Empamil binding protein inhibitor and its use

Abstract

Compound of formula (I): [Chemical 1] JPEG2025524910000176.jpg32165 or a pharmaceutically acceptable salt thereof is provided, which is useful for the inhibition of EBP and the treatment of various conditions or diseases mediated by EBP such as multiple sclerosis.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 391,578, filed on July 22, 2022. The entire contents of the foregoing application are hereby expressly incorporated by reference into this specification.

[0002] The present disclosure relates to inhibitors of emopamil binding protein (EBP) and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, their use in the treatment of diseases, their use in any combination with pharmaceutically acceptable carriers for the manufacture of pharmaceutical preparations, the use of pharmaceutical preparations in the treatment of diseases, and methods of treating diseases including administering an EBP inhibitor to a warm-blooded animal, particularly a human.

Background Art

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

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

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

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

[0007] The present disclosure provides compounds that are EBP inhibitors. In a first aspect, the present disclosure relates to a compound of formula I:

Chemical formula

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

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

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

DETAILED DESCRIPTION OF THE INVENTION

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

[0012] Compounds and Compositions In a first embodiment, the present disclosure provides a compound of formula (I):

Chem.

[0013] In a second embodiment, for the 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 with 1 to 3 substituents R 5 and the remaining variables are as described in the first embodiment.

[0014] In a third embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 is phenyl, pyrazinyl, pyrimidinyl, or pyrazolyl, each of which is optionally substituted with 1 to 3 substituents R 5 and the remaining variables are as described in the second embodiment.

[0015] In a fourth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 is of the following formula:

Chem.

[0016] In a fifth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 and R 2together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic heterocycle or a 7- to 10-membered bicyclic heterocycle, each of which is optionally substituted with 1 or 2 R 4 and the remaining variables are as described in the first, second, third, or fourth embodiment.

[0017] 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 form a group represented by the following formula:

Chemical formula

[0018] In a seventh embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 is H or C 4 alkyl optionally substituted with 1 to 3 R 1~3 and R 2 is C 1~3 alkyl, C 3~6 cycloalkyl, Het, or -Z-Het, where C 1~3 alkyl, C 3~6 cycloalkyl and Het are saturated 4- to 6-membered monocyclic heterocycles containing 1 to 2 heteroatoms selected from oxygen and nitrogen, at least one of which is oxygen, where the saturated 4- to 6-membered monocyclic heterocycle is optionally substituted with 1 to 3 R 4 and the remaining variables are as described in the first, second, third, or fourth embodiment.

[0019] 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 with 1 or 2 R 4is optionally replaced, and the remaining variables are as described in the seventh embodiment.

[0020] In the ninth embodiment, the compound of the present disclosure has the formula (II):

Chemical formula

[0021] In the tenth embodiment, for the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R 3 is the following formula:

Chemical formula

[0022] In the eleventh embodiment, for the compound of formula (II), or a pharmaceutically acceptable salt thereof, R 5 is independently selected, each occurrence, 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.

[0023] In the twelfth embodiment, for the compound of formula (II), or a pharmaceutically acceptable salt thereof, R 5 is independently selected, each occurrence, from -CH3, -CF3, -CF2CH3, -CH(CH3)2, and -OCHF2, and the remaining variables are as described in the eleventh embodiment.

[0024] In the thirteenth embodiment, for the compound of formula (II), or a pharmaceutically acceptable salt thereof, R 1 and R2 together with the nitrogen atom to which they are attached, form the following formula: [Chemical formula] forms a group represented by, and the remaining variables are as described in the 9th, 10th, 11th, or 12th embodiment.

[0025] In the 14th embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 1 is H, and R 2 is the following formula: [Chemical formula] represented by, and each of the above formulas is optionally substituted with one or two R 4 , and the remaining variables are as described in the 9th, 10th, 11th, or 12th embodiment. In an alternative 14th embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 1 is H, and R 2 is [Chemical formula] represented by, and each of the above formulas is optionally substituted with one or two R 4 , and the remaining variables are as described in the 9th, 10th, 11th, or 12th embodiment.

[0026] In the 15th embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 is the following formula [Chemical formula] represented by, and the remaining variables are as described in the 14th embodiment. In an alternative 15th embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 is the following formula [Chemical formula] represented by, and the remaining variables are as described in the 14th embodiment.

[0027] In the 16th embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 4 is, for each occurrence, independently selected from C 1~3 alkyl and 4- to 7-membered monocyclic heterocycles, and the remaining variables are as described in the 9th, 10th, 11th, 12th, 13th, 14th, or 15th embodiment.

[0028] In the 17th embodiment, for the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 4 is, for each occurrence, independently selected from -CH3 and tetrahydropyran, and the remaining variables are as described in the 16th embodiment.

[0029] In the 18th embodiment, the compound of the present disclosure is of formula (III) or (IV):

Chemical formula

[0030] In the 19th embodiment, the compound of the present disclosure is of formula (IIIA), (IIIB), (IVA), or (IVB):

Chemical formula

[0031] In the 20th embodiment, for the compound of formula (III), (IIIA), (IIIB), (IV), (IVA), or (IVB) or a pharmaceutically acceptable salt thereof, R3 is represented by the following formula: [Chemical formula] where the remaining variables are as described in the 18th or 19th embodiment.

[0032] In the 21st embodiment, for the compounds of formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 5 is, for each occurrence, independently selected from halo, cyano, C 1~2 alkyl, C 1~2 haloalkyl, and OR 5a and R 5a is C 1~2 alkyl or C 1~2 haloalkyl, and the remaining variables are as described in the 18th, 19th, or 20th embodiment.

[0033] In the 22nd embodiment, for the compounds of formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 5 is, for each occurrence, independently selected from F, Cl, cyano, -CH3, -CF3, -CHF2, -OCH3, and -OCHF2, and the remaining variables are as described in the 21st embodiment.

