Emopamil binding protein inhibitors and uses thereof

Abstract

Provided are compounds of Formula (I): # imgabs0 #, or a pharmaceutically acceptable salt thereof, which are useful for inhibiting EBP and treating a variety of EBP-mediated conditions or diseases, such as multiple sclerosis.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 391,578, filed on July 22, 2022. The entire contents of the foregoing application are expressly incorporated herein by reference. Technical Field

[0003] The present disclosure relates to inhibitors of emopamide binding protein (EBP) and pharmaceutically acceptable salts thereof, compositions of these compounds, methods for their preparation, their use in the treatment of diseases, their use, optionally in combination with a pharmaceutically acceptable carrier, for the manufacture of pharmaceutical preparations, the use of the pharmaceutical preparations in the treatment of diseases, and methods for treating diseases, the methods comprising administering the EBP inhibitors to warm-blooded animals, especially humans. Background Art

[0004] Emopamil binding protein (EBP) is a Δ8-Δ7 sterol isomerase that isomerizes the double bond in the sterol molecule, moving the double bond from the 8-9 position to the 7-8 position. Specifically, during the biosynthesis of cholesterol, EBP converts zymostenol to lathosterol, or converts zymostenol to dehydrolathosterol (Silve et al., 1996, J Biol Chem. 271 (37), 22434-22440). It has been confirmed that the accumulation of 8-9 unsaturated sterols activates the formation of oligodendrocytes 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. Demyelinating diseases or myelin-related diseases are the result of these myelin sheaths being damaged, degenerated or reduced in thickness. The loss of myelin sheaths can disrupt the electronic signals from the brain and may cause nerve damage, vision loss, numbness, muscle weakness, cognitive decline, motor function loss and other similar symptoms. In some myelin-related diseases, such as multiple sclerosis, the patient's immune system targets and decomposes its own myelin sheath. The ability to repair and regenerate myelin sheaths is the key to treating these myelin-related diseases. Due to the function of converting 8-9 sterols, inhibiting EBP is a potential target for activating myelin regeneration, because its inhibition can lead to an increase in these 8-9 sterol raw materials (Theodoropoulous et al., 2020, J.Am.Chem.Soc., 142, (13), 6128-6138).

[0006] In addition to its role in remyelination, EBP has been shown to be a key enzyme in certain colorectal cancers as it can reduce 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 O, CH2 or a bond;

[0012] R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 1-3 Haloalkyl, C 3-8 Cycloalkyl, Het and -Z-Het, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl and Het are each optionally substituted by one or more R 4 Replace, provided that R 1 and R 2 At least one of them is not H;

[0013] or R 1 and R 2 Together with the N atom to which they are attached, they form a 4- to 7-membered monocyclic heterocyclic ring or a 6- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or more R 4 replace;

[0014] Z is optionally replaced by one or more R 4 Substituted C 1-4 alkyl;

[0015] Het is a 4- to 6-membered monocyclic heterocyclic group or a 6- to 8-membered bicyclic heterocyclic group, each of which is optionally replaced by R 4 replace;

[0016] Each R 4 Independently selected from OR 4a , halo, C 1-3 Alkyl, C 1-3 haloalkyl and 4- to 7-membered monocyclic heterocyclic ring;

[0017] R 4a Selected from H, C 1-3 Alkyl and C 1-3 Haloalkyl;

[0018] R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 6 to 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 6 to 10-membered bicyclic heterocycle are each optionally substituted by one or more substituents R 5 replace;

[0019] Each R 5 Independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl, OR 5a , cyano and halo;

[0020] R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups;

[0021] The condition is R 1 and R 2 Together with the N atom to which they are attached they do not form unsubstituted pyrrolidine, unsubstituted piperidine or 4-methylpiperazine.

[0022] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

[0023] In another aspect, the present disclosure provides a method of 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 with a myelin-related disorder.

[0024] 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 is a compound described herein or a pharmaceutically acceptable salt thereof for use in treating a disease or condition responsive to inhibition of EBP. DETAILED DESCRIPTION

[0025] The present disclosure provides compounds and pharmaceutical compositions thereof, which can be used to treat diseases or disorders caused by mediating EBP function / activity, such as multiple sclerosis or other myelin-related disorders. In some embodiments, the compounds of the present disclosure are EBP inhibitors.

[0026] Compounds and compositions

[0027] In a first embodiment, the present disclosure provides a compound of formula (I):

[0028]

[0029] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined above in the first aspect.

[0030] In a second embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 is phenyl or a 5- or 6-membered monocyclic heteroaryl, each of which is optionally substituted by one to three substituents R 5 and the remaining variables are as described in the first embodiment.

[0031] In a third embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 is phenyl, pyridyl, pyrimidinyl or imidazolyl, each of which is optionally substituted by one to three substituents R 5 and the remaining variables are as described in the second embodiment.

[0032] In a fourth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one to three R 5 and the remaining variables are as described in the second embodiment.

[0033] In a fifth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the N atom to which they are attached, they form a saturated 4- to 6-membered monocyclic heterocyclic ring or a saturated 7- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or two R 4 and the remaining variables are as described in the first, second, third or fourth embodiment.

[0034] In a sixth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula: Wherein each formula depicted above is optionally replaced by one or two R 4 and the remaining variables are as described in the fifth embodiment.

[0035] In a seventh embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 is H or optionally one to three R 4 Substituted C 1-3 Alkyl; R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, Het or -Z-Het, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl; and Het is a saturated 4 to 6 membered monocyclic heterocyclic ring containing 1 to 2 heteroatoms selected from oxygen and nitrogen, at least one of the heteroatoms being oxygen, wherein the saturated 4 to 6 membered monocyclic heterocyclic ring is optionally substituted by one to three R 4 and the remaining variables are as described in the first, second, third or fourth embodiment.

[0036] In an eighth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, Het is selected from tetrahydropyran and oxetane, each of which is optionally substituted by one to two R 4 and the remaining variables are as described in the seventh embodiment.

[0037] In a ninth embodiment, the compounds of the present disclosure are represented by formula (II):

[0038]

[0039] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (II) are as defined in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

[0040] In a tenth embodiment, for a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula: And the remaining variables are as described in the ninth embodiment.

[0041] In an eleventh embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 5 In each occurrence, independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl and OR 5a ; and the remaining variables are as described in the ninth or tenth embodiment.

[0042] In a twelfth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R5 is independently selected at each occurrence from -CH3, -CF3, -CF2CH3, -CH(CH3)2, and -OCHF2; and the remaining variables are as described in the eleventh embodiment.

[0043] In a thirteenth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula: And the remaining variables are as described in the ninth, tenth, eleventh or twelfth embodiment.

[0044] In a fourteenth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 1 H and R 2 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one or two R 4 and the remaining variables are as described in the ninth, tenth, eleventh or twelfth embodiment. In an alternative fourteenth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 1 H and R 2 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one or two R 4 and the remaining variables are as described in the ninth, tenth, eleventh or twelfth embodiment.

[0045] In a fifteenth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 It is expressed by the following formula: and the remaining variables are as described in the fourteenth embodiment. In an alternative fifteenth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 It is expressed by the following formula: And the remaining variables are as described in the fourteenth embodiment.

[0046] In a sixteenth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 4 In each occurrence, independently selected from C 1-3 alkyl and a 4 to 7 membered monocyclic heterocycle; and the remainder of the variables are as described in the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

[0047] In a seventeenth embodiment, for a compound of formula (II) or a pharmaceutically acceptable salt thereof, R 4is independently selected at each occurrence from -CH3 and tetrahydropyran; and the remaining variables are as described in the sixteenth embodiment.

[0048] In an eighteenth embodiment, the compounds of the present disclosure are represented by formula (III) or (IV):

[0049]

[0050] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (III) or (IV) are as defined in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

[0051] In a nineteenth embodiment, the compound of the present disclosure is represented by Formula (IIIA), (IIIB), (IVA) or (IVB):

[0052]

[0053] or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (IIIA), (IIIB), (IVA) or (IVB) are as defined in the eighteenth embodiment.

[0054] In a twentieth embodiment, for a compound of Formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 3 It is expressed by the following formula:

[0055] And the remaining variables are as described in the eighteenth or nineteenth embodiment.

[0056] In a twenty-first embodiment, for a compound of Formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 5 is independently selected at each occurrence from halo, cyano, C 1-2 Alkyl, C 1-2 Haloalkyl and OR 5a ; and R 5a C 1-2 Alkyl or C 1-2 haloalkyl; and the remainder of the variables are as described in the eighteenth, nineteenth or twentieth embodiment.

[0057] In a twenty-second embodiment, for a compound of Formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 5is independently selected at each occurrence from F, Cl, cyano, -CH3, -CF3, -CHF2, -OCH3 and -OCHF2; and the remaining variables are as described in the twenty-first embodiment.

[0058] In a twenty-third embodiment, for a compound of Formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula: And the remaining variables are as described in the eighteenth, nineteenth, twentieth, twenty-first or twenty-second embodiment.

[0059] In a twenty-fourth embodiment, for a compound of Formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 1 H or C 1-3 alkyl; and R 2 C 1-3 Alkyl, C 3-6 cycloalkyl, -Z-Het or Het, each of which is optionally substituted by one to three R 4 and the remaining variables are as described in the eighteenth, nineteenth, twentieth, twenty-first or twenty-second embodiment.

[0060] In a twenty-fifth embodiment, for a compound of Formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 1 is H or -CH3, and R 2 is optionally replaced by an R 4 Substituted C 1-3 Alkyl or represented by the following formula: Wherein each formula depicted above is optionally replaced by one or two R 4 and the remaining variables are as described in the twenty-fourth embodiment.

[0061] In a twenty-sixth embodiment, for a compound of Formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 1 is H or -CH3, and R 2 It is expressed by the following formula: And the remaining variables are as described in the twenty-fifth embodiment.

[0062] In a twenty-seventh embodiment, for a compound of Formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 4 In each occurrence, independently selected from OR 4a , halo and C 1-3 alkyl; and wherein R 4a C 1-3 alkyl; and the remainder of the variables are as described in the eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth embodiment.

[0063] In a twenty-eighth embodiment, for a compound of Formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 4 is independently selected at each occurrence from halo, -CH3, and -OCH3; and the remainder of the variables are as described in the twenty-seventh embodiment.

[0064] In a twenty-ninth embodiment, the disclosure provides a compound described herein (eg, a compound of any one of Examples 1 to 83), or a pharmaceutically acceptable salt thereof.

[0065] In a thirtieth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0066] 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0067] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine;

[0068] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine;

[0069] 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0070] 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine;

[0071] 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane;

[0072] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)-2-azaspiro[3.3]hept-6-amine;

[0073] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine;

[0074] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]hept-6-amine;

[0075] 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine;

[0076] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-ylmethyl)-2-azaspiro[3.3]hept-6-amine;

[0077] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]hept-6-amine;

[0078] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine;

[0079] 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0080] 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane;

[0081] 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane;

[0082] 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0083] 2-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide;

[0084] 4-(2-((3-isopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine;

[0085] 2-((4-(difluoromethoxy)phenyl)sulfonyl)-6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane;

[0086] 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine;

[0087] 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-5-oxa-2-azaspiro[3.4]octane;

[0088] 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-(3-methoxyazetidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0089] N-(4,4-difluorocyclohexyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-amine;

[0090] N-(3,3-difluorocyclobutyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-amine;

[0091] 3-((7-((4,4-difluorocyclohexyl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-4-fluorobenzonitrile;

[0092] 4-Fluoro-3-((7-((tetrahydro-2H-pyran-4-yl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)benzonitrile;

[0093] 3-((7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-5-fluorobenzonitrile;

[0094] 4-(2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0095] 6-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)-2-oxa-6-azaspiro[3.3]heptane;

[0096] N-(4,4-difluorocyclohexyl)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine;

[0097] 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-2-azaspiro[3.4]octan-6-amine;

[0098] N-(2-methoxyethyl)-N-methyl-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine;

[0099] 4-(2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0100] 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0101] 4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0102] 4-(2-((4-chloro-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0103] 4-(2-((4-(difluoromethyl)-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0104] 4-(2-((6-methoxy-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0105] 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0106] 4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0107] 4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0108] 4-(2-(mesitylsulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0109] 4-(2-((4-(difluoromethoxy)phenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0110] 4-(2-((2,4-dimethylphenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0111] 4-(2-((2,4-difluorophenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0112] 4-(2-((4,6-dimethylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0113] 4-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0114] 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0115] (R)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0116] 3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile;

[0117] (R)-3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile;

[0118] 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0119] (S)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0120] 3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile;

[0121] (S)-3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile;

[0122] 2-(mesitylsulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane;

[0123] 2-((4-(difluoromethoxy)phenyl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0124] 2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0125] 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane;

[0126] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane;

[0127] (R)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane;

[0128] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane;

[0129] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane;

[0130] 3-((7-((4,4-difluorocyclohexyl)(methyl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-4-fluorobenzonitrile;

[0131] 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0132] (R)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0133] (S)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0134] 4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0135] (R)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0136] (S)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0137] 4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0138] (R)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0139] (S)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0140] 4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0141] (R)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0142] (S)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine;

[0143] 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane;

[0144] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine;

[0145] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine;

[0146] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine;

[0147] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine;

[0148] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine;

[0149] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine;

[0150] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine;

[0151] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine;

[0152] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine;

[0153] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine;

[0154] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine;

[0155] N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine;

[0156] N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine;

[0157] N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine; and

[0158] N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine;

[0159] or a pharmaceutically acceptable salt thereof.

[0160] In a thirty-first 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.

[0161] In the thirty-second embodiment, the present disclosure provides a method of treating a disease or condition mediated by EBP, the method comprising administering to a subject an effective amount of a compound according to any one of embodiments one to thirty or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the thirty-first embodiment.

[0162] In a thirty-third embodiment, the present disclosure provides a compound according to any one of embodiments one to thirty for use in treating a disease or condition mediated by EBP.

[0163] In a thirty-fourth embodiment, the present disclosure provides the use of a compound according to any one of embodiments one to thirty in the manufacture of a medicament for treating a disease or condition mediated by EBP.

[0164] The compounds and intermediates described herein can be separated and used as the compounds themselves. Alternatively, when there is a part capable of forming a salt, the compound or intermediate can be separated and used as its corresponding salt. As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the 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 compound described herein, and is generally not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are able to form acid salts and / or basic salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0165] 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, chlortheophyllonate, 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.

[0166] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0167] 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.

[0168] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0169] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0170] 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, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0171] The salt can be synthesized by a compound containing an alkaline or acidic part by conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, where feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Additional lists of suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0172] 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 an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed. In one embodiment, the present disclosure provides a deuterated compound as described herein or a pharmaceutically acceptable salt thereof.

[0173] Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, d6-acetone, d6-DMSO.

[0174] Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and may therefore 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 should be understood that substituents may be attached at the chiral center of a carbon atom. Therefore, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0175] "Enantiomer" is 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 specify a racemic mixture. When specifying the stereochemistry of the compound of the present invention, a single stereoisomer (e.g., (1S, 2S)) with relative and absolute configurations of two known chiral centers is specified using the conventional RS system. "Diastereomer" is a stereoisomer with at least two asymmetric atoms but not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. The unknown splitting compound of absolute configuration can be specified as (+) or (-) according to the direction (right-handed or left-handed) of rotating plane polarized light at the sodium D line wavelength. Alternatively, the splitting compound can be defined by the retention time of the corresponding enantiomer / diastereomer via chiral HPLC.

[0176] 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 which may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0177] 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 Corp.) RTM and CHIRALCEL RTM ) using an appropriate solvent or solvent mixture to achieve good separation). If the compound contains a double bond, the substituents may be in E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0178] How to use

[0179] 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 a bioassay described in the Examples and known in the art)).

[0180] In certain embodiments, the present disclosure provides a method of treating a disease or condition responsive to inhibition of EBP activity (referred to herein as "EBP-mediated disease or condition" or "disease or condition mediated by EBP") in a subject in need of treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to thirtieth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0181] 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 thirtieth 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 disorder or disease in a subject in need of treatment.

[0182] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound as described in any one of the first to thirtieth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing 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 treatment.

[0183] In certain embodiments, the EBP-mediated disorder is colorectal cancer.

[0184] In certain embodiments, the present disclosure provides a method for treating an autoimmune disease in a subject in need of 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 thirtieth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0185] 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 thirtieth 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 treatment.

[0186] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to thirtieth 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 treatment.

[0187] In certain embodiments, the autoimmune disease is multiple sclerosis (MS). The compounds disclosed herein can be used to treat all stages of MS, including relapsing multiple sclerosis (or relapsing forms of multiple sclerosis), relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and clinically isolated syndrome (hereinafter referred to as "CIS").

[0188] Relapsing forms of multiple sclerosis (or relapsing forms of multiple sclerosis) include clinically isolated syndrome, relapsing-remitting multiple sclerosis, and active secondary progressive multiple sclerosis.

[0189] Relapsing-remitting MS is a stage of MS characterized by unpredictable relapses followed by periods of relative calm (remissions) of months to years with no new signs of disease activity. Deficits experienced during an attack may resolve or may remain problems, the latter occurring in about 40% of attacks and more common the longer a person has had the disease. This describes the initial course of 80% of donors with MS.

[0190] Secondary progressive MS develops in about 65% of individuals with initial relapsing-remitting MS, who eventually experience progressive neurological decline between acute attacks without any clear remission periods. Occasional relapses and minor remissions may occur. The most common time interval from disease onset to conversion from relapsing-remitting MS to secondary progressive MS is 19 years.

[0191] Primary progressive MS is characterized by the same symptoms as secondary progressive MS, namely progressive neurological decline between acute attacks without any clear remission periods and without preceding relapsing-remitting episodes.

[0192] CIS is the first attack of neurological symptoms due to inflammation and demyelination of the central nervous system. This attack, which must last at least 24 hours by definition, is a feature of multiple sclerosis, but does not yet meet the diagnostic criteria for MS, because people who experience CIS may or may not go on to develop MS. When CIS is accompanied by lesions similar to those seen in MS on brain MRI (magnetic resonance imaging), the person has a high probability of secondary attacks of neurological symptoms and is diagnosed as relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on brain MRI, the person is much less likely to develop MS.

[0193] In certain embodiments, the present disclosure provides a method of promoting myelination in a subject with a myelin-related disease or condition in a subject in need of 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 30th embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0194] 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 thirtieth 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 suffering from a myelin-related disease or disorder in a subject in need of treatment.

[0195] In certain embodiments, the present disclosure provides a compound as described herein (e.g., a compound as described in any one of the first to thirtieth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof, for use in promoting myelination in a subject suffering from a myelin-related disease or disorder in a subject in need of treatment.

[0196] 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 disseminated encephalomyelitis (ADEM), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), white matter ablative encephalopathy, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease (Parkinson's disease), spinal cord injury, traumatic brain injury, post-radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, autism, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-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.

[0197] In certain embodiments, the present disclosure provides a method of treating cancer in a subject in need of 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 thirtieth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0198] 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 thirtieth 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 treatment.

[0199] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to thirtieth 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 treatment.

[0200] In certain embodiments, the cancer is colorectal cancer.

[0201] In certain embodiments, the disclosure relates to the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0202] As used herein, "effective amount" and "therapeutically effective amount" can be used interchangeably. It means an amount that is effective in treating one or more of the diseases, disorders or conditions described herein or reducing their severity. In some embodiments, the effective dose can be between 10 μg and 500 mg.

[0203] According to the methods of the present disclosure, the compounds and compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the above-mentioned diseases, disorders, or conditions.

