Emopamil binding protein inhibitors and uses thereof

Abstract

Provided is a compound of formula (I): [Formula 1] or a pharma- ceutically acceptable salt thereof, which is useful for inhibiting EBP and for treating various conditions or diseases mediated by EBP, such as multiple sclerosis.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 314,095, filed February 25, 2022. The entire contents of the foregoing application are expressly incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present disclosure relates to inhibitors of emopamil-binding protein (EBP) and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, their use in the treatment of diseases, their use in any combination with a pharmaceutically acceptable carrier for the manufacture of pharmaceutical preparations, the use of the pharmaceutical preparations in the treatment of diseases, and methods of treating diseases comprising administering EBP inhibitors to warm-blooded animals, particularly humans. [Background technology]

[0003] Emopamil-binding protein (EBP) is a Δ8-Δ7 sterol isomerase enzyme that isomerizes the double bond within a sterol molecule, transferring the double bond from the 8-9 position to the 7-8 position. Specifically, EBP converts zymostenol to lathosterol or zymosterol to dehydrolathosterol during cholesterol biosynthesis (Silve et al., 1996, J. Biol. Chem. 271(37), 22434-22440). Accumulation of 8-9 unsaturated sterols has been shown to stimulate 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 to protect them. Demyelinating diseases, or myelin-related diseases, result when these myelin sheaths are damaged, degraded, or reduced in thickness. Loss of myelin sheaths can interfere with 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. Due to its function in converting 8-9 sterols, inhibition of EBP is a potential target for activating remyelination, as inhibition of EBP 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] Therefore, 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 pharmaceutically acceptable salt thereof, wherein X is CH2 or O; Y is CH2 or O; If only one of X and Y is O, q1 is 1 or 2; When Y is CH2, q2 is 0 or 1, or when Y is O, q2 is 2; p1 is 1 or 2; When X is CH2, p2 is 0 or 1, or when X is O, p2 is 2; R 1 is C 2~6 alkyl, Het, or -Z-Het, where C 2~6 Alkyl is one or more R A Het is optionally substituted by one or more R 2 is optionally replaced by; Z is 1 or more halo or C 1~3 C optionally substituted with alkoxy 1~4 is alkyl; Het is C 3~6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, or 6- to 8-membered bicyclic heterocyclyl, each of which is R 2 is optionally replaced by; R A are independent for each occurrence, OR 2a , S.R. 2a , or C(O)OR 2a and; R 2 independently for each occurrence, C 1~6 Alkyl, halo, -CN or OR 2a In this case, C 1~6 Alkyl may be one or more halo or C 1~3 optionally substituted with alkoxy; R 2a is H, C 1~6 Alkyl, or C 3~6 cycloalkyl, wherein C 1~6 Alkyl may be one or more halo or C 1~3 optionally substituted with alkoxy; R 3 is C 1~4alkyl-phenyl, phenyl, 5- or 6-membered monocyclic heteroaryl, or 9- to 10-membered bicyclic heteroaryl, wherein the phenyl, 5- or 6-membered monocyclic heteroaryl, and 9- to 10-membered bicyclic heteroaryl each have one or more substituents R 4 is optionally replaced by; R 4 independently for each occurrence, halo, -OR 4a , -CN, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 alkenyl, phenyl, or 5- or 6-membered monocyclic heteroaryl, wherein C 1~6 Alkyl or C 3~6 Each cycloalkyl may have one or more C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl, or halo, or a 5- or 6-membered monocyclic heteroaryl may have one or more C 1~6 optionally substituted with alkyl; or The Two R's 4 together with the intervening atoms form a 5- to 7-membered heterocyclyl; R 4a is H or C 1~6 alkyl, wherein C 1~6 alkyl is optionally substituted with one or more halo; n is 1 or 2; m is 1 or 2; R 5 are independently generated for each occurrence: H, halo, C 1~3 Alkyl, or C 1~3 haloalkyl; or two R 5 Let's go together 1~3 Forming alkylene; R 6 are independently generated for each occurrence: H, halo, C 1~3 Alkyl, or C 1~3 haloalkyl; or two R 6 Let's go together 1~3 Forming alkylene; However, the compound is [ka] There is a condition that it is not.

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

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

[0010] Another aspect of the present disclosure relates to the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder responsive to the inhibition of EBP. Also provided are compounds described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder responsive to the inhibition of EBP. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful in treating diseases or disorders mediated by 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 pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined in the first embodiment above. In another embodiment, for the compound of formula (I): X is CH2 or O; Y is CH2 or O; If only one of X and Y is O, q1 is 1 or 2; When Y is CH2, q2 is 0 or 1, or when Y is O, q2 is 2; p1 is 1 or 2; When X is CH2, p2 is 0 or 1, or when X is O, p2 is 2; R 1 is C 2~6 alkyl, Het, or -Z-Het, where C 2~6 Alkyl is 1 or more OR 2a Het is replaced by 1 or more R 2 is optionally replaced by; Z is C optionally substituted with one or more halo 1~4 is alkyl; Het is R 2 a 4- to 6-membered monocyclic heterocyclyl or a 6- to 8-membered bicyclic heterocyclyl optionally substituted by R 2 independently for each occurrence, C 1~6 Alkyl, or OR 2a and; R2 a is H or C 1~6 alkyl, wherein C 1~6 alkyl is optionally substituted with one or more halo; R 3 is phenyl, a 5- or 6-membered monocyclic heteroaryl, or a 9- to 10-membered bicyclic heteroaryl, wherein the phenyl, the 5- or 6-membered monocyclic heteroaryl, and the 9- to 10-membered bicyclic heteroaryl each have one or more substituents R 4 is optionally replaced by; R 4independently for each occurrence, halo, -OR 4a , -CN, C 1~6 Alkyl, C 3~6 cycloalkyl, or 5- or 6-membered monocyclic heteroaryl, wherein C 1~6 The alkyl is optionally substituted with one or more halo, and the 5- or 6-membered monocyclic heteroaryl is optionally substituted with one or more C 1~6 optionally substituted with alkyl; or The Two R's 4 together with the intervening atoms form a 5- to 7-membered heterocyclyl; R 4a is H or C 1~6 alkyl, wherein C1~6 alkyl is optionally substituted with one or more halo; n is 1 or 2; m is 1 or 2; R 5 are independently generated for each occurrence: H, halo, C 1~3 Alkyl, or C 1~3 haloalkyl; or two R 5 Let's go together 1~3 Forming alkylene; R 6 are independently generated for each occurrence: H, halo, C 1~3 Alkyl, or C 1~3 haloalkyl; or two R 6 Let's go together 1~3 Forming alkylene; However, the compound is [ka] isn't it.

[0013] In a second embodiment, for compounds of Formula (I) or pharmaceutically acceptable salts thereof, Het is a 4-6 membered oxygen-containing monocyclic saturated heterocyclyl, or a 6-8 membered oxygen-containing bicyclic saturated heterocyclyl; the remaining variables are as described in the first aspect or first embodiment. In an alternative embodiment, for compounds of Formula (I) or pharmaceutically acceptable salts thereof, Het is each 1-3 R2 C optionally replaced by 3~6 and the remaining variables are as described in the first aspect or first embodiment. In a further alternative embodiment, for a compound of formula (I), or a pharmaceutically acceptable salt thereof, Het is cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, dioxanyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 6-oxabicyclo[3.2.1]octanyl, or 2-oxabicyclo[3.1.1]heptanyl, each of which is selected from the group consisting of 1 to 3 R 2 the remaining variables are as described in the first aspect or first embodiment.

[0014] In a third embodiment, the compound of the present disclosure has formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (II) are as defined in the first aspect or the first or second embodiment above, or any alternative embodiment described herein.

[0015] In a fourth embodiment, for a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R 3 is phenyl, pyridyl, thiazolyl, or pyrazolyl, each of which is selected from 1 to 3 R 4 and optionally substituted by: wherein n is an integer from 0 to 10; and wherein n is an integer from 1 to 2 ...

[0016] In a fifth embodiment, for compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, R 3 teeth, [ka] and each of the above formulas is R 1 to 3 4 and optionally substituted by: wherein n is an integer from 0 to 10; and wherein n is an integer from 1 to 2 ...

[0017] In a sixth embodiment, for compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, R 3 teeth, [ka] and the remaining variables are as described in the first aspect, or the first or second embodiment, or any alternative embodiment described herein.

[0018] In a seventh embodiment, for compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, R 4 independently for each occurrence: halo, -CN, -OR 4a , C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, and C 1~3 R is a 5- or 6-membered heteroaryl optionally substituted with alkyl; 4a is C 1~3 Alkyl or C 1~3 and haloalkyl; and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, or sixth embodiment, or any alternative embodiment described herein.

[0019] In an eighth embodiment, for compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, R 4is independently selected at each occurrence from —CH, —CF, —OCHF, —OCH, —CN, —F, —Cl, isopropyl, cyclopropyl, and 4-methylpyridin-2-yl, and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, or sixth embodiment, or any alternative embodiment described therein.

[0020] In a ninth embodiment, for compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, R 1 is OR 2a ; [ka] C replaced by 2~4 each of the formulas shown above is 1 to 3 R2 Optionally replaced by R 2 is independently C for each occurrence. 1~3 Alkyl or -OR 2a and;R 2a is independently H or C for each occurrence 1~3 is alkyl; and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment, or any alternative embodiment described therein.

[0021] In a tenth embodiment, for compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, R 1 teeth [ka] and;R 2 is independently C for each occurrence. 1~3 Alkyl or -OR 2a and;R 2a is independently H or C1 for each occurrence ~3 is alkyl; and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment, or any alternative embodiment described therein.

[0022] In an eleventh embodiment, for compounds of Formula (I) or (II), or pharmaceutically acceptable salts thereof, R 2 is independently selected at each occurrence from —CH and —OH; R 2a is independently at each occurrence H or -CH; 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, the compound of the present disclosure has formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (III) are as defined in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment above, or any alternative embodiment described therein.

[0024] In a thirteenth embodiment, for compounds of formula (III) or pharmaceutically acceptable salts thereof, R 1 teeth, [ka] and;R 2 is independently selected at each occurrence from —CH and OH; R 2a is independently selected at each occurrence from H or -CH3; R 3 teeth [ka] and;R 4 are independently -CH3, -CF3, -OCHF2, -OCH3, and -F.

[0025] In a fourteenth embodiment, the compound of the present disclosure has formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (IV) are as defined in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment above, or any alternative embodiment described therein.

[0026] In a fifteenth embodiment, the compound of the present disclosure has formula (IVA) or (IVB): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (IVA) or (IVB) are as defined in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment above, or any alternative embodiment described therein.

[0027] In a sixteenth embodiment, for compounds of formula (IV), (IVA) or (IVB), or pharmaceutically acceptable salts thereof, R 1 teeth [ka] and;R 2 is OH; R 3 teeth [ka] and;R 4 is independently selected at each occurrence from —CH, —CF, —OCH, —OCHF, —CN, isopropyl, —F, —Cl, and 4-methylpyridin-2-yl; and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, or any alternative embodiment described therein.

[0028] In a seventeenth embodiment, the compound of the present disclosure has formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (V) are as defined in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment above, or any alternative embodiment described therein.

[0029] In an eighteenth embodiment, for compounds of formula (V) or pharmaceutically acceptable salts thereof, R 1 teeth [ka] and;R 3 teeth [ka] and;R 4 is independently selected at each occurrence from —CH 3 , —F, and cyclopropyl.

[0030] In a nineteenth embodiment, the compound of the present disclosure has formula (VI): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (VI) are as defined in the first aspect or embodiment above.

[0031] In a twentieth embodiment, the compound of the present disclosure has formula (VII) or (VIII): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (VII) or (VIII) are as defined in the first aspect or first embodiment above.

[0032] In a twenty-first embodiment, for compounds of Formula (VI), (VII), or (VIII), or pharmaceutically acceptable salts thereof, R 3 is R 1 to 3 4 and the remainder of the variables are as described in the first aspect or embodiment.

[0033] In a twenty-second embodiment, for compounds of formula (VI), (VII), or (VIII), or pharmaceutically acceptable salts thereof, R 3 teeth [ka] and the remaining variables are as described in the twenty-first embodiment.

[0034] In a twenty-third embodiment, for compounds of formula (VI), (VII), or (VIII), or pharmaceutically acceptable salts thereof, R 4 independently for each occurrence: halo, CN, and OR 4a Selected from; R 4a is 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, twenty-first, or twenty-second embodiment.

[0035] In a twenty-fourth embodiment, for compounds of Formula (VI), (VII), or (VIII), or pharmaceutically acceptable salts thereof, R 4 is independently selected at each occurrence from -OCHF2, -F, and -CN; the remainder of the variables are as described in the first aspect or the first, twenty-first, or twenty-second embodiment.

[0036] In a twenty-fifth embodiment, for compounds of Formula (VI), (VII), or (VIII), or pharmaceutically acceptable salts thereof, R 1 HA-OR 2a or [ka] and R 1 to 3 2 C optionally replaced by 2~4 is alkyl; and the remainder of the variables are as described in the first aspect or the 1st, 21st, 22nd, 23rd, or 24th embodiment.

[0037] In a twenty-sixth embodiment, for compounds of formula (VI), (VII), or (VIII), or pharmaceutically acceptable salts thereof, R 1 teeth [ka] and the remaining variables are as described in the first aspect or the first, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment.

[0038] In a twenty-seventh embodiment, for compounds of Formula (VI), (VII), or (VIII), or pharmaceutically acceptable salts thereof, R 2 is independently selected at each occurrence from —CH and —OH; R 2a is independently selected at each occurrence from H and —CH; the remaining variables are as described in the first aspect or the first, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0039] In a twenty-eighth embodiment, the compound of the present disclosure has formula (IX): [ka] or a pharmaceutically acceptable salt thereof, wherein R 5 is H, or two R 5 Let's go together 1~3 Forms an alkylene; R 6 is H, or two R 6 Together C 1~3 forms an alkylene; and the remainder of the variables in formula (IX) are as defined in the first aspect or embodiment above.

[0040] In a 29th embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, p1 is 1 and p2 is 0, or p1 is 1 and p2 is 1, or p1 is 2 and p2 is 1; the remainder of the variables of formula (IX) are as defined in the 28th embodiment above.

[0041] In a thirtieth embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 3 Each of them is R 1 to 3 4 C optionally replaced by 1~4 and alkyl-phenyl, phenyl, pyridyl, thiazolyl, and pyrazolyl; and the remainder of the variables are as described in the first aspect or the first, twenty-eighth, or twenty-ninth embodiment. In an alternative embodiment, for a compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 3 Each of them is R 1 to 3 4 the remainder of the variables are as described in the first aspect or the 1st, 28th, or 29th embodiment.

[0042] In a thirty-first embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 3 Each of them is R 1 to 3 4 is optionally replaced by [ka] or R 3 is 1 or 2 R 4 is optionally replaced by [ka] and the remaining variables are as described in the first aspect or the first, twenty-eighth, or twenty-ninth embodiment. In an alternative embodiment, for a compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 3 Each of them is R 1 to 3 4is optionally replaced by [ka] or R 3 is 1 or 2 R 4 is optionally replaced by [ka] and the remaining variables are as described in the first aspect or the first, twenty-eighth, or twenty-ninth embodiment.

[0043] In a thirty-second embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 3 teeth, [ka] and the remaining variables are as described in the first aspect or the first, twenty-eighth, or twenty-ninth embodiment. In an alternative embodiment, for a compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 3 teeth [ka] and the remaining variables are as described in the first aspect or the first, twenty-eighth, or twenty-ninth embodiment.

[0044] In a thirty-third embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 4 are independently generated for each occurrence: halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, phenyl, and -OR 4a wherein C 3~6 Cycloalkyl is 1-3 halo or C 1~4 optionally substituted with haloalkyl, C 1~3 Alkyl has 1 or 2 C 3-4 optionally substituted with cycloalkyl; R4a is C 1~3 Alkyl or C 1~3 and the remainder of the variables are as described in the first aspect or the 1, 28, 29, 30, 31, or 32 embodiment. In an alternative embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 4 are halo, CN, and C independently for each occurrence. 1~3 Alkyl, C 1~3 Haloalkyl, C 3~6 Cycloalkyl, and -OR 4a Selected from; R 4a is C 1~3 Alkyl or C 1~3 haloalkyl, and the remainder of the variables are as described in the first aspect or the 1st, 28th, 29th, 30th, 31st, or 32nd embodiment.

[0045] In a thirty-fourth embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 4 independently at each occurrence -CH3, -CH2CH3, -CF2CH3, -CF(CH3)2, -CH=CH2, -CHF2, -CH(CH3)2, -CF3, -OCH3, -OCHF2, -OCF3, cyclopropyl, [ka] the remainder of the variables are as described in the first aspect or the 1, 28, 29, 30, 31, or 32 embodiment. In an alternative embodiment, for a compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 4 is independently selected at each occurrence from —CH, —CHF, —CF, —OCH, —OCHF, —OCF, cyclopropyl, —CN, and —F; the remaining variables are as described in the first aspect or the 1st, 28th, 29th, 30th, 31st, or 32nd embodiment.

[0046] In a thirty-fifth embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 1 teeth, [ka] and each of the formulas above is R 1 to 3 2 and the remaining variables are as described in the first aspect or the 1, 28, 29, 30, 31, 32, 33, or 34 embodiment. In an alternative embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 1 teeth, [ka] and each of the formulas above is R 1 to 3 2 and optionally replaced by: wherein n is 0, 1, 28, 29, 30, 31, 32, 33, or 34; and the remaining variables are as described in the first aspect or the 1st, 28th, 29th, 30th, 31st, 32nd, 33rd, or 34th embodiment.

[0047] In a thirty-sixth embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 1 teeth, [ka] and the remaining variables are as described in the first aspect, or the first, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment, or any alternative embodiment described therein. In an alternative embodiment, for a compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] and the remaining variables are as described in the first aspect, or the first, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment, or any alternative embodiment described therein.

[0048] In a thirty-seventh embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 2 is -CH3, -F, -OCH3-CN, -CH2CHOCH3, or -OH; and the remaining variables are as described in the first aspect or the 1, 28, 29, 30, 31, 32, 33, 34, 35, or 36th embodiment. In an alternative embodiment, for a compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 2 is OH; and the remaining variables are as described in the first aspect, or the first, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, or thirty-sixth embodiment, or any alternative embodiment described therein.

[0049] In a thirty-eighth embodiment, for compounds of formula (IX) or pharmaceutically acceptable salts thereof, R 1 is 1 or 2 R A C optionally replaced by 2~6 alkyl; R A is ORed independently for each occurrence 2a , S.R. 2a , or C(O)OR 2a and;R 2a is H, C 1~4 Alkyl, or C 3~6 cycloalkyl; 1~4 Alkyl has 1 or 2 C 1~3 and the remaining variables are as described in the first aspect or the 1, 28, 29, 30, 31, 32, 33, or 34 embodiment. In one embodiment, for compounds of formula (IX), or a pharmaceutically acceptable salt thereof, R 1 is -CH2CH3, -CH2CH2CH2SCH2CH3, -CH2CH2CH2O-cyclopentyl, -CH2CH2CH2CH2CH2OCH3, -CH2CH2OC(CH3)3, -CH2CH2CH2CH(CH3)OCH3, -CH2CH(CH3)CH2CH2C(O)OCH3, -CH2CH2C(CH3)2C(O)OCH3, or -CH2CH2CH2OCH2CH2OCH3.

[0050] In a thirty-ninth embodiment, the compound of the present disclosure has formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (X) are as defined in the first aspect or the 1, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38 embodiment above, or any alternative embodiment described therein.

[0051] In a fortieth embodiment, for compounds of formula (X), or pharmaceutically acceptable salts thereof, R 1 teeth [ka] and;R 2 is OH; R 3 is the following formula: [ka] Represented by;R 4 is —CH 3 , and the remainder of the variables are as defined in the 38th embodiment.

[0052] In a forty-first embodiment, the compound of the present disclosure has formula (XI): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (X) are as defined in the first aspect above or the 1, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38 embodiment above, or any alternative embodiment described therein.

[0053] In a forty-second embodiment, the compound of the present disclosure has formula (XIA) or (XIB): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (XIA) or (XIB) are as defined in the first aspect or the 1, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38 embodiment above, or any alternative embodiment described therein.

[0054] In a forty-third embodiment, for compounds of formula (X), (XIA), or (XIB), or a pharmaceutically acceptable salt thereof, R 1 teeth [ka] and;R 2 is OH and R 3 is the following formula: [ka] Represented by;R 4 are independently -CH3, -CF3, -OCH3, the remainder of the variables are as defined in the forty-first or forty-second embodiment.

[0055] In a forty-fourth embodiment, the compound of the present disclosure has formula (XII): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (XII) are as defined in the first aspect or the 1, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38 embodiment above, or any alternative embodiment described therein.

[0056] In a forty-fifth embodiment, for compounds of formula (XII), or pharmaceutically acceptable salts thereof, R 1 teeth [ka] and;R 2 is OH; R 3 is the following formula: [ka] Represented by;R 4 are independently -CH3, -CHF2, -CF3, the remainder of the variables are as defined in the forty-fourth embodiment.

[0057] In a forty-sixth embodiment, the compound of the present disclosure has formula (XII): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is Het or Z-Het; Z is CH2; Het has the following formula: [ka] Each of the formulas shown above is represented by 1 to 2 R 2 is optionally replaced by; R 2 is independently C for each occurrence. 1~4 alkyl, -OH, or halo; R 3 is pyridinyl or pyrazolyl; each of which is 1 to 2 R 4 is optionally replaced by; R 4 is independently C for each occurrence. 1~4 Alkyl or C 1~4 It is haloalkyl.

[0058] In a forty-seventh embodiment, for compounds of formula (XII) or pharmaceutically acceptable salts thereof, R 3 is the following formula: [ka] each of which is 1 to 2 R 4 and the remaining variables are as defined in the 46th embodiment.

[0059] In a forty-eighth embodiment, for compounds of formula (XII) or pharmaceutically acceptable salts thereof, R 3 is the following formula: [ka] the remaining variables are as defined in the 47th embodiment.

[0060] In a forty-ninth embodiment, for compounds of formula (XII) or pharmaceutically acceptable salts thereof, R 4 is independently at each occurrence -CH3, -CF3, or -CF2CH3; and the remaining variables are as defined in the 46th, 47th, or 48th embodiment.

[0061] In a fiftieth embodiment, the compound of the present disclosure has formula (XIIA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 40 is C 1~3 alkyl, and R 41 is C 1~3 haloalkyl; and the remainder of the variables are as defined in the 48th embodiment.

[0062] In a fifty-first embodiment, for compounds of formula (XIIA) or pharmaceutically acceptable salts thereof, R 40 is -CH3 and R 41 is —CF 3 or —CF 2 CH 3 ; the remainder of the variables are as defined in the 50th embodiment.

[0063] In a fifty-second embodiment, for compounds of formula (XII) or (XIIA), or pharmaceutically acceptable salts thereof, R 1 is the following formula: [ka] Each of the formulas shown above is represented by 1 to 2 R 2 and the remaining variables are as defined in the forty-sixth, forty-seventh, forty-eighth, forty-ninth, fiftieth, or fifty-first embodiment.

[0064] In a fifty-third embodiment, for compounds of formula (XII) or (XIIA), or pharmaceutically acceptable salts thereof, R 1 is the following formula: [ka] the remaining variables are as defined in the 52nd embodiment.

[0065] In a fifty-fourth embodiment, for compounds of formula (XII) or pharmaceutically acceptable salts thereof, R 2 is independently at each occurrence -CH3, OH, or -F; and the remaining variables are as defined in the 46th, 47th, 48th, 49th, 50th, 51st, 52nd, or 53rd embodiment.

[0066] In a fifty-fifth embodiment, the present disclosure provides a compound described herein (e.g., a compound of any one of Examples 1-229), or a pharmaceutically acceptable salt thereof.

[0067] In a fifty-sixth embodiment, the present disclosure provides a method for manufacturing a semiconductor device comprising: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((S)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (±)-(R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((S)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (±)-(R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((R)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-methylpropan-2-ol; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxy-2-methylpropyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 9-((2,4-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (S)-9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (R)-9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-6-oxa-2,9-diazaspiro[4.5]decane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane; 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane; 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((3,5-difluorophenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 4-((3,5-difluorophenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane; 7-((2,4-dimethylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane; 7-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane; 7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane; 1-((7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)tetrahydro-2H-pyran-4-ol; 7-((2,4-dimethylphenyl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonane; 8-((2-chloro-4-methylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 4-((6-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-(difluoromethyl)-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((4,6-dimethylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((4-(difluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]; 1-((1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol; (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]; (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]; 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((6-bromo-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-2-oxabicyclo[3.1.1]heptan-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)-1,6-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 4-((6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; (R)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-3-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methyl-3,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydrofuran-3-yl)-2,6-diazaspiro[3.3]heptane; (S)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((3-methyloxetan-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(2-fluoropropan-2-yl)-2-methyl-1,4-dihydropyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethoxy)-2-methyl-3,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((5-(difluoromethyl)-2-methyl-1H-2l4-pyrazol-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-methyl-2-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,6-bis(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((2-methyl-5-(trifluoromethyl)-2,5-dihydro-1H-pyrazol-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(difluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((1s,4s)-4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (1r,4r)-4-(6-((4-cyclopropyl-6-(trifluoromethyl)-2,3-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (1r,4r)-4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; (1s,4s)-4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((1R)-1-(tetrahydrofuran-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(1-(4-methyltetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(3-methyloxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2-methyltetrahydrofuran-2-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((S)-1-((S)-2-methyltetrahydrofuran-2-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((R)-1-((S)-tetrahydrofuran-2-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-2-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydrofuran-3-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((3-methyloxetan-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((3R,5R)-3,5-dimethyltetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((3R,5S)-3,5-dimethyltetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(4,4-difluorocyclohexyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-3-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-(tetrahydro-2H-pyran-4-yl)-6-((2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(2,2-difluorocyclopropyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-chloro-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-(1-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)ethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((6-methoxy-4-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-methyl-3-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole; 2-ethyl-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclopropane-1-carbonitrile; 2-(3-(2-methoxyethoxy)propyl)-6-((2-methyl-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (R)-2-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (1R,3R)-2,2-dimethyl-3-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclopropane-1-carbonitrile; 2-(((1S,2R,5S)-6-oxabicyclo[3.2.1]octan-2-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(3-(cyclopentyloxy)propyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; Methyl 2,2-dimethyl-4-(6-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)butanoate; 2-(2-cyclopropyl-2-methoxyethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(5-methoxypentyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(4-Methoxypentyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((1-(2-methoxyethyl)cyclobutyl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; Methyl 4-methyl-5-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pentanoate; 2-(3-(ethylthio)propyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(2-cyclopropylethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(2-(tert-butoxy)ethyl)-6-((2-methyl-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 4-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol; 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((3-isopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(1-(trifluoromethyl)cyclopropyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (1s,4s)-4-(6-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; (1s,4s)-4-(6-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 2-((2-methyl-5-(trifluoromethyl)-2,5-dihydro-1H-pyrazol-3-yl)sulfonyl)-6-(((R)-tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((tetrahydro-2H-pyran-4-yl)methyl)-6-((2-(trifluoromethyl)-3,4-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-(tetrahydro-2H-pyran-4-yl)-6-((6-(trifluoromethyl)-2-vinylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; (1r,4r)-4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; (1s,4s)-4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 2-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; 2-((3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-bis(trifluoromethyl)phenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-chloro-2-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-fluoro-4-(trifluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; (R)-2-((1,4-dioxan-2-yl)methyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((1,4-dioxan-2-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; 2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-fluoro-4-(trifluoromethoxy)phenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; (1s,4s)-1-methyl-4-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)cyclohexan-1-ol; (1s,4s)-1-methyl-4-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)cyclohexan-1-ol; 2-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((4-(difluoromethoxy)-2,6-difluorophenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((4-(difluoromethoxy)-2-fluorophenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((4-(difluoromethoxy)-2-fluorophenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile; and 2-((tetrahydro-2H-pyran-4-yl)methyl)-6-((6-(trifluoromethyl)-2,3-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; or a pharmaceutically acceptable salt thereof.

[0068] In a fifty-seventh embodiment, the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof.

[0069] In a 58th embodiment, the present disclosure provides a method for treating an EBP-mediated disease or disorder, comprising administering to a subject an effective amount of a compound described in any one of embodiments 1-56, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the 57th embodiment.

[0070] In a fifty-ninth embodiment, the present disclosure provides a compound according to any one of embodiments 1 to 56 for use in treating an EBP-mediated disease or disorder.

[0071] In a sixtieth embodiment, the present disclosure provides the use of a compound according to any one of embodiments 1 to 56 in the manufacture of a medicament for treating a disease or disorder mediated by EBP.

[0072] The compounds and intermediates described herein may be isolated and used as the compounds themselves. 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 that are not typically biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0073] 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 sulfate, and the like. Salts such as hydroxysalicylate, 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 can be formed using inorganic or organic acids.

[0074] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0075] Examples of organic acids from which salts can be derived include 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, and sulfosalicylic acid.

[0076] Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases.

[0077] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts. 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, and the like. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0078] Salts can be synthesized from compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate 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 an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable when 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).

[0079] Isotopically labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples and Preparations, substituting the appropriate isotopically labeled reagent for the previously used unlabeled reagent. In one embodiment, the present disclosure provides a deuterated compound described herein, or a pharmaceutically acceptable salt thereof.

[0080] Pharmaceutically acceptable solvates in accordance with the present invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, d6-acetone, and d6-DMSO.

[0081] Those skilled in the art will recognize that the compounds of the present disclosure 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 substituents may be bonded to chiral carbon atoms. Therefore, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0082] "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 specifying the stereochemistry of compounds of the invention, single stereoisomers in which the relative and absolute configurations of two chiral centers are known are designated using the conventional RS system (e.g., (1S,2S)). "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds can be defined by their respective retention times relative to the corresponding enantiomers / diastereomers via chiral HPLC.

[0083] Certain compounds described herein may contain one or more asymmetric centers or axes and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0084] 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 an appropriate solvent or solvent mixture to achieve good resolution). If the compound contains a double bond, the substituent may be in the E or Z configuration. If 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.

[0085] 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 a detectable decrease in EBP activity in vivo or in vitro (e.g., at least a 10% decrease in EBP activity, as measured by a given assay, such as the bioassay described in the Examples and known in the art).

[0086] In certain embodiments, the present 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 "EBP-mediated disease or disorder") in a subject in need thereof, the method comprising administering to the subject a compound described herein (e.g., a compound described in any one of the first through fifty-sixth embodiments), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0087] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first through fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically 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.

[0088] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first through fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating an EBP-mediated disorder or disease in a subject in need of treatment.

[0089] In certain embodiments, the EBP-mediated disorder is colon cancer.

[0090] 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 through 56), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0091] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first through fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an autoimmune disease in a subject in need thereof.

