Emopamil binding protein inhibitors and uses thereof

Abstract

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, which is useful for inhibiting EBP and treating a variety of EBP-mediated conditions or diseases, such as multiple sclerosis. # imgabs0 #

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 314,095, filed on February 25, 2022. The entire contents of the aforementioned application are expressly incorporated herein by reference. Technical Field

[0003] The present disclosure relates to emopamil-binding protein (EBP) and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, their use in treating diseases, their use in combination with a pharmaceutically acceptable carrier for manufacturing pharmaceutical preparations, the use of these pharmaceutical preparations in treating diseases, and methods for treating diseases, which methods comprise administering an EBP inhibitor to warm-blooded animals, particularly humans. Background Art

[0004] Emopamil binding protein (EBP) is a Δ8-Δ7 sterol isomerase that isomerizes double bonds in sterol molecules, moving the double bonds from the 8-9 position to the 7-8 position. Specifically, EBP converts zymostenol to 7-lathosterol or dehydrogenated 7-lathosterol during cholesterol biosynthesis (Silve et al., 1996, J Biol Chem. 271 (37), 22434-22440). It has been shown that the accumulation of 8-9 unsaturated sterols activates oligodendritic cell formation and remyelination (Hubler et al., 2019, Nature 560 (7718), 372-376).

[0005] Myelin is a lipid-based molecule that forms a protective layer (myelin sheath) around the axons of nerve cells and isolates the axons. Demyelination disease or myelin-related diseases are the result of these myelin sheaths being damaged, degenerated or reduced in thickness. The loss of myelin destroys the electronic signals from the brain and can lead to nerve damage, loss of vision, 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 decomposes its own myelin sheath. The ability to repair and regenerate myelin is the key to treating these myelin-related diseases. Because EBP has the function of converting 8-9 sterols, its inhibition is a potential target for activating myelin regeneration because its inhibition leads to an increase in these 8-9 sterol starting materials (Theodoropoulous et al., 2020, J.Am.Chem.Soc., 142, (13), 6128-6138).

[0006] In addition to its role in myelin regeneration, 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).

[0007] Therefore, there is a need for EBP inhibitors as potential therapeutic agents for treating diseases or conditions responsive to EBP inhibition. Summary of the Invention

[0008] The present disclosure provides compounds that are EBP inhibitors. In a first aspect, the present disclosure relates to compounds having Formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein:

[0011] X is CH2 or O;

[0012] Y is CH2 or O;

[0013] The premise is that only one of X and Y is O;

[0014] q1 is 1 or 2;

[0015] When Y is CH2, q2 is 0 or 1, or when Y is O, q2 is 2;

[0016] p1 is 1 or 2;

[0017] When X is CH2, p2 is 0 or 1, or when X is O, p2 is 2;

[0018] R 1 C 2-6 Alkyl, Het or -Z-Het, where C 2-6 The alkyl group is optionally substituted with one or more R A and Het is optionally substituted with one or more R 2 replace;

[0019] Z is optionally substituted with one or more halogen or C 1-3 Alkoxy-substituted C 1-4 alkyl;

[0020] Het is C 3-6 Cycloalkyl, 4 to 6 membered monocyclic heterocyclyl, or 6 to 8 membered bicyclic heterocyclyl, each of which is optionally substituted by R 2 replace;

[0021] R A OR independently at each occurrence 2aSR 2a or C(O)OR 2a ;

[0022] R 2 C independently at each occurrence 1-6 Alkyl, halo, -CN or OR 2a , where C 1-6 The alkyl group is optionally substituted with one or more halogen or C 1-3 Alkoxy substitution;

[0023] R 2a H, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein C 1-6 The alkyl group is optionally substituted with one or more halogen or C 1-3 Alkoxy substitution;

[0024] R 3 C 1-4 Alkyl-phenyl, phenyl, 5- or 6-membered monocyclic heteroaryl, or 9- to 10-membered bicyclic heteroaryl, wherein phenyl, 5- or 6-membered monocyclic heteroaryl and 9- to 10-membered bicyclic heteroaryl are each optionally substituted by one or more substituents R 4 replace;

[0025] R 4 is independently at 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 group is optionally substituted with one or more C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 substituted by cycloalkyl or halogen, and wherein the 5- or 6-membered monocyclic heteroaryl is optionally substituted by one or more C 1-6 Alkyl substitution; or

[0026] Two R's 4 Together with the atoms in between, they form a 5- to 7-membered heterocyclic group;

[0027] R 4a H or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halo groups;

[0028] n is 1 or 2;

[0029] m is 1 or 2;

[0030] R 5is independently H, halo, C 1-3 Alkyl or C 1-3 haloalkyl; or two R 5 Together they form C 1-3 alkylene;

[0031] R 6 is independently H, halo, C 1-3 Alkyl or C 1-3 haloalkyl; or two R 6 Together they form C 1-3 alkylene;

[0032] Provided that the compound is not:

[0033]

[0034] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

[0035] In another aspect, the present disclosure provides a method for treating a disease or condition responsive to inhibition of EBP in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating multiple sclerosis. In some embodiments, the present disclosure provides a method for promoting myelination in a subject suffering from a myelin-related disorder.

[0036] 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 treating a disease or condition responsive to inhibition of EBP. Also provided are compounds described herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition responsive to inhibition of EBP. Detailed Description of the Invention

[0038] The present disclosure provides compounds and pharmaceutical compositions thereof that are useful for treating diseases or disorders that mediate EBP function / activity, such as multiple sclerosis or other myelin-related disorders.In some embodiments, the compounds of the present disclosure are EBP inhibitors.

[0039] Compounds and compositions

[0040] In a first embodiment, the present disclosure provides a compound of formula (I):

[0041]

[0042] or a pharmaceutically acceptable salt thereof; wherein the variables in formula (I) are as defined above in the first embodiment. In another embodiment, for compounds of formula (I):

[0043] X is CH2 or O;

[0044] Y is CH2 or O;

[0045] The premise is that only one of X and Y is O;

[0046] q1 is 1 or 2;

[0047] When Y is CH2, q2 is 0 or 1, or when Y is O, q2 is 2;

[0048] p1 is 1 or 2;

[0049] When X is CH2, p2 is 0 or 1, or when X is O, p2 is 2;

[0050] R 1 C 2-6 Alkyl, Het or -Z-Het, where C 2-6 The alkyl group is substituted by one or more OR 2a and Het is optionally substituted with one or more R 2 replace;

[0051] Z is C optionally substituted with one or more halogen groups 1-4 alkyl;

[0052] Het is a 4- to 6-membered monocyclic heterocyclic group, or a 6- to 8-membered bicyclic heterocyclic group, each of which is optionally substituted by R 2 replace;

[0053] R 2 C independently at each occurrence 1-6 Alkyl or OR 2a ;

[0054] R 2a H or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halo groups;

[0055] R 3 is phenyl, 5- or 6-membered monocyclic heteroaryl, or 9- to 10-membered bicyclic heteroaryl, wherein phenyl, 5- or 6-membered monocyclic heteroaryl and 9- to 10-membered bicyclic heteroaryl are each optionally substituted by one or more substituents R 4 replace;

[0056] R 4 is independently at each occurrence halo, -OR 4a 、-CN、C 1-6 Alkyl, C 3-6 Cycloalkyl, or 5 or 6 membered monocyclic heteroaryl, wherein C 1-6The alkyl group is optionally substituted with one or more halo groups, and wherein the 5- or 6-membered monocyclic heteroaryl group is optionally substituted with one or more C 1-6 Alkyl substitution; or

[0057] Two R's 4 Together with the atoms in between, they form a 5- to 7-membered heterocyclic group;

[0058] R 4a H or C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more halo groups;

[0059] n is 1 or 2;

[0060] m is 1 or 2;

[0061] R 5 is independently H, halo, C 1-3 Alkyl or C 1-3 haloalkyl; or two R 5 Together they form C 1-3 alkylene;

[0062] R 6 is independently H, halo, C 1-3 Alkyl or C 1-3 haloalkyl; or two R 6 Together they form C 1-3 alkylene;

[0063] Provided that the compound is not:

[0064]

[0065] In a second embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, Het is a 4- to 6-membered oxygen-containing monocyclic saturated heterocyclic group, or a 6- to 8-membered oxygen-containing bicyclic saturated heterocyclic group; and the remaining variables are as described in the first aspect or the first embodiment. In an alternative embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, Het is C 3-6 Cycloalkyl, 4- to 6-membered oxygen-containing monocyclic saturated heterocyclic group or 6- to 8-membered oxygen-containing bicyclic saturated heterocyclic group, each of which is optionally substituted by one to three R 2and the remaining variables are as described in the first aspect or the first embodiment. In another alternative embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, Het is cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, dioxanyl, 2-oxaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 2-oxabicyclo[2.1.1]hexanyl, 6-oxabicyclo[3.2.1]octyl or 2-oxabicyclo[3.1.1]heptyl, each of which is optionally substituted with one to three R 2 and the remaining variables are as described in the first aspect or first embodiment.

[0066] In a third embodiment, the compounds of the present disclosure are represented by formula (II):

[0067]

[0068] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (II) are as defined above in the first aspect or first or second embodiment or any alternative embodiment described therein.

[0069] In a fourth embodiment, for the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 3 is phenyl, pyridyl, thiazolyl or pyrazolyl, each of which is optionally substituted by one to three R 4 and the remainder of the variables are as described in the first aspect, or first or second embodiment, or any alternative embodiment described therein.

[0070] In a fifth embodiment, for the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 3 for wherein each of the formulae depicted above is optionally substituted by one to three R 4 and the remainder of the variables are as described in the first aspect, or first or second embodiment, or any alternative embodiment described therein.

[0071] In a sixth embodiment, for the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 3 for and the remaining variables are as described in the first aspect or first or second embodiment or any alternative embodiment described therein.

[0072] In a seventh embodiment, for the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 4 is independently selected at each occurrence from halo, -CN, -OR 4a 、C1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl and optionally C 1-3 alkyl-substituted 5- or 6-membered heteroaryl; and R 4a C 1-3 Alkyl or C 1-3 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.

[0073] In an eighth embodiment, for the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 4 is independently selected at each occurrence from -CH3, -CF3, -OCHF2, -OCH3, -CN, -F, -Cl, isopropyl, cyclopropyl and 4-methylpyridin-2-yl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth or sixth embodiment or any alternative embodiment described therein.

[0074] In a ninth embodiment, for a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 1 For OR 2a Substituted C 2-4 alkyl; wherein each of the formulae depicted above is optionally substituted by one to three R 2 Replacement; R 2 C independently at each occurrence 1-3 Alkyl or -OR 2a ; R 2a H or C independently at each occurrence 1-3 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.

[0075] In a tenth embodiment, for a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 1 for R 2 C independently at each occurrence 1-3 Alkyl or -OR 2a ; R 2a H or C independently at each occurrence 1-3 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.

[0076] In an eleventh embodiment, for the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 2 R is independently selected at each occurrence from -CH3 and -OH; 2a and the remainder of the 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.

[0077] In a twelfth embodiment, the compounds of the present disclosure are represented by formula (III):

[0078]

[0079] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (III) are as defined above 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.

[0080] In a thirteenth embodiment, for the compound of formula (III) or a pharmaceutically acceptable salt thereof, R 1 for R 2 R is independently selected at each occurrence from -CH3 and OH; 2a is independently selected at each occurrence from H or -CH3; R 3 for And R 4 is independently selected at each occurrence from -CH3, -CF3, -OCHF2, -OCH3 and -F.

[0081] In a fourteenth embodiment, the compounds of the present disclosure are represented by formula (IV):

[0082]

[0083] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (IV) are as defined above 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.

[0084] In a fifteenth embodiment, the compounds of the present disclosure are represented by formula (IVA) or (IVB):

[0085]

[0086] or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (IVA) or (IVB) are as defined above in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment, or any of the alternative embodiments described therein.

[0087] In a sixteenth embodiment, for the compound of Formula (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 1 for R 2 OH; R 3 for R 4 is independently selected at each occurrence from -CH3, -CF3, -OCH3, -OCHF2, -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.

[0088] In a seventeenth embodiment, the compounds of the present disclosure are represented by formula (V):

[0089]

[0090] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (V) are as defined above 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.

[0091] In an eighteenth embodiment, for the compound of formula (V) or a pharmaceutically acceptable salt thereof, R 1 for R 3 for And R 4 is independently selected at each occurrence from -CH3, -F and cyclopropyl.

[0092] In a nineteenth embodiment, the compounds of the present disclosure are represented by formula (VI):

[0093]

[0094] or a pharmaceutically acceptable salt thereof; wherein the variables in Formula (VI) are as defined above in the first aspect or the first embodiment.

[0095] In a twentieth embodiment, the compounds of the present disclosure are represented by formula (VII) or (VIII):

[0096]

[0097] or a pharmaceutically acceptable salt thereof; wherein the variables in formula (VII) or (VIII) are as defined above in the first aspect or first embodiment.

[0098] In a twenty-first embodiment, for the compound of Formula (VI), (VII) or (VIII), or a pharmaceutically acceptable salt thereof, R 3 is optionally substituted with one to three R 4 substituted phenyl; and the remaining variables are as described in the first aspect or first embodiment.

[0099] In a twenty-second embodiment, for the compound of Formula (VI), (VII) or (VIII), or a pharmaceutically acceptable salt thereof, R 3 for And the remaining variables are as described in the twenty-first embodiment.

[0100] In a twenty-third embodiment, for the compound of Formula (VI), (VII) or (VIII), or a pharmaceutically acceptable salt thereof, R 4 is independently selected at each occurrence from halo, CN and OR 4a ; and R 4a C 1-3 Alkyl or C 1-3 and the remaining variables are as described in the first aspect or the first, twenty-first or twenty-second embodiment.

[0101] In a twenty-fourth embodiment, for the compound of Formula (VI), (VII) or (VIII), or a pharmaceutically acceptable salt thereof, R 4 is independently selected at each occurrence from -OCHF2, -F, and -CN; and the remainder of the variables are as described in the first aspect or the first, twenty-first, or twenty-second embodiment.

[0102] In a twenty-fifth embodiment, for the compound of Formula (VI), (VII) or (VIII), or a pharmaceutically acceptable salt thereof, R 1 For the -OR 2a Substituted C 2-4 Alkyl or optionally substituted with one to three R 2 Replaced and the remaining variables are as described in the first aspect or the first, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment.

[0103] In a twenty-sixth embodiment, for a compound of Formula (VI), (VII) or (VIII) or a pharmaceutically acceptable salt thereof, R 1 for and the remaining variables are as described in the first aspect or the first, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment.

[0104] In a twenty-seventh embodiment, for the compound of Formula (VI), (VII) or (VIII), or a pharmaceutically acceptable salt thereof, R 2 is independently selected at each occurrence from -CH3 and -OH; and R 2a is independently selected at each occurrence from H and -CH3; and the remainder of the 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.

[0105] In a twenty-eighth embodiment, the compounds of the present disclosure are represented by formula (IX):

[0106]

[0107] or a pharmaceutically acceptable salt thereof, wherein R 5 H, or two R 5 Together they form C 1-3 Alkylene; R 6 H, or two R 6 Together they form C 1-3 alkylene; and wherein the remaining variables in formula (IX) are as defined above in the first aspect or first embodiment.

[0108] In the twenty-ninth embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, p1 is 1 and p2 is 0; or p1 is 1 and p2 is 1; or p1 is 2 and p2 is 1; wherein the remaining variables in formula (IX) are as defined above in the twenty-eighth embodiment.

[0109] In a thirtieth embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 3 C 1-4 Alkyl-phenyl, phenyl, pyridyl, thiazolyl and pyrazolyl, each of which is optionally substituted with one to three R 4 and the remaining variables are as described in the first aspect or the first, twenty-eighth or twenty-ninth embodiment. In alternative embodiments, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 3 is phenyl, pyridyl or pyrazolyl, each of which is optionally substituted by one to three R 4 and the remaining variables are as described in the first aspect or the first, twenty-eighth or twenty-ninth embodiment.

[0110] In a thirty-first embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 3for Each of these groups is optionally substituted with one to three R 4 Substitute; or R 3 for It is optionally connected to one or two R 4 and the remaining variables are as described in the first aspect or the first, twenty-eighth or twenty-ninth embodiment. In alternative embodiments, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 3 for Each of these groups is optionally substituted with one to three R 4 Substitute; or R 3 for It is optionally connected to one or two R 4 and the remaining variables are as described in the first aspect or the first, twenty-eighth or twenty-ninth embodiment.

[0111] In a thirty-second embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 3 for

[0112] and the remaining variables are as described in the first aspect or the first, twenty-eighth or twenty-ninth embodiment. In alternative embodiments, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 3 for and the remaining variables are as described in the first aspect or the first, twenty-eighth or twenty-ninth embodiment.

[0113] In a thirty-third embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 4 independently selected at each occurrence from halo, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, phenyl and -OR 4a ; among them C 3-6 The cycloalkyl group is optionally substituted with one to three halogen or C 1-4 is substituted with a haloalkyl group, and C 1-3 The alkyl group is optionally substituted with one or two C 3-4 cycloalkyl substituted; and R 4a C 1-3 Alkyl or C 1-3 haloalkyl, and the remaining variables are as described in the first aspect or the first, twenty-eighth, twenty-ninth, thirtieth, thirty-first or thirty-second embodiment. In alternative embodiments, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R4 independently selected at each occurrence from halo, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl and -OR 4a ; and R 4a 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-eighth, twenty-ninth, thirtieth, thirty-first or thirty-second embodiment.

[0114] In a thirty-fourth embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 4 is independently selected at each occurrence from -CH3, -CH2CH3, -CF2CH3, -CF(CH3)2, -CH=CH2, -CHF2, -CH(CH3)2, -CF3, -OCH3, -OCHF2, -OCF3, cyclopropyl, -CH2-cyclopropyl, cyclobutyl, phenyl, -CN, -Cl, -Br and -F; and the remaining variables are as described in the first aspect or the first, twenty-eighth, twenty-ninth, thirtieth, thirty-first or thirty-second embodiment. In alternative embodiments, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 4 is independently selected at each occurrence from -CH3, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3, cyclopropyl, -CN and -F; and the remainder of the variables are as described in the first aspect or the first, twenty-eighth, twenty-ninth, thirtieth, thirty-first or thirty-second embodiment.

[0115] In a thirty-fifth embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 1 for

[0116] wherein each of the formulae depicted above is optionally substituted by one to three R 2 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. In alternative embodiments, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 1 for wherein each of the formulae depicted above is optionally substituted by one to three R 2 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.

[0117] In a thirty-sixth embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 1 for

[0118]

[0119] 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. In alternative embodiments, for a compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 1 for and the remainder of the 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.

[0120] In a thirty-seventh embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 2 is -CH3, -F, -OCH3-CN, -CH2CH2OCH3 or -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. In alternative embodiments, for a compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 2 is OH; and the remainder of the 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.

[0121] In a thirty-eighth embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 1 is optionally through one or two R A Substituted C 2-6 Alkyl; R A OR independently at each occurrence 2a SR 2a or C(O)OR 2a ; and R 2a H, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein C 1-4 The alkyl group is optionally substituted with one or two C 1-3and 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. In one embodiment, for the compound of formula (IX) or a pharmaceutically acceptable salt thereof, R 1 is -CH2CH3, -CH2CH2CH2SCH2CH3, -CH2CH2CH2O-cyclopentyl, -CH2CH2CH2CH2CH2OCH3, -CH2CH2OC(CH3)3, -CH2CH 2CH2CH(CH3)OCH3, -CH2CH(CH3)CH2CH2C(O)OCH3, -CH2CH2C(CH3)2C(O)OCH3, or -CH2CH2CH2OCH2CH2OCH3.

[0122] In a thirty-ninth embodiment, the compound of the present disclosure is represented by formula (X):

[0123]

[0124] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (X) are as defined above in the first aspect or the first, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh or thirty-eighth embodiment, or any alternative embodiment described therein.

[0125] In the fortieth embodiment, for the compound of formula (X) or a pharmaceutically acceptable salt thereof, R 1 for R 2 OH; R 3 It is expressed by the following formula: And R 4 The remaining variables are as defined in the thirty-eighth embodiment.

