these myelin sheaths being damaged, degraded, or reduced in thickness. Loss of myelin sheaths can disrupt electronic signals from the brain, leading to nerve damage, vision loss, numbness, muscle weakness, cognitive decline, loss of motor function, and other similar symptoms. In some myelin-related diseases, such as multiple sclerosis, the subject's immune system targets and destroys their own myelin sheath. The ability to repair and regenerate myelin sheaths is key to treating these myelin-related diseases. Inhibition of EBP, due to its function in converting 8-9 sterols, is a potential target for activating remyelination as its inhibition leads to an increase in these 8-9 sterol starting materials (Theodoropoulous et al, 2020, J. Am. Chem. Soc., 142, (13), 6128-6138).

[0005] In addition to its role in remyelination, EBP has also been shown to be a key enzyme in certain colorectal cancers due to the reduction of essential lipids such as cholesterol (Theodoropoulous et al., 2020, J. Am. Chem. Soc., 142, (13), 6128-6138).

[0006] Thus, there is a need for EBP inhibitors as potential therapeutic agents for treating diseases or disorders that respond to EBP inhibition. Summary of the Invention

[0007] The present disclosure provides compounds that are EBP inhibitors. In a first aspect, the present disclosure provides compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, C 1~6 Alkyl, C 3~8Cycloalkyl, Het, -Z-Het and ZC 3~8 cycloalkyl, where C 1~6 Alkyl, C 3~8 Cycloalkyl and Het each optionally contain one or more R 4 with the exception of R 1 and R 2 is not H, or R 1 and R 2 together with the nitrogen atom to which they are attached, optionally represent one or more substituents R 4 forming a 4- to 10-membered heterocyclyl substituted with Z is C optionally substituted with one or more halo. 1~4 is alkyl, Het is 4- to 7-membered monocyclic heterocyclyl or 6- to 10-membered bicyclic heterocyclyl, each of which is optionally selected from R 4 is replaced by R 3 is phenyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl, wherein the phenyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl each optionally contain one or more substituents R 5 is replaced by R 4 independently for each occurrence, C 1~6 Alkyl, halo, and -OR 4a where C 1~6 The alkyl group is optionally represented by -OR 4a is replaced by R 4a , H, C 1~6 Alkyl, or C 1~6 is haloalkyl, R 5 is, for each occurrence independently, halo, -OR 5a , C 1~6 Alkyl, C 3~6 cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, or phenyl, where C 1~6 Alkyl, C 3~6Cycloalkyl and 5-6 membered monocyclic heteroaryl are each optionally selected from one or more halo, C 1~4 Alkyl, or -OR 5a or The Two R's 5 together with their intervening atoms, C 1~6 Alkyl, oxo, halo, and -OR 5a one or more R independently selected from 6 forming a 5- to 7-membered heterocycle optionally substituted with R 5a , H, C 1~6 Alkyl, or C 1~6 haloalkyl, where C 1~6 The alkyl is optionally substituted with alkoxy; R 7 is H or OR 7a and R 7a , H, C 1~6 Alkyl, or C 1~6 haloalkyl, where C 1~6 The alkyl is optionally substituted with an alkoxy.

[0008] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharmaceutical carrier.

[0009] In yet another embodiment, the present disclosure provides a method for treating a disease or disorder responsive to inhibition of EBP in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating multiple sclerosis. In some embodiments, the present disclosure provides a method for promoting myelination in a subject with a myelin-related disorder.

[0010] Another embodiment of the present disclosure relates to the use of at least one compound as described herein, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder that responds to the inhibition of EBP.Also provided is a compound as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease or disorder that responds to the inhibition of EBP. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful in the treatment of diseases or disorders through the mediation of EBP function / activity, such as multiple sclerosis or other myelin-related disorders, in some embodiments, the compounds of the present disclosure are EBP inhibitors.

[0012] Compounds and Compositions In a first embodiment, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, C 1~6 Alkyl, C 3~8 cycloalkyl, Het, -Z-Het, where C 1~6 Alkyl, C 3~8 Cycloalkyl and Het each optionally contain one or more R 4 with the exception of R 1 and R 2 is not H, or R 1 and R 2 together with the nitrogen atom to which they are attached, optionally represent one or more substituents R 4 forming a 4- to 10-membered heterocyclyl substituted with Z is C optionally substituted with one or more halo. 1~4 is alkyl, Het is 4- to 7-membered monocyclic heterocyclyl or 6- to 10-membered bicyclic heterocyclyl, each of which is optionally selected from R 4 is replaced by R 3 is phenyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl, wherein the phenyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl each optionally contain one or more substituents R 5 is replaced by R 4 independently for each occurrence, C 1~6 Alkyl, halo and -OR 4a is selected from R 4a , H, C 1~6 Alkyl, or C 1~6 is haloalkyl, R 5 is, for each occurrence independently, halo, -OR 5a , C 1~6 Alkyl, C 3~6 cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, or phenyl, where C 1~6 Alkyl, and C 3~6 Each cycloalkyl is optionally selected from one or more halo, -OR 5a or The Two R's 5 together with their intervening atoms, C 1~6 Alkyl, oxo, halo, and -OR 5a one or more R independently selected from 6 forming a 5- to 7-membered heterocycle optionally substituted with R 5a , H, C 1~6 Alkyl, or C 1~6 haloalkyl, where C 1~6 The alkyl is optionally substituted with alkoxy; R 7 is H or OR 7a and R 7a , H, C 1~6 Alkyl, or C 1~6haloalkyl, where C 1~6 The alkyl is optionally substituted with an alkoxy.

[0013] In a second embodiment, the compound of the present disclosure has formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (II) are as defined in the first aspect or embodiment above.

[0014] In a third embodiment, the compound of the present disclosure has formula (IIA) or (IIB): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (IIA) and (IIB) are as defined in the first aspect or the first or second embodiment above.

[0015] In a fourth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 3 is selected from the group consisting of phenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, furanyl, oxadiazolyl, imidazopyridinyl, thiophenyl, thiazoyl, triazoyl, and indolyl, each of which is optionally selected from one to three R 5 and the remaining variables are as described in the first aspect or the first, second, or third embodiment. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, wherein R 3is selected from the group consisting of phenyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, furanyl, oxadiazolyl, imidazopyridinyl, and thiophenyl, each of which is optionally selected from one to three R 5 and the remaining variables are as described in the first aspect or the first, second or third embodiment.

[0016] In a fifth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] Each of these is optionally represented by 1 to 3 R 5 or R 3 is the following formula: [ka] Each of these is optionally represented by one or two R 6 and the remaining variables are as described in the first aspect, or the first, second, third, or fourth embodiment, or any alternative embodiment described therein. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, wherein R 3 is the following formula: [ka] Each of these is optionally represented by 1 to 3 R 5 or R 3 is the following formula: [ka] Each of these is optionally represented by one or two R 6and the remaining variables are as described in the first aspect, or the first, second, third or fourth embodiment, or any alternative embodiment described therein.

[0017] In a sixth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 3 is selected from the group consisting of phenyl, pyrazolyl, imidazolyl, oxazolyl, and pyridinyl, each of which is optionally selected from 1 to 3 R 5 and the remainder of the variables are as described in the fourth embodiment.

[0018] In a seventh embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] Each of these is optionally represented by one or two R 5 or R 3 is the following formula: [ka] Each of these is represented by one or two R 6 and the remaining variables are as described in the fifth embodiment.

[0019] In an eighth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] and the remaining variables are as described in the fifth embodiment. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R3 is the following formula: [ka] and the remainder of the variables are as described in the fifth embodiment.

[0020] In a ninth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] and the remainder of the variables are as described in the fifth embodiment.

[0021] In a tenth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence independently, halo, -OR 5a , C 1~6 alkyl, 4-7 membered monocyclic heterocyclyl, or phenyl, where C 1~6 The alkyl group is optionally represented by -OR 5a or halo, and the 5-6 membered monocyclic heteroaryl is optionally C 1~3 Alkyl-substituted, R 6 is C 1~3 and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or any alternative embodiment described therein. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, wherein R 5 is, for each occurrence independently, halo, -OR 5a , C 1~6 alkyl, 4-7 membered monocyclic heterocyclyl, or phenyl, where C 1~6 Each alkyl is optionally -OR 5a is replaced by R 6 is C 1~3alkyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment. In a further alternative embodiment, R 5 is, independently at each occurrence, -F, -Cl, -CH3, -CH2CH3, -CF3, -OCHF2, -OCH3, -CH2OCH3, tetrahydropyranyl, phenyl, pyridinyl; R 6 is -CH3, and optionally, R 5 is the following formula: [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or any alternative embodiment described therein.

[0022] In an eleventh embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 may optionally be one to three R 4 and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment, or any alternative embodiment described therein.

[0023] In a twelfth embodiment, for a compound of Formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic saturated heterocyclyl, or an 8- to 9-membered bicyclic heterocyclyl, each of which may optionally be selected from 1 to 3 R 4and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment, or any alternative embodiment described therein.

[0024] In a thirteenth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the nitrogen atom to which they are attached form the following formula: [ka] each of which optionally has 1 to 3 R 4 and the remaining variables are as described in the twelfth embodiment, or alternative embodiments described therein. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the nitrogen atom to which they are attached form the following formula: [ka] each of which optionally has 1 to 3 R 4 and the remaining variables are as described in the twelfth embodiment, or alternative embodiments described therein.

[0025] In a fourteenth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the nitrogen atom to which they are attached form the following formula: [ka] and the remaining variables are as described in the thirteenth embodiment, or alternative embodiments described therein. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the nitrogen atom to which they are attached form the following formula: [ka] and the remainder of the variables are as described in the thirteenth embodiment, or alternative embodiments described therein.

[0026] In a fifteenth embodiment, for a compound of Formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 Het, -C 1~3 Alkyl-Het, -C 1~3 Alkyl-C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, or C 1~6 alkyl, where C 3~6 Cycloalkyl and C 1~6 Each alkyl is optionally joined by one or two R 4 is replaced by R 2 is H or C 1~3 Het is a 4- to 6-membered monocyclic saturated heterocyclyl or a 6- to 7-membered bicyclic saturated heterocyclyl, the 4- to 6-membered monocyclic saturated heterocyclyl and the 6- to 7-membered bicyclic saturated heterocyclyl each containing one oxygen ring atom and each optionally containing one or two R 4 is replaced by R 4 is independently in each occurrence: -OR 4a , halo, or C 1~3 Alkyl, C 1~3 The alkyl group is optionally represented by -OR 4a is replaced by R 4a is H or C 1~3R is alkyl, and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment, or any alternative embodiment described therein. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 Het, -C 1~3 Alkyl-Het, C 3~6 Cycloalkyl or C 1~6 alkyl, where C 3~6 Cycloalkyl and C 1~6 Each alkyl is optionally joined by one or two R 4 Het is a 4- to 6-membered monocyclic saturated heterocyclyl or a 6- to 7-membered bicyclic saturated heterocyclyl, the 4- to 6-membered monocyclic saturated heterocyclyl and the 6- to 7-membered bicyclic saturated heterocyclyl each containing one oxygen ring atom and each optionally containing one or two R 4 is replaced by R 4 is independently in each occurrence -OH, halo, or C 1~3 is alkyl, R 2 is H or C 1~3 is alkyl, and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment, or any alternative embodiment described therein.

[0027] In a sixteenth embodiment, for compounds of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, Het is oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, 2-oxaspiro[3.3]heptanyl, or 5-oxabicyclo[2.1.1]hexanyl, each of which may optionally be joined by one R 4and the remaining variables are as described in the fifteenth embodiment, or any alternative embodiment described therein. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, Het is oxetanyl, tetrahydro-2H-pyranyl, or 5-oxabicyclo[2.1.1]hexanyl, each of which is optionally substituted with one R 4 and the remaining variables are as described in the fifteenth embodiment, or any alternative embodiment described therein.

[0028] In a seventeenth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 is the following formula: [ka] Each of them is optionally represented by one or two R 4 and the remaining variables are as described in the fifteenth embodiment, or alternative embodiments described therein. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 is the following formula: [ka] Each of them is optionally represented by one or two R 4 and the remaining variables are as described in the fifteenth embodiment, or alternative embodiments described therein.

[0029] In an eighteenth embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 is the following formula: [ka] and the remaining variables are as described in the fifteenth embodiment, or alternative embodiments described therein. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 1 is the following formula: [ka] and the remainder of the variables are as described in the fifteenth embodiment, or alternative embodiments described therein.

[0030] In a nineteenth embodiment, for a compound of Formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 2 is H or -CH3, and the remaining variables are as described in the fifteenth, sixteenth, seventeenth or eighteenth embodiment, or any alternative embodiment described therein. In an alternative embodiment, for a compound of formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, R 2 is H, and the remaining variables are as described in the fifteenth, sixteenth, seventeenth or eighteenth embodiment, or any alternative embodiment described therein.

[0031] In one embodiment, for a compound of Formula (I), (II), (IIA), or (IIB), or a pharma- ceutically acceptable salt thereof, each R 4 is independently at each occurrence -F, -CH, -CHCHOCH, -CHOH, -OH, or -OCH, and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment, or any alternative embodiment described therein.

[0032] In a twentieth embodiment, the compound of the present disclosure has formula (III) or (IV): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 3~6 cycloalkyl, Het, or -CH2-Het, where C 3~6 Cycloalkyl may optionally be one R 4 is replaced by Het is a 4- to 6-membered monocyclic saturated heterocyclyl or a 6- to 7-membered bicyclic saturated heterocyclyl, where the 4- to 6-membered monocyclic saturated heterocyclyl and the 6- to 7-membered bicyclic saturated heterocyclyl each contain one oxygen ring atom and optionally one R 4 is replaced by Ring A is a 4- to 6-membered monocyclic saturated heterocyclyl, or an 8- or 9-membered bicyclic heterocyclyl, each of which optionally contains one or two R 4 is replaced by R 3 is phenyl, pyridinyl, or 5-membered heteroaryl, each of which is optionally joined by one or two R 5 is replaced by R 4 represents independently at each occurrence -OH, halo and C 1~3 alkyl, R 5 is, for each occurrence independently, halo, -OR 5a , C 1~6 alkyl, 4- to 6-membered monocyclic heterocyclyl, or phenyl, where C 1~6 The alkyl group is optionally substituted with 1 to 3 halo or -OR 5a or The Two R's 5 together with their intervening atoms, C 1~6 1 to 3 R independently selected from alkyl, oxo, and halo; 6 forming a 6-membered heterocycle optionally substituted with R 5a , H, C 1~3 Alkyl, or C 1~3 haloalkyl, and the remainder of the variables are as described in the first aspect or the first or second embodiment.

[0033] In a twenty-first embodiment, for the compounds of formula (III) or (IV), or a pharma- ceutically acceptable salt thereof, Het is oxetanyl, tetrahydro-2H-pyranyl, or 5-oxabicyclo[2.1.1]hexanyl, each of which may optionally be joined by one R 4 is replaced by Ring A is [ka] Each of these may optionally be one to two R 4 is replaced by R 3 teeth, [ka] each of which may optionally contain one or two R 5 or R 3 teeth, [ka] each of which may optionally be one or two R 6 and the remainder of the variables are as described in the twentieth embodiment.

[0034] In a twenty-second embodiment, for a compound of formula (III) or (IV), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] and the remainder of the variables are as described in the twentieth or twenty-first embodiment.

[0035] In a twenty-third embodiment, for the compounds of formula (III) or (IV), or a pharma- ceutically acceptable salt thereof, Het is of the following formula: [ka] and the remainder of the variables are as described in the twentieth, twenty-first or twenty-second embodiment.

[0036] In a twenty-fourth embodiment, for a compound of formula (III) or (IV), or a pharma- ceutically acceptable salt thereof, R 4 is independently at each occurrence -CH3, -OH, or F, and the remaining variables are as described in the twentieth, twenty-first, twenty-second, or twenty-third embodiment.

[0037] In a twenty-fifth embodiment, for a compound of formula (III) or (IV), or a pharma- ceutically acceptable salt thereof, R 5 is independently for each occurrence -OCF3, -OCHF2, Cl, -CH2OCH3, -CH3, -CF3, -OCH3, -CH2CH3, [ka] and the remaining variables are as described in the twentieth, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment.

[0038] In a twenty-sixth embodiment, the compound of the present disclosure has formula V: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formula (V) are as defined in the first aspect or embodiment above.