[0092] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first through fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating an autoimmune disease in a subject in need thereof.

[0093] 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, and secondary progressive multiple sclerosis, as well as clinically isolated syndrome (hereinafter "CIS").

[0094] Relapsing multiple sclerosis (or relapsing form(s) of multiple sclerosis) includes clinically isolated syndrome, relapsing-remitting multiple sclerosis, and active secondary progressive multiple sclerosis.

[0095] Relapsing-remitting multiple sclerosis is a stage of MS characterized by unpredictable relapses followed by months to years of relatively quiet periods (remission) without new signs of disease activity. Deficits that occur during attacks can be problem-solving or problem-resolving, with the latter occurring in approximately 40% of attacks and becoming more common the longer a patient has the disease. This describes the initial course in 80% of multiple sclerosis patients.

[0096] Secondary progressive multiple sclerosis occurs in approximately 65% ​​of patients with initial relapsing-remitting multiple sclerosis and is characterized by progressive neurological decline without clear periods of remission between acute attacks. Occasional relapses and mild remissions may occur. The most common time from onset to progression from relapsing-remitting to secondary progressive multiple sclerosis is 19 years.

[0097] Primary progressive multiple sclerosis is characterized by the same symptoms as secondary progressive multiple sclerosis, i.e., progressive neurological deterioration between acute attacks without distinct periods of remission and without previous relapsing-remitting periods.

[0098] CIS is the first episode of neurological symptoms caused by inflammation and demyelination in the central nervous system. By definition, this symptom episode must last at least 24 hours and is characteristic of multiple sclerosis, but it does not yet meet the diagnostic criteria for MS, as individuals who experience 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, a second episode of neurological symptoms and a diagnosis of relapsing-remitting MS are more likely. If CIS is not accompanied by MS-like lesions on brain MRI, the individual is much less likely to develop MS.

[0099] In certain embodiments, the present disclosure provides a method of promoting myelination in a subject having a myelin-related disease or disorder in need of treatment, the method comprising administering to the subject a compound described herein (e.g., a compound described in any one of embodiments 1 through 56), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0100] In certain embodiments, the present disclosure provides use of a compound described herein (e.g., a compound described in any one of the first through fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for promoting myelination in a subject with a myelin-related disease or disorder in a subject in need of treatment.

[0101] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first through fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in promoting myelination in a subject with a myelin-related disease or disorder in a subject in need of treatment.

[0102] 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 myelolysis (CPM), adrenoleukodystrophy, Alexander disease, Pelizaeus-Merzbacher disease (PMD), vanishing white matter disease, Wallerian degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, The present invention relates to a method for treating a brain injury, a traumatic brain injury, post-radiation damage, neurological complications of chemotherapy, stroke, 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 encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination, e.g., neuromyelitis optica (NMO), optic neuritis, pediatric white matter disorder, neonatal white matter injury, age-related dementia, and schizophrenia.

[0103] 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 through 56), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0104] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first through fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

[0105] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of embodiments 1 through 56) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof.

[0106] In some embodiments, the cancer is colon cancer.

[0107] 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.

[0108] As used herein, the terms "effective amount" and "therapeutically effective amount" can be used interchangeably. They refer to 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 can be between 10 μg and 500 mg.

[0109] 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.

[0110] In certain embodiments, the present disclosure relates to the aforementioned methods wherein the compound is administered parenterally. In certain embodiments, the present disclosure relates to the aforementioned methods wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically, or intranasally. In certain embodiments, the present disclosure relates to the aforementioned methods wherein the compound is administered systemically.

[0111] The compounds of the present disclosure can be used as pharmaceutical compositions (e.g., a compound of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically 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 combinations thereof, which 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 insofar as a 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 comprising a compound of the present invention and a solvent (i.e., a solvate) or water (i.e., a hydrate).

[0112] Formulations may be prepared using conventional dissolution and mixing procedures. For example, a bulk drug substance (i.e., a compound of the 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 excipients described above. The compounds of the invention are typically formulated into pharmaceutical dosage forms to provide easily controllable drug dosage and to provide the patient with an elegant, easily manageable product.

[0113] Pharmaceutical compositions (or formulations) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, an 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, etc. 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.

[0114] Pharmaceutical compositions containing the compounds of the present disclosure are generally formulated for parenteral or oral administration, or for use as suppositories.

[0115] For example, oral pharmaceutical compositions of the present disclosure may be comprised 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 preservatives, stabilizers, wetting agents, emulsifying agents, and buffers, etc.

[0116] Generally, a pharmaceutical composition contains an 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) Tablets or gelatin capsules containing absorbents, colorants, flavorings and sweeteners.

[0117] Tablets may be film coated or enteric coated according to methods known in the art.

[0118] 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 may be 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 pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may 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.

[0119] 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, stabilizers, wetting agents or emulsifiers, solution enhancers, salts for regulating 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 to 7.5%, or about 1 to 50%, of the active ingredient.

[0120] The compounds of the present disclosure or pharmaceutical compositions thereof for use in a subject (e.g., human) are usually administered orally or parenterally in therapeutic doses. When administered intravenously by infusion, the dosage may depend on the infusion rate at which the IV preparation is administered. Generally, the therapeutically effective dosage of the compound, pharmaceutical composition, or combination thereof depends on the species, body weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, pharmacist, clinician, or veterinarian skilled in the art can easily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of the disorder or disease.

[0121] The above-mentioned dosage properties can be demonstrated in vitro and in vivo using advantageously mammalian animals, 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, e.g., aqueous solutions, and in vivo either enterally, parenterally, or advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro can range between about 10-3 molar and 10-9 molar.

[0122] definition As used herein, "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. This term includes mammals, such as humans. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a male or female human), 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.

[0123] 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.

[0124] As used herein, the terms "treat," "treating," or "treatment" of any disease, condition, or disorder refer to the management and care of a patient for the purpose of combating the disease, condition, or disorder, and include the administration of a compound of the invention to achieve a desired pharmaceutical and / or physiological effect. The effect can be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the severity of the disease, condition, or disorder; improving or ameliorating clinical symptoms, complications, or indicators associated with the disease, condition, or disorder; 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 can be preventing the onset of symptoms or complications of the disease, condition, or disorder.

[0125] As used herein, the term "cancer" has its commonly accepted meaning in the art. The term can broadly refer to abnormal cell growth.

[0126] As used herein, the term "autoimmune disease" has its meaning as commonly accepted in the art. The term can broadly refer to diseases in which a host's immune system targets or attacks the host's normal or healthy tissues.

[0127] As used herein, the term "myelination" has its commonly accepted meaning in the art. The term can broadly refer to the process by which myelin is produced.

[0128] 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 can broadly refer to diseases or disorders involving damage to myelin.

[0129] 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.

[0130] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "optionally substituted" refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and descriptions of the compounds and their examples. Unless otherwise specified, an "optionally substituted" group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at all positions.

[0131] 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. 1~3Alkyl" and "C 1~2 The 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 radical 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).

[0132] As used herein, the term "alkoxy" refers to a fully saturated, branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., -OC 1~4 Alkyl group (wherein C 1~4 Alkyl is 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 to 4 carbons, more preferably about 1 to 2 carbons. 1~2 The term "alkoxy" should be construed accordingly.

[0133] As used herein, "C 1~4 Alkoxy C 1~4 The term "alkyl" refers to a group in which at least one of the hydrogen atoms is C 1~4 C as defined herein, substituted with alkoxy 1~4 Refers to alkyl groups. 1~4 Alkoxy C 1~4 The alkyl group is linked to the remainder of the molecule described herein through the alkyl group.

[0134] 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.

[0135] "Halogen" or "halo" may be fluorine, chlorine, bromine, or iodine.

[0136] 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 with a halo atom. 1~4 Refers to alkyl groups. 1~4 The haloalkyl group is a monohalo-C 1~4 Alkyl, dihalo-C 1~4 Alkyl, or perhalo-C 1~4 Alkyl-containing polyhalo-C 1~4 It can be alkyl. 1~4 Alkyl can have one iodo, bromo, chloro or fluoro within 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. 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 Alkyl groups are C groups in which all hydrogen atoms have been replaced by halo atoms. 1~4 Refers to an alkyl group.

[0137] The term "aryl" refers to an aromatic carbocyclic single ring or two fused ring systems containing from 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0138] The term "heteroaryl" refers to a 5- to 12-membered aromatic radical containing 1 to 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.

[0139] 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, spiral, or bridged carbocyclic rings), or spiral ring. Bicyclic carbocyclyl 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 typically contain 4 to 10 ring members.

[0140] The term "C3-6 cycloalkyl" refers to a fully saturated carbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0141] The term "heterocycle" or "heterocyclyl" refers to a 4- to 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 heterocycle radicals include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperidinyl. Bicyclic heterocyclyl groups include, for example, unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, a cycloalkyl ring, an aryl ring, or a 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- to 6-membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 4- to 6-membered monocyclic saturated heterocyclyl group. In some embodiments, the heterocyclyl group is an 8- to 10-membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8- to 10-membered bicyclic saturated heterocyclyl group.

[0142] As used herein, the term "helical" ring refers to a bicyclic ring system in which both rings share one common atom. Examples of helical rings include 2-oxa-6-azaspiro[3.3]heptanyl, and the like.

[0143] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. Fused heterocycles have 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).

[0144] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety joined at two non-adjacent ring atoms (eg, 5-oxabicyclo[2.1.1]hexane).

[0145] The phrase "pharmaceutically 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 the mammal being treated with it.

[0146] Unless otherwise specified, the term "compounds of the disclosure" refers to compounds of formula (I), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution). Where moieties capable of forming salts are present, salts, particularly pharmaceutically acceptable salts, are also included.

[0147] As used herein, the terms "a," "an," "the," and similar terms used in the context of the present invention (particularly in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better elucidate the invention and does not limit the scope of the invention as otherwise claimed.

[0148] Intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms may be encompassed 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 an imidazole moiety, where a proton may migrate between the two ring nitrogens. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0149] In one embodiment, the disclosure relates to a compound of formula (I) as defined herein in free form. In one embodiment, the disclosure relates to a compound of formula (I) as defined herein in salt form. In one 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 the form of a pharmaceutically acceptable salt. In yet a further embodiment, the disclosure relates to a compound of formula (I) as defined herein in the form of a pharmaceutically acceptable acid addition salt. 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 the form of a pharmaceutically acceptable salt. In yet another embodiment, the disclosure relates to any one of the compounds of the examples in the form of a pharmaceutically acceptable acid addition salt.

[0150] The compounds of the present disclosure can be synthesized by synthetic routes, including processes similar to those well known in the chemical arts, especially in light of the description contained herein.Starting materials are generally available from commercial sources such as Sigma-Aldrich, or can be easily prepared by methods well known to those skilled in the art (for example, prepared by the methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967-1999 ed.), including dietary supplements (also available through Beilstein online database), or Beilstein's Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin).

[0151] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing key intermediates as well as compounds of the present disclosure. For a more detailed description of the individual reaction steps, see the Examples section below. While 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. [Example]

[0152] Abbreviation: 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 LC-MS = 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: means sodium sulfate; K2CO3 = Potassium Carbonate NaHCO3 = sodium bicarbonate NaBH(OAc)3 = STAB = sodium triacetoxyborohydride SiO2 = silicon dioxide or silica PDA = Photodiode array detection TosMIC = toluenesulfonylmethyl isocyanide TLC = thin layer chromatography LiHMDS = lithium bis(trimethylsilyl)amide DMA = dimethylamine DAST = diethylaminosulfur trifluoride ee = enantiomeric excess t R = retention time

[0153] 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 LC / MSD system: DAD\ELSD Alltech 3300 and Agilent LC\MSD 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.

[0154] HPLC analytical method specifications: Column: Agilent Poroshell 120 SB-C18, 4.6 x 30 mm, 2.7 μm with UHPLC Guard Infinity Lab Poroshell 120 SB-C18, 4.6 x 5 mm, 2.7 μm Column temperature: 60°C Injection volume, 0.5 μL Adjustment agent: 0.1% (v / v) concentrated formic acid Method: 99% water / 1% MeCN (initial condition), hold for 0.1 min, linear gradient to 0% water / 100% MeCN in 1.5 min, hold for 0% water / 100% MeCN until 1.73 min, linear gradient to 99% water / 1% MeCN at 1.74 min. Flow rate: 3.0 mL / min. UV scanning: 207-223nm, 246-262nm, 272-288nm

[0155] QC analytical LC / MS method conditions: Ammonium hydroxide (basic pH) conditions MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200-400nm scanning range Column: Waters ACQUITY UPLC BEH C18, 2.1 x 50 mm, 1.7 μm, part number 186002350 Adjuster: concentrated ammonium hydroxide 0.2% (v / v) Method: Linear gradient from 95% water / 5% MeCN (initial conditions) to 5% water / 95% MeCN in 3.75 min. 5% water / 95% MeCN, hold for 4 minutes. Flow rate, 0.8 mL / min.

[0156] Trifluoroacetic acid (acidic pH) conditions MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200~400nm scanning range Column: Waters ACQUITY UPLC BEH C18, 2.1 x 50 mm, 1.7 μm, part number 186002350 Adjustment agent: concentrated trifluoroacetic acid 0.1% (v / v) Method: Linear gradient from 95% water / 5% MeCN (initial conditions) to 5% water / 95% MeCN in 3.75 min. 3.75 min, hold 5% water / 95% MeCN until 4 min. Flow rate: 0.8 mL / min.

[0157] 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 scanning range Column: Waters XSELECT CSH C18 PREP, 19 x 100 mm, 5 μm, part number 186005421 Adjuster: concentrated ammonium hydroxide 0.2% (v / v) Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN in 8 minutes, increasing to 5% water / 95% MeCN in 8.5 minutes, and holding at 5% water / 95% MeCN until 10 minutes.

[0158] Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200-400nm scanning range Column: Waters XSELECT CSH C18 PREP, 30 x 100 mm, 5 μm, part number 186005425 Adjuster: 0.2% concentrated NH4OH (v / v) Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN in 8 minutes, increasing to 5% water / 95% MeCN in 8.5 minutes, and holding at 5% water / 95% MeCN until 10 minutes.

[0159] Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200-400nm scanning range Column: Waters XSELECT CSH C18 PREP, 30 x 50 mm, 5 μm, part number 186005423 Adjuster: 0.2% concentrated NH4OH (v / v) Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN in 8 minutes, increasing to 5% water / 95% MeCN in 8.5 minutes, and holding at 5% water / 95% MeCN until 10 minutes.

[0160] Trifluoroacetic acid (acidic pH) conditions Flow rate: 30mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200-400nm scanning range Column: Waters Sunfire OBD C18, PREP, 19 x 100 mm, 5 μm, part number 186002567 Adjustment agent: 0.1% concentrated trifluoroacetic acid (v / v) Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN in 8 minutes, increasing to 5% water / 95% MeCN in 8.5 minutes, and holding at 5% water / 95% MeCN until 10 minutes.

[0161] Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200-400nm scanning range Column: Waters Sunfire OBD C18, PREP, 30 x 100 mm, 5 μm, part number 186002572 Adjustment agent: 0.1% concentrated trifluoroacetic acid (v / v) Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN in 8 minutes, increasing to 5% water / 95% MeCN in 8.5 minutes, and holding at 5% water / 95% MeCN until 10 minutes.

[0162] Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 Daltons PDA: 200-400nm scanning range Column: Waters Sunfire OBD C18, PREP, 30 x 50 mm, 5 μm, part number 186002570 Adjustment agent: 0.1% concentrated trifluoroacetic acid (v / v) Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN in 8 minutes, increasing to 5% water / 95% MeCN in 8.5 minutes, and holding at 5% water / 95% MeCN until 10 minutes.

[0163] Example 1: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane; [ka] 1. Synthesis of tert-butyl 8-((4-(difluoromethoxy)phenyl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate [ka] To a solution of tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (commercially available, 200 mg, 0.9 mmol), DIPEA (460 μL, 2.6 mmol), and DMAP (21 mg, 0.2 mmol) in DCM (5 mL) was added 4-(difluoromethoxy)benzenesulfonyl chloride (234 mg, 1.0 mmol), and the reaction was stirred at room temperature for 1 h. The reaction mixture was washed with saturated aqueous NH4Cl, water, and brine. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to give tert-butyl 8-((4-(difluoromethoxy)phenyl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate, which was used without purification. LCMS m / z = 379.1 (M+H- t Bu) +

[0164] 2. Synthesis of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane trifluoroacetate [ka] To a solution of tert-butyl 8-((4-(difluoromethoxy)phenyl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (380 mg, 0.9 mmol) in DCM (4 mL) was added TFA (540 μL, 7.0 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (0-100% EtOH in heptane: 1:3 EtOAc (2% NH4OH)) to give the trifluoroacetate salt of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane (302 mg, 77%). LCMS m / z = 335 (M+H). + .

[0165] Synthesis of 3,8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane [ka] To the trifluoroacetate salt of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane (50 mg, 0.1 mmol) and tetrahydropyran-4-one (12 mg, 0.1 mmol) in DCM (2 mL) was added AcOH (10 μL, 0.2 mmol), and the reaction was stirred for 30 min. NaBH(OAc) (95 mg, 0.5 mmol) was added, and the reaction mixture was stirred at room temperature and monitored for completion. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (0–100% EtOH:EtOAc (2% NHOH) 1:3 in heptane) to give 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane (39 mg, 83%). LCMS m / z=419.1 (M+H) + . 1H NMR(500MHz,CD3OD)δ(ppm):7.89-7.80(m,2H),7.38(d,J=8.6Hz,2H),7.21-6.86(m,1H),3.99-3.88(m,2H),3.72-3.65(m,2H),3.45-3.33(m ,4H),3.11(s,2H),3.03(d,J=9.2Hz,2H),2.97-2.92(m,2H),2.39(tt,J=4.0,10.6Hz,1H),1.72(brdd,J=1.8,12.2Hz,2H),1.37-1.21(m,2H).

[0166] Example 2: 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane (racemic) [ka] Synthesis of tert-butyl 1,9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate [ka] To a solution of tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (commercially available, 200 mg, 0.8 mmol), DIPEA (430 μL, 2.5 mmol), and DMAP (20 mg, 0.2 mmol) in DCM (5 mL) was added 4-(difluoromethoxy)benzenesulfonyl chloride (220 mg, 0.9 mmol) at room temperature. After 1 h at room temperature, the reaction mixture was washed with saturated aqueous NH4Cl, water, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated to give tert-butyl 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (370 mg). The crude product was used in the next step without further purification. LCMS m / z = 434.1 (M+H-CH3). + .

[0167] Synthesis of 2,9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] To a solution of tert-butyl 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (370 mg, 0.8 mmol) in DCM (4 mL) was added TFA (500 μL, 6.6 mmol). The reaction mixture was stirred overnight at room temperature, concentrated, and the resulting residue was purified by column chromatography on silica gel (24 g, 0-100% EtOH:EtOAc (2% NH) in heptane). 4O Purification by 1:3) afforded the trifluoroacetate salt of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane (568 mg). LCMS m / z = 349.0 (M+H). + .

[0168] Synthesis of 3,9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] The title compound was prepared from the trifluoroacetate salt of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane (50 mg, 0.1 mmol) and tetrahydropyran-4-one (12 mg, 0.1 mmol) using a method similar to that described in Step 3 of Example 1. The crude product was purified by column chromatography on silica gel (24 g, 0-100% EtOH: EtOAc (2% NH4OH) 1:3 in heptane) to give 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane (17 mg, 35%). LCMS m / z = 433.1 (M+H). + . 1H NMR(500MHz,CD3OD)δ(ppm):7.83(d,J=8.6Hz,2H),7.38(d,J=9.2Hz,2H),7.20- 6.86(m,1H),4.00-3.89(m,2H),3.81-3.67(m,2H),3.40(brt,J=11.9Hz,2H),3. 03-2.89(m,3H),2.87-2.80(m,1H),2.79-2.75(m,1H),2.75-2.66(m,3H),2.29( tt,J=4.0,11.0Hz,1H),1.93-1.88(m,2H),1.87-1.78(m,2H),1.56-1.44(m,2H).

[0169] Examples 3 and 4: (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane and (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] The title compound was prepared from the trifluoroacetate salt of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane (Repeat of Step 3 of Example 2, 432 mg, 1.2 mmol) and tetrahydropyran-4-one (186 mg, 1.9 mmol) using a method similar to that described in Step 3 of Example 1 to give racemic 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane (Example 2, 310 mg).

[0170] The racemate was separated into its enantiomers with arbitrarily assigned stereochemistry by SFC separation using a CHIRALPAK AD-H 30 × 250 mm, 5 μm; 30% MeOH with 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C) to give the following:

[0171] Peak 1, enantiomer 1(S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane (85 mg, 16%, t R =2.02 min, 100%ee, LCMSm / z=433.1(M+H) + ) Peak 2, enantiomer 2(R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane (84 mg, 16%, t R =2.43min, 95.6%ee, LCMSm / z=433.1(M+H) + ) For both enantiomers: 1 H NMR(500MHz,CD3OD)δ(ppm):7.83(d,J=8.55Hz,2H),7.38(d,J=9.16Hz,2H),7.2 0-6.86(m,1H),4.00-3.89(m,2H),3.81-3.67(m,2H),3.40(brt,J=11.9Hz,2H),3 .03-2.89(m,3H),2.87-2.80(m,1H),2.79-2.75(m,1H),2.75-2.66(m,3H),2.29( tt,J=4.0,11.0Hz,1H),1.93-1.88(m,2H),1.87-1.78(m,2H),1.56-1.44(m,2H).

[0172] Example 5: 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] 1. Synthesis of 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] To a suspension of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (commercially available, 1.0 g, 3.9 mmol) and DIPEA (1.0 mL, 5.9 mmol) in DCM (20 mL) was added 4-(difluoromethoxy)benzenesulfonyl chloride (1.0 g, 4.3 mmol) at room temperature. The reaction was monitored until completion. The mixture was diluted with DCM (5 mL) and washed with saturated aqueous NH4Cl, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in EtOAc (40 mL), and HCl (4 M, 5.0 mL) was added at room temperature. The mixture was stirred overnight, and a white precipitate formed. Heptane (20 mL) was added and the solid was collected by filtration and dried to give 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (1.17 g, 75%), which was used without further purification. LCMS m / z=363.1 (M+H). + .

[0173] Synthesis of 2,4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] The title compound was prepared from 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride (75 mg, 0.2 mmol) and tetrahydropyran-4-one (100 mg, 0.2 mmol) using a similar method as described in Step 3 of Example 1. The mixture was purified by column chromatography on silica gel (12 g, 10-100% EtOH:EtOAc 1:3 in heptane) to give 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane (51 mg, 61%). LCMS m / z = 447.2 (M+H). + . 1H NMR(500MHz,CD3OD)δ(ppm):7.96-7.71(m,2H),7.36(d,J=9.2Hz,2H),7.22-6.80(m,1H),3.98(brdd,J=4.3,11.6Hz,2H),3.803.70-3.70(m ,2H),3.39(brt,J=11.3Hz,2H),2.98-2.92(m,2H),2.78(s,2H),2.71- 2.63(m,2H),2.57-2.45(m,3H),1.98-1.76(m,4H),1.67-1.47(m,4H).

[0174] Example 6: 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane (racemic) [ka] To a solution of 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride (Example 5, Step 1, 100 mg, 0.3 mmol) and tetrahydrofuran-3-one (27 mg, 0.3 mmol) in DCM (2.5 mL) and AcOH (45 mg, 0.8 mmol) was added NaBH(OAc) (159 mg, 0.8 mmol). The reaction mixture was stirred at room temperature for 2 h. An additional 1.25 equivalents of ketone was added and stirring was continued for 1 h. The reaction mixture was diluted with DCM (5 mL) and washed with saturated aqueous NaHCO, water, and brine. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (24 g, 0-100% EtOH in heptane: 1:3 EtOAc (2% NH4OH)) gave 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane (90 mg, 83%). LCMS m / z = 433.1 (M+H). + . 1H NMR(500MHz,CD3OD)δ(ppm):7.80-7.66(m,2H),7.27(d,J=8.6Hz,2H),7.12-6.74(m, 1H),3.86-3.73(m,2H),3.70-3.61(m,3H),3.53-3.49(m,1H),2.90(t,J=7.3Hz,1H),2 .87-2.80(m,2H),2.69(s,2H),2.60-2.49(m,1H),2.42-2.22(m,3H),2.05-1.95-(m, 1H),1.82(brdd,J=3.7,14.7Hz,2H),1.72(qd,J=8.3,12.3Hz,1H),1.56-1.45(m,2H).

[0175] Example 7: 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] A mixture of 1-bromo-2-methoxyethane (22.5 mg, 162 μmol), 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (Step 1 of Example 5, 58.7 mg, 162 μmol), and DIPEA (90 μL, 0.5 mmol) in DMF (2 mL) was stirred at room temperature. After 1 day, additional base (3 equivalents) and 1-bromo-2-methoxyethane (1 equivalent) were added. After 1 hour, the reaction was quenched with saturated aqueous NaHCO and extracted with EtOAc (×2). The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO, filtered, evaporated, and purified by HPLC (basic conditions) to give 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecane (17 mg, 25%, 100% purity). LCMS m / z=421.1 (M+H). + .LCMS t R (4 minutes) = 1.42 minutes.

[0176] Examples 8 and 9: (±)-(R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((S)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane and (±)-(R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((R)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] The title compound was prepared from 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane (Example 2, Step 2, 150 mg, 0.4 mmol) and tetrahydropyran-3-one (65 mg, 0.7 mmol) using a similar method as described in Example 1 to give a diastereomeric mixture of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane (200 mg crude). LCMS m / z=433.2 (M+H). + . Arbitrarily assigned stereochemistry: D1 (50 mg, 27%, t) was obtained by SFC chiral separation using a CHIRALPAK IC 30 × 250 mm, 5 μm column (40% IPA and 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 60 psi, column temperature 40 °C)). R = 1.92 min, 100% de) and D2 (50 mg, 27%, t R = 2.15 min, 88.1% de) to give 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane as a pair of two diastereomeric products.

[0177] Example 10 and Example 11: 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-methylpropan-2-ol and 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxy-2-methylpropyl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] Synthesis of 1,2-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid ethyl ester [ka] To a solution of 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride (Example 5, Step 1, 250 mg, 0.6 mmol) and NEt (110 μL, 0.8 mmol) in THF (2 mL) was added ethyl 2-bromoacetate (115 mg, 0.7 mmol) until complete consumption of the starting material as determined by LCMS. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous NH4Cl, water, and brine. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give ethyl 2-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (296 mg), which was used without further purification. LCMS m / z = 448.8 (M+H). + .

[0178] 2. Synthesis of 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-methylpropan-2-ol [ka] To a solution of ethyl 2-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (271 mg, 0.6 mmol) in 6 mL of THF at room temperature was added MeMgBr (2 M, 900 μL). The reaction mixture was stirred for 30 min, then diluted with 5 mL of EtOAc and washed with saturated aqueous NaHCO, water, and brine. The organic phase was dried over NaSO, filtered, concentrated, and purified by HPLC (acidic conditions) to give 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-methylpropan-2-ol trifluoroacetate (49 mg, 15%). LCMS m / z = 435.9 (M+H). + . 1 H NMR(500MHz,DMSO-d6)δ(ppm)7.79(brd,J=8.6Hz,2H),7.60-7.24(m,3H),4.21(q,J=7.1Hz,4H),3.70(t,J=4 .9Hz,2H),3.41-2.97(m,1H),2.93-2.69(m,4H),2.52-2.47(m,2H),2.23-1.58(m,5H),1.22(t,J=7.0Hz,3H).

[0179] Synthesis of 3,4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxy-2-methylpropyl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] Example 12: To a solution of 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-methylpropan-2-ol trifluoroacetate (50 mg, 0.1 mmol) and iodomethane (20 μL, 0.3 mmol) in THF (2 mL) at room temperature was added sodium hydride (10 mg, 0.3 mmol, 60% purity). The reaction mixture was stirred for 3 days, then diluted with EtOAc (5 mL) and washed with saturated aqueous NH4Cl, water, and brine. The organic phase was dried over Na2SO4, filtered, concentrated, and purified by HPLC (basic conditions) to give 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxy-2-methylpropyl)-1-oxa-4,9-diazaspiro[5.5]undecane (52 mg, 100%). LCMS m / z=449.1 (M+H) + . 1 H NMR(500MHz,CD3OD)δ(ppm):7.90-7.73(m,2H),7.37(d,J=8.6Hz,2H),7.26-6.80(m,1H),3.82-3.69(m,2H),3.20(s,3H),2 .98-2.91(m,2H),2.78(s,2H),2.71-2.49(m,4H),2.39(brs,2H),1.83(brd,J=13.4Hz,2H),1.72-1.53(m,2H),1.17(s,6H).

[0180] Examples 12 and 13 [ka] Examples 12 and 13 in Table A were prepared from tetrahydropyran-4-one (26 mg, 0.3 mmol) and the corresponding amine using a method similar to that described in Step 3 of Example 1. The sulfonamide starting material was prepared using the standard method described above, for example, in Example 1, Steps 1 and 2 (1.1 equivalents of sulfonyl chloride). Purification of the final product after reductive amination was carried out by HPLC under either acidic or basic conditions.

[0181] [Table 1]

[0182] Examples 14 and 15: (S)-9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane and (R)-9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] Racemic Example 15 was separated into enantiomers of arbitrarily assigned stereochemistry by chiral separation using a CHIRALPAK AD-H 30 x 250 mm, 5 μm; 20% MeOH and 0.1% DMEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C) to give peak 1, Enantiomer 1 (10.2 mg, 20%, t R = 1.90 min, 100% ee) and peak 2, enantiomer 2 (11.6 mg, 23%, t R = 2.03 min, 85.8% ee) was obtained.

[0183] E1 1 H NMR(600MHz,DMSO-d6)δ(ppm)7.72(brt,J=9.1Hz,1H),7.52(brd,J=4.4Hz,2H),3.84(brd,J=1 0.2Hz,4H),3.76-3.56(m,2H),3.05-2.72(m,3H),1.88-1.65(m,8H),1.34(brd,J=8.7Hz,4H). E2 1 H NMR(600MHz,DMSO-d6)δ(ppm)7.72(brt,J=9.1Hz,1H),7.52(brd,J=4.4Hz,2H),3.84(brd,J=1 0.2Hz,4H),3.73-3.56(m,2H),3.06-2.74(m,3H),1.84-1.66(m,8H),1.34(brd,J=8.0Hz,4H).

[0184] Example 16: 9-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] 1: Synthesis of tert-butyl 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate [ka] The title compound was prepared from tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (500 mg, 2.1 mmol) and 2-methoxy-5-methylpyridine-3-sulfonyl chloride (457 mg, 2.1 mmol) using a method similar to that described for the preparation of intermediate 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (Example 5, Step 1) to give tert-butyl 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (1.6 g).