[0126] In a forty-first embodiment, the compound of the present disclosure is represented by formula (XI):

[0127]

[0128] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (XI) are as defined above in the first aspect or the first, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh or thirty-eighth embodiment, or any alternative embodiment described therein.

[0129] In a forty-second embodiment, the compounds of the present disclosure are represented by formula (XIA) or (XIB):

[0130]

[0131] or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (XIA) or (XIB) are as defined above in the first aspect or the first, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh or thirty-eighth embodiment, or any of the alternative embodiments described therein.

[0132] In a forty-third embodiment, for a compound of Formula (X), (XIA), or (XIB), or a pharmaceutically acceptable salt thereof, R 1 for R 2 OH; R 3 It is expressed by the following formula: And R 4 is independently selected at each occurrence from -CH3, -CF3, -OCH3, -OCHF2, -OCF3, -CN, -F and cyclopropyl; and the remaining variables are as defined in the forty-first or forty-second embodiment.

[0133] In a forty-fourth embodiment, the compounds of the present disclosure are represented by formula (XII):

[0134]

[0135] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (XII) are as defined above in the first aspect or the first, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh or thirty-eighth embodiment, or any alternative embodiment described therein.

[0136] In a forty-fifth embodiment, for the compound of formula (XII) or a pharmaceutically acceptable salt thereof, R 1 for R 2 OH; R 3 It is expressed by the following formula: And R 4 is independently selected at each occurrence from -CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3; the remaining variables are as defined in the forty-fourth embodiment.

[0137] In a forty-sixth embodiment, the compounds of the present disclosure are represented by formula (XII):

[0138]

[0139] or a pharmaceutically acceptable salt thereof, wherein:

[0140] R 1 is Het or Z-Het;

[0141] Z is CH2;

[0142] Het is represented by the following formula: wherein each of the formulae depicted above is optionally substituted with one to two R 2 replace;

[0143] R 2 C independently at each occurrence 1-4 Alkyl, -OH or halide;

[0144] R 3 is pyridyl or pyrazolyl, each of which is optionally substituted by one to two R 4 replace;

[0145] R 4 C independently at each occurrence 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0146] In the forty-seventh embodiment, for the compound of formula (XII) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: wherein each of these formulae is optionally substituted with one to two R 4 and the remaining variables are as defined in the forty-sixth embodiment.

[0147] In a 48th embodiment, for the compound of formula (XII) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: and the remaining variables are as defined in the forty-sixth or forty-seventh embodiment.

[0148] In the forty-ninth embodiment, for the compound of formula (XII) or a pharmaceutically acceptable salt thereof, R 4 is independently at each occurrence -CH3, -CF3 or -CF2CH3; and the remaining variables are as defined in the forty-sixth, forty-seventh or forty-eighth embodiment.

[0149] In a fiftieth embodiment, the compounds of the present disclosure are represented by Formula (XIIA):

[0150]

[0151] or a pharmaceutically acceptable salt thereof, wherein R 40 C 1-3 Alkyl and R 41 C 1-3haloalkyl; and the remaining variables are as defined in the forty-eighth embodiment.

[0152] In a fifty-first embodiment, for the compound of formula (XIIA) or a pharmaceutically acceptable salt thereof, R 40 is -CH3 and R 41 is -CF3 or -CF2CH3; and the remaining variables are as defined in the fiftieth embodiment.

[0153] In a fifty-second embodiment, for the compound of Formula (XII) or (XIIA) or a pharmaceutically acceptable salt thereof, R 1 It is expressed by the following formula: wherein each of the formulae depicted above is optionally substituted with one to two R 2 and the remaining variables are as defined in the forty-sixth, forty-seventh, forty-eighth, forty-ninth, fiftieth or fifty-first embodiment.

[0154] In a fifty-third embodiment, for the compound of formula (XII) or (XIIA), or a pharmaceutically acceptable salt thereof, R 1 It is expressed by the following formula: And the remaining variables are as defined in the fifty-second embodiment.

[0155] In a fifty-fourth embodiment, for the compound of formula (XII) or a pharmaceutically acceptable salt thereof, R 2 is independently at each occurrence -CH3, OH, or -F; and the remaining variables are as defined in the forty-sixth, forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, or fifty-third embodiment.

[0156] In a fifty-fifth embodiment, the disclosure provides a compound described herein (e.g., a compound of any one of Examples 1-229), or a pharmaceutically acceptable salt thereof.

[0157] In a fifty-sixth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0158] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane;

[0159] 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0160] (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-

[0161] diazaspiro[4.5]decane;

[0162] (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-

[0163] diazaspiro[4.5]decane;

[0164] 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane;

[0165] 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane;

[0166] 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecane;

[0167] 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((S)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0168] (±)-(R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((S)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0169] (±)-(R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((R)-tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0170] 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)-2-methylpropan-2-ol;

[0171] 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxy-2-methylpropyl)-1-oxa-4,9-diazaspiro[5.5]undecane;

[0172] 9-((2,4-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0173] 9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0174] (S)-9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0175] (R)-9-((3,5-difluorophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0176] 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0177] 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0178] 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0179] 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane;

[0180] 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane;

[0181] 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane;

[0182] 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane;

[0183] 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0184] 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0185] 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0186] (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0187] (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0188] 9-((3,5-difluorophenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane;

[0189] 4-((3,5-difluorophenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane;

[0190] 9-((4-(difluoromethoxy)phenyl)sulfonyl)-4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane;

[0191] 7-((2,4-dimethylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane;

[0192] 7-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane;

[0193] 7-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane;

[0194] 1-((7-((2,4-Dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]non-2-yl)methyl)tetrahydro-2H-pyran-4-ol;

[0195] 7-((2,4-dimethylphenyl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonane;

[0196] 8-((2-chloro-4-methylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane;

[0197] 8-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane;

[0198] 8-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane;

[0199] 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane;

[0200] 8-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane;

[0201] 8-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane;

[0202] 8-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane;

[0203] 8-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane;

[0204] 2-((2,4-Dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0205] 4-((6-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)tetrahydro-2H-pyran-4-ol;

[0206] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0207] 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0208] 2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0209] 2-((4-(difluoromethyl)-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0210] 2-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0211] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0212] 2-((2,4-Dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane;

[0213] 2-((4,6-dimethylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane;

[0214] 2-((4-(difluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane;

[0215] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane;

[0216] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane;

[0217] 2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane;

[0218] 2-((2-methyl-4-(trifluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane;

[0219] 2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane;

[0220] 6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane;

[0221] (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];

[0222] 1-((1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol;

[0223] (1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane];

[0224] (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-(2-methoxy-2-methylpropyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane];

[0225] 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0226] 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0227] 2-((6-bromo-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0228] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0229] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0230] 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0231] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0232] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0233] 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;

[0234] 2-((1-methyl-2-oxabicyclo[3.1.1]hept-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)-1,6-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0235] 4-((6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)tetrahydro-2H-pyran-4-ol;

[0236] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0237] 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0238] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0239] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0240] (R)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-3-yl)-2,6-diazaspiro[3.3]heptane;

[0241] 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;

[0242] (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;

[0243] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0244] (R)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydrofuran-3-yl)-2,6-diazaspiro[3.3]heptane;

[0245] (S)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0246] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0247] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0248] (S)-2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0249] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((3-methyloxetan-3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0250] 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0251] 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0252] 2-((6-(2-fluoropropan-2-yl)-2-methyl-1,4-dihydropyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0253] 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0254] 2-((6-(difluoromethoxy)-2-methyl-3,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0255] 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0256] 2-((5-(difluoromethyl)-2-methyl-1H-214-pyrazol-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0257] 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0258] 2-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0259] 2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0260] 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0261] 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0262] 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0263] (S)-2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0264] 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0265] 2-((6-methyl-2-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0266] 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0267] 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0268] 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0269] 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0270] 2-((2,6-bis(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0271] 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0272] 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0273] 2-((2-oxaspiro[3.3]hept-6-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0274] 2-((2-oxaspiro[3.3]hept-6-yl)methyl)-6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0275] 2-((2-oxaspiro[3.3]hept-6-yl)methyl)-6-((2-methyl-5-(trifluoromethyl)-2,5-dihydro-1H-pyrazol-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0276] 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0277] 2-((2-cyclopropyl-6-(difluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((1s,4s)-4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane;

[0278] 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane;

[0279] 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0280] 2-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0281] 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0282] 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0283] (1r,4r)-4-(6-((4-cyclopropyl-6-(trifluoromethyl)-2,3-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol;

[0284] 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol;

[0285] 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0286] 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0287] (1r,4r)-4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol;

[0288] (1s,4s)-4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol;

[0289] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0290] 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((1R)-1-(tetrahydrofuran-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0291] (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;

[0292] (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(3-methyloxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0293] (S)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0294] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2-methyltetrahydrofuran-2-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0295] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((S)-1-((S)-2-methyltetrahydrofuran-2-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0296] (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0297] 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;

[0298] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((R)-1-((S)-tetrahydrofuran-2-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0299] (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-2-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0300] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydrofuran-3-yl)-2,6-diazaspiro[3.3]heptane;

[0301] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((3-methyloxetan-3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0302] (R)-2-(3,3-Dimethyltetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0303] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0304] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0305] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0306] 2-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0307] 2-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0308] 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;

[0309] 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;

[0310] 2-(4,4-difluorocyclohexyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0311] (R)-2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-3-yl)-2,6-diazaspiro[3.3]heptane;

[0312] 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0313] (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;

[0314] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0315] (S)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0316] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0317] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0318] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0319] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-(oxetan-3-yl)ethyl)-2,6-diazaspiro[3.3]heptane;

[0320] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0321] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0322] 2-(tetrahydro-2H-pyran-4-yl)-6-((2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0323] 2-((6-(2,2-difluorocyclopropyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0324] 2-((2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0325] 2-((6-chloro-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0326] 2-((3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0327] 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;

[0328] 2-((6-methoxy-4-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0329] 2-methyl-3-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]hept-2-yl)sulfonyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole;

[0330] 2-ethyl-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0331] 2-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)cyclopropane-1-carbonitrile;

[0332] 2-(3-(2-methoxyethoxy)propyl)-6-((2-methyl-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0333] (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;

[0334] (1R,3R)-2,2-dimethyl-3-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)cyclopropane-1-carbonitrile;

[0335] 2-(((1S,2R,5S)-6-oxabicyclo[3.2.1]oct-2-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0336] 2-(3-(cyclopentyloxy)propyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0337] methyl 2,2-dimethyl-4-(6-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)butanoate;

[0338] 2-(2-cyclopropyl-2-methoxyethyl)-6-((2-methyl-6-(trifluoromethyl)-pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0339] 2-(5-methoxypentyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0340] 2-(4-methoxypentyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0341] 2-((1-(2-methoxyethyl)cyclobutyl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0342] Methyl 4-methyl-5-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)pentanoate;

[0343] 2-(3-(Ethylthio)propyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0344] 2-(2-cyclopropylethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0345] 2-(2-(tert-Butoxy)ethyl)-6-((2-methyl-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0346] 2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0347] 4-((6-((2-methyl-6-(trifluoromethyl)-pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)tetrahydro-2H-pyran-4-ol;

[0348] 2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0349] 2-((3-Isopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0350] 2-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0351] 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;

[0352] 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0353] 2-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0354] 2-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0355] (1s,4s)-4-(6-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol;

[0356] (1s,4s)-4-(6-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol;

[0357] 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;

[0358] (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;

[0359] 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;

[0360] (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;

[0361] 2-((tetrahydro-2H-pyran-4-yl)methyl)-6-((2-(trifluoromethyl)-3,4-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0362] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0363] 2-(tetrahydro-2H-pyran-4-yl)-6-((6-(trifluoromethyl)-2-vinylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0364] 2-((2-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0365] 2-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0366] 2-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane;

[0367] (1r,4r)-4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol;

[0368] (1s,4s)-4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol;

[0369] 2-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0370] 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;

[0371] 2-((2,4-bis(trifluoromethyl)phenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0372] (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;

[0373] 2-((6-chloro-2-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0374] 2-((2-fluoro-4-(trifluoromethoxy)phenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0375] (R)-2-((1,4-Dioxan-2-yl)methyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0376] (R)-2-((1,4-Dioxan-2-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0377] 2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0378] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0379] 2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0380] 2-((2-fluoro-4-(trifluoromethoxy)phenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-

[0381] diazaspiro[3.3]heptane;

[0382] 2-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-

[0383] diazaspiro[3.3]heptane;

[0384] (1s,4s)-1-methyl-4-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)cyclohexan-1-ol;

[0385] (1s,4s)-1-methyl-4-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)cyclohexan-1-ol;

[0386] 2-((3-methyl-5-(trifluoromethyl)pyridin-2-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0387] 2-((4-(difluoromethoxy)-2,6-difluorophenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-

[0388] 2,6-diazaspiro[3.3]heptane;

[0389] 2-((4-(difluoromethoxy)-2-fluorophenyl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-

[0390] diazaspiro[3.3]heptane;

[0391] 2-((4-(difluoromethoxy)-2-fluorophenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane;

[0392] 2-((6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]hept-2-yl)sulfonyl)-5-

[0393] (Trifluoromethyl)benzonitrile; and

[0394] 2-((tetrahydro-2H-pyran-4-yl)methyl)-6-((6-(trifluoromethyl)-2,3-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0395] or a pharmaceutically acceptable salt thereof.

[0396] 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.

[0397] In the fifty-eighth embodiment, the present disclosure provides a method of treating a disease or condition mediated by EBP, comprising administering to a subject an effective amount of a compound according to any one of embodiments one to fifty-six, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the fifty-seventh embodiment.

[0398] In a fifty-ninth embodiment, the present disclosure provides a compound according to any one of embodiments one to fifty-six for use in treating a disease or condition mediated by EBP.

[0399] In a sixtieth embodiment, the present disclosure provides the use of a compound according to any one of embodiments one to fifty-six in the manufacture of a medicament for treating a disease or condition mediated by EBP.

[0400] The compounds and intermediates described herein can be separated and used as the compounds themselves. Alternatively, when there is a portion capable of forming a salt, the compound or intermediate can be separated and used in the form of its corresponding salt. As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound described herein. "Salt" particularly includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds described herein and is generally not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid salts and / or basic salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0401] Pharmaceutically acceptable acid addition salts can be formed with inorganic or organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate.

[0402] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0403] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0404] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

[0405] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from rows I to 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.

[0406] 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. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0407] Salts can be synthesized from compounds containing alkaline or acidic moieties by conventional chemical methods. Typically, these salts can be prepared by reacting these compounds in free acid form with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg, or K), or by reacting these compounds in free base form with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or an organic solvent or a mixture of the two. Typically, where feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of additional suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences," 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0408] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations using appropriate isotopically labeled reagents in place of the unlabeled reagents previously employed. In one embodiment, the present disclosure provides a deuterated compound as described herein or a pharmaceutically acceptable salt thereof.

[0409] Pharmaceutically acceptable solvates according to the present invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, d 6- Acetone, d6-DMSO.

[0410] Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and, therefore, may exist in different stereoisomeric forms. As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure. It is understood that substituents may be attached to the chiral center of a carbon atom. Therefore, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0411] "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. Where appropriate, the term "racemic" or "rac" is used to name a racemic mixture. When specifying the stereochemistry of the compounds of the present invention, the conventional RS system is used to specify single stereoisomers (e.g., (1S, 2S)) with known relative and absolute configurations of two chiral centers. "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 of each chiral carbon can be specified by R or S. Resolved compounds with unknown absolute configuration can be named (+) or (-) according to the direction (right-handed or left-handed) of their rotation in plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the respective retention times of the corresponding enantiomers / diastereomers via chiral HPLC.

[0412] Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0413] Unless otherwise indicated, 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 can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separation on a chiral SFC or HPLC column (such as CHIRALPAK available from DAICEL)). RTM and CHIRALCEL RTM ) are separated using an appropriate solvent or solvent mixture to achieve good separation. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0414] How to use

[0415] 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., a decrease in EBP activity of at least 10%, as measured by a given assay such as the bioassays described in the Examples and known in the art).

[0416] In certain embodiments, the present disclosure provides a method for treating a disease or condition responsive to inhibition of EBP activity (referred to herein as an "EBP-mediated disease or condition" or "a disease or condition mediated by EBP") in a subject in need of such treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0417] 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 to 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 treating an EBP-mediated condition or disease in a subject in need of such treatment.

[0418] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to 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 condition or disease in a subject in need of such treatment.

[0419] In certain embodiments, the EBP-mediated disorder is colorectal cancer.

[0420] In certain embodiments, the present disclosure provides a method for treating an autoimmune disease in a subject in need of the treatment. The method includes administering to the subject a compound as described herein (e.g., a compound described in any one of the first to fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof.

[0421] 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 to 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 treating an autoimmune disease in a subject in need of such treatment.

[0422] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to 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 of such treatment.

[0423] 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 MS (or one or more relapsing forms of MS), relapsing-remitting MS, primary progressive MS, secondary progressive MS, and clinically isolated syndrome (hereinafter referred to as "CIS").

[0424] Relapsing forms of multiple sclerosis (or one or more relapsing forms of multiple sclerosis) include clinically isolated syndrome, relapsing-remitting multiple sclerosis, and active secondary progressive multiple sclerosis.

[0425] Relapsing-remitting multiple sclerosis is a stage of MS characterized by unpredictable relapses followed by periods of relative calm (remission) with no new signs of disease activity for months to years. The deficits that occur during an attack may resolve or remain, the latter occurring in approximately 40% of attacks and becoming more common the longer a person has the disease. This describes the initial course of 80% of people with multiple sclerosis.

[0426] Secondary progressive MS occurs in about 65% of people who initially develop relapsing-remitting MS. These people eventually have progressive neurological decline without any clear remissions between acute attacks. Occasional relapses and minor remissions may occur. The most common length of time between disease onset and conversion from relapsing-remitting MS to secondary progressive MS is 19 years.

[0427] Primary progressive MS is characterized by the same symptoms as secondary progressive MS, namely, progressive neurological deterioration with no clear remissions between acute attacks and without preceding relapsing-remitting phases.

[0428] CIS is the first onset of neurological symptoms caused by inflammation and demyelination in the central nervous system. This attack, by definition, must last at least 24 hours and is a characteristic of multiple sclerosis, but does not yet meet the diagnostic criteria for MS because a person experiencing CIS may or may not go on to develop MS. When CIS is accompanied by lesions on a brain MRI (magnetic resonance imaging) similar to those seen in MS, the person is likely to experience a recurrence of neurological symptoms and be diagnosed with relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on a brain MRI, the person is much less likely to develop MS.

[0429] In certain embodiments, the present disclosure provides a method for promoting myelination in a subject in need of treatment for a subject with a myelin-related disease or condition. The method includes administering a compound as described herein (e.g., a compound described in any one of the first to fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof to the subject.

[0430] 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 to 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 having a myelin-related disease or disorder in a subject in need of treatment.

[0431] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to 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 having a myelin-related disease or disorder in a subject in need of treatment.

[0432] In certain embodiments, the myelin-related disease or disorder is selected from multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), acute diffuse encephalomyelitis (ADEM), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's 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, disease), spinal cord injury, traumatic brain injury, post-radiation injury, 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 diffuse encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillian-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination, such as neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, and schizophrenia.

[0433] In certain embodiments, the present disclosure provides a method for treating cancer in a subject in need of such treatment. The method comprises administering to the subject a compound as described herein (e.g., a compound described in any one of the first to fifty-sixth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0434] 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 to 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 treating cancer in a subject in need of such treatment.

[0435] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to 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 cancer in a subject in need of such treatment.

[0436] In certain embodiments, the cancer is colorectal cancer.

[0437] In certain embodiments, the present disclosure relates to the above methods, wherein the subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0438] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. They refer to an amount that is effective in treating or lessening the severity of one or more diseases, conditions, or disorders as described herein. In some embodiments, the effective dose may be between 10 μg and 500 mg.

[0439] According to the methods of the present disclosure, the compounds and compositions may be administered using any amount and any route of administration effective to treat or lessen the severity of one or more of the aforementioned diseases, conditions, or disorders.