[0034] In the 23rd embodiment, for the compounds 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, form a group represented by the following formula: [Chemical formula] and the remaining variables are as described in the 18th, 19th, 20th, 21st, or 22nd embodiment.

[0035] In the 24th embodiment, for the compound of formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 1 is H or C 1-3 alkyl, and R 2 is C 1~3 alkyl, C 3~6 cycloalkyl, -Z-Het, or Het, each of which is optionally substituted with 1 to 3 R 4 , and the remaining variables are as described in the 18th, 19th, 20th, 21st, or 22nd embodiment.

[0036] In the 25th embodiment, for the 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 C 4 alkyl optionally substituted with one R 1~3 , or is of the following formula:

Chemical formula

[0037] In the 26th embodiment, for the 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 of the following formula:

Chemical formula

[0038] In the 27th embodiment, for the compound of formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 4 is, for each occurrence, independently selected from OR 4a , halo, and C 1~3 alkyl, R 4a is C 1~3 alkyl, and the remaining variables are as described in the 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, or 26th embodiment.

[0039] In the 28th embodiment, for the compound of formula (III), (IIIA), (IIIB), (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, R 4 is, for each occurrence, independently selected from halo, -CH3, and -OCH3, and the remaining variables are as described in the 27th embodiment.

[0040] In the 29th embodiment, the present disclosure provides a compound described herein (for example, any one of the compounds of Examples 1 to 83), or a pharmaceutically acceptable salt thereof.

[0041] In the 30th embodiment, the present disclosure provides 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-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]heptan-6-amine; 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine; 6-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 4-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)morpholine; 6-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-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]heptan-6-amine; 2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; 4-(2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)morpholine; 2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-ylmethyl)-2-azaspiro[3.3]heptan-6-amine; 2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; 2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; 6-(2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.5]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-6-azaspiro[3.3]heptane; 6-(2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-6-azaspiro[3.3]heptane; 6-(2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 2-Methyl-N-(2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide; 4-(2-((3-Isopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-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]heptan-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]octane-7-amine; N-(3,3-Difluorocyclobutyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octane-7-amine; 3-((7-((4,4-Difluorocyclohexyl)amino)-5-oxa-2-azaspiro[3.4]octane-2-yl)sulfonyl)-4-fluorobenzonitrile; 4-Fluoro-3-((7-((tetrahydro-2H-pyran-4-yl)amino)-5-oxa-2-azaspiro[3.4]octane-2-yl)sulfonyl)benzonitrile; 3-((7-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)-5-oxa-2-azaspiro[3.4]octane-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]octane-6-amine; 2-((6-Methoxy-2-methylpyridin-3-yl)sulfonyl)-N-(2-methoxyethyl)-N-methyl-2-azaspiro[3.4]octane-6-amine; N-(2-Methoxyethyl)-N-methyl-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octane-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]octane-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]heptan-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]heptan-6-amine; 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-2-diazaspiro[3.3]heptan-6-amine; 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; 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; 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(2-oxaspiro[3.3]heptan-6-yl)-2-diazaspiro[3.3]heptan-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]heptan-6-amine; 2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((4-Methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine; N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-2-azaspiro[3.3]heptan-6-amine; N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; or a compound selected from the group consisting of pharmaceutically acceptable salts thereof.

[0042] In a 31st embodiment, the present disclosure provides a pharmaceutical composition comprising a compound described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof.

[0043] In a 32nd embodiment, the present disclosure provides a method for treating a disease or disorder mediated by EBP, the method comprising administering to a subject an effective amount of a compound described in any one of Embodiments 1 to 30, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the 31st embodiment.

[0044] In a 33rd embodiment, the present disclosure provides a compound described in any one of Embodiments 1 to 30 for use in the treatment of a disease or disorder mediated by EBP.

[0045] In a 34th embodiment, the present disclosure provides the use of a compound described in any one of Embodiments 1 to 30 for use in the manufacture of a medicament for the treatment of a disease or disorder mediated by EBP.

[0046] The compounds and intermediates described herein can be isolated and used as compounds themselves. Alternatively, if there are moieties capable of forming salts, the compounds or intermediates can be isolated and used as their corresponding salts. As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds described herein. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effects and properties of the compounds described herein and are generally not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure can form acidic salts and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups.

[0047] Pharmaceutically acceptable acid addition salts can be formed, for example, using inorganic or organic acids such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0048] Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0049] Examples of organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, and the like.

[0050] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0051] Examples of inorganic bases from which salts can be derived include ammonium salts and metals in Groups I - XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper. Particularly preferred salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0052] Examples of organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0053] Salts can be synthesized from compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.) or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable when feasible. A further list of suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0054] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those of ordinary skill in the art or by a process similar to those described in the appended examples and preparations using appropriate isotopically labeled reagents in place of the conventionally used unlabeled reagents. In one embodiment, the present disclosure provides a deuterium compound described herein, or a pharmaceutically acceptable salt thereof.

[0055] Pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent may be isotopically substituted, such as D2O, d6-acetone, and d6-DMSO.

[0056] It will be recognized by those skilled in the art that the compounds of the present invention may contain chiral centers and thus may exist in different stereoisomeric forms. As used herein, the terms "optical isomers" or "stereoisomers" refer to any of the various stereoisomeric structures that may exist for a given compound of the present disclosure. It is understood that substituents may be attached at chiral centers of carbon atoms. Accordingly, the present disclosure encompasses enantiomers, diastereomers, or racemates of the compounds.

[0057] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The terms "racemic" or "rac" are used to designate a racemic mixture where appropriate. When specifying the stereochemistry of a compound of the present invention, a single stereoisomer whose relative and absolute configuration of two chiral centers is known is designated using the conventional RS system (e.g., (1S,2S)). "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is designated according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated as either R or S. Resolved compounds of unknown absolute configuration can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) in which they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds can be defined by their respective retention times relative to the corresponding enantiomers / diastereomers via chiral HPLC.