[0185] Synthesis of 2,9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] To a solution of tert-butyl 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (300 mg, 0.7 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (15 mL) was added TFA (160 μL, 2.1 mmol) at 25° C. The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated to give the title compound (220 mg, 96%) as a pale yellow oil. LCMS: 328.3 (M+H)+ .

[0186] Step 3: 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] A solution of 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane (110 mg, 0.3 mmol) and tetrahydropyran-4-one (34 mg, 0.3 mmol) in MeOH (10 mL) was adjusted to pH 5-6 with AcOH, followed by the addition of NaBHCN (63 mg, 1.0 mmol). The reaction mixture was stirred at 95 °C for 12 h. The mixture was concentrated to give a residue that was purified by preparative HPLC (Column: Phenomenex, C18, 150 × 25 mm × 10 μm; Conditions: water (NH4HCO3)-ACN Start B 18%; End B: 48% Gradient time (min): 8; 100% B Retention time (min): 2; Flow rate (mL / min): 30) to give 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane as an off-white solid (29 mg, 20%). LCMS: 412.1 (M+H). + . 1 H NMR:(400MHz,CD3OD)δ(ppm):8.22(d,J=1.6Hz,1H),8.00(d,J=1.6Hz,1H),4.04(s,3H),3.96-3.90(m,2H),3.76-3.74(m,2H),3.46-3.37(m ,2H),3.30-3.22(m,2H),3.21-3.16(m,1H),3.12-3.03(m,1H),2.79- 2.63(m,4H),2.37-2.23(m,4H),1.95-1.76(m,4H),1.55-1.40(m,2H).

[0187] Examples 17 and 18 [ka] Examples 17 and 18 in Table B were prepared from 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane hydrochloride (Example 2, Step 2, 50 mg, 0.1 mmol) and the corresponding aldehyde using a method similar to that described in Step 3 of Example 1. Purification by HPLC, basic conditions [Table 2]

[0188] Examples 19 and 20: [ka] Examples 19 and 20 in Table C were prepared from 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (Example 5, Step 1, 50 mg, 0.1 mmol) and the corresponding aldehyde using a method similar to that described in Step 3 of Example 1. Purification by HPLC was performed under either acidic or basic conditions.

[0189] [Table 3]

[0190] Example 21: 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] The title compound was prepared from 2,2-dimethyltetrahydropyran-4-one (21 mg, 0.2 mmol) and 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride salt (Example 5, Step 1, 52 mg, 0.1 mmol) using a method similar to that described in Step 3 of Example 1 to give 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane (7 mg, 9%). LCMS m / z=475.3 (M+H). + . 1 H NMR(500MHz,CD3OD)δ(ppm)7.88-7.79(m,2H),7.42-7.31(m,2H),7.21-6.84(m,1H),3.78-3.63(m,4H),3.01-2.79 (m,4H),2.79-2.63(m,4H),2.46(tt,J=4.0,11.6Hz,1H),1.93-1.76(m,4H),1.42-1.31(m,1H),1.30-1.14(m,9H).

[0191] Example 22: 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane [ka] Synthesis of 1,8-((2-cyclopropylthiazol-5-yl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane [ka] The title compound was prepared from tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (commercially available, 60 mg, 0.3 mmol) and 2-cyclopropylthiazole-5-sulfonyl chloride (65 mg, 0.3 mmol) using a method similar to that described in Example 5, Step 1, to give tert-butyl 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate. The crude product was stirred with 1 N HCl to give the hydrochloride salt of 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane (83 mg), which was used without further purification. LCMS m / z = 316.0 (M+H). +

[0192] Synthesis of 2,8-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane [ka] The title compound was prepared from tetrahydropyran-4-one (26 mg, 0.3 mmol) and 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane hydrochloride salt (83 mg) using a method similar to that described in Step 3 of Example 1. Purification by column chromatography on silica gel (12 g, 10-100% EtOH: EtOAc 1:3 in heptane) afforded 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane (39 mg, 37%). LCMS m / z = 400.2 (M+H). + . 1H NMR(500MHz,CD3OD)δ(ppm)8.00(s,1H),3.97-3.86(m,2H),3.77-3.64(m,2H),3.47-3.33(m,4H) ,3.07-2.96(m,4H),2.50-2.32(m,2H),1.76-1.67(m,3H),1.34-1.22(m,5H),1.19-1.12(m,2H).

[0193] Example 23: 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] Synthesis of 1,9-((2-cyclopropylthiazol-5-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] To a solution of tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (50 mg, 0.2 mmol) and DIPEA (70 μL, 0.4 mmol) in DCM (2 mL) was added 2-cyclopropylthiazole-5-sulfonyl chloride (46 mg, 0.2 mmol) at room temperature. The reaction mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous NH4Cl, water, and brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated. LCMS m / z = 374.1 (M+H- t Bu) + . The crude product was dissolved in EtOAc (2 mL) and HCl (1 M in EtOAc, 1 mL) was added. The reaction mixture was stirred overnight, the organic layer was removed under reduced pressure, and the resulting hydrochloride salt of 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane was used in the next step without further purification, assuming a 100% yield (88.6 mg). LCMS m / z=330.0 (M+H). +

[0194] Synthesis of 2,9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] The title compound was prepared from tetrahydropyran-4-one (21 mg, 0.2 mmol) and 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane hydrochloride (45 mg, 0.1 mmol) using a similar method as described in Step 3 of Example 1 to give, after purification by HPLC (basic conditions), 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane (29 mg, 51%). LCMS m / z=414.2 (M+H). + . 1 H NMR(500MHz,DMSO-d6)δ(ppm)8.10(s,1H),3.82(brd,J=11.6Hz,2H),3.60- 3.77(m,2H),3.28(brs,1H),3.01-2.84(m,3H),2.82-2.62(m,3H),2.59-2. 55(m,1H),2.52-2.46(m,2H),2.43(brd,J=9.8Hz,1H),2.26-2.13(m,1H),1 .82-1.66(m,4H),1.40-1.26(m,2H),1.26-1.19(m,2H),1.15-1.06(m,2H).

[0195] Example 24: 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] The title compound was prepared from 2-oxa-spiro[3.3]heptan-6-one (23 mg, 0.2 mmol) and 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane hydrochloride salt (Example 23, Step 1, 45 mg, 0.1 mol) using a method similar to that described in Step 3 of Example 1 to give 9-((2-cyclopropylthiazol-5-yl)sulfonyl-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane (6.4 mg, 15%). LCMS m / z=426.2 (M+H). + . 1 H NMR(500MHz,DMSO-d6)δ(ppm)8.10(s,1H),4.55(s,2H),4.45(s,2H),3.75- 3.57(m,2H),3.06-2.91(m,2H),2.90-2.81(m,1H),2.75-2.64(m,2H),2.59- 2.52(m,1H),2.50(td,J=1.8,3.7Hz,2H),2.38-2.18(m,4H),1.97(dt,J=7. 9,10.7Hz,2H),1.75(t,J=6.7Hz,2H),1.30-1.18(m,2H),1.15-1.02(m,2H).

[0196] Examples 25, 26, and 27: Racemic 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane, (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane, and (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] Synthesis of 1,9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] To a solution of tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (750 mg, 3.1 mmol), DIPEA (800 mg, 6.2 mmol) and HCl (4 M, 3 mL) in DCM (25 mL) at room temperature was added 4-(difluoromethoxy)benzenesulfonyl chloride (788 mg, 3.3 mmol).

[0197] After 1 h at room temperature, the reaction mixture was washed with saturated 0.5 M aqueous HCl, water, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue (200 mg) was dissolved in DCM (5 mL), and TFA (152 mg, 1.3 mmol) was added and stirred at room temperature for 3 h. The product was isolated by filtration to give the trifluoroacetate salt of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane as a white solid, which was used in the next step without further purification assuming a 100% yield. LCMS: 349.1 (M+H). + .

[0198] 2. Synthesis of racemic 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] A solution of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane trifluoroacetate (200 mg, 0.6 mmol) and 2-oxaspiro[3.3]heptan-6-one (64 mg, 0.6 mmol) in MeOH (10 mL) was stirred at 18 °C for 10 min and adjusted to pH = 5-6 with AcOH, followed by the addition of NaBHCN (288 mg, 4.6 mmol). The reaction mixture was stirred at 18 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. Purification by preparative HPLC (column Welch Xtimate C18 150 x 25 mm x 5 μm; conditions: water (NH4HCO3)-ACN start 35% B end 65% B gradient time (min) 11; 100% B hold time (min) 2; flow rate (mL / min) 25) gave 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane as a yellow oil (111 mg, 43%, 100% purity). LCMS: 445.2 (M+H). + . 1 H NMR:(500MHz,CD3Cl)δ(ppm):7.80-7.73(m,2H),7.29(d,J=8.7Hz,2H),6.78 -6.46(m,1H),4.74-4.69(m,2H),4.60(s,2H),3.83-3.69(m,2H),3.03-2.90( m,3H),2.81(brd,J=10.1Hz,1H),2.67(brt,J=7.5Hz,1H),2.61-2.44(m,4H) ,2.36(brdd,J=6.9,11.4Hz,2H),2.16-2.03(m,2H),1.90(brt,J=6.8Hz,2H).

[0199] Chiral separation of 3,9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] Racemic 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane was separated into its enantiomers using a CHIRALPAK AD-H 30 × 250 mm, 5 μm, 40% MeOH and 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C) to give two enantiomers of arbitrarily assigned stereochemistry: Peak 1, Enantiomer 1: (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane (33 mg, t R =1.57 min, 99.9%ee); Peak 2, Enantiomer 2: (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane (35 mg, t R = 1.94 min, 98.8% ee) was obtained.

[0200] Example 28: 9-((3,5-difluorophenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane [ka] The title compound was prepared from the trifluoroacetate salt of 9-(3,5-difluorophenyl)sulfonyl-6-oxa-2,9-diazaspiro[4.5]decane (200 mg, 0.5 mol) and 2-oxaspiro[3.3]heptan-6-one (52 mg, 0.5 mmol) in MeOH (10 mL) using a method similar to that described in Step 2 of Example 27 to give 9-((3,5-difluorophenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane as a yellow oil (67 mg, 35%, 100% pure). LCMS m / z = 415.1 (M+H). + . 1 H NMR(500MHz,CD3OD)δ(ppm):7.48-7.42(m,2H),7.41-7.36(m,1H),4.73(s,2H),4.64-4.58(m,2H),3.81-3.70(m,2H),3.11-2.95(m,3H),2.89(b rd,J=11.6Hz,1H),2.80(sixtray,J=7.6Hz,1H),2.67(d,J=10.5Hz,1H),2.6 2-2.54(m,3H),2.46-2.36(m,2H),2.16-2.09(m,2H),1.96-1.87(m,2H).

[0201] Example 29: 4-((3,5-difluorophenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] Synthesis of 1,4-((3,5-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] The title compound was prepared from tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (commercially available, 100 mg, 0.4 mmol) and 3,5-difluorobenzenesulfonyl chloride (91 mg, 0.4 mmol) using a method similar to that described in Step 1 of Example 25, followed by HCl deprotection to give the hydrochloride salt of 4-((3,5-difluorophenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (theoretical yield 129 mg), which was used without further purification. LCMS m / z=333.1 (M+H). +

[0202] Synthesis of 2,4-((3,5-difluorophenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] The title compound was prepared from 4-((3,5-difluorophenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (65 mg, 0.2 mmol) and 3-methyloxetane-3-carbaldehyde (25 mg, 0.2 mmol) using a method similar to that described in Example 1 to give 4-((3,5-difluorophenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane (25 mg, 31%). LCMS m / z=417.2 (M+H). + .LCMS t R (4 minutes) = 1.25 minutes.

[0203] Example 30: 9-((4-(difluoromethoxy)phenyl)sulfonyl)-4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] Synthesis of tert-butyl 1,4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [ka] To a vial containing tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (commercially available, 300 mg, 1.2 mmol) in anhydrous DCM (6 mL) at 23 °C, tetrahydropyran-4-one (128 mg, 1.3 mmol) and NEt (360 μL, 2.6 mmol) were added dropwise, followed 15 min later by the dropwise addition of AcOH (170 μL, 2.9 mmol). The reaction mixture was stirred at 23 °C for 30 min, and then NaBH(OAc) (992 mg, 4.7 mmol) was added portionwise. The reaction was stirred at 23 °C. After 6 days, the reaction was quenched by the slow addition of saturated aqueous NaHCO, stirred at 23 °C for 10 min, and then extracted with EtOAc (3×). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude tert-butyl 4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (446 mg). LCMS m / z=341.2 (M+H). + .

[0204] Synthesis of 2,4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] Crude tert-butyl 4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (50 mg) in EtOAc (1 mL) was added dropwise to a stirred solution of HCl (1 M, 2.9 mL). After 1 day, the reaction mixture was evaporated to dryness to give 4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride salt (35 mg), which was used without further purification. LCMS m / z=241.1 (M+H). + .

[0205] Synthesis of 3,9-((4-(difluoromethoxy)phenyl)sulfonyl)-4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane [ka] To a vial containing 4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride (35 mg, 0.2 mmol) in THF (1.5 mL), DIPEA (180 μL, 1.0 mmol) was added dropwise, followed by stirring for 5 min. After this, DMAP (2 mg, 0.02 mmol) was added, followed by 4-(difluoromethoxy)benzenesulfonyl chloride (53 mg, 0.2 mmol). After 1 day, the reaction was quenched with saturated aqueous NaHCO and extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous NaCl, washed with NaCl solution, dried over MgSO, filtered, evaporated and purified by HPLC (basic conditions) to give 9-((4-(difluoromethoxy)phenyl)sulfonyl)-4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane (7 mg, 10%, 100% purity). LCMS m / z=447.1 (M+H). + . 1H NMR(500MHz,DMSO-d6)δ(ppm):7.81(brd,J=8.6Hz,2H),7.61-7.28(m,3H),3.98(brd,J=10.4Hz,2H),3.89-3.72(m,1H),3.71-3.41(m,1 H),3.33-3.19(m,1H),3.00-2.78(m,1H),2.48-2.21(m,5H),2.05-1.88(m,3H),1.78-1.67(m,1H),1.67-1.40(m,7H),1.39-1.25(m,1H).

[0206] Example 31: 7-((2,4-dimethylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane Synthesis of tert-butyl 1,7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate [ka] To a mixture of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (226 mg, 1.0 mmol) and 2,4-dimethylbenzenesulfonyl chloride (205 mg, 1.0 mmol) in DCM (5 mL) was added DIPEA (260 μL, 1.5 mmol). The reaction mixture was stirred overnight at room temperature and then washed with saturated aqueous NaHCO3 and water. The organic phase was concentrated and purified by column chromatography on silica gel (24 g, 10-50% EtOAc in heptane) to give tert-butyl 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate as a white foam (294 mg, 75%). LCMS m / z = 392.2 (M+H). + .

[0207] Synthesis of 2,7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane [ka] To a reaction vial containing tert-butyl 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (294 mg, 0.8 mmol) in 1,1,1,3.3,3-hexafluoropropan-2-ol (3 mL) at room temperature was added TFA (140 μL, 1.9 mmol) dropwise. The mixture was stirred at room temperature for 5 h, concentrated under reduced pressure, and coevaporated with MeCN (3×) to give the trifluoroacetate salt of 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane as a white solid (316 mg). This product was used without further purification. LCMS m / z = 295.0 (M+H). + .

[0208] 3: Synthesis of 7-((2,4-dimethylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane [ka] To a mixture of tetrahydropyran-4-one (13 mg, 0.1 mmol) and the trifluoroacetate salt of 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane (42 mg, 0.1 mmol) in DCM (2 mL) was added DIPEA (50 μL, 0.3 mmol). The reaction mixture was stirred for 5 min. AcOH (18 mg, 0.3 mmol) was added, followed by stirring for an additional 5 min, followed by the addition of NaBH(OAc) (64 mg, 0.3 mmol) in one portion. The mixture was stirred at room temperature overnight and quenched with saturated aqueous NaHCO. More DCM was added, and the mixture was stirred for 5 min, after which the layers were separated. The organic layer was washed with water, concentrated under reduced pressure, and purified by HPLC (basic conditions) to give 7-((2,4-dimethylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane (28 mg, 73%). LCMS m / z=379.1 (M+H). + . 1H NMR(500MHzDMSO-d6)δ(ppm):7.67(d,J=7.9Hz,1H),7.25(s,1H),7.21(d,J=7.9Hz,1H),3.7-3.8(m,2H),3.33(s,5H),3.23(d t,J=2.1,11.1Hz,2H),2.9-3.0(m,4H),2.83(s,3H),2.34(s,3H),1.6-1.8(m,4H),1.53(brd,J=11.6Hz,2H),1.0-1.1(m,2H).

[0209] Examples 32 and 33: 7-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane and 7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane The following Examples 32 and 33 were prepared from tetrahydropyran-4-one using a method similar to that described for 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane (Example 31). Data for intermediates in Tables D and E (Steps 1 and 2), data for Examples 32 and 33 in Table F (Step 3).

[0210] [Table 4] [Table 5] [Table 6]

[0211] Example 34: 4-((7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)tetrahydro-2H-pyran-4-ol [ka] To a mixture of 1,6-dioxaspiro[2.5]octane (10 mg, 0.1 mmol) and the trifluoroacetate salt of 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane in EtOH (1 mL) was added DIPEA (40 μL, 0.2 mmol). The mixture was stirred at 60 °C overnight and then partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was separated, concentrated, and purified by column chromatography on silica gel (12 g, EtOAc / EtOH 3:1) to give 1-((7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)cyclohexan-1-ol as a sticky solid (19 mg, 69%) after lyophilization. LCMS m / z = 409.2 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm):7.75(d,J=8.0Hz,1H),7.33-7.12(m,2H),3.87-3.60(m,4H),3.21(s,4H),3.13-3.0 4(m,4H),2.58(s,3H),2.55(s,2H),2.39(s,3H),1.88-1.75(m,4H),1.54-1.70(m,2H),1.44(brd,J=13.3Hz,2H).

[0212] Example 35: 7-((2,4-dimethylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonane [ka] The title compound 35 was prepared from the trifluoroacetate salt of 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane (42 mg, 0.1 mmol) and tetrahydro-4-carbaldehyde (15 mg, 0.1 mmol) using a method similar to that described in Example 31 to give 7-((2,4-dimethylphenyl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonane as a colorless oil (29 mg, 74%) after column chromatography on silica gel (12 g, EtOAc / EtOH 3:1). LCMS m / z=393.3 (M+H). + . 1 H NMR(400MHz,CD3OD):δ(ppm):7.79-7.73(m,1H),7.27-7.15(m,2H),3.91(brdd,J=11.4,4.4Hz,2H),3.43-3.35(m,2H),3.05-3 .13(m,8H),2.58(s,3H),2.42(brd,J=6.5Hz,2H),2.40-2.38(m,3H),1.85-1.77(m,4H),1.69-1.57(m,3H),1.33-1.18(m,2H).

[0213] Example 36: 8-((2-chloro-4-methylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane [ka] Synthesis of tert-butyl 1,2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate [ka] To tetrahydropyran-4-one (610 mg, 6.1 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (1.22 g, 5.1 mmol) in DCM (20 mL) was added AcOH (580 μL, 10.1 mmol), followed by the addition of NaBH(OAc) (4.0 g, 18.9 mmol) in four portions. The reaction mixture was stirred overnight at room temperature, then quenched with saturated aqueous NaHCO and extracted with DCM (3×). The organic layer was dried over MgSO, filtered, concentrated, and coevaporated with EtOAc to give tert-butyl 2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate as a pale yellow oil (1.69 g), which was used without further purification. LCMS m / z = 309.1 (M+CH). + .

[0214] Synthesis of 2,2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane [ka] To a solution of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (1.68 g) in EtOAc (2 mL) was added HCl (1 M in EtOAc, 15.2 mL) at room temperature. After 10 min, an additional 5 mL of 1 M HCl in EtOAc was added, and the reaction mixture was stirred at room temperature overnight. MeOH (2 mL) and 1 M HCl in EtOAc (5 mL) were added, and the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and co-evaporated with MeCN / MeOH to give the hydrochloride salt of 2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane as an off-white solid (1.52 g). LCMS m / z = 225.2 (M+H). + .

[0215] Synthesis of 3,8-((2-chloro-4-methylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane [ka] To 2-tetrahydropyran-4-yl-2,8-diazaspiro[4.5]decane hydrochloride (54 mg) and 2-chloro-4-methyl-benzenesulfonyl chloride (34 mg, 0.2 mmol) in DCM (3 mL) was added DIPEA (80 μL, 0.5 mmol). The mixture was stirred at room temperature for 3 days, then quenched with saturated aqueous NaHCO3 and water and stirred at room temperature for 5 minutes. The organic layer was separated, washed with water, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (12 g, 3:1 EtOAc / EtOH) to give 8-((2-chloro-4-methylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane as a sticky solid (43 mg, 69%) after lyophilization. LCMS m / z = 413.1 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm):7.91(d,J=8.0Hz,1H),7.47(s,1H),7.35-7.27(m,1H),3.95(brdd,J=11.3,3.3Hz,2H),3.48-3.35(m,2H),3.32-3.26(m, 2H),3.24-3.15(m,2H),2.73(t,J=6.9Hz,2H),2.54(s,2H),2.43(s,3H),2 .34-2.23(m,1H),1.89-1.78(m,2H),1.73-1.58(m,6H),1.57-1.44(m,2H).

[0216] Examples 37 to 43 Examples 37-43 in Table G below were prepared from 2-tetrahydropyran-4-yl-2,8-diazaspiro[4.5]decane hydrochloride (1 equivalent) and the corresponding sulfonyl chloride using a method similar to that described for Example 36.

[0217] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0218] Example 44: 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of 1,2-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] The title compound was prepared from tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (204 mg, 1.0 mmol) and 2,4-dimethylbenzenesulfonyl chloride (204 mg, 1.0 mmol) using a method similar to that described in Steps 1 and 2 for the intermediate in Example 31 and purified by column chromatography on silica gel (24 g, 10-20% EtOAc in heptane) to give tert-butyl 6-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (315 mg, 86%). 1 H NMR (400 MHz, CD3OD) δ (ppm) 7.79 (d, J = 8.0 Hz, 1H), 7.32-7.13 (m, 2H), 4.00 (s, 4H), 3.93 (s, 4H), 2.59 (s, 3H), 2.41 (s, 3H), 1.43 (s, 9H). TFA deprotection gave the trifluoroacetate salt of 2-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane (365 mg), which was used without further purification. 1H NMR(400MHz,CD3OD)δ(ppm):7.87-7.76(m,1H),7.33-7.15(m,2H),4.22(s,4H),4.02(d,J=2.0Hz,4H),2.59(s,3H),2.41(s,3H).

[0219] Synthesis of 2,2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] The title compound was prepared from the trifluoroacetate salt of 2-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane (47 mg) and tetrahydropyran-4-one (14 mg, 0.1 mol) using a method similar to that described in Example 31. The crude product was purified by column chromatography on silica gel (12 g, EtOAc / EtOH 3:1) to give 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane as a colorless oil (32 mg, 84%). LCMS m / z = 351.1 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm):7.79(d,J=8.0Hz,1H),7.26(s,1H),7.22(d,J=8.0Hz,1H),3.98-3.81(m,6H),3.41-3.35 (m,2H),3.34-3.33(m,4H),2.59(s,3H),2.40(s,3H),2.32-2.19(m,1H),1.66(brd,J=12.5Hz,2H),1.34-1.14(m,2H).

[0220] Example 45: 4-((6-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol [ka] The title compound was prepared from the trifluoroacetate salt of 2-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane (Example 45, Step 1, 43 mg, 100 μmol) and 1,6-dioxaspiro[2.5]octane (14.8 mg, 130 μmol) using a method similar to that described in Step 3 of Example 34 to give 4-((6-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol as a white solid (28 mg, 74%) after purification by column chromatography on silica gel (12 g, EtOAc / EtOH 3:1). LCMS m / z=381.2 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm):7.78(d,J=8.0Hz,1H),7.25(s,1H),7.22(dd,J=8.0,0.8Hz,1H),3.87(s,4H),3 .79-3.63(m,4H),3.39(s,4H),2.58(s,3H),2.43(s,2H),2.40(s,3H),1.65-1.55(m,2H),1.49-1.40(m,2H).

[0221] Example 46: 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] The title compound was prepared from 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane hydrochloride (commercially available, 26 mg, 0.1 mol) and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (27 mg, 0.1 mmol) using a method similar to that in Step 3 of Example 36 to give, after HPLC (acidic conditions), 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (49 mg, 67%). LCMS m / z=395.2 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm):7.23(s,1H),4.18(s,3H),4.04(s,4H),4.00-3.90(m,2H), 3.40-3.30(m,6H),2.28(tt,J=4.0,10.8Hz,1H),1.70-1.60(m,2H),1.30-1.20(m,2H).

[0222] Examples 47 to 50 Examples 47-50 in Table H below were prepared from 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane hydrochloride (25.5 mg, 100 μmol) and the corresponding sulfonyl chloride (110 μmol) using a method similar to that described for Example 36, unless otherwise noted. Purification by HPLC (acidic or basic conditions) unless otherwise noted.

[0223] [Table 8-1] [Table 8-2]

[0224] Example 51: 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Hunig's base (322.56 mg, 2.50 mmol, 434.72 μL) was added to a mixture of 2-tetrahydropyran-4-yl-2,6-diazaspiro[3.3]heptane (167.19 mg, 655.16 μmol, 2HCl) and 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (162 mg, 623.96 μmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2.5 h. The reaction was then quenched with saturated aqueous NaHCO3 and water, and the solution was stirred at room temperature for 5 min. The aqueous layer was removed, and the organic phase was washed with water and concentrated. The residue was purified by normal phase chromatography (24 g, 20–100% EtOAc / EtOH in heptane) to give the product as a colorless oil, which precipitated as a white solid upon addition of MeCN. The product was lyophilized overnight to give the desired product (208 mg, 82.22% yield) as a white solid. LCMS m / z=406.2 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm):8.46(d,J=8.3Hz,1H),7.83(d,J=8.3Hz,1H),4.04(s,4H),3.94-3.86(m,2 H),3.39-3.32(m,6H),2.86(s,3H),2.26(tt,J=10.7,4.1Hz,1H),1.72-1.60(m,2H),1.30-1.14(m,2H).

[0225] Example 52: 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane [ka] Synthesis of 1,6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane [ka] The title compound was prepared from tetrahydropyran-4-one (300 mg, 3.0 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (530 mg, 2.5 mmol) using a method similar to that described in Step 1 of Example 36 to give tert-butyl 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (448 mg, 60%), which was used without further purification. 1 H NMR(400MHz,CD3OD)δ(ppm):4.06-3.82(m,6H),3.42(brt,J=11.9Hz,2H),3.18(s,2H),3.02(t,J=7.3Hz,2H),2 .85-2.65(m,1H),2.21(t,J=7.3Hz,2H),1.98-1.91(m,2H),1.60(brdd,J=12.3,4.8Hz,2H),1.50-1.41(m,9H). Subsequent deprotection of tert-butyl 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate with HCl (Step 2 of Example 36) gave the hydrochloride salt of 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane (222 mg), which was used without further purification. LCMS m / z=365.2 (M+H). +

[0226] 2. Synthesis of 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]octane [ka] The title compound was prepared from 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane hydrochloride (38 mg, 0.1 mmol) and 2,4-dimethylbenzenesulfonyl chloride (25 mg, 0.1 mmol) using a method similar to Step 3 of Example 36. After purification by column chromatography on silica gel (12 g, 3:1 EtOAc / EtOH), 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane was obtained as an oil (13 mg, 29%). LCMS m / z = 365.2 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm):7.79(d,J=8.0Hz,1H),7.35-7.13(m,2H),4.06-3.88(m,2H),3.74(q,J=7.9Hz,4H),3.40(brt,J=11.8Hz,2H),2.76(s, 2H),2.69-2.62(m,2H),2.61(s,3H),2.41(s,3H),2.32-2.22(m,1H),2.02 (t,J=7.2Hz,2H),1.83(brd,J=12.8Hz,2H),1.48(qd,J=12.0,4.8Hz,2H).

[0227] Examples 53 to 59 Examples 53-59 in Table I below were prepared from 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane hydrochloride (0.1 mmol) and the corresponding sulfonyl chloride or carbonyl chloride (0.1 mmol) using a method similar to that described for Example 52, unless otherwise noted. Purification by HPLC (acidic or basic conditions) unless otherwise noted. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0228] Example 60: 6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane [ka] Synthesis of 1,2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane [ka] The title compound was prepared from tetrahydropyran-4-one (251 mg, 2.5 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (commercially available, 443 mg, 2.1 mmol) using a method similar to that described in Step 1 of Example 36 to give tert-butyl 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate as a yellow oil (548 mg), which was used without further purification. 1 H NMR(400MHz,CD3OD)δ(ppm):3.94(brdd,J=10.8,4.3Hz,2H),3.89-3.78(m,4H),3.39(td,J=11.9,2.0Hz,2H),2.83(s,2 H),2.68(t,J=7.2Hz,2H),2.36-2.21(m,1H),2.08(t,J=7.2Hz,2H),1.88-1.78(m,2H),1.57-1.44(m,2H),1.43(s,9H). Subsequent deprotection with HCl gave the hydrochloride salt of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane (87 mg), which was used without further purification. LCMS m / z=197.2 (M+H). +

[0229] Synthesis of 2,6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane [ka] The title compound was prepared from 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane hydrochloride (24 mg, 0.1 mmol) and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (22 mg, 0.1 mmol) using a method similar to Step 3 of Example 36. After purification by HPLC (basic conditions), 6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane was obtained as an oil (21 mg, 58%). LCMS m / z=409.2 (M+H). + .LCMS t R (2 minutes) = 0.60 minutes

[0230] Example 61: (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] [ka] 1. Synthesis of tert-butyl (1'R,5'S)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate [ka] The title compound was prepared from tetrahydropyran-4-one (143 mg, 1.43 mmol) and (1'R,5'S)-tert-butyl 8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (300 mg, 1.2 mmol) using a method similar to that described in Step 1 of Example 36, and after purification by column chromatography on silica gel (DCM / MeOH 9:1) gave (1'R,5'S)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate as a colorless oil (426 mg). LCMS m / z = 281.1 (M+Ht-Bu). + .