[0440] In certain embodiments, the present disclosure relates to the above methods, wherein the compound is administered parenterally. In certain embodiments, the present disclosure relates to the above methods, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectal, intrathecally, topically, or intranasally. In certain embodiments, the present disclosure relates to the above methods, wherein the compound is administered systemically.

[0441] The compounds of this invention can be used in the form of pharmaceutical composition (for example, the compounds of this invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (for example, antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, pharmaceutical stabilizers, buffers (for example, maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.) and combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with active ingredient, its use in treatment or pharmaceutical composition is covered. For the purposes of this disclosure, solvate and hydrate are considered to be pharmaceutical compositions comprising the compounds of this invention and solvent (i.e., solvate) or water (i.e., hydrate).

[0442] These formulations can be prepared using conventional dissolution and mixing procedures. For example, bulk drug substance (i.e., a compound of the invention or a stable form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the invention are typically formulated into pharmaceutical dosage forms to provide easily controllable drug dosages and to provide patients with an aesthetically pleasing and easy-to-handle product.

[0443] Depending on the method used to administer the drug, the pharmaceutical composition (or formulation) for application can be packaged in a variety of ways. Typically, the article for distribution includes a container in which the pharmaceutical formulation in an appropriate form is stored. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent inadvertent contact with the contents of the package. Additionally, the container may have a label placed thereon that describes the contents of the container. The label may also include appropriate warnings.

[0444] Pharmaceutical compositions containing compounds of the present disclosure are typically formulated for parenteral or oral administration or alternatively as suppositories.

[0445] For example, the oral pharmaceutical compositions of the present disclosure can be prepared in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations, such as sterilization, and / or can contain conventional inert diluents, lubricants or buffers, and adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and buffers.

[0446] Typically, the pharmaceutical composition contains a tablet or gelatin capsule containing the active ingredient and:

[0447] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0448] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets; also containing

[0449] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired

[0450] d) disintegrants, for example starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or

[0451] e) absorbents, colorants, flavorings and sweeteners.

[0452] Tablets can be film-coated or enteric-coated according to methods known in the art.

[0453] Suitable compositions for oral administration include compounds of the present disclosure in the form of lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and these compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, colorants, and preservatives to provide pharmaceutically aesthetic and palatable preparations. Lozenges may contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for making lozenges. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The lozenges are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0454] Parenteral compositions (e.g., intravenous (IV) formulations) are isotonic aqueous solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically valuable substances. Compositions are typically prepared according to conventional mixing, granulation, or coating methods, respectively, and contain from about 0.1% to 75% or from about 1% to 50% active ingredient.

[0455] The compounds of the present disclosure or their pharmaceutical compositions for use in subjects (e.g., humans) are typically administered orally or parenterally in therapeutic doses. When administered intravenously via infusion, the dosage may depend on the infusion rate of the IV formulation. Typically, the therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the species, body weight, age, and condition of the subject, the disorder or disease being treated, or its severity. Ordinary skilled physicians, pharmacists, clinicians, or veterinarians can easily determine the effective amount of each active ingredient required for preventing, treating, or suppressing disorder or disease progression.

[0456] The above-mentioned dosage properties can be advantageously confirmed in in vitro and in vivo tests using mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and preparations. The compounds of the present invention can be administered in vitro in the form of a solution (e.g., an aqueous solution) and can be administered in vivo in the form of a suspension or aqueous solution, for example, enterally, parenterally, advantageously intravenously. In vitro doses can range from about 10-3 molar to 10-9 molar concentrations.

[0457] definition

[0458] As used herein, "patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. The term includes mammals, such as humans. Typically, the animal is a mammal. Subject also refers to, for example, primates (e.g., male or female humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

[0459] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to reducing or suppressing a given condition, symptom, disorder, or disease, or significantly reducing the baseline activity of a biological activity or process.

[0460] 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 obtain the desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely alleviating the extent of the disease, condition, or disorder; improving or ameliorating clinical symptoms, complications, or indicators associated with the disease, condition, or disorder; or delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or disorder; or eliminating the disease, condition, or disorder. In certain embodiments, the effect may be preventing the onset of symptoms or complications of the disease, condition, or disorder.

[0461] As used herein, the term "cancer" has the generally accepted meaning in the art. The term can broadly refer to abnormal cell growth.

[0462] As used herein, the term "autoimmune disease" has the meaning generally accepted in the art. The term can broadly refer to a disease in which the host's immune system targets or attacks the host's normal or healthy tissues.

[0463] As used herein, the term "myelination" has the meaning generally accepted in the art. The term can broadly refer to the process of producing myelin.

[0464] As used herein, the terms "myelin-related disease or disorder," "demyelinating disorder," or "demyelation disorder" have the meaning generally accepted in the art. These terms can broadly refer to diseases or disorders involving myelin damage.

[0465] As used herein, a subject (preferably a human) is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from the treatment.

[0466] 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 hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent at each position may be the same or different.

[0467] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4"Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. The term "C 1-3 Alkyl" and "C 1-2 Alkyl" should be interpreted accordingly. "C 1-4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl portion of an alkoxy group (i.e., alkyl moiety) has the same definition as above. When indicated as "optionally substituted," the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (typically one to three substituents, except in the case of halogen substituents such as perchloroalkyl or perfluoroalkyl groups).

[0468] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (ie, --O--C 1-4 Alkyl, where 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, the alkoxy has about 1-4 carbon atoms, more preferably about 1-2 carbon atoms. The term "C 1-2 "Alkoxy" should be interpreted accordingly.

[0469] As used herein, the term "C 1-4 Alkoxy-C 1-4 "Alkyl" means a C 1-4 Alkyl groups, in which at least one hydrogen atom is replaced by a C 1-4 Alkoxy substitution. C 1-4 Alkoxy C 1-4 The alkyl group is attached through the alkyl group through the rest of the molecule described herein.

[0470] 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" refers to an alkyl group having 1 to 3 carbon atoms.

[0471] "Halogen" or "halo" may be fluorine, chlorine, bromine or iodine.

[0472] As used herein, the term "halo-substituted C 1-4 Alkyl" or "C 1-4 "Haloalkyl" refers to a C 1-4 Alkyl groups in which at least one hydrogen atom is replaced by a halogen atom. 1-4 The haloalkyl group may be a monohalogen-C 1-4 Alkyl, dihalogen-C 1-4 Alkyl or polyhalogen-C1-4 Alkyl, including perhalo-C 1-4 Alkyl. Monohalogen-C 1-4 The alkyl group may have one iodine, bromine, chlorine or fluorine within the alkyl group. 1-4 Alkyl and polyhalogen-C 1-4 The alkyl group may have two or more of the same halogen atoms or a combination of different halogen groups within the alkyl group. 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 refers to a C group in which all hydrogen atoms are replaced by halogen atoms. 1-4 alkyl.

[0473] The term "aryl" refers to an aromatic carbocyclic monocyclic or bifused ring system containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0474] The term "heteroaryl" refers to a 5- to 12-membered aromatic group containing 1-4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in the heteroaryl group may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroaromatic." A heteroaryl group may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridyl, furyl, oxadiazolyl, thienyl, 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 pyrazolopyridyl, pyrazolopyridyl, benzotriazolyl, imidazopyridyl, and indolyl.

[0475] The term "carbocycle" or "carbocyclyl" refers to a 4-12 membered saturated or partially saturated hydrocarbon ring and can exist in the form of a monocycle, a bicyclic (including fused, spiro or bridged carbocycles) or a spirocycle. Bicyclic carbocyclyls include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, a cycloalkyl or an aryl group, such as, for example, 2,3-dihydroindenyl, decahydronaphthyl and 1,2,3,4-tetrahydronaphthyl. Unless otherwise indicated, carbocycles typically contain 4 to 10 ring members.

[0476] The term "C 3-6 "Cycloalkyl" refers to a fully saturated carbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0477] The term "heterocycle" or "heterocyclyl" refers to a 4-12 membered saturated and / or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclyl group may be a monocyclic or bicyclic ring (e.g., a bridged bicyclic ring, a fused bicyclic ring, or a spirobicyclic ring). Examples of monocyclic saturated and / or partially unsaturated heterocyclic groups include, but are not limited to, oxetane, tetrahydrofuranyl, tetrahydropyranyl, and hexahydropyridinyl. Bicyclic heterocyclyl groups include, for example, unsaturated heterocyclic groups fused to another unsaturated heterocyclic group, cycloalkyl, aryl, or heteroaryl ring, such as, for example, tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridinyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxabicyclo[2.1.1]hexane, and 9-azabicyclo[3.3.1]nonane. In some embodiments, the heterocyclyl group is a 4-6 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.

[0478] As used herein, the term "spiro" ring refers to a bicyclic ring system in which the two rings share one common atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptanyl and the like.

[0479] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. A fused heterocycle has a ring system that contains at least one ring atom that is a heteroatom selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0480] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety that is linked at two non-adjacent ring atoms (eg, 5-oxabicyclo[2.1.1]hexane).

[0481] The phrase "pharmaceutically acceptable" indicates that the substance, composition or dosage form must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0482] Unless otherwise indicated, the term "compound of the present disclosure" refers to a compound of formula (I), as well as all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution). When there is a moiety capable of forming a salt, salts, especially pharmaceutically acceptable salts, are also included.

[0483] As used herein, unless otherwise indicated herein or clearly contradicted by context, the terms "a," "an," "the," and similar terms used in the context of the present invention (especially in the context of the claims) should be interpreted to cover both the singular and the plural. Unless otherwise claimed, the use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better illustrate the present invention and does not limit the scope of the present invention.

[0484] The intermediates and compounds of the present invention may also exist in different tautomeric forms, all of which are 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 proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0485] In one embodiment, the present disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in salt form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in acid addition salt form. In yet another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable salt form. In yet another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the embodiments in free form. In yet another embodiment, the present disclosure relates to any one of the compounds of the embodiments in salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the embodiments in acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the embodiments in pharmaceutically acceptable salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the embodiments in pharmaceutically acceptable acid addition salt form.

[0486] The compounds of the present disclosure can be synthesized, inter alia, according to the description contained herein, by synthetic routes including processes analogous to those well known in the chemical arts. Starting materials are generally available from commercial sources (such as Sigma-Aldrich) or readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vols. 1-19, Wiley, New York (1967-1999 editions), or including supplements in Beilsteins Handbuch der organischen Chemie, 4, Aufl. edition, Springer-Verlag, Berlin (also available via the Beilstein online database)).

[0487] For illustrative purposes, the reaction schemes depicted below provide potential pathways for synthesizing the compounds disclosed herein and key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions.

[0488] illustration

[0489] abbreviation:

[0490] PE = petroleum ether;

[0491] EtOAc=EA=ethyl acetate

[0492] ESI = Electrospray Ionization

[0493] MeOH = methanol

[0494] EtOH = ethanol

[0495] DCE = 1,2-dichloroethane

[0496] DCM = dichloromethane

[0497] CHCl3=chloroform

[0498] HCl = hydrochloric acid

[0499] H2O = water

[0500] IPA = Isopropyl alcohol

[0501] LCMS = Liquid Chromatography Mass Spectrometry

[0502] HFIP = Hexafluoro-2-propanol

[0503] HPLC = High Pressure Liquid Chromatography

[0504] THF = Tetrahydrofuran

[0505] MeCN=ACN=acetonitrile

[0506] MgSO4 = magnesium sulfate

[0507] DMSO = dimethyl sulfoxide

[0508] AcOH = acetic acid

[0509] TFA = trifluoroacetic acid

[0510] DIPEA = diisopropylethylamine

[0511] N2 = Nitrogen

[0512] NH4HCO3=ammonium bicarbonate

[0513] t-BuOH = tert-butyl alcohol

[0514] NH4Cl = ammonium chloride

[0515] NaH = Sodium Hydride

[0516] Na2SO4=Sodium sulfate

[0517] K2CO3=potassium carbonate

[0518] NaHCO3 = Sodium bicarbonate

[0519] NaBH(OAc)3=STAB=sodium triacetoxyborohydride

[0520] SiO2=silicon dioxide or silica

[0521] PDA = Photodiode Array Detection

[0522] TosMIC = Tosylmethyl isocyanide

[0523] TLC = Thin Layer Chromatography

[0524] LiHMDS = Lithium Bis(trimethylsilyl)amide

[0525] DMA = dimethylamine

[0526] DAST = diethylaminosulfur trifluoride

[0527] ee = enantiomeric excess

[0528] t R =Retention time

[0529] General approach

[0530] LCMS instrument specifications:

[0531] ●Agilent Technologies 1200 Series LC / MSD System: DAD\ELSD Alltech3300 and Agilent LC\MSD G6130A, G6120B mass spectrometers.

[0532] ●Agilent Technologies 1260 Infinity LC / MSD system: DAD\ELSD Alltech3300 and Agilent LC\MSD G6120B mass spectrometer.

[0533] ●Agilent Technologies 1260 Infinity II LC / MSD system: DAD\ELSDG7102A1290 Infinity II and Agilent LC\MSD G6120B mass spectrometer.

[0534] ●Agilent 1260 Series LC / MSD system: DAD\ELSD and Agilent LC\MSD (G6120B) mass spectrometer.

[0535] ●UHPLC Agilent 1290 Series LC / MSD system: DAD\ELSD and Agilent LC\MSD (G6125B) mass spectrometer.

[0536] HPLC assay method description:

[0537] Column: Agilent Poroshell 120SB-C18 4.6 × 30 mm 2.7 μm, with UHPLC GuardInfinity Lab Poroshell 120SB-C18 4.6 × 5 mm 2.7 μm

[0538] Column temperature: 60°C

[0539] Injection volume 0.5 μL

[0540] Modifier: 0.1% (v / v) formic acid

[0541] Method: 99% water / 1% MeCN (initial conditions), maintain initial conditions for 0.1 min, linear gradient to 0% water / 100% MeCN at 1.5 min, maintain 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.

[0542] UV scan: 207-223nm, 246-262nm, 272-288nm

[0543] QC determination LC / MS method conditions:

[0544] Ammonium hydroxide (alkaline pH) conditions

[0545] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0546] PDA: 200-400nm scanning range

[0547] Column: Waters ACQUITY UPLC BEH C18 2.1 × 50 mm, 1.7 μm; part number 186002350

[0548] Modifier: 0.2% (v / v) ammonium hydroxide

[0549] Method: 95% water / 5% MeCN (initial conditions): linear gradient from 95% water / 5% MeCN at 3.75 min to 5% water / 95% MeCN, maintained at 5% water / 95% MeCN until 4 min. Flow rate: 0.8 mL / min.

[0550] Trifluoroacetic acid (acidic pH) conditions

[0551] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0552] PDA: 200-400nm scanning range

[0553] Column: Waters ACQUITY UPLC BEH C18 2.1 × 50 mm, 1.7 μm; part number 186002350

[0554] Modifier: 0.1% (v / v) trifluoroacetic acid

[0555] Method: 95% water / 5% MeCN (initial conditions): linear gradient from 95% water / 5% MeCN at 3.75 min to 5% water / 95% MeCN, maintained at 5% water / 95% MeCN until 4 min. Flow rate: 0.8 mL / min.

[0556] General preparative HPLC conditions:

[0557] Ammonium hydroxide (alkaline pH) conditions

[0558] Flow rate: 30 mL / min

[0559] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0560] PDA: 200-400nm scanning range

[0561] Column: Waters XSELECT CSH C18 PREP 19 × 100 mm, 5 μm; part number 186005421

[0562] Modifier: 0.2% (v / v) ammonium hydroxide

[0563] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, linear change to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0564] Flow rate: 50 mL / min

[0565] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0566] PDA: 200-400nm scanning range

[0567] Column: Waters XSELECT CSH C18 PREP 30 × 100 mm, 5 μm; part number 186005425

[0568] Modifier: 0.2% (v / v) concentration NH4OH

[0569] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, linear change to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0570] Flow rate, 60mL / min

[0571] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0572] PDA: 200-400nm scanning range

[0573] Column: Waters XSELECT CSH C18 PREP 30 × 50 mm, 5 μm; part number 186005423

[0574] Modifier: 0.2% (v / v) concentration NH4OH

[0575] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, linear change to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0576] Trifluoroacetic acid (acidic pH) conditions

[0577] Flow rate, 30 mL / min

[0578] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0579] PDA: 200-400nm scanning range

[0580] Column: Waters Sunfire OBD C18 PREP 19×100 mm, 5 μm; Part No. 186002567 Modifier: 0.1% (v / v) trifluoroacetic acid

[0581] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, linear change to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0582] Flow rate, 50mL / min

[0583] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0584] PDA: 200-400nm scanning range

[0585] Column: Waters Sunfire OBD C18 PREP 30×100 mm, 5 μm; Part No. 186002572 Modifier: 0.1% (v / v) trifluoroacetic acid

[0586] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, linear change to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0587] Flow rate, 60mL / min

[0588] MS mode: MS:ESI+ scanning range 165-650 Daltons

[0589] PDA: 200-400nm scanning range

[0590] Column: Waters Sunfire OBD C18 PREP 30×50 mm, 5 μm; part number 186002570

[0591] Modifier: 0.1% (v / v) trifluoroacetic acid

[0592] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, linear change to 5% water / 95% MeCN at 8.5 min, maintain 5% water / 95% MeCN until 10 min.

[0593] Example 1: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane

[0594]

[0595] 1. Synthesis of tert-Butyl 8-((4-(difluoromethoxy)phenyl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate

[0596]

[0597] To a solution of tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (commercial, 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) + .

[0598] Synthesis of 2.8-((4-(difluoromethoxy)phenyl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane trifluoroacetate

[0599]

[0600] 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:EtOAc (2% NH4OH) 1:3) to give the trifluoroacetic acid salt of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane (302 mg, 77%). LCMS m / z = 335 (M+H) + .

[0601] 3. Synthesis of 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane

[0602]

[0603] To the trifluoroacetic acid 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 until completion. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0-100% EtOH in heptane:EtOAc (2% NH4OH) 1:3) 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(br dd,J=1.8,12.2Hz,2H),1.37-1.21(m,2H).

[0604] Example 2: 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane (racemate)

[0605]

[0606] 1. Synthesis of tert-Butyl 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate

[0607]

[0608] To a solution of tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (commercial, 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 material was used in the next step without further purification. LCMS m / z = 434.1 (M+H-CH3) + .

[0609] Synthesis of 2.9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane

[0610]

[0611] 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 at room temperature overnight, concentrated, and the resulting residue was purified by column chromatography on silica gel (24 g, 0-100% EtOH in heptane:EtOAc (2% NH 4 OH) 1:3) to afford the trifluoroacetic acid salt of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane (568 mg). LCMS m / z=349.0 (M+H) + .

[0612] 3. Synthesis of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0613]

[0614] The title compound was prepared from the trifluoroacetic acid 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 analogous to that described in Step 3 of Example 1. The crude material was purified by column chromatography on silica gel (24 g, 0-100% EtOH in heptane:EtOAc (2% NH4OH) 1:3) 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) + . 1 HNMR(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(br t,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,3 H), 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).

[0615] 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

[0616]

[0617] The title compound was prepared using a method analogous to that described in Step 3 of Example 1 from the trifluoroacetic acid 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) 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).

[0618] The racemate was separated into its enantiomers with arbitrarily specified stereochemistry by SFC separation using CHIRALPAK AD-H 30×250 mm, 5 μm; 30% MeOH with 0.1% DEA in CO 2 (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) to give:

[0619] 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 =2.02min,100%ee,LCMS m / z=433.1(M+H) + )

[0620] 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, LCMS m / z=433.1(M+H) + ).

[0621] For both enantiomers: 1H 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).

[0622] Example 5: 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0623]

[0624] 1. Synthesis of 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0625]

[0626] To a suspension of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (commercial, 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) + .

[0627] 2. Synthesis of 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0628]

[0629] The title compound was prepared using a similar method described in Step 3 of Example 1 from the hydrochloride salt of 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (75 mg, 0.2 mmol) and tetrahydropyran-4-one (100 mg, 0.2 mmol). 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) + . 1 H 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 (br dd, J = 4.3, 11.6Hz, 2H), 3.80 3.70-3.70(m,2H),3.39(br t,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).

[0630] Example 6: 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane (racemate)

[0631]

[0632] To a solution of the hydrochloride salt of 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (Step 1 of Example 5, 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 the 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:EtOAc (2% NH4OH) 1:3) 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) + . 1 H 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(br dd, J=3.7, 14.7Hz, 2H), 1.72 (qd, J=8.3, 12.3Hz, 1H), 1.56-1.45 (m, 2H).