[0058] Some of the compounds described herein contain one or more asymmetric centers or axes and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R) or (S) from the perspective of absolute stereochemistry.

[0059] Unless otherwise specified, the compounds of the present disclosure are intended to encompass all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. The optically active (R) and (S) stereoisomers may be prepared using a chiral synthon or chiral reagent, or may be resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp. using a solvent or solvent mixture appropriate to achieve good separation). When the compound contains a double bond, the substituents may be in the E or Z configuration. When the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have the cis or trans configuration. All tautomeric forms are also intended to be included.

[0060] Method of Use The compounds disclosed herein have EBP inhibitory activity. As used herein, "EBP inhibitory activity" refers to the ability of a compound or composition to induce a detectable decrease in EBP activity in vivo or in vitro (e.g., at least a 10% decrease in EBP activity as measured by a given assay such as the bioassays described in the Examples and known in the art).

[0061] In certain embodiments, the present disclosure provides to a subject in need of a method of treating a disease or disorder responsive to inhibition of EBP activity (referred to herein as an "EBP-mediated disease or disorder" or a "disease or disorder mediated by EBP"). The method includes administering to the subject a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0062] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an EBP-mediated disorder or disease in a subject in need of treatment.

[0063] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in the treatment of an EBP-mediated disorder or disease in a subject in need of treatment.

[0064] In certain embodiments, the EBP-mediated disorder is colorectal cancer.

[0065] 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 described herein (e.g., a compound described in any one of Embodiments 1 to 30) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0066] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an autoimmune disease in a subject in need of treatment.

[0067] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of autoimmune diseases in a subject in need thereof.

[0068] In certain embodiments, the autoimmune disease is multiple sclerosis (MS). The compounds of the present disclosure can be used to treat all stages of MS, including relapsing multiple sclerosis (or relapsing forms of multiple sclerosis), relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and clinically isolated syndromes (hereinafter, "CIS").

[0069] Relapsing multiple sclerosis (or relapsing forms of multiple sclerosis) includes clinically isolated syndromes, relapsing-remitting multiple sclerosis, and active secondary progressive multiple sclerosis.

[0070] Relapsing-remitting multiple sclerosis is a stage of MS characterized by unpredictable relapses followed by relatively quiet (remission) periods of months to years without new signs of disease activity. Deficits that occur during attacks may or may not resolve, with the latter occurring in about 40% of attacks and being more common the longer the patient has had the disease. This accounts for the initial course of 80% of patients with multiple sclerosis.

[0071] Secondary progressive multiple sclerosis occurs in about 65% of patients with initial relapsing-remitting multiple sclerosis, has no clear remission periods between acute attacks, and ultimately shows progressive neurological decline. Recurrences and mild remissions may occur from time to time. The most common period from onset to transition from relapsing-remitting to secondary progressive multiple sclerosis is 19 years.

[0072] Primary progressive multiple sclerosis is characterized by the same symptoms as secondary progressive multiple sclerosis, namely progressive neurological decline between acute attacks without a distinct remission phase, and there is no previous relapsing-remitting phase.

[0073] CIS is the first symptom of neurological symptoms caused by inflammation and demyelination in the central nervous system. The manifestation of this symptom must, by definition, last for at least 24 hours and is characteristic of multiple sclerosis. However, since some people who experience CIS may develop MS while others may not, they do not yet meet the diagnostic criteria for MS. If CIS is accompanied by lesions similar to those seen in MS on brain MRI (magnetic resonance imaging), the likelihood of the neurological symptoms reappearing and being diagnosed with relapsing-remitting MS is high when they occur a second time. If CIS is not accompanied by MS-like lesions on brain MRI, the likelihood of that person developing MS is much lower.

[0074] In certain embodiments, the present disclosure provides a method of promoting myelination in a subject having a myelin-related disease or disorder in a subject in need of treatment. The method includes administering to the subject a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0075] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for promoting myelination in a subject having a myelin-related disease or disorder in a subject in need of treatment.

[0076] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in promoting myelination in a subject having a myelin-related disease or disorder in need of treatment.

[0077] 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 disease, Pelizaeus-Merzbacher disease (PMD), vanishing white matter disease, Wohlfart-Chugan syndrome, Marchiafava-Bignami syndrome, autism, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Charcot-Marie-Tooth disease, Bell's palsy, and radiation-induced demyelination, such as neuromyelitis optica (NMO), optic neuritis, pediatric white matter disorder, neonatal white matter injury, age-related dementia, and schizophrenia.

[0078] 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 described herein (e.g., a compound described in any one of Embodiments 1 to 30) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0079] In certain embodiments, the present disclosure provides for the use of a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

[0080] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of Embodiments 1 to 30) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject in need thereof.

[0081] In some embodiments, the cancer is colorectal cancer.

[0082] In certain embodiments, the present disclosure relates to the aforementioned method where the subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0083] As used herein, "effective amount" and "therapeutically effective amount" may be used interchangeably. It means an amount effective to treat or reduce the severity of one or more of the diseases, disorders, or conditions enumerated herein. In some embodiments, the effective dosage can be from 10 μg to 500 mg.

[0084] The compounds and compositions according to the methods of the present disclosure can be administered using any amount and any route of administration effective to treat or reduce the severity of one or more of the diseases, disorders or conditions enumerated above.

[0085] In certain embodiments, the present disclosure relates to the aforementioned method, and the compound is administered parenterally. In certain embodiments, the present disclosure relates to the aforementioned method, and the compound is administered intramuscularly, intravenously, subcutaneously, orally, by inhalation, rectally, intrathecally, topically, or intranasally. In certain embodiments, the present disclosure relates to the aforementioned method, and the compound is administered systemically.