[0231] 2. Synthesis of (1'R,5'S)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] [ka] To a solution of tert-butyl (1'R,5'S)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (426 mg) in DCM (10 mL) was added TFA (2.0 mL, 25.3 mmol), and the reaction mixture was stirred at 20°C for 2 hours and then concentrated to give the trifluoroacetate of (1'R,5'S)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] as a brown oil (800 mg, crude), which was used without further purification. LCMS m / z = 237.1 (M+H). +

[0232] 3. Synthesis of (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] [ka] The title compound was prepared from the trifluoroacetate salt of (1'R,5'S)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] (350 mg) and 4-(difluoromethoxy)benzenesulfonyl chloride (276 mg, 1.1 mmol) using a method similar to that in Step 3 of Example 36 to give (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] as a beige solid (160 mg, 48%) after column chromatography on silica gel (DCM / MeOH 19:1). LCMS m / z = 443.2 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm):7.94-7.87(m,2H),7.30(d,J=8.8Hz,2H),7.21-6.81(m ,1H),4.23(brd,J=2.8Hz,2H),3.91(brdd,J=2.4,11.6Hz,2H),3.38-3.33(m,3H),3. 30-3.27(m,1H),3.01(s,2H),2.35-2.23(m,1H),2.14(dd,J=2.4,14.0Hz,2H),1.91 (brdd,J=3.2,13.6Hz,2H),1.71-1.58(m,4H),1.52-1.39(m,2H),1.31-1.15(m,2H).

[0233] Example 62: 1-((1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol 1. Synthesis of tert-butyl (1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Potassium 2-methylpropan-2-olate (1 M, 110 mmol) was suspended in DME (160 mL) at -10 °C under a N atmosphere. TosMIC (13.0 g, 66.6 mmol) dissolved in DME (10 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Isopropanol (7.0 mL, 88.8 mmol) was added at -10 °C, and the reaction mixture was stirred for an additional 30 minutes. Then, tert-butyl (1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10 g, 44.4 mmol) dissolved in DME (10 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, then heated at 50 °C for 16 hours, and then filtered through Celite. The residue was washed with ethyl acetate (100 mL, 2x). The organic layers were combined and evaporated, and the resulting residue was purified by column chromatography on silica gel (PE / EtOAc 3:1) to give tert-butyl (1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate as a white solid (8.0 g, 76%). Rf (TLC, PE / EtOAc 1:1) 0.43.

[0234] 2. Synthesis of 8-(tert-butyl)3-ethyl (1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate [ka] LiHMDS (50 mL, 1 M in THF) was added dropwise to a solution of tert-butyl (1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate (6.0 g, 25.0 mmol) in anhydrous THF (120 mL) at −78° C. The reaction mixture was stirred for 1 h, followed by the addition of ethyl carbonochloride (5.7 g, 52.3 mmol) at −78° C., followed by stirring for 1 h. The mixture was warmed to 0° C. and stirred for 1 h, then quenched with aqueous NaHCO (1 M, 50 mL) and extracted with EtOAc (50 mL, 3×). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (PE / EtOAc 1:1) to give 8-(tert-butyl)3-ethyl (1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate as a yellow liquid (7.8 g, 100%). 1 H NMR(400MHz, CDCl3)δ(ppm):4.43-4.22(m,4H),2.36(brdd,J=3.2,14.4Hz,2H) ,2.27(q,J=7.6Hz,2H),2.16-2.04(m,4H),1.47(s,9H),1.31(t,J=7.2Hz,3H).

[0235] 3. Synthesis of tert-butyl (1R,5S)-3-cyano-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of 8-(tert-butyl)3-ethyl (1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate (7.8 g, 25.3 mmol) in MeOH (120 mL) was added NaBH (1.5 g, 39.6 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 1 h, then quenched with saturated NH Cl (20 mL) and extracted with EtOAc (30 mL, 3×). The combined organic phases were washed with brine (20 mL, 2×), dried over anhydrous NaSO, filtered, and concentrated to give a residue which was purified by column chromatography on silica gel (PE / EtOAC 3:1 to 1:1) to give tert-butyl (1R,5S)-3-cyano-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate as a white solid (6.3 g, 94%). 1 H NMR(400MHz,CDCl3)δ(ppm):4.29(brs,2H),3.54(s,2H),2.26-2.18(m,2H),2.13-2.04(m,2H),2.01-1.94(m,2H),1.90-1.83(m,2H),1.45(s,9H).

[0236] 4. Synthesis of tert-butyl (1R,5S)-3-cyano-3-((tosyloxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl (1R,5S)-3-cyano-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.3 g, 23.6 mmol), DMAP (289 mg, 2.4 mmol), and TEA (10 mL, 71.0 mmol) in DCM (150 mL) was added 4-methylbenzenesulfonyl chloride (9.0 g, 47.3 mmol). The reaction mixture was stirred at 25 °C for 16 h and then concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 3:1 to 1:1) to give tert-butyl (1R,5S)-3-cyano-3-((tosyloxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate as a colorless oil (9.1 g, 92%). Rf (TLC, PE / EtOAc 1:1) 0.64.

[0237] 5. Synthesis of tert-butyl (1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate [ka] To a solution of tert-butyl (1R,5S)-3-cyano-3-((tosyloxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (7.1 g, 16.9 mmol) in THF (60 mL) was added LiAlH (30 mL, 1 M in THF) at 0 °C, and the mixture was stirred at 25 °C for 3 h. The reaction was quenched with NaSO × 10HO (1 g), filtered, washed with THF (20 mL), and concentrated to give tert-butyl (1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate as a yellow solid (3.1 g, 73%), which was used without further purification. 1 H NMR(400MHz,CD3OD)δ(ppm):4.22-4.14(m,2H),3.69(s,2H),3.25(brs,2H),(brd,J=11.8Hz,2H),1.94-1.84(m,2H),1.82-1.70(m,4H),1.45(s,9H).

[0238] 6. Synthesis of tert-butyl (1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate [ka] To a solution of tert-butyl (1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (300 mg, 1.2 mmol) in DCM (6.0 mL) was added DIPEA (620 μL, 3.6 mmol) and 2,4-dimethylbenzenesulfonyl chloride (365 mg, 1.8 mmol) at 0° C. The reaction mixture was stirred at 20° C. for 4 h and then extracted with DCM (30 mL, 3×). The combined organic phases were washed with brine (30 mL, 3×), dried over anhydrous NaSO, filtered, and concentrated to give a residue that was purified by column chromatography on silica gel (PE / EtOAc 1:1) to give tert-butyl (1′R,5′S)-1-((2,4-dimethylphenyl)sulfonyl)-8′-azaspiro[azetidine-3,3′-bicyclo[3.2.1]octane]-8′-carboxylate as a white solid (420 mg, 84%). LCMS m / z=365.2 (M+H-Boc). + .

[0239] 7. Synthesis of (1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] [ka] A solution of tert-butyl (1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate in DCM (5.0 mL) and TFA (1.0 mL, 13.1 mmol) was stirred at 20°C for 2 hours. The mixture was concentrated in vacuo to give the trifluoroacetate salt of (1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] as a white oil (320 mg, crude). LCMS m / z = 321.2 (M+H). +

[0240] 8. Synthesis of 1-((1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol [ka] (1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] trifluoroacetate (200 mg, 0.5 mmol), DIPEA (240 μL, 1.4 mmol), and 2,2-dimethyloxirane (1.6 g, 22.5 mmol) in THF (1 mL) were added to a microwave tube. The sealed tube was heated in a microwave at 80° C. for 3 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (column Welch Xtimate C18 150 x 25 mm x 5 μm; conditioned water (10 mM NH4HCO3)-ACN start B 50% end B 80% flow rate (mL / min) 25) to give 1-((1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol as a white solid (55 mg, 30%, 100% purity). LCMS m / z = 393.2 (M+H). + . 1H NMR(400MHz,CD3OD)δ(ppm)7.75(d,J=8.1Hz,1H),7.23(s,1H),7.19(d,J=8.1Hz,1H),3.77(s,2H),3.46-3.40(m,2H) ),3.16(brs,2H),2.57(s,3H),2.38(s,3H),2.20(brs,2H),1.92-1.79(m,6H),1.56(brd,J=7.9Hz,2H),1.12(s,6H).

[0241] Example 63: (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] [ka] 1. Synthesis of tert-butyl (1'R,5'S)-1-(2-ethoxy-2-oxoethyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate [ka] A solution of tert-butyl (1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (Example 63, Step 5, 500 mg, 2.0 mmol) and ethyl 2-oxoacetate (809 mg, 4.0 mmol) in DCM (10 mL) was adjusted to pH 5-6 with AcOH, and the reaction mixture was stirred at 18 °C for 30 min. NaBH(OAc) (2.1 g, 9.9 mmol) was added. The mixture was stirred at 18 °C for 16 h, then quenched with saturated aqueous NaHCO (30 mL) and extracted with DCM (30 mL, 3x). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated to give a residue that was purified by column chromatography on silica gel (PE / EtOAC 1:1 to EtOAc) to give tert-butyl (1'R,5'S)-1-(2-ethoxy-2-oxoethyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate as a colorless oil (530 mg, 79%). LCMS m / z=283.1 [M+Ht-Bu] + .

[0242] 2. Synthesis of 2-((1'R,5'S)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-1-yl)ethyl acetate [ka] To a solution of tert-butyl (1'R,5'S)-1-(2-ethoxy-2-oxoethyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (510 mg, 1.5 mmol) in 20 mL of EtOAc, HCl (4 M, 11.3 mL) was added, and the reaction mixture was stirred at 20°C for 6 hours, then concentrated to give ethyl 2-((1'R,5'S)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-1-yl)acetate hydrochloride salt as a white solid (460 mg). LCMS m / z = 239.2 (M+H). + .

[0243] 3. Synthesis of ethyl 2-((1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-1-yl)acetate [ka] To a solution of ethyl 2-((1'R,5'S)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]-1-yl]acetate (280 mg, 0.9 mmol) and TEA (380 μL, 2.7 mmol) in DCM (10 mL) was added 4-(difluoromethoxy)benzenesulfonyl chloride (327 mg, 1.4 mmol), and the reaction mixture was stirred at 20° C. for 4 h. The mixture was diluted with water (10 mL) and extracted with DCM (20 mL, 3×). The combined organic phases were washed with brine (10 mL, 3×), dried over anhydrous NaSO, filtered, and concentrated to give a residue that was purified by column chromatography on silica gel (DCM / MeOH 19:1) to give ethyl 2-((1′R,5′S)-8′-((4-(difluoromethoxy)phenyl)sulfonyl)-8′-azaspiro[azetidin-3,3′-bicyclo[3.2.1]octan]-1-yl)acetate as a white solid (180 mg, 45%). LCMS m / z=445.2 (M+H). +

[0244] 4. Synthesis of 1-((1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-1-yl)-2-methylpropan-2-ol [ka] To a solution of ethyl 2-((1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-1-yl)acetate (180 mg, 0.4 mmol) in 5 mL of THF was added bromo(methyl)magnesium (3 M, 2.8 mmol) in a Schlenk tube stirred at 0° C. The reaction mixture was stirred at 20° C. for 3 h, then quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (20 mL, 3×). The combined organic layers were washed with brine (10 mL, 3×), dried over anhydrous NaSO, filtered, and concentrated to give 1-((1′R,5′S)-8′-((4-(difluoromethoxy)phenyl)sulfonyl)-8′-azaspiro[azetidin-3,3′-bicyclo[3.2.1]octan]-1-yl)-2-methylpropan-2-ol as a yellow oil (150 mg, crude). LCMS m / z=431.1 (M+H). +

[0245] 5. Synthesis of (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] [ka] To a mixture of 1-((1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-1-yl)-2-methylpropan-2-ol (150 mg, 0.4 mmol) in THF (10 mL) was added NaH (70 mg, 1.7 mmol, 60% purity) and MeI (130 μL, 2.2 mmol). The mixture was stirred at 0° C. for 10 min and then warmed to 20° C. for 16 h. The mixture was quenched with HO (10 mL, 3×) and the combined organic layers were washed with DCM (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue that was purified by preparative HPLC (column Welch Xtimate C18 150 × 25 mm × 5 μm, conditions water (10 mM NH4HCO3)-ACN, start B 41%, finish B 71%, flow rate (mL / min) 25) to give (1′R,5′i)-8′-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(2-methoxy-2-methylpropyl)-8′-azaspiro[azetidine-3,3′-bicyclo[3.2.1]octane] as a brown solid (20 mg, 13%). LCMS m / z=445.3 (M+H) + . 1 H NMR(400MHz,CD3OD)δ(ppm):7.91(d,J=8.8Hz,2H),7.29(d,J=8.8Hz,2H),7.20-6.81(m,1H),4.21(brs,2H),3.38(brs,2H),3.16(s,3H), 3.07(brs,2H),2.47(brs,2H),2.18(brd,J=12.4Hz,2H),1.87(dd,J=2.4,13.8Hz,2H),1.67-1.56(m,2H),1.50-1.36(m,2H),1.09(s,6H).

[0246] Example 64: (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] [ka] 1. Synthesis of tert-butyl (1'R,5'S)-1-((4-difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate [ka] To a solution of tert-butyl (1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (Example 63, Step 5, 200 mg, 0.8 mmol) in DCM (6.0 mL) was added DIPEA (410 μL, 2.4 mmol) and 4-difluoromethoxybenzenesulfonyl chloride (192 mg, 0.8 mmol) at 0° C. The reaction mixture was stirred at 20° C. for 3 h and then extracted with DCM (30 mL, 3×). The combined organic phases were washed with brine (30 mL, 3×), dried over anhydrous NaSO, filtered, and concentrated to give a residue that was purified by column chromatography on silica gel (PE / EtOAc 1:1) to give tert-butyl (1′R,5′S)-1-((4-difluoromethoxy)phenyl)sulfonyl)-8′-azaspiro[azetidine-3,3′-bicyclo[3.2.1]octane]-8′-carboxylate as a white solid (300 mg, 83%). LCMS m / z=403.1 (M+H-Boc). +

[0247] 2. Synthesis of (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] [ka] To a solution of tert-butyl (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (300 mg, 0.7 mmol) in DCM (5.0 mL) was added TFA (1.0 mL, 13.1 mmol). The mixture was stirred at 20°C for 2 hours and then concentrated in vacuo to give (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] trifluoroacetate (250 mg, crude) as a white solid. LCMS m / z = 359.1 (M+H). +

[0248] 3. Synthesis of 1-((1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol [ka] (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] trifluoroacetate (150 mg, 0.3 mmol), DIPEA (220 μL, 1.3 mmol), and 2,2-dimethyloxirane (1.2 g, 17.1 mmol) were dissolved in THF (1 mL) in a microwave tube. The sealed tube was heated in a microwave at 80° C. for 3 h. The mixture was concentrated in vacuo, diluted with water (10 mL), and extracted with EtOAc (20 mL, 3×). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (DCM / MeOH 1:1) to give 1-((1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol as a white solid (130 mg, 95%). LCMS m / z=431.1 (M+H).+

[0249] 4. Synthesis of (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] [ka] To a solution of 1-((1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol (130 mg, 0.3 mmol) in THF (10 mL) was added NaH (60 mg, 1.5 mmol, 60% purity) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 30 min. Iodomethane (60 μL, 0.9 mmol) was added dropwise to the reaction mixture at 0 °C under N2. The reaction mixture was stirred at 20 °C for 16 h and then extracted with DCM (10 mL, 3×). The combined organic layers were washed with brine (10 mL, 3×), dried over anhydrous NaSO, filtered, and concentrated to give a residue that was purified by preparative HPLC (Column: Welch Xtimate C18 150 × 25 mm × 5 μm; Conditions: water (NHHCO)-CAN; Start B: 51%; End B: 81%; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (mL / min): 25) followed by preparative TLC (DCM / MeOH 10:1) to give (1′R,5′S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8′-(2-methoxy-2-methylpropyl)-8′-azaspiro[azetidine-3,3′-bicyclo[3.2.1]octane] as a yellow solid (49 mg, 49%). LCMS m / z=445.2 (M+H). + . 1H NMR:(400MHz,DMSO-d6)δ(ppm):7.94-7.83(m,2H),7.69-7.24(m,3H),3.71(s,2H),3.11-2.9 3(m,5H),2.09(s,2H),1.77-1.55(m,4H),1.53-1.33(m,4H),1.29-1.19(m,2H),1.01(s,6H).

[0250] Example 65: 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 2-((1-(Cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane was prepared from 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane hydrochloride (75 mg, 411 mol) and 2-(cyclopropylmethyl)-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (91 mg, 316 mol) using a method similar to that described for Example 36. The crude product was purified by column chromatography in EtOH {20-100%: EtOAc:EtOH (3:1): 0.2% NH3OH} to give the title compound as an off-white residue (137 mg, 94% yield). LCMS m / z = 435.3 (M+H). + . 1 H NMR (chloroform-d,400MHz)δ(ppm)7.00(s,1H),4.30(d,2H,J=7.5Hz),4.00(s,4H),3.93(td,2H,J=3.8,11.5Hz),3.34(dt,2H,J=2.3,11. 4Hz),3.25(s,4H),2.1-2.2(m,1H),1.6-1.6(m,2H),1.45(tquin,1H,J=4.9,7.7Hz),1.2-1.3(m,2H),0.6-0.6(m,2H),0.5-0.5(m,2H).

[0251] Example 66: 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of tert-butyl 1,6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] Tetrahydropyran-4-carbaldehyde (2.06 g, 18.09 mmol) was added to a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate; oxalic acid (4 g, 8.22 mmol); and TEA (2.50 g, 24.66 mmol, 3.44 mL) in MeOH (60 mL). Acetic acid (493.67 mg, 8.22 mmol, 470.61 μL) was added at 0 °C for 30 min until the pH reached 5–6. Sodium cyanoborohydride (2.58 g, 41.11 mmol) was added, and the mixture was stirred at 20 °C for 2 h. The mixture was filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (MeOH / DCM = 10 / 1) to give the desired compound (3.36 g, 68.94% yield) as a white oil. LCMS m / z=297.2(M+H) + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 4.07 (s, 4H), 3.97-3.93 (m, 2H), 3.79 (brs, 4H), 3.39-3.32 (m, 2H),2.68-2.64(m,2H),1.72-1.62(m,1H),1.63-1.58(m,2H),1.42(s,9H),1.33-1.27(m,2H).

[0252] Synthesis of 2,2-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of tert-butyl 6-(tetrahydropyran-4-ylmethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (350 mg, 1.18 mmol) in HFiPA (262.24 mg, 1.18 mmol, 197.17 uL) was added TFA (134.64 mg, 1.18 mmol, 90.42 uL), and the reaction mixture was stirred at 15 °C for 2 hours. LCMS indicated that the mass of the desired product was observed. The mixture was concentrated to give crude 2-(tetrahydropyran-4-ylmethyl)-2,6-diazaspiro[3.3]heptane (420 mg, crude, TFA) as a colorless oil. LCMS m / z = 197.2 (M+H). + . 1 H NMR(Chloroform-d,400MHz)δ(ppm)4.52(s,4H),4.34(s,4H),3.96-3.90(m,2H),3.44-3.36(m,2H),3 .23-3.18(m,1H),3.12(d,J=7.2Hz,2H),1.92-1.86(m,1H),1.63-1.58(m,2H),1.37-1.33(m,2H).

[0253] 3. Synthesis of 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] 2-((1-(Cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane was prepared from the hydrochloride salt of 2-(tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane and 2-(cyclopropylmethyl)-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (71 mg, 248 mol) using a method similar to that described for Example 46. The crude product was purified by column chromatography in EtOH {20-100%: EtOAc:EtOH (3:1): 0.2% NH3OH} to give the title compound as an off-white residue (69 mg, 62% yield). LCMS m / z = 449.3 (M+H). + . 1 H NMR (chloroform-d,400MHz)δ(ppm)6.99(s,1H),4.29(d,2H,J=7.5Hz),3.99(s,4H),3.9-4.0(m,2H),3.34(dt, 2H,J=2.0,11.8Hz),3.24(s,4H),2.25(d,2H,J=6.5Hz),1.4-1.6(m,4H),1.2-1.3(m,2H),0.5-0.6(m,4H).

[0254] Example 67: 2-((6-bromo-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 2-((6-Bromo-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane was prepared from 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane hydrochloride (350 mg, 1.6 mmol) and 6-bromo-2-methyl-pyridine-3-sulfonyl chloride (333.00 mg, 1.23 mmol) using a method similar to that described for Example 46. The crude product was purified by column chromatography in EtOH {0-100%: EtOAc:EtOH (3:1): 0.2% NH3OH} to give the title compound (512 mg, 70% yield). LCMS m / z = 418.0 (M+H). + . 1 H NMR (chloroform-d,500MHz)δ(ppm)7.93(d,1H,J=8.2Hz),7.40(d,1H,J=8.2Hz),3.85(s,2H),3.74(s,2H ),3.60(brd,4H,J=4.3Hz),2.74(s,3H),2.53(quin,1H,J=7.6Hz),2.1-2.3(m,6H),1.9-2.0(m,2H).

[0255] Example 68: rac-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] rac-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane was prepared from 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane hydrochloride (75 mg, 172 mol) and 2-oxaspiro[3.3]heptan-6-one (20.4 mg, 181 mol) using a method similar to that described in Example 31. The crude product was purified by column chromatography in EtOH {0-100%: EtOAc:EtOH (3:1); 0.2% NH3OH} to give the title compound (23 mg, 32% yield). LCMS m / z = 418.1 (M+H). + . 1 H NMR 1 H NMR(Chloroform-d,500MHz)δ(ppm)8.36(brd,1H,J=8.2Hz),7.65(brd,1H,J=8.2Hz),4.5-4.8(m,4H), 4.03(s,4H),3.21(s,4H),2.89(s,3H),2.81(brt,1H,J=7.0Hz),2.2-2.4(m,2H),1.9-2.0(m,2H).

[0256] Example 69: rac-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] rac-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane was prepared from 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane hydrochloride (90 mg, 207 mol) and 1-oxaspiro[3.3]heptan-6-one (24.41 mg, 217.74 umol) using a method similar to that described in Example 31. The crude product was purified by column chromatography in EtOH {0-100%: EtOAc:EtOH (3:1): 0.2% NH3OH} to give the title compound (58 mg, 67% yield). LCMS m / z = 418.1 (M+H). + . 1 H NMR(chloroform-d,500MHz)δ(ppm)8.36(brd,1H,J=7.9Hz),7.65(brd,1H,J=7.9Hz),4.4-4.6(m,2H),3.9-4.1(m, 4H),3.58(brd,1H,J=6.7Hz),3.2-3.3(m,4H),2.90(s,3H),2.5-2.7(m,2H),2.2-2.4(m,2H),2.0-2.1(m,2H).

[0257] Examples 70 and 71: 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4s,6s)-1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane and 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4r,6r)-1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] rac-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane was purified via SFC (CHIRALPAK IG 30 x 250 mm, 5 um method: 0.1% DEA and 30% EtOH in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C)) to give two cis-trans isomers: 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4s,6s)-1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane (5.8 mg, 100% ee, t R =1.56 min, LCMSm / z=418.1(M+H) + ). and 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4r,6r)-1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane (10.3 mg, 97.5% ee, t R =1.88 min, LCMSm / z=418.1(M+H) + ).

[0258] Example 72: 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of tert-butyl 1,6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] tert-Butyl 3,3-bis(bromomethyl)azetidine-1-carboxylate (350 mg, 1.02 mmol) and (4-methyltetrahydropyran-4-yl)methanamine (131.82 mg, 1.02 mmol) were dissolved in anhydrous DMF (4 mL) and stirred under nitrogen. DBU (341.71 mg, 2.24 mmol, 335.67 uL) was added and the reaction was stirred at 60 °C. The reaction was cooled to room temperature, diluted with EtOAc, and washed with water (4x). The solvent was removed in vacuo, and the crude material was purified by silica gel chromatography (EtOAc to EtOAc / EtOH (0-40%) to give the title compound (150 mg, 47% yield). LCMS m / z = 311.1 (M+H). + .

[0259] Synthesis of 2.2-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] To a flask containing tert-butyl 6-[(4-methyltetrahydropyran-4-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (900 mg, 2.90 mmol) in HFiPA (4 mL) at <5° C., TFA (1.30 g, 11.43 mmol, 875.50 uL) was carefully added dropwise. Upon complete addition of TFA, the mixture was warmed to 23° C. and monitored by LCMS. After 19 hours, the mixture was concentrated under reduced pressure to give a dark yellow residue, which was triturated with ethanol and the solvent removed to give an off-white solid. No further purification was performed. LCMS m / z=211.1 (M+H). +

[0260] 3. Synthesis of 2-((6-bromo-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] To a vial containing 2-[(4-methyltetrahydropyran-4-yl)methyl]-2,6-diazaspiro[3.3]heptane (128 mg, 395.88 μmol, trifluoroacetate) in anhydrous dichloromethane (2 mL) was added Hunig's base (321.63 mg, 2.49 mmol, 433.47 μL). After 5 minutes, 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (98.42 mg, 395.88 μmol) was carefully added to the solution. Upon complete addition of the sulfonyl chloride, the reaction was stirred at room temperature and monitored by LCMS. After 3 hours, the reaction was carefully quenched with water. The solution was extracted three times with dichloromethane. The organic extracts were pooled and then washed with NaHCO3 (saturated aqueous solution) and water. The crude material was purified by column chromatography in EtOH {0-100%: EtOAc:EtOH (3:1): 0.2% NH3OH} to give the title compound (78 mg, 47% yield). LCMS m / z = 423.1 (M+H). + . 1 H NMR(chloroform-d,500MHz)δ(ppm)6.99(s,1H),4.14(s,3H),3.99(s,4H),3.6-3.7(m,2H),3.5-3 .6(m,2H),3.31(s,4H),2.22(s,2H),1.4-1.5(m,2H),1.19(brd,2H,J=13.4Hz),0.93(s,3H).

[0261] Example 73: 2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] 1. Synthesis of (6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanone [ka] A mixture of 2-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane (200 mg, 622.44 μmol) and T3P (594.14 mg, 933.65 μmol, 555.79 μL, 50% purity) and DIPEA (402.22 mg, 3.11 mmol, 542.07 μL) in DMF (2 mL) was heated at 80 °C for 10 min. 1-Methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (106.18 mg, 746.92 μmol) in DMF (2 mL) was added at 80 °C, and the reaction was stirred for 3 h. The reaction mixture was diluted with DCM (5 mL) and washed with saturated aqueous NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The solvent was removed and the crude material was purified by silica gel chromatography (12 g SiO, 50-100% EtOH:EtOAC 1:3 in heptane) to give the title compound (270 mg, 97% yield). LCMS m / z=446.0 (M+H). + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 8.37 (brd, 1H, J = 8.2 Hz), 7.67 (brd, 1 H, J = 7.9 Hz), 4.32 (brs,2H),4.1-4.2(m,6H),3.87(s,2H),2.8-2.9(m,3H),1.8-2.0(m,4H),1.44(s,3H).

[0262] Synthesis of 2,2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] (1-Methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-[2-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptan-6-yl]methanone (270 mg, 606.12 mmol) was dissolved in THF (1 mL). 1 M borane-THF (2.4 mL, 2.4 mmol) was added dropwise, and the solution was heated to 50 °C overnight. The reaction was cooled to room temperature and quenched with 5 mL of MeOH. The reaction was reheated to 50 °C and stirred overnight. The reaction was cooled to room temperature, and the solvent was removed in vacuo. The crude product was purified by column chromatography eluting with {0-100% EtOAc:EtOH (3:1):0.2% NH3OH} in EtOH to give the title compound (68 mg, 26%). LCMS m / z=432.0(M+H) + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 8.36 (brd, 1H, J = 7.9Hz), 7.65 (brd, 1H, J = 8.2Hz), 4.04 (s,4H),3.61(s,2H),3.33(s,4H),2.90(s,3H),2.70(s,2H),1.50(s,4H),1.40(s,3H).

[0263] Example 74: 2-((1-methyl-2-oxabicyclo[3.1.1]heptan-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] 1. Synthesis of (6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-methyl-2-oxabicyclo[3.1.1]heptan-5-yl)methanone [ka] A mixture of 2-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane (200 mg, 622.44 μmol) and T3P (594.14 mg, 933.65 μmol, 555.79 μL, 50% purity) and DIPEA (402.22 mg, 3.11 mmol, 542.07 μL) in DMF (2 mL) was heated at 80 °C for 10 min. A solution of 1-methyl-2-oxabicyclo[3.1.1]heptane-5-carboxylic acid (116.65 mg, 746.92 μmol) in DMF (2 mL) was added, and the reaction was stirred at 80 °C for 4 h. The reaction mixture was diluted with DCM (5 mL) and washed with saturated aqueous NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The solvent was removed and the crude material was purified by silica gel chromatography (12 g SiO, 50-100% EtOH:EtOAC 1:3 in heptane) to give the title compound (195 mg, 68% yield). LCMS m / z=446.1 (M+H). + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 8.37 (brd, 1H, J = 7.9Hz), 7.67 (brd, 1H, J = 8.2Hz), 4.30 (brs,2H),4.1-4.2(m,8H),2.90(s,3H),2.1-2.2(m,4H),2.0-2.1(m,2H),1.24(s,3H).

[0264] Synthesis of 2,2-((1-methyl-2-oxabicyclo[3.1.1]heptan-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] (1-Methyl-2-oxabicyclo[3.1.1]heptan-5-yl)-[2-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptan-6-yl]methanone (180 mg, 391.75 μmol) was dissolved in THF (1 mL). Borane:tetrahydrofuran (1 M, 1.57 mL) was added dropwise, and the solution was heated to 50 °C overnight. The reaction was cooled to room temperature and quenched with 5 mL of MeOH. The reaction was again heated to 50 °C and stirred overnight. The reaction was cooled to room temperature, and the solvent was removed. The crude product was purified by column chromatography using {0-100% EtOAc:EtOH (3:1) with 0.2% NH3OH} in EtOH to give the title compound (130 mg, 74%). LCMS m / z=446.1 (M+H) + . 1 H NMR (chloroform-d,500MHz)δ(ppm)8.36(brd,1H,J=8.2Hz),7.65(d,1H,J=7.9Hz),3.9-4.1(m,6H),3.29(s,4H),2.90( s,3H),2.33(s,2H),1.87(brt,2H,J=6.7Hz),1.82(brdd,2H,J=2.0,7.2Hz),1.55(brd,2H,J=7.9Hz),1.21(s,3H).

[0265] Example 75: 4-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol [ka] To a mixture of 2-[[6-(1,1-difluoroethyl)-2-methyl-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane (150 mg, 472.66 μmol, hydrochloride salt) and 1,6-dioxaspiro[2.5]octane (80.93 mg, 708.99 μmol) in EtOH (4 mL) was added Hunig's base (122.17 mg, 945.32 μmol, 164.65 μL). The mixture was heated at 55°C for 30 minutes and then allowed to stand at room temperature overnight. The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic phase was further washed with water and concentrated. The residue was purified by column chromatography (12 g, 3 / 1 50-100% EtOAc / EtOH in heptane) to give the title compound (200 mg, 98% yield). LCMS m / z=432.3 (M+H) + . 1 H NMR(500MHz,chloroform-d)δ(ppm)8.21(d,J=8.24Hz,1H),7.54(d,J=8.24Hz,1H),3.94(s,4H),3.60-3.71(m,4H),3 .38(s,4H),2.78(s,3H),2.31(s,2H),1.94(brt,J=18.77Hz,3H),1.39-1.50(m,2H),1.28(brd,J=12.82Hz,2H).