[0633] Example 7: 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0634]

[0635] A mixture of 1-bromo-2-methoxy-ethane (22.5 mg, 162 μmol), 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (Example 5, Step 1, 58.7 mg, 162 μmol), and DIPEA (90 μL, 0.5 mmol) in DMF (2 mL) was stirred at room temperature. After 1 d, additional base (3 eq) and 1-bromo-2-methoxyethane (1 eq) were added. After 1 h, the reaction was quenched with saturated aqueous NaHCO solution and extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous NaCl solution, dried over MgSO 4 , 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 (4min)=1.42min.

[0636] 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

[0637]

[0638] The title compound was prepared using a procedure similar to that described for Example 1 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) 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) + .

[0639] Chiral separation by SFC using a CHIRALPAK IC 30×250 mm, 5 μm (40% IPA with 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 60 psi, column temperature 40° C.)) yielded 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-3-yl)-6-oxa-2,9-diazaspiro[4.5]decane as two diastereomeric pairs of arbitrarily specified stereochemistry: D1 (50 mg, 27%, t R =1.92min,100%de) and D2(50mg,27%,t R =2.15min,88.1%de).

[0640] Example 10 and Example 11: 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)-2-methylpropan-2-ol and 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxy-2-methylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)-2-methylpropan-2-ol

[0641]

[0642] 1. Synthesis of ethyl 2-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)acetate

[0643]

[0644] To a solution of 4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride (Step 1 of Example 5, 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 was determined by LCMS. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous NHCl, water, and brine. The organic phase was dried over NaSO, filtered, and evaporated to dryness to give ethyl 2-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)acetate (296 mg) which was used without further purification. LCMS m / z = 448.8 (M+H) + .

[0645] 2. Synthesis of 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)-2-methylpropan-2-ol

[0646]

[0647] To a solution of ethyl 2-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)acetate (271 mg, 0.6 mmol) in THF (6 mL) was added MeMgBr (2 M, 900 μL) at room temperature. The reaction mixture was stirred for 30 min, then diluted with EtOAc (5 mL) 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 the trifluoroacetic acid salt of 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)-2-methylpropan-2-ol (49 mg, 15%). LCMS m / z = 435.9 (M+H) + . 1 H NMR(500MHz,DMSO-d6)δ(ppm)7.79(br d,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).

[0648] 3. Synthesis of 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxy-2-methylpropyl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0649]

[0650] To a solution of Example 12, 1-(4-((4-(difluoromethoxy)phenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)-2-methylpropan-2-ol, trifluoroacetate (50 mg, 0.1 mmol) and iodomethane (20 μL, 0.3 mmol) in THF (2 mL) was added sodium hydride (10 mg, 0.3 mmol, 60% purity) at room temperature. The reaction mixture was stirred for 3 d, then diluted with EtOAc (5 mL) and washed with saturated aqueous NHCl, water, and brine. The organic phase was dried over NaSO, 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(br s, 2H), 1.83 (br d, J = 13.4Hz, 2H), 1.72-1.53 ​​(m, 2H), 1.17 (s, 6H).

[0651] Examples 12 and 13

[0652]

[0653] Examples 12 and 13 in Table A were prepared from tetrahydropyran-4-one (26 mg, 0.3 mmol) and the corresponding amine using a similar method as described in Step 3 of Example 1. The sulfonamide starting material (1.1 equivalents of sulfonyl chloride) was prepared using standard methods as described above (e.g., in Steps 1 and 2 of Example 1). Purification of the final product after reductive amination was performed by HPLC under acidic or basic conditions.

[0654] Table A

[0655]

[0656]

[0657] 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

[0658]

[0659] Racemic Example 15 was separated into its enantiomers of arbitrarily specified stereochemistry by chiral separation using a CHIRALPAK AD-H 30×250 mm, 5 μm; 20% MeOH containing 0.1% DMEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.) to afford 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).

[0660] E1 1 H NMR (600MHz, DMSO-d6) δ (ppm) 7.72 (br t, J=9.1Hz, 1H), 7.52

[0661] (br d,J=4.4Hz,2H),3.84(br d,J=10.2Hz,4H),3.76-3.56(m,2H),3.05-2.72(m,3H),1.88-1.65(m,8H),1.34(br d,J=8.7Hz,4H).

[0662] E2 1 H NMR (600MHz, DMSO-d6) δ (ppm) 7.72 (br t, J=9.1Hz, 1H), 7.52

[0663] (br d,J=4.4Hz,2H),3.84(br d,J=10.2Hz,4H),3.73-3.56(m,2H),3.06-2.74(m,3H),1.84-1.66(m,8H),1.34(br d,J=8.0Hz,4H).

[0664] Example 16: 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0665]

[0666] 1: Synthesis of tert-butyl 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate

[0667]

[0668] 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 similar method as 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).

[0669] 2: Synthesis of 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane

[0670]

[0671] 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 light yellow oil. LCMS: 328.3 (M+H) + .

[0672] Step 3: 9-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0673]

[0674] 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 NaBH3CN (63 mg, 1.0 mmol). The reaction mixture was stirred at 95°C for 12 h. The mixture was concentrated to give a residue, which was purified by preparative HPLC (column: Phenomenex C18 150×25 mm×10 μm; conditions: water (NH4HCO3)-ACN starting B 18%; ending B: 48% gradient time (min): 8; 100% B holding 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 (29 mg, 20%) as an off-white solid. LCMS: 412.1 (M+H) + . 1 HNMR: (400MHz, CD3OD) δ (ppm): 8.22 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 1.6 Hz, 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).

[0675] Examples 17 and 18

[0676]

[0677] Examples 17 and 18 in Table B were prepared from the hydrochloride salt of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane (Example 2, Step 2, 50 mg, 0.1 mmol) and the corresponding aldehyde using a similar method described in Step 3 of Example 1. Purification was by HPLC (basic conditions).

[0678] Table B

[0679]

[0680]

[0681] Examples 19 and 20:

[0682]

[0683] 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 similar method described in Step 3 of Example 1. Purification was by HPLC (acidic or basic conditions).

[0684] Table C

[0685]

[0686] Example 21: 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0687]

[0688] The title compound was prepared using a similar method as described in Step 3 of Example 1 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 (Example 5, Step 1, 52 mg, 0.1 mmol) 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).

[0689] Example 22: 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane

[0690]

[0691] Synthesis of 1.8-((2-cyclopropylthiazol-5-yl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane

[0692]

[0693] The title compound was prepared using a similar method as described for Example 5, Step 1, from tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (commercial, 60 mg, 0.3 mmol) and 2-cyclopropylthiazole-5-sulfonyl chloride (65 mg, 0.3 mmol) to afford tert-butyl 8-((2-cyclopropylthiazol-5-yl)sulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate. The crude material was stirred with 1N HCl to afford 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) + .

[0694] Synthesis of 2.8-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane

[0695]

[0696] The title compound was prepared using a similar method as described in Step 3 of Example 1 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 (83 mg). Purification by column chromatography on silica gel (12 g, 10-100% EtOH:EtOAc 1:3 in heptane) gave 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) + . 1 H 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).

[0697] Example 23: 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0698]

[0699] 1. Synthesis of 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane

[0700]

[0701] 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) + .

[0702] The crude material 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 hydrochloric acid 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 100% yield (88.6 mg). LCMS m / z = 330.0 (M+H) + .

[0703] Synthesis of 2.9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0704]

[0705] The title compound was prepared using a similar method as described in Step 3 of Example 1 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) to give 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane (29 mg, 51%) after purification by HPLC (basic conditions). LCMS m / z = 414.2 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm) 8.10 (s, 1H), 3.82 (br d, J = 11.6Hz, 2H), 3.60-3.77 (m, 2H), 3.28 (br s,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(br d,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).

[0706] Example 24: 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0707]

[0708] The title compound was prepared using a similar method as described in Step 3 of Example 1 from 2-oxa-spiro[3.3]hept-6-one (23 mg, 0.2 mmol) and 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane hydrochloride (Example 23, Step 1, 45 mg, 0.1 mol) to afford 9-((2-cyclopropylthiazol-5-yl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane (6.4 mg, 15%). LCMS m / z = 426.2 (M+H) + . 1H 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).

[0709] Examples 25, 26, and 27: Racemic 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane, (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane, and (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0710]

[0711] 1. Synthesis of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decane

[0712]

[0713] 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) was added 4-(difluoromethoxy)benzenesulfonyl chloride (788 mg, 3.3 mmol) at room temperature. After 1 h at room temperature, the reaction mixture was washed with saturated aqueous 0.5 M HCl, water, and brine. The organic phase was dried over NaSO, 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 trifluoroacetic acid 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) + .

[0714] 2. Synthesis of racemic 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0715]

[0716] 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 NaBH 3 CN (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 layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The product was purified by preparative HPLC (column Welch Xtimate C18 150×25 mm×5 μm; conditions: water (NH4HCO3)-ACN, start B 35%, end B 65%, gradient time (min) 11, 100% B hold time (min) 2; flow rate (mL / min) 25) to give 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane (111 mg, 43%, 100% purity) as a yellow oil. 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(br d,J=10.1Hz,1H),2.67(br t,J=7.5Hz,1H),2.61-2.44(m,4H),2.36(br dd,J=6.9,11.4Hz,2H),2.16-2.03(m,2H),1.90(br t,J=6.8Hz,2H).

[0717] Chiral Separation of 3.9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0718]

[0719] Racemic 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-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 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 specified stereochemistry:

[0720] Peak 1, enantiomer 1 (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane (33 mg, t R =1.57min,99.9%ee).

[0721] Peak 2, enantiomer 2(S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane (35 mg, t R =1.94 min, 98.8% ee).

[0722] Example 28: 9-((3,5-difluorophenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane

[0723]

[0724] The title compound was prepared using a method similar to that described for step 2 in Example 27 from the trifluoroacetic acid salt of 9-(3,5-difluorophenyl)sulfonyl-6-oxa-2,9-diazaspiro[4.5]decane (200 mg, 0.5 mmol) and 2-oxaspiro[3.3]hept-6-one (52 mg, 0.5 mmol) in MeOH (10 mL) to afford 9-((3,5-difluorophenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane (67 mg, 35%, 100% purity) as a yellow oil. LCMS m / z = 415.1 (M+H) + . 1 H NMR (500 MHz, 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 (brd, J = 11.6 Hz, 1H), 2.80 (quintet, J = 7.6 Hz, 1H), 2.67 (d, J = 10.5 Hz, 1H), 2.62-2.54 (m, 3H), 2.46-2.36 (m, 2H), 2.16-2.09 (m, 2H), 1.96-1.87 (m, 2H).

[0725] Example 29: 4-((3,5-difluorophenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0726]

[0727] 1. Synthesis of 4-((3,5-difluorophenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0728]

[0729] The title compound was prepared using a similar method as described for step 1 of Example 25 from tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (commercial, 100 mg, 0.4 mmol) and 3,5-difluorobenzenesulfonyl chloride (91 mg, 0.4 mmol), followed by HCl deprotection to afford the hydrochloride salt of 4-((3,5-difluorophenyl)sulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane (129 mg theoretical yield), which was used without further purification. LCMS m / z = 333.1 (M+H) + .

[0730] 2. Synthesis of 4-((3,5-difluorophenyl)sulfonyl)-9-((3-methyloxetan-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0731]

[0732] The title compound was prepared using a procedure similar to that described for Example 1 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) to afford 4-((3,5-difluorophenyl)sulfonyl)-9-((3-methyloxetane-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane (25 mg, 31%). LCMS m / z = 417.2 (M+H) + LCMS t R (4min)=1.25min.

[0733] Example 30: 9-((4-(difluoromethoxy)phenyl)sulfonyl)-4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0734]

[0735] 1. Synthesis of tert-Butyl 4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

[0736]

[0737] To a vial of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (commercial, 300 mg, 1.2 mmol) in anhydrous DCM (6 mL) at 23° C. was added tetrahydropyran-4-one (128 mg, 1.3 mmol) and NEt (360 μL, 2.6 mmol) dropwise, followed by AcOH (170 μL, 2.9 mmol) 15 min later. The reaction mixture was stirred at 23° C. for 30 min, followed by the portionwise addition of NaBH(OAc) (992 mg, 4.7 mmol). The reaction was stirred at 23° C. After 6 d, the reaction was quenched by the slow addition of saturated aqueous NaHCO solution, stirred at 23° C. for 10 min, and then extracted with EtOAC (3×). The combined organic layers were washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, 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) + .

[0738] 2. Synthesis of 4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0739]

[0740] 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).

[0741] After 1 d, the reaction mixture was evaporated to dryness to give the hydrochloride salt of 4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane (35 mg), which was used without further purification. LCMS m / z = 241.1 (M+H) + .

[0742] 3. Synthesis of 9-((4-(difluoromethoxy)phenyl)sulfonyl)-4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

[0743]

[0744] To a vial containing the hydrochloride salt of 4-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane (35 mg, 0.2 mmol) in THF (1.5 mL) was added DIPEA (180 μL, 1.0 mmol) and DMAP (2 mg, 0.02 mmol) dropwise, followed by the addition of 4-(difluoromethoxy)benzenesulfonyl chloride (53 mg, 0.2 mmol) after stirring for 5 min. After 1 d, the reaction was quenched with saturated aqueous NaHCO solution and extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous NaCl solution, dried over MgSO 4 , 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) + . 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.81 (br d, J=8.6Hz, 2H), 7.61-7.28 (m, 3H), 3.98 (br d,J=10.4Hz,2H),3.89-3.72(m,1H),3.71-3.41(m,1H),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).

[0745] Example 31: 7-((2,4-dimethylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane

[0746] 1. Synthesis of tert-Butyl 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0747]

[0748] 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 at room temperature overnight and then washed with saturated aqueous NaHCO 3 and water. The organic phase was concentrated and purified by column chromatography on silica gel (24 g, EtOAc 10-50% in heptane) to give tert-butyl 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (294 mg, 75%) as a white foam. LCMS m / z=392.2 (M+H) + .

[0749] Synthesis of 2.7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane

[0750]

[0751] 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) was added TFA (140 μL, 1.9 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 5 h, concentrated under reduced pressure, and co-evaporated with MeCN (3×) to give the trifluoroacetic acid salt of 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane (316 mg) as a white solid. The product was used without further purification. LCMS m / z = 295.0 (M+H) + .

[0752] 3: Synthesis of 7-((2,4-dimethylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[3.5]nonane

[0753]

[0754] To a mixture of tetrahydropyran-4-one (13 mg, 0.1 mmol) and the trifluoroacetic acid 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 and, after stirring for an additional 5 min, NaBH(OAc) (64 mg, 0.3 mmol) was added in one portion. The mixture was stirred at room temperature overnight and then quenched with saturated aqueous NaHCO. More DCM was added and the mixture was stirred for 5 min before 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) + . 1 H NMR(500MHz DMSO-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(dt,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(br d,J=11.6Hz,2H),1.0-1.1(m,2H).

[0755] 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

[0756] The following Examples 32 and 33 were prepared from tetrahydropyran-4-one using a similar method as described for 7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane (Example 31). Data for the intermediates are in Tables D and E (Steps 1 and 2), and data for Examples 32 and 33 are in Table F (Step 3).

[0757] Table D: Intermediates of Step 1

[0758]

[0759] Table E: Intermediates of Step 2

[0760]

[0761]

[0762] Table F: Examples 32 and 33

[0763]

[0764] Example 34: 4-((7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]non-2-yl)methyl)tetrahydro-2H-pyran-4-ol

[0765]

[0766] To a mixture of 1,6-dioxaspiro[2.5]octane (10 mg, 0.1 mmol) and the trifluoroacetic acid 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 NaHCO 3 . The organic phase was separated, concentrated, and purified by column chromatography on silica gel (12 g, EtOAc / EtOH 3:1) to afford 1-((7-((2,4-dimethylphenyl)sulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)cyclohexan-1-ol (19 mg, 69%) as a sticky solid 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 .13-3.04(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(br d,J=13.3Hz,2H).

[0767] Example 35: 7-((2,4-dimethylphenyl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonane

[0768]

[0769] The title compound 35 was prepared using a method similar to that described for Example 31 from the trifluoroacetic acid 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). After column chromatography on silica gel (12 g, EtOAc / EtOH 3:1), 7-((2,4-dimethylphenyl)sulfonyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonane (29 mg, 74%) was obtained as a colorless oil. 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 (br dd,J=11.4,4.4Hz,2H),3.43-3.35(m,2H),3.05-3.13(m,8H),2.58(s,3H),2.42(br d,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).

[0770] Example 36: 8-((2-chloro-4-methylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane

[0771]

[0772] 1. Synthesis of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate

[0773]

[0774] 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)3 (4.0 g, 18.9 mmol) in four portions. The reaction mixture was stirred at room temperature overnight, then quenched with saturated aqueous NaHCO3 and extracted with DCM (3×). The organic layer was dried over MgSO4, filtered, concentrated, and co-evaporated with EtOAc to give tert-butyl 2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (1.69 g) as a light yellow oil, which was used without further purification. LCMS m / z = 309.1 (M+CH3) + .

[0775] 2. Synthesis of 2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane

[0776]

[0777] 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 (1.52 g) as an off-white solid. LCMS m / z = 225.2 (M+H) + .

[0778] 3. Synthesis of 8-((2-chloro-4-methylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane

[0779]

[0780] To the hydrochloride salt of 2-tetrahydropyran-4-yl-2,8-diazaspiro[4.5]decane (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 d, then quenched with saturated aqueous NaHCO₃ and water and stirred at room temperature for 5 min. 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, EtOAc / EtOH 3:1) to give 8-((2-chloro-4-methylphenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decane (43 mg, 69%) as a sticky solid 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 (br dd,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).

[0781] Examples 37-43

[0782] Examples 37-43 in Table G below were prepared using a similar procedure as described for Example 36 from the hydrochloride salt of 2-tetrahydropyran-4-yl-2,8-diazaspiro[4.5]decane (1 equivalent) and the corresponding sulfonyl chloride.

[0783] Table G:

[0784]

[0785]

[0786]

[0787]

[0788] Example 44: 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0789]

[0790] 1. Synthesis of 2-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0791]

[0792] The title compound was prepared using a similar method described in steps 1 and 2 of the intermediate of Example 31 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) and purified by column chromatography on silica gel (24 g, EtOAc in heptane 10-20%) 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 trifluoroacetic acid salt of 2-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane (365 mg), which was used without further purification. 1 H 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).

[0793] 2. Synthesis of 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0794]

[0795] The title compound was prepared from the trifluoroacetic acid 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 similar method as described for Example 31. The crude material 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 (32 mg, 84%) as a colorless oil. 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(br d,J=12.5Hz,2H),1.34-1.14(m,2H).

[0796] Example 45: 4-((6-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)tetrahydro-2H-pyran-4-ol

[0797]

[0798] The title compound was prepared using a similar method described in step 3 of Example 34 from the trifluoroacetic acid 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) to afford 4-((6-((2,4-dimethylphenyl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)tetrahydro-2H-pyran-4-ol (28 mg, 74%) as a white solid after purification by column chromatography on silica gel (12 g, EtOAc / EtOH 3:1). LCMS m / z = 381.2 (M+H) + . 1H 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).

[0799] Example 46: 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0800]

[0801] The title compound was prepared using a procedure analogous to that described in Step 3 of Example 36 from 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane hydrochloride (commercial, 26 mg, 0.1 μmol) and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (27 mg, 0.1 mmol) to give 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%) after HPLC under acidic conditions. LCMS m / z = 395.2 (M+H) + . 1 HNMR(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).

[0802] Examples 47-50:

[0803] Unless otherwise noted, Examples 47-50 in Table H below were prepared from the hydrochloride salt of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (25.5 mg, 100 μmol) and the corresponding sulfonyl chloride (110 μmol) using a similar method as described for Example 36. Unless otherwise noted, purification was by HPLC (acidic or basic conditions).