[0086] The compositions of the present invention can be used as pharmaceutical compositions (e.g., a compound of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term “pharmaceutically acceptable carrier” includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, butyric acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.) and the like and combinations thereof that are generally recognized as safe (GRAS) by those skilled in the art (see, e.g., Remington’s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Its use in therapeutic or pharmaceutical compositions is contemplated, except where any conventional carrier is incompatible with the active ingredient. For the purposes of the present disclosure, solvates and hydrates are considered to be pharmaceutical compositions that include a compound of the present disclosure and a solvent (i.e., a solvate) or water (i.e., a hydrate).

[0087] Formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk drug substance (i.e., a 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 excipients described above. The compounds of the present invention are typically formulated into pharmaceutical dosage forms in order to provide a drug with an easily adjustable dosage and to provide a product that is simple and easy to handle for the patient.

[0088] Pharmaceutical compositions (or formulations) for use may be packaged in a variety of ways depending on the method used to administer the drug. Generally, dispensing articles include a container having the pharmaceutical formulation disposed therein in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include an anti-tampering assembly to prevent inadvertent access to the contents of the package. In addition, the container has a label thereon that describes the contents of the container. The label may also include appropriate cautions.

[0089] Pharmaceutical compositions containing the compounds of the present disclosure are generally formulated for parenteral or oral administration, or alternatively for use as suppositories.

[0090] For example, the oral pharmaceutical compositions of the present disclosure can be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical processes such as sterilization and / or contain conventional inert diluents, lubricants, or buffering agents, and in addition, adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, and buffer solutions.

[0091] Typically, the pharmaceutical composition is a tablet or gelatin capsule, and the active ingredient is a) diluents such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine, b) lubricants such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol, and in the case of tablets, further c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired, d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or foaming mixtures, and / or e) Absorbents, colorants, flavors and sweeteners, are included.

[0092] The tablets may be film-coated or enteric-coated according to methods known in the art.

[0093] Compositions suitable for oral administration include tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or the compounds of the present disclosure in the form of syrups or elixirs. Compositions for oral use are prepared by any method known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binding agents such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be utilized. Preparations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0094] The parenteral composition (e.g., intravenous (IV) formulation) is an aqueous isotonic solution or suspension. The parenteral composition may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting agents, or emulsifying agents, solubilizing agents, salts and / or buffers for adjusting osmotic pressure. Further, they may also contain other therapeutically valuable substances. The compositions are generally prepared by conventional mixing, granulating, or coating methods respectively, and contain from about 0.1 to 75% of the active ingredient or contain from about 1 to 50% of the active ingredient.

[0095] The compounds or pharmaceutical compositions of the present disclosure for use in a subject (e.g., a human) are usually administered orally or parenterally at a therapeutic dose. When administered intravenously by infusion, the dosage may depend on the infusion rate at which the IV formulation is administered. Generally, the therapeutically effective dosage of the compound, pharmaceutical composition, or a combination thereof depends on the species, body weight, age and individual condition of the subject, the disorder or disease being treated, or the severity thereof. A physician, pharmacist, clinician or veterinarian who is skilled in the art can readily determine the respective effective amount of the active ingredient necessary to prevent, treat or inhibit the progression of the disorder or disease.

[0096] The above administration characteristics can be advantageously demonstrated in in vitro and in vivo tests 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 a solution, e.g., an aqueous solution, and in vivo either enterically, parenterally, preferably intravenously, e.g., in a suspension or an aqueous solution. The dosage in vitro can be in the range of about 10−3 molar concentration to 10−9 molar concentration.

[0097] Definitions As used herein, the terms "patient", "subject", or "individual" are used interchangeably and refer to either a human or a non-human animal. This term includes mammals such as humans. Typically, the animal is a mammal. The subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

[0098] As used herein, the terms "inhibit", "inhibition", or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder or disease, or a significant decrease in the baseline activity of a biological activity or biological process.

[0099] As used herein, the terms "treat", "treating", or "treatment" with respect to any disease, condition, or disorder refer to the management and care of a patient for the purpose of combating the disease, condition, or disorder and include the administration of a compound of the invention to obtain the desired pharmacological and / or physiological effect. The effect can be therapeutic and includes partially or substantially achieving one or more of the following results: partially or completely reducing the degree of the disease, condition, or disorder; remitting or improving the clinical symptoms, complications, or indicators associated with the disease, condition, or disorder; or delaying, inhibiting, or reducing the likelihood of progression of the disease, disorder, or disorder. Or, eliminating the disease, disorder, or disorder. In certain embodiments, the effect can be to prevent the onset of symptoms or complications of the disease, condition, or disorder.

[0100] As used herein, the term "cancer" has the meaning commonly accepted in the art. Broadly, this term can refer to abnormal cell growth.

[0101] As used herein, the term "autoimmune disease" has the meaning commonly accepted in the art. Broadly, this term can refer to a disease in which the host's immune system targets or attacks the host's normal or healthy tissue.

[0102] As used herein, the term "myelination" has the meaning commonly accepted in the art. Broadly, this term can mean the process by which myelin is produced.

[0103] As used herein, the terms "myelin-related disease or disorder", "demyelinating disease" or "demyelinating disorder" have the meaning commonly accepted in the art. Broadly, these terms can refer to a disease or disorder associated with myelin damage.

[0104] As used herein, a subject (preferably a human) "requires" a treatment if the subject would benefit biologically, medically, or in terms of quality of life from such treatment.

[0105] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" refers to the replacement of a hydrogen radical in a given structure with a radical of a designated substituent. Specific substituents are described in the definitions as well as in the description of the compounds and their examples. Unless otherwise specified, an optionally substituted group may have substituents at each substitutable position of the group, and where two or more positions in any given structure may be substituted with two or more substituents selected from the designated groups, the substituents may be the same or different at all positions. In some embodiments, an optionally substituted group may be substituted with one or more substituents, each of which may be the same or different. In some embodiments, the "one or more" substituents may be 1, 2, 3, 4, 5, 6, etc. substituents, each of which may be the same or different. In some embodiments, the "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.