[0204] In certain embodiments, the disclosure relates to the aforementioned methods, wherein the compound is administered parenterally. In certain embodiments, the disclosure relates to the aforementioned methods, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectal, intrathecal, topically or intranasally. In certain embodiments, the disclosure relates to the aforementioned methods, wherein the compound is administered systemically.

[0205] The compounds of the present invention can be used as pharmaceutical compositions (e.g., compounds of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, pharmaceutical stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), etc. and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th edition Mack Printing Company, 1990, pages 1289-1329). In addition to any conventional carrier being incompatible with the active ingredient, its use in treatment or pharmaceutical compositions is considered. For the purposes of this disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising compounds of the present invention and solvents (i.e., solvates) or water (i.e., hydrates).

[0206] The formulation can be prepared using conventional dissolution and mixing procedures. For example, the raw drug substance (i.e., the compound of the present invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compound of the present invention is usually formulated into a pharmaceutical dosage form to provide a drug dosage that can be easily controlled and to provide a beautiful and easy-to-handle product for the patient.

[0207] The pharmaceutical composition (or preparation) for application can be packaged in a variety of ways according to the method for administering the drug. Generally speaking, the article for distribution includes a container in which a pharmaceutical preparation in an appropriate form is placed. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-proof component to prevent inadvertent contact with the contents of the package. In addition, a label describing the contents of the container is also placed on the container. The label may also include appropriate warnings.

[0208] Pharmaceutical compositions containing compounds of the present disclosure are typically formulated for use as suppositories for parenteral or oral administration or alternatively.

[0209] For example, the pharmaceutical oral composition of the present disclosure can be prepared into solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical composition 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, etc.

[0210] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with

[0211] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0212] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also

[0213] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary,

[0214] d) disintegrants, for example starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or

[0215] e) absorbents, colorants, flavorings and sweeteners.

[0216] Tablets may be film-coated or enteric-coated according to methods known in the art.

[0217] Suitable compositions for oral administration include compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives, so as to provide pharmaceutically elegant and palatable preparations. Tablets may contain active ingredients mixed with nontoxic pharmaceutically acceptable excipients suitable for making tablets. 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; adhesives such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, and thereby provide sustained action 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 in which the active ingredient is mixed with an inert solid diluent (e.g. calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g. peanut oil, liquid paraffin or olive oil).

[0218] Parenteral compositions (e.g., intravenous (IV) preparations) are aqueous isotonic solutions or suspensions. Parenteral compositions can 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. The compositions are usually prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75% or about 1-50% active ingredient.

[0219] The compounds of the present disclosure or their pharmaceutical compositions for subjects (e.g., humans) are generally administered orally or parenterally at therapeutic doses. When administered intravenously via infusion, the dosage may depend on the infusion rate of the IV preparation. Generally speaking, the therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the species, body weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, pharmacist, clinician, or veterinarian of ordinary skill can easily determine the effective amount of each active ingredient required for preventing, treating, or inhibiting the progression of a disorder or disease.

[0220] The above-mentioned dosage characteristics can be demonstrated by in vitro and in vivo tests, advantageously using mammals, such as mice, rats, dogs, monkeys or their isolated organs, tissues and preparations. The compounds of the present invention can be applied in vitro in the form of solutions, such as aqueous solutions, and can be applied in vivo enterally, parenterally, advantageously intravenously, such as as a suspension or in the form of aqueous solutions. The in vitro dosage may range between about 10-3 molar to 10-9 molar concentrations.

[0221] definition

[0222] As used herein, "patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. The terms include mammals, such as humans. Typically, the animal is a mammal. Subject also refers to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the animal is a primate. Preferably, the subject is a human.

[0223] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to a reduction or suppression of a given disorder, symptom or condition or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0224] As used herein, the terms "treat," "treating," or "treatment" of any disease, disorder, or condition refers to the management and care of a patient for the purpose of combating the disease, disorder, or condition, and includes the administration of the compounds of the invention to obtain the desired pharmacological and / or physiological effects. The effect may be therapeutic, including partial or substantial achievement of one or more of the following results: partial or complete reduction in the extent of the disease, disorder, or condition; improvement or modification of clinical symptoms, complications, or indicators associated with the disease, disorder, or condition; or delay, inhibition, or reduction in the likelihood of progression of the disease, disorder, or condition; or elimination of the disease, disorder, or condition. In certain embodiments, the effect may be prevention of the onset of symptoms or complications of the disease, disorder, or condition.

[0225] As used herein, the term "cancer" has the generally accepted meaning in the art. The term can broadly refer to abnormal cell growth.

[0226] 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.

[0227] As used herein, the term "myelination" has the meaning generally accepted in the art. The term can broadly refer to the process of myelin production.

[0228] As used herein, the term "myelin-related disease or disorder", "demyelinating disorder" or "demyelinating disorder" has the generally accepted meaning in the art. These terms can broadly refer to diseases or disorders involving myelin damage.

[0229] 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 such treatment.

[0230] 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 by radicals of specified substituents. 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 by more than one substituent selected from a specified group, the substituent at each position may be the same or different. In some embodiments, an optionally substituted group may be substituted by one or more substituents, each of which may be the same or different. In some embodiments, "one or more" substituents may be 1, 2, 3, 4, 5, 6, etc., each of which may be the same or different. In some embodiments, "one or more" substituents may be 1 to 6, 1 to 4, 1 to 3, or 1 to 2 substituents, each of which may be the same or different.

[0231] 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 "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 (generally one to three substituents, except for halogen substituents (such as perchloro or perfluoroalkyl)).

[0232] 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 1-4Alkyl 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 carbons, more preferably about 1-2 carbons. The term "C 1-2 "Alkoxy" should be interpreted accordingly.

[0233] As used herein, the term “C 1-4 Alkoxy C 1-4 "Alkyl" means a C 1-4 An alkyl group in which at least one of the hydrogen atoms is replaced by a C 1-4 Alkoxy substitution. 1-4 Alkoxy C 1-4 The alkyl group is attached to the rest of the molecule described herein through the alkyl group.

[0234] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx ", where x and xx are integers. For example, "C 1-3 "Alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0235] "Halogen" or "halo" may be fluorine, chlorine, bromine or iodine.

[0236] As used herein, the term "halo-substituted C 1-4 Alkyl" or "C 1-4 "Haloalkyl" refers to a C 1-4 Alkyl group in which at least one of the hydrogen atoms is replaced by a halogen atom. 1-4 The haloalkyl group may be a monohalogenated -C 1-4 Alkyl, dihalogenated-C 1-4 Alkyl or polyhalogenated-C 1-4 Alkyl (including perhalogenated-C 1-4 alkyl). Monohalogenated-C 1-4 The alkyl group may have one iodo, bromo, chloro or fluoro group within the alkyl group. 1-4 Alkyl and polyhalogenated-C 1-4 The alkyl group may have two or more identical halogenated atoms or a combination of different halogenated 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 halogen 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-alkyl group in which all hydrogen atoms are replaced by halogen atoms. 1-4 Alkyl group.

[0237] The term "aryl" refers to an aromatic carbocyclic monocyclic ring or two fused ring systems containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0238] The term "heteroaryl" refers to a 5 to 12-membered aromatic group containing 1 to 4 heteroatoms selected from N, O and S. In some cases, the nitrogen atom in the heteroaryl can be quaternized. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic". The heteroaryl group can be a monocyclic or bicyclic ring. Monocyclic heteroaryl includes, for example, pyrazolyl, imidazolyl, oxazolyl, pyridyl, furyl, oxadiazolyl, thienyl, etc. Bicyclic heteroaryl includes a group in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaromatic rings. Non-limiting examples include pyrazolopyridyl, pyrazolopyridyl, benzotriazolyl, imidazopyridyl and indolyl.

[0239] The term "carbocycle" or "carbocyclyl" refers to a 4 to 12-membered saturated or partially unsaturated hydrocarbon ring and may exist as a monocyclic, bicyclic (including fused, spiral or bridged carbocyclic rings) or spirocyclic ring. Bicyclic carbocyclyl groups include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, cycloalkyl or aryl, such as 2,3-dihydroindenyl, decahydronaphthyl and 1,2,3,4-tetrahydronaphthyl. Unless otherwise indicated, carbocycles typically contain 4 to 10 ring members.

[0240] The term "C 3-6 "Cycloalkyl" refers to a fully saturated carbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0241] The term "heterocycle" or "heterocyclyl" refers to a 4 to 12-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O and S. The heterocyclyl group can be a monocyclic or bicyclic ring (e.g., bridged, fused or spiral bicyclic). Examples of monocyclic saturated or partially unsaturated heterocyclyls include, but are not limited to, oxetane, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl. Bicyclic heterocyclyl groups include, for example, unsaturated heterocyclyls fused to another unsaturated heterocyclyl, cycloalkyl, aryl or heteroaryl ring, such as tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridinyl, 2-oxa-6-azaspiro[3.3]heptyl, 5-oxabicyclo[2.1.1]hexyl and 9-azabicyclo[3.3.1]nonyl. In some embodiments, the heterocyclyl group is a 4 to 6-membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 4- to 6-membered monocyclic saturated heterocyclyl group. In some embodiments, the heterocyclyl group is an 8- to 10-membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8- to 10-membered bicyclic saturated heterocyclyl group.

[0242] As used herein, the term "spiro" ring means a bicyclic ring system in which the two rings share a common carbon atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptyl and the like.

[0243] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. A fused heterocyclic ring has at least one ring system containing a ring atom that is a heteroatom selected from O, N and S (eg, 3-oxabicyclo[3.1.0]hexane).

[0244] 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).

[0245] The language "pharmaceutically acceptable" means that the substance, composition or dosage form must be compatible chemically and / or toxicologically with the other ingredients making up the formulation and / or the mammal to be treated therewith.

[0246] Unless otherwise indicated, the term "compound of the present disclosure" refers to compounds of formula (I) and all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, isotope-labeled compounds (including deuterium substitution). When there is a part capable of forming a salt, the salt (particularly a pharmaceutically acceptable salt) is also included.

[0247] As used herein, the terms "a / an", "the", and similar terms used in the context of the present invention (particularly in the context of the claims) should be interpreted as covering both the singular and the plural, unless otherwise indicated herein or clearly contradictory to the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention, and will not limit the scope of the present invention as originally claimed.

[0248] The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0249] In one embodiment, the disclosure relates to compounds of formula (I) as defined herein in free form. In another embodiment, the disclosure relates to compounds of formula (I) as defined herein in salt form. In another embodiment, the disclosure relates to compounds of formula (I) as defined herein in acid addition salt form. In yet another embodiment, the disclosure relates to compounds of formula (I) as defined herein in pharmaceutically acceptable salt form. In yet another embodiment, the disclosure relates to compounds of formula (I) as defined herein in pharmaceutically acceptable acid addition salt form. In yet another embodiment, the disclosure relates to any one of the compounds in the Examples in free form. In yet another embodiment, the disclosure relates to any one of the compounds in the Examples in salt form. In yet another embodiment, the disclosure relates to any one of the compounds in the Examples in acid addition salt form. In yet another embodiment, the disclosure relates to any one of the compounds in the Examples in pharmaceutically acceptable salt form. In yet another embodiment, the disclosure relates to any one of the compounds in the Examples in pharmaceutically acceptable acid addition salt form. In yet another embodiment, the disclosure relates to any one of the compounds in the Examples in pharmaceutically acceptable acid addition salt form.

[0250] The disclosed compounds can be synthesized by synthetic routes including methods analogous to those well known in the chemical arts, particularly in light of the description contained herein. Starting materials are generally available from commercial sources such as Sigma-Aldrich, or 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 Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0251] For the purpose of illustration, the reaction scheme described below provides a possible approach for synthesizing compounds disclosed herein and key intermediates. For a more detailed description of each reaction step, see the Examples section below. Although specific starting materials and reagents are described in the scheme and discussed below, other starting materials and reagents can be easily replaced to provide multiple derivatives and / or reaction conditions.

[0252] Example

[0253] abbreviation:

[0254] PE = Petroleum Ether

[0255] EtOAc=EA=ethyl acetate

[0256] ESI = Electrospray Ionization

[0257] MeOH = methanol

[0258] EtOH = ethanol

[0259] DCE = 1,2-dichloroethane

[0260] DCM = dichloromethane

[0261] CHCl3=Chloroform

[0262] HCl = Hydrochloric acid

[0263] H2O=water

[0264] IPA = Isopropyl Alcohol

[0265] LCMS = Liquid Chromatography Mass Spectrometry

[0266] HFIP = Hexafluoro-2-isopropanol

[0267] HPLC = High Pressure Liquid Chromatography

[0268] THF = Tetrahydrofuran

[0269] MeCN=ACN=acetonitrile

[0270] MgSO4 = Magnesium sulfate

[0271] DMSO = dimethyl sulfoxide

[0272] AcOH = acetic acid

[0273] TFA = trifluoroacetic acid

[0274] DIPEA = diisopropylethylamine

[0275] N2 = Nitrogen

[0276] NH4HCO3=ammonium bicarbonate

[0277] t-BuOH = tert-butyl alcohol

[0278] NH4Cl = Ammonium chloride

[0279] NaH = Sodium hydride

[0280] Na2SO4=Sodium sulfate

[0281] K2CO3=Potassium carbonate

[0282] NaHCO3 = Sodium bicarbonate

[0283] NaBH(OAc)3=STAB=sodium triacetoxyborohydride

[0284] SiO2=silicon dioxide or silica

[0285] PDA = Photodiode Array Detection

[0286] TosMIC = Tosylmethyl isocyanide

[0287] TLC = Thin Layer Chromatography

[0288] LiHMDS = lithium bis(trimethylsilyl)amide;

[0289] General approach

[0290] LCMS instrument specifications:

[0291] Agilent Technologies 1200 Series LC / MSD system: DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B mass spectrometers.

[0292] Agilent Technologies 1260 Infinity LC / MSD system: DAD\ELSD Alltech 3300 and Agilent LC\MSD G6120B mass spectrometer.

[0293] Agilent Technologies 1260Infinity II LC / MSD system: DAD\ELSD G7102A1290Infinity II and Agilent LC\MSD G6120B mass spectrometer.

[0294] Agilent 1260 Series LC / MSD System: DAD\ELSD and Agilent LC\MSD (G6120B) mass spectrometer.

[0295] UHPLC Agilent 1290 Series LC / MSD System: DAD\ELSD and Agilent LC\MSD (G6125B) mass spectrometer.

[0296] HPLC analysis method specifications:

[0297] ·Column: Agilent Poroshell 120SB-C18 4.6x 30mm 2.7μm, equipped with UHPLC GuardInfinity Lab Poroshell 120SB-C18 4.6x 5mm 2.7μm

[0298] Column temperature, 60°C

[0299] Injection volume 0.5μL

[0300] Modifier: Formic acid concentration 0.1% (v / v)

[0301] Method: 99% water / 1% MeCN (initial condition), hold initial condition for 0.1 min, linear gradient to 0% water / 100% MeCN at 1.5 min, hold 0% water / 100% MeCN to 1.73 min, linear gradient to 99% water / 1% MeCN at 1.74 min. Flow rate, 3.0 mL / min.

[0302] UV scanning: 207-223nm, 246-262nm, 272-288nm

[0303] QC analysis LC / MS method conditions:

[0304] Ammonium Hydroxide (Alkaline pH) Conditions

[0305] MS mode: MS: ESI + scan range 165-650 Daltons

[0306] PDA: 200-400nm scanning range

[0307] Column: Waters ACQUITY UPLC BEH C18 2.1x50 mm, 1.7 μm; Part No. 186002350

[0308] Modifier: ammonium hydroxide concentration 0.2% (v / v)

[0309] Method: Linear gradient from 95% water / 5% MeCN (initial conditions) at 3.75 minutes to 5% water / 95% MeCN, hold 5% water / 95% MeCN until 4 minutes. Flow rate, 0.8 mL / min.

[0310] Trifluoroacetic acid (acidic pH) conditions

[0311] MS mode: MS: ESI + scan range 165-650 Daltons

[0312] PDA: 200-400nm scanning range

[0313] Column: Waters ACQUITY UPLC BEH C18 2.1x50 mm, 1.7 μm; Part No. 186002350

[0314] Modifier: trifluoroacetic acid concentration 0.1% (v / v)

[0315] Method: Linear gradient from 95% water / 5% MeCN (initial conditions) at 3.75 minutes to 5% water / 95% MeCN, hold 5% water / 95% MeCN until 4 minutes. Flow rate, 0.8 mL / min.

[0316] General preparative HPLC conditions:

[0317] Ammonium Hydroxide (Alkaline pH) Conditions

[0318] Flow rate: 30mL / min

[0319] MS mode: MS: ESI + scan range 165-650 Daltons

[0320] PDA: 200-400nm scanning range

[0321] Column: Waters XSELECT CSH C18 PREP 19x100 mm, 5μm; Part No. 186005421

[0322] Modifier: 0.2% ammonium hydroxide (v / v) concentration

[0323] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, hold at 5% water / 95% MeCN until 10 min.

[0324] Flow rate: 50mL / min

[0325] MS mode: MS: ESI + scan range 165-650 Daltons

[0326] PDA: 200-400nm scanning range

[0327] Column: Waters XSELECT CSH C18 PREP 30x100 mm, 5 μm; Part No. 186005425

[0328] Modifier: 0.2% NH4OH (v / v) concentration

[0329] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, hold at 5% water / 95% MeCN until 10 min.

[0330] Flow rate, 60 mL / min

[0331] MS mode: MS: ESI + scan range 165-650 Daltons

[0332] PDA: 200-400nm scanning range

[0333] Column: Waters XSELECT CSH C18 PREP 30x50 mm, 5 μm; Part No. 186005423

[0334] Modifier: 0.2% NH4OH (v / v) concentration

[0335] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, hold at 5% water / 95% MeCN until 10 min.

[0336] Trifluoroacetic acid (acidic pH) conditions

[0337] Flow rate, 30 mL / min

[0338] MS mode: MS: ESI + scan range 165-650 Daltons

[0339] PDA: 200-400nm scanning range

[0340] Column: Waters Sunfire OBD C18 PREP 19x100 mm, 5 μm; Part No. 186002567

[0341] Modifier: 0.1% trifluoroacetic acid (v / v) concentration

[0342] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, hold at 5% water / 95% MeCN until 10 min.

[0343] Flow rate, 50 mL / min

[0344] MS mode: MS: ESI + scan range 165-650 Daltons

[0345] PDA: 200-400nm scanning range

[0346] Column: Waters Sunfire OBD C18 PREP 30x100 mm, 5 μm; Part No. 186002572

[0347] Modifier: 0.1% trifluoroacetic acid (v / v) concentration

[0348] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, hold at 5% water / 95% MeCN until 10 min.

[0349] Flow rate, 60 mL / min

[0350] MS mode: MS: ESI + scan range 165-650 Daltons

[0351] PDA: 200-400nm scanning range

[0352] Column: Waters Sunfire OBD C18 PREP 30x50 mm, 5 μm; Part No. 186002570

[0353] Modifier: 0.1% trifluoroacetic acid (v / v) concentration

[0354] Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN at 8 min, increase to 5% water / 95% MeCN at 8.5 min, hold at 5% water / 95% MeCN until 10 min.