[0804] Table H

[0805]

[0806]

[0807]

[0808] Example 51: 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0809]

[0810] Hunigs base (322.56 mg, 2.50 mmol, 434.72 uL) 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 rt for 2.5 h. The reaction was then quenched with saturated NaHCO and water, and the solution was stirred at rt 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, EtOAc / EtOH 3 / 1 20-100% in heptane) to give the product as a colorless oil, which precipitated as a white solid after the addition of MeCN. The product was lyophilized overnight to give the desired product as a white solid (208 mg, 82.22% yield). 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).

[0811] Example 52: 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane

[0812]

[0813] Synthesis of 1.6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane

[0814]

[0815] 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 similar method as described for 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 (br t,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(br dd,J=12.3,4.8Hz,2H),1.50-1.41(m,9H).

[0816] Subsequent deprotection of tert-butyl 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate with HCl (Step 2 in Example 36) afforded 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) + .

[0817] 2. Synthesis of 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane

[0818]

[0819] The title compound was prepared using a method similar to that in step 3 of Example 36 from the hydrochloride salt of 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane (38 mg, 0.1 mmol) and 2,4-dimethylbenzenesulfonyl chloride (25 mg, 0.1 mmol) to afford 2-((2,4-dimethylphenyl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane (13 mg, 29%) as an oil after purification by column chromatography on silica gel (12 g, EtOAc / EtOH 3:1). LCMS m / z = 365.2 (M+H) + . 1H 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 (br t,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).

[0820] Examples 53-59

[0821] Unless otherwise noted, Examples 53-59 in Table 1 below were prepared from the hydrochloride salt of 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane (0.1 mmol) and the corresponding sulfonyl chloride or carbonyl chloride (0.1 mmol) using a similar method as described for Example 52. Purification was by HPLC (acidic or basic conditions) unless otherwise noted.

[0822] Table I

[0823]

[0824]

[0825]

[0826] Example 60: 6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane

[0827]

[0828] 1. Synthesis of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane

[0829]

[0830] The title compound was prepared using a similar method described in step 1 of Example 36 from tetrahydropyran-4-one (251 mg, 2.5 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (commercial, 443 mg, 2.1 mmol) to afford tert-butyl 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (548 mg) as a yellow oil which was used without further purification. 1 H NMR (400MHz, CD3OD) δ (ppm): 3.94 (br dd,J=10.8,4.3Hz,2H),3.89-3.78(m,4H),3.39(td,J=11.9,2.0Hz,2H),2.83(s,2H),2.68(t,J=7.2 Hz, 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).

[0831] 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) + .

[0832] 2. Synthesis of 6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane

[0833]

[0834] The title compound was prepared using a method similar to that in step 3 of Example 36 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) to afford 6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.4]octane (21 mg, 58%) as an oil after purification by HPLC (basic conditions). LCMS m / z = 409.2 (M+H) + LCMS t R (2min) = 0.60min

[0835] 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]

[0836]

[0837] 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

[0838]

[0839] The title compound was prepared using a similar method described in step 1 of Example 36 from tetrahydropyran-4-one (143 mg, 1.43 mmol) and v-butyl (1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (300 mg, 1.2 mmol) to afford 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) as a colorless oil after purification by column chromatography on silica gel (DCM / MeOH 9:1). LCMS m / z = 281.1 (M+Ht-Bu) + .

[0840] 2. Synthesis of (1'R,5'S)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]

[0841]

[0842] 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 h then concentrated to give the trifluoroacetic acid salt of (1'R,5'S)-1-(tetrahydro-2H-pyran-4-yl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] (800 mg, crude) as a brown oil which was used without further purification. LCMS m / z = 237.1 (M+H) + .

[0843] 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]

[0844]

[0845] The title compound was prepared using a method analogous to step 3 of Example 36 from the trifluoroacetic acid 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) to afford (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] (160 mg, 48%) as a beige solid 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 (br d, J = 2.8Hz, 2H), 3.91 (br dd,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(br dd,J=3.2,13.6Hz,2H),1.71-1.58(m,4H),1.52-1.39(m,2H),1.31-1.15(m,2H).

[0846] Example 62: 1-((1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol

[0847] 1. Synthesis of tert-butyl (1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate

[0848]

[0849] Potassium 2-methylpropan-2-ol (1 M, 110 mmol) was suspended in DME (160 mL) at -10°C under a N2 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 h. Isopropyl alcohol (7.0 mL, 88.8 mmol) was added at -10°C and the reaction mixture was stirred for an additional 30 min. 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 h, then heated at 50°C for 16 h, and then filtered through Celite. The residue was washed with ethyl acetate (100 mL, 2×). 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 (8.0 g, 76%) as a white solid. Rf (TLC, PE / EtOAc 1:1) 0.43.

[0850] 2. Synthesis of 8-(tert-butyl)-3-ethyl (1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate

[0851]

[0852] 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 chloroformate (5.7 g, 52.3 mmol) at -78°C and then stirred 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 material 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 (7.8 g, 100%) as a yellow liquid. 1H NMR (400MHz, CDCl3) δ (ppm): 4.43-4.22 (m, 4H), 2.36 (br dd,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).

[0853] 3. Synthesis of tert-butyl (1R,5S)-3-cyano-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0854]

[0855] To a solution of 8-(tert-butyl)ethyl 3-(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 NaBH4 (1.5 g, 39.6 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 1 h, then quenched with saturated NH4Cl (20 ml) and extracted with EtOAc (30 mL, 3×). The combined organic phases were washed with brine (20 mL, 2×), dried over anhydrous Na 2 SO 4 , 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 (6.3 g, 94%) as a white solid. 1 H NMR (400MHz, CDCl3) δ (ppm): 4.29 (br s,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).

[0856] 4. Synthesis of tert-butyl (1R,5S)-3-cyano-3-((tosyloxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0857]

[0858] 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-toluenesulfonyl chloride (9.0 g, 47.3 mmol) and the reaction mixture was stirred at 25° C. for 16 h before being 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 (9.1 g, 92%) as a colorless oil. Rf (TLC, PE / EtOAc 1:1) 0.64.

[0859] 5. Synthesis of tert-butyl (1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate

[0860]

[0861] 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 LiAlH4 (30 mL, 1 M in THF) at 0° C. and the mixture was stirred for 3 h at 25° C. The reaction was quenched with Na2SO4×10H2O (1 g), then 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 (3.1 g, 73%) as a yellow solid 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 (br s, 2H), (br d,J=11.8Hz,2H),1.94-1.84(m,2H),1.82-1.70(m,4H),1.45(s,9H).

[0862] 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

[0863]

[0864] 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 Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel (PE / EtOAC 1:1) to afford tert-butyl (1′R,5′S)-1-((2,4-dimethylphenyl)sulfonyl)-8′-azaspiro[azetidine-3,3′-bicyclo[3.2.1]octane]-8′-carboxylate (420 mg, 84%) as a white solid. LCMS m / z=365.2 (M+H-Boc) + .

[0865] 7. Synthesis of (1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]

[0866]

[0867] 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 (400 mg, 1.0 mmol) in DCM (5.0 mL) and TFA (1.0 mL, 13.1 mmol) was stirred at 20° C. for 2 h. The mixture was concentrated in vacuo to give the trifluoroacetic acid salt of (1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] (320 mg, crude) as a white oil. LCMS m / z=321.2 (M+H) + .

[0868] 8. Synthesis of 1-((1'R,5'S)-1-((2,4-dimethylphenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol

[0869]

[0870] (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 at 80° C. in a microwave for 3 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column Welch Xtimate C18 150×25 mm×5 μm; conditions: 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[azetidine-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol (55 mg, 30%, 100% purity) as a white oil. LCMS m / z=393.2 (M+H) + . 1 H 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 (br s,2H),2.57(s,3H),2.38(s,3H),2.20(br s,2H),1.92-1.79(m,6H),1.56(br d,J=7.9Hz,2H),1.12(s,6H).

[0871] 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]

[0872]

[0873] 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

[0874]

[0875] A solution of (1'R,5'S)-tert-butyl 8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (Step 5 of Example 63, 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) 3 (2.1 g, 9.9 mmol) was added. The mixture was stirred at 18° C. for 16 h, then quenched with saturated aqueous NaHCO 3 (30 mL) and extracted with DCM (30 mL, 3×). The combined organic phases were dried over anhydrous Na2SO4, 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 (530 mg, 79%) as a colorless oil. LCMS m / z = 283.1 [M+Ht-Bu] + .

[0876] 2. Synthesis of ethyl 2-((1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octan]-1-yl)acetate

[0877]

[0878] To a solution of tert-butyl (1'R,5'S)-1-(2-ethoxy-2-oxoethyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (510 mg, 1.5 mmol) in EtOAc (20 mL) was added HCl (4M, 11.3 mL) and the reaction mixture was stirred at 20 °C for 6 h, then concentrated to give ethyl 2-((1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-1-yl)acetate hydrochloride (460 mg) as a white solid. LCMS m / z = 239.2 (M+H) + .

[0879] Synthesis of ethyl 2-((1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octyl]-1-yl)acetate

[0880]

[0881] To a solution of ethyl 2-((1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octan]-1-yl)acetate hydrochloride (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 for 4 h at 20° C. 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 Na 2 SO 4 , filtered, and concentrated to give a residue that was purified by column chromatography on silica gel (DCM / MeOH 19:1) to afford ethyl 2-((1′R,5′S)-8′-((4-(difluoromethoxy)phenyl)sulfonyl)-8′-azaspiro[azetidine-3,3′-bicyclo[3.2.1]octan]-1-yl)acetate (180 mg, 45%) as a white solid. LCMS m / z=445.2 (M+H) + .

[0882] 4. Synthesis of 1-((1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octan]-1-yl)-2-methylpropan-2-ol

[0883]

[0884] In a Schlenk tube, to a stirred solution of ethyl 2-((1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octan]-1-yl)acetate (180 mg, 0.4 mmol) in THF (5 mL) at 0° C. was added bromo(methyl)magnesium (3 M, 2.8 mmol). The reaction mixture was stirred at 20° C. for 3 h, then quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (20 mL, 3×). The combined organic layers were washed with brine (10 ml, 3×), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give 1-((1′R,5′S)-8′-((4-(difluoromethoxy)phenyl)sulfonyl)-8′-azaspiro[azetidine-3,3′-bicyclo[3.2.1]octan]-1-yl)-2-methylpropan-2-ol (150 mg, crude) as a yellow oil. LCMS m / z=431.1 (M+H) + .

[0885] 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]

[0886]

[0887] To a mixture of 1-((1'R,5'S)-8'-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-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. over 16 h. The mixture was quenched with H2O (10 mL, 3×), the combined organic layers were washed with DCM (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue, which was purified by preparative HPLC (column Welch Xtimate C18 150×25 mm×5 μm, conditions: water (10 mM NH4HCO3)-ACN, start B 41%, end 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] (20 mg, 13%) as a brown solid.

[0888] LCMS m / z=445.3(M+H) + . 1 H NMR(400MHz,CD3OD)δ(ppm):7.91(d,

[0889] J=8.8Hz,2H),7.29(d,J=8.8Hz,2H),7.20-6.81(m,1H),4.21(br s,2H),3.38(br s,2H),3.16(s,3H),3.07(br s,2H),2.47(br s,2H),2.18(br d,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).

[0890] 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]

[0891]

[0892] 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

[0893]

[0894] To a solution of tert-butyl (1'R,5'S)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]-8'-carboxylate (Step 5 of Example 63, 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 layers were washed with brine (30 mL, 3×), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel (PE / EtOAc 1:1) to afford 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, 83%) as a white solid. LCMS m / z=403.1 (M+H-Boc) + .

[0895] 2. Synthesis of (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane]

[0896]

[0897] 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 h, then concentrated in vacuo to afford the trifluoroacetic acid salt of (1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octane] (250 mg, crude) as a white solid. LCMS m / z=359.1 (M+H) + .

[0898] 3. Synthesis of 1-((1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol

[0899]

[0900] (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 taken up in a microwave tube in THF (1 mL). The sealed tube was heated at 80°C in a microwave 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, which was purified by column chromatography on silica gel (DCM / MeOH 1:1) to afford 1-((1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-3,3'-bicyclo[3.2.1]octan]-8'-yl)-2-methylpropan-2-ol (130 mg, 95%) as a white solid. LCMS m / z = 431.1 (M+H) + .

[0901] 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]

[0902]

[0903] To a solution of 1-((1'R,5'S)-1-((4-(difluoromethoxy)phenyl)sulfonyl)-8'-azaspiro[azetidine-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 Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm; conditions: water (NH 4 HCO 3 )-CAN; start B: 51%; end B: 81%; gradient time (min): 10; 100% B hold 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] (49 mg, 49%) as a yellow solid. LCMS m / z=445.2(M+H) + . 1 H 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).

[0904] Example 65: 2-((1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0905]

[0906] 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 the hydrochloride salt of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (75 mg, 411 μmol) and 2-(cyclopropylmethyl)-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (91 mg, 316 μmol) using a similar method described for Example 36. The crude product was purified by column chromatography using {20-100%: EtOAc:EtOH (3:1) in EtOH with 0.2% NH3OH} to give the title compound (137 mg, 94% yield) as an off-white residue. 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, 11.4H z),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).

[0907] 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

[0908]

[0909] 1. Synthesis of tert-Butyl 6-((Tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0910]

[0911] 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. until pH = 5-6 for 30 min, 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 (from 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 (br s,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).

[0912] 2. Synthesis of 2-((Tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0913]

[0914] 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 h. LCMS showed that the desired product mass 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) + . 1H NMR (chloroform-d, 400 MHz) 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=7.2 Hz, 2H), 1.92-1.86 (m, 1H), 1.63-1.58 (m, 2H), 1.37-1.33 (m, 2H).

[0915] 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

[0916]

[0917] 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 μmol) using a method similar to that described for Example 46. The crude product was purified by column chromatography using {20-100%: EtOAc:EtOH (3:1) with 0.2% NH3OH} in EtOH to give the title compound (69 mg, 62% yield) as an off-white residue. 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).

[0918] Example 67: 2-((6-Bromo-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0919]

[0920] 2-((6-Bromo-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane was prepared from the hydrochloride salt of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (350 mg, 1.6 mmol) and 6-bromo-2-methyl-pyridine-3-sulfonyl chloride (333.00 mg, 1.23 mmol) using a similar method as described for Example 46. The crude product was purified by column chromatography using {0-100%: EtOAc:EtOH (3:1) in EtOH with 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 (br d, 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).

[0921] Example 68: rac-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[0922]

[0923] Racemic 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane was prepared from the hydrochloride salt of 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (75 mg, 172 μmol) and 2-oxaspiro[3.3]hept-6-one (20.4 mg, 181 μmol) using a method similar to Example 31. 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 (23 mg, 32% yield). LCMS m / z = 418.1 (M+H) + . 1 H NMR 1H NMR (chloroform-d, 500MHz) δ (ppm) 8.36 (br d, 1H, J = 8.2Hz), 7.65 (br d, 1H, J = 8.2Hz), 4.5-4.8 (m, 4H), 4.03 (s, 4H), 3.21 (s, 4H), 2.89 (s, 3H), 2.81 (br t,1H,J=7.0Hz),2.2-2.4(m,2H),1.9-2.0(m,2H).

[0924] Example 69: rac-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[0925]

[0926] Racemic 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane was prepared from the hydrochloride salt of 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (90 mg, 207 μmol) and 1-oxaspiro[3.3]hept-6-one (24.41 mg, 217.74 μmol) using a method similar to Example 31. 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 (58 mg, 67% yield). LCMS m / z = 418.1 (M+H) + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 8.36 (br d, 1H, J = 7.9Hz), 7.65 (br d, 1H, J = 7.9Hz), 4.4-4.6 (m, 2H), 3.9-4.1 (m, 4H), 3.58 (br d,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).

[0927] Examples 70 and 71: 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4s,6s)-1-oxaspiro[3.3]hept-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]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[0928] and

[0929] Racemic-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane was purified via SFC (CHIRALPAK IG 30×250 mm, 5 μm method: 30% EtOH with 0.1% DEA in CO (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40° C.)) to give two cis-trans isomers:

[0930] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4s,6s)-1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane (5.8 mg, 100% ee, t R =1.56min,LCMS m / z=418.1(M+H) + ).

[0931] and 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((4r,6r)-1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane (10.3 mg, 97.5% ee, t R =1.88min,LCMS m / z=418.1(M+H) + ).

[0932] 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

[0933]

[0934] 1. Synthesis of tert-Butyl 6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0935]

[0936] 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 (4×). The solvent was removed in vacuo and the crude material was purified by silica gel chromatography (EtOAc-EtOAc / EtOH (0-40%) to give the title compound (150 mg, 47% yield). LCMS m / z = 311.1 (M+H) + .

[0937] 2. Synthesis of 2-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0938]

[0939] 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) was carefully added TFA (1.30 g, 11.43 mmol, 875.50 μL) dropwise at <5°C. After the addition of TFA was complete, 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) + .

[0940] 3. Synthesis of 2-((6-bromo-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0941]

[0942] Han's base (321.63 mg, 2.49 mmol, 433.47 uL) was added to a vial of 2-[(4-methyltetrahydropyran-4-yl)methyl]-2,6-diazaspiro[3.3]heptane (128 mg, 395.88 μmol, trifluoroacetate) in anhydrous dichloromethane (2 mL). After 5 minutes, 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (98.42 mg, 395.88 μmol) was carefully added to the solution. After the completion 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 NaHCO (saturated aqueous) and water. The crude material was purified by column chromatography using {0-100%: EtOAc:EtOH (3:1) in EtOH with 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(br d,2H,J=13.4Hz),0.93(s,3H).

[0943] 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

[0944]

[0945] 1. Synthesis of (6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanone

[0946]

[0947] A mixture of 2-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl]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) in DMF (2 mL) and DIPEA (402.22 mg, 3.11 mmol, 542.07 μL) 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 hr. 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 2 , 50-100% EtOH in heptane: EtOAc 1:3) 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 (br d, 1H, J = 8.2Hz), 7.67 (br d, 1H, J = 7.9Hz), 4.32 (br s,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).

[0948] 2. Synthesis of 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

[0949]

[0950] (1-Methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-[2-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl]sulfonyl]-2,6-diazaspiro[3.3]heptan-6-yl]methanone (270 mg, 606.12 μmol) 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 RT and quenched with the addition of 5 ml of MeOH. The reaction was heated to 50° C. again and stirred overnight. The reaction was cooled to RT and the solvent was removed in vacuo. The crude product was purified by column chromatography using {0-100%: EtOAc:EtOH (3:1) in EtOH with 0.2% NH 3 OH} to provide the title compound (68 mg, 26%). LCMS m / z=432.0(M+H) + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 8.36 (br d, 1H, J = 7.9Hz), 7.65 (br d,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).

[0951] Example 74: 2-((1-methyl-2-oxabicyclo[3.1.1]hept-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0952]

[0953] 1. Synthesis of (6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)(1-methyl-2-oxabicyclo[3.1.1]hept-5-yl)methanone

[0954]

[0955] A mixture of 2-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl]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) in DMF (2 mL) and DIPEA (402.22 mg, 3.11 mmol, 542.07 μL) 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 hours. 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 2 , 50-100% EtOH in heptane: EtOAc 1:3) to give the title compound (195 mg, 68% yield). LCMS m / z=460.1 (M+H) + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 8.37 (br d, 1H, J = 7.9Hz), 7.67 (br d, 1H, J = 8.2Hz), 4.30 (br s,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).

[0956] 2. Synthesis of 2-((1-methyl-2-oxabicyclo[3.1.1]hept-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0957]

[0958] (1-Methyl-2-oxabicyclo[3.1.1]hept-5-yl)-[2-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl]sulfonyl]-2,6-diazaspiro[3.3]hept-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 RT and quenched with the addition of 5 ml of MeOH. The reaction was heated to 50°C again and stirred overnight. The reaction was cooled to RT and the solvent was removed. The crude product was purified by column chromatography using {0-100%: EtOAc:EtOH (3:1) in EtOH with 0.2% NH3OH} to provide the title compound (130 mg, 74%). LCMS m / z=446.1(M+H) + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 8.36 (br d, 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 (br t, 2H, J = 6.7Hz), 1.82 (br dd, 2H, J = 2.0, 7.2Hz), 1.55 (brd, 2H, J = 7.9Hz), 1.21 (s, 3H).