[0039] In a twenty-seventh embodiment, the compound of the present disclosure has formula (VA) or (VB): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables in formulae (VA) and (VB) are as defined in the twenty-sixth embodiment above.

[0040] In a twenty-eighth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 3 is selected from the group consisting of phenyl, pyrazolyl, isoxazoyl, and pyridinyl, each of which is optionally selected from 1 to 3 R 5 and the remaining variables are as described in the twenty-sixth or twenty-seventh embodiment.

[0041] In a twenty-ninth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] Each of the formulas shown above may optionally contain one to three R 5 and the remaining variables are as described in the twenty-sixth, twenty-seventh, or twenty-eighth embodiment.

[0042] In a thirtieth embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 3 is the following formula: [ka] and the remainder of the variables are as described in the twenty-sixth, twenty-seventh, twenty-eighth or twenty-ninth embodiment.

[0043] In a thirty-first embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 5 is, for each occurrence independently, halo, -OR 5a , or C 1~6 alkyl, and the remaining variables are as described in the twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth or thirtieth embodiment.

[0044] In a thirty-second embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R7 is H or OH, and the remaining variables are as described in the twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth or thirty-first embodiment.

[0045] In a thirty-third embodiment, for a compound of formula (V), (VA), or (VB), or a pharma- ceutically acceptable salt thereof, R 1 and R 2 together with the nitrogen atom to which they are attached form the following formula: [ka] and the remainder of the variables are as described in the twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first or thirty-second embodiment.

[0046] In a thirty-fourth embodiment, the compound of the present disclosure has formula (VI) or (VII): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, Het, -CH2-C 3~4 cycloalkyl, or -CH2-Het, where C 1~6 Alkyl, C 3~6 Cycloalkyl, and -CH2-C 3~4 Each cycloalkyl optionally has one or two R 4 is replaced by Het is a 4-6 membered monocyclic saturated heterocyclyl containing one oxygen ring atom; Ring A is a 4- to 6-membered monocyclic saturated heterocyclyl, or an 8- or 9-membered bicyclic saturated heterocyclyl, each of which optionally contains one or two R 4 is replaced by R 4 is, independently for each occurrence, -OR 4a , -CH2-OR 4a , and C 1~3alkyl, R 4a is H or C 1~3 is alkyl, R 5 -OR 5a and R 5a is C 1~3 haloalkyl, and the remainder of the variables in formulae (VI) and (VII) are as defined in the third embodiment.

[0047] In a thirty-fifth embodiment, for compounds of formula (VI) or (VII), or a pharma- ceutically acceptable salt thereof, Het is tetrahydropyranyl or oxetanyl, and the remaining variables are as defined in the thirty-fourth embodiment.

[0048] In a thirty-sixth embodiment, for a compound of formula (VI) or (VII), or a pharma- ceutically acceptable salt thereof, R 1 teeth, (i) One or two R 4 C optionally substituted with 1~6 Is it an alkyl group? (ii) the following formula: [ka] or (iii) the formula: [ka] Each of these is optionally represented by one or two R 4 and the remaining variables are as defined in the thirty-fourth or thirty-fifth embodiment.

[0049] In a thirty-seventh embodiment, for compounds of formula (VI) or (VII), or a pharma- ceutically acceptable salt thereof, R 1 is -CH(CH3)CH2CH2OCH3 or CH2C(CH3)2OH, or R 1 is the following formula: [ka] and the remainder of the variables are as defined in the thirty-sixth embodiment.

[0050] In a thirty-eighth embodiment, for compounds of formula (VI) or (VII), or a pharma- ceutically acceptable salt thereof, ring A is [ka] each of which may optionally contain one or two R 4 and the remaining variables are as defined in the thirty-fourth embodiment.

[0051] In a thirty-ninth embodiment, for compounds of formula (VI) or (VII), or a pharma- ceutically acceptable salt thereof, ring A is [ka] and the remainder of the variables are as defined in the thirty-eighth embodiment.

[0052] In a fortieth embodiment, for a compound of formula (VI) or (VII), or a pharma- ceutically acceptable salt thereof, each R 4 is independently -OH, -OCH3, -CH2OH, or -CH3, and the remaining variables are as described in the thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment.

[0053] In a forty-first embodiment, for compounds of formula (VI) or (VII), or a pharma- ceutically acceptable salt thereof, each R 5 is -OCHF2, and the remaining variables are as described in the thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth or fortieth embodiment.

[0054] In a forty-second embodiment, the disclosure provides a compound described herein (eg, a compound described in any one of Examples 1-77), or a pharma- ceutically acceptable salt thereof.

[0055] In a forty-third embodiment, the present disclosure provides a method for producing a composition comprising: 3-methyl-4-(((1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-1,2,5-oxadiazole, 5-(((1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)oxazole, (1R,3s,5S)-8-((2-methoxy-6-methylpyridin-3-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((4-chloro-1-(methoxymethyl)-1H-pyrazol-5-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 3,3-dimethyl-6-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-3,4-dihydroquinolin-2(1H)-one, 5-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)oxazole, (1R,3s,5S)-8-(isochroman-7-ylsulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((5-(methoxymethyl)furan-2-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 2-methyl-3-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole, (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-((3-phenyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octane, 5-methyl-2-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, (1R,3s,5S)-8-((1,4-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 2-((8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)cyclobutan-1-ol, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, 9-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3,3-difluoro-9-azabicyclo[3.3.1]nonane, 4-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)tetrahydro-2H-pyran-4-ol, 4-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)tetrahydro-2H-pyran-4-ol, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 6-((1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxa-6-azaspiro[3.3]heptane, 6-((1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxa-6-azaspiro[3.3]heptane, (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol, 4-(((1R,3s,5S)-8-((4-(difluoromethoxy)-2,6-difluorophenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, 4-(((1R,3s,5S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, 4-(((1R,3r,5S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, 4-(((1R,3s,5S)-8-((3,5-dimethylisoxazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, 4-(((1R,3s,5S)-8-((4,6-dimethylpyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, (1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-((1-(4-methylpyridin-2-yl)-1H-pyrazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-((1-(4-methylpyridin-2-yl)-1H-pyrazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octane, 4-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-(trifluoromethyl)thiazole, (1R,3s,5S)-8-((2,6-difluoro-4-methoxyphenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-((1-phenyl-1H-1,2,3-triazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octane, 1,3-dimethyl-5-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-1H-pyrazolo[3,4-b]pyridine, (1R,3s,5S)-8-((3,5-dimethylpyridin-2-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((2,6-dimethylpyridin-3-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 1-((8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)propan-2-ol, 1-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-methylpyrrolidin-3-ol, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(3-methoxypyrrolidin-1-yl)-8-azabicyclo[3.2.1]octane, 6-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxa-6-azaspiro[3.4]octane, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(4-methoxybutan-2-yl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8,8'-diaza-3,8'-bi(bicyclo[3.2.1]octane), 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(3-(2-methoxyethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(3-methoxybutan-2-yl)-8-azabicyclo[3.2.1]octan-3-amine, rac-((1R,2S)-2-(((8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclopropyl)methanol, 3-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.1]heptane, 8'-((4-(difluoromethoxy)phenyl)sulfonyl)-3,8'-diaza-3,3'-bi(bicyclo[3.2.1]octane), rac-4-(((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)butan-2-ol, rac-4-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)butan-2-ol, (1R,3r)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol, (1R,3r)-3-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3yl)amino)methyl)cyclobutan-1-ol, (1S,3s)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol, (1S,3s)-3-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, 4-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((R)-tetrahydrofuran-3-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-fluorooxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, 1-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-methylpropan-2-ol, and 1-(((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-methylpropan-2-ol The present invention provides a compound selected from the group consisting of:

[0056] In a forty-fourth embodiment, the present disclosure provides a pharmaceutical composition comprising a compound described in any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof.

[0057] In a forty-fifth embodiment, the present disclosure provides a method for treating a disease or disorder mediated by EBP, the method comprising administering to a subject an effective amount of a compound described in any one of embodiments 1 to 44, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the forty-fourth embodiment.

[0058] In a forty-sixth embodiment, the present disclosure provides a compound according to any one of embodiments 1 to 44 for use in treating a disease or disorder mediated by EBP.

[0059] In a forty-seventh embodiment, the present disclosure provides the use of a compound according to any one of embodiments 1 to 44 for use in the manufacture of a medicament for the treatment of a disease or disorder mediated by EBP.

[0060] The compounds and intermediates described herein may be isolated and used as such. Alternatively, if moieties capable of forming salts are present, the compounds or intermediates may be isolated and used as their corresponding salts. As used herein, the term "salt" or "salts" refers to acid addition or base addition salts of the compounds described herein. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds described herein and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0061] Pharmaceutically acceptable acid addition salts include, for example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl Salts may be formed using inorganic or organic acids, such as sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0062] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0063] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0064] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0065] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table, in certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0066] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0067] Salts can be synthesized by conventional chemical methods from compounds that contain a basic or acidic site. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable where feasible. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0068] Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those of skill in the art or by processes analogous to those described in the accompanying examples and preparations, substituting an appropriate isotopically labeled reagent for the unlabeled reagent previously used. In one embodiment, the present disclosure provides a deuterated compound as described herein, or a pharma- ceutically acceptable salt thereof.

[0069] Pharmaceutically acceptable solvates in accordance with the present invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0070] Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and therefore may exist in different stereoisomeric forms.As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure.It is understood that a substituent may be bonded at a chiral center of a carbon atom.Therefore, the present disclosure includes the enantiomers, diastereomers, or racemates of the compounds.

[0071] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The terms "racemic" or "rac" are used to designate racemic mixtures where appropriate. When designating the stereochemistry of the compounds of the invention, single stereoisomers in which the relative and absolute configurations of the two chiral centers are known are designated using the conventional RS system (e.g., (1S,2S)). "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is defined according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated as either R or S. Separated compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds may be defined by their respective retention times relative to the corresponding enantiomers / diastereomers via chiral HPLC.

[0072] Certain compounds described herein contain one or more asymmetric centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0073] Unless otherwise specified, the compounds of the present disclosure are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R) and (S) stereoisomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp., using a suitable solvent or solvent mixture to achieve good separation). When the compound contains a double bond, the substituent may be in the E or Z configuration. When the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0074] How to use The compounds disclosed herein have EBP inhibitory activity. As used herein, "EBP inhibitory activity" refers to the ability of a compound or composition to induce detectable reduction in EBP activity in vivo or in vitro (e.g., at least 10% reduction in EBP activity when measured by a given assay, such as the bioassay described in the Examples and known in the art).

[0075] In certain embodiments, the disclosure provides a method of treating a disease or disorder responsive to inhibition of EBP activity (referred to herein as an "EBP-mediated disease or disorder" or "a disease or disorder mediated by EBP") in a subject in need of such treatment. The method includes administering to the subject a compound described herein (e.g., a compound described in any one of the first to forty-third embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0076] In certain embodiments, the disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to forty-three embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an EBP-mediated disorder or disease in a subject in need thereof.

[0077] In certain embodiments, the disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-three embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in treating an EBP-mediated disorder or disease in a subject in need thereof.

[0078] In certain embodiments, the EBP-mediated disorder is colorectal cancer.

[0079] In certain embodiments, the present disclosure provides a method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a compound described herein (e.g., a compound described in any one of embodiments 1-43), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0080] In certain embodiments, the disclosure provides for the use of a compound described herein (e.g., a compound described in any one of the first to forty-three embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an autoimmune disease in a subject in need thereof.

[0081] In certain embodiments, the disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-three embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in the treatment of an autoimmune disease in a subject in need thereof.

[0082] In certain embodiments, the autoimmune disease is multiple sclerosis (MS). The compounds of the present disclosure can be used to treat all stages of MS, including relapsing multiple sclerosis (or relapsing form(s) of multiple sclerosis), relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and clinically isolated syndrome (hereinafter "CIS").

[0083] Relapsing multiple sclerosis (or relapsing form(s) of multiple sclerosis) includes clinically isolated syndrome, relapsing remitting multiple sclerosis, and active secondary progressive multiple sclerosis.

[0084] Relapsing-remitting multiple sclerosis is a stage of MS characterized by unpredictable relapses followed by relatively quiet (remission) periods of months to years without new signs of disease activity. Deficits occurring during attacks may resolve or remain problematic, the latter occurring in approximately 40% of attacks and becoming more common the longer the patient has had the disease. This accounts for the initial course in 80% of individuals with multiple sclerosis.

[0085] Secondary progressive multiple sclerosis occurs in approximately 65% ​​of patients with initial relapsing-remitting multiple sclerosis and eventually results in progressive neurological decline during acute attacks without clear periods of remission. Occasional relapses and mild remissions may occur. The most common time from disease onset to conversion from relapsing-remitting to secondary progressive multiple sclerosis is 19 years.

[0086] Primary progressive multiple sclerosis is characterized by the same symptoms as secondary progressive multiple sclerosis, i.e., progressive neurological deterioration during acute attacks without prior relapsing-remitting periods and with no distinct periods of remission.

[0087] CIS is the first episode of neurological symptoms caused by inflammation and demyelination of the central nervous system. By definition, this episode, which must last at least 24 hours, is characteristic of multiple sclerosis, but does not yet meet the criteria for a diagnosis of MS, as a person who experiences CIS may or may not develop MS. If CIS is accompanied by lesions on brain MRI (magnetic resonance imaging) similar to those seen in MS, the person is more likely to have a second episode of neurological symptoms and a diagnosis of relapsing-remitting MS. If CIS is not accompanied by MS-like lesions on brain MRI, the person is much less likely to develop MS.

[0088] In certain embodiments, the disclosure provides a method of promoting myelination in a subject having a myelin-related disease or disorder in a subject in need of treatment, comprising administering to the subject a compound described herein (e.g., a compound described in any one of embodiments 1-43), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0089] In certain embodiments, the disclosure provides for the use of a compound described herein (e.g., a compound described in any one of the first to forty-three embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for promoting myelination in a subject having a myelin-related disease or disorder in a subject in need of treatment.

[0090] In certain embodiments, the disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-three embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in promoting myelination in a subject having a myelin-related disease or disorder in a subject in need of treatment.

[0091] In certain embodiments, the myelin-related disease or disorder is multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), acute disseminated encephalomyelitis (ADEM), central pontine myelitis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus-Merzbacher disease (PMD), vanishing white matter, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, radiation damage. In some embodiments, the disease is selected from the group consisting of neuropathies, neurological complications of chemotherapy, seizures, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, autism, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination, e.g., neuromyelitis optica (NMO), optic neuritis, childhood leukodystrophy, neonatal white matter injury, age-related dementia, and schizophrenia.

[0092] In certain embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound described herein (e.g., a compound described in any one of embodiments 1-43) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0093] In certain embodiments, the disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to forty-three embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

[0094] In certain embodiments, the disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-three embodiments), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer in a subject in need thereof.

[0095] In certain embodiments, the cancer is colorectal cancer.

[0096] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a mammal, hi certain embodiments, the subject is a primate, hi certain embodiments, the subject is a human.

[0097] As used herein, "effective amount" and "therapeutically effective amount" may be used interchangeably. Means an amount effective to treat or reduce the severity of one or more of the diseases, disorders, or conditions described herein. In some embodiments, an effective dose may be from 10 μg to 500 mg.

[0098] The compounds and compositions according to the disclosed methods may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the above-listed diseases, disorders, or conditions.

[0099] In certain embodiments, the disclosure relates to the aforementioned method, wherein the compound is administered parenterally. In certain embodiments, the disclosure relates to the aforementioned method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically, or intranasally. In certain embodiments, the disclosure relates to the aforementioned method, wherein the compound is administered systemically.

[0100] The compounds of the present invention are used as pharmaceutical compositions (e.g., a compound of the present invention and at least one pharma- ceutically acceptable carrier). As used herein, the term "pharma- ceutically acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and the like, and combinations thereof, that are generally recognized as safe (GRAS), as understood by those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the event that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. For purposes of this disclosure, solvates and hydrates are considered to be pharmaceutical compositions that include a compound of the present invention and a solvent (i.e., a solvate) or water (i.e., a hydrate).

[0101] The formulations can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the compound of the present invention, or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide an easily controllable drug dosage and to provide the patient with an elegant and easily handled product.