[0355] Experimental Procedure

[0356] Example 1

[0357] 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane

[0358]

[0359] 1. Synthesis of 1-(5-bromo-6-methylpyridin-2-yl)ethan-1-one

[0360]

[0361] To a solution of 3,6-dibromo-2-methylpyridine (10 g, 39.9 mmol) in toluene (200 mL) was added n-BuLi (2.5 M, 17.5 mL) at -78 ° C under N2 atmosphere, and the solution was stirred for 1 hour. DMA (10.4 g, 119.6 mmol) was added, the mixture was stirred at -78 ° C for 1 hour, and the temperature was slowly raised to 20 ° C. The reactant was poured into a saturated NH4Cl aqueous solution, extracted with EtOAc, and the combined organic extracts were concentrated in vacuo. The extract was purified by silica gel column chromatography (PE / EtOAc=1 / 0 to 8 / 1) to give 1-(5-bromo-6-methylpyridin-2-yl)ethane-1-one (8.1 g, 95%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δppm 7.92 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 2.72 (s, 3H), 2.69 (s, 3H).

[0362] 2. Synthesis of 3-bromo-6-(1,1-difluoroethyl)-2-methylpyridine

[0363]

[0364] A solution of 1-(5-bromo-6-methylpyridin-2-yl)ethan-1-one (8.1 g, 37.8 mmol) in DAST (30 mL, 227.1 mmol) was stirred at 60 ° C for 4 hours. The reaction was quenched with saturated NaHCO3 aqueous solution until pH = 7 and extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by (PE / EtOAc=20 / 1 to 10 / 1) to obtain 3-bromo-6-(1,1-difluoroethyl)-2-methylpyridine (4.5 g, 50%) as a colorless oil. LCMS m / z=236.0 [M+H] + .

[0365] 3. Synthesis of 3-(Benzylthio)-6-(1,1-difluoroethyl)-2-methylpyridine

[0366]

[0367] To a solution of 3-bromo-6-(1,1-difluoroethyl)-2-methylpyridine (2.2 g, 9.3 mmol) in dioxane (20 mL) was added DIPEA (4.9 mL, 28.0 mmol), Pd(tBu3P)2 (476 mg, 0.9 mmol) and BnSH (2.3 mL, 19.7 mmol), and the mixture was stirred at 100 ° C under N2 for 16 hours. The mixture was quenched with H2O (100 mL) and extracted with DCM (50 mL x 5). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give 3-(benzylthio)-6-(1,1-difluoroethyl)-2-methylpyridine (4 g, crude) as a yellow oil. LCMS m / z=280.1[M+H] + .

[0368] 4. Synthesis of 6-(1,1-difluoroethyl)-2-methylpyridine-3-sulfonyl chloride

[0369]

[0370] To a solution of 3-(benzylthio)-6-(1,1-difluoroethyl)-2-methylpyridine (1 g, 3.6 mmol) in DCM (10 mL) and water (2 mL) was added SO2Cl2 (2.1 mL, 25.1 mmol) at 0 ° C, and the reactant was stirred at 0 ° C under N2 for 1 hour. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 5). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to give 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (650 mg, thick) as a yellow oil. 1 H NMR (400MHz, CDCl3): δppm 8.44 (d, J = 8.4Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 3.05 (s, 3H), 2.05 (t, J = 18.8Hz, 3H).

[0371] 5. Synthesis of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one

[0372]

[0373] To a solution of 2-azaspiro [3.3] heptane-6-one TFA salt (530 mg, 2.4 mmol) in DCM (10 mL) was added DIPEA (6820 μL, 4.7 mmol), followed by 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro [3.3] heptane-6-one (605 mg, 2.36 mmol) in DCM (2 mL). The mixture was stirred at 20 ° C for 1 hour, then diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with water (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (0% to 6% MeOH in DCM) to give 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (260 mg, 33%) as a yellow solid. LCMS m / z = 331.1 [M+H] + .

[0374] 6. Synthesis of 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane

[0375]

[0376] A solution of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptane-6-one (80 mg, 0.2 mmol) and 2-oxa-6-azaspiro[3.3]heptane oxalate (68 mg, 0.4 mmol) in MeOH (3 mL) was adjusted to pH 5-6 using AcOH, and the solution was stirred for 0.5 h at 20° C. NaBH3CN (76 mg, 1.2 mmol) was added and the mixture was stirred at 20° C. for 1 h. The mixture was purified by preparative HPLC (Welch Xtimate C18 150 x 25 mm x 5 μm, conditions: water (NH4HCO3)-MeCN, 28% to 48%, flow rate (mL / min): 25) to give 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane (32 mg, 32%) as a white solid. LCMS m / z=414.1[M+H] + . 1H NMR (400MHz, MeOH-d4): δppm 8.34(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),4.70(s,4H),3.89(s,2H),3.82(s,2H) ,3.32(s,4H),2.97-2.92(m,1H),2.83(s,3H),2.23-2.19(m,2H),2.04-1.93(m,5H).

[0377] Example 2

[0378] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine

[0379]

[0380] A solution of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (Example 1, Step 5, 80 mg, 0.2 mmol) and tetrahydropyran-4-amine (37 mg, 0.4 mmol) in MeOH (3 mL) was adjusted to pH 5-6 using acetic acid and stirred at 20° C. for 0.5 h. NaBH3CN (76 mg, 1.2 mmol) was added and the mixture was stirred at 20° C. for 1 h. The mixture was purified by preparative HPLC (Welch Xtimate C18 150 x 25 mm x 5 μm, conditions: water (NH4HCO3)-MeCN, 37% to 52%, flow rate (mL / min): 25) to give 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine (25 mg, 25%) as a white solid. LCMS m / z=416.2 [M+H] + . 1 H NMR (400MHz, MeOH-d4): δppm 8.36(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),3.93(s,2H),3.90-3.88(m,2H),3.81(s,2H),3.40-3.34(m,2H),3.28-3. 25(m,1H),2.84(s,3H),2.70-2.65(m,1H),2.45-2.43(m,2H),2.05-1.94(m,5H),1.77-1.72(m,2H),1.37-1.35(m,2H).

[0381] Example 3

[0382] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine

[0383]

[0384] 1. Synthesis of 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one

[0385]

[0386] DIPEA (1.1 mL, 6.3 mmol) was added dropwise to a vial containing 2-azaspiro [3.3] heptane-6-one hydrochloride (300 mg, 2.0 mmol) in anhydrous DCM (8 mL) at <5 °C. After 5 minutes, 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (704 mg, 2.7 mmol) was added and the reactants were warmed to 23 °C. After 30 minutes, the reactants were quenched by slowly adding a 1M NaOH aqueous solution, the mixture was stirred at 23 °C for 20 minutes, and then the biphasic mixture was extracted with DCM (3x). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-60% EtOAc in heptane) to give 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (450 mg, 67%) as a white solid. LCMS m / z=335.0 [M+H] + .

[0387] 2. Synthesis of 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine

[0388]

[0389] To a mixture of 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (67 mg, 0.2 mmol) and tetrahydropyran-4-amine HCl salt (46 mg, 0.3 mmol) in DCM (3 mL) was added AcOH (34 μL, 0.6 mmol). NaBH(OAc) (170 mg, 0.8 mmol) was added once and the reaction mixture was stirred at room temperature for 3 days. The reactant was quenched with saturated NaHCO, stirred at room temperature for 5 minutes, more DCM and water were added, and the mixture was stirred for another 5 minutes. The aqueous layer was removed, the organic phase was washed with water and concentrated. The residue was purified by silica gel column (50% to 100% EtOAc / EtOH (3 / 1)) to give 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine (61 mg, 73%) as a white solid. LCMS m / z=420.2[M+H] + . 1H NMR (400MHz, MeOH-d4): δ (ppm) 8.47 (d, J = 8.0Hz, 1H), 7.85 (d, J = 8.0Hz, 1H), 4.01 (s, 2H), 3.95 (dd, J = 11.0, 4.0Hz, 2H), 3.89 (s, 2H) ,3.50-3.36(m,3H),2.89(s,3H),2.85(s,1H),2.58-2.48(m,2H),2.16-2.06(m,2H),1.88-1.77(m,2H),1.44(qd,J=12.2,4.5Hz,2H)

[0390] Example 4

[0391] 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane

[0392]

[0393] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptane-6-one (Example 3, Step 1, 75 mg, 0.2 mmol) and 2-oxa-6-azaspiro[3.3]heptane (22 mg, 0.2 mmol) were dissolved in MeOH (6 mL). NaBH3CN (71 mg, 1.1 mmol) and AcOH (30 μL, 0.5 mmol) were added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with ammonium chloride (saturated aqueous solution), the mixture was diluted with DCM and the layers were separated. The organic phase was washed with water and brine, and the solvent was removed in vacuo. The crude product was purified by silica gel column (0%-100% EtOAc to 3:1 EtOAc:EtOH (w / 2% NH3OH)) to give 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane (65 mg, 69%). LCMS m / z=418.3[M+H] + . 1 H NMR (500MHz, CDCl3): δppm 8.36-8.13(m,1H),7.58(d,J=8.2Hz,1H),4.64(s,4H),3.83(d,J=16.5H z,4H),3.20(s,4H),2.86-2.70(m,4H),2.22-2.05(m,2H),1.86(m,2H).

[0394] Example 5

[0395] 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine

[0396]

[0397] Following the procedure described in Example 4, 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine (9 mg, 10%) was obtained from 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-one (Example 3, Step 1) and morpholine. LCMS m / z=406.3[M+H] + . 1H NMR (500MHz, CDCl3): δppm 8.29(d,J=7.9Hz,1H),7.58(d,J=7.9Hz,1H),3.92(s,2H),3.81(s,2H),3.63(br s,4H),2.83(s,3H),2.55(br t,J=7.6Hz,1H),2.32-2.15(m,6H),1.99(br t,J=9.5Hz,2H).

[0398] Example 6

[0399] 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane

[0400]

[0401] Following the procedure described in Example 4, 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane (67 mg, 72%) was obtained from 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-one (Example 3, Step 1) and 1-oxa-6-azaspiro[3.3]heptane. LCMS m / z=418.3 [M+H] + . 1 H NMR (500MHz, CDCl3): δppm 8.28 (d, J = 8.2Hz, 1H), 7.57 (d, J = 7.9Hz, 1H), 4.43 (t, J = 7.6Hz, 2H), 3.92-3.74 (m, 4H), 3.45 (br d, J = 8.6Hz, 2H), 3.02 (br d,J=9.2Hz,2H),2.92-2.85(m,1H),2.82(s,3H),2.76(t,J=7.5Hz,2H),2.26-2.10(m,2H),1.92-1.81(m,2H).

[0402] Example 7

[0403] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)-2-azaspiro[3.3]hept-6-amine

[0404]

[0405] Following the procedure described in Example 4, 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (Example 3, Step 1) and 1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)-2-azaspiro[3.3]heptan-6-amine (80 mg, 39%) was obtained from 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (Example 3, Step 1) and 1-(tetrahydro-2H-pyran-4-yl)cyclopropan-1-amine. LCMS m / z=460.3[M+H] + . 1 H NMR (400MHz, MeOH-d4): δppm 8.38 (d, J = 8.5Hz, 1H), 7.77 (d, J = 8.0Hz, 1H), 4.70 (br s,1H),4.00-3.70(m,5H),3.36-3.14(m,4H),2.80(s,3H),2.46-2.31(m,2H),1.97-1. 85(m,2H),1.72-1.55(m,1H),1.54-1.43(m,2H),1.27-1.03(m,2H),0.45-0.33(m,4H).

[0406] Example 8

[0407] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine

[0408]

[0409] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (Example 3, Step 1) (80 mg, 0.2 mmol) was dissolved in MeOH (1 mL) and DCM (3 mL). AcOH (30 μL, 0.5 mmol) was added, and NaBH was added after 15 minutes. CN (75 mg, 1.2 mmol) was stirred at room temperature for 24 hours. The reactant was diluted with EtOAc and quenched with NaHCO (saturated aqueous solution), and the mixture was extracted with EtOAc (3x). The combined organic extracts were washed with water and then concentrated in vacuo. The residue was purified by silica gel column chromatography using 0%-100% EtOAc to 3:1 EtOAc:EtOH (w / 2% NH3OH) to give 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine (63 mg, 67%). LCMS m / z=392.0 [M+H] + .1 H NMR (500MHz, CDCl3): δppm 8.28(d,J=8.2Hz,1H),7.58(d,J=8.2Hz,1H),4.71(t,J=6.7Hz,2H),4.32(t,J=6.4Hz, 2H),3.94-3.77(m,5H),3.10(t,J=7.3Hz,1H),2.83(s,3H),2.36(m,2H),1.84(m,3H).

[0410] Example 9

[0411] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]hept-6-amine

[0412]

[0413] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (Example 3, Step 1) (69 mg, 0.2 mmol) was dissolved in MeOH (1 mL) and DCM (3 mL). (3-methyloxetane-3-yl)methylamine (25 mg, 0.3 mmol) and AcOH (25 μL, 0.4 mmol) were added, and the solution was stirred for 15 minutes. NaBH(OAc) (220 mg, 1.0 mmol) was added and the reactant was stirred at room temperature for 24 hours. The reactant was diluted with EtOAc and quenched with NaHCO aqueous solution. The solution was extracted with EtOAc (3x), and the combined organic extracts were washed with water and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with (0%-100%: EtOAc: EtOH (3: 1) in EtOH containing 0.2% NH3OH) to give 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]hept-6-amine (60 mg, 69%). LCMS m / z=420.1 [M+H] + . 1 H NMR (500MHz, CDCl3): δppm 8.36 (br d, J=7.9Hz, 1H), 7.65 (br d,J=7.9Hz,1H),4.51-4.28(m,4H),4.04-3.78(m,4H),3.19(m,1H),2.91(s,3H),2.67(s,2H),2.46(m,2H),2.03-1.77(m,2H),1.27(s,4H).

[0414] Example 10

[0415] 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine

[0416]

[0417] 1. Synthesis of 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one

[0418]

[0419] Following the procedure described in Example 3, Step 1, 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (404 mg, 62%) was obtained as a colorless film from 2-azaspiro[3.3]heptan-6-one and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride. 1 H NMR (400MHz, DCM-d2): δppm 7.05 (s, 1H), 4.16 (s, 3H), 4.12 (s, 4H), 3.28 (s, 4H).

[0420] 2. Synthesis of 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine

[0421]

[0422] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (75mg, 0.2mmol) and morpholine hydrochloride (32mg, 0.3mmol) are dissolved in DCM (4mL).NaBH3CN (73mg, 1.2mmol) and AcOH (30 μL, 0.5mmol) are added and the reactant is stirred at room temperature for 6 hours.The reactant is quenched with ammonium chloride (saturated aqueous solution) and diluted with DCM.Separate each layer, wash the organic phase with water and brine, then concentrate in vacuo. The residue was purified by silica gel column (0%-100% EtOAc to 3:1 EtOAc:EtOH (w / 2% NH3OH)) to give 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine (25 mg, 27%). LCMS m / z=395.3[M+H] + .1 H NMR (500MHz, CDCl3): δppm 6.92(s,1H),4.07(s,3H),3.87(s,2H),3.78(s,2H),3.62(br s,4H),2.54(br t,J=7.6Hz,1H),2.32-2.16(m,6H),1.98(brd,J=7.9Hz,2H).

[0423] Embodiment 11

[0424] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-ylmethyl)-2-azaspiro[3.3]hept-6-amine

[0425]

[0426] Following the procedure described in Example 8, 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (Example 10, Step 1) and oxetan-3-ylmethanamine were obtained (67 mg, 68%). LCMS m / z=395.1 [M+H] + . 1 H NMR (500MHz, CDCl3): δppm 6.99 (s, 1H), 5.55 (br s, 1H), 4.79 (br t, J = 6.9Hz, 2H), 4.36 (br t,J=6.0Hz,2H),4.15(s,3H),3.92(s,2H),3.86(s,2H),3.22–3.11(m,1H),3.06-2.95(m,1H),2.82(br d,J=7.3Hz,2H),2.43(m,2H),1.90-1.81(m,2H).

[0427] Example 12

[0428] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]hept-6-amine

[0429]

[0430] Following the procedure described in Example 8, 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (Example 10, Step 1) and (3-methyloxetan-3-yl)methanamine were obtained (60 mg, 59%). LCMS m / z=409.1 [M+H] + . 1 H NMR (500MHz, CDCl3): δppm7.00(s,1H),4.43-4.33(m,4H),4.15(s,3H),3.92(s,2H),3.90- 3.85(m,2H),3.18(m,1H),2.66(s,2H),2.46-2.38(m,2H),1.91-1.83(m,2H),1.27(s,4H).

[0431] Embodiment 13

[0432] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine

[0433]

[0434] 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (Example 10, Step 1, 80 mg, 0.3 mmol) was dissolved in MeOH (1 mL) and DCM (3 mL). Oxetanes-3-amine (22 mg, 0.3 mmol) and AcOH (30 μL, 0.5 mmol) were added, the solution was stirred for 15 minutes, then NaBH was added CN (78 mg, 1.2 mmol). The reactant was stirred at room temperature for 24 hours, then diluted with EtOAc, and quenched with NaHCO aqueous solution. The solution was extracted with EtOAc (3x), the combined organic extracts were washed with water and concentrated in vacuo. The crude product was purified by column chromatography eluting with (0%-100%: EtOAc: EtOH (3: 1) in EtOH containing 0.2% NH3OH) to give 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine (52 mg, 55%). LCMS m / z=381.0 [M+H] + . 1H NMR (500MHz, CDCl3): δppm 6.92(s,1H),5.59-5.35(m,1H),4.71(t,J=6.9Hz,2H),4.31(t,J=6.4Hz,2H), 4.07(s,3H),3.89-3.73(m,5H),3.14-3.03(m,1H),2.32(m,2H),1.81(m,2H).

[0435] Embodiment 14

[0436] 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane

[0437]

[0438] 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane (8 mg, 8%) was obtained from 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-one (Example 10, Step 1) and 2-oxa-6-azaspiro[3.3]heptane following the procedure described in Example 4. LCMS m / z=407.3 [M+H] + . 1 H NMR (500MHz, CDCl3): δppm 6.91(s,1H),4.64(s,4H),4.07(s,3H),3.79(d,J=7.9Hz,4H),3.18(s,4H),2.76(m,1H),2.17-2.01(m,2H),1.86-1.72(m,2H).

[0439] Embodiment 15

[0440] 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane

[0441]

[0442] Following the procedure described in Example 4, 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane (37 mg, 39%) was obtained from 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-one (Example 10, Step 1) and 1-oxa-6-azaspiro[3.3]heptane. LCMS m / z=407.3 [M+H] + . 1 H NMR (500MHz, CDCl3): δppm 6.91 (s, 1H), 4.43 (t, J = 7.5Hz, 2H), 4.14-3.95 (m, 3H), 3.79 (d, J = 13.1Hz, 4H), 3.49-3.32 (m, 2H), 2.99 (br d,J=9.5Hz,2H),2.90-2.79(m,1H),2.76(t,J=7.5Hz,2H),2.26-2.06(m,2H),1.88-1.75(m,2H).

[0443] Example 16

[0444] 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane

[0445]

[0446] 1. Synthesis of 5-(benzylthio)-4-methyl-2-(trifluoromethyl)pyrimidine

[0447]

[0448] To a solution of 5-bromo-4-methyl-2-(trifluoromethyl)pyrimidine (600 mg, 2.5 mmol) and BnSH (550 μL, 4.5 mmol) in dioxane (15 mL) was added DIPEA (1.3 mL, 7.5 mmol) and Pd(tBu3P)2 (190.8 mg, 0.373 mmol), and the reaction mixture was stirred at 100 ° C under N2 atmosphere for 12 hours. The mixture was diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc in PE = 0% to 8%) to give 5-(benzylthio)-4-methyl-2-(trifluoromethyl)pyrimidine (670 mg, 95% yield) as a yellow solid. LCMS m / z=285.0[M+H] +

[0449] 2. Synthesis of 4-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride

[0450]

[0451] To a solution of 5-(benzylthio)-4-methyl-2-(trifluoromethyl)pyrimidine (550 mg, 1.9 mmol) in DCM (5 mL) and water (1 mL) was added a solution of SO2Cl2 (1.10 mL, 13.6 mmol) in DCM (1 mL) dropwise at <5°C over 5 minutes. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride (350 mg, crude) as a pale yellow oil. 1 H NMR (400MHz, CDCl3): δppm 9.36 (s, 1H), 3.10 (s, 3H).