[0959] Example 75: 4-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)tetrahydro-2H-pyran-4-ol

[0960]

[0961] Han's base (122.17 mg, 945.32 μmol, 164.65 uL) was added 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) and 1,6-dioxaspiro[2.5]octane (80.93 mg, 708.99 μmol) in EtOH (4 mL). The mixture was heated at 55 °C for 30 min, then at RT overnight. The reaction was diluted with EtOAc and washed with saturated NaHCO. The organic phase was further washed with water and concentrated. The residue was purified by column chromatography (12 g, EtOAc / EtOH 3 / 1 50-100% 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(br t,J=18.77Hz,3H),1.39-1.50(m,2H),1.28(br d,J=12.82Hz,2H).

[0962] 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

[0963]

[0964] 1. Synthesis of 4-(6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)tetrahydro-2H-pyran-4-carbonitrile

[0965]

[0966] 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 hr. The reaction was cooled to RT 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 HNMR (chloroform-d, 500MHz) δ (ppm) 7.03 (s, 1H), 4.15 (s, 3H), 4.05 (s, 4H), 3.90 (br d, 2H, J = 12.2Hz), 3.5-3.7 (m, 2H), 3.42 (br s, 4H), 1.77 (br d,2H,J=13.1Hz),1.4-1.6(m,2H).

[0967] 2. Synthesis of 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0968]

[0969] 4-[2-[2-Methyl-5-(trifluoromethyl)pyrazol-3-yl]sulfonyl-2,6-diazaspiro[3.3]hept-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 warmed 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 was removed in vacuo. The crude material was purified by column chromatography using {0-100%: EtOAc:EtOH (3:1) in EtOH with 0.2% NH3OH}. LCMS m / z = 409.1 (M+H) + . 1 H NMR (chloroform-d, 500 MHz) 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).

[0970] Example 77: 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0971]

[0972] 1. Synthesis of 4-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)tetrahydro-2H-pyran-4-carbonitrile

[0973]

[0974] 4-Hydroxytetrahydropyran-4-carbonitrile (49.46 mg, 389.02 μmol) and 2-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl]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 hr. The reaction was cooled to RT 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) + . 1 H NMR (chloroform-d, 500MHz) δ (ppm) 8.37 (br d, 1H, J = 7.9Hz), 7.66 (br d, 1H, J = 7.9Hz), 4.09 (s, 3H), 4.0-4.0 (m, 1H), 3.91 (br d,2H,J=12.2Hz),3.60(brt,2H,J=10.2Hz),3.46(s,4H),2.91(s,3H),1.78(br d,2H,J=13.4Hz),1.5-1.6(m,2H).

[0975] 2. Synthesis of 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methyltetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0976]

[0977] 4-[2-[[2-Methyl-6-(trifluoromethyl)-3-pyridinyl]sulfonyl]-2,6-diazaspiro[3.3]hept-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 warmed 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 was removed in vacuo. The crude material was purified by column chromatography using {0-100%: EtOAc:EtOH (3:1) in EtOH, containing 0.2% NH3OH} to give the target compound (108 mg, 59%). LCMS m / z=420.0 (M+H) + . 1H NMR (chloroform-d, 500MHz) δ (ppm) 8.37 (br d, 1H, J = 7.9Hz), 7.66 (br d,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).

[0978] Example 78: 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[0979]

[0980] 1. Synthesis of 3-bromo-6-(1,1-difluoroethyl)-2,3-dimethylpyridine

[0981]

[0982] 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. Thereafter, a saturated aqueous ammonium chloride solution was added to quench the reaction, and extraction and liquid separation were performed. 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 = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 2.73 (s, 3H), 2.70 (s, 3H).

[0983] 2. Synthesis of 3-(Benzylthio)-6-(1,1-difluoroethyl)-2-methylpyridine

[0984]

[0985] 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(tBu3P)2 (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 N2 for 16 h. The mixture was quenched with H2O (100 mL). The reaction mixture was extracted with DCM (50 mL×5), and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, 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).

[0986] 3. Synthesis of 6-(1,1-difluoroethyl)-2-methylpyridine-3-sulfonyl chloride

[0987]

[0988] 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) was added SO₂Cl₂ (3.38 g, 25.06 mmol, 2.03 mL) at 0° C. The mixture was stirred at 0° C. under N₂ for 1 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL×5). The combined organic phases were 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).

[0989] 4. Synthesis of tert-Butyl 6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0990]

[0991] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (500 mg, 1.75 mmol, oxalate) 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 x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (EtOAc in petroleum ether = 30% to 50%) 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).

[0992] 5. Synthesis of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0993]

[0994] 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 mmol) 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 h. 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).

[0995] 6. Synthesis of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[0996]

[0997] 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) until pH = 8. The solution was stirred at 20° C. for 20 minutes, then adjusted to pH = 6 using acetic acid. Stirring was continued at 20° C. for 30 minutes. NaBH 3 CN (146.02 mg, 2.32 mmol) was added, and the reaction mixture was stirred at 20° C. for 14 hours. 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: C18-1150*30mm*5μm, conditions: water (NH4HCO3)-ACN, 32% to 62%, flow rate (mL / min): 25) to give the title compound (53.23 mg, 128.74 μmol, 27.70% yield) as a white oil. LCMS m / z=414.1 (M+H) + . 1 HNMR(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, 4H),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).

[0998]

[0146] Examples 79-89 in the table below were prepared using a similar procedure described in step 4 of Example 78 from the TFA salt of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (1 equiv) and the corresponding aldehyde or ketone (SM).

[0999]

[1000]

[1001]

[1002]

[1003] Example 90: 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1004]

[1005] 1. Synthesis of 6-bromo-2-methylnicotinaldehyde

[1006]

[1007] 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 minutes. After stirring at -78 ° C for 2.5 hours, DMF (1.05 g, 14.35 mmol, 1.11 mL) was added dropwise. The mixture was stirred at -78 ° C for 1 hour, then slowly warmed to 15 ° C. After stirring at 15 ° C for 3 hours, NH4Cl (100 mL) was added dropwise to terminate the reaction. 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, 400 mg) as a white solid.

[1008] 1.50 mmol, 18.82% yield). 1 H NMR (500MHz, CDCl3) δ (ppm) 10.01 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 2.77 (s, 3H).

[1009] 2. Synthesis of 6-bromo-3-(difluoromethyl)-2-methylpyridine

[1010]

[1011] To a solution of 6-bromo-2-methylnicotinaldehyde (2.0 g, 10.00 mmol) in DCM (5 mL) cooled to -78 ° C was added DAST (4.83 g, 30.00 mmol, 3.96 mL) portionwise under N atmosphere. The mixture was stirred at 25 ° C for 4 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (30 mL) at 0 ° C. The mixture was extracted with DCM (15 mL × 3). The combined organic phases were 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. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.95 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.56 (t, J = 55.2 Hz, 1H), 2.70 (s, 3H).

[1012] 3. Synthesis of 6-(Benzylthio)-3-(Difluoromethyl)-2-methylpyridine

[1013]

[1014] 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(tBu3P)2 (534.00 mg, 1.04 mmol) and BnSH (2.51 g, 20.21 mmol, 2.37 mL). The mixture was then stirred at 100 ° C under N2 for 16 h. The mixture was quenched with saturated NaClO (200 mL). The reaction mixture was extracted with DCM (40 mL×3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the desired compound (4.9 g, crude) as a yellow oil. LCMS m / z=266.1 (M+H) + . 1 HNMR (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).

[1015] Synthesis of 4.5-(Difluoromethyl)-6-methylpyridine-2-sulfonyl chloride

[1016]

[1017] To a solution of 6-(benzylthio)-3-(difluoromethyl)-2-methylpyridine (1.6 g, 6.03 mmol) in DCM (15 mL) and water (3 mL) was added SO₂Cl₂ (5.70 g, 42.21 mmol, 3.42 mL) at -10°C. The mixture was then stirred at -10°C under N₂ for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (25 mL×3). The combined organic phases were 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 = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 54.8 Hz, 1H), 3.05 (s, 3H).

[1018] 5. Synthesis of 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1019]

[1020] 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 h. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were 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*5μm; conditions: water (NH4HCO3)-ACN; start B: 26; end B: 56; flow rate (mL / min): 25) to obtain the target compound (170 mg, 438.77 μmol, 43.19% yield) as a white solid. LCMS m / z=388.1 (M+H) + . 1H 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).

[1021] Example 91: 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1022]

[1023] 1. Synthesis of tert-Butyl 6-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[1024]

[1025] 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 (EtOAc in petroleum ether = 1% to 10%) 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 = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 6.62 (t, J = 54.8 Hz, 1H), 4.06 (s, 4H), 4.03 (s, 4H), 2.86 (s, 3H), 1.42 (s, 9H).

[1026] 2. Synthesis of 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[1027]

[1028] 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 h. 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 HNMR (500MHz, MeOD) δ (ppm) 8.41 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 6.74 (t, J = 55.0 Hz 1H), 4.24 (s, 4H), 4.16 (s, 4H), 2.84 (s, 3H).

[1029] 3. Synthesis of 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1030]

[1031] A solution of 2-((6-(difluoromethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (400 mg, 960.75 μmol, TFA salt) and TEA (291.65 mg, 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 the pH was adjusted to 5-6 by the addition of HOAc at 0° C. for 30 min. NaBH 3 CN (181.13 mg, 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×3). The combined organic phases were washed with brine (20 mL×1), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5μm; conditions: water (NH4HCO3)-ACN; start B: 27; end B: 57; flow rate (mL / min): 25) to obtain the target compound (88 mg, 23% yield) as a colorless oil. LCMS m / z=400.1 (M+H) + . 1H 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).

[1032] Example 92: 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1033]

[1034] 1. Synthesis of 2-(6-bromo-2-methylpyridin-3-yl)propan-2-ol

[1035]

[1036] 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) at -70°C under nitrogen. 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) indicated 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, washed with saturated 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 (EtOAc in petroleum ether = 0% to 30%) 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).

[1037] 2. Synthesis of 6-bromo-3-(2-fluoropropan-2-yl)-2-methylpyridine

[1038]

[1039] 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 adding saturated aqueous NaHCO solution (350 mL) at -5 ° C, diluted with water (30 mL), and extracted with DCM (50 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc in petroleum ether = 0% to 10%) to give the desired compound (3.3 g, 93% yield) as a yellow oil. 1 H NMR (400 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).

[1040] 3. Synthesis of 6-(Benzylthio)-3-(2-fluoropropyl-2-yl)-2-methylpyridine

[1041]

[1042] 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(tBu3P)2 (726.64 mg, 1.42 mmol) and BnSH (3.07 g, 24.72 mmol, 2.90 mL). The mixture was then stirred at 100 ° C under N2 for 16 h. LCMS showed that the desired product mass was observed. The mixture was quenched with H2O (130 mL). The reaction mixture was extracted with DCM (50 mL×5). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, 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).

[1043] 4. Synthesis of 5-(2-fluoropropan-2-yl)-6-methylpyridine-2-sulfonyl chloride

[1044]

[1045] 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) was added SO₂Cl₂ (6.18 g, 45.75 mmol, 3.71 mL) at -10°C. The mixture was then stirred at 25°C under N₂ for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were 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).

[1046] 5. Synthesis of tert-Butyl 6-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[1047]

[1048] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (220 mg, 768.48 μmol, oxalate) and DIPEA (496.59 mg, 3.84 mmol, 669.26 μL) in DCM (10 mL) was added 5-(2-fluoroprop-2-yl)-6-methylpyridine-2-sulfonyl chloride (483.57 mg, 1.92 mmol) at 0° C. under N2. The mixture was stirred at 25° C. for 3 h. LCMS showed that the desired product mass was observed. The reaction mixture was diluted with water (30 mL) and extracted with DCM (20 mL×3). The combined organic phases were 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) + . 1 H 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).

[1049] 6. Synthesis of 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[1050]

[1051] 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) at 25 °C under N2. The mixture was stirred at 25 °C for 16 h. LCMS showed that the desired product mass 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 = 8.0 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 4.25 (s, 4H), 4.07 (s, 4H), 2.78 (s, 3H), 1.72 (s, 3H), 1.68 (s, 3H).

[1052] 7. Synthesis of 2-((6-(2-fluoropropan-2-yl)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1053]

[1054] 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. NaBH 3 CN (221.06 mg, 3.52 mmol) was added and the reaction mixture was stirred at 25° C. for 6 h. LCMS indicated the reaction was complete. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm, 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).

[1055] 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

[1056]

[1057] 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) was added DIPEA (295.44 mg, 2.29 mmol, 398.17 μL) and 5-(2-fluoroprop-2-yl)-6-methylpyridine-2-sulfonyl chloride (287.7 mg, 1.14 mmol) at 0°C under N2. The mixture was stirred at 25°C for 4 h. LCMS showed that the desired product mass was observed. The mixture was quenched by the addition of water (5 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; conditions: water (NH3.H2O+NH4HCO3)-ACN; start B: 40; end B: 70; flow rate: 25mL / min) to give the title compound (43mg, 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), 3.37-3.31 ( 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).

[1058] Example 94: 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1059]

[1060] 1. Synthesis of 6-(difluoromethoxy)-2-methyl-3-nitropyridine

[1061]

[1062] 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 x 2) and extracted with EtOAc (150 mL x 2). The combined layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using 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).

[1063] 2. Synthesis of 6-(difluoromethoxy)-2-methylpyridin-3-amine

[1064]

[1065] To a solution of 6-(difluoromethoxy)-2-methyl-3-nitropyridine (1 g, 4.90 mmol) was added Pd / C (1.00 g, 939.67 μmol, 10% purity) at 25° C. under N . The mixture was purged with H 2 several times and stirred at 95° C. under H 2 (15 Psi) for 16 h. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (EtOAc in petroleum ether, 0% to 50%) to give the desired compound (300 mg, 35% yield) as a yellow oil. LCMS m / z=175.2 (M+H) + . 1 H 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).

[1066] 3. Synthesis of 6-(difluoromethoxy)-2-methylpyridine-3-sulfonyl chloride

[1067]

[1068] SOCl2 (2 mL) was added to water (10 mL) over 10 min while maintaining a temperature of 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 another flask, a solution of 6-(difluoromethoxy)-2-methylpyridin-3-amine (300 mg, 1.72 mmol) in HCl (12 M, 1.44 mL) was added dropwise at -5°C to a solution of NaNO2 (130.74 mg, 1.89 mmol) in water (2 mL) while maintaining a temperature of -5 to 0°C. When the addition was complete, the solution was then added to a pre-cooled thionyl chloride solution and stirred at -2°C for 0.5 h, then at 0°C for 2 h. The mixture was diluted with water (80 ml) and extracted with EtOAc (50 mL x 3). The combined organic phases were 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).

[1069] 4. Synthesis of 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1070]

[1071] 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: C18150*25mm*5μm; conditions: water (NH4HCO3)-ACN; start B: 24%; end B: 54%; flow rate (mL / min): 25) to give 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).

[1072] Example 95: 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1073]

[1074] 1. Synthesis of tert-butyl 6-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[1075]

[1076] 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 min. The mixture was stirred at 20° C. for 2 h. 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, which 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).

[1077] 2. Synthesis of 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[1078]

[1079] 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 h. 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) + . 1 H 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 (br s, 4H), 4.11 (s, 4H), 2.73 (s, 3H).

[1080] 3. Synthesis of 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1081]

[1082] A solution of 2-((6-(difluoromethoxy)-2-methylpyridin-3-yl)sulfonyl)-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 at 20° C. under N for 1 h. NaBH 3 CN (145.35 mg, 2.31 mmol) was added, and the mixture was stirred at 20° C. under N 2 for another 2 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. The residue was purified by preparative HPLC (column: Welch Xtimate: C18 150*25mm*5μm; conditions: water (NH4HCO3)-ACN; start B: 33%; end B: 63%; flow rate (mL / min): 25) to give 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).

[1083] Example 96: 2-((3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1084]

[1085] 1. Synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole

[1086]

[1087] DAST (30.74 g, 190.71 mmol, 25.20 mL) was added dropwise to a -20 ° C solution of 1-methyl-1H-pyrazole-3-carbaldehyde (7 g, 63.57 mmol) in DCM (100 mL) and the reaction mixture was stirred at 15 ° C for 2 h. The mixture was quenched with saturated aqueous NaHCO (40 mL) and extracted with DCM (30 mL × 2). The combined organic phases were 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).

[1088] 2. Synthesis of lithium 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfinate

[1089]

[1090] To a -50 ° C solution of 3-(difluoromethyl)-1-methyl-1H-pyrazole (3 g, 22.71 mmol) in THF (60 mL) was added n-BuLi (2.5 M, 14.53 mL) dropwise over 10 min under nitrogen. The mixture was stirred at -50 ° C for 1 h. Excess SO gas was bubbled into the THF solution (10 mL) for 10 min and 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 a 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).

[1091] 3. Synthesis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfonyl chloride

[1092]

[1093] To a 0°C solution of 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfinate lithium (4.5 g, 22.27 mmol) in DCM (35 mL) and water (35 mL) was added NCS (4.46 g, 33.40 mmol) under nitrogen, and the mixture was then 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 (EtOAc in petroleum ether=0%-10%) 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).

[1094] 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

[1095]

[1096] To a 0-5° C. 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) was added 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-sulfonyl chloride (139.19 mg, 603.53 μmol), and the mixture was stirred at 15° C. for 1 h. The mixture was concentrated in vacuo and purified by preparative HPLC (column: Welch Xtimate C18 150*30 mm*5 μm, conditions: water (10 mM NH 4 HCO 3 )-ACN, 22% to 52%, flow rate (mL / min): 25) to give 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).

[1097] Example 97: 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1098]

[1099] 1. Synthesis of 3-methoxy-1-methyl-1H-pyrazole

[1100]

[1101] 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 N2 for 16 h. TLC showed that a new spot was detected. The mixture was quenched with H2O (20 mL) and extracted with DCM (80 mL×2). The combined organic phases were washed with brine (40 mL×1), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column (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).

[1102] 2. Synthesis of lithium 3-methoxy-1-methyl-1H-pyrazole-5-sulfinate

[1103]

[1104] 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 at -65 ° C over 5 min and the reaction mixture was stirred at 0 ° C under N 2 for 1 h. SO 2 was bubbled into THF (10 mL) at -20 ° C for 10 min and then slowly added to the solution over 10 min. The resulting mixture was stirred at -65 ° C for 1 h and then at 25 ° C for 1 h. The mixture was concentrated in vacuo and the residue was triturated in 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).

[1105] 3. Synthesis of 3-methoxy-1-methyl-1H-pyrazole-5-sulfonyl chloride

[1106]

[1107] 3-Methoxy-1-methyl-1H-pyrazole-5-sulfinic acid lithium (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 under vigorous stirring. The reaction mixture was further stirred at 5 ° C for 30 min. LCMS showed that the reaction was complete. The mixture was diluted with water (30 mL). The mixture was extracted with DCM (30 mL × 3). The combined organic phases were 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).

[1108] 4. Synthesis of tert-Butyl 6-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[1109]

[1110] 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 h, then diluted with water (15 mL). The reactants were extracted with DCM (15 mL x 3). The combined organic phases were 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 (EtOAc in petroleum ether = 15% to 50%) 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).

[1111] 5. Synthesis of 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[1112]

[1113] 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 h. The mixture was concentrated in vacuo to give the desired compound (1.2 g, 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).

[1114] 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

[1115]

[1116] 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). The pH was adjusted to 5-6 at 0° C. by the addition of acetic acid (187.01 mg, 3.11 mmol, 178.28 μL) in one portion, and the solution was stirred for 30 min. NaBH 3 CN (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×3). The combined organic phases were washed with brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction was purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm; 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) + . 1H 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).

[1117] Example 98: 2-((2-chloro-6-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1118]

[1119] 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 h. LCMS showed that the expected mass was observed. The mixture was diluted with water (35 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5μm, conditions: water (NH4HCO3)-ACN, flow rate (mL / min): 25) to give the title compound (79 mg, 50% yield) as a white solid. 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).

[1120] Example 99: 2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1121]

[1122] 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 similar method described for Example 98. The crude product was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5μm, conditions: water (NH4HCO3)-ACN, flow rate (mL / min): 25) to give the title compound (62 mg, 39.47% yield) as a white solid.