[0106] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. The term "C 1~4 alkyl" refers to an alkyl having 1 to 4 carbon atoms. The terms "C 1~3 alkyl" and "C 1~2 alkyl" should be interpreted accordingly. Representative examples of "C 1~4 alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl portion (i.e., moiety) of an alkoxy has the same definition as above. When indicated as "optionally substituted", the alkane radical or alkyl portion may be unsubstituted or may be substituted with one or more substituents (generally 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0107] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety bonded through an oxygen bridge (i.e., -O-C 1~4 alkyl group, where C 1~4 alkyl is as described herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, etc. Preferably, the alkoxy group has from about 1 to 4 carbons, more preferably 1 to 2 carbons. The term "C 1~2 alkoxy" should be construed accordingly.

[0108] As used herein, the term "C 1~4 alkoxyC 1~4 alkyl" refers to a C 1~4 alkyl group as defined herein, wherein at least one hydrogen atom is replaced by C 1~4 alkoxy. The C 1~4 alkoxyC 1~4 alkyl group is linked to the remainder of the molecule described herein through the alkyl group.

[0109] The number of carbon atoms in the group is denoted 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.

[0110] "Halogen" or "halo" can be fluorine, chlorine, bromine, or iodine.

[0111] As used herein, the term "halo-substituted-C 1~4 alkyl" or "C 1~4 haloalkyl" refers to a C 1~4 alkyl group as described herein, wherein at least one hydrogen atom is replaced by a halo atom. The C 1~4 haloalkyl group is mono-halo-C 1~4Alkyl, dihalo-C 1~4 Alkyl, or perhalo-C 1~4 Polyhalo-C containing alkyl 1~4 Can be alkyl. Monohalo-C 1~4 Alkyl can have one iodine, bromo, chloro or fluoro within the alkyl group. Dihalo-C 1~4 Alkyl and polyhalo-C 1~4 The alkyl group can have two or more of the same halo atoms or a combination of different halo groups within the alkyl group. Typically, polyhalo-C 1~4 The alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. C 1~4 Non-limiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Perhalo-C 1~4 An alkyl group refers to a C 1~4 alkyl group in which all hydrogen atoms are replaced by halo atoms.

[0112] The term "aryl" refers to an aromatic carbocyclic monocyclic or two-fused ring system containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0113] The term "heteroaryl" refers to a 5- to 12-membered aromatic radical having 1 to 4 heteroatoms selected from N, O, and S. Optionally, a nitrogen atom in the heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". A heteroaryl group may be monocyclic or bicyclic. Examples of monocyclic heteroaryls include, for example, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, furanyl, oxadiazolyl, thiophenyl, and the like. Bicyclic heteroaryls include groups in which one or more monocyclic heteroaryl rings are fused to one or more aryl or heteroaryl rings. Non-limiting examples include pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, imidazopyridinyl, and indolyl.

[0114] The term "carbocycle" or "carboscyclic" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring and may exist as a monocyclic, bicyclic (including fused, spiro or bridged carbocycles) or spiro ring. Examples of bicyclic carbocyclic groups include, for example, an unsaturated carbocyclic radical fused to another unsaturated carbocyclic radical, cycloalkyl, or aryl, such as 2,3-dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless otherwise specified, carbocycles generally contain 4 to 10 ring members.

[0115] "C 3~6 ycloalkyl" refers to a completely saturated carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0116] The term "heterocyclic ring" or "heterocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclyl group can be monocyclic or bicyclic (e.g., bridged, fused, or spirobicyclic rings). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperidinyl. Examples of bicyclic heterocyclyl groups include, for example, those in which an unsaturated heterocyclic radical is fused to another unsaturated heterocyclic radical, a cycloalkyl, aryl, or heteroaryl ring, such as tetrahydro-3H-[1,2,3]triazolo[4,5-c]pyridinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-oxabicyclo[2.1.1]hexanyl, and 9-azabicyclo[3.3.1]nonanyl. In some embodiments, the heterocyclyl group is a 4- 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.

[0117] As used herein, the term "spiro" ring means a bicyclic system in which both rings share a common atom. Examples of spiro rings include 2-oxa-6-azaspiro[3.3]heptanyl and the like.

[0118] The term "fused" ring refers to a two-ring system that shares two adjacent ring atoms. The fused heterocyclic ring contains ring atoms that are heteroatoms selected from O, N, and S in at least one of the ring systems (e.g., 3-oxabicyclo[3.1.0]hexane).

[0119] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety that is linked by two non-adjacent ring atoms (e.g., 5-oxabicyclo[2.1.1]hexane).

[0120] The term "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other components that make up the formulation and / or the mammalian subject being treated thereby.

[0121] Unless otherwise specified, the term "compounds 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 moieties capable of forming salts are present, salts, particularly pharmaceutically acceptable salts, are likewise included.

[0122] 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 following claims) are to be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is merely intended to better clarify the invention and does not impose a limitation on the scope of the invention unless otherwise claimed.

[0123] It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions by the movement of protons, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety where a proton can move between two ring nitrogens. Valence tautomers include interconversions by some rearrangement of bonding electrons.