[0102] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, the article for distribution includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, a label is disposed on the container that describes the contents of the container. The label may also include appropriate warnings.

[0103] Pharmaceutical compositions containing the compounds of the present disclosure will generally be formulated for parenteral or oral administration or for use as suppositories.

[0104] For example, oral pharmaceutical compositions of the present disclosure may be configured in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in a liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical processes, such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, and the like.

[0105] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient. a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol, also in the case of tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, optionally d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) together with absorbents, colorants, flavorants and sweeteners.

[0106] Tablets may be film coated or enteric coated according to methods known in the art.

[0107] Compositions suitable for oral administration include the compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide pharma-ceutically elegant and palatable preparations. Tablets may contain the active ingredient in a mixture with non-toxic, pharma-ceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin, or acacia; and lubricants, for example, magnesium stearate, stearic acid, or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be utilized.Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0108] Parenteral compositions (e.g., intravenous (IV) preparations) are aqueous, isotonic solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizing agents, wetting agents or emulsifying agents, dissolution promoters, salts for controlling osmotic pressure, and / or buffers. In addition, they may contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating, or coating methods, respectively, and contain about 0.1-75% or about 1-50% of the active ingredient.

[0109] The compound of the present disclosure or its pharma- ceutically acceptable salt used in a subject (e.g., human) is typically administered orally or parenterally at a therapeutic dose of about 100 mg / kg or less, about 75 mg / kg or less, about 50 mg / kg or less, about 25 mg / kg or less, about 10 mg / kg or less, about 7.5 mg / kg or less, about 5.0 mg / kg or less, about 3.0 mg / kg or less, about 1.0 mg / kg or less, about 0.5 mg / kg or less, about 0.05 mg / kg or less, or about 0.01 mg / kg or less, but preferably about 0.0001 mg / kg or more. When administered intravenously by infusion, the dosage may depend on the infusion rate at which the IV formulation is administered. In general, the therapeutically effective dosage of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, pharmacist, clinician or veterinarian having ordinary skill in the art can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the progress of a disorder or disease.

[0110] The above-mentioned administration properties are demonstrable in in vitro and in vivo tests, preferably using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, for example aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, for example in suspension or aqueous solution. The dosage in vitro may range from about 10-3 molar to 10-9 molar.

[0111] definition As used herein, "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. The term includes mammals, such as humans. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

[0112] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0113] As used herein, the terms "treat", "treating" or "treatment" of any disease, condition or disorder refer to the management and care of a patient with the goal of combating the disease, condition, or disorder, and include the administration of a compound of the present invention to obtain a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the extent of the disease, condition, or disorder; ameliorating or improving clinical symptoms, complications, or indicators associated with the disease, condition, or disorder; or delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or disorder; or eliminating the disease, condition, or disorder. In certain embodiments, the effect may be preventing the onset of symptoms or complications of the disease, condition, or disorder.

[0114] As used herein, the term "cancer" has its commonly accepted meaning in the art. The term may broadly refer to abnormal cell growth.

[0115] As used herein, the term "autoimmune disease" has its commonly accepted meaning in the art. The term may broadly refer to diseases in which the host's immune system targets or attacks the host's normal or healthy tissues.

[0116] As used herein, the term "myelination" has its commonly accepted meaning in the art. The term may refer broadly to the process by which myelin is produced.

[0117] As used herein, the terms "myelin-related disease or disorder," "demyelinating disorder," or "demyelinating disorder" have their commonly accepted meanings in the art. These terms may refer broadly to diseases or disorders involving damage to myelin.

[0118] As used herein, a subject is "in need of" a treatment if such subject (preferably a human) would benefit biologically, medically, or in quality of life from such treatment.

[0119] As used herein, the phrase "optionally substituted" is used synonymously with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" refers to replacing hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and descriptions of the compounds and examples thereof. Unless otherwise stated, an optionally substituted group may have a substituent at each substitutable position of the group, and when two or more positions in any given structure may be substituted with two or more substituents selected from a specified group, the substituents may be the same or different at all positions.

[0120] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1~4 "Alkyl" refers to an alkyl having 1 to 4 carbon atoms. 1~3 Alkyl" and "C 1~2The term "alkyl" should be construed accordingly. 1~4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy has the same definition as above. When indicated as "optionally substituted," the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0121] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., --O--C 1~4 Alkyl group, C 1~4 Alkyl refers to an alkyl group as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. Preferably, an alkoxy group has about 1-4 carbons, more preferably about 1-2 carbons. 1~2 The term "alkoxy" should be construed accordingly.

[0122] As used herein, "C 1~4 Alkoxy C 1~4 The term "alkyl" means that at least one of the hydrogen atoms is C 1~4 C, as defined herein, which is replaced by alkoxy. 1~4 Refers to an alkyl group. 1~4 Alkoxy C 1~4 The alkyl group is linked through the remainder of the molecule described herein via the alkyl group.

[0123] The number of carbon atoms in a group is indicated herein by the prefix "C x~xx " where x and xx are integers. For example, "C 1~3"Alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0124] "Halogen" or "halo" can be fluorine, chlorine, bromine, or iodine.

[0125] As used herein, "halo-substituted C 1~4 Alkyl" or "C 1~4 The term "haloalkyl" refers to a C alkyl group, as defined herein, in which at least one of the hydrogen atoms is replaced by a halo atom. 1~4 Refers to an alkyl group. 1~4 The haloalkyl group is a monohalo-C 1~4 Alkyl, dihalo-C 1~4 Alkyl, or perhalo-C 1~4 Polyhalo-C containing alkyl 1~4 It can be alkyl. 1~4 The alkyl may have one iodo, bromo, chloro or fluoro in the alkyl group. Dihalo-C 1~4 Alkyl groups and polyhalo-C 1~4 The alkyl group may have two or more of the same halo atoms or a combination of different halo groups within the alkyl group. Typically, polyhalo-C 1~4 The alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. 1~4 Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. 1~4 An alkyl group is one in which all hydrogen atoms have been replaced by halo atoms -C 1~4 Refers to an alkyl group.

[0126] The term "aryl" refers to an aromatic carbocyclic monocyclic or two fused ring system containing from 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0127] The term "heteroaryl" refers to a 5-12 membered aromatic radical having 1-4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in a heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic compound". Heteroaryl groups may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, furanyl, oxadiazolyl, thiophenyl, and the like. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, imidazopyridinyl, and indolyl.

[0128] The term "carbocyclic ring" or "carbocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring, which may exist as a monocyclic, bicyclic (including fused, helical, or bridged carbocyclic rings), or helical ring. Bicyclic carbocyclic groups include, for example, unsaturated carbocyclic radicals fused to another unsaturated carbocyclic radical, a cycloalkyl, or an aryl, such as 2,3-dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless otherwise specified, carbocyclic rings generally contain from 4 to 10 ring members.

[0129] "C 3~6 The term "cycloalkyl" refers to fully saturated carbocyclic rings (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0130] The term "heterocycle" or "heterocyclyl" refers to a 4-12 membered saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from N, O, and S. Heterocyclyl groups can be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic rings). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperidinyl. Bicyclic heterocyclyl groups include, for example, an unsaturated heterocyclic radical fused to another unsaturated heterocyclic radical, a cycloalkyl, aryl, or heteroaryl ring, such as tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-oxabicyclo[2.1.1]hexanyl, and 9-azabicyclo[3.3.1]nonanyl. In some embodiments, the heterocyclyl group is a 4-6 membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 4-6 membered monocyclic saturated heterocyclyl group. In some embodiments, the heterocyclyl group is an 8-10 membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8-10 membered bicyclic saturated heterocyclyl group.

[0131] As used herein, the term "spiral" ring refers to a bicyclic ring system in which both rings share one common atom. Examples of spiral rings include 2-oxa-6-azaspiro[3.3]heptanyl, and the like.

[0132] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. A fused heterocycle has at least one ring system that contains a ring atom that is a heteroatom selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0133] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety connected at two non-adjacent ring atoms (eg, 5-oxabicyclo[2.1.1]hexane).

[0134] The phrase "pharmacologically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or with the mammal being treated therewith.

[0135] Unless otherwise specified, the term "compounds of the disclosure" refers to compounds of formula (I) and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). Salts, particularly pharmaceutically acceptable salts, are also included where moieties capable of forming salts are present.

[0136] As used herein, "a," "an," "the," and similar terms used within the context of the present invention (particularly within the context of the claims) should be construed to include both the singular and the plural, unless otherwise specified herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to better elucidate the invention and does not limit the scope of the invention as otherwise claimed.

[0137] It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via rearrangement of some of the bond electrons.

[0138] In one embodiment, the disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in salt form. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in acid addition salt form. In a further embodiment, the disclosure relates to a compound of formula (I) as defined herein in pharma- ceutically acceptable salt form. In yet a further embodiment, the disclosure relates to a compound of formula (I) as defined herein in pharma- ceutically acceptable acid addition salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in free form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in acid addition salt form. In yet a further embodiment, the disclosure relates to any one of the compounds of the examples in pharma- ceutically acceptable salt form. In yet another embodiment, the disclosure relates to any one of the compounds of the examples in pharma- ceutically acceptable acid addition salt form.

[0139] The compounds of the present disclosure can be synthesized by synthetic routes, including processes similar to those well known in the chemical arts, particularly in light of the description contained herein.Starting materials are generally available from commercial sources such as Sigma-Aldrich, or can be easily prepared using methods well known to those skilled in the art (e.g., Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der ananischen Chemie, 4, Aufl.ed. Springer-Verlag, Germany (including supplements) (also available via Beilstein online database)).

[0140] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds and key intermediates of the present disclosure. For more detailed descriptions of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. EXAMPLES

[0141] Short description: PE=petroleum ether EtOAc = EA = ethyl acetate ESI = electrospray ionization MeOH = methanol EtOH = ethanol DCE = 1,2-dichloroethane DCM = dichloromethane CHCl3 = chloroform HCl = Hydrochloric Acid H2O = Water IPA = Isopropyl alcohol LCMS = Liquid Chromatography Mass Spectrometry HFIP = hexafluoro-2-propanol HPLC = High Pressure Liquid Chromatography THF = tetrahydrofuran MeCN = ACN = Acetonitrile MgSO4 = Magnesium sulfate DMSO = dimethyl sulfoxide AcOH = acetic acid TFA = trifluoroacetic acid DIPEA = diisopropylethylamine N2 = Nitrogen NH4HCO3 = Ammonium bicarbonate t-BuOH = tert-butanol NH4Cl = Ammonium chloride NaH = sodium hydride Na2SO4 = Sodium sulfate K2CO3 = Potassium Carbonate NaHCO3 = Sodium bicarbonate NaBH(OAc)3 = STAB = sodium triacetoxyborohydride SiO2 = Silicon Dioxide or Silica PDA = Photodiode Array Detector

[0142] General method LCMS instrument specifications: Agilent Technologies 1200 Series LC / MSD system: DAD\ELSD Alltech 3300 and Agilent LC / MSD G6130A, G6120B mass spectrometers. ·Agilent Technologies 1260 Infinity LCMSD system: DAD\ELSD Alltech 3300 and Agilent LCMSD G6120B mass spectrometer. Agilent Technologies 1260 Infinity II LC / MSD system: DAD\ELSD G7102A 1290 Infinity II and Agilent LC\MSD G6120B mass spectrometer. Agilent 1260 Series LC / MSD system: DAD\ELSD and Agilent LC\MSD (G6120B) mass spectrometer. UHPLC Agilent 1290 Series LC / MSD system DAD\ELSD and Agilent LC\MSD (G6125B) mass spectrometer.

[0143] HPLC analysis method specifications: ·Column: Agilent Poroshell 120 SB-C18 4.6×30mm 2.7μm, UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6×5mm 2.7μm Column temperature: 60°C ·Injection volume 0.5μL Modifier: 0.1% (v / v) concentrated formic acid Method: 99% water / 1% MeCN (initial condition), HOLD initial condition 0.1 min, linear gradient to 0% water / 100% MeCN in 1.5 min, HOLD 0% water / 100% MeCN in 1.73 min, linear gradient to 99% water / 1% MeCN in 1.74 min. Flow rate, 3.0 mL / min. UV scan: 207~223nm, 246~262nm, 272~288nm

[0144] QC analysis LC / MS method conditions: Ammonium hydroxide (basic pH) conditions MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 μm, part number 186002350 Modifier: Ammonium hydroxide 0.2% (v / v) concentrated Method: 95% water / 5% MeCN (initial condition), linear gradient in 3.75 min to 5% water / 95% MeCN, HOLD 4 min to 5% water / 95% MeCN. Flow rate, 0.8 mL / min.

[0145] Trifluoroacetic acid (acidic pH) conditions MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 μm, part number 186002350 Modifier: Trifluoroacetic acid 0.1% (v / v) concentrated Method: 95% water / 5% MeCN (initial condition), linear gradient in 3.75 min to 5% water / 95% MeCN, HOLD 4 min to 5% water / 95% MeCN. Flow rate, 0.8 mL / min.

[0146] General preparative HPLC conditions: Ammonium hydroxide (basic pH) conditions Flow rate: 30mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters XSELECT CSH C18 PREP 19 x 100 mm, 5 μm, part number 186005421 Modifier: 0.2% ammonium hydroxide (v / v) in water Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, ramp to 5% water / 95% MeCN in 8.5 min, HOLD 5% water / 95% MeCN in 10 min. Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters XSELECT CSH C18 PREP 30×100 mm, 5 μm, part number 186005421 Modifier: 0.2% NH4OH (v / v) Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, ramp to 5% water / 95% MeCN in 8.5 min, HOLD 5% water / 95% MeCN in 10 min. Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters XSELECT CSH C18 PREP 30 x 50 mm, 5 μm, part number 186005423 Modifier: 0.2% NH4OH (v / v) Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, ramp to 5% water / 95% MeCN in 8.5 min, HOLD 5% water / 95% MeCN in 10 min.

[0147] Trifluoroacetic acid (acidic pH) conditions Flow rate: 30mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters Sunfire OBD C18 PREP 19 x 100 mm, 5 μm, part number 186002567 Modifier: 0.1% trifluoroacetic acid (v / v) Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, ramp to 5% water / 95% MeCN in 8.5 min, HOLD 5% water / 95% MeCN in 10 min. Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters Sunfire OBD C18 PREP 30 x 100 mm, 5 μm, part number 186002572 Modifier: 0.1% trifluoroacetic acid (v / v) Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, ramp to 5% water / 95% MeCN in 8.5 min, HOLD 5% water / 95% MeCN in 10 min. Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scan range Column: Waters Sunfire OBD C18 PREP 30 x 50 mm, 5 μm, part number 186002570 Modifier: 0.1% trifluoroacetic acid (v / v) Method: A% water / B% MeCN (initial condition), linear gradient to A% water / B% MeCN in 8 min, ramp to 5% water / 95% MeCN in 8.5 min, HOLD 5% water / 95% MeCN in 10 min.

[0148] Preparation of intermediates Intermediate 1: (1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane [ka] 1. Synthesis of tert-butyl (1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of tert-butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (15 g, 66.3 mmol), 1,5-dibromo-3-methylpentane (17.79 g, 72.9 mmol) and DIPEA (25.4 mL, 145.8 mmol) in IPA (250 mL) was heated under reflux for 72 h. The solvent was removed in vacuo and the residue was diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4), filtered and evaporated to dryness to give tert-butyl (1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (19 g, crude; 90% purity), which was used in the next step without further purification. LCMS m / z=309.2 [M+H] + .

[0149] 2. Synthesis of (1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane [ka] To a solution of tert-butyl (1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (18.8 g, 61.0 mmol) in DCM (100 mL) was added TFA (14 mL, 183 mmol) and the resulting solution was stirred at room temperature for 48 h. The reaction mixture was evaporated to dryness in vacuo and the residue was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3 x 50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to give (1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane as a yellow solid (11.2 g, 88%) which was used without further purification. LCMS m / z=209.2[M+H] + .

[0150] Intermediate 2: (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane [ka] 1. Synthesis of tert-butyl (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.9 mol) and 1,5-dibromo-3-methyl-pentane (237 mg, 1.0 mmol) in IPA (10 mL) was added DIPEA (340 μL, 1.9 mmol) and the reaction mixture was heated under reflux for 72 h. The reaction mixture was evaporated to dryness in vacuo. The residue was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organics were dried (Na2SO4), filtered and evaporated to dryness to give tert-butyl (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (200 mg, crude), which was used without further purification. LCMS m / z=309.2[M+H] + .