[0266] Example 76: 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of 1,4-(6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)tetrahydro-2H-pyran-4-carbonitrile [ka] 4-Hydroxytetrahydropyran-4-carbonitrile (90.14 mg, 709.00 μmol) and 2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]sulfonyl-2,6-diazaspiro[3.3]heptane (220 mg, 709.00 μmol) were dissolved in ethanol (3 mL) in a sealed tube and heated to 65° C. Heating was continued for 4 hours. The reaction was cooled to room temperature and stirred overnight. The solvent was removed in vacuo, and the crude material was purified by column chromatography (0-100% EtOAc in heptane) to give the desired compound (220 mg, 74%). LCMS m / z=420.1 (M+H). + . 1 H NMR(chloroform-d,500MHz)δ(ppm)7.03(s,1H),4.15(s,3H),4.05(s,4H),3.90(brd,2H,J =12.2Hz),3.5-3.7(m,2H),3.42(brs,4H),1.77(brd,2H,J=13.1Hz),1.4-1.6(m,2H).

[0267] Synthesis of 2.2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 4-[2-[2-Methyl-5-(trifluoromethyl)pyrazol-3-yl]sulfonyl-2,6-diazaspiro[3.3]heptan-6-yl]tetrahydropyran-4-carbonitrile (200 mg, 476.85 μmol) was dissolved in THF (5 mL) and cooled to 0 °C. Methylmagnesium bromide (1.4 M, 1.36 mL) was added dropwise and the reaction was stirred. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of NaHCO₃ and extracted with EtOAc. The organics were combined and the solvent removed in vacuo. The crude material was purified by column chromatography {0-100%: EtOAc:EtOH (3:1) with 0.2% NH₃OH} in EtOH. LCMS m / z = 409.1 (M+H). + .1 H NMR(chloroform-d,500MHz)δ(ppm)6.9-7.1(m,1H),4.15(s,3H),4.01(s,4H),3.7-3.9( m,2H),3.5-3.6(m,2H),3.24(s,4H),1.3-1.5(m,2H),1.2-1.3(m,2H),0.93(s,3H).

[0268] Example 77: 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of 1,4-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)tetrahydro-2H-pyran-4-carbonitrile [ka] 4-Hydroxytetrahydropyran-4-carbonitrile (49.46 mg, 389.02 μmol) and 2-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane (125 mg, 389.02 μmol) were dissolved in ethanol (3 mL) in a sealed tube and heated to 65° C. Heating was continued for 4 hours. The reaction was cooled to room temperature and stirred overnight. The solvent was removed in vacuo, and the crude material was purified by column chromatography (0-100% EtOAc in heptane) to give the desired compound (220 mg, 74%). LCMS m / z=431.0 (M+H). + . 1H NMR (chloroform-d,500MHz)δ(ppm)8.37(brd,1H,J=7.9Hz),7.66(brd,1H,J=7.9Hz),4.09(s,3H),4.0-4.0(m,1H),3.91 (brd,2H,J=12.2Hz),3.60(brt,2H,J=10.2Hz),3.46(s,4H),2.91(s,3H),1.78(brd,2H,J=13.4Hz),1.5-1.6(m,2H).

[0269] Synthesis of 2.2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 4-[2-[2-Methyl-5-(trifluoromethyl)-3-pyridyl]sulfonyl-2,6-diazaspiro[3.3]heptan-6-yl]tetrahydropyran-4-carbonitrile (185 mg, 429.79 μmol) was dissolved in THF (5 mL) and cooled to 0 °C. Methylmagnesium bromide (1.4 M, 1.23 mL) was added dropwise and the reaction was stirred. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of NaHCO₃ and extracted with EtOAc. The organics were combined and the solvent removed in vacuo. The crude material was purified by column chromatography {0-100%: EtOAc:EtOH (3:1) with 0.2% NH₃OH} in EtOH to give the target compound (108 mg, 59%). LCMS m / z = 420.0 (M+H). + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 8.37 (brd, 1H, J = 7.9Hz), 7.66 (brd, 1H, J = 7.9Hz), 4.05 (s, 4H), 3.7-3 .8(m,2H),3.4-3.7(m,2H),3.29(s,4H),2.91(s,3H),1.3-1.5(m,2H),1.2-1.3(m,2H),0.94(s,3H).

[0270] Example 78: 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of 1,3-bromo-6-(1,1-difluoroethyl)-2,3-dimethylpyridine [ka] To a solution of 1-(5-bromo-6-methylpyridin-2-yl)ethan-1-one (4 g, 15.94 mmol) in toluene (100 mL) was added n-BuLi (2.5 M, 6.50 mL) at -78 °C under a nitrogen atmosphere. After stirring for 1 h, DMA (8.38 g, 47.82 mmol, 4.5 mL) was added, and the mixture was stirred at -78 °C for 1 h and slowly warmed to 20 °C. The reaction was then quenched with saturated aqueous ammonium chloride, followed by extraction and liquid separation. The extract was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 8 / 1) to give the title compound (2.6 g, 12.15 mmol, 76.19% yield) as a white solid. LCMS m / z = 216.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)7.93(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),2.73(s,3H),2.70(s,3H).

[0271] Synthesis of 2.3-(benzylthio)-6-(1,1-difluoroethyl)-2-methylpyridine [ka] To a solution of 3-bromo-6-(1,1-difluoroethyl)-2,3-dimethylpyridine (1.9 g, 8.05 mmol) in dioxane (20 mL) was added DIEA (3.12 g, 24.15 mmol, 4.21 mL), Pd(tBuP) (411.34 mg, 804.89 μmol), and BnSH (2.43 g, 19.56 mmol, 2.30 mL). The mixture was then stirred at 100 °C under N for 16 h. The mixture was quenched with H O (100 mL). The reaction mixture was extracted with DCM (50 mL × 5), and the combined organic layers were washed with brine (50 mL), dried over Na SO , filtered, and concentrated to give the title compound (3 g, crude) as a yellow oil. LCMS m / z = 280.1 [M+H]. 1 H NMR(500MHz,CDCl3)δ(ppm)7.47(d,J=8.0Hz,1H),7.31(d,J=8.5Hz,1H),7.27-7.17(m,5H),4.08(s,2H),2.51(s,3H),1.93(t,J=19.0Hz,3H).

[0272] 3. Synthesis of 6-(1,1-difluoroethyl)-2-methylpyridine-3-sulfonyl chloride [ka] To a solution of 3-(benzylthio)-6-(1,1-difluoroethyl)-2-methylpyridine (1 g, 3.58 mmol) in DCM (10 mL) and water (2 mL) at 0 °C was added SO2Cl2 (3.38 g, 25.06 mmol, 2.03 mL). The mixture was stirred under N2 at 0 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 5). The combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired compound (550 mg, crude) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ(ppm)8.44(d,J=8.4Hz,1H),7.74(d,J=8.0Hz,1H),3.05(s,3H),2.05(t,J=18.4Hz,3H).

[0273] 4. Synthesis of tert-butyl 6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (500 mg, 1.75 mmol, oxalate salt) in DCM (10 mL) was added DIPEA (677.17 mg, 5.24 mmol, 912.63 μL) and 6-(1,1-difluoroethyl)-2-methylpyridine-3-sulfonyl chloride (535.84 mg, 2.10 mmol) at 0 °C. The mixture was stirred at 20 °C for 14 h. Water (50 mL) was added and extracted with DCM (50 mL × 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (30% to 50% EtOAc in petroleum ether) to give the desired compound (720 mg, 1.72 mmol, 98.75% yield) as a white solid. LCMS m / z=418.1 (M+H) + . 1 H NMR(400MHz,MeOD)δ(ppm)8.37(d,J=8.4Hz,1H),7.70(d,J=8.0Hz,1H),4.06(s,4H),4.03(s,4H),2.84(s,3H),2.04-1.94(m,3H),1.41(s,9H).

[0274] 5. Synthesis of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of tert-butyl 6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (700 mg, 1.68 mol) in HFIP (15.96 g, 94.98 mmol, 10 mL) was added TFA (573.55 mg, 5.03 mmol, 385.19 μL) at 20° C. The mixture was stirred at 20° C. for 3 hours. The mixture was concentrated to give the desired compound (700 mg, crude, TFA) as a yellow oil. LCMS m / z=318.1 (M+H) + . 1 H NMR(400MHz,MeOD)δ(ppm)8.37(d,J=8.0Hz,1H),7.71(d,J=8.4Hz,1H),4.24(s,4H),4.15(s,4H),2.84(s,3H),1.99(t,J=18.8Hz,3H).

[0275] 6. Synthesis of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (200 mg, 464.72 μmol, TFA) and 2-oxaspiro[3.3]heptan-6-one (78.16 mg, 697.08 μmol) in MeOH (5 mL) was added TEA (141.07 mg, 1.39 mmol, 194.32 μL) to pH=8. The solution was stirred at 20°C for 20 min and then adjusted to pH=6 using acetic acid. Stirring was continued at 20°C for 30 min. NaBHCN (146.02 mg, 2.32 mmol) was added and the reaction mixture was stirred at 20°C for 14 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (column: C18-1 150 * 30mm *Purification by 5 μm chromatography (Conditions: Water (NH4HCO3)-ACN, 32%-62%, Flow rate (mL / min): 25) gave the title compound (53.23 mg, 128.74 μmol, 27.70% yield) as a white oil. LCMS m / z = 414.1 (M+H). + . 1 H NMR(400MHz,MeOD)δ(ppm)8.36(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),4.67-4.56(m,4H),2.80-3.98(s,4 H),3.27(s,4H),2.94-2.87(m,1H),2.83(s,3H),2.33-2.26(m,2H),2.05-1.97(m,3H),1.97-1.93(m,2H).

[0276] Examples 79-89 in the table below were prepared from the TFA salt of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl-2,6-diazaspiro[3.3]heptane (1 equivalent) and the corresponding aldehyde or ketone (SM) using a method similar to that described in step 4 for Example 78. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0277] Example 90: 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of 1,6-bromo-2-methylnicotinaldehyde [ka] 3,6-Dibromo-2-methylpyridine (2 g, 7.97 mmol) was dissolved in toluene (30 mL). The solution was cooled to -78 °C under an argon atmosphere, and n-BuLi (2.5 M, 4.78 mL) was added dropwise over 15 min. After stirring at -78 °C for 2.5 h, DMF (1.05 g, 14.35 mmol, 1.11 mL) was added dropwise. The mixture was stirred at -78 °C for 1 h and then slowly warmed to 15 °C. After stirring at 15 °C for 3 h, the reaction was quenched by the dropwise addition of NH4Cl (100 mL). The aqueous phase was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc / petroleum ether=1% to 6%) to give the desired compound (300 mg, 1.50 mmol, 18.82% yield) as a white solid. 1 H NMR(500MHz,CDCl3)δ(ppm)10.01(s,1H),7.99(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),2.77(s,3H).

[0278] Synthesis of 2,6-bromo-3-(difluoromethyl)-2-methylpyridine [ka] To a solution of 6-bromo-2-methylnicotinaldehyde (2.0 g, 10.00 mmol) in DCM (5 mL) cooled to -78 °C under a N atmosphere, DAST (4.83 g, 30.00 mmol, 3.96 mL) was added portionwise. The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched at 0 °C by adding saturated aqueous NH Cl (30 mL). The mixture was extracted with DCM (15 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired compound (1.67 g, crude) as a yellow oil. 1H NMR(400MHz,CDCl3)δ(ppm)7.95(d,J=8.0Hz,1H),7.34(d,J=8.0Hz,1H),6.56(t,J=55.2Hz,1H),2.70(s,3H).

[0279] 3. Synthesis of 6-(benzylthio)-3-(difluoromethyl)-2-methylpyridine [ka] To a solution of 6-bromo-3-(difluoromethyl)-2-methylpyridine (2.9 g, 10.45 mmol) in dioxane (40 mL) was added DIEA (4.05 g, 31.35 mmol, 5.46 mL), Pd(tBuP) (534.00 mg, 1.04 mmol), and BnSH (2.51 g, 20.21 mmol, 2.37 mL). The mixture was then stirred under N at 100 °C for 16 h. The mixture was quenched with saturated aqueous NaClO (200 mL). The reaction mixture was extracted with DCM (40 mL × 3). The combined organic phase was washed with 100 mL of brine, dried over NaSO, filtered, and concentrated to give the desired compound (4.9 g, crude) as a yellow oil. LCMS m / z = 266.1 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)7.56(d,J=8.0Hz,1H),7.36(d,J=8.0Hz,1H),7.35-7.28(m,5H),6.56(t,J=55.5Hz,1H),4.15(s,2H),2.57(s,3H).

[0280] 4. Synthesis of 5-(difluoromethyl)-6-methylpyridine-2-sulfonyl chloride [ka] To a solution of 6-(benzylthio)-3-(difluoromethyl)-2-methylpyridine (1.6 g, 6.03 mmol) in DCM (15 mL) and water (3 mL) at −10° C. was added SO2Cl2 (5.70 g, 42.21 mmol, 3.42 mL). The mixture was then stirred under N2 at −10° C. for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (25 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the desired compound (1.56 g, crude) as a yellow oil. 1 H NMR(500MHz,CDCl3)δ(ppm)8.48(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),6.65(t,J=54.8Hz,1H),3.05(s,3H).

[0281] 5. Synthesis of 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 5-(Difluoromethyl)-6-methylpyridine-2-sulfonyl chloride (294.61 mg, 1.22 mmol) was added to a solution of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (300 mg, 1.02 mmol, TFA) and DIEA (393.92 mg, 3.05 mmol, 530.89 μL) in DCM (6 mL) at 0-5°C. The mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (column: Welch Xtimate C18 150 * 25mm *Purification by 5 μm; conditions: water (NH4HCO3)-ACN; start B: 26; end B: 56; flow rate (mL / min): 25) gave the target compound (170 mg, 438.77 μmol, 43.19% yield) as a white solid. LCMS m / z = 388.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)8.33(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),6.62(t,J=55.2Hz,1H),4.03(s,4H),3.96- 3.90(m,2H),3.37-3.30(m,2H),3.28(s,4H),2.86(s,3H),2.19-2.07(m,1H),1.56-1.50(m,2H),1.33-1.23(m,2H).

[0282] Example 91: 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of tert-butyl 1,6-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] 5-(Difluoromethyl)-6-methylpyridine-2-sulfonyl chloride (380 mg, 1.57 mmol) was added to a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (260 mg, 1.31 mmol) in DCM (10 mL) and DIEA (508.46 mg, 3.93 mmol, 685.25 μL). The reaction mixture was stirred at 15 °C for 2 h. The mixture was concentrated in vacuo to give the crude product, which was purified by flash column chromatography (1% to 10% EtOAc in petroleum ether) to give the desired compound (330 mg, 817.96 μmol, 62.37% yield) as a white solid. LCMS m / z = 404.1 (M+H). + .1 H NMR(400MHz,CDCl3)δ(ppm)8.33(d,J=8.0Hz,1H),7.61(d,J=8.0Hz,1H),6.62(t,J=54.8Hz,1H),4.06(s,4H),4.03(s,4H),2.86(s,3H),1.42(s,9H).

[0283] Synthesis of 2.2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of tert-butyl 6-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (320 mg, 793.17 μmol) in HFIP (10 mL) was added TFA (2 mL) and the reaction mixture was stirred at 15° C. for 2 hours. The mixture was concentrated in vacuo to give the desired compound (400 mg, crude, TFA salt) as a colorless oil. LCMS m / z=304.1 (M+H). + . 1 H NMR(500MHz,MeOD)δ(ppm)8.41(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),6.74(t,J=55.0Hz1H),4.24(s,4H),4.16(s,4H),2.84(s,3H).

[0284] 3. Synthesis of 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (400 mg, 960.75 μmol, TFA salt) A solution of 291.65 mg and TEA (2.88 mmol, 401.73 μL) in MeOH (10 mL) was cooled to 0-5°C. 2-Oxaspiro[3.3]heptan-6-one was added portionwise. The mixture was stirred at 0-5°C for 5 min and then rapidly adjusted to pH 5-6 with HOAc at 0°C for 30 min. NaBH3CN (181.13 g, 2.88 mmol) was added, and the mixture was stirred at 20°C for 3 h. The mixture was diluted with water (15 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150 * 25mm * Purification by HPLC (5 μm; conditions: water (NH4HCO3)-ACN; start B: 27; end B: 57; flow rate (mL / min): 25) gave the target compound (88 mg, 23% yield) as a colorless oil. LCMS m / z = 400.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)8.31(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,1H),6.61(t,J=54.8Hz,1H),4.64(s,2H), 4.58(s,2H),3.99(s,4H),3.20(s,4H),2.85(s,3H),2.84-2.75(m,1H),2.29-2.21(m,2H),1.95-1.86(m,2H).

[0285] Example 92: 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] 1. Synthesis of 2-(6-bromo-2-methylpyridin-3-yl)propan-2-ol [ka] n-BuLi (2.5 M, 8.77 mL) was added dropwise to a stirred solution of 3,6-dibromo-2-methylpyridine (5 g, 19.93 mmol) in toluene (100 mL) under nitrogen at −70° C. The mixture was stirred at −70° C. for 1 h. Acetone (2.31 g, 39.85 mmol, 2.93 mL) was added dropwise, and the mixture was stirred at −70° C. for 1 h. TLC (petroleum ether / EtOAc = 3 / 1, R f =0.5), indicating the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl at 0 °C and warmed to 25 °C. The organic layer was separated and washed with saturated aqueous NaHCO3 (50 mL) and brine (30 mL). The material was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0% to 30% EtOAc in petroleum ether) to give the desired compound (3.52 g, 77% yield) as a yellow oil. 1 H NMR (500 MHz, chloroform-d) δ (ppm) 7.79 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 2.66 (s, 3H), 1.52 (s, 6H).

[0286] 2. Synthesis of 6-bromo-3-(2-fluoropropan-2-yl)-2-methylpyridine [ka] To a stirred solution of 2-(6-bromo-2-methylpyridin-3-yl)propan-2-ol (3.5 g, 15.21 mmol) in DCM (35 mL) was added DAST (9.81 g, 60.84 mmol, 8.04 mL) at −78 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO (350 mL) at −5 °C, diluted with water (30 mL), and extracted with DCM (50 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in petroleum ether) to give the desired compound (3.3 g, 93% yield) as a yellow oil. 1H NMR (500 MHz, chloroform-d) δ (ppm) 7.79 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 2.64 (s, 3H), 1.72 (s, 3H), 1.66 (s, 3H).

[0287] 3. Synthesis of 6-(benzylthio)-3-(2-fluoropropan-2-yl)-2-methylpyridine [ka] To a solution of 2-(6-bromo-2-methylpyridin-3-yl)propan-2-ol (3.3 g, 14.22 mmol) in dioxane (35 mL) was added DIPEA (5.51 g, 42.66 mmol, 7.43 mL), Pd(tBuP) (726.64 mg, 1.42 mmol), and BnSH (3.07 g, 24.72 mmol, 2.90 mL). The mixture was then stirred under N at 100 °C for 16 h. LCMS showed that a mass of the desired product was observed. The mixture was quenched with H O (130 mL). The reaction mixture was extracted with DCM (50 mL × 5). The combined organic phase was washed with brine (50 mL), dried over Na SO , filtered, and concentrated to give the desired compound (5.4 g, crude) as a yellow oil. LCMS m / z=276.1 (M+H) + . 1 H NMR (400 MHz, chloroform-d) δ (ppm) 7.47 (d, J = 8.0 Hz, 1H), 7.33-7.27 (m, 3H), 7.26-7.18 (m, 3H), 4.05 (s, 2H), 2.51 (s, 3H), 1.70-1.62 (m, 6H).

[0288] 4. Synthesis of 5-(2-fluoropropan-2-yl)-6-methylpyridine-2-sulfonyl chloride [ka] To a solution of 6-(benzylthio)-3-(2-fluoropropan-2-yl)-2-methylpyridine (1.8 g, 6.54 mmol) in DCM (10 mL) and water (2 mL) at −10° C. was added SO2Cl2 (6.18 g, 45.75 mmol, 3.71 mL). The mixture was then stirred under N2 at 25° C. for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the desired compound (900 mg, crude) as a yellow oil. 1 H NMR (500 MHz, chloroform-d) δ (ppm) 8.23 ​​(d, J = 8.0 Hz, 1H), 7.55-7.51 (m, 1H), 2.89 (s, 3H), 1.65 (s, 3H), 1.61 (s, 3H).

[0289] 5. Synthesis of tert-butyl 6-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (220 mg, 768.48 μmol, oxalate salt) and DIPEA (496.59 mg, 3.84 mmol, 669.26 μL) in DCM (10 mL) was added 5-(2-fluoropropan-2-yl)-6-methylpyridine-2-sulfonyl chloride (483.57 mg, 1.92 mmol) under N at 0° C. The mixture was stirred at 25° C. for 3 hours. LCMS showed that a mass of the desired product was observed. The mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired compound (300 mg, crude) as a yellow oil. LCMS m / z = 414.1 (M+H). + . 1H NMR (500 MHz, chloroform-d) δ (ppm) 8.19 (d, J = 8.0 Hz, 1H), 7.53-7.50 (m, 1H), 4.05-4.02 (m, 8H), 2.81 (s, 3H), 1.73 (s, 3H), 1.69 (s, 3H), 1.43 (s, 9H).

[0290] 6. Synthesis of 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] TFA (248.17 mg, 2.18 mmol, 166.67 uL) was added to a solution of tert-butyl 6-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg, 725.50 μmol) in HFIP (31.92 g, 189.95 mmol, 20 mL) under N at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed that the mass of the desired product was observed. The mixture was concentrated to give the desired compound (300 mg, crude, TFA salt) as a yellow oil. LCMS m / z = 314.1 (M+H). + . 1 H NMR(500MHz,chloroform-d)δ(ppm)8.16(d,J=8.0Hz,1H),7.52(d,J=8.5Hz,1H),4.25(s,4H),4.07(s,4H),2.78(s,3H),1.72(s,3H),1.68(s,3H).

[0291] 7. Synthesis of 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] A solution of 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (300 mg, 703.56 μmol, TFA salt) and 2-oxaspiro[3.3]heptan-6-one (236.66 mg, 2.11 mmol) in MeOH (5 mL) was adjusted to pH=6 using acetic acid. Stirring was continued at 25° C. for 1 h. NaBH3CN (221.06 mg, 3.52 mmol) was added and the reaction mixture was stirred at 25° C. for 6 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Boston Prime C18 150 * 30mm * 5 μm], conditions: water (NH3.H2O + NH4HCO3)-ACN, start B: 43; end B: 73; flow rate (mL / min): 25) to give the title compound (90 mg, 31% yield) as a white solid. LCMS m / z = 410.2 (M+H). + . 1 H NMR(500MHz,DMSO-d6)δ(ppm)8.25-8.19(m,1H),7.58(d,J=8.0Hz,1H),4.54-4.37(m,4H),3.90-3.89(m,4H),3. 32-3.30(m,1H),3.09-3.06(m,4H),2.73(s,3H),2.16-2.09(m,2H),1.85-1.77(m,2H),1.68(s,3H),1.64(s,3H).

[0292] Example 93: 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (100 mg, 457.20 μmol, HCl salt) in DCM (5 mL) under N2 at 0 °C, DIPEA (295.44 mg, 2.29 mmol, 398.17 μL) and 5-(2-fluoropropan-2-yl)-6-methylpyridine-2-sulfonyl chloride (287.7 mg, 1.14 mmol) were added. The mixture was stirred at 25 °C for 4 h. LCMS showed that the mass of the desired product was observed. The mixture was quenched with water (5 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Boston Prime C18150 * 30mm * Conditions: water (NH3.H2O + NH4HCO3)-ACN; Start B: 40; End B: 70; Rate: 25 mL / min) to give the title compound (43 mg, 23.66% yield) as a white solid. LCMS m / z = 398.1 (M+H). + . 1 H NMR(500MHz,chloroform-d)δ(ppm)8.18(d,J=8.0Hz,1H),7.50(d,J=7.5Hz,1H),4.00(s,4H),3.97-3.91(m,2H),3.37-3.3 1(m,2H),3.28(s,4H),2.81(s,3H),2.19-2.07(m,1H),1.72(s,3H),1.68(s,3H),1.61-1.57(m,2H),1.36-1.23(m,2H).

[0293] Example 94: 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of 1,6-(difluoromethoxy)-2-methyl-3-nitropyridine [ka] To a solution of 6-methyl-5-nitropyridin-2(1H)-one (5 g, 32.44 mmol) in CH3CN (150 mL) was added NaH (2.60 g, 64.88 mmol, 60% purity) at 0 °C. After stirring at 15 °C for 30 min, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (8.67 g, 48.66 mmol, 5.03 mL) was added to the mixture and stirred at 15 °C for 1 h. The mixture was diluted with water (100 mL × 2) and extracted with EtOAc (150 mL × 2). The combined phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel with petroleum ether and ethyl acetate (0% to 9% EtOAc in petroleum ether) to give the desired compound (3.1 g, 47% yield) as a yellow oil. LCMS m / z = 205.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)8.41(d,J=8.8Hz,1H),7.55(t,J=72.0Hz,1H),6.88(d,J=8.8Hz,1H),2.83(s,3H).

[0294] Synthesis of 2.6-(difluoromethoxy)-2-methylpyridin-3-amine [ka] To a solution of 6-(difluoromethoxy)-2-methyl-3-nitropyridine (1 g, 4.90 mmol) under N2 at 25 °C was added Pd / C (1.00 g, 939.67 μmol, 10% purity). The mixture was purged with H2 several times and stirred under H2 (15 psi) at 95 °C for 16 h. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel with petroleum ether and ethyl acetate (0% to 50% EtOAc in petroleum ether) to give the desired compound (300 mg, 35% yield) as a yellow oil. LCMS m / z = 175.2 (M+H). + . 1H NMR(400MHz,CDCl3)δ(ppm)7.32(t,J=74.0Hz,1H),7.13(s,1H),7.00(d,J=8.4Hz,1H),6.61(d,J=8.4Hz,1H),2.32(s,3H).

[0295] 3. Synthesis of 6-(difluoromethoxy)-2-methylpyridine-3-sulfonyl chloride [ka] SOCl2 (2 mL) was added to water (10 mL) over 10 min while maintaining the temperature at 0–7 °C. The solution was stirred at 15 °C for 16 h. CuCl (3.41 mg, 34.45 μmol) was added and cooled to −3 °C. In a separate flask, a solution of 6-(difluoromethoxy)-2-methylpyridin-3-amine (300 mg, 1.72 mmol) in 12 M HCl (1.44 mL) was added dropwise to a solution of NaNO2 (130.74 mg, 1.89 mmol) in water (2 mL) at −5 °C, maintaining the temperature at −5–0 °C. Upon completion of the addition, this solution was then added to the pre-cooled thionyl chloride solution and stirred at −2 °C for 0.5 h and then at 0 °C for 2 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the desired compound (300 mg, crude) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ(ppm)8.34(d,J=8.4Hz,1H),7.56(t,J=72.0Hz,1H),6.92(d,J=8.8Hz,1H),2.93(s,3H).

[0296] 4. Synthesis of 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg, 508.00 μmol, TFA salt) and DIPEA (196.97 mg, 1.52 mmol, 265.45 μL) in DCM (3 mL) was added 6-(difluoromethoxy)-2-methylpyridine-3-sulfonyl chloride (143.97 mg, 558.80 μmol) in DCM (1 mL) at 0° C. for 5 min. The mixture was then stirred at 20° C. for 2 h. The mixture was diluted with water (50 mL) and extracted with DCM (60 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was purified by preparative HPLC (column: Welch Xtimate: C18 150 * 25mm * Purification by 5 μm; conditions: water (NH4HCO3)-ACN, starting B: 24%, ending B: 54%, flow rate (mL / min): 25) gave the title compound (62.2 mg, 30% yield) as a yellow oil. LCMS m / z = 404.1 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm)8.27(d,J=8.4Hz,1H),7.65(t,J=72.0Hz,1H),6.96(d,J=8.4Hz,1H),3.94(s,4H),3.93-3.88(m,2 H),3.38-3.36(m,1H),3.35-3.33(m,1H),3.33(s,4H),2.75(s,3H),2.28-2.22(m,1H),1.68-1.63(m,2H),1.27-1.16(m,2H).

[0297] Example 95: 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of tert-butyl 1,6-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 1.01 mmol) and DIPEA (391.13 mg, 3.03 mmol, 527.13 μL) in DCM (3 mL) was added 6-(difluoromethoxy)-2-methylpyridine-3-sulfonyl chloride (285.89 mg, 1.11 mmol) in DCM (1 mL) at 0 °C for 5 minutes. The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with water (100 mL) and extracted with DCM (40 mL × 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue that was purified by silica gel column chromatography to give the desired compound (220 mg, 52% yield) as a white solid. LCMS m / z = 420.1 (M+H). + . 1 H NMR(500MHz,CD3OD)δ(ppm)8.26(d,J=8.5Hz,1H),7.64(t,J=72.5Hz,1H),6.96(d,J=8.5Hz,1H),4.01(s,4H),4.00(s,4H),2.75(s,3H),1.41(s,9H).

[0298] Synthesis of 2.2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] TFA (2.98 g, 26.12 mmol, 2 mL) was added to a solution of tert-butyl 6-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 476.82 μmol) in HFIP (10 mL). The mixture was stirred at 25° C. for 2 hours. The residue was concentrated in vacuo to give the desired compound (200 mg, crude, TFA salt) as a yellow oil. LCMS m / z=320.1 (M+H). + . 1H NMR(500MHz,CDCl3)δ(ppm)8.19(d,J=9.0Hz,1H),7.53(t,J=72.0Hz,1H),6.84(d,J=8.5Hz,1H),4.33(brs,4H),4.11(s,4H),2.73(s,3H).

[0299] 3. Synthesis of 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] A solution of 2,6-diazaspiro[3.3]heptane (200 mg, 462.60 μmol, TFA salt) and 2-oxaspiro[3.3]heptan-6-one (155.61 mg, 1.39 mmol) in DCM (3 mL) was stirred under N at 20 °C for 1 h. NaBHCN (145.35 mg, 2.31 mmol) was added, and the mixture was stirred under N at 20 °C for an additional 2 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate: C18 150 * 25mm * Purification by 5 μm; conditions: water (NH4HCO3)-ACN; starting B: 33%; ending B: 63%; flow rate (mL / min): 25) gave the title compound (23.12 mg, 12% yield) as a yellow oil. LCMS m / z = 416.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.23(d,J=8.8Hz,1H),7.78(t,J=72.0Hz,1H),7.12(d,J=8.8Hz,1H),4.48(s,2H) ,4.42(s,2H),3.86(s,4H),3.07(s,4H),2.80-2.71(m,1H),2.68(s,3H),2.15-2.08(m,2H),1.84-1.77(m,2H).