[1123] LCMS m / z=388.1(M+H) + . 1 H NMR (400MHz, CDCl3) δ (ppm) 8.26 (d,

[1124] 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).

[1125] Example 100: 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1126]

[1127] 1. Synthesis of 2,4-dimethyl-6-(trifluoromethyl)pyridin-3-amine

[1128]

[1129] 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 μmol) were added at 25 °C under N2. The mixture was stirred at 100 °C under N2 for 16 h. LCMS showed that the desired product mass was observed. The mixture was filtered and diluted with water (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (EtOAc in petroleum ether = 0% to 70%) 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 (br s, 2H), 2.48 (s, 3H), 2.23 (s, 3H).

[1130] 2. Synthesis of 2,4-dimethyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride

[1131]

[1132] SOCl2 (0.5 mL) was added to water (3 mL) while maintaining the temperature at 0-7°C, and the solution was then stirred at 25°C for 16 h. CuCl (1.04 mg, 10.52 μmol) was added and the solution was cooled to -3°C. In another flask, a solution of 2,4-dimethyl-6-(trifluoromethyl)pyridin-3-amine (100 mg, 525.86 μmol) in aqueous HCl (12 M, 625.00 uL) was added dropwise at -5°C to a solution of NaNO2 (38.10 mg, 552.15 μmol) in water (0.25 mL) while maintaining the temperature between -5°C and 0°C. When the addition was complete, the solution was then added to a pre-cooled thionyl chloride solution and stirred at -2°C for 10 min, then at 0°C for 2 h. TLC (DCM / MeOH = 9 / 1, R f =0.9) showed that a new spot was observed. The mixture was extracted with DCM (10 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired compound (60 mg, crude) as a yellow oil. 1H NMR (500MHz, CDCl3) δ (ppm) 7.57 (s, 1H), 3.08 (s, 3H), 2.89 (s, 3H).

[1133] 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

[1134]

[1135] 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 μmol) 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 desired product mass was observed. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL×2). The combined organic phases were 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*5μm; conditions: water (NH4HCO3)-ACN; start B: 35; end B: 65; flow rate: 25mL / min) to obtain the target compound (13mg, 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 (br d, J = 11.0Hz, 2H), 3.39-3.27 (m, 6H), 2.93 (s, 3H), 2.74 (s, 3H), 2.14 (br s,1H),1.61(br d,J=12.5Hz,2H),1.33-1.26(m,2H).

[1136] Example 101: 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1137]

[1138] 1. Synthesis of tert-Butyl 6-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[1139]

[1140] 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) at 0° C. under N 2 . The mixture was stirred at 25° C. for 3 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL×2). The combined organic phases were 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 (400MHz, 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).

[1141] 2. Synthesis of 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[1142]

[1143] TFA (78.55 mg, 688.93 μmol, 52.76 μL) was added to a solution of tert-butyl 6-((2,4-dimethyl-6-(trifluoromethyl)pyridin-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 h. 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).

[1144] 3. Synthesis of 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-azaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1145]

[1146] To a solution of 2-oxaspiro[3.3]heptane-6-one (90 mg, 268.38 μmol), 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 NaBH3CN (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 x 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*5μm, conditions: water (NH3.H2O+NH4HCO3)-ACN, 37% to 67%, flow rate (mL / min): 25) to give 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).

[1147] Example 102: 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1148]

[1149] 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-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). The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30 mm*5 μm; conditions: water (10 mM NH4HCO3)-ACN; start B: 38; end B: 68; gradient time (min): 10; 100% B holding 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).

[1150] Example 103: Racemic-2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-((tetrahydrofuran-3-yl)methyl)-2-azaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1151]

[1152]

[0266] Racemic-2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-((tetrahydrofuran-3-yl)methyl)-2-azaspiro[3.3]hept-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). The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm; conditions: water (10mM NH4HCO3)-ACN; start B: 35; end B: 65; gradient time (min): 10; 100% B holding time (min): 2; flow rate (mL / min): 25; detection wavelength: 220nm) to obtain the target compound (35mg, 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).

[1153] Example 104: 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-(oxetan-3-ylmethyl)-2-azaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1154]

[1155] 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-(oxetan-3-ylmethyl)-2-azaspiro[3.3]hept-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)). The crude product was purified by preparative HPLC (Phenomenex C18150*40mm*5μm, 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.

[1156] LCMS m / z=406.1(M+H) + . 1 H NMR (400MHz, CDCl3) δ (ppm) 7.44 (s,

[1157] 1H),4.76-4.72(m,2H),4.35(t,J=6.0Hz,2H),4.01(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).

[1158] Example 105: 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1159]

[1160] 1. Synthesis of 6-chloro-2-(trifluoromethyl)pyridine-3-sulfonyl chloride

[1161]

[1162] While maintaining the temperature at 0-7 ° C, SOCl2 (5 mL) was added to water (25 mL) over 10 min. 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 another flask, a solution of 6-methyl-2-(trifluoromethyl)pyridin-3-amine (900 mg, 4.58 mmol) in HCl (12 M, 3.36 mL) was added dropwise to a solution of NaNO2 (338.03 mg, 4.90 mmol) in water (2 mL) at -5 ° C while maintaining a temperature of -5 ° C to 0 ° C. When the addition was complete, the solution was then added to a 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) showed the reaction was complete. The reactant was added into water H2O (50 mL) and extracted with DCM (50 mL x 5), dried over anhydrous Na2SO4, 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 = 8.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H).

[1163] 2. Synthesis of 2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1164]

[1165] 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) + .

[1166] Synthesis of 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1167]

[1168] 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) 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) under N2. 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*5μm, conditions: water (NH3.H2O+NH4HCO3)-ACN, 37% to 67%, flow rate: 25mL / min) to give the title compound (44.80mg, 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).

[1169] Example 106: 2-((6-methyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane

[1170]

[1171] 1. Synthesis of tert-butyl 6-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[1172]

[1173] 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 extracted with DCM (50 mL×3). The organic layer was washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by column chromatography (EtOAc in petroleum ether = 30% to 50%) to give the desired compound (800 mg, 1.81 mmol, 90% yield) as a white solid. LCMS m / z=486.1 (M t-Bu+H) + .

[1174] 2. Synthesis of 2-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[1175]

[1176] 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 h. 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) + . 1 H NMR (400MHz, MeOD) δ (ppm) 8.51 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 4.25-4.22 (m, 8H).

[1177] 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

[1178]

[1179] 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) was added TEA (178.01 mg, 1.76 mmol, 245.20 μL) at 20° C. The mixture 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. NaBH 3 CN (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 (EtOAc in petroleum ether = 30% to 50%) 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).

[1180] 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

[1181]

[1182] 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) 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) under N2. 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*5μm, conditions: water (NH3.H2O+NH4HCO3)-ACN, 40% to 70%, flow rate: 25mL / min) to give the title compound (43.29mg, 103.20μmol, 45.40% yield) as a white solid. LCMS m / z=420.1 (M+H) + . (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, 2 H),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).

[1183] Example 107: 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1184]

[1185] 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*5μm, conditions: water (NH3.H2O+NH4HCO3)-ACN, 39% to 69%, flow rate: 25mL / min) to give the title compound (106.28mg, 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).

[1186] Example 108: 2-((6-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane

[1187]

[1188] 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) 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) 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*5μm; conditions: water (NH3.H2O+NH4HCO3)-ACN; 47% to 77%; flow rate: 25 mL / min) and further purified by preparative HPLC (column: WelchXtimate C18 150*25mm*5μm; conditions: water (NH4HCO3)-ACN; 40% to 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).

[1189] Example 109: 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1190]

[1191] 1. Synthesis of N-(2,6-bis(trifluoromethyl)pyridin-3-yl)-1,1-diphenylmethanimine

[1192]

[1193] To a solution of 3-bromo-2,6-bis(trifluoromethyl)pyridine (100 mg, 340.15 μmol) in toluene (3 mL) was added Xantphos (19.68 mg, 34.01 μmol), CsCO (332.48 mg, 1.02 mmol), diphenylformimine (123.29 mg, 680.29 μmol, 114.16 μL) and Pd(dba) (15.57 mg, 17.01 μmol) under N. The mixture was stirred at 100°C for 16 h. The reaction mixture was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (20 mL x 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).

[1194] 2. Synthesis of 2,6-bis(trifluoromethyl)pyridin-3-amine

[1195]

[1196] A solution of N-(2,6-bis(trifluoromethyl)pyridin-3-yl)-1,1-diphenylcarbamidine (130 mg, 329.69 μmol) in HCl / dioxane (2 mL) was stirred at 20° C. for 16 h. 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) + . 1 H NMR (400MHz, CDCl3) δ (ppm) 7.61 (d, J = 8.4Hz, 1H), 7.19 (d, J = 8.8Hz, 1H), 4.57 (br s, 2H).

[1197] 3. Synthesis of 2,6-bis(trifluoromethyl)pyridine-3-sulfonyl chloride

[1198]

[1199] SOCl2 (1 mL) was added to water (5 mL) while maintaining a temperature of 0-7°C, and the solution was then stirred at 15°C for 14 h. CuCl (1 mg, 10.10 μmol) was added and cooled to -3°C. In another flask, a solution of 2,6-bis(trifluoromethyl)pyridin-3-amine (80 mg, 347.66 μmol) in HCl (12 M, 1 mL) was added dropwise at -5°C to a solution of NaNO2 (25.67 mg, 372.00 μmol) in water (0.5 mL) while maintaining a temperature of -5 to 0°C. When the addition was complete, the solution was then added to a 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) showed the reaction was complete. The reactant was added to H2O (20 mL) and extracted with DCM (30 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated to give the desired compound (80 mg, crude) as a yellow oil. 1 HNMR (400MHz, CDCl3) δ (ppm) 8.88 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H).

[1200] 4. Synthesis of tert-Butyl 6-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[1201]

[1202] 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 (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).

[1203] 5. Synthesis of 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[1204]

[1205] TFA (71.95 mg, 631.04 μmol, 48.32 μL) was added to a 20° C. 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). The mixture was stirred at 20° C. for 3 h. 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 = 8.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 4.27 (s, 4H), 4.24 (s, 4H).

[1206] 6. Synthesis of 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1207]

[1208] 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 NaBH3CN (34.75 mg, 552.93 μmol) at 20°C. The mixture was stirred at 20°C for 3 h. The mixture was concentrated and purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm, conditions: water (NH4HCO3)-ACN, 32% to 62%, flow rate (mL / min): 25) to give the title compound (50.69 mg, 65% yield) as a white solid. LCMS m / z=460.1(M+H) + . 1H 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).

[1209] Examples 110-112:

[1210] Examples 110-112 in the table below were prepared using a similar procedure as described for Example 109 from the TFA salt of 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (1 equiv) and the corresponding aldehyde or ketone.

[1211]

[1212]

[1213] Example 113: 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1214]

[1215] Synthesis of 1.4-(2-oxaspiro[3.3]hept-6-yl)methyl toluenesulfonate

[1216]

[1217] 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]hept-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 H2O (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography ( 12g Purification by silica flash column, 0-50% ethyl acetate / petroleum ether gradient eluent at 30 mL / min) afforded the desired compound (590 mg, 48% yield) as a yellow oil. 1HNMR (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).

[1218] 2. Synthesis of 2-((2,6-bis(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1219]

[1220] To a solution of (2-oxaspiro[3.3]hept-6-yl)methyl 4-toluenesulfonate (100 mg, 318.75 μmol) and 2-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl]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 150×25 mm×10 μm; mobile phase: [water(NH 4 HCO 3 )-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).

[1221] Examples 114 and 115:

[1222] Using a similar method as described for Example 113, Examples 114 and 115 in the table below were prepared from (2-oxaspiro[3.3]hept-6-yl)methyl 4-toluenesulfonate and the corresponding 2,6-diazaspiro[3.3]heptanesulfonamide.

[1223]

[1224]

[1225] Example 116: 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1226]

[1227] 1. Synthesis of 2-bromo-6-(difluoromethyl)pyridin-3-amine.

[1228]

[1229] 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 at 0°C under nitrogen for 20 min, and then the reaction mixture was concentrated in vacuo. The crude material 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 (br s, 2H).

[1230] 2. Synthesis of 2-cyclopropyl-6-(difluoromethyl)pyridin-3-amine.

[1231]

[1232] 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) was added S-Phos (134 mg, 327 μmol), K 3 PO 4 (2.08 g, 9.82 mmol) and Pd 2 (dba) 3 (300 mg, 327 μmol) at 20° C. The mixture was stirred at 100° C. under nitrogen for 3 h. The reaction mixture was filtered and concentrated under vacuum. 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) + .

[1233] 3. Synthesis of 2-cyclopropyl-6-(difluoromethyl)pyridine-3-sulfonyl chloride.

[1234]

[1235] Thionyl chloride (1 mL, 13.7 mmol) was slowly added to water (2 mL) at 0 ° C over 10 minutes. During the addition to the water, the temperature was maintained between 0-5 ° C. After being added to the water, the solution was warmed to 15 ° C, followed by the addition of copper chloride (13 mg, 135 μmol). 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. During the addition, the temperature was maintained between 0-5 ° C. The mixture was slowly added to the solution prepared above to maintain a temperature between 0-5 ° C. After the addition, the mixture was stirred for another 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 2-cyclopropyl-6-(difluoromethyl)pyridine-3-sulfonyl chloride as a yellow oil which was used without purification. 1 H 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).

[1236] Synthesis of tert-butyl 6-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.

[1237]

[1238] 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) at 0° C. under nitrogen. The mixture was stirred at 25° C. for 1 h. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL×2). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. 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).

[1239] 5. Synthesis of 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate.

[1240]

[1241] 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 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate as a yellow oil, 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).

[1242] 6. Synthesis of 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane.

[1243]

[1244] 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 minutes, the mixture was adjusted to pH 5-6 with acetic acid and stirred at 20° C. for 30 minutes. Sodium cyanoborohydride (55 mg, 880 μmol) was added to the mixture and stirred at 20° C. for 1 hour. The mixture was diluted with water (30 mL) and extracted with DCM (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5μm, conditions: water (NH4HCO3)-ACN, flow rate (mL / min): 25) to give 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 light 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).

[1245] 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

[1246] and

[1247] The title compound was prepared using a method analogous to step 6 of Example 116 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) to give the following compound:

[1248] 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane (trans) (first peak emerging from preparative HPLC) after HPLC (basic conditions) (48 mg, 24%). LCMS m / z = 442.2 (M+H) + . 1H NMR (500 MHz, CDCl3) δ (ppm) 8.27 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 6.51 (t, J = 55.0 Hz,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(br s,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).

[1249] 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(4-methoxycyclohexyl)-2,6-diazaspiro[3.3]heptane (cis) (second peak from preparative HPLC) after HPLC (basic conditions) (46 mg, 23%). LCMS m / z = 442.1 (M+H) + . 1 H NMR (500 MHz, CDCl3) δ (ppm) 8.27 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 6.51 (t, J = 55.0 Hz,1H),4.00(s,4H),3.30-3.29(m,1H),3.26(s,3H),3.21(s,4H),2.92-2.87(m,1H),1.94(br s,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).

[1250] Example 119: 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1251]

[1252] The title compound was prepared using a method analogous to that described in step 6 of Example 116 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]hept-6-one (25 mg, 225 μmol) to afford 2-((2-cyclopropyl-6-(difluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-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).

[1253] Example 120: 2-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[1254]

[1255] 1. Synthesis of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole.

[1256]

[1257] To a solution of 1-cyclopropylpyrazole-3-carboxaldehyde (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 by saturated NH4Cl (20 mL) at 15 ° C, then diluted with H2O (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).

[1258] Synthesis of 2.5-bromo-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole.

[1259]

[1260] 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, followed by the addition of carbon tetrabromide (3.54 g, 10.7 mmol) in THF (4 mL) at -65°C and stirring 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 H2O (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were 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).

[1261] 3. Synthesis of N-(1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)-1,1-diphenylformimine.

[1262]

[1263] To a solution of 5-bromo-1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole (1.6 g, 6.7 mmol) and diphenylformamide (2.3 mL, 13.5 mmol) in dioxane (30 mL) was added Pd2(dba)3 (618 mg, 675 μmol), Xantphos (781 mg, 1.35 mmol), and K2CO3 (2.80 g, 20.2 mmol), followed by stirring at 100°C for 16 h. The mixture was filtered. The organic phase was diluted with water (20 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by flash column (0% to 10% ethyl acetate in petroleum ether) 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).

[1264] 4. Synthesis of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-amine.

[1265]

[1266] To a solution of N-(1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)-1,1-diphenylcarbamylamine (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. Aqueous NaHCO 3 (50 mL) solution was added dropwise to quench the reaction, 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 in DCM = 0% to 8%) to give 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-amine (450 mg, 80%) as a yellow oil. LCMS m / z=174.1 (M+H) + .

[1267] 5. Synthesis of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole-5-sulfonyl chloride.

[1268]

[1269] 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 stirred at 20°C for 12 hours. Copper chloride (14 mg, 144 μmol) was added, and the mixture was cooled to -3°C. In another flask, a solution of 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-amine (250 mg, 1.44 mmol) in HCl (12 M, 3.7 mL) was added dropwise at -5°C to a solution of sodium nitrite (100 mg, 1.46 mmol) in water (0.5 mL) while maintaining the temperature between -5 and 0°C for 1 hour. When the addition was complete, the solution was added to the pre-cooled thionyl chloride solution and stirred at -2°C for 10 min, followed by stirring at 0°C for 75 min. The mixture was extracted with DCM (30 mL x 3). The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated to give 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole-5-sulfonyl chloride, which was used without purification. 1 H 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).

[1270] Synthesis of 2-((1-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane.

[1271]

[1272] 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) at 0°C was added 1-cyclopropyl-3-(difluoromethyl)-1H-pyrazole-5-sulfonyl chloride (100 mg, 195 μmol) in DCM (3 mL). The mixture was stirred at 20°C for 1 hour. The mixture was diluted with water (30 mL) and extracted with DCM (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Boston Green ODS150*30 mm*5 μm, conditions: water (formic acid)-ACN, 8% to 38%, flow rate (mL / min): 25) to obtain 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) + . 1 H 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).

[1273] Example 121: 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1274]

[1275] 1. Synthesis of 4-cyclopropyl-6-(trifluoromethyl)pyridin-3-amine.

[1276]

[1277] 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) was added S-Phos (255 mg, 622 μmol), Pd2(dba)3 (570 mg, 622 μmol), and K3PO4 (3.96 g, 18.7 mmol) at 20°C. The mixture was stirred at 100°C under nitrogen for 3 hours. After cooling to room temperature, the reaction was diluted with water (15 mL) and then extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by flash column (ethyl acetate in petroleum ether = 10-50%) 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) + . 1 H NMR (500MHz, CDCl3) δ (ppm) 8.06 (s, 1H), 7.24 (s, 1H), 4.25 (br s, 2H), 1.72-1.61 (m, 1H), 1.06-1.01 (m, 2H), 0.70-0.66 (m, 2H).

[1278] 2. Synthesis of 4-cyclopropyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride.

[1279]

[1280] Thionyl chloride (3 mL) was added to water (18 mL) over 10 minutes while maintaining the temperature at 0-5 ° C. The solution was then stirred at 20 ° C for 12 hours. Copper chloride (3 mg, 35 μmol) was added and the mixture was cooled to -3 ° C. In another flask, a solution of 4-cyclopropyl-6-(trifluoromethyl)pyridine-3-amine (350 mg, 1.73 mmol) in HCl (12 M, 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 to 0 ° C. for 1 hour. When the addition was complete, the solution was added to the pre-cooled thionyl chloride solution and stirred at -2 ° C. for 10 minutes, then at 0 ° C. for 75 minutes. The mixture was concentrated and 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 Na 2 SO 4 , filtered, and concentrated to give 4-cyclopropyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride as a yellow oil which was used without further purification. 1H 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).

[1281] Synthesis of tert-butyl 6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.

[1282]

[1283] 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 then extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. 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 (br s,2H),1.05-1.02(m,2H).

[1284] Synthesis of 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate.

[1285]

[1286] 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 HNMR (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).

[1287] 5. Synthesis of 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane.