[0151] 2. Synthesis of (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane [ka] To a solution of tert-butyl (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (18.5 g, 60 mmol) in DCM (100 mL) was added TFA (13.8 mL, 180 mmol) and the resulting solution was stirred at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in saturated aqueous NaHCO3 and extracted with EtOAc (3 x 50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and evaporated to dryness in vacuo. The resulting yellow oil was crystallized from DCM / hexane (100 / 300 mL) and the solid was collected by cold filtration and air-dried to give (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane as a yellow solid (6.3 g, 50%). LCMS m / z=209.2 [M+H] + .

[0152] Intermediate 3: (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] 1. Synthesis of tert-butyl ((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate [ka] To a solution of tert-butyl ((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (1.13 g, 5.0 mmol) and DIPEA (1.74 mL, 10.0 mmol) in DCM (25 mL) was added 4-(difluoromethoxy)benzenesulfonyl chloride (1.21 g, 5 mmol) and the mixture was stirred at room temperature overnight. The organic phase was washed with saturated aqueous NaHCO3 and water, dried (MgSO4), filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography (24 g SiO2, 10-40% EtOAc in heptane) to give tert-butyl ((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate as a white solid (1.42 g, 66%). LCMS m / z=433.1 [M+H] +

[0153] 2. Synthesis of (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] To a solution of tert-butyl ((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (468 mg, 1.1 mmol) in HFIP (3 mL) was added dropwise TFA (200 μL, 2.71 mmol) at room temperature and the resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo and the resulting residue was co-evaporated with MeCN (×3) to give (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine as a white solid (543 mg, 100%). LCMS m / z=333.1 [M+H] + .

[0154] Intermediate 4: (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] 1. Synthesis of tert-butyl ((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate [ka] To a solution of tert-butyl ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (1.13 g, 5.0 mmol) and DIPEA (1.74 mL, 10.0 mmol) in DCM (25 mL) was added 4-(difluoromethoxy)benzenesulfonyl chloride (1.21 g, 5 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and water, dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting residue was triturated with MeCN to give tert-butyl ((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)-sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate as a white solid (1.88 g, 87%). LCMS m / z=433.1[M+H] + .

[0155] 2. Synthesis of (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] To a solution of tert-butyl ((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (468 mg, 1.1 mmol) in HFIP (3 mL) was added dropwise TFA (220 μL, 2.9 mmol) at room temperature and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness in vacuo and the resulting residue was coevaporated with MeCN (×3) to give (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine trifluoroacetate as a white solid (521 mg, 100%). LCMS m / z=333.1 [M+H] + .

[0156] Intermediate 5: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one [ka] To a mixture of (1S,5R)-8-azabicyclo[3.2.1]octan-3-one hydrochloride (666 mg, 4.1 mmol) and 4-(difluoromethoxy)benzenesulfonyl chloride (656 μL, 4.1 mmol) in DCM (8 mL) was added DIPEA (2.15 mL, 12.4 mmol). The reaction mixture was stirred at room temperature for 6 h. The organic phase was washed with saturated aqueous NaHCO3, water, dried (MgSO4), filtered and evaporated to dryness. The resulting residue was purified by column chromatography (80 g SiO2, 10-40% EtOAc in heptane) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one as a white solid (1.85 g, 79%). LCMS m / z=332.0 [M+H] + .

[0157] Intermediate 6. 8-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one [ka] To a solution of 8-azabicyclo[3.2.1]octan-3-one hydrochloride (177 mg, 1.1 mmol) and 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (263 mg, 1.0 mmol) in DCM (5 mL) was added DIPEA (92 μL, 0.5 mmol) dropwise and the resulting mixture was stirred at room temperature overnight.

[0158] The mixture was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO3 and water, dried (MgSO4), filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography (24 g SiO2, 20-50% EtOAc in heptane) to give 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one as a colorless oil (322 mg, 91%). LCMS m / z=349.1 [M+H]+ .

[0159] Intermediate 7. 4-(((1R,3s,5S)-8-Azabicyclo[3.2.1]octan-3-yl)methyl)morpholine [ka] 1. Synthesis of tert-butyl (1R,3s,5S)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl (1R,3s,5S)-3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate (27.5 g, 115 mmol) and morpholine (10.52 g, 121 mmol) in DCE (300 mL) was added NaBH(OAc)3 (36.54 g, 172 mmol) portionwise at room temperature and the resulting mixture was stirred at room temperature overnight. MeOH (150 mL) was added and the reaction mixture was evaporated to dryness. The residue was quenched with 15% potassium carbonate solution and extracted with EtOAc (2 x 250 mL). The combined organics were washed with water, dried (Na2SO4), filtered and evaporated in vacuo to give tert-butyl (1R,3s,5S)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (27.4 g, 77%).

[0160] 2. Synthesis of 4-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine [ka] tert-Butyl (1R,3s,5S)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (27.4 g, 88.3 mmol) was dissolved in HCl solution in MeOH (150 mL) and stirred overnight. The solvent was evaporated and THF (150 mL) was added to the residue. The precipitate was collected by filtration, washed with THF (2×75 mL) and dried to give 4-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine dihydrochloride as a white solid (17.6 g, 70%). 1 H NMR(500MHz,DMSO-d6)δ(ppm):3.89(dd,J=14.4,10.3Hz,6H),3.45(d,J=12.6Hz,2H),2.99(q,J=12.6,11. 8Hz,2H), 2.91(t,J=6.0Hz,2H),2.33(dt,J=11.8,6.2Hz,1H),1.96-1.83(m,6H),1.63(t,J=12.6Hz),2H).

[0161] Intermediate 8. 4-(((1R,3r,5S)-8-Azabicyclo[3.2.1]octan-3-yl)methyl)morpholine [ka] Using a similar two-step procedure described in Intermediate 7, 4-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine was prepared from tert-butyl (1R,3r,5S)-3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate and morpholine. 1 H NMR(400MHz,DMSO-d6)δ(ppm):4.02-3.82(m,6H),3.47(d,J=12.4Hz,2H),3.08- 2.85 (m, 4H), 2.36 (dd, J=11.4, 5.9Hz, 1H), 2.00-1.82 (m, 6H), 1.71-1.58 (m, 2H). LCMS m / z=211.2[M+H] + .

[0162] Intermediate 9. (1R,3s,5S)8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] 1. Synthesis of tert-butyl (1R,3s,5S)-3-(2,2,2-trifluoroacetamido)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] tert-Butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (2.5 g, 11 mmol) was dissolved in dry DCM (50 mL) and trimethylamine (1.11 g, 11 mmol) was added. The mixture was cooled to 0° C. and trifluoroacetic anhydride (2.31 g, 11 mmol) was added dropwise. The reaction mixture was warmed to 20° C. and stirred for 18 h. The resulting mixture was washed with water (100 mL) and aqueous NaHSO4 (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl (1R,3s,5S)-3-(2,2,2-trifluoroacetamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (3.38 g, 95% yield) as a yellow oil.

[0163] 2. Synthesis of N-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2,2,2-trifluoroacetamide [ka] tert-Butyl (1R,3s,5S)-3-(2,2,2-trifluoroacetamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (3.38 g, 10.5 mmol) was dissolved in 4N HCl / dioxane solution and the reaction mixture was stirred for 4 h at 20° C. The volatiles were removed in vacuo and the residue was washed with diethyl ether (50 mL) and dried in vacuo to give N-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2,2,2-trifluoroacetamide (2.64 g, 97% yield) as a white solid.

[0164] 3. 2,2,2-Trifluoro-N-((1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)acetamide [ka] N-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2,2,2-trifluoroacetamide (1 g, 4.5 mmol) was suspended in dry DCM (50 mL) and the mixture was cooled to 0 °C. Then, 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (1 g, 3.9 mmol) was added in one portion, followed by the slow addition of DIPEA (1 g, 7.8 mmol). The reaction mixture was allowed to warm to 20 °C and stirred at 20 °C for 18 h. The resulting mixture was washed with water (100 mL) and aqueous NaHCO3 (100 mL), dried over Na2SO4, and filtered through silica gel (100 mL) that was washed with MTBE (100 mL). The volatiles were removed in vacuo to give 2,2,2-trifluoro-N-((1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)acetamide as a viscous yellow oil (1.7 g, 97% yield).

[0165] 4. Synthesis of (1R,3s,5S)8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] 2,2,2-Trifluoro-N-((1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)acetamide (1.7 g, 3.8 mmol) was dissolved in methanol (50 mL) and a solution of NaOH (0.76 g, 19 mmol) in water (10 mL) was added. The resulting mixture was stirred at 20 °C for 72 h. The volatiles were removed in vacuo and the residue was diluted with aqueous NaHSO4 (250 mL) and washed with MTBE (100 mL). The aqueous layer was made basic with NaOH and extracted with MTBE (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (1.3 g, 3.7 mmol, 98% yield) as a yellow oil. 1 H NMR (500MHz, chloroform-d) δ8.44(d,J=8.0Hz,1H),7.65(d,J=8.1Hz,1H),4.28-4.14(m,2H),3.11(tt,J=11.6,5.9Hz,1H ),2.94(d,J=1.7Hz,3H),2.15-1.98(m,2H),1.90(ddd,J=13.5,5.5,2.8Hz,2H),1.81-1.70(m,2H),1.57-1.30(m,4H).

[0166] Examples 1, 2 and 40 The title compounds were prepared using a single-step library protocol as described below: Each reaction was carried out on a scale of approximately 50 mg of target product. [ka] The appropriate sulfonyl chloride (RSOC1, 1.1 equiv.) was added to a solution of (1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane (Intermediate 1, 1.0 equiv.) and DIPEA (2.5 equiv.) in dry MeCN (1.2 mL), and the resulting mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo, the residue was dissolved in DMSO (800 μL), and purified by preparative HPLC (YMC Actus Trial C18 20×100 mm, 5 μm; MeOH / water+0.1% NHOH) to give the title compounds. The gradient was optimized for each compound. [Table 1]

[0167] Examples 3 to 13 and 41 to 47 General Procedure B The title compound was prepared using a single step library protocol, as described below, on a approx. 50 mg target product scale. [ka] The appropriate sulfonyl chloride (RSOC1) (1.1 equiv.) was added to a solution of (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane (Intermediate 2, 1.0 equiv.) and DIPEA (2.5 equiv.) in dry MeCN (1.2 mL) and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated to dryness in vacuo and the residue was dissolved in DMSO (800 μL) and purified by preparative HPLC to give the title compounds. The solvent gradient was optimized for each compound. Preparative HPLC-A:Waters Sunfire C18 19×100mm, 5μm, water / MeOH Preparative HPLC-B:YMC Actus Trial C18 20×100mm, 5μm, water / MeCN+0.1%NH4OH [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0168] Examples 14 to 16 and 48 to 58 Primary (RNH2) and secondary amines (R 1 R 2 General Procedure for the Reductive Amination of (NH) [ka] The title compound was prepared using a single step reductive amination protocol on a approx. 50 mg target product scale using either the primary or secondary amine protocols outlined below.

[0169] Primary amine protocol: The appropriate primary amine (RNH2, 1.3 equiv.), 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (intermediate 5, 1.0 equiv.) and NaBH(OAc)3 (4.0 equiv.) were dissolved in CHCl3 (1.2 mL) and AcOH (1.2 equiv.) and the mixture was then stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in 5% ammonia in MeOH (1.2 mL) and stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and the residue was dissolved in DMSO (0.7 mL) and purified by preparative HPLC (YMC Actus Triart C18 20×100 mm, 5 μm; gradient mixture water-MeOH+0.1% NH4OH) to give the title compound. When the primary amine was used as the HCl salt, an additional 1.4 equivalents of DIPEA was added to the reaction mixture for each equivalent of acid. The molar ratios of starting materials and overall reaction conditions were not changed.

[0170] Secondary amine protocol: NaBH(OAc)3 (3.0 equiv.) was reacted with 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 5, 1.0 equiv.) and the appropriate secondary amine (R 1 R 2 NH, 1.1 equiv.) and the resulting solution was stirred at 50° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in saturated aqueous NaHCO3 and extracted with EtOAc (2×10 mL). The combined organics were washed with water (10 mL), brine (10 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was dissolved in DMSO (500 μL) and purified by preparative HPLC (YMC Actus Triart C18 20×100 mm, 5 μm; gradient mixture water-MeOH+0.1% NH4OH) to give the title compound. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0171] Example 17: 4-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)tetrahydro-2H-pyran-4-ol [ka] To a mixture of 1,6-dioxaspiro[2.5]octane (11 mg, 0.1 mmol) and (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 3, 41 mg, 0.1 mmol) in EtOH (2 mL) was added DIPEA (36 μL, 0.2 mmol) and the mixture was stirred overnight at 60° C. Additional 1,6-dioxaspiro[2.5]octane was added and heating was continued at 60° C. overnight. The reaction mixture was evaporated to dryness, dissolved in DMSO and purified by preparative HPLC (Waters Xselect CSH Prep C18 30x100mm, 5μm; 5-55% MeCN in water (+NH4OH)) to give 4-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)tetrahydro-2H-pyran-4-ol as a white solid (16mg, 44%). LCMS m / z=447.1[M+H] + ,t R =0.56 minutes.

[0172] Example 18: 4-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)tetrahydro-2H-pyran-4-ol [ka] The title compound was prepared from 1,6-dioxaspiro[2.5]octane and (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 4) using a procedure similar to that described for Example 17 to give the desired compound (16 mg, 44%) as a white solid (7.1 mg, 18%). LCMS m / z=446.8 [M+H] + ,t R =0.55 minutes.

[0173] Example 19: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] Acetic acid (34 μL, 0.6 mmol) was added to a mixture of tetrahydropyran-4-ylmethanamine (28 mg, 0.2 mmol) and 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 5, 66 mg, 0.2 mmol) in DCM (3 mL). NaBH(OAc)3 (170 mg, 0.8 mmol) was added in one portion to the above solution, then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl solution and stirred at room temperature for 5 min. The mixture was diluted with DCM and saturated aqueous NaHCO3 and stirred for another 5 min. The organic phase was washed with water and evaporated to dryness in vacuo. The residue was dissolved in DMSO and purified by preparative HPLC (Waters Xselect CSH Prep C18 30×100 mm, 5 μm; 5-70% MeCN in water (+NH4OH)) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine as a white solid (24 mg, 28%). LCMS m / z=431.2 [M+H] + ,t R =0.58 minutes.

[0174] Examples 20 and 21: (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane and (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane [ka] 1. Synthesis of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane [ka] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane was prepared from 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 5) and 4-methylpiperidine using a method similar to that described in Example 19. Purification by preparative HPLC (Waters Sunfire C18 19*100 5mkm column; gradient mixture water-ACN-FA 0.1% as mobile phase) gave the title compound (91 mg, 30%). LCMS m / z=415.2 [M+H] + .

[0175] Chiral separation of 2.8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane [ka] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane (60 mg) was separated into its stereoisomers using a CHIRALPAK AD-H 4.6×150 mm, 5 μm, 30% MeOH and 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.).