[0300] Example 96: 2-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of 1,3-(difluoromethyl)-1-methyl-1H-pyrazole [ka] DAST (30.74 g, 190.71 mmol, 25.20 mL) was added dropwise to a solution of 1-methyl-1H-pyrazole-3-carbaldehyde (7 g, 63.57 mmol) in DCM (100 mL) at −20° C., and the reaction mixture was stirred at 15° C. for 2 h. The mixture was quenched with saturated NaHCO (40 mL) and extracted with DCM (30 mL × 2). The combined organic phase was washed with brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-(difluoromethyl)-1-methyl-1H-pyrazole (6.5 g, crude) as a brown oil. 1 H NMR(400MHz,CDCl3)δ(ppm)7.38(d,J=2.0Hz,1H),6.67(t,J=55.2Hz,1H),6.48-6.42(m,1H),3.92(s,3H).

[0301] Synthesis of lithium 2,3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfinate [ka] To a solution of 3-(difluoromethyl)-1-methyl-1H-pyrazole (3 g, 22.71 mmol) in THF (60 mL) at −50° C. under nitrogen, n-BuLi (2.5 M, 14.53 mL) was added dropwise over 10 min. The mixture was stirred at −50° C. for 1 h. Excess SO gas was bubbled into the THF (10 mL) solution for 10 min, which was then added to the above solution at −50° C. The resulting mixture was warmed to 15° C. and stirred for 2 h. TLC (petroleum ether / EtOAc = 3 / 1) showed the formation of one new spot. The mixture was concentrated to give the desired compound (4.5 g, crude) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ(ppm)6.87(t,J=55.2Hz,1H),6.29(s,1H),3.91(s,3H).

[0302] 3. Synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfonyl chloride [ka] To a solution of lithium 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfinate (4.5 g, 22.27 mmol) in DCM (35 mL) and water (35 mL) at 0°C under nitrogen, NCS (4.46 g, 33.40 mmol) was added, and the mixture was stirred at 0-5°C for 1 h. TLC (petroleum ether / EtOAc = 3 / 1) showed the formation of a new spot. The mixture was diluted with water (10 mL) and extracted with DCM (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (0% to 10% EtOAc in petroleum ether) to give the desired compound (1.26 g, 24% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ(ppm)7.22(s,1H),6.69(t,J=54.4Hz,1H),4.24(s,3H).

[0303] 4. Synthesis of 2-((3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (100 mg, 548.66 μmol) and DIPEA (212.73 mg, 1.65 mmol, 286.70 μL) in DCM (4 mL) at 0-5°C, 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfonyl chloride (139.19 mg, 603.53 μmol) was added, and the mixture was stirred at 15°C for 1 hour. The mixture was concentrated in vacuo and purified by preparative HPLC (column: Welch Xtimate C18 150 * 30mm * Purification by 5 μm, conditions: water (10 m MNH4HCO3)-ACN, 22%-52%, flow rate (mL / min): 25) gave the title compound (24.89 mg, 12% yield) as a yellow oil. LCMS m / z = 377.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)6.95(s,1H),6.66(t,J=54.8Hz,1H),4.10(s,3H),3.99(s,4H),3.95-3. 89(m,2H),3.36-3.29(m,2H),3.25(s,4H),2.22-2.06(m,1H),1.63-1.53(m,2H),1.34-1.22(m,2H).

[0304] Example 97: 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of 1,3-methoxy-1-methyl-1H-pyrazole [ka] To a solution of 1-methyl-1H-pyrazol-3-ol (8.0 g, 81.55 mmol) in THF (200 mL) was added NaH (4.89 g, 122.32 mmol, 60% purity) at 0 °C. After 30 min, MeI (28.94 g, 203.87 mmol, 12.69 mL) was added, and the mixture was stirred at 25 °C under N for 16 h. TLC showed that a new spot was detected. The mixture was quenched with HO (20 mL) and extracted with DCM (80 mL × 2). The combined organic phase was washed with brine (40 mL × 1), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (10% to 30% EtOAc in petroleum ether) to give the desired compound (2.5 g, 27% yield) as a colorless oil. 1 H NMR(500MHz, CDCl3), δ(ppm):7.11(d,J=2.5Hz,1H),5.59(s,1H),3.86(s,3H),3.72(s,3H).

[0305] Synthesis of lithium 2,3-methoxy-1-methyl-1H-pyrazole-5-sulfinate [ka] To a solution of 3-methoxy-1-methyl-1H-pyrazole (500 mg, 4.46 mmol) in THF (10 mL) was added n-BuLi (2.5 M, 2.85 mL) dropwise over 5 minutes at −65° C., and the reaction mixture was stirred under N at 0° C. for 1 hour. SO was bubbled into THF (10 mL) at −20° C. for 10 minutes and then slowly added to the solution over 10 minutes. The resulting mixture was stirred at −65° C. for 1 hour and then at 25° C. for 1 hour. The mixture was concentrated in vacuo, and the residue was triturated with petroleum ether (100 mL) and then filtered. The filter cake was collected and dried in vacuo to give the desired compound (1 g, crude) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ(ppm)5.44(s,1H),3.70(s,3H),3.67(s,3H).

[0306] 3. Synthesis of 3-methoxy-1-methyl-1H-pyrazole-5-sulfonyl chloride [ka] Lithium 3-methoxy-1-methyl-1H-pyrazole-5-sulfinate (1.1 g, 6.04 mmol) was dissolved in DCM (10 mL) and water (12 mL). NCS (1.29 g, 9.66 mmol) was added portionwise and stirred vigorously. The reaction mixture was stirred at 5° C. for an additional 30 minutes. LCMS showed the reaction was complete. The reaction mixture was diluted with water (30 mL). The mixture was extracted with DCM (30 mL×3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired compound (1.0 g, crude) as a yellow oil. LCMS m / z=211.0 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)6.37(s,1H),4.05(s,3H),3.90(s,3H).

[0307] 4. Synthesis of tert-butyl 6-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of 3-methoxy-1-methyl-1H-pyrazole-5-sulfonyl chloride (847.12 mg, 4.27 mmol) and DIEA (1.66 g, 12.82 mmol, 2.23 mL) in DCM (10 mL) was added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (900 mg, 4.27 mmol) at 0-5°C. The reaction mixture was stirred at 15°C for 2 hours and then diluted with water (15 mL). The reaction mixture was extracted with DCM (15 mL x 3). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (15% to 50% EtOAc in petroleum ether) to give the desired compound (1.1 g, 69% yield) as a white solid.1 H NMR(400MHz,CDCl3)δ(ppm)6.14(s,1H),3.98(s,4H),3.97(s,4H),3.94(s,3H),3.89(s,3H),1.41(s,9H).

[0308] 5. Synthesis of 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] TFA (2.98 g, 26.12 mmol, 2 mL) was added to a solution of tert-butyl 6-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.1 g, 2.95 mmol) in HFIP (10 mL), and the reaction mixture was stirred at 15° C. for 2 hours. The mixture was concentrated in vacuo to give the desired compound (1.2 mg, crude, TFA salt) as a colorless oil. LCMS m / z=273.1 (M+H). + . 1 H NMR(500MHz,MeOD)δ(ppm)6.25(s,1H),4.19(s,4H),4.07(s,4H),3.93(s,3H),3.87(s,3H).

[0309] 6. Synthesis of 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Tetrahydro-4H-pyran-4-one (374.13 mg, 3.74 mmol, 345.14 μL) was added to a solution of 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl-2,6-diazaspiro[3.3]heptane (1.2 g, 3.11 mmol, TFA) and TEA (945.36 mg, 9.34 mmol, 1.30 mL) in MeOH (12 mL), and acetic acid (187.01 mg, 3.11 mmol) The pH was adjusted to 5-6 by adding NaBH3CN (587.10 mg, 9.34 mmol) in one portion at 0°C, and the solution was stirred for 30 min. NaBH3CN (587.10 mg, 9.34 mmol) was added, and the mixture was stirred at 20°C for 2 h. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phase was washed with brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction mixture was analyzed by preparative HPLC (column: Welch Xtimate C18 150 * 25mm * Conditions: water (NH4HCO3)-ACN; Start B: 16; End B: 46; Flow rate (mL / min): 25) to give the title compound (1.0 g, 90% yield) as a white solid. LCMS m / z = 357.1 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)6.14(s,1H),3.94(s,3H),3.94(s,4H),3.93-3.90(m,2H),3.89(s, 3H),3.36-3.30(m,2H),3.22(s,4H),2.15-2.06(m,1H),1.59-1.54(m,2H),1.31-1.22(m,2H).

[0310] Example 98: 2-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 2-Chloro-6-methoxypyridine-3-sulfonyl chloride (98.05 mg, 405.02 μmol) was added to a solution of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (120 mg, 405.02 μmol, TFA salt) and DIPEA (157.03 mg, 1.22 mmol, 211.63 μL) in DCM (10 mL) at 0° C. The mixture was stirred at 20° C. for 1 hour. LCMS showed that the desired mass was observed. The mixture was diluted with water (35 mL) and extracted with DCM (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Welch Xtimate C18 150 * 25mm * 5 μm, Conditions: water (NH4HCO3)-ACN, Flow rate (mL / min): 25) to give the title compound as a white solid (79 mg, 50% yield). LCMS m / z=388.1 (M+H) + . 1 H NMR(400MHz,CDCl3)δ(ppm)8.14(d,J=8.4Hz,1H),6.73(d,J=8.4Hz,1H),4.10(s,4H),4.01(s,3H),3.9 6-3.91(m,2H),3.37-3.31(m,2H),3.27(s,4H),2.16-2.09(m,1H),1.59-1.57(m,2H)1.33-1.23(m,2H).

[0311] Example 99: 2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 2-((5-Chloro-2-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane was prepared from 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (120 mg, 405.02 μmol, TFA salt) and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (98.05 mg, 405.02 μmol) using a method similar to that described for Example 98. The crude product was purified by preparative HPLC (Welch Xtimate C18 150 * 25mm * 5 μm, Conditions: water (NH 4 HCO 3 )-ACN, Flow rate (mL / min): 25) to give the title compound as a white solid (62 mg, Yield 39.47%). LCMS m / z=388.1(M+H) + . 1 H NMR(400MHz,CDCl3)δ(ppm)8.26(d,J=2.8Hz,1H),8.10(d,J=2.8Hz,1H),4.13(s,4H),4.06(s,3H),3.96-3 .93(m,2H),3.37-3.33(m,2H),3.31-3.28(m,4H),2.18-2.13(m,1H),1.61-1.57(m,2H),1.31-1.29(m,2H).

[0312] Example 100: 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 1. Synthesis of 2,4-dimethyl-6-(trifluoromethyl)pyridin-3-amine [ka] Methylboronic acid (467.80 mg, 7.81 mmol) was added to a solution of 2,4-dibromo-6-(trifluoromethyl)pyridin-3-amine (500 mg, 1.56 mmol) in dioxane (10 mL) and water (1 mL). KCO (864.07 mg, 6.25 mmol) and Pd(dppf)Cl.DCM (114.36 mg, 156.30 mmol) were added under N at 25 °C. The mixture was stirred at 100 °C for 16 h under N. LCMS showed that the mass of the desired product was observed. The mixture was filtered, diluted with water (20 mL), and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0% to 70% EtOAc in petroleum ether) to give the desired compound (240 mg, 603.79 μmol, 91.89% yield) as a yellow oil. LCMS m / z = 191.1 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)7.27(s,1H),3.87(brs,2H),2.48(s,3H),2.23(s,3H).

[0313] 2. Synthesis of 2,4-dimethyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride [ka] While maintaining the temperature between 0 and 7°C, SOCl2 (0.5 mL) was added to water (3 mL), and the solution was then stirred at 25°C for 16 hours. CuCl (1.04 mg, 10.52 μmol) was added, and the solution was cooled to -3°C. In a separate flask, 2,4-dimethyl-6-(trifluoromethyl)pyridin-3-amine (100 mg, 525.86 μmol) in 12 M HCl (625.00 μL) was added dropwise to a solution of NaNO2 (38.10 mg, 552.15 μmol) in water (0.25 mL) at -5°C, while maintaining the temperature between -5 and 0°C. Upon completion of the addition, this solution was then added to the pre-cooled thionyl chloride solution and stirred at -2°C for 10 minutes, then at 0°C for 2 hours. TLC (DCM / MeOH = 9 / 1, R f =0.9) showed that one new spot was observed. The mixture was extracted with DCM (10 mL × 4). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired compound (60 mg, crude) as a yellow oil. 1 H NMR(500MHz,CDCl3)δ(ppm)7.57(s,1H),3.08(s,3H),2.89(s,3H).

[0314] 3. Synthesis of 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 2,4-Dimethyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride was added to a solution of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (50 mg, 274.33 umol) and DIPEA (141.82 mg, 1.10 mmol, 191.13 uL) in DCM (4 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 3 h. LCMS showed that the mass of the desired product was observed. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 * 25mm * Purification by 5 μm; conditions: water (NH4HCO3)-ACN; start B: 35; end B: 65; flow rate: 25 mL / min) gave the target compound (13 mg, 11% yield) as a yellow solid. LCMS m / z = 420.2 (M+H). + . 1 H NMR(500MHz,chloroform-d)δ(ppm)7.45(s,1H),4.05(s,4H),3.95(brd,J=11.0Hz,2H),3.39-3.27 (m,6H),2.93(s,3H),2.74(s,3H),2.14(brs,1H),1.61(brd,J=12.5Hz,2H),1.33-1.26(m,2H).

[0315] Example 101: 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of tert-butyl 1,6-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] 2,4-Dimethyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (125.61 mg, 458.99 μmol) in DCM (1 mL) was added to a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (70 mg, 353.07 μmol) and DIPEA (182.52 mg, 1.41 mmol, 245.99 μL) under N at 0°C. The mixture was stirred at 25°C for 3 hours. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired compound (140 mg, crude) as a yellow oil. LCMS m / z = 436.2 (M+H). + . 1 H NMR (400 MHz, chloroform-d) δ (ppm) 7.45 (s, 1H), 4.07 (s, 4H), 4.05 (s, 4H), 2.91 (s, 3H), 2.73 (s, 3H), 1.42 (s, 9H).

[0316] Synthesis of 2,2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] TFA (78.55 mg, 688.93 μmol, 52.76 μL) was added to a solution of tert-butyl 6-((2,4-dimethyl-6-(trifluoromethyl)ylidin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (120 mg, 275.57 μmol) in HFIP (57.46 g, 341.92 mmol, 36 mL). The mixture was stirred at 25° C. for 3 hours. The mixture was neutralized with DIPEA and concentrated to give the desired compound (110 mg, crude) as a yellow oil. LCMS m / z=336.1 (M+H). + . 1 H NMR (400 MHz, chloroform-d) δ (ppm) 7.45 (s, 1H), 4.11 (s, 4H), 4.08 (s, 4H), 2.90 (s, 3H), 2.71 (s, 3H).

[0317] 3. Synthesis of 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-azaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-oxaspiro[3.3]heptan-6-one (90 mg, 268.38 μmol) and 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (180.55 mg, 1.61 mmol) in DCM (5 mL) was added NaBHCN (284.40 mg, 1.34 mmol). The reaction was stirred at 25 °C for 16 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (column: Boston Prime C18 150 * 30mm * Purification by 5 μm chromatography (Conditions: water (NH3.H2O + NH4HCO3)-ACN, 37%-67%, Flow rate (mL / min): 25) gave the title compound (12.20 mg, 10% yield) as a white oil. LCMS m / z = 432.1 (M+H). + . 1 H NMR(400MHz,MeOD)δ(ppm)7.67(s,1H),4.66(s,2H),4.58(s,2H),4.01(s,4H),3.30(s, 4H),2.97-2.90(m,1H),2.87(s,3H),2.73(s,3H),2.34-2.27(m,2H),2.00-1.94(m,2H).

[0318] Example 102: 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] 2-((2,4-Dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane was prepared from 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (50 mg, 111.52 μmol, TFA salt) and tetrahydro-2H-pyran-4-carbaldehyde (25.46 mg, 223.04 μmol) using a similar method as described for Step 3 of Example 101. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150 * 30mm * Conditions: water (10 mM NH4HCO3)-ACN; Start B: 38; End B: 68; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (mL / min): 25; Detection wavelength: 220 nm) to give the title compound (39 mg, 80% yield) as a white solid. LCMS m / z = 434.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)7.44(s,1H),4.03(s,4H),3.96-3.91(m,2H),3.38-3.29(m, 6H),2.91(s,3H),2.72(s,3H),2.28-2.25(m,2H),1.58-1.55(m,3H),1.29-1.21(m,2H).

[0319] Example 103: rac-2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-((tetrahydrofuran-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] rac-2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-((tetrahydrofuran-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane was prepared from 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (50 mg, 111.52 μmol, TFA salt) and tetrahydrofuran-3-carbaldehyde (22.33 mg, 223.04 μmol) using a similar method as described for Step 3 of Example 101. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150 * 30mm * Purification by 5 μm; Conditions: water (10 mM NH4HCO3)-ACN; Start B: 35; End B: 65; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (mL / min): 25; Detection wavelength: 220 nm gave the target compound (35 mg, 75% yield) as a white solid. LCMS m / z = 420.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)7.44(s,1H),4.03(s,4H),3.84-3.79(m,2H),3.73-3.70(m,1H),3.42-3.39(m,1H),3. 30(s,4H),2.91(s,3H),2.73(s,3H),2.40-2.37(m,2H),2.17-2.15(m,1H),1.99-1.96(m,1H),1.53-1.49(m,1H).

[0320] Example 104: 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-(oxetan-3-ylmethyl)-2-azaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] 2-((2,4-Dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-(oxetan-3-ylmethyl)-2-azaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane was prepared from 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (150 mg, 333.80 μmol, TFA salt) and oxetane-3-carbaldehyde (57.47 mg, 667.60 μmol)) using a method similar to that described in Step 3 of Example 101. The crude product was purified by preparative HPLC (Phenomenex C18 150 * 40mm * 5 μm, Conditions: water (NH3·H2O+NH4HCO3)-ACN, 20%-50%, Flow rate (mL / min): 60) to give the title compound (46 mg, 34% yield) as a white solid. LCMS m / z=406.1 (M+H) + . 1 H NMR(400MHz,CDCl3)δ(ppm)7.44(s,1H),4.76-4.72(m,2H),4.35(t,J=6.0Hz,2H),4.0 1(s,4H),3.28(s,4H),2.96-2.92(m,1H),2.91(s,3H),2.72(s,3H),2.70-2.68(m,2H).

[0321] Example 105: 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 1. Synthesis of 6-chloro-2-(trifluoromethyl)pyridine-3-sulfonyl chloride [ka] While maintaining the temperature between 0 and 7 °C, SOCl2 (5 mL) was added to water (25 mL) over 10 min, and the solution was stirred at 15 °C for 14 h. CuCl (9.07 mg, 91.58 μmol) was added, and the temperature was maintained at -3 °C. In a separate flask, a solution of 6-methyl-2-(trifluoromethyl)pyridin-3-amine (900 mg, 4.58 mmol) in HCl (12 M, 3.36 mL) at -5 °C was added with NaN while maintaining the temperature between -5 °C and 0 °C. O2 To a solution of 338.03 mg (4.90 mmol) of thionyl chloride in 2 mL of water was added dropwise. Upon completion of the addition, this solution was then added to the pre-cooled thionyl chloride solution and stirred at -3°C for 10 min, then at 0°C for 75 min. TLC (petroleum ether / EtOAc = 3 / 1, R f =0.7) indicated the reaction was complete. Water HO (50 mL) was added to the reaction, which was extracted with DCM (50 mL × 5), dried over anhydrous NaSO, filtered, and concentrated to give the desired compound (1 g, crude) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ(ppm)8.58(d,J=8.0Hz,1H),7.82(d,J=8.4Hz,1H).

[0322] Synthesis of 2.2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] A solution of 6-chloro-2-(trifluoromethyl)pyridine-3-sulfonyl chloride (210.06 mg, 750.07 μmol), 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (124.28 mg, 681.89 μmol, TFA salt), and DIEA (264.38 mg, 2.05 mmol, 356.31 μL) in DCM (5 mL) was stirred at 0° C. for 1 h. The mixture was concentrated to give the desired compound (250 mg, crude) as a yellow oil. LCMS m / z=426.1 (M+H). +

[0323] Synthesis of 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (100 mg, 234.82 μmol) in dioxane (5 mL) and water (0.5 mL) under N was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (147.39 mg, 1.17 mmol, 164.13 μL), KCO (97.36 mg, 704.47 μmol), and PEPPSI-IPr catalyst (32.01 mg, 46.96 μmol). The mixture was stirred at 100 °C for 3 h. The reaction was filtered and concentrated. The residue was purified by preparative HPLC (column: Boston Prime C18 150 * 30mm * 5 μm, Conditions: water (NH3.H2O + NH4HCO3)-ACN; 37%-67%, Flow rate: 25 mL / min) to give the title compound (44.80 mg, 47% yield) as a white solid. LCMS m / z = 406.1 (M+H). + . 1 H NMR(400MHz,MeOD)δ(ppm)8.38(d,J=8.4Hz,1H),7.68(d,J=8.0Hz,1H),4.04(s,4H),3.93-3.88(m,2H) ,3.38-3.34(m,2H),3.33(s,4H),2.67(s,3H),2.30-2.22(m,1H),1.68-1.63(m,2H),1.27-1.16(m,2H).

[0324] Example 106: 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of tert-butyl 1,6-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] A solution of 6-chloro-2-(trifluoromethyl)pyridine-3-sulfonyl chloride (621.52 mg, 2.22 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (400 mg, 2.02 mmol), and DIPEA (782.24 mg, 6.05 mmol, 1.05 mL) in DCM (10 mL) was stirred at 0 °C for 1 h. Water (50 mL) was added, and the mixture was extracted with DCM (50 mL × 3). The organic layer was washed with brine (30 mL), dried over Na SO , filtered, and concentrated. The crude product was purified by column chromatography (30% to 50% EtOAc in petroleum ether) to give the desired compound (800 mg, 1.81 mmol, 90% yield) as a white solid. LCMS m / z = 486.1 (Mt-Bu + H). + .

[0325] Synthesis of 2,2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of tert-butyl 6-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (800 mg, 1.81 mmol) in HFIP (10 mL) was added TFA (619.32 mg, 5.43 mmol, 415.93 μL) at 20° C. The mixture was stirred at 20° C. for 14 hours. The mixture was concentrated to give the desired compound (800 mg, crude, TFA salt) as a yellow oil. LCMS m / z=342.1 (M+H). + . 1H NMR(400MHz,MeOD)δ(ppm)8.51(d,J=8.8Hz,1H),7.91(d,J=8.4Hz,1H),4.25-4.22(m,8H).

[0326] 3. Synthesis of 2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (800 mg, 1.76 mmol, TFA salt) and tetrahydro-2H-pyran-4-carbaldehyde (301.20 mg, 2.64 mmol) in MeOH (10 mL) at 20 °C, TEA (178.01 mg, 1.76 mmol, 245.20 μL) was added, and the mixture was stirred at 20 °C for 20 min, then adjusted to pH = 6 using acetic acid. Stirring was continued at 20 °C for 30 min. NaBHCN (552.76 mg, 8.80 mmol) was added at 20 °C, and the mixture was stirred at 20 °C for 14 h. The mixture was concentrated and purified by column chromatography (30% to 50% EtOAc in petroleum ether) to give the title compound (350 mg, 54% yield) as a clear oil. LCMS m / z=440.1 (M+H). + . 1 H NMR(400MHz,MeOD)δ(ppm)8.50(d,J=8.4Hz,1H),7.91(d,J=8.8Hz,1H),4.19(s,3H),3.98(s,3H),3.92(dd,J=11.6Hz,3. 6Hz,2H),3.43-3.35(m,2H),3.25-3.18(m,3H),2.82(d,J=7.2Hz,2H),1.98(s,1H),1.82-1.72(m,1H),1.61-1.56(m,2H).

[0327] 1. Synthesis of 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane (100 mg, 227.34 μmol) in dioxane (5 mL) and water (0.5 mL) under N was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (142.69 mg, 1.14 mmol, 158.90 μL), KCO (94.26 mg, 682.01 μmol), and PEPPSI-IPr catalyst (30.98 mg, 45.47 μmol). The mixture was stirred at 100 °C for 3 h. The reaction was filtered and concentrated. The residue was purified by preparative HPLC (column: Boston Prime C18 150 * 30mm * Purification by LCMS m / z = 420.1 (M+H) was performed using a 5 μm column, conditions: water (NH3.H2O + NH4HCO3)-ACN; 40% to 70%, flow rate: 25 mL / min) to give the title compound (43.29 mg, 103.20 μmol, 45.40% yield) as a white solid. + .(400MHz,MeOD)δ(ppm)8.37(d,J=8.4Hz,1H),7.68(d,J=8.0Hz,1H),4.04(s,4H),3.89(dd,J=11.2Hz,4.0Hz, 2H),3.40-3.36(m,2H),3.34(s,4H),2.67(s,3H),2.32(d,J=6.4Hz,2H),1.64-1.54(m,3H),1.27-1.16(m,2H).

[0328] Example 107: 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (120 mg, 281.79 μmol) and cyclopropylboronic acid (48.41 mg, 563.58 μmol) in toluene (5 mL) and water (0.5 mL) was added Pd(dba) (25.80 mg, 28.18 μmol), SPhos (11.57 mg, 28.18 μmol), and KPO (179.45 mg, 845.36 μmol) under N. The mixture was stirred at 100 °C for 3 h. The reaction was filtered and concentrated. The residue was purified by preparative HPLC (column: Boston Prime C18 150 * 30mm * Purification by HPLC (5 μm, conditions: water (NH3.H2O + NH4HCO3)-ACN; 39%-69%, flow rate: 25 mL / min) gave the title compound (106.28 mg, 86% yield) as a clear oil. LCMS m / z = 432.1 (M+H). + . 1 H NMR(400MHz,MeOD)δ(ppm)8.30(d,J=8.4Hz,1H),7.67(d,J=8.4Hz,1H),4.02(s,4H),3.90(d,J=10.8Hz, 2H),3.38-3.32(m,6H),2.30-2.21(m,2H),1.65(d,J=11.6Hz,2H),1.26-1.18(m,2H),1.17-1.13(m,4H).

[0329] Example 108: 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane (100 mg, 227.34 μmol) and cyclopropylboronic acid (39.05 mg, 454.67 μmol) in toluene (5 mL) and water (0.5 mL) under N was added Pd(dba) (20.82 mg, 22.73 μmol), SPhos (9.33 mg, 22.73 μmol), and KPO (144.77 mg, 682.01 μmol). The mixture was stirred at 100 °C for 3 h. The reaction was filtered and concentrated. The residue was purified by preparative HPLC (column: Boston Prime C18 150 * 30mm * 5 μm; conditions: water (NH3.H2O + NH4HCO3)-ACN; 47%-77%; flow rate: 25 mL / min) and further purified by preparative HPLC (column: Welch Xtimate C18 150 * 25mm * 5 μm; Conditions: water (NH4HCO3)-ACN; 40%-70%; Flow rate: 25 mL / min) to give the title compound (22.64 mg, 17% yield) as a clear oil. LCMS m / z = 446.1 (M+H). + . 1 H NMR(400MHz,MeOD)δ(ppm)8.30(d,J=8.4Hz,1H),7.67(d,J=8.4Hz,1H),4.01(s,4H),3.89(dd,J=11.2,4.0Hz,2H),3.40-3.34(m,2H) ,3.33(s,4H),2.32(d,J=6.8Hz,2H),2.29-2.23(m,1H),1.62-1.55(m,3H),1.27-1.19(m,2H),1.18-1.16(m,1H),1.16-1.12(m,3H).

[0330] Example 109: 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 1. Synthesis of N-(2,6-bis(trifluoromethyl)pyridin-3-yl)-1,1-diphenylmethanimine [ka] To a solution of 3-bromo-2,6-bis(trifluoromethyl)pyridine (100 mg, 340.15 μmol) in toluene (3 mL) under N was added Xantphos (19.68 mg, 34.01 μmol), CsCO (332.48 mg, 1.02 mol), diphenylmethanimine (123.29 mg, 680.29 μmol, 114.16 μL), and Pd(dba) (15.57 mg, 17.01 μmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was extracted with DCM (30 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated to give the desired compound (130 mg, crude) as a yellow oil. LCMS m / z = 395.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)7.60(d,J=7.6Hz,2H),7.55-7.41(m,8H),7.00(d,J=8.4Hz,1H).

[0331] 2. Synthesis of 2,6-bis(trifluoromethyl)pyridin-3-amine [ka] A solution of N-(2,6-bis(trifluoromethyl)pyridin-3-yl)-1,1-diphenylmethanimine (130 mg, 329.69 μmol) in HCl / dioxane (2 mL) was stirred at 20° C. for 16 hours. The mixture was concentrated in vacuo to give a residue, which was purified by Combi-Flash (petroleum ether / EtOAc = 1 / 0 to 3 / 1) to give the desired compound (80 mg, 300.11 μmol, 91.03% yield) as a yellow oil. LCMS m / z = 231.1 (M+H). + . 1H NMR(400MHz,CDCl3)δ(ppm)7.61(d,J=8.4Hz,1H),7.19(d,J=8.8Hz,1H),4.57(brs,2H).

[0332] 3. Synthesis of 2,6-bis(trifluoromethyl)pyridine-3-sulfonyl chloride [ka] While maintaining the temperature between 0 and 7°C, SOCl2 (0.1 mL) was added to water (5 mL), and the solution was then stirred at 15°C for 14 h. CuCl (1 mg, 310.10 μmol) was added and cooled to -3°C. In a separate flask, a solution of 2,6-bis(trifluoromethyl)pyridin-3-amine (80 mg, 347.66 μmol) in HCl (12 M, 1 mL) at -5°C was added dropwise to a solution of NaNO2 (25.67 mg, 372.00 μmol) in water (0.5 mL) while maintaining the temperature between -5°C and 0°C. Upon completion of the addition, this solution was then added to the pre-cooled thionyl chloride solution and stirred at -2°C for 10 min, then at 0°C for 75 min. TLC (petroleum ether / EtOAc = 3 / 1, R f =0.7), the reaction was shown to be complete. The reaction was added HO (20 mL), extracted with DCM (30 mL × 5), dried over anhydrous NaSO, filtered, and concentrated to give the desired compound (80 mg, crude) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ(ppm)8.88(d,J=8.4Hz,1H),8.19(d,J=8.4Hz,1H).

[0333] 4. Synthesis of tert-butyl 6-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] A solution of 2,6-bis(trifluoromethyl)pyridine-3-sulfonyl chloride (80 mg, 255.10 μmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (50.58 mg, 255.10 μmol), and DIPEA (98.91 mg, 765.29 μmol, 133.30 μL) in DCM (2 mL) was stirred at 0 °C for 1 h. The mixture was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (0% to 30% petroleum ether in EtOAc) to give the desired compound (260 mg, 33% yield) as a yellow solid. LCMS m / z = 420.1 (Mt-Bu + H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)8.68(d,J=8.4Hz,1H),8.03(d,J=8.0Hz,1H),4.21(s,4H),4.06(s,4H),1.44(s,9H).