[0452] 3. Synthesis of 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one

[0453]

[0454] Following the procedure described in Example 1, Step 4, 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (1.0 g, 34%) was obtained as a yellow solid from 2-azaspiro[3.3]heptan-6-one (TFA salt) and 4-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride. LCMS m / z=336.0 [M+H]+ . 1 H NMR (500MHz, CDCl3): δppm9.21(s,1H),4.25(s,4H),3.36(s,4H),2.93(s,3H).

[0455] 4. Synthesis of 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane

[0456]

[0457] A solution of 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptane-6-one (70 mg, 0.2 mmol) and 1-oxa-6-azaspiro[3.3]heptane hemioxalate (51 mg, 0.3 mmol) in MeOH (10 mL) was adjusted to pH 5-6 by adding AcOH, and the reactants were stirred at 20 ° C for 0.5 hours. NaBH3CN (39 mg, 0.6 mmol) was added and the reactants were stirred at 20 ° C for 1 hour. The mixture was diluted with water (30 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 (Phenomenex C18150*40mm*5μm, conditions: water (NH4HCO3)-MeCN, 23% to 53%, flow rate (mL / min): 60) to give 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane (25 mg, 29%) as a white solid. LCMS m / z=419.1[M+H] + . 1 H NMR (400MHz, CDCl3): δppm 9.17(s,1H),4.50(t,J=7.6Hz,2H),3.98(s,2H),3.95(s,2H),3.51-3.49(m,2H),3.08-3.06(m,2 H),2.96-2.93(m,1H),2.90(s,3H),2.83(t,J=7.6Hz,2H),2.26-2.21(m,2H),1.98-1.93(m,2H).

[0458] Embodiment 17

[0459] 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane

[0460]

[0461] 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane (27 mg, 31%) was obtained as a white solid from 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-one (Example 16, Step 3) and 2-oxa-6-azaspiro[3.3]heptane oxalate following the procedure described in Example 1, Step 4. LCMS m / z = 419.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δppm 9.17(s,1H),4.71(s,4H),3.99-3.95(m,4H),3.26(s,4H),2.90(s,3H),2.87-2.82(m,1H),2.23-2.18(m,2H),1.95-1.90(m,2H).

[0462] Embodiment 18

[0463] 2-Methyl-N-(2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

[0464]

[0465] 1. Synthesis of tert-butyl 6-((2-methyl-6-(trifluoromethyl)pyridine)-3-sulfonamido)-2-azaspiro[3.3]heptane-2-carboxylate

[0466]

[0467] DIPEA (4.0 mL, 23.0 mmol) was added dropwise to a solution of 6-amino-2-azaspiro [3.3] heptane-2-formic acid tert-butyl ester (1.24 g, 5.9 mmol) in anhydrous DCM (20 mL) at <5 °C. After 5 minutes, 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride (2.01 g, 7.7 mmol) was added to the cold solution, and after completion of the addition, the reactant was warmed to 23 °C and stirred for 90 minutes. The reactant was quenched by slowly adding a 1 M NaOH aqueous solution. The mixture was stirred at 23 °C for 20 minutes, and then the biphasic mixture was extracted with DCM (3x). The combined organic extracts were dried over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was loaded onto a silica gel column and purified with (10% - 60% EtOAc in heptane) to afford tert-butyl 6-((2-methyl-6-(trifluoromethyl)pyridine)-3-sulfonamido)-2-azaspiro[3.3]heptane-2-carboxylate (1.95 g, 77%) as a white solid. 1 H NMR (500MHz, DMSO-d6): δppm 8.56(d,J=8.2Hz,1H),8.38(d,J=8.2Hz,1H),7.96(d,J=8.2Hz,1H),3.82-3.65(m,4H ),3.58-3.51(m,1H),2.82(s,3H),2.26-2.20(m,2H),2.01-1.95(m,2H),1.32(s,9H).

[0468] 2. Synthesis of 2-methyl-N-(2-azaspiro[3.3]hept-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

[0469]

[0470] To a solution of tert-butyl 6-((2-methyl-6-(trifluoromethyl)pyridine)-3-sulfonamido)-2-azaspiro[3.3]heptane-2-carboxylate (522 mg, 1.2 mmol) in anhydrous DCM (8 mL) was added TFA (0.6 mL, 7.8 mmol) dropwise at <5°C. The reaction was stirred at room temperature for 21 hours and then concentrated under reduced pressure to give 2-methyl-N-(2-azaspiro[3.3]hept-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide (606 mg, crude, TFA salt) as a light brown residue which was used without purification. LCMS m / z=336.2 [M+H] +

[0471] 3. Synthesis of 2-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

[0472]

[0473] A solution of 2-methyl-N-(2-azaspiro[3.3]heptyl-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide (269 mg, 0.6 mmol, TFA salt) in anhydrous MeOH (4 mL) was cooled in an ice-water bath, and DIPEA (0.7 mL, 4.0 mmol) was then added, and the solution was stirred for 20 minutes. Tetrahydropyran-4-one (120 μL, 1.30 mmol) and AcOH (300 μL, 4.9 mmol) were added to the cooled mixture, the solution was stirred for 15 minutes, and NaBH(OAc) (803.3 mg, 3.79 mmol) was then added in batches. The reactant was maintained at <5 °C and stirred for 2 hours. The reactant was quenched by slowly adding saturated NaHCO aqueous solution, the mixture was stirred for 30 minutes at 23 °C, and then extracted with DCM (3x). The combined organic extracts were dried over anhydrous MgSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column and purified with (40%-100% 3:1 EtOAc:EtOH in heptane) to give 2-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide (88 mg, 33.3% yield) as a colorless film. LCMS m / z=420.3 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 8.54(br d,J=8.2Hz,1H),8.38(d,J=7.9Hz,1H),7.97(d,J=8.2Hz,1H),3.75(br dd,J=5.3,1.1Hz,2H),3.59-3.52(m,1H),3.24-3.18(m,2H),3.03-2.89(m,3H),2.83(s,3H),2.12(br s,2H),2.05-1.87(m,4H),1.59-1.41(m,2H),1.07-1.00(m,2H).

[0474] Embodiment 19

[0475] 4-(2-((3-isopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine

[0476]

[0477] To a mixture of 4- (2- azaspiro [3.3] heptane -6- bases) morpholine 2HCl salt (29mg, 0.2mmol) and 3- isopropyl -1- methyl -1H- pyrazole -5- sulfonyl chloride (36mg, 0.2mmol) in DCM (5mL), DIPEA (110 μL, 0.6mmol) is added, and the reaction mixture is stirred at room temperature for 3 hours. The reactant is quenched with saturated NaHCO3, diluted with water, and stirred at room temperature for 5 minutes. The water layer is removed, and the organic phase is washed with water and concentrated. The residue is purified by silica gel column (50% -100% EtOAc / EtOH 3 / 1 in heptane), 4- (2- ((3- isopropyl -1- methyl -1H- pyrazole -5- bases) sulfonyl) -2- azaspiro [3.3] heptane -6- bases) morpholine (18mg, 31%) is obtained as an off-white solid after lyophilization. LCMS m / z=369.2[M+H] + . 1 H NMR (400MHz, MeOH-d4): δ (ppm) 6.68 (s, 1H), 4.04 (s, 3H), 3.89 (s, 2H), 3.78 (s, 2H), 3.72-3.63 (m, 4H), 3.08-2.90 (m, 1H), 2.73-2.57 (m, 1H), 2.32 (br s, 4H), 2.26-2.18 (m, 2H), 2.03-1.94 (m, 2H), 1.28 (d, J = 7.0Hz, 6H).

[0478] Embodiment 20

[0479] 2-((4-(difluoromethoxy)phenyl)sulfonyl)-6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane

[0480]

[0481] 1. Synthesis of tert-butyl 6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0482]

[0483] NaBH(OAc)3 (307 mg, 1.5 mmol) was added to a mixture of 4-methylpiperidine (79 mg, 0.8 mmol), tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (153 mg, 0.7 mmol) and AcOH (50 μL, 0.8 mmol) in DCM (5 mL), and the reaction was stirred at room temperature for 3 days. The reaction mixture was washed with 10% aqueous KOH and water, dried over Na2SO4 and the solvent was evaporated to give tert-butyl 6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate, which was used in the next step without purification.

[0484] 2. Synthesis of 6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane

[0485]

[0486] Tert-butyl 6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate was dissolved in DCM (2 mL) and 10% HCl in dioxane (1.5 mL) was added. The solution was placed in an ultrasonic bath (40 °C) for 4 hours and then stirred at room temperature for 16 hours. The solvent was evaporated in vacuo to give 6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane as the HCl salt, which was used in the next step without purification.

[0487] 3. Synthesis of 2-((4-(difluoromethoxy)phenyl)sulfonyl)-6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane

[0488]

[0489] 4-(Difluoromethoxy)benzene-1-sulfonyl chloride (176 mg, 0.7 mmol) was added to a mixture of 6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane as the hydrochloride salt and TEA (500 μL, 3.6 mmol) in anhydrous DCM (5 mL) at -10°C. The reaction was allowed to warm to room temperature and stirred at this temperature for 16 hours. The reaction mixture was washed with water, the solvent was removed in vacuo, the residue was dissolved in DMSO (1 mL) and purified by preparative HPLC (Waters SunFire C18 19*100 5mkm column; H2O-MeCN as mobile phase) to give 2-((4-(difluoromethoxy)phenyl)sulfonyl)-6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane. LCMS m / z=401.2 [M+H] +1H NMR (400MHz, CDCl3): δppm 8.23(d,J=1.6Hz,1H),7.99(d,J=2.0Hz,1H),4.03(s,3H),4.03-3.96(m,2H),3.95-3.89(m,5H),3.58-3.50(m,2H),3.43- 3.36(m,2H),2.70-2.65(m,1H),2.40-2.34(m,1H),2.33(s,3H),1.98-1.92(m,1H),1.85-1.79(m,2H),1.38-1.30(m,2H).

[0490] Embodiment 21

[0491] 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine

[0492]

[0493] 1. Synthesis of 5-oxa-2-azaspiro[3.4]octan-7-one

[0494]

[0495] To a solution of tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (900 mg, 4.0 mmol) in DCM (9 mL) was added TFA (3.0 mL, 39.2 mmol) and the reaction was stirred for 3 h at 25 °C. The mixture was concentrated in vacuo to give 5-oxa-2-azaspiro[3.4]octan-7-one (900 mg, crude, TFA salt) as a white oil, which was used directly in the next step without further purification. 1 H NMR (400MHz, MeOH-d4): δppm 4.32-4.28(m,1H), 4.26-4.22(m,1H), 4.18-4.15(m,2H), 3.88(d,J=8.8Hz,1H), 3.75(d,J=8.8Hz,1H), 2.38(s,2H).

[0496] 2. Synthesis of 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-one

[0497]

[0498] 2-methoxy-5-methylpyridine-3-sulfonyl chloride (761.47 mg, 3.44 mmol) was added to a solution of 5-oxa-2-azaspiro [3.4] octane-7-one (750 mg, 3.1 mmol, TFA salt) and DIPEA (1.6 mL, 9.4 mmol) in DCM (3 mL) at 0 ° C, and the mixture was stirred at 20 ° C under N2 for 2 hours. The mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by silica gel chromatography (2%-5% MeOH in DCM) to give 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro [3.4] octane-7-one (650 mg, 67%) as a brown oil. LCMS m / z=313.0[M+H] + . 1 H NMR (500MHz, MeOH-d4): δppm 8.16-8.14(m,1H),7.97(s,1H),4.22(d,J=9.5Hz,2H),4.09(d,J=9.5Hz,2H),4.06(s,3H),3.99(s,2H),2.73(s,2H),2.32(s,3H).

[0499] 3. Synthesis of 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine

[0500]

[0501] To a solution of 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-one (120 mg, 0.4 mmol) and tetrahydro-2H-pyran-4-amine (58 mg, 0.6 mmol) in MeOH (6 mL) at 20°C were added AcOH (25 μL, 0.4 mmol) and NaBH3CN (121 mg, 1.9 mmol), and the mixture was stirred at 20°C under N2 for 15 h. The mixture was concentrated in vacuo and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm, condition: water (NH4HCO3)-MeCN, 22% to 52%, flow rate (mL / min): 25) to give 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine (52 mg, 34%) as a white solid. LCMS m / z=398.1[M+H] + . 1 H NMR (400MHz, MeOH-d4): δppm 8.23(d,J=2.0Hz,1H),7.99(d,J=1.6Hz,1H),4.03(s,3H),4.03-3.96(m,2H),3.95-3.89(m,5H),3.58-3.50(m,2H),3.43- 3.36(m,2H),2.70-2.65(m,1H),2.40-2.34(m,1H),2.33(s,3H),1.98-1.92(m,1H),1.85-1.79(m,2H),1.38-1.30(m,2H).

[0502] Embodiment 22

[0503] 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-5-oxa-2-azaspiro[3.4]octane

[0504]

[0505] Following the procedure described in Example 21, Step 4, 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-one (Example 21, Step 3) and 2-oxa-6-azaspiro[3.3]heptane oxalate were obtained as a brown oil (64 mg, 42%). LCMS m / z=396.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δppm 8.23(d,J=2.4Hz,1H),7.99(s,1H),4.70(s,4H),4.03(s,3H),4.01-3.98(m,1H),3.95-3.89(m,3H),3.68-3.66(m,1H),3.5 8-3.55(m,1H),3.38-3.35(m,2H),3.32-3.30(m,2H),2.99-2.95(m,1H),2.33(s,3H),2.09-2.04(m,1H),1.98-1.93(m,1H).

[0506] Embodiment 23

[0507] 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-(3-methoxyazetidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[0508]

[0509] Following the procedure described in Example 21, Step 4, 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-(3-methoxyazetidin-1-yl)-5-oxa-2-azaspiro[3.4]octane was obtained as a brown oil from 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-one (Example 21, Step 3) and 3-methoxyazetidine hydrochloride. LCMS m / z=384.1 [M+H] + . 1H NMR (400MHz, CDCl3): δppm8.22(s,1H),7.98(d,J=2.0Hz,1H),4.03(s,3H),4.01-3.98(m,2H),3.98-3.96(m,1H),3.95-3.91(m,2H),3.72-3.69(m ,1H),3.60-3.51(m,3H),3.23(s,3H),3.07-3.03(m,1H),2.95-2.91(m,1 H),2.89-2.86(m,1H),2.33(s,3H),2.12-2.07(m,1H),1.99-1.95(m,1H).

[0510] Embodiment 24

[0511] N-(4,4-difluorocyclohexyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-amine

[0512]

[0513] N-(4,4-difluorocyclohexyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-amine (42 mg, 19%) was obtained as a white solid from 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-one (Example 21, Step 3) and 4,4-difluorocyclohexan-1-amine hydrochloride following a procedure similar to that described in Example 21, Step 4, except that the crude product was purified by preparative HPLC (column: Boston Prime C18 150 x 30 mm x 5 μm, conditions: water (NH4HCO3)-MeCN, 32% to 62%, flow rate (mL / min): 25). LCMS m / z = 432.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δppm 8.13(d,J=2.0Hz,1H),7.95(d,J=2.4Hz,1H),4.07-4.04(m,1H),4.03(s,3H),4.03-4.00(m,2H),3.96-3.88(m,2H),3.54- 3.46(m,2H),2.60-2.56(m,1H),2.29(s,3H),2.28-2.23(m,1H),2.10-1.99(m,3H),1.90-1.71(m,4H),1.45-1.36(m,3H).

[0514] Embodiment 25

[0515] N-(3,3-Difluorocyclobutyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-amine

[0516]

[0517] N-(3,3-difluorocyclobutyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-amine (78 mg, 31% yield) was obtained as a white solid from 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-one (Example 21, Step 3) and 3,3-difluorocyclobutylamine following a procedure similar to that described in Example 21, Step 4, except that the crude product was purified by preparative HPLC (column: Boston Prime C18 150 x 30 mm x 5 μm, conditions: water (NH4HCO3)-MeCN, 28% to 58%, flow rate (mL / min): 25). LCMS m / z = 404.1 [M+H] +1 H NMR (400MHz, CDCl3): δppm 8.14-8.12(m,1H),7.96(d,J=2.0Hz,1H),4.08-4.06(m,1H),4.04(s,3H),4.04-4.01(m,1H),3.96(d,J=8.4Hz,1H),3.89-3.86(m,1H), 3.58-3.55(m,1H),3.40-3.31(m,1H),3.24-3.14(m,1H),2.88-2.74(m,2H),2.30(s,3H),2.29-2.15(m,3H),2.06-1.99(m,1H),1.58(br s,2H).

[0518] Embodiment 26

[0519] 3-((7-((4,4-difluorocyclohexyl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-4-fluorobenzonitrile

[0520]

[0521] 1. Synthesis of 4-fluoro-3-((7-oxo-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)benzonitrile

[0522]

[0523] DIPEA (2.0 mL, 11.2 mmol) and 5-cyano-2-fluorobenzenesulfonyl chloride (988 mg, 4.5 mmol) were added to a solution of 5-oxa-2-azaspiro [3.4] octan-7-one (Example 21, Step 1, 900 mg, 3.8 mmol, TFA salt) in DCM (10 mL) at 0 ° C, and the reactant was stirred at 0 ° C for 1 hour. Water (50 mL) was added and the mixture was extracted with DCM (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (EtOAc in PE, 30% to 50%) to give 4-fluoro-3-((7-oxo-5-oxa-2-azaspiro [3.4] octan-2-yl) sulfonyl) benzonitrile (750 mg, 65%) as a white solid. LCMS m / z=311.0[M+H] +

[0524] 2. Synthesis of 3-((7-((4,4-difluorocyclohexyl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-4-fluorobenzonitrile

[0525]

[0526] To a solution of 4-fluoro-3-((7-oxo-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile (130 mg, 0.4 mmol) and 4,4-difluorocyclohexylamine (86 mg, 0.5 mmol, HCl salt) in MeOH (5 mL) was added TEA (120 μL, 0.8 mmol), and the solution was stirred at 20 ° C for 20 minutes. The pH of the solution was adjusted to 5 to 6 using AcOH, and the solution was stirred at 20 ° C for 30 minutes. NaBH3CN (132 mg, 2.1 mmol) was added and the reactant was stirred at 20 ° C for 14 hours. 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 product was purified by preparative HPLC ((column: Boston Prime C18 150x30mm x 5μm, condition: water (NH3·H2O+NH4HCO3)-MeCN, 41% to 71%, flow rate (mL / min): 25)) to give 3-((7-((4,4-difluorocyclohexyl)amino)-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)-4-fluorobenzonitrile (56 mg, 31%) as a white solid. LCMS m / z=430.1[M+H] + . 1H NMR (500MHz, MeOH-d4): δppm 8.24(dd,J=6.5,2.5Hz,1H),8.15-8.11(m,1H),7.61(t,J=9.0Hz,1H),4.05(d,J=8.5Hz,1H),3.99-3.95(m,2H),3.92-3.87(m,2H),3.53-3.48 (m,2H),2.62-2.57(m,1H),2.37-2.32(m,1H),2.06-2.00(m,2H),1.98 -1.94(m,1H),1.93-1.88(m,2H),1.86-1.72(m,2H),1.44-1.32(m,2H).