[0176] Peak 1, Example 20, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane (31 mg, t R = 2.01 min, 99.9% ee). 1H NMR(400MHz,CD3OD)δ(ppm):8.01-7.91(m,2H),7.32(d,J=8.8Hz,2H),7.26-6.75(m,1H),4.31(br s,2H),2.90(br d, J=11.2Hz, 2H), 2.76-2.61(m, 1H), 2.12(br t, J=11.6Hz, 2H), 1.96-1.84(m, 2H), 1.78-1.49(m,8H), 1.38(br s, 1H), 1.27-1.12 (m, 2H), 0.94 (d, J=6.4Hz, 3H). LCMS m / z=415.2[M+H] +

[0177] Peak 2, Example 21, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane (4 mg, t R =2.32 min, 89.2% ee). 1 H NMR(400MHz,CD3OD)δ(ppm):7.99-7.83(m,2H),7.32(d,J=8.8Hz,2H),7.25-6.80(m,1H),4.25(br s,2H),3.00(br d,J=9.4Hz,2H),2.47(br s,1H),2.36-2.22(m,2H),1.95(br s,2H),1.74-1.51(m,8H),1.44-1.29(m,1H),1.25-1.12(m,2H),0.93(d,J=6.4Hz,3H). LCMS m / z=415.2[M+H] +

[0178] Examples 22 and 23: 6-((1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxa-6-azaspiro[3.3]heptane and 6-((1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin)-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] *Arbitrarily assigned stereochemistry 6-((1R,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxa-6-azaspiro[3.3]heptane was prepared from 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 6) and 2-oxa-6-azaspiro[3.3]heptane using a method similar to that described in Example 19. Purification by column chromatography (24 g SiO2, 20-50-100% EtOAc / EtOH (3 / 1) in heptane) gave: *Peak 1, Example 22; white solid (42 mg, 49%). 1 H NMR(400MHz,CD3OD)δ(ppm):8.50(d,J=8.3Hz,1H),7.81(d,J=8.0Hz,1H),4.69(s,4H),4.09(dd,J=4.4,2.9Hz, 2H), 3.21(s,4H), 2.88(s,3H), 2.35(t,J=5.6Hz, 1H), 2.16-2.05(m,2H), 1.89-1.74(m,4H),1.69-1.60(m,2H). LCMS m / z=432.2[M+H] + . *Peak 2, Example 23; oil (6 mg, 6%). 1 H NMR(400MHz,CD3OD)δ(ppm):8.61-8.43(m,1H),7.81(d,J=8.0Hz,1H),4.69(s,4H),4.28-4.20(m,2H), 3.34(s,4H),2.89(s,3H),2.59-2.45(m,1H),2.05-1.93(m,2H),1.87-1.73(m,4H),1.38-1.26(m,2H). LCMS m / z=432.1[M+H] + .

[0179] Examples 24 and 25: (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine and (1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] *Arbitrarily assigned stereochemistry (1R,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine was prepared from 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 6) and tetrahydropyran-4-ylmethanamine using a method similar to that described in Example 19. Purification by column chromatography (24 g SiO2, 20-100% EtOAc / EtOH (3 / 1) in heptane) gave: *Peak 1, Example 24: White solid (56 mg, 63%). 1 H NMR(400MHz,CD3OD)δ(ppm):8.57-8.46(m,1H),7.82(d,J=8.0Hz,1H),4.15(br d,J=2.8Hz,2H), 3.99-3.87(m,2H),3.40(td,J=11.7,1.9Hz,2H),2.96-2.84(m,4H),2.43(d,J=6.3Hz ,2H), 2.28-2.19(m,2H), 2.10-1.96(m, 2H), 1.94-1.82(m, 2H), 1.79-1.55(m, 5H), 1.37-1.17(m, 2H). LCMS m / z=448.2[M+H] + . *Peak 2, Example 25: Oil (5.5 mg, 6%). 1H NMR(400MHz,CD3OD)δ(ppm):8.53(d,J=8.3Hz,1H),7.82(d,J=8.0Hz,1H),4.35-4.20(m,2H),3.98-3.85(m,2H),3.39(td,J =11.8,2.0Hz,2H),2.92(s,4H),2.45(d,J=6.3Hz,2H),2.07-1.93(m,4H),1.81(d,J=7.5Hz,2H),1.70-1.61(m,3H),1.48(br s,2H),1.27-1.18(m,2H). LCMS m / z=448.1[M+H] + .

[0180] Examples 26 and 27: (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine and (1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] *Arbitrarily assigned stereochemistry (1R,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine was prepared from 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 6) and (3-methyloxetan-3-yl)methanamine using a method similar to that described in Example 19. Purification by column chromatography (24 g SiO2, 20-100% EtOAc / EtOH (3 / 1) in heptane) gave: *Peak 1, Example 26: White solid (46 mg, 53%). 1H NMR(400MHz,CD3OD)δ(ppm):8.52(d,J=8.0Hz,1H),7.82(d,J=8.3Hz,1H),4.48(d,J=5.8Hz,2H)),4.34(d,J=5.5Hz,2H) ),4.20-4.10(m,2H),2.90(s,4H),2.72(s,2H),2.30-2.19(m,2H),2.08-1.96(m,2H),1.93-1.74(m,4H),1.31(s,3H). LCMS m / z =434.2[M+H] + . *Peak 2, Example 27: White solid (6 mg, 7%). 1 H NMR(400MHz,CD3OD)δ(ppm):8.57-8.49(m,1H),7.82(d,J=8.0Hz,1H),4.42(d,J=5.8Hz,2H),4.32(d,J=5.8Hz,2H),4.27(br dd,J=4.1,2.9Hz,2H),3.00-2.88(m,4H),2.77(s,2H),2.06-1.95(m,4H),1.86-1.78(m,2H),1.56-1.43(m,2H),1.28(s,3H). LCMS m / z=434.2[M+H] + .

[0181] Example 28: (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] To a mixture of (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 4, 45 mg, 0.1 mmol) and 3-methyloxetane-3-carbaldehyde (14 mg, 0.1 mmol) in DCM (3 mL) was added acetic acid (17 μL, 0.3 mmol). NaBH(OAc)3 (85 mg, 0.4 mmol) was added in one portion and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and the mixture was stirred at room temperature for 5 min. Additional DCM and saturated NaHCO3 were added and the reaction mixture was stirred for an additional 5 min. The organic phase was washed with water and then evaporated to dryness in vacuo. The residue was dissolved in DMSO and purified by preparative HPLC (Waters Xselect CSH Prep C18 30×100 mm, 5 μm; 5-55% MeCN in water (+NH4OH)) to give (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine as a white solid (27 mg, 64%). LCMS m / z=417.1 [M+H] + ,t R =0.57 minutes.

[0182] Example 29: (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] Acetic acid (21 μL, 0.4 mmol) and NaBH(OAc)3 (105 mg, 0.5 mmol) were added to a mixture of (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine trifluoroacetate (Intermediate 4, 55 mg, 0.1 mmol) and tetrahydropyran-4-carbaldehyde (15.5 mg, 0.1 mmol) in DCM (2 mL) and the mixture was stirred at room temperature for 2 h. The reaction was washed with saturated aqueous NaHCO3, diluted with DCM and stirred for 5 min. The organic phase was washed with water, dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (12 g SiO2, EtOAc / EtOH 3 / 1) to give (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine as a white solid (32 mg, 60%). 1 H NMR(400MHz,CD3OD)δ(ppm):8.01-7.89(m,2H),7.32(d,J=8.5Hz,2H),7.23-6.78(m,1H),4.29(br s,2H),3.94(br dd,J=11.4,4.1Hz,2H), 3.42(t,J=11.7Hz,2H),2.91(dt,J=11.2,5.6Hz,1H),2 .46(d,J=6.5Hz, 2H), 2.09-1.94(m, 2H), 1.79-1.45(m, 9H), 1.38-1.15(m, 2H). LCMS m / z=431.2[M+H] + .

[0183] Example 30: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] DIPEA (70 μL, 0.4 mmol) was added to a mixture of 1-methyl-2-oxabicyclo[2.1.1]hexane-4-amine HCl salt (36 mg, 0.2 mmol) and 8-[4-(difluoromethoxy)phenyl]sulfonyl-8-azabicyclo[3.2.1]octan-3-one (66 mg, 0.2 mmol) in DCM (3 mL). NaBH(OAc)3 (170 mg, 0.8 mmol) was added in one portion to the above solution and the mixture was stirred at room temperature overnight. Additional NaBH(OAc)3 (85 mg, 0.4 mmol) was added and stirring was continued at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and stirred at room temperature for 5 min. The reaction mixture was diluted with DCM and saturated aqueous NaHCO3 and stirred for an additional 5 min. The organic phase was washed with water and concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (Waters Xselect CSH Prep C18 30×100 mm, 5 μm; 5-70% MeCN in water (+NH4OH)) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-8-azabicyclo[3.2.1]octan-3-amine as a white solid (20 mg, 23%). LCMS m / z=429.1 [M+H] + ,t R =0.60 minutes.

[0184] Example 31: (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine was prepared as a white solid (23.8 mg, 59%) from (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 4) and oxetane-3-carbaldehyde using a procedure similar to that described for Example 28 to give the desired compound (31 mg, 76%). LCMS m / z=402.9 [M+H] + ,t R =0.56 minutes.

[0185] Example 32: (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine (35 mg, 75%) was prepared from (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 3) and tetrahydro-2H-pyran-4-carbaldehyde using a method similar to that described for Example 28. LCMS m / z=431.2 [M+H] + ,t R =0.59 minutes.

[0186] Example 33: (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol [ka] 1. Synthesis of tert-butyl (1R,3r,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate [ka] Trimethylsulfoxonium iodide (2.93 g, 13.32 mmol) was added to a suspension of NaH (533 mg, 13.3 mmol, 60% purity) in DMSO (5 mL) and stirred at 25 °C under N2 for 1 h, followed by addition of a solution of tert-butyl (1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2 g, 8.9 mmol) in DMSO (5 mL). After consumption of the starting material, water (20 mL) was added and then the resulting mixture was extracted with DCM (3 x 50 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4), filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 0-17% EtOAc / PE) to give the compound tert-butyl (1R,3r,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate as a colorless oil (1.5 g, 71%). LCMS m / z=183.9[M- t- Bu+H] + .

[0187] 2. tert-Butyl (1R,3r,5S)-3-hydroxy-3-(morpholinomethyl) Synthesis of 8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Morpholine (145 μL, 1.7 mmol) was added to a solution of tert-butyl (1R,3r,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate (200 mg, 0.8 mmol) in EtOH (5 mL) and the resulting mixture was stirred under N2 at 25 °C for 1 h and then at 100 °C for an additional 15 h. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, 30-90% EtOAc / PE) to give tert-butyl (1R,3r,5S)-3-hydroxy-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate as a colorless oil (130 mg, 48%). LCMS m / z=327.1[M+H] + .

[0188] 3. Synthesis of (1R,3r,5S)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol trifluoroacetate [ka] TFA (2.98 g, 26.1 mmol, 2.00 mL) was added to a solution of tert-butyl (1R,3r,5S)-3-hydroxy-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.4 mmol) compound in DCM (10 mL) and the mixture was stirred under N2 at 25° C. for 0.5 h. The reaction mixture was evaporated to dryness in vacuo to give (1R,3r,5S)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol trifluoroacetate as a yellow oil (150 mg, crude) which was used without further purification. 1 H NMR (400MHz, CD3OD) δ (ppm): 3.58 (br s, 2H), 3.18 (s, 4H), 2.54-2.46 (m, 4H), 2.16-2.13 (m, 6H), 2.11-2.06 (m, 4H).

[0189] 4. Synthesis of (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol [ka] 4-(Difluoromethoxy)benzenesulfonyl chloride (100 mg, 0.4 mmol) was added to a solution of (1R,3r,5S)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol trifluoroacetate (100 mg, 0.4 mmol) and DIPEA (340 μL, 1.9 mmol) in DCM (20 mL) at 0° C., and the resulting mixture was stirred at 25° C. under N2 for 1 h. Water (10 mL) was added to the reaction mixture and extracted with DCM (3×30 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4), filtered, and evaporated to dryness in vacuo. The residue was purified by preparative HPLC (Welch Xtimate C18 25 × 150 mm, 5 mm; 50-80% MeCN / water (10 mM NH4HCO3)) to give (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol as a white solid (80 mg, 49%). 1 H NMR(400MHz,CD3OD)δ(ppm):7.92(d,J=8.8Hz,2H),7.29(d,J=8.4Hz,2H),7.00(t,J=73.2Hz,1H)),4.21(br s,2H), 3.67-3.63(m, 4H), 2.55-2.52(m, 4H), 2.14-2.08(m, 4H), 1.89-1.84(m, 2H), 1.76-1.72(m, 4H)m,2H), 1.42-1.40(m,2H). LCMS m / z(ESI):433.1[M+H] + .

[0190] Example 34: (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol [ka] 1. Synthesis of tert-butyl (1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Methyl(triphenyl)phosphonium bromide (55.50 g, 155.4 mmol) was added to a solution of potassium tert-butoxide (1 M, 155.4 mL) in THF (40 mL) at 0° C. under N2, and the resulting mixture was stirred at 0° C. for 15 min and then heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and a solution of tert-butyl (1S,5R)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (7 g, 31.1 mmol) in THF (60 mL) was added dropwise and stirred at 25° C. for 15 h. The reaction mixture was diluted with acetone (30 mL) and the resulting solid was removed by filtration. The filtrate was diluted with water (80 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4), filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluting with a gradient of 5-20% EtOAc / PE) to give tert-butyl (1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate as a colorless oil (5 g, 72%). LCMS m / z (ESI): 168.1 [M- t- Bu+H] + .

[0191] 2. tert-Butyl (1R,3r,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate and tert-Butyl (1R,3s,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate and [ka] 3-Chlorobenzenecarboperoxoic acid (22.7 g, 112 mmol, 85% purity) was added to a solution of tert-butyl (1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate (10 g, 44.8 mmol) in DCM (100 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 24 h, after which additional 3-chlorobenzenecarboperoxoic acid (9.09 g, 44.8 mmol, 85% purity) was added and stirring was continued at 25 °C for another 24 h. The resulting solid was removed by filtration and saturated aqueous NaHCO3 (50 mL) was added to the filtrate. The aqueous phase was extracted with DCM (3 x 80 mL). The combined organics were washed with saturated aqueous Na2SO3 (50 mL), brine (20 mL), dried (Na2SO4), filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, 15-35% EtOAc / PE) to give Peak 1: tert-Butyl (1R,3s,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate (white solid) (2.5 g, 23%). 1 H NMR(400MHz,CDCl3)δ(ppm):4.29(brs,2H),2.72(s,2H),2.32-2.11(m,2H),2.02-1.92(m,2H),1.72(br d,J=7.6Hz,2H),1.50-1.42(m,9H),1.25(br d,J=7.2Hz,2H). LCMS m / z(ESI):140.1[M-Boc+H] + . Peak 2: tert-Butyl (1R,3r,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate (4.5 g, 42%). 1 H NMR(400MHz, CDCl3)δ(ppm):4.42-4.19(m,2H),2.48-2.19(m,4H),2.10-1.96(m,4H),1.46(s,9H),1.17(br d,J=14.0Hz,2H).

[0192] 3. Synthesis of tert-butyl (1R,3s,5S)-3-(aminomethyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of tert-butyl (1R,3s,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylate (1 g, 4.2 mmol) and ammonia (7 M, 13.3 mL) in water was heated in an autoclave at 60° C. for 96 h. The mixture was concentrated under reduced pressure to give tert-butyl (1R,3s,5S)-3-(aminomethyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (1 g, crude), which was used without further purification. 1 H NMR(400MHz,CD3OD)δ(ppm):4.35-4.21(m,2H),2.76(s,2H),2.10-1.93(m,4H),1.81(br d,J=7.2Hz),2H),1.47(s,9H),1.29(br d,J=12.4Hz,2H). LCMS m / z(ESI):201.1[M- t Bu+H] + .

[0193] 4. Synthesis of tert-butyl (1R,3s,5S)-3-hydroxy-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Oxybis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (2.91 g, 7.0 mmol) was added to a mixture of tert-butyl (1R,3s,5S)-3-(aminomethyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 4.7 mmol) and K2CO3 (1.94 g, 14.0 mmol) in MeCN (30 mL) under N2, and the mixture was stirred at 80° C. for 15 h. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column; 0-10% MeOH / DCM) and then by preparative HPLC (YMC-Actus Triart C18 150×30 mm, 5 μm, 4-60% MeCN / water (0.05% NH4OH)) to give tert-butyl (1R,3s,5S)-3-hydroxy-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate as a white solid (22 mg, 1.44%). 1 H NMR(400MHz,DMSO-d6)δ(ppm):4.27(s,1H),4.00(br s,2H),3.56(br t,J=4.0Hz,4H),3.44-3.38(m,4H),2.36(s,2H),1.96(brs,2H),1.80(brs,2H),1.71-1.54(m,4H),1.41(s,9H). LCMS m / z(ESI):327.2[M+H] + .

[0194] 5. Synthesis of (1R,3s,5S)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol hydrochloride [ka] HCl / dioxane (4M, 2 mL) was added to a solution of tert-butyl (1R,3s,5S)-3-hydroxy-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (25 mg, 0.1 mmol) in MeOH (2 mL) and the resulting mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give (1R,3s,5S)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol hydrochloride as a yellow oil (35 mg) which was used without further purification. LCMS m / z (ESI): 227.1 [M+H] + .