[0124] In one embodiment, the present disclosure relates to the free form of the compounds of formula (I) as defined herein. In another embodiment, the present disclosure relates to the salt form of the compounds of formula (I) as defined herein. In another embodiment, the present disclosure relates to the acid addition salt form of the compounds of formula (I) as defined herein. In a further embodiment, the present disclosure relates to the pharmaceutically acceptable salt form of the compounds of formula (I) as defined herein. In yet another further embodiment, the present disclosure relates to the pharmaceutically acceptable acid addition salt form of the compounds of formula (I) as defined herein. In yet another further embodiment, the present disclosure relates to any one of the compounds of the examples in free form. In yet another further embodiment, the present disclosure relates to any one of the compounds of the examples in salt form. In yet another further embodiment, the present disclosure relates to any one of the compounds of the examples in acid addition salt form. In yet another further embodiment, the present disclosure relates to any one of the compounds of the examples in pharmaceutically acceptable salt form. In still another embodiment, the present disclosure relates to any one of the compounds of the examples in pharmaceutically acceptable acid addition salt form.

[0125] The compounds of the present disclosure can be synthesized by synthetic routes including processes similar to those well-known in the chemical art, particularly in view of the descriptions included herein. The starting materials are generally available from commercial suppliers such as Sigma-Aldrich or can be readily prepared using methods known to those skilled in the art (e.g., generally, by the methods described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin (also available via the Beilstein online database) including appendices).

[0126] For illustrative purposes, the reaction schemes shown below provide potential routes for synthesizing the compounds and key intermediates of the present disclosure. For a more detailed description of the individual reaction steps, refer to the Examples section below. Specific starting materials and reagents are illustrated in the schemes and discussed below, but other starting materials and reagents can be readily replaced to provide various derivatives and / or reaction conditions.

Examples

[0127] Abbreviations: PE = petroleum ether EtOAc = EA = ethyl acetate ESI = electrospray ionization MeOH = methanol EtOH = ethanol DCE = 1,2-dichloroethane DCM = dichloromethane CHCl3 = chloroform HCl = hydrochloric acid H2O = water IPA = isopropyl alcohol LC-MS = liquid chromatography mass spectrometry HFIP = hexafluoro-2-propanol HPLC = high performance liquid chromatography THF = tetrahydrofuran MeCN = ACN = acetonitrile MgSO4 = magnesium sulfate DMSO = dimethyl sulfoxide AcOH = acetic acid TFA = trifluoroacetic acid DIPEA = diisopropylethylamine; N2 = nitrogen NH4HCO3 = ammonium bicarbonate t-BuOH = tert-butanol NH4Cl = ammonium chloride NaH = sodium hydride Na2SO4: means sodium sulfate; K2CO3 = potassium carbonate NaHCO3 = Sodium hydrogen carbonate NaBH(OAc)3 = STAB = Sodium triacetoxyborohydride SiO2 = Silicon dioxide or silica PDA = Photodiode array detection TosMIC = Tosylmethyl isocyanide TLC = Thin layer chromatography LiHMDS = Lithium bis(trimethylsilyl)amide

[0128] General method Specifications of LCMS instrument: · Agilent Technologies 1200 series LC / MSD system: DAD￥ELSD Alltech 3300 and Agilent LC￥MSD G6130A, G6120B mass spectrometers. · Agilent Technologies 1260 Infinity LC / MSD system: DAD￥ELSD Alltech 3300 and Agilent LC￥MSD G6120B mass spectrometers. · Agilent Technologies 1260 Infinity II LC / MSD system: DAD￥ELSD G7102A 1290 Infinity II and Agilent LC￥MSD G6120B mass spectrometers. · Agilent 1260 series LC / MSD system: DAD￥ELSD and Agilent LC￥MSD (G6120B) mass spectrometers. · UHPLC Agilent 1290 series LC / MSD system: DAD￥ELSD and Agilent LC￥MSD (G6125B) mass spectrometers.

[0129] Specifications of HPLC analysis method: · Column: UHPLC guard Infinity Lab Poroshell 120 SB-C18, 4.6×5mm, 2.7μm and Agilent Poroshell 120 SB-C18, 4.6×30mm, 2.7μm · Column temperature: 60 °C · Injection volume: 0.5 μL · Modifier: 0.1% (v / v) formic acid · Method: 99% water / 1% MeCN (initial condition), hold for 0.1 min at initial condition, linear gradient to 0% water / 100% MeCN in 1.5 min, hold at 0% water / 100% MeCN until 1.73 min, linear gradient to 99% water / 1% MeCN at 1.74 min. Flow rate: 3.0 mL / min. · UV scanning: 207 - 223 nm, 246 - 262 nm, 272 - 288 nm

[0130] QC analysis LC / MS method conditions: Ammonium hydroxide (basic pH) conditions MS mode: MS: ESI+ scan range 165 - 650 Dalton PDA: 200 - 400 nm scan range Column: Waters ACQUITY UPLC BEH C18, 2.1×50 mm, 1.7 μm, part number 186002350 Modifier: 0.2% (v / v) concentrated ammonium hydroxide Method: Linear gradient from 95% water / 5% MeCN (initial condition) to 5% water / 95% MeCN in 3.75 min Hold 5% water / 95% MeCN for 4 min. Flow rate: 0.8 mL / min.

[0131] Trifluoroacetic acid (acidic pH) conditions MS mode: MS: ESI+ scan range 165 - 650 Dalton PDA: 200 - 400 nm scan range Column: Waters ACQUITY UPLC BEH C18, 2.1×50 mm, 1.7 μm, part number 186002350 Modifier: 0.1% (v / v) concentrated trifluoroacetic acid Method: Linear gradient from 95% water / 5% MeCN (initial condition) to 5% water / 95% MeCN in 3.75 min Hold 5% water / 95% MeCN from 3.75 min to 4 min. Flow rate: 0.8 mL / min.

[0132] General preparative HPLC conditions: Ammonium hydroxide (basic pH) conditions Flow rate: 30 mL / min MS mode: MS: ESI+ Scan range 165 - 650 daltons PDA: 200 - 400 nm scan range Column: Waters XSELECT CSH C18 PREP, 19×100 mm, 5 μm, part number 186005421 Modifier: Concentrated ammonium hydroxide 0.2% (v / v) Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN in 8 minutes, rising to 5% water / 95% MeCN in 8.5 minutes and holding at 5% water / 95% MeCN for up to 10 minutes.