[0334] 5. Synthesis of 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane [ka] TFA (71.95 mg, 631.04 μmol, 48.32 μL) was added to a solution of tert-butyl 6-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 210.35 μmol) in HFIP (3 mL) at 20° C. The mixture was stirred at 20° C. for 3 hours. The mixture was concentrated to give the desired compound (100 mg, crude, TFA salt) as a yellow solid. LCMS m / z=376.1 (M+H). + . 1 H NMR(400MHz,MeOD)δ(ppm)8.80(d,J=8.0Hz,1H),8.29(d,J=8.4Hz,1H),4.27(s,4H),4.24(s,4H).

[0335] 6. Synthesis of 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (90 mg, 184.31 μmol, TFA salt) and tetrahydro-4H-pyran-4-one (36.90 mg, 368.62 μmol, 34.05 μL) in MeOH (5 mL) was added NaBHCN (34.75 mg, 552.93 μmol) at 20° C. The mixture was stirred at 20° C. for 3 hours. The mixture was concentrated and purified by preparative HPLC (column: Welch Xtimate C18 150 * 25mm * Purification by 5 μm chromatography (Conditions: water (NH4HCO3)-ACN, 32%-62%, Flow rate (mL / min): 25) gave the title compound (50.69 mg, 65% yield) as a white solid. LCMS m / z = 460.1 (M+H). + . 1 H NMR(400MHz,MeOD)δ(ppm)8.79(d,J=8.4Hz,1H),8.28(d,J=8.0Hz,1H),4.14(s,4H),3.94 -3.88(m,2H),3.38-3.34(m,6H),2.31-2.23(m,1H),1.68-1.64(m,2H),1.28-1.16(m,2H).

[0336] Examples 110 to 112 Examples 110-112 in the table below were prepared from the TFA salt of 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (1 equivalent) and the corresponding aldehyde or ketone using a method similar to that described for Example 109. [Table 11]

[0337] Example 113: 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of (2-oxaspiro[3.3]heptan-6-yl)methyl 1,4-methylbenzenesulfonate [ka] DMAP (476.59 mg, 3.90 mmol) and DIEA (1.51 g, 11.70 mmol, 2.04 mL) were added to a solution of (2-oxaspiro[3.3]heptan-6-yl)methanol (500 mg, 3.90 mmol) and TsCl (1.12 g, 5.85 mmol) in DCM (10 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with HO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, 0–50% ethyl acetate / petroleum ether gradient eluent @ 30 mL / min) to give the desired compound (590 mg, 48% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ(ppm)7.78(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),4.64(s,2H),4.52(s,2 H),3.91(d,J=6.0Hz,2H),2.45(s,3H),2.43-2.37(m,1H),2.35-2.27(m,2H),1.99-1.89(m,2H).

[0338] Synthesis of 2.2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of (2-oxaspiro[3.3]heptan-6-yl)methyl 4-methylbenzenesulfonate (100 mg, 318.75 μmol) and 2-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane (154.18 mg, 318.75 μmol, TFA salt) in CHCN (10 mL) was added KCO (220.27 mg, 1.59 mmol). The mixture was stirred at 80 °C for 12 h. LCMS indicated the reaction was complete. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 150 x 25 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%, 8 min) to give the title compound (29.3 mg, 21% yield) as a yellow solid. LCMS m / z = 432.1 (M+H). + . 1 H NMR(400MHz,MeOD)δ(ppm)8.45(d,J=8.0Hz,1H),7.83(d,J=8.0Hz,1H),4.69(s,2H),4.54(s,2H),4.02(s,4H) ),3.32(s,4H),2.86(s,3H),2.40(d,J=7.2Hz,2H),2.35-2.27(m,2H),2.15-2.01(m,1H),1.91-1.82(m,2H).

[0339] Examples 114 and 115 Examples 114 and 115 in the table below were prepared from (2-oxaspiro[3.3]heptan-6-yl)methyl 4-methylbenzenesulfonate and the corresponding 2,6-diazaspiro[3.3]heptanesulfonamide using a method similar to that described for Example 113. [Table 12]

[0340] Example 116: 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 1. Synthesis of 2-bromo-6-(difluoromethyl)pyridin-3-amine [ka] To a solution of 6-(difluoromethyl)pyridin-3-amine (550 mg, 3.82 mmol) in ACN (20 mL) was added NBS (679 mg, 3.82 mmol) at 0 °C. The mixture was stirred under nitrogen at 0 °C for 20 minutes, and then the reaction mixture was concentrated in vacuo. The crude product was purified by flash column (10% to 30% ethyl acetate in petroleum ether) to give 2-bromo-6-(difluoromethyl)pyridin-3-amine (760 mg, 89%) as a white solid. 1 H NMR(500MHz, CDCl3)δ=7.40(d,J=8.0Hz,1H),7.07(d,J=8.5Hz,1H),6.52(t,J=55.5Hz,1H),4.38(brs,2H).

[0341] Synthesis of 2.2-cyclopropyl-6-(difluoromethyl)pyridin-3-amine [ka] To a solution of 2-bromo-6-(difluoromethyl)pyridin-3-amine (730 mg, 3.27 mmol) and cyclopropylboronic acid (562 mg, 6.55 mmol) in toluene (30 mL) and water (2 mL) at 20 °C, S-Phos (134 mg, 327 μmol), KPO (2.08 g, 9.82 mmol), and Pd(dba) (300 mg, 327 μmol) were added. The mixture was stirred at 100 °C under nitrogen for 3 h. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by flash column (10% to 20% ethyl acetate in petroleum ether) to give 2-cyclopropyl-6-(difluoromethyl)pyridin-3-amine (350 mg, 58%) as a red oil, which was used without further purification. LCMS m / z = 185.1 (M+H). + .

[0342] 3. Synthesis of 2-cyclopropyl-6-(difluoromethyl)pyridine-3-sulfonyl chloride. [ka] Thionyl chloride (1 mL, 13.7 mmol) was slowly added to water (2 mL) at 0°C over 10 minutes. The temperature was maintained between 0 and 5°C during the water addition. After the water addition, the solution was warmed to 15°C, and then copper chloride (13 mg, 135 μmol) was added. The solution was cooled back to 0°C. A solution of sodium nitrite (100 mg, 1.45 mmol) in water (2 mL) was slowly added to a solution of 2-cyclopropyl-6-(difluoromethyl)pyridin-3-amine (250 mg, 1.36 mmol) in concentrated HCl (1 mL) at 0°C. The temperature was maintained between 0 and 5°C during the addition. This mixture was slowly added to the solution prepared above, maintaining the temperature between 0 and 5°C. After the addition, the mixture was stirred for an additional 1 hour, and then the mixture was extracted three times with dichloromethane. The organic extracts were pooled, then dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil as 2-cyclopropyl-6-(difluoromethyl)pyridine-3-sulfonyl chloride, which was used without purification. 1H NMR(400MHz,CDCl3)δ(ppm)8.41(d,J=8.0Hz,1H),7.55(d,J=8.4Hz,1H),6.5 3(t,J=54.8Hz,1H),3.03-2.98(m,1H),1.41-1.39(m,2H),1.31-1.28(m,2H).

[0343] 4. Synthesis of tert-butyl 6-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (130 mg, 658 μmol) and DIPEA (0.43 mL, 2.5 mmol) in DCM (10 mL) was added 2-cyclopropyl-6-(difluoromethyl)pyridine-3-sulfonyl chloride (220 mg, 822 μmol) under nitrogen at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column (5% to 20% ethyl acetate in petroleum ether) to give tert-butyl 6-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (260 mg, 52%) as a yellow solid. LCMS m / z=430.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)8.28(d,J=8.4Hz,1H),7.47(d,J=8.4Hz,1H),6.51(t,J=55.2Hz,1H), 4.05(s,4H),4.00(s,4H),2.89-2.83(m,1H),1.42(s,9H),1.31-1.27(m,2H),1.16-1.13(m,2H).

[0344] 5. Synthesis of 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate. [ka] To a solution of tert-butyl 6-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (250 mg, 582 μmol) in HFiPA (10 mL) was added TFA (0.22 mL, 2.9 mmol) at 15° C. After 3 h, the mixture was concentrated under reduced pressure to give a yellow oil as 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate, which was used without purification. LCMS m / z=330.1 (M+H). + . 1 H NMR(400MHz,CD3OD)δ(ppm)8.36(d,J=8.0Hz,1H),7.57(d,J=8.0Hz,1H),6.64(t,J=55.2H z,1H),4.22(s,4H),4.15(s,4H),2.94-2.88(m,1H),1.28-1.24(m,2H),1.19-1.13(m,2H).

[0345] 6. Synthesis of 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] A solution of 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (130 mg, 293 μmol) and tetrahydropyran-4-one (29 mg, 293 μmol) in MeOH (10 mL) was adjusted to pH 7-8 by dropwise addition of triethylamine. After 10 min, the mixture was adjusted to pH 5-6 with acetic acid and stirred at 20 °C for 30 min. Sodium cyanoborohydride (55 mg, 880 μmol) was added to the mixture and stirred at 20 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (Welch Xtimate C18 150 * 25mm * Purification by 5 μm, conditions: water (NH4HCO3)-ACN, flow rate (mL / min): 25) gave 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (51 mg, 42%) as a pale yellow solid. LCMS m / z=414.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)8.28(d,J=8.4Hz,1H),7.47(d,J=8.0Hz,1H),6.51(t,J=54.8Hz,1H),4.02(s,4H),3.95-3.90(m,2H) ,3.36-3.30(m,2H),3.25(s,4H),2.93-2.86(m,1H),2.15-2.08(m,1H),1.60-1.56(m,2H),1.30-1.26(m,4H),1.15-1.12(m,2H).

[0346] Examples 117 and 118: 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane and 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane [ka] The title compound was prepared from 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (200 mg, 451 μmol) and 4-methoxycyclohexanone (58 mg, 451 μmol) using a method similar to step 6 of Example 116 to give the following compound: After HPLC (basic conditions), 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane (TRANS) (first peak off preparative HPLC) (48 mg, 24%). LCMS m / z=442.2 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)8.27(d,J=8.0Hz,1H),7.46(d,J=8.5Hz,1H),6.51(t,J=55.0Hz,1H),4.01(s,4H),3.32(s,3H),3.25(s,4H),3.10- 3.05(m,1H),2.92-2.86(m,1H),2.03-2.01(m,2H),1.90(brs,1H),1.74 -1.72(m,2H),1.30-1.27(m,2H),1.16-1.11(m,4H),0.99-0.97(m,2H). After HPLC (basic conditions), 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane (CIS) (second peak off preparative HPLC) (46 mg, 23%). LCMS m / z=442.1 (M+H).+ . 1 H NMR(500MHz,CDCl3)δ(ppm)8.27(d,J=8.0Hz,1H),7.46(d,J=8.5Hz,1H),6.51(t,J=55.0Hz,1H),4.00(s,4H),3.30-3.29(m,1H),3.2 6(s,3H),3.21(s,4H),2.92-2.87(m,1H),1.94(brs,1H),1.83-1.81(m,2H),1.38-1.35(m,6H),1.30-1.27(m,2H),1.15-1.12(m,2H).

[0347] Example 119: 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] The title compound was prepared from 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (1000 mg, 225 μmol) and oxaspiro[3.3]heptan-6-one (25 mg, 225 μmol) using a method similar to Step 6 of Example 116 to give 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane (48 mg, 50%) after HPLC (basic conditions). LCMS m / z=426.2 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)8.27(d,J=8.0Hz,1H),7.46(d,J=8.0Hz,1H),6.50(t,J=55.2Hz,1H),4.64(s,2H),4.58(s,2H) ,3.99(s,4H),3.19(s,4H),2.91-2.79(m,2H),2.27-2.22(m,2H),1.94-1.89(m,2H),1.30-1.25(m,2H),1.15-1.11(m,2H).

[0348] Example 120: 2-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] 1. Synthesis of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole. [ka] To a solution of 1-cyclopropylpyrazole-3-carbaldehyde (2.2 g, 16 mmol) in DCM (40 mL) was added DAST (5.3 mL, 40 mmol) at -30 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was carefully quenched with saturated NH4Cl (20 mL) at 15 °C, then diluted with HO (20 mL) and extracted with DCM (40 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (0% to 12% ethyl acetate in petroleum ether) to give 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (1.3 g, 51%) as a colorless oil. LCMS m / z = 159.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)7.47(s,1H),6.66(t,J=55.0Hz,1H),6.44(s,1H),3.61-3.60(m,1H),1.15-1.13(m,2H),1.07-1.03(m,2H).

[0349] Synthesis of 2,5-bromo-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole [ka] To a solution of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (1.3 g, 8.2 mmol) in THF (20 mL) was added butyllithium (2.5 M, 3.95 mL) at −65° C. The mixture was stirred at −65° C. for 1 hour, and then carbon tetrabromide (3.54 g, 10.7 mmol) in THF (4 mL) was added to the mixture at −65° C. and stirred for 0.5 hours. The mixture was warmed to 25° C. and stirred for 1 hour. The reaction mixture was carefully quenched with saturated NH4Cl (20 mL) at 0° C., then diluted with HO (20 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (0% to 8% ethyl acetate in petroleum ether) to give 5-bromo-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (1.6 g, 82%) as a colorless oil. LCMS m / z=238.9 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)6.57(t,J=55.2Hz,1H),6.52(s,1H),3.52-3.47(m,1H),1.24-1.20(m,2H),1.14-1.08(m,2H).

[0350] 3. Synthesis of N-(1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)-1,1-diphenylmethanimine. [ka] To a solution of 5-bromo-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (1.6 g, 6.7 mmol) and diphenylmethanimine (2.3 mL, 13.5 mmol) in dioxane (30 mL), Pd(dba) (618 mg, 675 μmol), Xantphos (781 mg, 1.35 mmol), and KCO (2.80 g, 20.2 mmol) were added and stirred at 100 °C for 16 h. The mixture was filtered. The organic phase was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column (ethyl acetate in petroleum ether 0% to 10%) to give N-(1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)-1,1-diphenylmethanimine as a yellow oil, which was used without further purification. LCMS m / z=338.1 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)7.82-7.81(m,5H),7.81-7.80(m,5H),6.43(t,J=55. 0Hz,1H),4.95(s,1H),3.99-3.95(m,1H),1.32-1.28(m,2H),1.09-1.05(m,2H).

[0351] 4. Synthesis of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-amine. [ka] To a solution of N-(1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)-1,1-diphenylmethanimine (2.2 g, 3.3 mmol) in THF (40 mL) and water (8 mL) was added HCl (2 M, 11 mL), and the mixture was stirred at 25 °C for 1 h. The reaction was quenched by dropwise addition of aqueous NaHCO (50 mL), and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column (MeOH = 0% to 8% in DCM) to give 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-amine (450 mg, 80%) as a yellow oil. LCMS m / z = 174.1 (M + H) +

[0352] 5. Synthesis of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole-5-sulfonyl chloride. [ka] Thionyl chloride (2.5 mL, 34 mmol) was added to water (5 mL) over 10 min while maintaining the temperature at 0–5°C, and the solution was then stirred at 20°C for 12 h. Copper chloride (14 mg, 144 μmol) was added, and the mixture was then cooled to −3°C. In a separate flask, a solution of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-amine (250 mg, 1.44 mmol) in 12 M HCl (3.7 mL) was added dropwise to a solution of sodium nitrite (100 mg, 1.46 mmol) in water (0.5 mL) at −5°C while maintaining the temperature at −5–0°C for 1 h. Upon completion of the addition, this solution was added to the pre-cooled thionyl chloride solution and stirred at −2°C for 10 min, then at 0°C for 75 min. The mixture was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, and concentrated to give 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole-5-sulfonyl chloride, which was used without purification. 1H NMR(400MHz,CDCl3)δ(ppm)6.55(t,J=54.8Hz,1H),6.42(s,1H),3.51-3.45(m,1H),1.25-1.20(m,2H),1.13-1.08(m,2H).

[0353] 6. Synthesis of 2-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (69 mg, 234 μmol) and DIPEA (0.1 mL, 584 μmol) in DCM (15 mL) was added 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole-5-sulfonyl chloride (100 mg, 195 μmol) in DCM (3 mL) at 0° C. The mixture was stirred at 20° C. for 1 hour. The mixture was diluted with water (30 mL) and extracted with DCM (40 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30mm * Purification by 5 μm, conditions: water (formic acid)-ACN, 8% to 38%, flow rate (mL / min): 25) gave 2-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (4 mg, 6%) as a white solid. LCMS m / z=403.1 (M+H). + . 1H NMR(500MHz,CD3OD)δ(ppm)7.05(s,1H),6.75(t,J=54.5Hz,1H),4.22-4.18(m,1H),4.12(s,4H),3.97-3.95(m,2H),3.75( s,4H),3.38-3.35(m,2H),2.75-2.72(m,1H),1.77-1.75(m,2H),1.37-1.32(m,2H),1.30-1.25(m,2H),1.15-1.11(m,2H).

[0354] Example 121: 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of 1,4-cyclopropyl-6-(trifluoromethyl)pyridin-3-amine [ka] To a solution of 4-bromo-6-(trifluoromethyl)pyridin-3-amine (1.5 g, 6.2 mmol) and cyclopropylboronic acid (1.1 g, 12 mmol) in toluene (20 mL) and water (2 mL) at 20 °C, S-Phos (255 mg, 622 μmol), Pd(dba) (570 mg, 622 μmol), and KPO (3.96 g, 18.7 mmol) were added. The mixture was stirred at 100 °C under nitrogen for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and then extracted with DCM (20 mL × 3). The combined organic phase was washed with brine (15 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column (10-50% ethyl acetate in petroleum ether) to give 4-cyclopropyl-6-(trifluoromethyl)pyridin-3-amine (900 mg, 71%) as a brown solid, which was used without further purification. LCMS m / z=203.1 (M+H). + . 1H NMR(500MHz,CDCl3)δ(ppm)8.06(s,1H),7.24(s,1H),4.25(brs,2H),1.72-1.61(m,1H),1.06-1.01(m,2H),0.70-0.66(m,2H).

[0355] 2. Synthesis of 4-cyclopropyl-6-(difluoromethyl)pyridine-3-sulfonyl chloride. [ka] Thionyl chloride (3 mL) was added to water (18 mL) over 10 min while maintaining the temperature at 0–5°C, and the solution was then stirred at 20°C for 12 h. Copper chloride (3 mg, 35 μmol) was added, and the mixture was then cooled to −3°C. In a separate flask, a solution of 4-cyclopropyl-6-(trifluoromethyl)pyridin-3-amine (350 mg, 1.73 mmol) in 12 M HCl (4.5 mL) was added dropwise to a solution of sodium nitrite (125 mg, 1.82 mmol) in water (1.5 mL) at −5°C while maintaining the temperature at −5–0°C for 1 h. Upon completion of the addition, this solution was then added to the pre-cooled thionyl chloride solution and stirred at −2°C for 10 min, then at 0°C for 75 min. The mixture was concentrated, and then water (10 mL) was added. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give 4-cyclopropyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride as a yellow oil, which was used without further purification. 1 H NMR(500MHz,CDCl3)δ(ppm)9.25(s,1H),7.28(s,1H),3.00-2.93(m,1H),1.62-1.48(m,2H),1.21-1.13(m,2H).

[0356] Synthesis of tert-butyl 3.6-((4-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of 4-cyclopropyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (380 mg, 1.33 mmol) and DIPEA (0.7 mL, 4 mmol) in DCM (10 mL) was added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (316 mg, 1.60 mmol) at 0° C. The mixture was stirred at 20° C. for 2 hours. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic phase was washed with brine (15 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give tert-butyl 6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl-2,6-diazaspiro[3.3]heptane-2-carboxylate) (370 mg, 62%) as a white solid. 1 H NMR(500MHz,CDCl3)δ(ppm)9.08(s,1H),7.12(s,1H),4.08(s,4H),4.03(s,4H),2.84-2.75(m,1H),1.42(s,9H),1.32(brs,2H),1.05-1.02(m,2H).

[0357] 4. Synthesis of 2-((4-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate. [ka] To a solution of tert-butyl 6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (120 mg, 268 μmol) in HFiPA (3 mL) was added TFA (0.5 mL, 6.5 mmol). The reaction mixture was stirred at 15° C. for 2 hours. The mixture was concentrated in vacuo to give 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate as a yellow oil, which was used without purification.1 H NMR(500MHz,CD3OD)δ(ppm)9.03(s,1H),7.37(s,1H),4.24(s,4H),4.18(s,4H),2.85-2.79(m,1H),1.41-1.36(m,2H),1.15-1.11(m,2H).

[0358] 5. Synthesis of 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (130 mg, 282 μmol) and TEA (0.12 mL, 847 μmol) in MeOH (3 mL) was added 2-oxaspiro[3.3]heptan-6-one (38 mg, 339 μmol). The pH of the mixture was adjusted to pH = 5-6 by dropwise addition of acetic acid at 0 °C. After 30 min, sodium cyanoborohydride (53 mg, 847 μmol) was added, and the mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL × 3). The combined organic phase was washed with brine (15 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 * 30mm * Purification by 10 μm; conditions: water (NH4HCO3)-ACN; start B: 31; end B: 61; flow rate (mL / min): 50) gave 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane (60 mg, 48%) as a white solid. LCMS m / z=444.1 (M+H). + . 1H NMR(500MHz,CDCl3)δ(ppm)9.07(s,1H),7.11(s,1H),4.64(s,2H),4.58(s,2H),4.02(s,4H),3.20(b rs,4H),2.88-2.73(m,2H),2.30-2.18(m,2H),1.92(brs,2H),1.42-1.32(m,2H),1.04-0.98(m,2H).

[0359] Example 122: 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] To a solution of 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (100 mg, 287 μmol) and TEA (0.12 mL, 847 μmol) in MeOH (5 mL) was added tetrahydropyran-4-carbaldehyde (33 mg, 287 μmol). The pH of the mixture was adjusted to pH=5-6 by dropwise addition of acetic acid at 0°C. After 30 min, sodium cyanoborohydride (54 mg, 863 μmol) was added, and the mixture was stirred at 20°C for 2 h. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL × 3). The combined organic phase was washed with brine (15 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (column: Welch Xtimate C18 150 * 25mm * Conditions: water (NH4HCO3)-ACN; Start B: 35; End B: 65; Flow rate (mL / min): 25) to give 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane (25 mg, 19%) as a white solid. LCMS m / z=446.1 (M+H). + . 1H NMR(500MHz,CDCl3)δ(ppm)9.08(s,1H),7.11(s,1H),4.04(s,4H),3.95-3.90(m,2H),3.37-3.30(m,2H),3.27(s,4H),2.88-2. 80(m,1H),2.26(brd,J=6.5Hz,2H),1.57(brs,1H),1.54-1.46(m,2H),1.39-1.35(m,2H),1.28-1.22(m,2H),1.04-1.00(m,2H).

[0360] Examples 123 and 124: 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol and 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol [ka] To a solution of 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (280 mg, 608 μmol) and TEA (0.25 mL, 1.8 mL) in MeOH (5 mL) was added 4-hydroxy-4-methyl-cyclohexanone (86 mg, 669 μmol). The pH of the mixture was adjusted to pH = 5-6 by dropwise addition of acetic acid at 0 °C. After 30 min, sodium cyanoborohydride (115 mg, 1.8 mmol) was added, and the mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL × 3). The combined organic phase was washed with brine (15 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 * 30mm *10 μm; Conditions: water (NH4HCO3)-ACN; Start B: 32; End B: 62; Flow rate (mL / min): 50) and preparative HPLC (column: Boston Prime C18 150 * 30mm * 5um; Conditions: water (NH3H2O ​​+ NH4HCO3)-ACN; Start B: 40; End B: 70; Flow rate (mL / min): 25) to give the following compounds: After HPLC (basic conditions), 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol (TRANS) (first peak off preparative HPLC) (22 mg, 8%). LCMS m / z=460.1 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)9.07(s,1H),7.11(s,1H),4.04(s,4H),3.29(s,4H),2.88-2.79(m,1H),2. 03(brs,1H),1.68-1.64(m,4H),1.40-1.34(m,4H),1.21(s,3H),1.20-1.12(m,2H),1.04-0.99(m,2H). After HPLC (basic conditions), 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol (CIS) (second peak off preparative HPLC) (22 mg, 8%). LCMS m / z=460.2 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)9.08(s,1H),7.11(s,1H),4.05(s,4H),3.33(s,4H),2.88-2.79(m,1H),1. 92(brs,1H),1.66-1.62(m,2H),1.57-1.47(m,2H),1.42-1.30(m,6H),1.20(s,3H),1.04-0.97(m,2H).

[0361] Example 125: 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; [ka] Synthesis of 1.6-(trifluoromethyl)-4-vinylpyridin-3-amine [ka] To a solution of 4-bromo-6-(trifluoromethyl)pyridin-3-amine (1.0 g, 4.15 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (767 mg, 4.98 mmol) in toluene (20 mL) and water (1 mL) at 20 °C, S-Phos (170 mg, 415 μmol), Pd(dba) (380 mg, 415 μmol), and KPO (2.64 g, 12.5 mmol) were added. The mixture was stirred at 100 °C under nitrogen for 3 h. The reaction mixture was cooled, then filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (0% to 20% ethyl acetate in petroleum ether) to give 6-(trifluoromethyl)-4-vinylpyridin-3-amine (650 mg, 83%) as a red oil, which was used without further purification. CML Sm / z=189.1(M+H) + . 1 H NMR(500MHz,CDCl3)δ(ppm)8.11(s,1H),7.50(s,1H),6.70-6.64(m,1H),5.85(d,J=17.0Hz,1H),5.59(d,J=11.0Hz,1H),4.11(brs,2H).

[0362] Synthesis of 2,4-ethyl-6-(trifluoromethyl)pyridin-3-amine [ka] To a solution of 6-(trifluoromethyl)-4-vinylpyridin-3-amine (650 mg, 3.45 mmol) in MeOH (10 mL) at 20° C. was added 10% Pd / C (100 mg, 95 μmol). The mixture was stirred under hydrogen (15 psi) at 20° C. for 16 hours. Nitrogen was bubbled through the reaction solution for 10 minutes, and then the reaction was filtered and concentrated in vacuo to give 4-ethyl-6-(trifluoromethyl)pyridin-3-amine as a yellow solid, which was used without purification. 1 H NMR(400MHz,CDCl3)δ(ppm)8.06(s,1H),7.36(s,1H),2.53(q,J=7.6Hz,2H),1.30(t,J=7.6Hz,3H). 3. Synthesis of 4-ethyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride [ka] Thionyl chloride (2.5 mL, 34 mmol) was added to water (5 mL) over 10 min while maintaining the temperature at 0–5 °C, and the solution was then stirred at 20 °C for 12 h. Copper chloride (22 mg, 226 μmol) was added, and the mixture was cooled to −3 °C. In a separate flask, a solution of 4-ethyl-6-(trifluoromethyl)pyridin-3-amine (430 mg, 2.26 mmol) in 12 M HCl (4 mL) was added dropwise to a solution of sodium nitrite (158 mg, 2.28 mmol) in water (2 mL) at −5 °C while maintaining the temperature at −5–0 °C for 1 h. Upon completion of the addition, this solution was added to the pre-cooled thionyl chloride solution and stirred at −2 °C for 10 min, then at 0 °C for 75 min. The mixture was extracted with DCM (30 mL × 3). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated to give 4-ethyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride as a yellow oil, which was used without purification. 1 H NMR(400MHz,CDCl3)δ(ppm)9.27(s,1H),7.80(s,1H),3.30(q,J=7.6Hz,2H),1.44(t,J=7.6Hz,3H).

[0363] Synthesis of tert-butyl 4,6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (319 mg, 1.61 mmol) and DIPEA (0.77 mL, 4.39 mmol) in DCM (20 mL) was added 4-ethyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (400 mg, 1.46 mmol) in DCM (5 mL) at 0 °C, and the mixture was stirred at 20 °C for 1 hour. The mixture was diluted with water (30 mL) and extracted with DCM (40 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column (5% to 35% ethyl acetate in petroleum ether) to give tert-butyl 6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (400 mg, 63%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ(ppm)9.11(s,1H),7.69(s,1H),4.08(s,4H),4.04(s,4H),3.09(q,J=7.6Hz,2H),1.42(s,9H),1.35(t,J=7.6Hz,3H).

[0364] 5. Synthesis of 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate. [ka] To a solution of tert-butyl 6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (400 mg, 919 μmol) in HFiPA (20 mL) was added TFA (0.35 mL, 4.59 mmol). The mixture was stirred at 20° C. for 10 hours. The mixture was concentrated in vacuo to give 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate as a yellow solid, which was used without purification. LCMS m / z=336.1 (M+H). + 6. Synthesis of 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane [ka] A solution of 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (100 mg, 222 μmol), 2-oxaspiro[3.3]heptan-6-one (25 mg, 222 μmol), and triethylamine in MeOH (10 mL) was adjusted to pH 5-6 with acetic acid. The mixture was stirred at 20°C for 0.5 h, and then sodium cyanoborohydride (42 mg, 668 μmol) was added to the mixture. The mixture was stirred at 20°C for 1 h. The mixture was diluted with aqueous NaHCO3 (15 mL) and water (20 mL), and then extracted with DCM (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex C18 150 * 40mm *Purification by 5 μm, conditions: water (NH4HCO3)-ACN, 23% to 53%, flow rate (mL / min): 60) gave 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane (39 mg, 41%) as a white solid. LCMS m / z = 432.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)9.10(s,1H),7.68(s,1H),4.64(s,2H),4.59(s,2H),4.02(s,4H),3.21(s,4H) ),3.09(q,J=7.2Hz,2H),2.84-2.78(m,1H),2.28-2.23(m,2H),1.94-1.90(m,2H),1.34(t,J=7.2Hz,3H).

[0365] Example 126: 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] A solution of 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (60 mg, 134 μmol), tetrahydropyran-4-carbaldehyde (15 mg, 134 μmol), and triethylamine in MeOH (10 mL) was adjusted to pH 5-6 with acetic acid. The mixture was stirred at 20 °C for 0.5 h, and then sodium cyanoborohydride (25 mg, 400 μmol) was added to the mixture. The mixture was stirred at 20 °C for 1 h. The mixture was diluted with aqueous NaHCO (15 mL), water (20 mL), and then extracted with DCM (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column (MeOH in DCM 0% to 8%) to give 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane (25 mg, 43%) as a white solid. LCMS m / z=434.1 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)9.11(s,1H),7.68(s,1H),4.04(s,4H),3.95-3.91(m,2H),3.37-3.29(m,6H) ,3.09(q,J=7.2Hz,2H),2.28-2.27(m,2H),1.62-1.56(m,2H),1.35(t,J=7.2Hz,3H),1.29-1.19(m,3H).