[0195] 6. Synthesis of (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol [ka] To a solution of compound (1R,3s,5S)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (30 mg, 0.1 mmol) in DCM (3 mL) was added DIPEA (60 μL, 0.3 mmol) and 4-(difluoromethoxy)benzenesulfonyl chloride (41.6 mg, 0.2 mmol) at 0° C. The mixture was stirred at 20° C. for 3 h and quenched with water (10 mL). The reaction mixture was extracted with DCM (3×10 mL) and the combined organics were washed with brine (3×10 mL), dried (Na2SO4), filtered and evaporated to dryness in vacuo. The residue was purified by preparative HPLC (Welch XtimateC18 25×150 mm, 5 μm; 33-63% MeCN / water (10 mM NH4HCO3)) to give (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol as a white solid (14.5 mg, 29%). 1H NMR(400MHz,DMSO-d6)δ(ppm):7.90(d,J=8.8Hz,2H),7.39-7.08(m,3H),4.40(s,1H),4.13(br s,2H),3.50(d,J=4.2Hz,2H),2.43-2.40(m,6H),2.22(s,2H),2.07(d,J=14.4H z, 2H), 1.72 (dd, J=4.0, 13.2Hz, 2H), 1.44 (d, J=8.0Hz, 2H), 1.26-1.12 (m, 2H). LCMS m / z(ESI):433.1[M+H] + .

[0196] Example 35: 4-(((1R,3s,5S)-8-((4-(difluoromethoxy)-2,6-difluorophenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine [ka] DIPEA (70 μL, 0.4 mmol) was added to a mixture of 4-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine dihydrochloride (Intermediate 7, 31 mg, 0.1 mmol) and 4-(difluoromethoxy)-2,6-difluoro-benzenesulfonyl chloride (28 mg, 0.1 mmol) in DCM (2 mL) and the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCO3, diluted with water and stirred at room temperature for 5 min. The organic phase was washed with water and evaporated to dryness in vacuo. The residue was triturated with a small amount of MeCN to give 4-(((1R,3s,5S)-8-((4-(difluoromethoxy)-2,6-difluorophenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine as a white solid (22 mg, 48%). 1 H NMR(400MHz,CD3OD)δ(ppm):7.33-6.81(m,3H),4.33(br d,J=2.3Hz,2H),3.79-3.59(m,4H),2.50-2.31(m,4H),2.20-2.03(m,3H),1.82-1.66(m,6H),1.45-1.34(m,2H). LCMS m / z=453.1[M+H]+ .

[0197] Example 36: 4-(((1R,3s,5S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine [ka] 4-(((1R,3s,5S)-8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine was prepared as a white solid (43 mg, 90%) from 4-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine dihydrochloride (Intermediate 7) and 2,5-dimethylpyrazole-3-sulfonyl chloride using a method similar to that described for Example 35. Purified by column chromatography (12 g, SiO2, 7:1 EtOAc / EtOH). 1 H NMR(400MHz,CD3OD)δ(ppm):6.62(s,1H),4.36-4.18(m,2H),4.00(s,3H),3.77-3.62(m,4H),2.51-2 .32(m,4H),2.25(s,3H),2.21-2.15(m,2H),2.15-2.04(m,1H),1.83-1.70(m,6H),1.45-1.34(m,2H). LCMS m / z=369.2[M+H] + .

[0198] Example 37: 4-(((1R,3r,5S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine [ka] 4-(((1R,3r,5S)-8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine was prepared from 4-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine dihydrochloride (Intermediate 8) and 2,5-dimethylpyrazole-3-sulfonyl chloride using a method similar to that described for Example 35 as a colorless oil (29 mg, 70%). 1 HNMR(400MHz,CD3OD)δ(ppm):6.60(s,1H), 4.30-4.17(m,2H),3.97(s,3H),3.70-3.62(m,4H),2.40(br d, J=4.5Hz,4H),2.23(s,3H),2.19-2.04(m),3H),1.82-1.67(m,6H),1.44-1.31(m,2H). LCMS m / z =369.2[M+H] + .

[0199] Example 38: 4-(((1R,3s,5S)-8-((3,5-dimethylisoxazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine [ka] 4-(((1R,3r,5S)-8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine was prepared from 4-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine dihydrochloride (Intermediate 7) and 3,5-dimethylisoxazole-4-sulfonyl chloride as a white solid (46 mg, 83%) using a method similar to that described for Example 35. 1H NMR(400MHz,CD3OD)δ(ppm):4.26-4.13(m,2H),3.76-3.59(m,4H),2.63(s,3H),2.48 -2.28(m,7H),2.18-2.14(m,2H),2.12-1.98(m,1H),1.91-1.63(m,6H),1.35(s,2H). LCMS m / z=370.2[M+H] + .

[0200] Example 39: 4-(((1R,3s,5S)-8-((4,6-dimethylpyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine [ka] 4-(((1R,3s,5S)-8-((4,6-dimethylpyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine was prepared from 4-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine dihydrochloride (Intermediate 7) and 4,6-dimethylpyridine-3-sulfonyl chloride as a white solid (38 mg, 50%) using a method similar to that described for Example 35. 1 H NMR(400MHz,CD3OD)δ(ppm):8.82(s,1H),7.34(s,1H),4.17(br s,2H),3.71-3.60(m,4H),2.64(s,3H),2.57(s,3H),2.38(br s,4H), 2.17-2.12(m,2H),2.12-2.04(m,1H),1.97-1.90(m,2H),1.80-1.68(m,4H),1.32(br t,J=10.9Hz,2H). LCMS m / z =380.2[M+H] + .

[0201] Example 59: rac-4-(((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)butan-2-ol [ka] 1. Synthesis of tert-butyl (1R,3r,5S)-3-(3-hydroxybutanamido)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] 3-Hydroxybutanoic acid (193.20 mg, 1.86 mmol), tert-butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 1.77 mmol) and NMI (507.90 mg, 6.19 mmol, 493.11 μL) were combined and dissolved in MeCN (15 mL). TCFH (743.87 mg, 2.65 mmol) was added in one portion and the reaction was monitored by LCMS. After 12 h, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude mixture was dissolved in MeOH (10 mL) and K2CO3 (488.54 mg, 3.53 mmol) was added. The resulting mixture was stirred at 22° C. for 1 h, then diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column (MeOH in DCM=0%-1%) to give the desired compound (380 mg, 69% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δppm6.67(d,J=7.2Hz,1H),4.21-4.13(m,4H),2.24-2.15(m,2H),2.0 5-2.00(m, 4H), 1.85-1.80(m, 2H), 1.70-1.61(m, 2H), 1.46(s, 9H), 1.25(d, J=6.0Hz, 3H). LCMS m / z=257.1[M+H- t Bu] +

[0202] 2. Synthesis of N-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-3-hydroxybutanamide [ka] A solution of tert-butyl (1R,3r,5S)-3-((3-hydroxybutyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (380.00 mg, 1.22 mmol) in HCl / MeOH (4 M, 6 mL) was stirred for 1 h at 20° C. Evaporation in vacuo afforded crude N-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-3-hydroxybutanamide (300 mg, hydrochloride) as a colorless oil. 1 H NMR (400MHz, CD3OD) δppm4.21-4.09(m,1H),4.05-3.96(m,3H),2.41-2.22(m,6H),2.17-2.03(m,4H),1.22(d,J=6.0Hz,3H). LCMS m / z=212.9[M+H] +

[0203] 3. Synthesis of N-((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-hydroxybutanamide [ka] To a solution of 4-(((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)amino)butan-2-ol (300.00 mg, 1.21 mmol, hydrochloride) and DIPEA (623.47 mg, 4.82 mmol, 840.26 μL) in DCM (6 mL) was added 4-(difluoromethoxy)benzenesulfonyl chloride (438.93 mg, 1.81 mmol, 288.20 μL) at 0-5 °C. The mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (15 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column (MeOH in DCM=0.5% to 2%) to give the desired compound (320 mg, 63% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δppm7.91-7.85(m,2H),7.25-7.17(m,2H),6.80-6.40(m,2H),4.24(br s,2H),4.19-4.08(m,2H),2.94(br s, 1H), 2.37-2.18 (m, 4H), 1.85-1.72 (m, 6H), 1.22 (d, J=6.0Hz, 3H). LCMS m / z=419.0[M+H] + .

[0204] 4. Synthesis of rac-4-(((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)butan-2-ol [ka] To a solution of N-((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-hydroxybutanamide (100 mg, 238.97 μmol) in THF (8 mL), BH .DMS (10M, 95.59μL) was added at 20℃ and the reaction mixture was stirred at 70℃ under nitrogen for 1 h. The mixture was quenched with methanol (10mL) at 20℃ and then heated at 70℃ for 0.5 h. Concentration in vacuum gave the crude product, which was separated by preparative HPLC (column: Boston Prime C18 150*30mm*5um, condition: water (0.05% ammonium hydroxide v / v)-ACN, 50%~80%, flow rate (ml / min): 30) to give the title compound (111mg, 37% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δppm7.94-7.89(m,2H),7.32-7.26(m,2H),7.00(t,J=73.2Hz,1H),4.17(br s,2H), 3.90-3.80(m, 1H), 2.89-2.81(m, 1H), 2.66(t, J=6.4Hz, 2H), 2.18-2.03(m, 2H), 1.97- 1.86 (m, 2H), 1.79-1.69 (m, 2H), 1.64-1.48 (m, 2H), 1.47-1.41 (m, 2H), 1.14 (d, J=6.0Hz, 3H). LCMS m / z=405.1[M+H] + .

[0205] Example 60: rac-4-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)butan-2-ol [ka] rac-4-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)butan-2-ol was prepared as a white solid following a method similar to that described for Example 59 using tert-butyl (1R,3s,5S)-3-(3-hydroxybutanamido)-8-azabicyclo[3.2.1]octane-8-carboxylate from step 1 and 3-hydroxybutanoic acid (200 mg, 42%). 1H NMR (400MHz, methanol-d4) δ=7.99-7.95(m,2H),7.34(d,J=8.8Hz,2H),7.24-6.86(m,1H),4.41(br s,2H),3.93-3.84(m,1H),3.60-3.47(m,1H),3.16-3.09(m,2H),2.19-2.14(m,2H ), 1.86-1.78(m, 3H), 1.72-1.64(m, 3H), 1.58-1.52(m, 2H), 1.23(d, J=6.4Hz, 3H). LCMS m / z=405.2[M+H] + .

[0206] Examples 61 and 62: (1R,3r)-3-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol and (1R,3r)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol [ka] *Arbitrarily assigned stereochemistry (1R,3r)-3-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol and (1R,3r)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol were prepared according to general procedure C using (1r,3r)-3-(aminomethyl)cyclobutan-1-ol (HCl salt) as the secondary amine. The crude reaction mixture was subjected to SFC separation (column: DAICEL CHIRALPAK Conditions: 0.1% NH3H2OETOH; Start B: 40%; End B: 40%; Flow rate (ml / min): 200) to obtain (1R,3r)-3-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol (233.15 mg, 23% yield), and the crude (1R,3r)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol was further purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; Conditions: water(HCl)-CAN; Start B: 20; End B: 40; Flow rate (ml / min): 25) to give the second isomer (200mg, 20% yield) as a white solid.

[0207] *Peak 1, Example 61: 1H NMR(400MHz,CD3OD)δppm7.91(d,J=8.8Hz,2H),7.31-7.27(m,2H),7.01(t,J=72.8Hz,1H),4.32-4.24(m,1H),4.17(br s,2H),2.91-2.87(m,1H),2.57(d,J=7.6Hz,2H),2.11-2.07(m,1H),2.06-1.97(m,8H),1.73-1.68(m,2H),1.44-1.41(m,2H). LCMS m / z=417.1[M+H] + .

[0208] *Peak 2, Example 62: 1 H NMR(400MHz,CD3OD)δppm7.95(d,J=8.8Hz,2H),7.32(d,J=8.8Hz,2H),7.03(t,J=72.8Hz,1H),4.43-4.30(m,3H) ,3.51(m,1H),3.08(d,J=8.0Hz,2H),2.59-2.45(m,1H),2.22-2.10(m,6H),1.89-1.75(m,2H),1.69-1.51(m,4H). LCMS m / z=417.1[M+H] + .

[0209] Examples 63 and 64: (1S,3s)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol and (1S,3s)-3-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol [ka] *Arbitrarily assigned stereochemistry (1S,3s)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol and (1S,3s)-3-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol were prepared according to general procedure C using (1s,3r)-3-(aminomethyl)cyclobutan-1-ol (HCl salt) as the secondary amine. The crude reaction mixture was purified by flash silica gel chromatography (DCM / MeOH=10 / 1) to give a mixture of isomers as a white solid. The isomers were then separated by SFC (column DAICEL CHIRALPAK IG (250mm*30mm, 10um); conditions: 0.1% NH3 . HOMEOH; start B: 45%; end B: 45%; flow rate (ml / min): 80) to give (1S,3s)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy))phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol (75.75 mg, 6% yield) as a white solid, and (1S,3s)-3-(((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol (237.56 mg, 19% yield) as a white solid.

[0210] *Peak 1, Example 63: 1H NMR (500MHz, DMSO-d6) δppm7.95-7.84(m,2H),7.55-7.23(m,3H),4.88-4.88(m,1H),4.16(brs,2H),4.18-4.13(m,1H),3.91-3.74(m,1H) ), 2.46-2.42(m,2H), 2.24-2.16(m,2H),1.88-1.80(m,2H), 1.75-1.60(m,1H),1.52-1.44(m,2H),1.40-1.37(m,2H),1.32-1.15(m,5H). LCMS m / z=417.1[M+H] + .

[0211] *Peak 2, Example 64: 1 H NMR500MHz, DMSO-d6)δppm7.92-7.87(m,2H),7.56-7.19(m,3H),4.85(d,J=6.5Hz,1H),4.08(br s,2H),3.90-3.83(m,1H),2.79(t,J=5.5Hz,1H),2.42-2.40(m,2H),2.24-2.16(m,2H) ,1.98-1.92(m,2H),1.86-1.80(m,2H),1.73-1.66(m,3H),1.43-1.34(m,2H),1.28(br s,1H),1.23-1.15(m,2H). LCMS m / z=417.1[M+H] + .

[0212] Example 65: (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] 1. Synthesis of (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 3, 100 mg, 0.3 mmol) as the hydrochloride salt and tetrahydro-4H-pyran-4-one (36 μL, 0.4 mmol) were taken up in DCM (2 mL). To this was added DIPEA (160 μL, 0.9 mmol) with stirring. After 10 min, acetic acid (52 μL, 0.9 mmol) was added with stirring. After 10 min, sodium triacetoxyborohydride (255 mg, 1.2 mmol) was added with stirring. Additional DCM (2 mL) was added and the reaction was stirred at room temperature overnight. The reaction mixture was poured into saturated sodium bicarbonate, extracted with ethyl acetate and the organics were evaporated. The residue was purified by silica gel chromatography using 0-100% 3:1 ethyl acetate / ethanol in heptane (+2% NH4OH) as eluent to give (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine (117 mg, 93%). 1 H NMR(400MHz,CD3OD)δ(ppm):7.85-7.99(m,2H),7.26-7.33(m,2H),6.79-7.21(m,1H),4.21( dt, J=4.83, 2.48Hz, 2H), 3.93(dt, J=10.10, 2.10Hz, 2H), 3.40(td, J=11.86, 2.13Hz, 2H), 3.1 8(tt, J=6.65, 3.51Hz, 1H), 2.81(tt,J=10.95,4.11Hz,1H),2.21(dt,J=13.68,5.96Hz,2H),1 .91-1.97(m,3H),1.78-1.85(m,2H),1.57-1.65(m,2H),1.41-1.52(m,2H)1.25-1.38(m,1H). LCMS m / z=417.2[M+H] + .