[0133] Flow rate: 50 mL / min MS mode: MS: ESI+ Scan range 165 - 650 daltons PDA: 200 - 400 nm scan range Column: Waters XSELECT CSH C18 PREP, 30×100 mm, 5 μm, part number 186005425 Modifier: 0.2% concentrated NH4OH (v / v) Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN in 8 minutes, rising to 5% water / 95% MeCN in 8.5 minutes and holding at 5% water / 95% MeCN for up to 10 minutes.

[0134] Flow rate: 60 mL / min MS mode: MS: ESI+ Scan range 165 - 650 daltons PDA: 200 - 400 nm scan range Column: Waters XSELECT CSH C18 PREP, 30×50 mm, 5 μm, part number 186005423 Modifier: 0.2% concentrated NH4OH (v / v) Method: Linear gradient from A% water / B% MeCN (initial conditions) to A% water / B% MeCN in 8 minutes, rising to 5% water / 95% MeCN in 8.5 minutes and holding at 5% water / 95% MeCN for up to 10 minutes.

[0135] Trifluoroacetic acid (acidic pH) conditions Flow rate: 30 mL / min MS mode: MS: ESI+ Scanning range 165 - 650 daltons PDA: Scanning range 200 - 400 nm Column: Waters Sunfire OBD C18, PREP, 19×100 mm, 5 μm, Part number 186002567 Adjusting agent: 0.1% concentrated trifluoroacetic acid (v / v) Method: Linear gradient from A% water / B% MeCN (initial condition) to A% water / B% MeCN in 8 minutes, rising to 5% water / 95% MeCN in 8.5 minutes, and holding at 5% water / 95% MeCN for up to 10 minutes.

[0136] Flow rate: 50 mL / min MS mode: MS: ESI+ Scanning range 165 - 650 daltons PDA: Scanning range 200 - 400 nm Column: Waters Sunfire OBD C18, PREP, 30×100 mm, 5 μm, Part number 186002572 Adjusting agent: 0.1% concentrated trifluoroacetic acid (v / v) Method: Linear gradient from A% water / B% MeCN (initial condition) to A% water / B% MeCN in 8 minutes, rising to 5% water / 95% MeCN in 8.5 minutes, and holding at 5% water / 95% MeCN for up to 10 minutes.

[0137] Flow rate: 60 mL / min MS mode: MS: ESI+ Scanning range 165 - 650 daltons PDA: Scanning range 200 - 400 nm Column: Waters Sunfire OBD C18, PREP, 30×50 mm, 5 μm, Part number 186002570 Adjusting agent: 0.1% concentrated trifluoroacetic acid (v / v) Method: Linear gradient from A% water / B% MeCN (initial condition) to A% water / B% MeCN in 8 minutes, rising to 5% water / 95% MeCN in 8.5 minutes, and holding at 5% water / 95% MeCN for up to 10 minutes.

[0138] Experimental procedure Example 1 6-(2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane

Chemical formula

Chemical formula

[0139] 2. Synthesis of 3-bromo-6-(1,1-difluoroethyl)-2-methylpyridine

Chemical formula

[0140] 3. Synthesis of 3-(benzylthio)-6-(1,1-difluoroethyl)-2-methylpyridine

Chemical formula

[0141] 4. Synthesis of 6-(1,1-difluoroethyl)-2-methylpyridine-3-sulfonyl chloride

Chemical formula

[0142] 5. Synthesis of 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one

Chemical formula

[0143] 6.6-(2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane Synthesis

Chem.

[0144] Example 2 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine

Chem.

[0145] Example 3 2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine

Chemical formula

[0146] 2.2-Synthesis of 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine [Chemistry] 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)3 (170 mg, 0.8 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 3 days. The reaction was quenched with saturated NaHCO3, stirred at room temperature for 5 minutes, and further DCM and water were added and the mixture was stirred for a further 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 - 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]heptan-6-amine (61 mg, 73%) as a white solid. LCMS m / z = 420.2 [M+H] + .1H NMR (400 MHz, MeOH-d4): δ (ppm) 8.47 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 4.01 (s, 2H), 3.95 (dd J = 11.0, 4.0 Hz, 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, 4.5 Hz, 2H)

[0147] Example 4 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane

Chemical Structure

[0148] Example 5 4-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)morpholine

Chem.

[0149] Example 6 6-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-6-azaspiro[3.3]heptane

Chemical Structure

[0150] Example 7 2 - ((2 - Methyl - 6 - (trifluoromethyl)pyridin - 3 - yl)sulfonyl)-N-(1 - (tetrahydro - 2H - pyran - 4 - yl)cyclopropyl)-2 - azaspiro[3.3]heptan - 6 - amine [Chemical Structure] Following the procedure described in Example 4, 2 - ((2 - Methyl - 6 - (trifluoromethyl)pyridin - 3 - yl)sulfonyl)-N-(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 1H NMR (400 MHz, MeOH - d4): δ ppm 8.38 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.0 Hz, 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).

[0151] Example 8 2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine

Chem.

[0152] Example 9 2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]heptan-6-amine

Chem.

[0153] Example 10 4-(2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)morpholine

Chemical Structure

Chem.

[0154] Synthesis of 4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)morpholine

Chem.