[1288]

[1289] 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 minutes, sodium cyanoborohydride (53 mg, 847 μmol) was added, and the mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30 mm*10 μm; conditions: water (NH4HCO3)-ACN; start B: 31; end B: 61; flow rate (mL / min): 50) to give 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-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 (br s,4H),2.88-2.73(m,2H),2.30-2.18(m,2H),1.92(br s,2H),1.42-1.32(m,2H),1.04-0.98(m,2H).

[1290] Example 122: 2-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane

[1291]

[1292] 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 mixture was adjusted to pH = 5-6 by dropwise addition of acetic acid at 0°C. After 30 minutes, sodium cyanoborohydride (54 mg, 863 μmol) was added, and the mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by preparative HPLC (column: Welch Xtimate C18150*25mm*5μm; 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(br d,J=6.5Hz,2H),1.57(br s,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).

[1293] Examples 123 and 124: 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol and 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol

[1294] and

[1295] 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 mmol) in MeOH (5 mL) was added 4-hydroxy-4-methyl-cyclohexanone (86 mg, 669 μmol). The mixture was adjusted to pH = 5-6 by dropwise addition of acetic acid at 0°C. After 30 minutes, sodium cyanoborohydride (115 mg, 1.8 mmol) was added, and the mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; condition: water (NH 4 HCO 3 )-ACN; start B: 32; end B: 62; flow rate (mL / min): 50) and by preparative HPLC (column: Boston Prime C18 150*30 mm*5 μm; condition: water (NH 3 H 2 O+NH 4 HCO 3 )-ACN; start B: 40; end B: 70; flow rate (mL / min): 25) to give the following compounds:

[1296] 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol (trans) (first peak emerging from preparative HPLC) (22 mg, 8%) after HPLC (basic conditions). 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 (br s,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).

[1297] 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol (cis) (second peak emerging from preparative HPLC) after HPLC (basic conditions) (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 (br s,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).

[1298] Example 125: 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane

[1299]

[1300] 1. Synthesis of 6-(trifluoromethyl)-4-vinylpyridin-3-amine.

[1301]

[1302] 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) was added S-Phos (170 mg, 415 μmol), Pd2(dba)3 (380 mg, 415 μmol) and K3PO4 (2.64 g, 12.5 mmol) at 20°C. The mixture was stirred at 100°C under nitrogen for 3 hours. The reaction mixture was cooled, then filtered and concentrated under vacuum. The crude material was purified by flash column (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. LCMS m / 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 (br s, 2H).

[1303] 2. Synthesis of 4-ethyl-6-(trifluoromethyl)pyridin-3-amine.

[1304]

[1305] To a solution of 6-(trifluoromethyl)-4-vinylpyridin-3-amine (650 mg, 3.45 mmol) in MeOH (10 mL) was added 10% Pd / C (100 mg, 95 μmol) at 20° C. The mixture was stirred at 20° C. under hydrogen (15 psi) for 16 hours. Nitrogen was bubbled through the reaction solution for 10 minutes, then the reaction was filtered and concentrated under vacuum 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).

[1306] 3. Synthesis of 4-ethyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride.

[1307]

[1308] Thionyl chloride (2.5 mL, 34 mmol) was added to water (8 mL) over 10 minutes while maintaining the temperature at 0-5 ° C. The solution was then stirred at 20 ° C for 12 hours. Copper chloride (22 mg, 226 μmol) was added and the mixture was cooled to -3 ° C. In another flask, a solution of 4-ethyl-6-(trifluoromethyl)pyridin-3-amine (430 mg, 2.26 mmol) in HCl (12 M, 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 to 0 ° C. for 1 hour. When the addition was complete, the solution was added to the pre-cooled thionyl chloride solution and stirred at -2 ° C. for 10 minutes, then at 0 ° C. for 75 minutes. The mixture was extracted with DCM (30 mL × 3). The combined organic phases were dried over Na 2 SO 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).

[1309] Synthesis of tert-butyl 6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.

[1310]

[1311] 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 x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. 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. 1H 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).

[1312] 5. Synthesis of 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate.

[1313]

[1314] 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 under vacuum 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) + .

[1315] Synthesis of 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane.

[1316]

[1317] 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 NaHCO (15 mL), water (20 mL), and then extracted with DCM (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex C18 150*40mm*5μm, conditions: water (NH4HCO3)-ACN, 23% to 53%, flow rate (mL / min): 60) to give 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane (39 mg, 41%) as a white solid. LCMS m / z = 432.1 (M+H) + . 1 HNMR(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).

[1318] Example 126: 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane

[1319]

[1320] 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, followed by the addition of sodium cyanoborohydride (25 mg, 400 μmol). 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column (0% to 8% MeOH in DCM) 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), 3.3 7-3.29(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=7.2 Hz,3H),1.29-1.19(m,3H).

[1321] Examples 127 and 128: 4...

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is CH2 or O; Y is CH2 or O; The premise is that 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 C 2-6 Alkyl, Het or -Z-Het, wherein the C 2-6 The alkyl group is optionally substituted with one or more R A and Het is optionally substituted by one or more R 2 replace; Z is optionally substituted with one or more halogen or C 1-3 Alkoxy substituted C 1-4 alkyl; Het is C 3-6 cycloalkyl, 4 to 6 membered monocyclic heterocyclic group, or 6 to 8 membered bicyclic heterocyclic group, each of which is optionally substituted by R 2 replace; R A OR independently at each occurrence 2a , SR 2a C(O)OR 2a ; R 2 C independently at each occurrence 1-6 Alkyl, halogen, -CN or OR 2a , wherein the C 1-6 The alkyl group is optionally substituted with one or more halogen or C 1-3 Alkoxy substitution; R 2a H, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogen or C 1-3 Alkoxy substitution; R 3 C 1-4 Alkyl-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 are each optionally substituted by one or more substituents R 4 replace; R 4 is independently at 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 the C 1-6 Alkyl or C 3-6 The cycloalkyl groups are each optionally substituted with one or more C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or halogen, and wherein the 5 or 6-membered monocyclic heteroaryl is optionally substituted by one or more C 1-6 Alkyl substitution; or Two R's 4 Together with the atoms in between them, they form a 5- to 7-membered heterocyclic group; R 4a H or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halo groups; n is 1 or 2; m is 1 or 2; R 5 is independently H, halo, C 1-3 Alkyl or C 1-3 haloalkyl; or two R 5 Together they form C 1-3 Alkylene; R 6 is independently H, halo, C 1-3 Alkyl or C 1-3 haloalkyl; or two R 6 Together they form C 1-3 Alkylene; Provided that the compound is not:

2. The compound of claim 1, wherein the compound is represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is CH2 or O; Y is CH2 or O; The premise is that 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 C 2-6 Alkyl, Het or -Z-Het, wherein the C 2-6 The alkyl group is substituted by one or more OR 2a and Het is optionally substituted by one or more R 2 replace; Z is C optionally substituted by one or more halogen groups 1-4 alkyl; Het is a 4- to 6-membered monocyclic heterocyclic group, or a 6- to 8-membered bicyclic heterocyclic group, each of which is optionally substituted by R 2 replace; R 2 C independently at each occurrence 1-6 Alkyl or OR 2a ; R 2a H or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halo groups; R 3 is 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 are each optionally substituted by one or more substituents R 4 replace; R 4 is independently at each occurrence halo, -OR 4a 、-CN、C 1-6 Alkyl, C 3-6 Cycloalkyl, or 5 or 6-membered monocyclic heteroaryl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halo groups, and wherein the 5 or 6-membered monocyclic heteroaryl group is optionally substituted with one or more C 1-6 Alkyl substitution; or Two R's 4 Together with the atoms in between them, they form a 5- to 7-membered heterocyclic group; R 4a H or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halo groups; n is 1 or 2; m is 1 or 2; R 5 is independently H, halo, C 1-3 Alkyl or C 1-3 haloalkyl; or two R 5 Together they form C 1-3 Alkylene; R 6 is independently H, halo, C 1-3 Alkyl or C 1-3 haloalkyl; or two R 6 Together they form C 1-3 Alkylene; Provided that the compound is not:

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

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Het is C 3-6 cycloalkyl, 4- to 6-membered oxygen-containing monocyclic saturated heterocyclic group or 6- to 8-membered oxygen-containing bicyclic saturated heterocyclic group, each of which is optionally substituted by one to three R 2 replace.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Het is cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, dioxanyl, 2-oxaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 2-oxabicyclo[2.1.1]hexanyl, 6-oxabicyclo[3.2.1]octanyl or 2-oxabicyclo[3.1.1]heptyl, each of which is optionally substituted with one to three R 2 replace.

6. The compound of any one of claims 1 to 5, wherein the compound is represented by formula II: or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of phenyl, pyridyl, thiazolyl and pyrazolyl, each of which is optionally substituted with one to three R 4 replace.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: wherein each of the formulae depicted above is optionally substituted by one to three R 4 replace.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from halo, -CN, -OR 4a , C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and optionally C 1-3 alkyl-substituted 5-membered or 6-membered heteroaryl, and R 4a C 1-3 Alkyl or C 1-3 Halogenated alkyl.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from -CH3, -CF3, -OCHF2, -OCH3, -CN, -F, -Cl, isopropyl, cyclopropyl and 4-methylpyridin-2-yl.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 1 For OR 2a Substituted C 2-4 Alkyl, or represented by the formula: wherein each of the formulae depicted above is optionally substituted by one to three R 2 Substitution; wherein R 2 C independently at each occurrence 1-3 Alkyl or -OR 2a ; and R 2a H or C independently at each occurrence 1-3 alkyl.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula:

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected at each occurrence from -CH3 and -OH; and R 2a is independently H or -CH3 at each occurrence.

15. The compound of any one of claims 1 to 14, wherein the compound is represented by formula III: or a pharmaceutically acceptable salt thereof.

16. A compound of formula 15, wherein: R 1 It is expressed by the following formula: R 2 is independently selected at each occurrence from -CH3 and OH; R 2a is independently selected at each occurrence from H or -CH3; R 3 It is expressed by the following formula: and R 4 is independently selected at each occurrence from -CH3, -CF3, -OCHF2, -OCH3 and -F.

17. The compound of any one of claims 1 to 14, wherein the compound is represented by formula IV: or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17, wherein the compound is represented by formula (IVA) or (IVB): or a pharmaceutically acceptable salt thereof.

19. The compound of claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein: R 1 It is expressed by the following formula: R 2 for OH; R 3 It is expressed by the following formula: and R 4 is independently selected at each occurrence from -CH3, -CF3, -OCH3, -OCHF2, -CN, isopropyl, -F, -Cl and 4-methylpyridin-2-yl.

20. The compound of any one of claims 1 to 14, wherein the compound is represented by formula V: or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20, wherein: R 1 It is expressed by the following formula: R 3 It is expressed by the following formula: and R 4 is independently selected at each occurrence from -CH3, -F and cyclopropyl.

22. The compound of claim 1 or 2, wherein the compound is represented by Formula VI: or a pharmaceutically acceptable salt thereof.

23. The compound of claim 22, wherein the compound is represented by Formula VII or VIII: or a pharmaceutically acceptable salt thereof.

24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally treated with one to three R 4 Substituted phenyl.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

26. The compound of any one of claims 22 to 25, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from halo, CN and OR 4a ; and R 4a C 1-3 Alkyl or C 1-3 Halogenated alkyl.

27. The compound of any one of claims 22 to 26, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from -OCHF2, -F and -CN.

28. The compound of any one of claims 22 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 For the -OR 2a Substituted C 2-4 Alkyl, or represented by the formula: The formula is optionally substituted by one to three R 2 replace.

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula:

30. The compound of any one of claims 22 to 29, or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected at each occurrence from -CH3 and -OH; and R 2a is independently selected at each occurrence from H and -CH3.

31. The compound of claim 1 or 2, wherein the compound is represented by Formula IX: or a pharmaceutically acceptable salt thereof, wherein R 5 H, or two R 5 Together they form C 1-3 Alkylene; and R 6 H, or two R 6 Together they form C 1-3 Alkylene.

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

33. The compound of claim 31 or 32, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of phenyl, pyridyl and pyrazolyl, each of which is optionally substituted by one to three R 4 replace.

34. The compound of claim 31 or 32, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of: C 1-4 Alkyl-phenyl, phenyl, pyridyl, thiazolyl and pyrazolyl, each of which is optionally substituted with one to three R 4 replace.

35. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Each of these formulae is optionally substituted with one to three R 4 replace; or R 3 It is expressed by the following formula: It is optionally connected via one or two R 4 replace.

36. The compound of claim 34 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Each of these formulae is optionally substituted with one to three R 4 replace; or R 3 It is expressed by the following formula: It is optionally connected via one or two R 4 replace.

37. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

38. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

39. The compound of any one of claims 31 to 38, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from halo, CN, 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 The cycloalkyl group is optionally substituted with one to three halogen or C 1-4 is substituted with a haloalkyl group, and the C 1-3 The alkyl group is optionally substituted with one or two C 3-4 Cycloalkyl substituted; and R 4a C 1-3 Alkyl or C 1-3 Halogenated alkyl.

40. The compound of any one of claims 31 to 38, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl and -OR 4a ; and R 4a C 1-3 Alkyl or C 1-3 Halogenated alkyl.

41. The compound of any one of claims 31 to 40, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from -CH3, -CH2CH3, -CF2CH3, -CF(CH3)2, -CH=CH2, -CHF2, -CH(CH3)2, -CF3, -OCH3, -OCHF2, -OCF3, cyclopropyl, -CH2-cyclopropyl, cyclobutyl, phenyl, -CN, -Cl, -Br and -F.

42. The compound of any one of claims 31 to 40, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from -CH3, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3, cyclopropyl, -CN and -F.

43. The compound of any one of claims 31 to 42, or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula: wherein each of the formulae depicted above is optionally substituted by one to three R 2 replace.

44. The compound of any one of claims 31 to 42, or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula: wherein each of the formulae depicted above is optionally substituted by one to three R 2 replace.

45. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula:

46. ​​The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula:

47. The compound of any one of claims 31 to 46, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -CH3, -F, -OCH3, -CN, -CH2CH2OCH3 or -OH.

48. The compound of any one of claims 31 to 46, or a pharmaceutically acceptable salt thereof, wherein R 2 For OH.

49. The compound of any one of claims 31 to 42, or a pharmaceutically acceptable salt thereof, wherein: R 1 is optionally through one or two R A Substituted C 2-6 alkyl; R A OR independently at each occurrence 2a , SR 2a C(O)OR 2a ;and R 2a H, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or two C 1-3 Alkoxy substitution.

50. The compound of claim 49 or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH2CH3, -CH2CH2CH2SCH2CH3, -CH2CH2CH2O-cyclopentyl, -CH2CH2CH2CH2CH2OCH3, -CH2CH2OC(CH3)3, -CH2CH 2CH2CH(CH3)OCH3, -CH2CH(CH3)CH2CH2C(O)OCH3, -CH2CH2C(CH3)2C(O)OCH3, or -CH2CH2CH2OCH2CH2OCH3.

51. The compound of any one of claims 31 to 48, wherein the compound is represented by formula X: or a pharmaceutically acceptable salt thereof.

52. The compound of claim 51, wherein: R 1 It is expressed by the following formula: R 2 for OH; R 3 It is expressed by the following formula: and R 4 It is -CH3.

53. The compound of any one of claims 31 to 48, wherein the compound is represented by formula XI: or a pharmaceutically acceptable salt thereof.

54. The compound of claim 53, wherein the compound is represented by formula (XIA) or (XIB): or a pharmaceutically acceptable salt thereof.

55. The compound of claim 53 or 54, wherein: R 1 It is expressed by the following formula: R 2 for OH; R 3 It is expressed by the following formula: and R 4 is independently selected at each occurrence from -CH3, -CF3, -OCH3, -OCHF2, -OCF3, -CN, -F and cyclopropyl.

56. The compound of any one of claims 31 to 50, wherein the compound is represented by Formula XII: or a pharmaceutically acceptable salt thereof.

57. The compound of claim 56 or a pharmaceutically acceptable salt thereof, wherein: R 1 It is expressed by the following formula: R 2 for OH; R 3 It is expressed by the following formula: and R 4 is independently selected at each occurrence from -CH3, -CHF2, -CF3, -OCH3, -OCHF2 and -OCF3.

58. The compound of any one of claims 31 to 48, wherein the compound is represented by Formula XII: or a pharmaceutically acceptable salt thereof, wherein: R 1 is Het or Z-Het; Z is CH2; Het is represented by the following formula: wherein each of the formulae depicted above is optionally substituted by one to two R 2 replace; R 2 C independently at each occurrence 1-4 Alkyl, -OH or halide; R 3 is pyridyl or pyrazolyl, each of which is optionally substituted by one to two R 4 replace; R 4 C independently at each occurrence 1-4 Alkyl or C 1-4 Halogenated alkyl.

59. The compound of claim 58 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Each of these formulae is optionally substituted with one to two R 4 replace.

60. The compound of claim 59 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

61. The compound of any one of claims 58 to 60, or a pharmaceutically acceptable salt thereof, wherein R 4 is independently at each occurrence -CH3, -CF3 or -CF2CH3.

62. The compound of claim 60, wherein the compound is represented by Formula XIIA: or a pharmaceutically acceptable salt thereof, wherein R 40 C 1-3 Alkyl and R 41 C 1-3 Halogenated alkyl.

63. The compound of claim 62 or a pharmaceutically acceptable salt thereof, wherein R 40 is -CH3 and R 41 It is -CF3 or -CF2CH3.

64. The compound of any one of claims 58 to 63, or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula: wherein each of the formulae depicted above is optionally substituted by one to two R 2 replace.

65. The compound of claim 64 or a pharmaceutically acceptable salt thereof, wherein R 1 It is expressed by the following formula:

66. The compound of any one of claims 58 to 65, or a pharmaceutically acceptable salt thereof, wherein R 2 is independently at each occurrence -CH3, OH or -F.

67. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 8-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-5-oxa-2,8-difluoromethoxyphenyl Azaspiro[3.5]nonane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl)-6-oxa-2,9-difluoromethoxyphenyl Azaspiro[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-difluoromethoxyphenyl Azaspiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(tetrahydrofuran-3-yl)-1-oxa-4,9-diazepine Spiro[5.5]undecane; 4-((4-(difluoromethoxy)phenyl)sulfonyl)-9-(2-methoxyethyl)-1-oxa-4,9-diazepine Spiro[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]undecane-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]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (R)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; (S)-9-((4-(difluoromethoxy)phenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-6-yl)-6-oxa-2,9-diazaspiro[4.5]decane; 9-((3,5-difluorophenyl)sulfonyl)-2-(2-oxaspiro[3.3]hept-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]hept-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[azetidine-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]hept-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-6-yl)-2,6-diazaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(1-oxaspiro[3.3]hept-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]hept-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]hept-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]hept-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]hept-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]hept-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]hept-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]hept-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]hept-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]hept-6-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-oxaspiro[3.3]hept-6-yl)methyl)-6-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-oxaspiro[3.3]hept-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]hept-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]hept-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]hept-2-yl)-1-methylcyclohexan-1-ol; 4-(6-((4-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol; 2-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(2-oxaspiro[3.3]hept-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]hept-2-yl)-1-methylcyclohexan-1-ol; (1s,4s)-4-(6-((4-ethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-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]hept-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]hept-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]hept-2-yl)methyl)cyclopropane-1-carbonitrile; 2-(((1S,2R,5S)-6-oxabicyclo[3.2.1]oct-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; 2,2-dimethyl-4-(6-((2-methyl-6-(trifluoromethyl)-1,4-dihydropyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)butanoic acid methyl ester; 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; 4-methyl-5-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)pentanoic acid methyl ester; 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]hept-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]hept-2-yl)-1-methylcyclohexan-1-ol; (1s,4s)-4-(6-((2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-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]hept-6-yl)-2,6-diazaspiro[3.3]heptane; (1r,4r)-4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-methylcyclohexan-1-ol; (1s,4s)-4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-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]hept-2-yl)cyclohexan-1-ol; (1s,4s)-1-methyl-4-(6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-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]hept-2-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile; and 2-((Tetrahydro-2H-pyran-4-yl)methyl)-6-((6-(trifluoromethyl)-2,3-dihydropyridin-3-yl)sulfonyl 1-(2-(4-(2-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane); or a pharmaceutically acceptable salt thereof.

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

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

70. A method of treating an autoimmune disease in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68.

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

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

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