[0527] Embodiment 27

[0528] 4-Fluoro-3-((7-((tetrahydro-2H-pyran-4-yl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)benzonitrile

[0529]

[0530] A solution of 4-fluoro-3-((7-oxo-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile (Example 26, Step 1, 130 mg, 0.4 mmol) and tetrahydro-2H-pyran-4-amine (64 mg, 0.6 mmol) in MeOH (5 mL) was adjusted to pH=6 using AcOH, and the solution was stirred at 20 ° C for 30 minutes. NaBH3CN (132 mg, 2.1 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 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 150x30mm x 5μm, condition: water (NH3·H2O+NH4HCO3)-MeCN, 31% to 61%, flow rate (mL / min): 25)) to give 4-fluoro-3-((7-((tetrahydro-2H-pyran-4-yl)amino)-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile (54 mg, 32%) as a white solid. LCMS m / z=396.0[M+H] + . 1H NMR (500MHz, CDCl3): δppm8.20-8.17(m,1H),7.92-7.88(m,1H),7.39(t,J=8.5Hz,1H),4.09(d,J=9.0Hz,1H),4.00(s,3H),3.99-3.94(m,3H),3.93 -3.90(m,1H),3.59-3.53(m,2H),3.41-3.34(m,2H),2.67-2.60(m,1H),2. 27-2.25(m,1H),2.09-2.05(m,1H),1.82-1.78(m,2H),1.50-1.27(m,2H).

[0531] Embodiment 28

[0532] 3-((7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-5-fluorobenzonitrile

[0533]

[0534] 1. Synthesis of 3-fluoro-5-((7-oxo-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)benzonitrile

[0535]

[0536] Following a procedure analogous to that described in Example 18, Step 1, 3-fluoro-5-((7-oxo-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile (86 mg, 32%) was obtained as a light yellow film from 5-oxa-2-azaspiro[3.4]octan-7-one HCl salt and 3-cyano-5-fluoro-benzenesulfonyl chloride. 1 H NMR (500MHz, DCM-d2): δppm 7.96(s,1H),7.81(td,J=1.9,7.6Hz,1H),7.69(td,J=1.2,7.7Hz,1H),4.04-4.01(m,2H),3.97-3.94(m,4H),2.72(s,2H).

[0537] 2. Synthesis of 3-((7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-5-fluorobenzonitrile

[0538]

[0539] AcOH (20 μL, 0.4 mmol) was added to a vial containing 3-fluoro-5-((7-oxo-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile (86 mg, 0.3 mmol) in anhydrous DCM (3 mL), followed by dropwise addition of 2-oxa-6-azaspiro[3.3]heptane (58 mg, 0.6 mmol) at 23 °C. After 15 minutes, NaBH(OAc) (223 mg, 1.1 mmol) was added in portions, and the reaction was stirred at 23 °C for 1 hour. The reaction was quenched by slowly adding 1 M NaOH aqueous solution, the mixture was stirred at 23 °C for 20 minutes, and the biphasic mixture was then extracted with DCM (3x). The combined organic extracts were dried over anhydrous MgSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (50%-100% 3:1 EtOAc:EtOH in heptane) to give 3-((7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)-5-fluorobenzonitrile (25 mg, 22%) as a colorless film. LCMS m / z=394.2[M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 8.34 (br d,J=8.5Hz,1H),8.22(s,1H),8.13-8.10(m,1H),4.56(s,4H),3.89(d,J=9.5Hz,1H),3.82(d,J=9.2Hz,1H),3.76(d,J=9.5H z,1H),3.65(d,J=9.5Hz,1H),3.50(dd,J=9.0,4.4Hz,1H),3.39-3.36(m,1H),3.31-3.29(m,1H),3.21-3.15(m,4H),2.80(br s,1H),1.81-1.77(m,1H).

[0540] Embodiment 29

[0541] 4-(2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0542]

[0543] 1. Synthesis of 2-azaspiro[3.4]octan-6-one

[0544]

[0545] To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (600 mg, 2.7 mmol) in HFIPA (20 mL) was added TFA (810 μL, 10.7 mmol) and the reaction was stirred for 2 hours at 25° C. The mixture was evaporated in vacuo to give 2-azaspiro[3.4]octan-6-one as a TFA salt as a colorless oil and used without further purification. 1 HNMR (400MHz, MeOH-d4): δppm 4.11-4.08(m,2H), 4.04-4.01(m,2H), 2.57(s,2H), 2.31(s,4H).

[0546] 2. Synthesis of 2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one

[0547]

[0548] DIPEA (300 μL, 1.7 mmol) was added dropwise to a solution of 2-azaspiro [3.4] octan-6-one (132 mg, 0.5 mmol, TFA salt) in anhydrous THF (1 mL) at room temperature, and the solution was stirred for 10 minutes and then concentrated to give a brown film. 2-Methyl-2-butanol (1 mL), 3,5-dimethylpyridine-2-sulfonyl fluoride (51 mg, 0.3 mmol) were added in batches, followed by Ca (NTf2) 2 (169 mg, 0.3 mmol), and the reactants were heated to 60 ° C and stirred for 19 hours. The reaction mixture was cooled to room temperature and then quenched by slowly adding 2M NaOH aqueous solution. The heterogeneous mixture was loaded onto a silica gel column and purified with (20%-80% EtOAc in heptane) to give 2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one (42 mg, 53%) as a colorless film which was used without further purification. LCMS m / z=295.0 [M+H] + .

[0549] 3. Synthesis of 4-(2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0550]

[0551] To a solution of 2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one (42 mg, 0.1 mmol) in anhydrous DCM (1 mL) was added AcOH (10 μL, 0.2 mmol) at 23 °C, followed by dropwise addition of morpholine (30 μL, 0.3 mmol). After 15 minutes, NaBH(OAc)3 (116 mg, 0.6 mmol) was added in batches, and the reactants were stirred at 23 °C for 2 hours. The reactants were quenched by slowly adding 1 M NaOH aqueous solution, the mixture was stirred at 23 °C for 20 minutes, and the biphasic mixture was then extracted with DCM (3x). The combined organic extracts were dried over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column, eluted with (20%-100% 3:1 EtOAc:EtOH in heptane). The product was further purified by HPLC using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5%-50% B (0.2% NH4OH final v / v% modifier) ​​at a flow rate of 80 mL / min to give 4-(2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (101 mg, 21%) as a white solid. LCMS m / z=366.1 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δppm 8.39-8.36(m,1H),7.76-7.73(m,1H),4.05-4.02(m,2H),4.00-3.96(m,4H),3.95-3.93(m,2H),2.48(s,3H),2.36-2.35(m,3H),2.06(br dd,J=7.3,12.4Hz,2H),1.92-1.87(m,2H),1.83-1.78(m,2H),1.77-1.74(m,1H),1.69-1.63(m,2H),1.45-1.37(m,2H).

[0552] Embodiment 30

[0553] 6-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)-2-oxa-6-azaspiro[3.3]heptane

[0554]

[0555] 1. Synthesis of 2-azaspiro[3.4]octan-6-one

[0556]

[0557] A flask containing tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (1.03 g, 4.6 mmol) in MeOH (10 mL) was cooled in an ice-water bath, and then 4M HCl in dioxane (4M, 3.6 mL) was added dropwise. The reaction was warmed to 23 ° C and stirred for 6 hours. The reaction was concentrated under reduced pressure, the residue was triturated with EtOAc, and a few drops of MeOH were added to give 2-azaspiro[3.4]octan-6-one (721 mg, 97%) as an off-white solid as the HCl salt, which was used without purification. 1 H NMR (500MHz, DMSO-d6): δppm 9.40-9.09(m,2H), 3.95-3.89(m,2H), 3.86-3.80(m,2H), 3.65-3.36(m,2H), 2.23-2.17(m,3H).

[0558] 2. Synthesis of 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one

[0559]

[0560] DIPEA (1.5mL, 8.6mmol) was added dropwise to a solution of 2-azaspiro [3.4] octane-6-one (333mg, 2.1mmol, HCl salt) in anhydrous DCM (10mL) at <5°C, and the solution was stirred for 5 minutes. 6-methoxy-2-methyl-pyridine-3-sulfonyl chloride (577.1mg, 2.60mmol) was added, and the reactant was warmed to 23°C and stirred for 30 minutes. The reaction mixture was quenched by slowly adding 1M NaOH aqueous solution. The mixture was stirred at 23°C for 10 minutes, and then the biphasic mixture was loaded onto a silica gel column and purified with (10%-55% EtOAc in heptane) to obtain 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro [3.4] octane-6-one (190mg, 30% yield) as a white solid, which was used without further purification. LCMS m / z=311.1[M+H] + .

[0561] 3. Synthesis of 6-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]oct-6-yl)-2-oxa-6-azaspiro[3.3]heptane

[0562]

[0563] 6-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)-2-oxa-6-azaspiro[3.3]heptane (34 mg, 29%) was obtained as a colorless film from 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one (Example 30, Step 2) and 2-oxa-6-azaspiro[3.3]heptane. LCMS m / z=394.2[M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm8.02(d,J=8.5Hz,1H),6.85(d,J=9.2Hz,1H),4.54(s,4H),3.93(s,3H),3.60-3.54(m,4H),3.12( q,J=7.3Hz,4H),2.67(s,3H),2.54-2.52(m,1H),1.79-1.72(m,1H),1.66-1.59(m,2H),1.52-1.41(m,2H),1.27-1.21(m,1H).

[0564] Embodiment 31

[0565] N-(4,4-difluorocyclohexyl)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine

[0566]

[0567] 4,4-difluorocyclohexylamine (165mg, 1.0mmol, HCl salt) is added to a solution of 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one (Example 30, Step 2, 149mg, 0.5mmol) in DCM (3.1mL), and the solution is stirred at room temperature for 5 minutes. AcOH (230 μL, 3.8mmol) is added dropwise, the solution is stirred for another 15 minutes, then NaBH(OAc)3 (407mg, 1.9mmol) is added, and the reactant is stirred at room temperature for 3 days. The reactant is quenched by slowly adding a 1M NaOH aqueous solution, the mixture is stirred at ambient temperature for 20 minutes, and then the biphasic mixture is extracted with DCM (3x). The combined organics are washed with water and brine, then concentrated in vacuo. The crude material was purified by silica gel column (0%-100% EtOAc to 3:1 EtOAc:EtOH (w / 2% NH4OH)) to give N-(4,4-difluorocyclohexyl)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine (126 mg, 61%) as a white solid. LCMS m / z=430.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 8.03(d,J=9.2Hz,1H),6.85(d,J=9.2Hz,1H),5.09(br d,J=16.5Hz,1H),3.98-3.89(m,3H),3.69-3.52(m,4H),3.09(br s,1H),2.68(s,3H),2.17(br d,J=7.3Hz,1H),2.02-1.85(m,3H),1.85-1.67(m,6H),1.66-1.60(m,1H),1.46(br dd,J=12.8,6.1Hz,1H),1.36-1.20(m,3H).

[0568] Embodiment 32

[0569] 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-2-azaspiro[3.4]octan-6-amine

[0570]

[0571] Following the procedure described in Example 31, 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-2-azaspiro[3.4]octan-6-amine (75 mg, 41%) was obtained as an orange oil from 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one (Example 30, Step 2) and 2-methoxy-N-methylethylamine. LCMS m / z=384.0 [M+H] +1 H NMR (500MHz, DMSO-d6): δppm 8.03(d,J=9.2Hz,1H),6.85(d,J=8.5Hz,1H),3.93(s,3H),3.66-3.51(m,4H), 3.39-3.33(m,2H),3.20(s,3H),2.72-2.62(m,4H),2.46-2.35(m,2H),2.09(br s,3H),1.94-1.82(m,1H),1.79-1.61(m,3H),1.55-1.46(m,1H),1.38-1.29(m,1H).

[0572] Embodiment 33

[0573] N-(2-methoxyethyl)-N-methyl-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine

[0574]

[0575] 1. Synthesis of 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one

[0576]

[0577] Following a procedure analogous to that described in Example 18, Step 1, 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one (161 mg 28%) was obtained from 2-azaspiro[3.4]octan-6-one HCl salt (Example 30, Step 1) and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride. 1 H NMR (500MHz, DCM-d2): δppm 7.07-7.03(m,1H), 4.22-4.14(m,3H), 3.90-3.82(m,4H), 2.40(s,2H), 2.28-2.22(m,2H), 2.20-2.13(m,2H).

[0578] 2. Synthesis of N-(2-methoxyethyl)-N-methyl-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine

[0579]

[0580] N-(2-methoxyethyl)-N-methyl-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine (50 mg, 47%) was obtained as a colorless film from 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one and 2-methoxy-N-methylethan-1-amine following a procedure similar to that described in Example 29, Step 3, except that it was purified by HPLC using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5% to 65% B (0.2% NH4OH final v / v % modifier) ​​at 60 mL / min. LCMS m / z=411.3[M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 7.53(s,1H),4.14(s,3H),3.80-3.76(m,2H),3.74-3.69(m,2H),3.37-3.33(m,2H),3.20(s,3H),2.69-2.63(m,1H),2.43- 2.39(m,2H),2.08(s,3H),1.84-1.78(m,1H),1.73-1.66(m,2H),1.63-1.57(m,1H),1.49-1.44(m,1H),1.38-1.30(m,1H).

[0581] Embodiment 34

[0582] 4-(2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0583]

[0584] 1. Synthesis of 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one

[0585]

[0586] Following a procedure analogous to that described in Example 26, Step 1, 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one (420 mg, 71%) was obtained as a white solid from 2-azaspiro[3.4]octan-6-one (Example 29, Step 1) and 3-methoxy-1-methyl-1H-pyrazole-5-sulfonyl chloride. LCMS m / z=300.1 [M+H] + . 1 HNMR (400MHz, CDCl3) δppm 6.17(s,1H),3.96(s,3H),3.89(s,3H),3.81(s,4H),2.39(s,2H),2.29-2.25(m,2H),2.17-2.14(m,2H).

[0587] 2. Synthesis of 4-(2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0588]

[0589] A solution of 2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one (200 mg, 0.668 mmol) and morpholine (90 μL, 1.0 mmol) in MeOH (10 mL) was adjusted to pH 5-6 with AcOH at 25° C. The mixture was stirred at 25° C.-30° C. for 0.5 h, then NaBH 3 CN (126 mg, 2.0 mmol) was added and the reaction was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative-HPLC (Boston Green ODS 150 x 30 mm x 5 μm, conditions: water (NH4HCO3)-MeCN, flow rate (mL / min) 25) to give 4-(2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (140 mg, 57%) as a colorless oil. LCMS m / z=371.1 [M+H] + . 1H NMR (400MHz, CDCl3) δppm6.14(s,1H),3.95(s,3H),3.89(s,3H),3.77-3.70(m,4H),3.69-3.65(m,4H),2.51-2.44(m,2 H),2.42-2.41(m,2H),2.04-2.00(m,1H),1.92-1.82(m,2H),1.77-1.73(m,2H),1.64-1.60(m,1H),1.51-1.43(m,1H).

[0590] Embodiment 35

[0591] 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0592]

[0593] 1. Synthesis of tert-butyl 6-morpholino-2-azaspiro[3.4]octane-2-carboxylate

[0594]

[0595] AcOH (250 μ L, 4.2 mmol) was added to a vial containing 6-oxo-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (904 mg, 4.0 mmol) in anhydrous DCM (20 mL) at 23 ° C, followed by dropwise addition of morpholine (730 μ L, 8.4 mmol), and the solution was stirred for 15 minutes. NaBH (OAc) 3 (2.9 g, 13.7 mmol) was added in batches, and the reactant was stirred at 23 ° C for 7 hours. The reactant was quenched by slowly adding a 1M NaOH aqueous solution, the mixture was stirred at 23 ° C for 20 minutes, and then the biphasic mixture was extracted with DCM (3x). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give 6-morpholino-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (1.19 g, crude), which was used without further purification. LCMS m / z=297.1[M+H] +

[0596] 2. Synthesis of 4-(2-azaspiro[3.4]octan-6-yl)morpholine

[0597]

[0598] A solution of tert-butyl 6-morpholino-4-yl-2-azaspiro[3.4]octane-2-carboxylate (1.19 g, 4.0 mmol) in MeOH (2.50 mL) was cooled in an ice-water bath, and then 1 M HCl in EtOAc (1 M, 14 mL) was added dropwise. After the addition was complete, the mixture was warmed to 23 ° C and stirred at room temperature for 5 days. The reaction was concentrated under reduced pressure, and the residue was triturated with heptane and EtOAc to give 4-(2-azaspiro[3.4]octan-6-yl)morpholine as the HCl salt of a gummy white solid, which was used without purification. LCMS m / z=197.1[M+H] +

[0599] 3. Synthesis of 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0600]

[0601] To a solution of 4-(2-azaspiro[3.4]octan-6-yl)morpholine (79 mg, 0.3 mmol, HCl salt) in anhydrous THF (2 mL) was added DIPEA (390 μL, 2.3 mmol) dropwise at <5°C. After 5 minutes, 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (124 mg, 0.5 mmol) was added to the cold solution and the reaction was warmed to 23°C and stirred for 30 minutes. The reaction was quenched by slowly adding 1 M NaOH aqueous solution and the mixture was stirred at 23°C for 10 minutes. The biphasic mixture was loaded onto a silica gel column and purified with (15%-75% 3:1 EtOAc:EtOH in heptane) to give 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (83 mg, 54%) as a colorless film. LCMS m / z = 409.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 7.53(s,1H),4.14(s,3H),3.77(s,2H),3.75-3.71(m,2H),3.54-3.50(m,4H),2.46-2.39(m,1H),2.34-2.21(m,4H),1.87 -1.83(m,1H),1.76-1.68(m,2H),1.65-1.59(m,1H),1.52-1.47(m,1H),1.39-1.30(m,1H).

[0602] Embodiment 36

[0603] 4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0604]

[0605] Following the procedure described in Example 35, Step 3, 4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (43 mg, 33% yield) was obtained as a colorless film from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (Example 35, Step 2, HCl salt) and 2,5-dimethylpyrazole-3-sulfonyl chloride. LCMS m / z=355.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 6.70(s,1H),3.96(s,3H),3.66(s,2H),3.64-3.60(m,2H),3.52(br t,J=4.6Hz,4H),2.45-2.39(m,1H),2.34-2.24(m,4H),2.21(s,3H),1.86-1.81(m ,1H),1.75-1.68(m,2H),1.63-1.57(m,1H),1.52-1.46(m,1H),1.38-1.31(m,1H).

[0606] Embodiment 37

[0607] 4-(2-((4-chloro-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0608]

[0609] Following the procedure described in Example 35, Step 3, 4-(2-((4-chloro-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (68 mg, 36%) was obtained as a light orange film from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (Example 35, Step 2, HCl salt) and 4-chloro-2,5-dimethylpyrazole-3-sulfonyl chloride. LCMS m / z=389.2 [M+H] + . 1H NMR (500MHz, DMSO-d6): δppm 3.99(s,3H),3.78-3.74(m,2H),3.74-3.69(m,2H),3.52(t,J=4.6Hz,4H),2.47-2.40(m,1H),2.34-2.24(m,4H),2.2 1(s,3H),1.87(dd,J=12.8,7.3Hz,1H),1.78-1.68(m,2H),1.67-1.61(m,1H),1.54-1.49(m,1H),1.40-1.32(m,1H).