[0213] 2. Synthesis of (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine (40 mg, 0.1 mmol) was taken up in DMF (1 mL). To this was added sodium hydride (60% purity, 8 mg, 0.2 mmol) followed by iodomethane (24 μL, 0.4 mmol). The reaction was stirred at room temperature for 45 min to 1.5 h. The reaction was quenched by the addition of saturated sodium bicarbonate solution, extracted with ethyl acetate and the organics were evaporated. The residue was dissolved in DMSO and purified by preparative HPLC (Waters Sunfire Prep C18 5μm OBD 30×100mm; 5-55% MeCN in water (+TFA)) to give (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine (trifluoroacetate) as a white solid (19mg, 36%). LCMS m / z=431.3[M+H] + ,t R =1.38 minutes.

[0214] Example 66: (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] The title compound (trifluoroacetate salt) was prepared from (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 4 as the hydrochloride salt) as a clear oil using a procedure similar to that described for Example 65 (18 mg, 38%, in two steps). LCMS m / z=431.3 [M+H] + ,t R =1.39 minutes.

[0215] Example 67: 4-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine [ka] 4-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine was prepared from 4-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine dihydrochloride (Intermediate 7) and 4-(difluoromethoxy)benzenesulfonyl chloride as a white solid (48 mg, 89%) using a method similar to that described in Example 35 and purified by preparative HPLC (Welch Xtimate C18 25×150 mm, 5 μm; 33-63% MeCN / water (10 mM NH4HCO3) to give the desired compound (48 mg, 89%). LCMS m / z=417.2 [M+H] + .t R =0.59 minutes.

[0216] Examples 68 and 69: (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-8-azabicyclo[3.2.1]octan-3-amine and (1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] *Arbitrarily assigned stereochemistry (1R,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-8-azabicyclo[3.2.1]octan-3-amine was prepared from 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 6) and 2-oxaspiro[3.3]heptan-6-amine using a method similar to that described in Example 19 and purified by column chromatography (24 g SiO, 20-50-100% EtOAc / EtOH (3 / 1) in heptane) to give: *Peak 1, Example 68; white solid (35 mg, 36%). 1 H NMR(400MHz,CD3OD)δ(ppm):8.53(d,J=9.0Hz,1H),7.84(d,J=8.0Hz,1H),4.72(s,2H),4.59(s,2H),4.16(br s,2H),3.05-3.17(m,1H),2.84-2.94(m,4H),2.46-2.57(m,2H),2.12-2.22(m,2H),1.99-2.11(m,2H),1.85-1.97(m,4H),1.65(br d,J=15.0Hz,2H). LCMS m / z=446.2[M+H] + . *Peak 2, Example 69; white solid (22 mg, 23%). 1H NMR(400MHz,CD3OD)δ(ppm):8.54(d,J=8.0Hz,1H),7.85(d,J=8.0Hz,1H),4.21(br s,2H),3.63-3.75(m,3H),2.92(s,3H),2.71-2.78(m,1H),2.59(br s,2H),2.17-2.23(m,2H),2.04-2.14(m,2H),1.93(dt,J=6.3,3.4Hz,2H),1.86(br s,2H),1.58(br d,J=15.0Hz,2H),1.45(dd,J=5.0,2.0Hz,2H). LCMS m / z=446.2[M+H] + .

[0217] Example 70: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((R)-tetrahydrofuran-3-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(((R)-tetrahydrofuran-3-yl)-8-azabicyclo[3.2.1]octan-3-amine was prepared from 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 5) and (R)-tetrahydrofuran-3-amine using a method similar to that described in Example 19 and purified by column chromatography (12 g SiO, 50-100% EtOAc in heptane) to give a white powder after lyophilization (15 mg, 19%). 1 H NMR(400MHz,CD3OD)δ(ppm):7.86-8.00(m,2H),7.31(d,J=8.8Hz,2H),6.76-7.24(m,1H),4.19(br s, 2H), 3.68-3.97(m, 3H), 3.37-3.52(m, 2H), 2.99(br t, J=6.0Hz, 1H), 1.96-2.21(m, 5H), 1.60-1.78(m, 3H), 1.34-1.53(m, 2H). LCMS m / z=403.1[M+H] + .

[0218] Example 71: (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-fluorooxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-fluorooxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine (stereochemistry arbitrarily assigned) was prepared from 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (intermediate 5) and (3-fluorooxetan-3-yl)methanamine using a method similar to that described in Example 19 and purified by column chromatography (12 g SiO2, 20-50-100% EtOAc / EtOH3 / 1 in heptane) to give a white powder after lyophilization (6.3 mg, 7%, more polar isomer, stereochemistry arbitrarily assigned). LCMS m / z=421.1 [M+H] + .t R =0.58 minutes.

[0219] Example 72: (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine [ka] (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine was prepared from (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 3) and oxetane-3-carbaldehyde using a method similar to that described in Example 19 and purified by preparative HPLC (Welch Xtimate C18 25× 150 mm, 5 μm; 33-63% MeCN / water (10 mM NH4HCO3) to give the desired compound (48 mg, 76%). LCMS m / z=403.1 [M+H] + .t R =0.56 minutes.

[0220] Example 73: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine was prepared from 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 5) and tetrahydro-2H-pyran-4-amine using a method similar to that described in Example 19 and purified by preparative HPLC (Welch Xtimate C18 25×150 mm, 5 μm; 33-63% MeCN / water (10 mM NH4HCO3)) to give the desired compound (18 mg, 22%). LCMS m / z=417.2 [M+H] + .t R =0.58 minutes.

[0221] Example 74: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-amine was prepared from 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 5) and cyclobutanamine using a method similar to that described in Example 19 and purified by preparative HPLC (Welch Xtimate C18 25×150 mm, 5 μm; 33-63% MeCN / water (10 mM NH4HCO3)) to give the desired compound (61 mg, 67%). LCMS m / z=389.1 [M+H] + .t R =0.55 minutes.

[0222] Example 75: (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine [ka] (1R,3s,5S)-8-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine was prepared from (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 9) and tetrahydro-4H-pyran-4-one using a method similar to that described in Example 19 and purified by column chromatography (12 g SiO2, 50-100% EtOAc / EtOH 3 / 1 in heptane) to give a white sticky solid (65 mg, 63%). 1H NMR (methanol-d4,400MHz): δ(ppm)8.55(d,J=8.5Hz,1H),7.84(d,J=8.0Hz,1H),4.28(dd,J=4.0,3.0Hz,2H),3.94(dd,J=11.0,4.0Hz,2H),3.40(td,J=12. 0,2.0Hz,2H),3.16(tt,J=11.3,5.5Hz,1H),2.95(s,3H),2.71-2.88(m,1H), 1.94-2.05(m,4H),1.78-1.87(m,4H),1.45-1.55(m,2H),1.30-1.43(m,2H). LCMS m / z=434.2[M+H] + .

[0223] Example 76: 1-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-methylpropan-2-ol [ka] 1-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-methylpropan-2-ol was prepared from (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 4) and 2,2-dimethyloxirane using a method similar to that described in Example 17 and purified by column chromatography (12 g SiO2, 100% EtOAc to 100% EtOAc / EtOH 3 / 1) to give a white powder after lyophilization (30 mg, 74%). 1 H NMR(400MHz,CD3OD)δ(ppm):7.88-8.05(m,2H),7.33(d,J=7.3Hz,2H),6.77-7.24(m,1H),4.34(br s,2H),3.07-3.24(m,1H),2.72(s,2H),2.08(br d,J=13.1Hz,2H),1.45-1.81(m,6H),1.24(d,J=1.0Hz,6H)LCMS m / z=405.1[M+H] +.

[0224] Example 77: 1-(((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-methylpropan-2-ol [ka] 1-(((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-methylpropan-2-ol was prepared from (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine (Intermediate 3) and 2,2-dimethyloxirane using a method similar to that described in Example 17 and purified by column chromatography (12 g SiO2, 100% EtOAc) to give a white powder after lyophilization (12 mg, 30%). 1 H NMR(400MHz,CD3OD)δ(ppm):7.94(dd,J=8.8,1.0Hz,2H),7.31(d,J=7.8Hz,2H),6.77-7.22(m,1H),4.18(br s,2H),2.89(br t,J=5.8Hz,1H),2.48(s,2H),1.97-2.17(m,4H),1.76(br d,J=14.1Hz,2H),1.34-1.55(m,2H),1.20(d,J=1.0Hz,6H). LCMS m / z=405.1[M+H] + .

[0225] Assay EBP functional assay The EBP immunoaffinity (IA) LC-MS assay measures the potency of small molecule inhibitors of EBP by quantifying the concentration-dependent changes in the enzyme's substrate and product using liquid chromatography atmospheric pressure chemical ionization multiple reaction monitoring mass spectrometry (LC-APCI MRM MS). HEK293T cells were utilized as a source of EBP enzyme. The enzyme was incubated with small molecule inhibitors at various concentrations for 30 min. Then, a deuterated form of the EBP substrate, zymosterol-d5 (Avanti Polar Lipids, Cat. No. 700068P-1mg), was added and the plate was incubated at 37°C for 4 h. Finally, the sterol isomers were extracted and injected into the LC-APCI MRM MS. The MRM transitions used for quantification of both zymosterol and dihydrolatosterol (substrate and product of the EBP enzyme reaction, respectively) are 372.3-203.2, CE30, and DP80 in positive ion mode. The percent conversion of zymosterol-d5 to dehydrolatosterol-d5 was used to determine the IC 50 Curves were derived. Tacine-1 (1'-[(4-methoxyphenyl)sulfonyl]-4-methyl-1,4'-bipiperidine, CAS 792927-06-1) was used as a reference small molecule inhibitor. [ka]

[0226] The percent conversion data versus compound concentration was fitted to the following 4-parameter logistic model to obtain IC 50 The curve was created:

number

Claims

1. A compound represented by formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, A is CH ２ or a bond, R １ and R ２ are each independently H, C １～６ Alkyl, C ３～８ Cycloalkyl, Het, -Z-Het, and -Z-C ３～８ cycloalkyl, wherein said C １～６ Alkyl, C ３～８ Cycloalkyl and Het each optionally include one or more R ４ with the proviso that R １ and R ２ is not H; or R １ and R ２ together with the nitrogen atom to which they are attached, optionally represent one or more substituents R ４ forming a 4- to 10-membered heterocyclyl substituted with Z is a C optionally substituted with one or more halo. １～４ is alkyl, Het is 4- to 7-membered monocyclic heterocyclyl or 6- to 10-membered bicyclic heterocyclyl, each of which is optionally selected from R ４ is replaced by R ３ is phenyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl, wherein the phenyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl each optionally contain one or more substituents R ５ is replaced by R ４ is expressed independently for each occurrence as C １～６ Alkyl, halo, and -OR ４ａ wherein said C １～６ The alkyl group may optionally be -OR ４ａ is replaced by R ４ａ is H, C １～６ Alkyl, or C １～６ is haloalkyl, R ５ independently for each occurrence: halo, -OR ５ａ , C １～６ Alkyl, C ３～６ cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, or phenyl, wherein １～６ Alkyl, C ３～６ Cycloalkyl and 5- to 6-membered monocyclic heteroaryl each optionally include one or more halo, C １～４ Alkyl, or -OR ５ａ or Two R's ５ together with their intervening atoms, C １～６ Alkyl, oxo, halo, and -OR ５ａ one or more R independently selected from ６ forming a 5- to 7-membered heterocycle optionally substituted with R ５ａ is H, C １～６ Alkyl, or C １～６ haloalkyl, wherein said C １～６ The alkyl is optionally substituted with alkoxy; R ７ is H or OR ７ａ and R ７ａ is H, H, C １～６ Alkyl, or C １～６ haloalkyl, wherein said C １～６ The alkyl is optionally substituted with alkoxy, or a pharma- ceutically acceptable salt thereof.

2. In the formula, R １ and R ２ Each independently represents H, C １～６ Alkyl, C ３～８ cycloalkyl, Het, -Z-Het, wherein １～６ Alkyl, C ３～８ Cycloalkyl and Het each optionally include one or more R ４ with the proviso that R １ and R ２ is not H; or R １ and R ２ together with the nitrogen atom to which they are attached, optionally one or more substituents R ４ forming a 4- to 10-membered heterocyclyl substituted with Z is C optionally substituted with one or more halo １～４ is alkyl, Het is 4- to 7-membered monocyclic heterocyclyl or 6- to 10-membered bicyclic heterocyclyl, each of which is optionally selected from R ４ is replaced by R ３ is phenyl, 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl, wherein the phenyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered bicyclic heteroaryl each optionally contain one or more substituents R ５ is replaced by R ４ But for each occurrence, C １～６ Alkyl, halo and -OR ４ａ is selected from R ４ａ But, H, C １～６ Alkyl, or C １～６ is haloalkyl, R ５ independently for each occurrence: halo, -OR ５ａ , C １～６ Alkyl, C ３～６ cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, or phenyl, １～６ Alkyl, and C ３～６ Each cycloalkyl is optionally selected from one or more halo, or -OR ５ａ or Two R's ５ together with their intervening atoms, C １～６ Alkyl, oxo, halo, and -OR ５ａ one or more R independently selected from ６ forming a 5- to 7-membered heterocycle optionally substituted with R ５ａ But, H, C １～６ Alkyl, or C １～６ haloalkyl, wherein said C １～６ The alkyl is optionally substituted with alkoxy; R ７ is H or OR ７ａ and R ７ａ But, H, C １～６ Alkyl, or C １～６ haloalkyl, wherein said C １～６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the alkyl is optionally substituted with alkoxy.

3. The compound has formula II: 【Chemistry 2】 3. The compound of claim 1 or 2, which is represented by: or a pharma- ceutically acceptable salt thereof.

4. The compound has formula (IIA) or (IIB): 【Chemistry 3】 4. The compound of claim 3, wherein the compound is represented by the formula:

5. In the formula, R ３ is selected from the group consisting of phenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, furanyl, oxadiazolyl, imidazopyridinyl, thiophenyl, thiazoyl, triazoyl, and indolyl, each of which is optionally selected from one to three R ５ 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, substituted with:

6. In the formula, R ３ is selected from the group consisting of phenyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, furanyl, oxadiazolyl, imidazopyridinyl, thiophenyl, and indoyl, each of which is optionally selected from one to three R ５ 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, substituted with:

7. In the formula, R ３ is expressed by the following formula: 【Chemistry 4】 Each of these is optionally represented by 1 to 3 R ５ or R ３ is expressed by the following formula: 【Chemistry 5】 Each of these is optionally represented by one or two R ６ 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, substituted with:

8. In the formula, R ３ is expressed by the following formula: 【Chemistry 6】 Each of these is optionally represented by 1 to 3 R ５ or R ３ is expressed by the following formula: 【Chemistry 7】 Each of these is optionally represented by one or two R ６ 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, substituted with:

9. In the formula, R ３ is selected from the group consisting of phenyl, pyrazolyl, imidazolyl, oxazolyl, and pyridinyl, each of which is optionally selected from 1 to 3 R ５ 7. The compound of claim 5 or 6, or a pharma- ceutically acceptable salt thereof, substituted with:

10. In the formula, R ３ is expressed by the following formula: 【Chemistry 8】 Each of these is optionally represented by one or two R ５ or Or R ３ is expressed by the following formula: 【Chemistry 9】 Each of these is optionally represented by one or two R ６ 9. The compound of claim 7 or 8, or a pharma- ceutically acceptable salt thereof, substituted with:

11. In the formula, R ３ is expressed by the following formula: 【Chemistry 10】 8. The compound according to claim 7, represented by: or a pharma- ceutically acceptable salt thereof.

12. In the formula, R ３ is expressed by the following formula: 【Chemistry 11】 9. The compound according to claim 8, wherein the compound is represented by the formula: or a pharma- ceutically acceptable salt thereof.

13. In the formula, R ３ is expressed by the following formula: 【Chemistry 12】 13. The compound according to claim 11 or 12, wherein the compound is represented by the formula: or a pharma- ceutically acceptable salt thereof.

14. In the formula, R ５ independently for each occurrence: halo, -OR ５ａ , C １～６ alkyl, 4- to 7-membered monocyclic heterocyclyl, or phenyl, １～６ The alkyl group may optionally be -OR ５ａ or halo, wherein said 5-6 membered monocyclic heteroaryl is optionally substituted with C １～３ substituted with alkyl, R ６ But, C １～３ 14. The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, which is alkyl.