[0366] Examples 123 and 128: 4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol (TRANS) and 4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol (CIS) [ka] A solution of 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (300 mg, 668 μmol), 4-hydroxy-4-methyl-cyclohexanone (94 mg, 734 μmol), and triethylamine in MeOH (15 mL) was adjusted to pH 5-6 with acetic acid. The mixture was stirred at 20°C for 0.5 h, and then sodium cyanoborohydride (42 mg, 400 μmol) was added to the mixture. The mixture was stirred at 20°C for 1 h. The mixture was diluted with aqueous NaHCO3 (15 mL), water (20 mL), and then extracted with DCM (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex C18 150 * 40mm * 5 μm, Conditions: Water (NH4HCO3)-ACN, 25%-55%, Flow rate (mL / min): 60) to give the following compound as a white solid: After HPLC (basic conditions), 4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol (TRANS) (first peak off preparative HPLC) (43 mg, 14%). LCMS m / z=448.2 (M+H). + . 1 H NMR(400MHz,CDCl3)δ(ppm)9.11(s,1H),7.68(s,1H),4.04(s,4H),3.26(s,4H),3.10(q,J=7.6H z,2H),2.03-1.99(m,1H),1.68-1.66(m,4H),1.40-1.33(m,5H),1.22(s,3H),1.18-1.12(m,2H). After HPLC (basic conditions), 4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol (CIS) (second peak off preparative HPLC) (79 mg, 26%). LCMS m / z=448.2 (M+H). + .1 H NMR(400MHz,CDCl3)δ(ppm)9.11(s,1H),7.68(s,1H),4.04(s,4H),3.29(s,4H),3.09(q,J=7.6H z,2H),1.89-1.85(m,1H),1.69-1.63(m,4H),1.55-1.51(m,2H),1.36-1.29(m,5H),1.20(s,3H).

[0367] Example 129: 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] Synthesis of tert-butyl 1,6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a vial containing tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hydrochloride (730 mg, 3.11 mmol) in anhydrous dichloromethane (12 mL), Hunig's base (1.7 mL, 10 mmol) was carefully added dropwise at <5 °C. After 5 min, 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (922 mg, 3.55 mmol) was carefully added to the cold solution. Upon complete addition of the sulfonyl chloride, the reaction was warmed to 23 °C and monitored by LCMS. After 30 min, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate. The mixture was stirred at 23 °C for 20 min, and then the biphasic mixture was extracted three times with dichloromethane. The organic extracts were pooled and then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was applied to a silica gel column and purified (10–60% ethyl acetate in heptane). The desired fractions were pooled and concentrated under reduced pressure to give tert-butyl 6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.23 g, 94%) as a white solid, which was used without further purification. 1 H NMR(500MHz,DMSO-d6)δ(ppm)8.43(brd,J=7.9Hz,1H),7.98(brd,J=7.9Hz,1H),4.05(s,4H),3.94(brs,4H),2.81(s,3H),1.34(s,9H).

[0368] Synthesis of 2.2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate. [ka] To a flask containing tert-butyl 6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (23 g in 1, 2.92 mmol) in HFiPA (20 mL) at <5° C., TFA (0.67 mL, 8.75 mmol) was carefully added dropwise. Upon complete addition of TFA, the mixture was warmed to 23° C. and monitored by LCMS. After 19 h, the mixture was concentrated under reduced pressure to give a dark yellow residue, which was triturated with methanol to give a white solid as 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (551 mg, 41%), which was used without purification. LCMS m / z=322.0 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ(ppm)8.51(brs,1H),8.45(brd,J=8.2Hz,1H),7.99(brd,J=8.2Hz,1H),4.14-4.08(m,8H),2.81(s,3H).

[0369] 3. Synthesis of 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane [ka] A solution of 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (100 mg, 230 μmol), 4-methyltetrahydropyran-4-carbaldehyde (35 mg, 276 μmol), and triethylamine in MeOH (10 mL) was adjusted to pH 5-6 with acetic acid. The mixture was stirred at 20°C for 0.5 h, and then sodium cyanoborohydride (43 mg, 669 μmol) was added to the mixture. The mixture was stirred at 20°C for 20 h. The mixture was diluted with aqueous NaHCO3 (15 mL), water (20 mL), and then extracted with DCM (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Welch Xtimate C18 150 * 25mm * Purification by 5 μm, conditions: water (NH4HCO3)-ACN, flow rate (mL / min): 25) gave 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (62 mg, 63%) as a white solid. LCMS m / z=434.1 (M+H). + . 1 H NMR(500MHz,CDCl3)δ(ppm)8.35(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),4.03(s,4H),3.68-3.65(m,2H),3. 59-3.56(m,2H),3.34(s,4H),2.90(s,3H),2.22(s,2H),1.59-1.44(m,2H),1.20-1.18(m,2H),0.94(s,3H).

[0370] Examples 130 to 154 Examples 130-154 in the following table were prepared from 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (1 equivalent) and an aldehyde or ketone (1.2 equivalents, unless otherwise noted) using a method similar to that described for Example 129. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8] [Table 13-9]

[0371] Examples 156 and 157: (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane and (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane [ka] rac-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane (Example 153) was purified via SFC (CHIRALPAK AD-H 30 × 250 mm, 5 μm, Method: 30% MeOH with 0.1% DEA in CO (Flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C)) to afford two enantiomers of arbitrarily assigned stereochemistry. (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane (16 mg, 99.4% ee, t R =1.20 min, LCMS m / z=434.1(M+H) + ) and (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane (17.5 mg, 97.8% ee, t R =1.36 min, LCMS m / z=434.1(M+H) + ).

[0372] Examples 158 and 159: (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane and (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane [ka] rac-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane (Example 155) was purified via SFC (LUX Cellulose-4LC, 30 × 250 mm, 5 um, Method: 30% MeOH with 0.1% DEA in CO (Flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C)) to afford two enantiomers of arbitrarily assigned stereochemistry: (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)eth...

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein X is CH ２ or O; Y is CH ２ or O; If only one of X and Y is O, q1 is 1 or 2; Y is CH ２ when Y is O, q2 is 2; p1 is 1 or 2; X is CH ２ When X is O, then p2 is 0 or 1, or when X is O, then p2 is 2; R １ is C ２～６ alkyl, Het, or -Z-Het, ２～６ Alkyl is one or more R Ａ Het is optionally substituted by one or more R ２ Optionally replaced by; Z is one or more halo or C １～３ C optionally substituted with alkoxy １～４ is alkyl; Het is C ３～６ cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, or 6- to 8-membered bicyclic heterocyclyl, each of which is R ２ Optionally replaced by; R Ａ are independent for each occurrence, OR ２ａ , S.R. ２ａ or C(O)OR ２ａ and R ２ is independent for each occurrence, C １～６ Alkyl, halo, -CN or OR ２ａ In this case, C １～６ Alkyl is one or more halo or C １～３ optionally substituted with alkoxy; R ２ａ is H, C １～６ Alkyl, or C ３～６ cycloalkyl, where C １～６ Alkyl is one or more halo or C １～３ optionally substituted with alkoxy; R ３ is C １～４ alkyl-phenyl, phenyl, 5- or 6-membered monocyclic heteroaryl, or 9-10-membered bicyclic heteroaryl, wherein the phenyl, 5- or 6-membered monocyclic heteroaryl, and 9-10-membered bicyclic heteroaryl each have one or more substituents R ４ Optionally replaced by; R ４ independently for each occurrence: halo, -OR ４ａ , -C.N., C. １～６ Alkyl, C ３～６ Cycloalkyl, C ２～６ alkenyl, phenyl, or 5- or 6-membered monocyclic heteroaryl, where C １～６ Alkyl or C ３～６ Each cycloalkyl is selected from the group consisting of one or more C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, or halo, or 5- or 6-membered monocyclic heteroaryl may have one or more C １～６ optionally substituted with alkyl; or Two R's ４ together with the intervening atoms form a 5- to 7-membered heterocyclyl; R ４ａ is H or C １～６ alkyl, where C １～６ The alkyl is optionally substituted with one or more halo; n is 1 or 2; m is 1 or 2; R ５ are independently assigned to each occurrence: H, halo, C １～３ Alkyl, or C １～３ haloalkyl; or two R ５ Together C １～３ Forming an alkylene; R ６ are independently assigned to each occurrence: H, halo, C １～３ Alkyl, or C １～３ haloalkyl; or two R ６ Let's C together １～３ Forming an alkylene; However, the compound is 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, which is not:

2. The compound has the formula (I): 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, wherein X is CH ２ or O; Y is CH ２ or O; If only one of X and Y is O, q1 is 1 or 2; Y is CH ２ when Y is O, q2 is 2; p1 is 1 or 2; X is CH ２ When X is O, then p2 is 0 or 1, or when X is O, then p2 is 2; R １ is C2 ～６ alkyl, Het, or -Z-Het, ２～６ Alkyl is one or more OR ２ａ Het is substituted by one or more R ２ Optionally replaced by; Z is C optionally substituted with one or more halo. １～４ is alkyl; Het is R ２ is a 4-6 membered monocyclic heterocyclyl or a 6-8 membered bicyclic heterocyclyl optionally substituted by R ２ is independent for each occurrence, C １～６ Alkyl, or OR ２ａ and R ２ａ is H or C １～６ alkyl, where C １～６ The alkyl is optionally substituted with one or more halo; R ３ is phenyl, a 5- or 6-membered monocyclic heteroaryl, or a 9- to 10-membered bicyclic heteroaryl, wherein the phenyl, the 5- or 6-membered monocyclic heteroaryl, and the 9- to 10-membered bicyclic heteroaryl each have one or more substituents R ４ Optionally replaced by; R ４ independently for each occurrence: halo, -OR ４ａ , -C.N., C. １～６ Alkyl, C ３～６ cycloalkyl, or 5- or 6-membered monocyclic heteroaryl, where C １～６ The alkyl is optionally substituted with one or more halo, and the 5- or 6-membered monocyclic heteroaryl is optionally substituted with one or more C １～６ optionally substituted with alkyl; or Two R's ４ together with the intervening atoms form a 5- to 7-membered heterocyclyl; R ４ａ is H or C １～６ alkyl, where C １～６ The alkyl is optionally substituted with one or more halo; n is 1 or 2; m is 1 or 2; R ５ are independently assigned to each occurrence: H, halo, C １～３ Alkyl, or C １～３ haloalkyl; or two R ５ Together C １～３ Forming an alkylene; R ６ are independently assigned to each occurrence: H, halo, C １～３ Alkyl, or C １～３ haloalkyl; or two R ６ Let's C together １～３ Forming an alkylene; However, the compound is 【Chemistry 4】 The compound of claim 1 which is not:

3. 3. The compound according to claim 1 or 2, wherein Het is a 4- to 6-membered oxygen-containing monocyclic saturated heterocyclyl, or a 6- to 8-membered oxygen-containing bicyclic saturated heterocyclyl, or a pharma- ceutically acceptable salt thereof.

4. Het is C ３～６ cycloalkyl, 4- to 6-membered oxygen-containing monocyclic saturated heterocyclyl, or 6- to 8-membered oxygen-containing bicyclic saturated heterocyclyl, each of which is selected from 1 to 3 R ２ 2. The compound of claim 1, optionally substituted by:

5. Het is cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, dioxanyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 6-oxabicyclo[3.2.1]octanyl, or 2-oxabicyclo[3.1.1]heptanyl, each of which is selected from 1 to 3 R ２ 2. The compound of claim 1, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

6. The compound has formula II: 【Chemistry 5】 The compound according to any one of claims 1 to 5, which is represented by: or a pharma- ceutically acceptable salt thereof.

7. R ３ is selected from the group consisting of phenyl, pyridyl, thiazolyl, and pyrazolyl, each of which is selected from 1 to 3 R ４ 7. The compound of any one of claims 1 to 6, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

8. R ３ is expressed by the following formula: 【Chemistry 6】 Each of the formulas shown above is represented by R ４ 8. The compound of claim 7, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

9. R ３ is of the formula: 【Chemistry 7】 9. The compound of claim 8, represented by: or a pharma- ceutically acceptable salt thereof.

10. R ４ independently for each occurrence, halo, -CN, -OR ４ａ , C １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, and C １～３ R is selected from 5- or 6-membered heteroaryl optionally substituted with alkyl; ４ａ C １～３ Alkyl or C １～３ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

11. R ４ independently for each occurrence, -CH ３ , -CF ３ , -OCHF ２ , -OCH ３ 11. The compound of any one of claims 1 to 10, wherein the aryl group is selected from -CN, -F, -Cl, isopropyl, cyclopropyl, and 4-methylpyridin-2-yl, or a pharma- ceutically acceptable salt thereof.

12. R １ But, OR ２ａ C replaced by ２～４ alkyl or of the formula: 【Chemistry 8】 Each of the formulas shown above is represented by 1 to 3 R ２ Optionally replaced by; At that time, R ２ is independent for each occurrence, C １～３ Alkyl or -OR ２ａ and R ２ａ is independently for each occurrence H or C １～３ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, which is alkyl.

13. R １ is of the formula: 【Chemistry 9】 13. The compound of claim 12, represented by: or a pharma- ceutically acceptable salt thereof.

14. R ２ independently for each occurrence, -CH ３ and —OH; R ２ａ is independently for each occurrence H or -CH ３ 14. The compound according to any one of claims 1 to 13, which is: or a pharma- ceutically acceptable salt thereof.

15. The compound has the formula (III) 【Chemistry 10】 The compound of any one of claims 1 to 14, which is represented by: or a pharma- ceutically acceptable salt thereof.

16. A compound of formula 15, R １ is the following formula: 【Chemistry 11】 Represented by: R ２ Each occurrence is independently -CH ３ and OH; R ２ａ is independently for each occurrence H or -CH ３ Selected from: R ３ is the following formula: 【Chemistry 12】 Represented by: R ４ independently for each occurrence, -CH ３ , -CF ３ , -OCHF ２ , The compound is selected from -OCH3, and -F.

17. The compound has the formula (IV): 【Chemistry 13】 The compound of any one of claims 1 to 14, which is represented by: or a pharma- ceutically acceptable salt thereof.

18. The compound has formula (IVA) or (IVB): 【Chemistry 14】 18. The compound of claim 17, which is represented by: or a pharma- ceutically acceptable salt thereof.

19. R １ is of the formula: 【Chemistry 15】 Represented by: R ２ is OH; R ３ is of the formula: 【Chemistry 16】 Represented by: R ４ independently for each occurrence, -CH ３ , -CF ３ , -OCH ３ , -OCHF ２ 19. The compound of claim 17 or 18, wherein the aryl group is selected from -CN, -isopropyl, -F, -Cl, and 4-methylpyridin-2-yl, or a pharma- ceutically acceptable salt thereof.

20. The compound has formula (V): 【Chemistry 17】 The compound of any one of claims 1 to 14, which is represented by: or a pharma- ceutically acceptable salt thereof.

21. R １ is of the formula: 【Chemistry 18】 Represented by: R ３ is of the formula: 【Chemistry 19】 Represented by: R ４ independently for each occurrence, -CH ３ 21. The compound of claim 20, wherein the aryl group is selected from: -F, -C, and cyclopropyl.

22. The compound has the formula (VI): 【Chemistry 20】 3. The compound of claim 1 or 2, which is represented by: or a pharma- ceutically acceptable salt thereof.

23. The compound has the formula VII or VIII: 【Chemistry 21】 23. The compound of claim 22, which is represented by: or a pharma- ceutically acceptable salt thereof.

24. R ３ R is 1 to 3 ４ 24. The compound of claim 22 or 23, which is phenyl optionally substituted by: or a pharma- ceutically acceptable salt thereof.

25. R ３ is of the formula: 【Chemical 22】 25. The compound of claim 24, represented by: or a pharma- ceutically acceptable salt thereof.

26. R ４ independently for each occurrence halo, CN and OR ４ａ is selected from; ４ａ C １～３ Alkyl or C １～３ 26. The compound of any one of claims 22 to 25, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

27. R ４ -OCHF for each occurrence independently ２ 27. The compound of any one of claims 22 to 26, or a pharma- ceutically acceptable salt thereof, wherein the group is selected from -F and -CN.

28. R １ But, -OR ２ａ C replaced by ２～４ alkyl, or 1 to 3 R ２ The following formulae optionally substituted by: 【Chemistry 23】 28. The compound according to any one of claims 22 to 27, represented by: or a pharma- ceutically acceptable salt thereof.

29. R １ is of the formula: 【Chemistry 24】 30. The compound of claim 28, represented by: or a pharma- ceutically acceptable salt thereof.

30. R ２ independently for each occurrence, -CH ３ and —OH; R ２ａ is independently for each occurrence H or -CH ３ 30. The compound according to any one of claims 22 to 29, or a pharma- ceutically acceptable salt thereof, selected from:

31. The compound has the formula (IX): 【Chemistry 25】 or a pharma- ceutically acceptable salt thereof, ５ is H, or two R ５ Together C １～３ Forms an alkylene; R ６ is H, or two R ６ Together C １～３ The compound according to claim 1 or 2, which forms an alkylene.

32. 32. The compound of claim 31, wherein p1 is 1 and p2 is 0; or p1 is 1 and p2 is 1; or p1 is 2 and p2 is 1, or a pharma- ceutically acceptable salt thereof.

33. R ３ is selected from the group consisting of phenyl, pyridyl, and pyrazolyl, each of which is selected from 1 to 3 R ４ 33. The compound of claim 31 or 32, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

34. R ３ But, C １～４ alkyl-phenyl, phenyl, pyridyl, thiazolyl, and pyrazolyl, each of which is selected from the group consisting of 1 to 3 R ４ 33. The compound of claim 31 or 32, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

35. R ３ is of the formula: 【Chemistry 26】 each of which is represented by 1 to 3 R ４ Optionally replaced by Or R ３ is one or two R ４ The following formula, optionally substituted by: 【Chemical 27】 34. The compound of claim 33, represented by: or a pharma- ceutically acceptable salt thereof.

36. R ３ is of the formula: 【Chemistry 28】 each of which is represented by 1 to 3 R ４ Optionally replaced by Or R ３ is 1 or 2 R ４ The following formula, optionally substituted by: 【Chemical 29】 35. The compound of claim 34, represented by: or a pharma- ceutically acceptable salt thereof.

37. R ３ is of the formula: 【Chemistry 30】 36. The compound of claim 35, represented by: or a pharma- ceutically acceptable salt thereof.

38. R ３ is of the formula: 【Chemistry 31】 37. The compound of claim 36, represented by: or a pharma- ceutically acceptable salt thereof.

39. R ４ Each occurrence is independent of halo, CN, and C. １～３ Alkyl, C １～３ Haloalkyl, C ２～４ Alkenyl, C ３～６ Cycloalkyl, phenyl, and -OR ４ａ wherein said C ３～６ Cycloalkyl is 1 to 3 halo or C １～４ Optionally substituted with haloalkyl, １～３ Alkyl is 1 or 2 C ３～４ optionally substituted by cycloalkyl; R ４ａ is C １～３ Alkyl or C １～３ 39. The compound of any one of claims 31 to 38, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

40. R ４ Each occurrence is independent of halo, CN, and C. １～３ Alkyl, C １～３ Haloalkyl, C ３～６ Cycloalkyl and -OR ４ａ - R ４ａ C １～３ Alkyl or C １～３ 39. The compound of any one of claims 31 to 38, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

41. R ４ independently for each occurrence, -CH ３ , -CH ２ CH ３ , -CF ２ CH ３ , -CF(CH ３ ) ２ , -CH=CH ２ , -CHF ２ , -CH(CH ３ ) ２ , -CF ３ , -OCH ３ , -OCHF ２ , -OCF ３ , cyclopropyl, 【Chemistry 32】 -CH ２ 41. The compound of any one of claims 31 to 40, wherein the compound is selected from -cyclopropyl, cyclobutyl, phenyl, -CN, -Cl, -Br, and -F, or a pharma- ceutically acceptable salt thereof.

42. R ４ independently for each occurrence, -CH ３ , -CHF ２ , -CF ３ , -OCH ３ , -OCHF ２ , -OCF ３ 41. The compound of any one of claims 31 to 40, wherein the aryl group is selected from -cyclopropyl, -CN, and -F, or a pharma- ceutically acceptable salt thereof.

43. R １ is expressed by the following formula: 【Chemical 33】 Each of the formulas shown above is represented by R ２ 43. The compound of any one of claims 31 to 42, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

44. R １ is expressed by the following formula: 【Chemical 34】 Each of the formulas shown above is represented by R ２ 43. The compound of any one of claims 31 to 42, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

45. R １ is expressed by the following formula: 【Chemistry 35】 44. The compound of claim 43, represented by: or a pharma- ceutically acceptable salt thereof.

46. R １ is expressed by the following formula: 【Chemical 36】 45. The compound of claim 44, represented by: or a pharma- ceutically acceptable salt thereof.

47. R ２ But -CH ３ , -F, -OCH ３ -CN, -CH ２ CH ２ OCH ３ or -OH, or a pharma- ceutically acceptable salt thereof.

48. R ２ The compound according to any one of claims 31 to 46, or a pharma- ceutically acceptable salt thereof, wherein is OH.

49. R １ R is 1 or 2 Ａ C optionally substituted by ２～６ is alkyl; R Ａ are independently applied to each occurrence, OR ２ａ , S.R. ２ａ or C(O)OR ２ａ and R ２ａ H, C １～４ Alkyl, or C ３～６ cycloalkyl, wherein said C １～４ Alkyl is 1 or 2 C １～３ 43. The compound of any one of claims 31 to 42, or a pharma- ceutically acceptable salt thereof, optionally substituted by alkoxy.

50. R １ But -CH ２ CH ３ , -CH ２ CH ２ CH ２ SCH ２ CH ３ , -CH ２ CH ２ CH ２ O-Cyclopentyl, -CH ２ CH ２ CH ２ CH ２ CH ２ OCH ３ , -CH ２ CH ２ O.C. (CH ３ ) ３ , -CH ２ CH ２ CH ２ CH (CH ３ ) OCH ３ , -CH ２ CH (CH ３ ) CH ２ CH ２ C(O)OCH ３ , -CH ２ CH ２ C (CH ３ ) ２ C(O)OCH ３ , or -CH ２ CH ２ CH ２ OCH ２ CH ２ OCH ３ 50. The compound of claim 49, which is: or a pharma- ceutically acceptable salt thereof.

51. The compound has the formula X: 【Chemical 37】 49. The compound of any one of claims 31 to 48, which is represented by: or a pharma- ceutically acceptable salt thereof.

52. R １ is of the formula: 【Chemical 38】 Represented by: R ２ is OH; R ３ is of the formula: 【Chemical Formula 39】 Represented by: R ４ Ga-CH ３ 52. The compound of claim 51, wherein:

53. The compound has formula XI: 【Chemistry 40】 49. The compound of any one of claims 31 to 48, which is represented by: or a pharma- ceutically acceptable salt thereof.

54. The compound has formula (XIA) or (XIB): 【Chemistry 41】 54. The compound of claim 53, which is represented by: or a pharma- ceutically acceptable salt thereof.

55. R １ is of the formula: 【Chemistry 42】 Represented by: R ２ is OH; R ３ is of the formula: 【Chemistry 43】 Represented by: R ４ independently for each occurrence, -CH ３ , -CF ３ , -OCH ３ , -OCHF ２ , -OCF ３ 55. The compound of claim 53 or 54, wherein the aryl group is selected from -CN, -F, and cyclopropyl.

56. The compound has formula XII: 【Chemistry 44】 51. The compound of any one of claims 31 to 50, which is represented by: or a pharma- ceutically acceptable salt thereof.

57. R １ is of the formula: 【Chemistry 45】 Represented by: R ２ is OH; R ３ is of the formula: 【Chemistry 46】 Represented by: R ４ independently for each occurrence, -CH ３ , -CHF ２ , -CF ３ , -OCH ３ , -OCHF ２ , and -OCF ３ 57. The compound of claim 56, selected from:

58. The compound has formula XII: 【Chemistry 47】 or a pharma- ceutically acceptable salt thereof, wherein R １ is Het or Z-Het; Z is CH ２ and Het has the formula: 【Chemistry 48】 Each of the formulas shown above is represented by one or two R ２ Optionally replaced by; R ２ Each occurrence is independent, C １～４ alkyl, -OH, or halo; R ３ is pyridinyl or pyrazolyl, each of which is 1 to 2 R ４ Optionally replaced by; R ４ Each occurrence of C １～４ Alkyl, or C １～４ The compound of any one of claims 31 to 48, which is haloalkyl.

59. R ３ is of the formula: 【Chemistry 49】 each of which is represented by 1 to 2 R ４ 60. The compound of claim 58, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

60. R ３ is of the formula: 【Chemistry 50】 60. The compound of claim 59, represented by: or a pharma- ceutically acceptable salt thereof.

61. R ４ independently for each occurrence, -CH ３ , -CF ３ , or -CF ２ CH ３ 61. The compound according to any one of claims 58 to 60, which is: or a pharma- ceutically acceptable salt thereof.

62. The compound has formula XIIA: 【Chemistry 51】 or a pharma- ceutically acceptable salt thereof, ４０ is C １～３ alkyl, R ４１ is C １～３ 61. The compound of claim 60 which is a haloalkyl.

63. R ４０ Ga-CH ３ and R ４１ Ga-CF ３ or -CF ２ CH ３ 63. The compound of claim 62, which is: or a pharma- ceutically acceptable salt thereof.

64. R １ is of the formula: 【Chemistry 52】 Each of the above formulas is represented by 1 to 2 R ２ 64. The compound of any one of claims 58 to 63, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

65. R １ is of the formula: 【Chemistry 53】 65. The compound of claim 64, represented by: or a pharma- ceutically acceptable salt thereof.

66. R ２ Each occurrence is independently -CH ３ , OH or -F, or a pharma- ceutically acceptable salt thereof.

67. The compound is 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((S)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (±)-(R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((S)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (±)-(R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((R)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-methylpropan-2-ol; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxy-2-methylpropyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 9-((2,4-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (S)-9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (R)-9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-6-oxa-2,9-diazaspiro[4.5]decane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane; 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane; 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((3,5-difluorophenyl)sulfonyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 4-((3,5-difluorophenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane; 7-((2,4-dimethylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane; 7-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane; 7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane; 1-((7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)tetrahydro-2H-pyran-4-ol; 7-((2,4-dimethylphenyl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonane; 8-((2-chloro-4-methylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane; 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 4-((6-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-(difluoromethyl)-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((4,6-dimethylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((4-(difluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; 6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane; (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]; 1-((1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidin-3,3'-bicyclo[3.2.1]octane]-8'-yl)-2-methylpropan-2-ol; (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]; (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]; 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((6-bromo-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-2-oxabicyclo[3.1.1]heptan-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)-1,6-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 4-((6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; (R)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-3-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methyl-3,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydrofuran-3-yl)-2,6-diazaspiro[3.3]heptane; (S)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((3-methyloxetan-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(2-fluoropropan-2-yl)-2-methyl-1,4-dihydropyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethoxy)-2-methyl-3,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((5-(difluoromethyl)-2-methyl-1H-214-pyrazol-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-methyl-2-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,6-bis(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((2-methyl-5-(trifluoromethyl)-2,5-dihydro-1H-pyrazol-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(difluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((1s,4s)-4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (1r,4r)-4-(6-((4-cyclopropyl-6-(trifluoromethyl)-2,3-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (1r,4r)-4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; (1s,4s)-4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((1R)-1-(tetrahydrofuran-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(1-(4-methyltetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(3-methyloxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2-methyltetrahydrofuran-2-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((S)-1-((S)-2-methyltetrahydrofuran-2-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((R)-1-((S)-tetrahydrofuran-2-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-2-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydrofuran-3-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((3-methyloxetan-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-(3,3-dimethyltetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((3R,5R)-3,5-dimethyltetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((3R,5S)-3,5-dimethyltetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(4,4-difluorocyclohexyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-3-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-(tetrahydro-2H-pyran-4-yl)-6-((2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((6-(2,2-difluorocyclopropyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-chloro-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-(1-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)ethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((6-methoxy-4-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-methyl-3-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole; 2-ethyl-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclopropane-1-carbonitrile; 2-(3-(2-methoxyethoxy)propyl)-6-((2-methyl-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (R)-2-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (1R,3R)-2,2-dimethyl-3-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclopropane-1-carbonitrile; 2-(((1S,2R,5S)-6-oxabicyclo[3.2.1]octan-2-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(3-(cyclopentyloxy)propyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; Methyl 2,2-dimethyl-4-(6-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)butanoate; 2-(2-cyclopropyl-2-methoxyethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(5-methoxypentyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(4-methoxypentyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((1-(2-methoxyethyl)cyclobutyl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; Methyl 4-methyl-5-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pentanoate; 2-(3-(ethylthio)propyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(2-cyclopropylethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(2-(tert-butoxy)ethyl)-6-((2-methyl-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 4-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol; 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((3-isopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(1-(trifluoromethyl)cyclopropyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (1s,4s)-4-(6-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; (1s,4s)-4-(6-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 2-((2-methyl-5-(trifluoromethyl)-2,5-dihydro-1H-pyrazol-3-yl)sulfonyl)-6-(((R)-tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-5-(trifluoromethyl)-1H-214-pyrazol-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (S)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((tetrahydro-2H-pyran-4-yl)methyl)-6-((2-(trifluoromethyl)-3,4-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-(tetrahydro-2H-pyran-4-yl)-6-((6-(trifluoromethyl)-2-vinylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane; (1r,4r)-4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; (1s,4s)-4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methylcyclohexan-1-ol; 2-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; 2-((3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2,4-bis(trifluoromethyl)phenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane; 2-((6-chloro-2-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-fluoro-4-(trifluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; (R)-2-((1,4-dioxan-2-yl)methyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; (R)-2-((1,4-dioxan-2-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane; 2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((2-fluoro-4-(trifluoromethoxy)phenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; (1s,4s)-1-methyl-4-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)cyclohexan-1-ol; (1s,4s)-1-methyl-4-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)cyclohexan-1-ol; 2-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((4-(difluoromethoxy)-2,6-difluorophenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((4-(difluoromethoxy)-2-fluorophenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-((4-(difluoromethoxy)-2-fluorophenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile; and 2-((tetrahydro-2H-pyran-4-yl)methyl)-6-((6-(trifluoromethyl)-2,3-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2. The compound of claim 1, selected from:

68. 68. A pharmaceutical composition comprising a compound according to any one of claims 1 to 67, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

69. A method for treating a disease mediated by emopamil binding protein, comprising administering to a subject an effective amount of a compound described in any one of claims 1 to 67 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in claim 68.

70. 69. A method of 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 67, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 68.

71. 71. The method of claim 70, wherein the autoimmune disease is multiple sclerosis.

72. 72. The method of claim 71, wherein said compound or pharmaceutical composition repairs myelin sheath or forms new myelin sheath in said subject.

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