[0610] Embodiment 38

[0611] 4-(2-((4-(difluoromethyl)-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0612]

[0613] Following the procedure described in Example 35, Step 3, 4-(2-((4-(difluoromethyl)-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (69 mg, 37%) was obtained as a light orange film from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (Example 35, Step 2, HCl salt) and 4-(difluoromethyl)-1,3-dimethyl-1H-pyrazol-5-sulfonyl chloride. LCMS m / z=405.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 7.07(t,J=54.0Hz,1H),4.00(s,3H),3.75-3.73(m,2H),3.72-3.67(m,2H),3.52(t,J=4.6Hz,4H),2.46-2.40(m,1H), 2.38-2.25(m,7H),1.90(dd,J=12.8,6.7Hz,1H),1.80-1.62(m,3H),1.53(dd,J=12.8,8.5Hz,1H),1.41-1.32(m,1H).

[0614] Embodiment 39

[0615] 4-(2-((6-methoxy-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0616]

[0617] 4-(2-((6-methoxy-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (77 mg, 43%) was obtained as a colorless film from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (Example 35, Step 2, HCl salt) and 6-methoxy-2-(trifluoromethyl)pyridine-3-sulfonyl chloride according to the procedure described in Example 35, Step 3. LCMS m / z=436.5 [M+H] + ; 1 H NMR (500MHz, DMSO-d6): δppm 8.34(d,J=8.5Hz,1H),7.33(d,J=8.5Hz,1H),4.00(s,3H),3.74-3.69(m,3H),3.68-3.65(m,1H),3.52(t,J=4.6Hz,4H),2.46-2.40(m,1H) ,2.34-2.25(m,4H),1.94(dd,J=13.1,7.0Hz,1H),1.82-1.77(m,1H),1.76-1.68(m,2H),1.55(dd,J=12.8,9.2Hz,1H),1.40-1.32(m,1H).

[0618] Embodiment 40

[0619] 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0620]

[0621] Following the procedure described in Example 35, Step 3, 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (65 mg, 43%) was obtained as a colorless film from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (Example 35, Step 2, HCl salt) and 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride. LCMS m / z=420.5 [M+H] + . 1H NMR (500MHz, DMSO-d6): δppm 8.45(d,J=8.5Hz,1H),7.99(d,J=8.5Hz,1H),3.78-3.73(m,3H),3.72-3.69(m,1H),3.52(t,J=4.6Hz,4H),2.83(s,3H),2.47-2.41( m,1H),2.36-2.22(m,4H),1.96(dd,J=12.8,6.7Hz,1H),1.85-1.79(m,1H),1.77-1.68(m,2H),1.59-1.54(m,1H),1.41-1.32(m,1H).

[0622] Embodiment 41

[0623] 4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0624]

[0625] 4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (59 mg, 39%) was obtained as a yellow film from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (Example 35, Step 2, HCl salt) and 4-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride according to the procedure described in Example 35, Step 3. LCMS m / z=420.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 9.03(s,1H),8.14(s,1H),3.78–3.75(m,2H),3.75–3.69(m,2H),3.52(t,J=4.6Hz,4H),2.70(s,3H),2.47–2.41(m,1H ),2.35–2.25(m,4H),1.96–1.90(m,1H),1.82–1.77(m,1H),1.76–1.67(m,2H),1.58–1.52(m,1H),1.40–1.33(m,1H).

[0626] Embodiment 42

[0627] 4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0628]

[0629] Following the procedure described in Example 35, Step 3, 4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (176 mg, 49%) was obtained as a light brown film from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (Example 35, Step 2, HCl salt) and 6-chloro-2-methylpyridine-3-sulfonyl chloride. LCMS m / z=386.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 8.18(d,J=8.5Hz,1H),7.61(d,J=7.9Hz,1H),3.70-3.62(m,4H),3.52(t,J=4.6Hz,4H),2.73(s,3H),2.47-2.41(m,1H),2. 35-2.26(m,4H),1.94(dd,J=12.8,7.3Hz,1H),1.81-1.76(m,1H),1.75-1.67(m,2H),1.57-1.51(m,1H),1.40-1.33(m,1H).

[0630] Embodiment 43

[0631] 4-(2-(mesitylsulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0632]

[0633] 1. Synthesis of 4-(2-azaspiro[3.4]octan-6-yl)morpholine

[0634]

[0635] A solution of tert-butyl 6-morpholino-4-yl-2-azaspiro[3.4]octane-2-carboxylate (Example 35, Step 1, 918 mg, 3.1 mmol) in HFIP (9 mL) was cooled in an ice-water bath, and TFA (840 μL, 11.0 mmol) was added dropwise. After the addition was complete, the reaction was allowed to warm to 23 °C and stirred for 7.5 hours. The reaction was evaporated under reduced pressure to give 4-(2-azaspiro[3.4]octan-6-yl)morpholine (as TFA salt) as a colorless film, which was used without purification. LCMS m / z=197.1 [M+H] + .

[0636] 2. Synthesis of 4-(2-(mesitylsulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0637]

[0638] DIPEA (0.5mL, 2.9mmol) and DMAP (6mg, 0.1mmol) were added dropwise to a solution of 4-(2-azaspiro[3.4]octan-6-yl)morpholine (144mg, 0.5mmol, TFA salt) in anhydrous THF (1.5mL) at <5°C. After 5 minutes, 2,4,6-trimethylbenzenesulfonyl chloride (153mg, 0.7mmol) was added to the cold heterogeneous solution, and the reactant was warmed to 23°C and stirred for 30 minutes. The reactant was quenched by slowly adding 1M NaOH aqueous solution, the mixture was stirred at 23°C for 10 minutes, and then the biphasic mixture was extracted with EtOAc (3x). The combined organics were washed with saturated NaHCO3 aqueous solution (2x) and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with (5%-55% 3:1 EtOAc:EtOH in heptane) to give 4-(2-(mesitylsulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (33 mg, 18%). LCMS m / z=379.2 [M+H] + ; 1 H NMR (500MHz, DMSO-d6): δppm 7.07(s,2H),3.63-3.56(m,3H),3.55-3.50(m,5H),2.53(s,6H),2.47-2.41(m,1H),2.41-2.28(m,4H),2.27(s,3H), 1.97(dd,J=12.8,6.7Hz,1H),1.84-1.78(m,1H),1.77-1.68(m,2H),1.56(dd,J=12.8,9.2Hz,1H),1.42-1.33(m,1H).

[0639] Embodiment 44

[0640] 4-(2-((4-(difluoromethoxy)phenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0641]

[0642] 4-(2-((4-(difluoromethoxy)phenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (19 mg, 8%) was obtained as a colorless film as its TFA salt from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (TFA salt, Example 43, Step 1) and 4-(difluoromethoxy)benzenesulfonyl chloride following a procedure analogous to that described in Example 43, Step 2, except that the product was additionally purified by preparative HPLC using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with a mobile phase of HO (A) and MeCN (B) and a gradient of 5% to 55% B (0.2% TFA final v / v % modifier). LCMS m / z=403.2 [M+H] + .

[0643] H NMR (500MHz, DMSO-d6)δ=8.04-7.83(m,2H),7.65-7.30(m,2H),4.03-3.91(m,1H),3.73-3.41(m,4H),3.40-3.25(m,2H),3.06- 2.92(m,1H),2.62-2.41(m,3H),2.31-2.15(m,1H),2.13-2.00(m,1H),1.97-1.84(m,1H),1.82-1.50(m,4H),1.50-1.21(m,2H).

[0644] Embodiment 45

[0645] 4-(2-((2,4-dimethylphenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0646]

[0647] Following a procedure similar to that described in Example 43, Step 2, except that DMAP was not used as a catalyst, 4-(2-((2,4-dimethylphenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (73 mg, 41%) was obtained as a colorless film from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (TFA salt, Example 43, Step 1) and 2,4-dimethylbenzenesulfonyl chloride. LCMS m / z=365.1 [M+H] + . 1H NMR (500MHz, DMSO-d6): δppm 7.70(br d,J=7.9Hz,1H),7.28(br s,1H),7.24(br d,J=7.9Hz,1H),3.60-3.50(m,8H),2.52(br s,3H),2.42(br s,1H),2.35(br s,3H),2.29(br s,4H),1.92-1.85(m,1H),1.79-1.68(m,2H),1.64(brdd,J=11.3,7.6Hz,1H),1.50(br t,J=10.4Hz,1H),1.35(br d,J=9.2Hz,1H).

[0648] Embodiment 46

[0649] 4-(2-((2,4-difluorophenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0650]

[0651] Following a procedure similar to that described in Example 35, Step 3, 4-(2-((2,4-difluorophenyl)sulfonyl)-2-azaspiro[3.4]oct-6-yl)morpholine (34 mg, 18%) was obtained as a colorless film from 4-(2-azaspiro[3.4]oct-6-yl)morpholine (TFA salt, Example 43, Step 1) and 2,4-difluorobenzenesulfonyl chloride. The product was further purified by preparative HPLC using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5%-55% B (0.2% NH4OH final v / v% modifier) ​​at a flow rate of 80 mL / min. LCMS m / z=373.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 7.89(dt,J=8.4,6.4Hz,1H),7.71-7.64(m,1H),7.38(dt,J=8.4,2.1Hz,1H), 3.78-3.49(m,7H),2.45-2.12(m,2H),1.88-1.65(m,5H),1.64-1.29(m,5H).

[0652] Embodiment 47

[0653] 4-(2-((4,6-dimethylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0654]

[0655] 4-(2-((4,6-dimethylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (22 mg, 19%) was obtained from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (TFA salt, Example 43, Step 1) and 4,6-dimethylpyridin-3-sulfonyl chloride following a procedure similar to that described for Example 35, Step 3, except that the product was further purified by HPLC Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with mobile phases of H2O (A) and MeCN (B) and a gradient of 5% to 45% B (0.2% NH4OH final v / v % modifier) ​​at a flow rate of 80 mL / min. LCMS m / z=366.1 [M+H] + ; 1 H NMR (500MHz, DMSO-d6): δppm 8.60(s,1H),7.28(s,1H),3.64-3.43(m,4H),2.43-2.40(m,3H),2.40-2.38(m,3H),2.17(br s,4H),1.78(br dd,J=11.6,7.9Hz,2H),1.67-1.48(m,5H),1.40(br dd,J=12.5,8.9Hz,2H),1.28-1.18(m,2H).

[0656] Embodiment 48

[0657] 4-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0658]

[0659] Following a procedure analogous to that described for Example 35, Step 3, 4-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (60 mg, 37%) was obtained as a colorless film from 4-(2-azaspiro[3.4]octan-6-yl)morpholine (TFA salt, Example 43, Step 1) and 6-methoxy-2-methylpyridine-3-sulfonyl chloride. LCMS m / z=382.5 [M+H] + . 1H NMR (500MHz, DMSO-d6): δppm 8.03(d,J=8.5Hz,1H),6.85(d,J=8.5Hz,1H),3.93(s,3H),3.64-3.58(m,3H),3.56-3.51(m,5H),2.68(s,3H),2.45-2.39(m ,1H),2.34-2.24(m,4H),1.91(dd,J=12.8,7.3Hz,1H),1.80-1.65(m,3H),1.52(dd,J=12.8,9.2Hz,1H),1.40-1.31(m,1H).

[0660] Embodiment 49

[0661] (R)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0662]

[0663] 1. Synthesis of (R)-6-morpholino-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester

[0664]

[0665] At 23 ° C under N2, to (R) -6- amino -2- azaspiro [3.4] octane -2- carboxylic acid tert-butyl ester (950mg, 4.2mmol) and 1- bromo -2- (2- bromoethoxy) ethane (1.48g, 6.4mmol) in MeCN (45mL) solution in batches K2CO3 (2.29g, 16.6mmol), and the reactant was heated to 90 ° C for 19 hours. The reactant was cooled to room temperature, then filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM and then purified by silica gel column, eluted with (10% -65% 3: 1EtOAc: EtOH in heptane) to give (R) -6- morpholino -2- azaspiro [3.4] octane -2- carboxylic acid tert-butyl ester (986mg, 79%) as an oil, which was used without purification. LCMS m / z=297.1[M+H] + .

[0666] 2. Synthesis of (R)-4-(2-azaspiro[3.4]octan-6-yl)morpholine

[0667]

[0668] A solution of (R)-tert-butyl 6-morpholino-2-azaspiro[3.4]octane-2-carboxylate (986 mg, 3.3 mmol) in MeOH (4 mL) was cooled in an ice-water bath, then 4M HCL in dioxane (4M, 2.5 mL) was added dropwise. The reaction was allowed to warm to 23 °C and stirred for 2 hours, then evaporated under reduced pressure to give (R)-4-(2-azaspiro[3.4]octan-6-yl)morpholine as an HCl salt, which was used without purification. LCMS m / z=197.1 [M+H] + .

[0669] 3. Synthesis of (R)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0670]

[0671] Under cooling in an ice-water bath, DIPEA (410 μL, 2.4 mmol) was added dropwise to a solution of 4-(2-azaspiro[3.4]octan-6-yl)morpholine (103 mg, 0.4 mmol) HCl salt in anhydrous DCM (2 mL). After 5 minutes, 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride (111 mg, 0.5 mmol) was added, and the reactant was warmed to 23 ° C and stirred for 30 minutes. The reactant was quenched by slowly adding 1M NaOH aqueous solution. The mixture was stirred at 23 ° C for 20 minutes, and then the biphasic mixture was extracted with DCM (3x). The combined organic extracts were dried over magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (25%-80% 3: 1 EtOAc: EtOH in heptane). The product was further purified by HPLC using a Waters XSelect CSH C18, 5 μm, 50 mm×100 mm column with a mobile phase of H2O (A) and MeCN (B) and a gradient of 5%-55% B (0.2% NH4OH final v / v% modifier) ​​at a flow rate of 60 mL / min to give 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (57 mg, 30%) as a colorless film. LCMS m / z=409.2[M+H] + . 1H NMR (500MHz, MeOH-d4): δppm 7.21(s,1H),4.17(s,3H),3.85-3.79(m,2H),3.79-3.73(m,2H),3.67(t,J=4.6Hz,4H),2.60-2.53(m,1H),2.51-2.42(m, 4H), 2.04(dd,J=12.8,7.3Hz,1H),1.93-1.86(m,2H),1.80-1.73(m,1H),1.61(dd,J=12.8,9.2Hz,1H),1.50-1.43(m,1H).

[0672] Embodiment 50

[0673] (R)-3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile

[0674]

[0675] Following a procedure analogous to that described in Example 49, Step 3, (R)-3-fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile (29 mg, 18%) was obtained as a colorless film from (R)-4-(2-azaspiro[3.4]octan-6-yl)morpholine HCl salt (Example 49, Step 2) and 3-cyano-5-fluoro-benzenesulfonyl chloride. LCMS m / z=380.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 8.33(br d,J=8.2Hz,1H),8.16(s,1H),8.08-8.04(m,1H),3.70-3.68(m,2H),3.67-3.62(m,2H),3.51(br t,J=4.4Hz,4H),2.40-2.34(m,1H),2.32-2.17(m,4H),1.74(dd,J=7.3,12.8Hz,1H),1 .69-1.59(m,2H),1.54-1.47(m,1H),1.40(dd,J=8.5,12.8Hz,1H),1.35-1.26(m,1H).

[0676] Embodiment 51

[0677] (S)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0678]

[0679] 1. Synthesis of tert-butyl (R)-6-((methylsulfonyl)oxy)-2-azaspiro[3.4]octane-2-carboxylate

[0680]

[0681] A solution of (R)-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (1.1 g, 4.9 mmol) in anhydrous DCM (40 mL) was cooled in an ice-water bath, and then TEA (1.4 mL, 10.0 mmol) and DMAP (32 mg, 0.3 mmol) were added under cooling in an ice-water bath, and the solution was stirred for 10 minutes. Methanesulfonyl chloride (1.26 g, 11 mmol) was added dropwise, and the reactant was warmed to room temperature and stirred for 5 hours. The reactant was concentrated under reduced pressure, the residue was diluted with DCM, and then filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel column eluting with (5% - 80% EtOAc in heptane) to afford (R)-tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.4]octane-2-carboxylate (1.36 g, 91%) as an oil which was used without further purification. 1 H NMR (500MHz, DCM-d2): δppm 5.10(td,J=6.0,2.8Hz,1H),3.88(d,J=8.5Hz,1H),3.79-3.75(m,3H),2.97(s,3H),2.25-2.20( m,1H),2.18-2.13(m,1H),2.11-2.03(m,2H),2.02-1.95(m,1H),1.88-1.82(m,1H),1.41(s,9H).

[0682] 2. Synthesis of tert-butyl (S)-6-morpholino-2-azaspiro[3.4]octane-2-carboxylate

[0683]

[0684] To the flask containing morpholine (0.3mL, 3.4mmol) and (R)-6-methylsulfonyloxy-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (1.36g, 4.5mmol) in anhydrous MeCN (22mL) at room temperature, K2CO3 (1.21g, 8.8mmol) was added in batches. After completion of the addition, the reactant was stirred at 95°C for 28 hours. The reactant was cooled to room temperature and then stirred for 4 more days. The reactant was concentrated under reduced pressure, the residue was diluted with DCM, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was then purified by a silica gel column (10%-65% 3:1 EtOAc:EtOH in heptane) to obtain (S)-6-morpholino-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (463mg, 46% yield) as an oil. LCMS m / z=297.1[M+H] + .

[0685] 3. Synthesis of (S)-4-(2-azaspiro[3.4]octan-6-yl)morpholine

[0686]

[0687] A vial containing (6S)-6-morpholino-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (463 mg, 1.6 mmol) in HFIPA (2 mL) was cooled in an ice-water bath, and TFA (0.4 mL, 5.2 mmol) was then added dropwise. After the addition was complete, the mixture was warmed to 23 ° C and stirred for 19 hours. The reactant was concentrated under reduced pressure, the residue was dissolved in a mixture of DCM and MeOH (about 9: 1), and Na2CO3 (1.8 g, 17 mmol) was added, and the heterogeneous mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give (S)-4-(2-azaspiro [3.4] octan-6-yl) morpholine as a light yellow film. LCMS m / z=197.1[M+H] + .

[0688] 4. Synthesis of (S)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0689]

[0690] Following a procedure analogous to that described in Example 49, Step 3, (S)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (12 mg, 6%) was obtained as a colorless film from (S)-4-(2-azaspiro[3.4]octan-6-yl)morpholine and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride. LCMS m / z=409.2 [M+H] + . 1 HNMR (500MHz, DCM-d2): δppm 7.02(s,1H),4.14(s,3H),3.82-3.79(m,1H),3.77-3.70(m,3H),3.65-3.60(m,4H),2.51-2.46(m,1H),2.44-2.34 (m,4H),1.99(dd,J=12.8,7.3Hz,1H),1.91-1.81(m,2H),1.78-1.72(m,1H),1.66-1.61(m,1H),1.50-1.43(m,1H).

[0691] Embodiment 52

[0692] (S)-3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile

[0693]

[0694] Following a similar procedure as described in Example 49, Step 3, (S)-3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile (14 mg, 11%) was obtained as a colorless film from (S)-4-(2-azaspiro[3.4]octan-6-yl)morpholine (Example 51, Step 3) and 3-cyano-5-fluoro-benzenesulfonyl chloride, except that the product was not additionally purified by HPLC. LCMS m / z=380.2 [M+H] + . 1H NMR (500MHz, DMSO-d6): δppm 8.33 (br d, J=8.5Hz, 1H), 8.16 (s, 1H), 8.05 (br d,J=7.9Hz,1H),3.71-3.68(m,2H),3.67-3.62(m,2H),3.51(t,J=4.4Hz,4H),2.41-2.34(m,1H),2.32-2.18(m,4H), 1.74(dd,J=13.0,7.2Hz,1H),1.69-1.59(m,2H),1.54-1.48(m,1H),1.40(dd,J=13.0,8.7Hz,1H),1.34-1.27(m,1H).