15. In the formula, R ５ independently for each occurrence: halo, -OR ５ａ , C1 ～６ alkyl, 4- to 7-membered monocyclic heterocyclyl, or phenyl, １～６ The alkyl group may optionally be -OR ５ａ 14. The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, substituted with:

16. In the formula, R ５ is independently at each occurrence -F, -Cl, -CH ３ , -CH ２ CH ３ , -CF ３ , -OCHF ２ , -OCH ３ , -CH ２ OCH ３ , tetrahydropyranyl, phenyl, pyridinyl; ６ But -CH ３ and optionally, R ５ is expressed by the following formula: 【Chemistry 13】 15. The compound of claim 14, wherein:

17. In the formula, R １ and R ２ together with the nitrogen atom to which they are attached, optionally 1 to 3 R ４ 17. The compound according to any one of claims 1 to 16, which forms a 4-9 membered heterocyclyl substituted with: or a pharma- ceutically acceptable salt thereof.

18. In the formula, R １ and R ２ together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic saturated heterocyclyl, or an 8- to 9-membered bicyclic saturated heterocyclyl, each of which optionally comprises 1 to 3 R ４ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, substituted with:

19. In the formula, R １ and R ２ together with the nitrogen atom to which they are attached form the following formula: 【Chemistry 14】 each of which optionally has 1 to 3 R ４ 20. The compound of claim 18, or a pharma- ceutically acceptable salt thereof, substituted with:

20. In the formula, R １ and R ２ together with the nitrogen atom to which they are attached form the following formula: 【Chemistry 15】 each of which optionally has 1 to 3 R ４ 20. The compound of claim 18, or a pharma- ceutically acceptable salt thereof, substituted with:

21. In the formula, R １ and R ２ together with the nitrogen atom to which they are attached form the following formula: 【Chemistry 16】 20. The compound of claim 19, which forms a group represented by:

22. In the formula, R １ and R ２ together with the nitrogen atom to which they are attached form the following formula: 【Chemistry 17】 21. The compound of claim 20, which forms a group represented by:

23. In the formula, R １ Het, -C １～３ Alkyl-Het, -C １～３ Alkyl-C ３～６ Cycloalkyl, C ３～６ Cycloalkyl, or C １～６ alkyl, wherein said C ３～６ Cycloalkyl and the C １～６ Each alkyl group may optionally be one or two R ４ is replaced by R ２ is H or C １～３ is alkyl, Het is 4- to 6-membered monocyclic saturated heterocyclyl, or 6- to 7-membered bicyclic saturated heterocyclyl, wherein the 4- to 6-membered monocyclic saturated heterocyclyl and the 6- to 7-membered bicyclic saturated heterocyclyl contain one oxygen ring atom, each optionally containing one or two R ４ is replaced by R ４ is, independently for each occurrence, -OR ４ａ , halo, and C １～３ alkyl, wherein said C １～３ The alkyl group may optionally be -OR ４ａ is replaced by R ４ａ is H or C １～３ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

24. In the formula, R １ Het, -C １～３ Alkyl-Het, C ３～６ Cycloalkyl, or C １～６ alkyl, wherein said C ３～６ Cycloalkyl and the C １～６ Each alkyl group may optionally be one or two R ４ is replaced by R ２ is H or C １～３ is alkyl, Het is 4- to 6-membered monocyclic saturated heterocyclyl, or 6- to 7-membered bicyclic saturated heterocyclyl, wherein the 4- to 6-membered monocyclic saturated heterocyclyl and the 6- to 7-membered bicyclic saturated heterocyclyl contain one oxygen ring atom, each optionally containing one or two R ４ is replaced by R ４ is independently at each occurrence -OH, halo or C １～３ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

25. Het is oxetanyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, 2-oxaspiro[3.3]heptanyl, or 5-oxabicyclo[2.1.1]hexanyl, each of which is optionally joined by one R ４ 24. The compound of claim 23, or a pharma- ceutically acceptable salt thereof, substituted with:

26. Het is oxetanyl, tetrahydro-2H-pyranyl, or 5-oxabicyclo[2.1.1]hexanyl, each of which is optionally joined by one R ４ 25. The compound of claim 24, or a pharma- ceutically acceptable salt thereof, substituted with:

27. In the formula, R １ is expressed by the following formula: 【Chemistry 18】 Each of these is optionally represented by one or two R ４ 24. The compound of claim 23, or a pharma- ceutically acceptable salt thereof, substituted with:

28. In the formula, R １ is expressed by the following formula: 【Chemistry 19】 Each of these is optionally represented by one or two R ４ 25. The compound of claim 24, or a pharma- ceutically acceptable salt thereof, substituted with:

29. In the formula, R １ is expressed by the following formula: 【Chemistry 20】 24. The compound of claim 23, wherein:

30. In the formula, R １ is expressed by the following formula: 【Chemistry 21】 29. The compound of claim 28, wherein:

31. In the formula, R ２ is H or -CH ３ 31. The compound according to any one of claims 23 to 30, which is: or a pharma- ceutically acceptable salt thereof.

32. In the formula, R ２ The compound according to any one of claims 23 to 30, wherein is H, or a pharma- ceutically acceptable salt thereof.

33. In the formula, each R ４ is independently for each occurrence F, -CH ３ , -CH ２ CH ２ OCH ３ , -CH ２ OH, -OH, or -OCH ３ 33. The compound according to any one of claims 1 to 32, which is: or a pharma- ceutically acceptable salt thereof.

34. The compound has formula (III) or (IV): 【Chemical 22】 or a pharma- ceutically acceptable salt thereof, wherein R １ is C ３～６ Cycloalkyl, Het, or -CH ２ -Het, wherein said C ３～６ Cycloalkyl can optionally be one R ４ is replaced by Het is a 4- to 6-membered monocyclic saturated heterocyclyl, or a 6- to 7-membered bicyclic saturated heterocyclyl, wherein said 4- to 6-membered monocyclic saturated heterocyclyl and said 6- to 7-membered bicyclic saturated heterocyclyl contain one oxygen ring atom, each optionally containing one R ４ is replaced by Ring A is a 4- to 6-membered monocyclic saturated heterocyclyl, or an 8- or 9-membered bicyclic heterocyclyl, each of which optionally contains one or two R ４ is replaced by R ３ is phenyl, pyridinyl, or 5-membered heteroaryl, each of which is optionally joined by one or two R ５ is replaced by R ４ is independently selected from each occurrence -OH, halo and C １～３ alkyl, R ５ independently for each occurrence: halo, -OR ５ａ , C １～６ alkyl, 4- to 6-membered monocyclic heterocyclyl, or phenyl, wherein １～６ Alkyl optionally contains 1 to 3 halo or -OR ５ａ or Two R's ５ together with their intervening atoms, C １～６ 1 to 3 R independently selected from alkyl, oxo, and halo; ６ forming a 6-membered heterocycle optionally substituted with R ５ａ is H, C １～３ Alkyl, or C １～３ The compound of claim 3 which is a haloalkyl.

35. wherein Het is oxetanyl, tetrahydro-2H-pyranyl, or 5-oxabicyclo[2.1.1]hexanyl, each of which may optionally be selected from the group consisting of one R ４ is replaced by Ring A is 【Chemistry 23】 each of which optionally represents one to two R ４ is replaced by R ３ but, 【Chemistry 24】 each of which optionally contains one or two R ５ or Or R ３ but, 【Chemistry 25】 each of which optionally contains one or two R ６ 35. The compound of claim 34, or a pharma- ceutically acceptable salt thereof, substituted with:

36. In the formula, R ３ is expressed by the following formula: 【Chemistry 26】 36. The compound of claim 35, wherein:

37. wherein Het is of the following formula: ​ The compound according to any one of claims 34 to 36, which is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

38. In the formula, R ４ independently for each occurrence, -CH ３ 38. The compound of any one of claims 34 to 37, wherein R is 0, 1 or 2; OH or F; or a pharma- ceutically acceptable salt thereof.

39. In the formula, R ５ independently for each occurrence, -OCF ３ , -OCHF ２ , Cl, -CH ２ OCH ３ 、-CH ３ 、-CF ３ ,-OCH ３ 、-CH ２ CH ３ 、 【Chemistry 28】 39. The compound according to any one of claims 34 to 38, which is: or a pharma- ceutically acceptable salt thereof.

40. The compound has the formula (V): 【Chemical 29】 3. The compound of claim 1 or 2, which is represented by: or a pharma- ceutically acceptable salt thereof.

41. The compound has the formula (VA) or (VB): 【Chemistry 30】 41. The compound of claim 40, wherein said compound is represented by: or a pharma- ceutically acceptable salt thereof.

42. In the formula, R ３ is selected from the group consisting of phenyl, pyrazolyl, isoxazolyl, and pyridinyl, each of which is optionally selected from 1 to 3 R ５ 42. The compound of claim 40, or a pharma- ceutically acceptable salt thereof, substituted with:

43. In the formula, R ３ is expressed by the following formula: 【Chemistry 31】 It is expressed as Each of the formulas shown above may optionally contain one to three R ５ 43. The compound of any one of claims 40 to 42, or a pharma- ceutically acceptable salt thereof, substituted with:

44. In the formula, R ３ is expressed by the following formula: 【Chemistry 32】 The compound according to any one of claims 40 to 43, which is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

45. In the formula, R ５ independently for each occurrence: halo, -OR ５ａ Or C １～６ 45. The compound of any one of claims 40 to 44, or a pharma- ceutically acceptable salt thereof, which is alkyl.

46. In the formula, R ７ The compound according to any one of claims 40 to 45, wherein is H or OH.

47. In the formula, R １ and R ２ together with the nitrogen atom to which they are attached form the formula: 【Chemical 33】 The compound according to any one of claims 40 to 46, which forms a group represented by: or a pharma- ceutically acceptable salt thereof.

48. The compound has formula (VI) or (VII): 【Chemical Formula 34】 or a pharma- ceutically acceptable salt thereof, wherein R １ is C １～６ Alkyl, C ３～６ Cycloalkyl, Het, -CH ２ -C ３～４ Cycloalkyl, or -CH ２ -Het, wherein said C １～６ Alkyl, C ３～６ Cycloalkyl and -CH ２ -C ３～４ Each cycloalkyl optionally has one or two R ４ is replaced by Het is a 4-6 membered monocyclic saturated heterocyclyl containing one oxygen ring atom; Ring A is a 4- to 6-membered monocyclic saturated heterocyclyl, or an 8- or 9-membered bicyclic saturated heterocyclyl, each of which optionally contains one or two R ４ is replaced by R ４ is independently for each occurrence: -OR ４ａ , -CH ２ -OR ４ａ , and C １～３ alkyl, R ４ａ is H or C １～３ is alkyl, R ５ is -OR ５ａ and R ５ａ is C １～３ 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

49. 49. The compound of claim 48, or a pharma- ceutically acceptable salt thereof, wherein Het is tetrahydropyranyl or oxetanyl.

50. In the formula, R １ but, (i) one or two R ４ C optionally substituted with １～６ Is it an alkyl group? (ii) a compound of the formula 【Chemistry 35】 or (iii) a compound of the formula: 【Chemical 36】 Each of these is optionally represented by one or two R ４ 50. The compound of claim 48 or 49, substituted with:

51. In the formula, R １ is -CH(CH ３ ) CH ２ CH ２ OCH ３ Or CH ２ C (CH ３ ) ２ OH or R １ is expressed by the following formula: 【Chemical 37】 51. The compound of claim 50, represented by: or a pharma- ceutically acceptable salt thereof.

52. In the formula, ring A is 【Chemical Formula 38】 each of which optionally contains one or two R ４ 50. The compound of claim 48, or a pharma- ceutically acceptable salt thereof, substituted with:

53. In the formula, ring A is 【Chemical 39】 53. The compound of claim 52, which is: or a pharma- ceutically acceptable salt thereof.

54. In the formula, each R ４ are independently -OH, -OCH ３ , -CH ２ OH, or -CH ３ 54. The compound according to any one of claims 48 to 53, which is: or a pharma- ceutically acceptable salt thereof.

55. In the formula, R ５ But -OCHF ２ 55. The compound according to any one of claims 48 to 54, which is: or a pharma- ceutically acceptable salt thereof.

56. The compound is 3-methyl-4-(((1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-1,2,5-oxadiazole, 5-(((1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)oxazole, (1R,3s,5S)-8-((2-methoxy-6-methylpyridin-3-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((4-chloro-1-(methoxymethyl)-1H-pyrazol-5-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 3,3-dimethyl-6-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-3,4-dihydroquinolin-2(1H)-one, 5-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)oxazole, (1R,3s,5S)-8-(isochroman-7-ylsulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((5-(methoxymethyl)furan-2-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 2-methyl-3-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole, (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-((3-phenyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octane, 5-methyl-2-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, (1R,3s,5S)-8-((1,4-dimethyl-1H-pyrazol-5-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 2-((8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)cyclobutan-1-ol, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, 9-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3,3-difluoro-9-azabicyclo[3.3.1]nonane, 4-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)tetrahydro-2H-pyran-4-ol, 4-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)tetrahydro-2H-pyran-4-ol, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 6-((1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxa-6-azaspiro[3.3]heptane, 6-((1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxa-6-azaspiro[3.3]heptane, (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(morpholinomethyl)-8-azabicyclo[3.2.1]octan-3-ol, 4-(((1R,3s,5S)-8-((4-(difluoromethoxy)-2,6-difluorophenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, 4-(((1R,3s,5S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, 4-(((1R,3r,5S)-8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, 4-(((1R,3s,5S)-8-((3,5-dimethylisoxazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, 4-(((1R,3s,5S)-8-((4,6-dimethylpyridin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, (1R,3r,5S)-3-(4-methylpiperidin-1-yl)-8-((1-(4-methylpyridin-2-yl)-1H-pyrazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-((1-(4-methylpyridin-2-yl)-1H-pyrazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octane, 4-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-(trifluoromethyl)thiazole, (1R,3s,5S)-8-((2,6-difluoro-4-methoxyphenyl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-((1-phenyl-1H-1,2,3-triazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octane, 1,3-dimethyl-5-(((1R,3s,5S)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-1H-pyrazolo[3,4-b]pyridine, (1R,3s,5S)-8-((3,5-dimethylpyridin-2-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, (1R,3s,5S)-8-((2,6-dimethylpyridin-3-yl)sulfonyl)-3-(4-methylpiperidin-1-yl)-8-azabicyclo[3.2.1]octane, 1-((8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)propan-2-ol, 1-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-methylpyrrolidin-3-ol, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(3-methoxypyrrolidin-1-yl)-8-azabicyclo[3.2.1]octane, 6-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxa-6-azaspiro[3.4]octane, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(4-methoxybutan-2-yl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-8,8'-diaza-3,8'-bi(bicyclo[3.2.1]octane), 8-((4-(difluoromethoxy)phenyl)sulfonyl)-3-(3-(2-methoxyethyl)azetidin-1-yl)-8-azabicyclo[3.2.1]octane, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(3-methoxybutan-2-yl)-8-azabicyclo[3.2.1]octan-3-amine, rac-((1R,2S)-2-(((8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclopropyl)methanol, 3-(8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.1]heptane, 8'-((4-(difluoromethoxy)phenyl)sulfonyl)-3,8'-diaza-3,3'-bi(bicyclo[3.2.1]octane), rac-4-(((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)butan-2-ol, rac-4-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)butan-2-ol, (1R,3r)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol, (1R,3r)-3-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3yl)amino)methyl)cyclobutan-1-ol, (1S,3s)-3-((((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol, (1S,3s)-3-((((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)methyl)cyclobutan-1-ol, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, 4-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)morpholine, (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((R)-tetrahydrofuran-3-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-((3-fluorooxetan-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, 8-((4-(difluoromethoxy)phenyl)sulfonyl)-N-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-amine, (1R,3s,5S)-8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-amine, 1-(((1R,3s,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-methylpropan-2-ol, and 1-(((1R,3r,5S)-8-((4-(difluoromethoxy)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-2-methylpropan-2-ol 2. The compound of claim 1, which is:

57. 57. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

58. A method for treating a disease or disorder mediated by emopamil binding protein, comprising administering to a subject an effective amount of a compound described in any one of claims 1 to 56 or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described in claim 57.

59. A method for treating an autoimmune disease in a subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 56 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57.

60. 60. The method of claim 59, wherein the autoimmune disorder is multiple sclerosis.

61. 61. The method of claim 60, wherein the compound or pharmaceutical composition repairs the myelin sheath or forms a new myelin sheath in the subject.

62. 58. A method of promoting myelination in a subject having a myelin-related disease or disorder, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 56, or a pharma- ceutical composition according to claim 57.

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