[0695] Embodiment 53

[0696] 2-(mesitylsulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

[0697]

[0698] 1. Synthesis of tert-butyl 7-morpholino-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0699]

[0700] Morpholine (0.8mL, 9.2mmol) and TEA (480 μL, 3.4mmol) were added dropwise to a solution of 7-oxo-5-oxa-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (692mg, 3.05mmol) in anhydrous DCM (50mL) at 23°C. After 15 minutes, AcOH (440 μL, 7.3mmol) was added dropwise to the reaction mixture to a pH of about 5-6. After completion of the addition, the reactant was stirred at 23°C for 30 minutes, and NaBH (OAc) was then added in batches (5.33g, 25.2mmol). The reactant was stirred at 23°C for 19 hours (additional anhydrous DCM (50mL) was added to the thick white paste to help stirring), and then quenched by slowly adding a saturated aqueous ammonium chloride solution. The mixture was stirred at 23°C for 15 minutes, and the biphasic mixture was then extracted with DCM (3x). The combined organic extracts were washed with brine (2x) and then dried over anhydrous magnesium sulfate. The mixture was filtered and evaporated under reduced pressure to give (7S)-tert-butyl 7-morpholino-5-oxa-2-azaspiro[3.4]octane-2-carboxylate, which was used without purification. LCMS m / z=299.1 [M+H] + .

[0701] 2. Synthesis of 7-morpholino-5-oxa-2-azaspiro[3.4]octane

[0702]

[0703] A solution of (7S)-7-morpholino-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (908 mg, 3.0 mmol) in HFIP (7 mL) was cooled in an ice-water bath, and TFA (0.7 mL, 9.1 mmol) was added dropwise. The mixture was allowed to warm to 23 ° C and stirred for 8 hours. The reaction was evaporated under reduced pressure to give 7-morpholino-5-oxa-2-azaspiro[3.4]octane (TFA salt) (950 mg) as a light yellow residue, which was used without purification. LCMS m / z=199.1 [M+H] + .

[0704] 3. Synthesis of 2-(mesitylenesulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

[0705]

[0706] DIPEA (460 μL, 2.6mmol) and DMAP (6mg, 0.1mmol) were added dropwise to a solution of 7-morpholino-5-oxa-2-azaspiro [3.4] octane (143mg, 0.5mmol, TFA salt) in anhydrous THF (1.5mL) at <5°C. After 5 minutes, 2,4,6-trimethylbenzenesulfonyl chloride (147mg, 0.7mmol) was added to the cold heterogeneous solution, and the reactant was warmed to 23°C and stirred for 30 minutes. The reactant was quenched by slowly adding a 1M NaOH aqueous solution, the mixture was stirred at 23°C for 10 minutes, and then the biphasic mixture was extracted with EtOAc (3x). The combined organics were washed with saturated NaHCO3 aqueous solution (2x) and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with (10%-70% 3:1 EtOAc:EtOH in heptane) to give 2-(mesitylsulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane (66 mg, 36%) as a colorless film. LCMS m / z=381.2 [M+H] + . 1H NMR (500MHz, DMSO-d6): δppm 7.08(s,2H),3.82(dd,J=8.5,6.7Hz,1H),3.77(s,2H),3.71-3.64(m,2H),3.58-3.51(m,5H),2. 90-2.83(m,1H),2.53(s,6H),2.36(dt,J=4.0,2.4Hz,2H),2.31-2.24(m,6H),2.02-1.97(m,1H).

[0707] Embodiment 54

[0708] 2-((4-(difluoromethoxy)phenyl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[0709]

[0710] 1. Synthesis of tert-butyl 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0711]

[0712] Following the procedure described in Example 35, Step 1, tert-butyl 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (742 mg, 95%) was obtained from tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate and 4-methylpiperidine. LCMS m / z=311.2[M+H] + .

[0713] 2. Synthesis of 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[0714]

[0715] Following the procedure described in Example 35, Step 2, 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane was obtained as an off-white solid from tert-butyl 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate as the HCl salt. LCMS m / z=211.2 [M+H] +

[0716] 3. Synthesis of 2-((4-(difluoromethoxy)phenyl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[0717]

[0718] Following the procedure described in Example 35, Step 3, 2-((4-(difluoromethoxy)phenyl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (50 mg, 56%) was obtained as a colorless film from 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (HCl salt) and 4-(difluoromethoxy)benzenesulfonyl chloride. LCMS m / z=417.5 [M+H] + . 1 HNMR (500MHz, DMSO-d6): δppm 7.92-7.86(m,2H),7.64-7.32(m,3H),3.83(d,J=9.2Hz,1H),3.78-3.70(m,2H),3.63(d,J=8.5Hz,1H),3.51(d,J=8.5Hz,1H),3.40( t,J=7.9Hz,1H),2.78-2.71(m,1H),2.71-2.66(m,1H),2.56-2.51(m,1H),2.09(dd,J=12.8,7.3Hz,1H),1.87-1.75(m,3H),1.51(br t,J=14.6Hz,2H),1.32-1.22(m,1H),1.09-0.98(m,2H),0.84(d,J=6.7Hz,3H).

[0719] Embodiment 55

[0720] 2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[0721]

[0722] Following the procedure described in Example 35, Step 3, 2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (47 mg, 44%) was obtained as a colorless film from 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (HCl salt) (Example 54, Step 2) and (1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl chloride. LCMS m / z=369.2 [M+H] + . 1H NMR (500MHz, MeOH-d4): δppm 6.65(s,1H),4.01(s,3H),3.96-3.89(m,3H),3.85-3.81(m,1H),3.78- 3.74(m,1H),3.61(t,J=8.2Hz,1H),2.98-2.87(m,2H),2.73-2.66(m,1 H),2.40-2.34(m,1H),2.28-2.25(m,3H),2.08-1.94(m,3H),1.70-1.6 2(m,2H),1.45-1.36(m,1H),1.26-1.16(m,2H),0.93(d,J=6.7Hz,3H).

[0723] Embodiment 56

[0724] 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

[0725]

[0726] Following the procedure described in Example 35, Step 3, 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (11 mg, 9%) was obtained as a colorless film from 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane (HCl salt) (Example 54, Step 2) and 6-methoxy-2-methylpyridine-3-sulfonyl chloride. LCMS m / z=396.2 [M+H] + . 1 H NMR (500MHz, MeOH-d4): δppm 8.06(d,J=8.5Hz,1H),6.74(d,J=9.2Hz,1H),3.98(s,3H),3.97-3.93(m,1H),3.92-3. 89(m,1H),3.88-3.85(m,1H),3.78-3.73(m,2H),3.63(t,J=7.9Hz,1H),3.00-2.88(m, 2H),2.74-2.72(m,3H),2.72-2.67(m,1H),2.43(dd,J=13.1,7.6Hz,1H),2.10-1.97(m ,3H),1.70-1.62(m,2H),1.45-1.35(m,1H),1.27-1.16(m,2H),0.92(d,J=6.7Hz,3H).

[0727] Embodiment 57

[0728] (R)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

[0729]

[0730] 1. Synthesis of tert-butyl (S)-7-((methylsulfonyl)oxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[0731]

[0732] Following the procedure described in Example 51, Step 1, (S)-tert-butyl 7-((methylsulfonyl)oxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (1.28 g, 95%) was obtained as a white solid from tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate. LCMS m / z=308.0 [M+H] +

[0733] 2. Synthesis of (R)-7-morpholino-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester

[0734]

[0735] Following the procedure described in Example 51, Step 2, (R)-7-morpholino-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (124 mg, 11%) was obtained as a white solid from (S)-7-((methylsulfonyl)oxy)-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester and morpholine. LCMS m / z=299.1 [M+H] +

[0736] 3. Synthesis of (R)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

[0737]

[0738] A solution of (R)-7-morpholino-5-oxa-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (124 mg, 0.4 mmol) in MeOH (1 mL) was cooled in an ice-water bath, and then 4M HCL in dioxane (4M, 0.32 mL) was added dropwise. The mixture was allowed to warm to 23 °C and stirred for 20 hours. The reaction was filtered and rinsed with EtOAc to give (R)-7-morpholino-5-oxa-2-azaspiro[3.4]octane as a hydrochloride salt, which was used without purification. LCMS m / z=199.1 [M+H] + .

[0739] 4. Synthesis of (R)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

[0740]

[0741] Following the procedure described in Example 51, step 4), (R)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane was obtained as a colorless film from (R)-7-morpholino-5-oxa-2-azaspiro[3.4]octane (hydrochloride) and 2-methyl-5-(trifluoromethyl)pyrazole-3-sulfonyl chloride. LCMS m / z=411.1 [M+H] +1 H NMR (500MHz, DCM-d2): δppm 7.04(s,1H),4.14(s,3H),3.98(s,2H),3.92-3.88(m,3H),3.69-3.65(m,1H),3.63(t,J=4.9Hz,4 H), 2.88 (quin, J = 7.0Hz, 1H), 2.45-2.40 (m, 2H), 2.34-2.27 (m, 3H), 2.07 (dd, J = 12.8, 7.9Hz, 1H).

[0742] Embodiment 58

[0743] (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

[0744]

[0745] Following the procedure described in Example 49, Step 3, (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane (HCl salt) (Example 57, Step 3) and 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride were obtained as a colorless film (32 mg, 41%). LCMS m / z = 422.2 [M+H] + . 1 H NMR (400MHz, DCM-d2): δppm 8.37(d,J=8.0Hz,1H),7.67(d,J=8.3Hz,1H),4.06(d,J=8.3Hz,1H),3.98-3.90(m,3H),3.85(d,J=8.3Hz,1H),3.68(dd,J=8. 5,7.0Hz,1H),3.63(t,J=4.6Hz,4H),2.93-2.86(m,4H),2.46-2.39(m,2H),2.36-2.29(m,3H),2.07(dd,J=12.9,7.9Hz,1H).

[0746] Embodiment 59

[0747] 3-((7-((4,4-difluorocyclohexyl)(methyl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-4-fluorobenzonitrile

[0748]

[0749] 3-((7-((4,4-difluorocyclohexyl)amino)-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)-4-fluorobenzonitrile (Example 26, 90 mg, 0.2 mmol) and (CH2O) were reacted with AcOH. n(63mg, 2.1mmol) in MeOH (3mL) solution was adjusted to pH=6. NaBHCn (65.85mg, 1.05mmol) was added and the reaction mixture was stirred at 20°C for 14 hours. The mixture was diluted with water (50mL) and extracted with DCM (50mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC ((column: Boston Prime C18 150x 30mm x5μm, condition: water (NH3H2O+NH4HCO3)-MeCN, 45% to 75%, flow rate (mL / min): 25)) to obtain 3-((7-((4,4-difluorocyclohexyl)(methyl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-4-fluorobenzonitrile (40mg, 43%) as a white solid. LCMS m / z=444.2[M+H] + . 1 H NMR (400MHz, MeOH-d4): δppm 8.24(dd,J=6.4,2.0Hz,1H),8.15-8.10(m,1H),7.61(t,J=9.6Hz,1H),4.07-4.04(m,1H),4.00-3.83(m,4H),3.57(t,J=8.0Hz,1H), 3.41-3.34(m,1H),2.59(t,J=11.6Hz,1H),2.38-2.35(m,1H),2.15(s,3H),2.06-1.96(m,3H),1.88-1.71(m,4H),1.65-1.57(m,2H).

[0750] Implementation 60 and 61

[0751] (R)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine and (S)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0752]

[0753] 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (Example 40) was subjected to SFC using a Chiralpak IG 30 x 250 mm, 5 μm column with 20%

[0754] MeOH containing 0.1% DMEA in CO2; flow rate: 100 mL / min; ABPR 120 bar; MBPR 40 psi, column temperature 40°C further purification; obtained:

[0755] Peak 1, (R)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine or (S)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (13 mg, 24%) as an off-white solid. LCMS m / z=420.2[M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 8.48-8.43(m,1H),8.00(s,1H),3.79-3.74(m,3H),3.72-3.69(m,1H),3.54-3.51(m,4H),2.83(s,3H),2.48-2.41(m,1 H),2.37-2.27(m,4H),1.99-1.93(m,1H),1.85-1.78(m,1H),1.77-1.68(m,2H),1.59-1.53(m,1H),1.41-1.34(m,1H).

[0756] Peak 2, (S)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine or (R)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (14 mg, 27%) as an off-white solid. LCMS m / z=420.2[M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 8.45(d,J=7.9Hz,1H),7.99(d,J=8.5Hz,1H),3.79-3.73(m,3H),3.72-3.69(m,1H),3.52(t,J=4.6Hz,4H),2.83(s,3H),2.46-2.41( m,1H),2.38-2.27(m,4H),1.96(dd,J=12.8,7.3Hz,1H),1.84-1.78(m,1H),1.76-1.68(m,2H),1.59-1.53(m,1H),1.41-1.33(m,1H).

[0757] The stereochemistry of stereoisomers is arbitrarily specified.

[0758] Embodiment 62 and 63:

[0759] (R)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine and (S)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0760]

[0761] 4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (Example 41, 76 mg, 0.2 mmol) was further purified by chiral SFC using a Chiralpak IA 30 x 250 mm, 5 μm column using 30% MeOH in CO2; flow rate: 100 mL / min; ABPR 120 bar; MBPR 40 psi, column temperature 40°C to give:

[0762] Peak 1, (R)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine or (S)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (21 mg, 26%) as an off-white solid. LCMS m / z=420.2[M+H] + . 1 H NMR (500MHz, MeOH-d4): δppm 9.05(s,1H),7.91(s,1H),3.89-3.86(m,1H),3.83-3.80(m,2H),3.76-3.74(m,1H),3.67(t,J=4.6Hz,4H),2.75(s,3H),2.61-2.54( m,1H),2.51-2.43(m,4H),2.12(dd,J=7.3,12.8Hz,1H),1.97-1.89(m,2H),1.85-1.78(m,1H),1.69-1.64(m,1H),1.53-1.44(m,1H).

[0763] Peak 2, (S)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine and (R)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (22 mg, 28%) as off-white solids. LCMS m / z=420.2[M+H] +1 H NMR (500MHz, MeOH-d4): δppm 9.05(s,1H),7.91(s,1H),3.88-3.86(m,1H),3.83-3.80(m,2H),3.77-3.74(m,1H),3.67(t,J=4.6Hz,4H),2.75(s,3H),2.60-2.55(m,1H) ,2.52-2.44(m,4H),2.12(dd,J=12.8,7.3Hz,1H),1.96-1.88(m,2H),1.85-1.79(m,1H),1.66(dd,J=12.8,9.2Hz,1H),1.51-1.44(m,1H).

[0764] The stereochemistry of stereoisomers is arbitrarily specified.

[0765] Embodiment 64 and 65:

[0766] (R)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine and (S)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0767]

[0768] 4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (Example 42, 169 mg, 0.4 mmol) was further purified by SFC using a Chiralpak IA 30x250 mm, 5 μm column using 30% MeOH containing 0.1% DMEA in CO2; flow rate: 100 mL / min; ABPR 120 bar; MBPR 40 psi, column temperature 40°C to give:

[0769] Peak 1, (R)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine or (S)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (51 mg, 28%) as an off-white solid. LCMS m / z=386.1[M+H] + . 1 H NMR (500MHz, MeOH-d4): δppm 8.21(d,J=8.5Hz,1H),7.48(d,J=8.5Hz,1H),3.83-3.80(m,1H),3.77-3.74(m,2H),3.71-3.67(m,5H),2.79(s,3H),2.62-2.55(m,1H), 2.53-2.45(m,4H),2.12(dd,J=12.8,7.3Hz,1H),1.95-1.88(m,2H),1.84-1.78(m,1H),1.66(dd,J=12.8,9.2Hz,1H),1.51-1.45(m,1H).

[0770] Peak 2, (S)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine or (R)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (55 mg, 31%) as an off-white solid. LCMS m / z=386.1[M+H] + . 1 H NMR (500MHz, MeOH-d4): δppm 8.21(d,J=7.9Hz,1H),7.48(d,J=7.9Hz,1H),3.83-3.80(m,1H),3.77-3.75(m,2H),3.71-3.67(m,5H),2.79(s,3H),2.60-2.54(m,1H), 2.52-2.45(m,4H),2.12(dd,J=13.1,7.0Hz,1H),1.96-1.88(m,2H),1.84-1.78(m,1H),1.66(dd,J=13.1,9.5Hz,1H),1.51-1.44(m,1H).

[0771] The stereochemistry of stereoisomers is arbitrarily specified.

[0772] Examples 66 and 67:

[0773] (R)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine and (S)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

[0774]

[0775] 4-(2-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (Example 36, 254 mg, 0.7 mmol) was further purified by SFC using a Chiralpak AD-H 30 x 250 mm, 5 μm column using 40% MeOH containing 0.1% DEA in CO2; flow rate: 100 mL / min; ABPR 120 bar; MBPR 40 psi, column temperature 40°C to give the following compound, which was concentrated to dryness and then lyophilized:

[0776] Peak 1, (R)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine or (S)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (95 mg, 34%) as a brown oil. LCMS m / z=355.2[M+H] + . 1 H NMR (500MHz, DMSO-d6): δppm 6.70(s,1H),3.96(s,3H),3.66(s,2H),3.64-3.59(m,2H),3.55-3.50(m,4H),2.46-2.39(m,1H),2.35-2.23(m,4H),2.21(s ,3H),1.84(dd,J=12.8,7.0Hz,1H),1.75-1.68(m,2H),1.64-1.57(m,1H),1.48(dd,J=13.0,8.7Hz,1H),1.39-1.29(m,1H).

[0777] Peak 2, (S)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine or (R)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine (68 mg, 24%) as a brown oil. LCMS m / z=355.2[M+H] + . 1H NMR (500MHz, DMSO-d6): δppm 6.70(s,1H),3.96(s,3H),3.66(s,2H),3.65-3.59(m,2H),3.52(br s,4H),2.47-2.39(m,1H),2.39-2.23(m,4H),2.21(s,3H),1.84(br dd,J=12.8,7.0Hz,1H),1.75-1.68(m,2H),1.65-1.56(m,1H),1.52-1.45(m,1H),1.40-1.30(m,1H).

[0778] The stereochemistry of stereoisomers is arbitrarily specified.

[0779] Embodiment 68

[0780] 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane

[0781]

[0782] Following the procedure described in Example 1, Step 6, 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane (67 mg, 54%) was obtained from 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-one (100 mg, 302.71 μmol) and 1-oxa-6-azaspiro[3.3]heptane (73.65 mg, 393.52 μmol, oxalate salt). LCMS m / z=414.1[M+H] + . 1 HNMR (400MHz, CDCl3): δppm 8.27(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,1H),4.50(t,J=8.0Hz 2H),3.89(s,2H),3.84(s,2H),3.50-3.47(m,2H),3.07-3.05(m,2H),2.95-2.88(m,1H),2.85 (s,3H),2.82(t,J=7.6Hz,2H),2.23-2.18(m,2H),2.01(t,J=18.8Hz,3H),1.95-1.90(m,2H).

[0783] Embodiment 69

[0784] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine

[0785]

[0786] According to the procedure described in Example 1, Step 6, 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (200 mg, 605.4 μmol) and oxetane-3-amine (66.4 mg, 908.1 μmol) was obtained as 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(oxetane-3-yl)-2-azaspiro[3.3]heptan-6-amine (150 mg, 64%). LCMS m / z=388.1[M+H] + . 1 HNMR (400MHz, CDCl3): δppm8.27(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,1H),4.78(t,J=6.8Hz,2H),4.39(t,J=6.4Hz,2H),3.9 3-3.88(m,3H),3.85(s,2H),3.19-3.12(m,1H),2.86(s,3H),2.44-2.39(m,2H),2.01(t,J=18.8Hz,3H),1.91-1.86(m,2H).

[0787] Embodiment 70

[0788] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine

[0789]

[0790] Following the procedure described in Example 1, Step 6, 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (200 mg, 605.4 μmol) and 2-oxaspiro[3.3]heptan-6-amine (108.70 mg, 726.50 μmol, HCl salt) was obtained as 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-amine (160 mg, 62%). LCMS m / z=428.1 [M+H] + .1 HNMR (400MHz, CDCl3): δppm 8.27(d,J=8.0Hz,1H),7.59(d,J=8.4Hz,1H),4.68(s,2H),4.57(s,2H),3.92(s,2H),3.83(s,2H ),3.14-2.97(m,2H),2.86(s,3H),2.51-2.39(m,4H),2.01(t,J=18.8Hz,3H),1.88-1.81(m,4H).

[0791] Embodiment 71

[0792] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine

[0793]

[0794] Following the procedure described in Example 1, Step 6, 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (100 mg, 302.7 μmol) and (tetrahydro-2H-pyran-4-yl)methanamine (38.35 mg, 332.98 μmol) was obtained as 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-amine (43 mg, 33%). LCMS m / z=430.1 [M+H] + . 1 HNMR (400MHz, CDCl3): δppm 8.28(d,J=8.4Hz,1H),7.59(d,J=8.4Hz,1H),3.97-3.93(m,4H),3.86(s,2H),3.39-3.33(m,2H),3.18-3.11(m,1H),2.86(s,3H),2.47- 2.42(m,2H),2.36(d,J=6.0Hz,2H),2.01(t,J=18.8Hz,3H),1.89-1.84(m,2H),1.66-1.62(m,2H),1.55-1.49(m,1H),1.31-1.21(m,2H).

[0795] Embodiment 72

[0796] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine

[0797]

[0798] Following the procedure described in Example 1, Step 6, 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (100 mg, 302.7 μmol) and 1-(tetrahydro-2H-pyran-4-yl)ethan-1-amine (104.59 mg, 908.13 μmol) was obtained as 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine (68 mg, 52%). LCMS m / z=430.2[M+H] + . 1 HNMR (400MHz, CDCl3): δppm 8.28(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),4.03-3.99(m,2H),3.95(s,2H),3.83(s,2H),3.37-3.31(m,2H),3.04-3.00(m,1H),2 .86(s,3H),2.62-2.57(m,1H),2.34-2.29(m,2H),2.10-2.07(m,3H),2.01(t,J=18.8Hz,3H),1.66-1.60(m,3H),1.58-1.55(m,3H).

[0799] Embodiment 73

[0800] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine

[0801]

[0802] Following the procedure described in Example 59, 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (100 mg, 302.7 μmol) and (CH2O) were used to prepare the 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (100 mg, 302.7 μmol) n(70.3 mg, 2.0 mmol) obtained 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine (55 mg, 53%). LCMS m / z=402.1[M+H] + . 1 HNMR (400MHz, CDCl3): δppm 8.27(d,J=8.0Hz,1H),7.59(d,J=8.4Hz,1H),4.64(t,J=6.4Hz,2H),4.56(t,J=6.4Hz,2H),3.93(s,2H) ,3.82(s,2H),3.63-3.56(m,1H),2.86(s,3H),2.69-2.59(m,1H),2.26-2.21(m,2H),2.07-1.96(m,8H).

[0803] Embodiment 74

[0804] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine

[0805]

[0806] Following the procedure described in Example 59, 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine (100 mg, 233.9 μmol) and (CHCl) were added. n (79.7 mg, 2.34 mmol) obtained 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine (158 mg, 67%). LCMS m / z=442.2[M+H] + . 1 HNMR (400MHz, CDCl3): δppm 8.27(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,1H),4.68(s,2H),4.55(s,2H),3.93(s,2H),3.80( s,2H),2.86(s,3H),2.63-2.46(m,2H),2.34-2.23(m,4H),2.08-1.96(m,7H),1.92(s,3H).

[0807] Embodiment 75

[0808] 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine

[0809]

[0810] Following the procedure described in Example 1, Step 6, 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (100 mg, 302.7 μmol) and N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine (50.8 mg, 394 μmol) was obtained as 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-amine (71 mg, 53%). LCMS m / z=444.2[M+H] + . 1 HNMR (400MHz, CDCl3): δppm 8.28(d,J=8.0Hz,1H),7.59(d,J=8.4Hz,1H),3.96-3.92(m,4H),3.83(s,2H),3.39-3.33(m,2H),2.86( s,3H),2.60-2.54(m,1H),2.30-2.25(m,2H),2.06-1.97(m,10H),1.64-1.62(m,3H),1.24-1.14(m,2H).

[0811] Embodiment 76

[0812] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine

[0813]

[0814] Following the procedure described in Example 16, Step 4, 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (70 mg, 208.77 μmol) and tetrahydro-2H-pyran-4-amine (63 mg, 626 μmol) was obtained as 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-amine (15 mg, 17%). LCMS m / z=421.1 [M+H] + . 1 HNMR (400MHz, CDCl3): δppm9.18(s,1H),4.03(s,2H),3.97-3.93(m,4H),3.40-3.29(m,3H),2.91(s, 3H),2.66-2.62(m,1H),2.53-2.48(m,2H),1.95-1.90(m,2H),1.74-1.71(m,2H),1.41-1.31(m,2H).

[0815] Embodiment 77

[0816] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine

[0817]

[0818] Following the procedure described in Example 16, Step 4, 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (180 mg, 536.8 μmol) and oxetan-3-amine (47 mg, 644 μmol) was obtained as 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine (115 mg, 54%). LCMS m / z=393.1 [M+H] + . 1 HNMR (400MHz, CDCl3): δppm 9.17(s,1H),4.78(t,J=7.0Hz,2H),4.39(t,J=6.5Hz,2H),4.01(s,2H),3.96(s,2H),3. 94-3.86(m,1H),3.22-3.14(m,1H),2.90(s,3H),2.47-2.40(m,2H),1.95-1.88(m,2H).

[0819] Embodiment 78

[0820] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine

[0821]

[0822] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine (100 mg, 47%) was obtained from 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-one (160 mg, 477.1 μmol) and 2-oxaspiro[3.3]hept-6-amine (92.8 mg, 620 μmol) according to the procedure described in Example 16, Step 4. LCMS m / z=433.1 [M+H] + . 1 HNMR (400MHz, CDCl3): δppm9.17(s,1H),4.68(s,2H),4.58(s,2H),4.01(s,2H),3.94(s,2H ),3.17-3.10(m,1H),3.07-2.98(m,1H),2.90(s,3H),2.53-2.42(m,4H),1.94-1.87(m,4H).

[0823] Embodiment 79

[0824] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine

[0825]

[0826] Following the procedure described in Example 16, Step 4, 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (60 mg, 178.9 μmol) and (tetrahydro-2H-pyran-4-yl)methanamine (24.7 mg, 214.7 μmol) was obtained as 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-amine (13 mg, 17%). LCMS m / z=435.1 [M+H] + . 1HNMR (400MHz, CDCl3): δppm 9.18(s,1H),4.03(s,2H),3.98(s,2H),3.96-3.93(m,2H),3.39-3.33(m,2H),3.26-3.22(m,1H),2.90(s ,3H),2.53-2.48(m,2H),2.43(d,J=6.4Hz,2H),2.07-2.06(m,1H),1.75-1.69(m,2H),1.34-1.24(m,4H).

[0827] Embodiment 80

[0828] N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine

[0829]

[0830] Following the procedure described in Example 16, Step 4, N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (70 mg, 208.8 μmol) and N-methyltetrahydro-2H-pyran-4-amine (36.1 mg, 313.1 μmol) was obtained as N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine (22 mg, 23%). LCMS m / z=435.1 [M+H] + . 1 HNMR (400MHz, CDCl3): δppm 9.18(s,1H),4.04-3.99(m,4H),3.93(s,2H),3.37-3.31(m,2H),3.07-2.99(m,1H), 2.91(s,3H),2.63-2.57(m,1H),2.36-2.31(m,2H),2.08(s,3H),1.66-1.51(m,6H).

[0831] Embodiment 81

[0832] N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine

[0833]

[0834] Following the procedure described in Example 59, 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine (50 mg, 127.4 μmol) and (CH2O) were used to prepare the 5-amino-2-nitropropenesulfonyl-4-ylthiocyanate (50 mg, 127.4 μmol). n (764 mg, 637 μmol) N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine (35 mg, 67.6%) was obtained. LCMS m / z=407.1[M+H] + . 1 HNMR (400MHz, CDCl3): δppm 9.17(s,1H),4.64(t,J=6.5Hz,2H),4.56(t,J=6.5Hz,2H),4.02(s,2H),3.92(s,2H),3.63-3. 57(m,1H),2.90(s,3H),2.68-2.62(m,1H),2.28-2.22(m,2H),2.10-2.05(m,2H),2.04(s,3H).

[0835] Embodiment 82

[0836] N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine

[0837]

[0838] Following the procedure described in Example 59, 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine (80 mg, 185 μmol) and (CH2O) were used to prepare the 5-amino-2-nitropropenesulfonyl-4-ylthiocyanate (50 mg, 10 μmol) n (63 mg, 1.85 mmol) obtained N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine (20 mg, 24%). LCMS m / z=447.1[M+H] + . 1HNMR (400MHz, CDCl3): δppm 9.17(s,1H),4.69(s,2H),4.56(s,2H),4.03(s,2H),3.92(s,2H),2.90(s, 3H),2.63-2.49(m,2H),2.33-2.29(m,4H),2.11-2.01(m,4H),1.94(s,3H).

[0839] Embodiment 83

[0840] N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine

[0841]

[0842] Following the procedure described in Example 16, Step 4, N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (60 mg, 178.9 μmol) and N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine (27.7 mg, 214.7 μmol) was obtained as N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-amine (38 mg, 45.6%). LCMS m / z=449.2 [M+H] + . 1 HNMR (400MHz, CDCl3): δppm 9.18(s,1H),4.01(s,2H),3.99-3.93(m,4H),3.40-3.34(m,2H),2.91(s,3H),2.64-2.56(m,1H),2.33- 2.28(m,2H),2.06(s,3H),2.02-1.95(m,4H),1.69-1.67(m,1H),1.67-1.64(m,2H),1.24-1.14(m,2H).

[0843] Determination

[0844] EBP functional assay

[0845] EBP immunoaffinity (IA) LC-MS assay measures the potency of EBP small molecule inhibitors by quantifying the concentration-dependent changes in substrates and products of the enzyme using liquid chromatography atmospheric pressure chemical ionization multiple reaction monitoring mass spectrometry (LC-APCI MRM MS). HEK293T cells were utilized as a source of EBP enzyme. The enzyme was incubated with various concentrations of small molecule inhibitors for 30 min. The deuterated form of the EBP substrate, zymosterol-d5 (Avanti Polar Lipids, catalog number 700068P-1mg), was then added and the plate was incubated at 37 °C for 4 h. Finally, the sterol isomers were extracted and injected into the LC-APCI MRM MS. The MRM transitions used to quantify zymosterol and dihydrocholestanol, the substrate and product of the EBP enzymatic reaction, respectively, were 372.3-203.2, CE 30, and DP 80 in the positive ion mode. The percentage conversion of zymosterol-d5 to dehydrocholestanol-d5 was used to derive the IC 50 Tasin-1 (1′-[(4-methoxyphenyl)sulfonyl]-4-methyl-1,4′-bipiperidine, CAS 792927-06-1) was used as a reference small molecule inhibitor.

[0846]

[0847] The percent conversion versus compound concentration data were fitted to the following 4-parameter logistic model to generate the IC 50 curve:

[0848]

[0849] Data of the Example

[0850]

[0851]

[0852]

[0853] *N / A means >3 μM; + means 3 μM to >0.5 μM; ++ means 0.1-0.5 μM; +++ means <0.1 μM; NT = not tested

Claims

1. A compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is O, CH2 or a bond; R 1 and R 2 Each independently selected from H, C 1-6 Alkyl, C 1-3 Haloalkyl, C 3-8 Cycloalkyl, Het and -Z-Het, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl and Het are each optionally substituted by one or more R 4 Replace, provided that R 1 and R 2 At least one of them is not H; or R 1 and R 2 Together with the N atom to which they are attached, they form a 4- to 7-membered monocyclic heterocyclic ring or a 6- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or more R 4 replace; Z is optionally replaced by one or more R 4 Substituted C 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 replaced by R 4 replace; Each R 4 Independently selected from OR 4a , halo, C 1-3 Alkyl, C 1-3 haloalkyl and 4- to 7-membered monocyclic heterocyclic ring; R 4a Selected from H, C 1-3 Alkyl and C 1-3 Haloalkyl; R 3 is phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl or 6 to 10-membered bicyclic heterocycle, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and 6 to 10-membered bicyclic heterocycle are each optionally substituted by one or more substituents R 5 replace; Each R 5 Independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl, OR 5a , cyano and halo; R 5a Selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halo groups; The condition is R 1 and R 2 Together with the N atom to which they are attached they do not form unsubstituted pyrrolidine, unsubstituted piperidine or 4-methylpiperazine.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl or a 5- or 6-membered monocyclic heteroaryl, each of which is optionally substituted by one to three substituents R 5 replace.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, pyridyl, pyrimidinyl or pyrazolyl, each of which is optionally substituted by one to three substituents R 5 replace.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one to three R 5 replace.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 1 and R 2 Together with the N atom to which they are attached, they form a saturated 4- to 6-membered monocyclic heterocyclic ring or a saturated 7- to 10-membered bicyclic heterocyclic ring, each of which is optionally substituted by one or two R 4 replace.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula: Wherein each formula depicted above is optionally replaced by one or two R 4 replace.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: R 1 is H or optionally one to three R 4 Substituted C 1-3 alkyl; R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, Het or -Z-Het, wherein the C 1-3 Alkyl, C 3-6 cycloalkyl; and Het is a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 to 2 heteroatoms selected from oxygen and nitrogen, at least one of the heteroatoms being oxygen, wherein the saturated 4- to 6-membered monocyclic heterocyclic ring is optionally replaced by one to three R 4 replace.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein Het is selected from tetrahydropyran and oxetane, each of which is optionally substituted by one to two R 4 replace.

9. The compound according to any one of claims 1 to 8, wherein the compound is represented by formula (II): or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

11. The compound according to claim 9 or 10, or a pharmaceutically acceptable salt thereof, wherein R 5 In each occurrence, independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl and OR 5a .

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected at each occurrence from -CH3, -CF3, -CF2CH3, -CH(CH3)2 and -OCHF2.

13. A compound according to any one of claims 9 to 12 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

14. A compound according to any one of claims 9 to 12 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or -CH3, and R 2 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one or two R 4 replace.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 9 to 12, wherein R 1 H and R 2 It is expressed by the following formula: Wherein each formula depicted above is optionally replaced by one or two R 4 replace.

16. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 2 It is expressed by the following formula:

17. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein R 2 It is expressed by the following formula:

18. A compound according to any one of claims 9 to 17 or a pharmaceutically acceptable salt thereof, wherein R 4 In each occurrence, independently selected from C 1-3 Alkyl and 4 to 7 membered monocyclic heterocyclic ring.

19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from -CH3 and tetrahydropyran.

20. The compound of any one of claims 1 to 8, wherein the compound is represented by formula (III) or (IV): or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20, wherein the compound is represented by formula (IIIA), (IIIB), (IVA) or (IVA): or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 20 or 21, or a pharmaceutically acceptable salt thereof, wherein R 3 It is expressed by the following formula:

23. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 20 to 22, wherein R 5 is independently selected at each occurrence from halo, cyano, C 1-2 Alkyl, C 1-2 Haloalkyl and OR 5a ; and R 5a C 1-2 Alkyl or C 1-2 Halogenated alkyl.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected at each occurrence from F, Cl, cyano, -CH3, -CF3, -CHF2, -OCH3 and -OCHF2.

25. A compound as described in any one of claims 20 to 24, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a group represented by the formula:

26. A compound according to any one of claims 20 to 25 or a pharmaceutically acceptable salt thereof, wherein: R 1 H or C 1-3 Alkyl; and R 2 C 1-3 Alkyl, C 3-6 cycloalkyl, -Z-Het or Het, each of which is optionally substituted by one to three R 4 replace.

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or -CH3, and R 2 is optionally replaced by an R 4 Substituted C 1-3 Alkyl may be represented by the following formula: Wherein each formula depicted above is optionally replaced by one or two R 4 replace.

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or -CH3, and R 2 It is expressed by the following formula:

29. A compound as described in any one of claims 20 to 28, or a pharmaceutically acceptable salt thereof, wherein R 4 In each occurrence, independently selected from OR 4a , halo and C 1-3 alkyl; and wherein R 4a C 1-3 alkyl.

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from halo, -CH3 and -OCH3.

31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine; 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine; 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)-2-azaspiro[3.3]hept-6-amine; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]hept-6-amine; 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-ylmethyl)-2-azaspiro[3.3]hept-6-amine; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]hept-6-amine; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine; 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane; 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane; 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 2-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide; 4-(2-((3-isopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)morpholine; 2-((4-(difluoromethoxy)phenyl)sulfonyl)-6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane; 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine; 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-5-oxa-2-azaspiro[3.4]octane; 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-7-(3-methoxyazetidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; N-(4,4-difluorocyclohexyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-amine; N-(3,3-difluorocyclobutyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-amine; 3-((7-((4,4-difluorocyclohexyl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-4-fluorobenzonitrile; 4-Fluoro-3-((7-((tetrahydro-2H-pyran-4-yl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)benzonitrile; 3-((7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-5-fluorobenzonitrile; 4-(2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 6-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)-2-oxa-6-azaspiro[3.3]heptane; N-(4,4-difluorocyclohexyl)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine; 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-2-azaspiro[3.4]octan-6-amine; N-(2-methoxyethyl)-N-methyl-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine; 4-(2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((4-chloro-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((4-(difluoromethyl)-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((6-methoxy-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-(mesitylsulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((4-(difluoromethoxy)phenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((2,4-dimethylphenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((2,4-difluorophenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((4,6-dimethylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (R)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile; (R)-3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile; 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (S)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile; (S)-3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile; 2-(mesitylsulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane; 2-((4-(difluoromethoxy)phenyl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; 2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane; 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane; (R)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane; (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane; 3-((7-((4,4-difluorocyclohexyl)(methyl)amino)-5-oxa-2-azaspiro[3.4]oct-2-yl)sulfonyl)-4-fluorobenzonitrile; 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (R)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (S)-4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (R)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (S)-4-(2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (R)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (S)-4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (R)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; (S)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine; 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-1-oxa-6-azaspiro[3.3]heptane; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine; 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine; 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine; 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine; 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine; 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine; N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]hept-6-amine; N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]hept-6-amine; N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]hept-6-yl)-2-azaspiro[3.3]hept-6-amine; and N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]hept-6-amine; or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

33. A method for treating a disease mediated by emopamide binding protein, the method comprising administering to a subject an effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, or the pharmaceutical composition according to claim 32.

34. A method of treating an autoimmune disease in a subject, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32.

35. The method of claim 34, wherein the autoimmune disease is multiple sclerosis.

36. The method of claim 35, wherein the compound or pharmaceutical composition repairs or forms new myelin sheaths in the subject.

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