[0155] Example 11 2 - ((1 - Methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 5 - yl)sulfonyl) - N - (oxetan - 3 - ylmethyl) - 2 - azaspiro[3.3]heptan - 6 - amine

Chemical formula

[0156] Example 12 2 - ((1 - Methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 5 - yl)sulfonyl) - N - ((3 - methyloxetan - 3 - yl)methyl) - 2 - azaspiro[3.3]heptan - 6 - amine

Chemical formula

[0157] Example 13 2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine

Chemical Structure

[0158] Example 14 6-(2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.5]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane

Chemical Structure

[0159] Example 15 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-6-azaspiro[3.3]heptane

Chemical formula

[0160] Example 16 6-(2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-6-azaspiro[3.3]heptane

Chemical formula

Chemical formula

[0161] 2. Synthesis of 4-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride [Chemical formula] To a solution of 5-(benzylthio)-4-methyl-2-(trifluoromethyl)pyrimidine (550 mg, 1.9 mmol) in DCM (5 mL) and water (1 mL), a solution of SO2Cl2 (1.10 mL, 13.6 mmol) in DCM (1 mL) was added dropwise at a temperature below 5 °C over 5 minutes, and then the reaction mixture was stirred at a temperature below 5 °C for 15 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 4). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 4-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride (350 mg, crude) as a yellowish oil. 1 H NMR (400 MHz, CDCl3) δ ppm 9.36 (s, 1H), 3.10 (s, 3H).

[0162] Synthesis of 3.2-((4-methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one [Chemical formula] Following the procedure described in Step 4 of Example 1, 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one was obtained as a yellow solid (1.0 g, 34%) 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 (500 MHz, CDCl3): δ ppm 9.21 (s, 1H), 4.25 (s, 4H), 3.36 (s, 4H), 2.93 (s, 3H).

[0163] Synthesis of 4.6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-6-azaspiro[3.3]heptane [Chemistry] A solution of 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-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 the addition of AcOH, and the reaction mixture was stirred at 20 °C for 0.5 h. NaBH3CN (39 mg, 0.6 mmol) was added, and the reaction mixture was stirred at 20 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex C18 150*40mm*5um, conditions: water (NH4HCO3)-MeCN, 23% - 53%, flow rate (mL / min): 60) to give 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-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 (400 MHz, CDCl3): δ ppm 9.17 (s, 1H), 4.50 (t, J = 7.6 Hz, 2H), 3.98 (s, 2H), 3.95 (s, 2H), 3.51 - 3.49 (m, 2H), 3.08 - 3.06 (m, 2H), 2.96 - 2.93 (m, 1H), 2.90 (s, 3H), 2.83 (t, J = 7.6 Hz, 2H), 2.26 - 2.21 (m, 2H), 1.98 - 1.93 (m, 2H).

[0164] Example 17 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane [Chemistry] According to the procedure described in Step 4 of Example 1, 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane was obtained as a white solid (27 mg, 31%) from 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (Example 16, Step 3) and 2-oxa-6-azaspiro[3.3]heptane oxalate. LCMS m / z = 419.1 [M+H] + . 1 H NMR(400MHz,CDCl3):δppm9.17(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).

[0165] Example 18 2-Methyl-N-(2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

Chemical formula

Chemical formula

[0166] Synthesis of 2-methyl-N-(2-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

Chemical Structure

[0167] 3.2 Synthesis of 2-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide

Chemical Structure

[0168] Example 19 4-(2-((3-Isopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)morpholine

Chemical Structure

[0169] Example 20 2-((4-(Difluoromethoxy)phenyl)sulfonyl)-6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane

Chemical formula

Chemical formula

[0170] 2. Synthesis of 6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane

Chemical formula

[0171] 3. Synthesis of 2-((4-(difluoromethoxy)phenyl)sulfonyl)-6-(4-methylpiperidin-1-yl)-2-azaspiro[3.3]heptane

Chemical formula

[0172] Example 21 2-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine

Chemical Structure

Chemical Structure

[0173] Synthesis of 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-one

Chemical Structure

[0174] Synthesis of 3.2 - ((2 - methoxy - 5 - methylpyridin - 3 - yl)sulfonyl)-N-(tetrahydro - 2H - pyran - 4 - yl)-5 - oxa - 2 - azaspiro[3.4]octan - 7 - amine

Chemical Structure

[0175] Example 22 2 - ((2 - Methoxy - 5 - methylpyridin - 3 - yl)sulfonyl)-7-(2 - oxa - 6 - azaspiro[3.3]heptan - 6 - yl)-5 - oxa - 2 - azaspiro[3.4]octane

Chemical Structure

[0176] Example 23 2-((2-Methoxy-5-methylpyridin-3-yl)sulfonyl)-7-(3-methoxyazetidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

Chem.

[0177] Example 24 N-(4,4-Difluorocyclohexyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octane-7-amine

Chem.

[0178] Example 25 N-(3,3-difluorocyclobutyl)-2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-5-oxa-2-azaspiro[3.4]octan-7-amine

Chemical Structure

[0179] Example 26 3-((7-((4,4-Difluorocyclohexyl)amino)-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)-4-fluorobenzonitrile

Chemical formula

Chemical formula

[0180] 2. Synthesis of 3-((7-((4,4-difluorocyclohexyl)amino)-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)-4-fluorobenzonitrile

Chemical Structure

[0181] Example 27 4-Fluoro-3-((7-((tetrahydro-2H-pyran-4-yl)amino)-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile

Chemical Structure

[0182] Example 28 3-((7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)-5-fluorobenzonitrile

Chemical formula

Chemical formula

[0183] Synthesis of 2.3 - ((7 - (2 - oxa - 6 - azaspiro[3.3]heptan - 6 - yl) - 5 - oxa - 2 - azaspiro[3.4]octan - 2 - yl)sulfonyl) - 5 - fluorobenzonitrile [Chemical Structure] 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), AcOH (20 μL, 0.4 mmol) was added followed by 2 - oxa - 6 - azaspiro[3.3]heptane (58 mg, 0.6 mmol) dropwise at 23 °C. After 15 minutes, NaBH(OAc)3 (223 mg, 1.1 mmol) was added portionwise and the reaction was stirred at 23 °C for 1 hour. The reaction was quenched by slowly adding 1 M aqueous NaOH and the mixture was stirred at 23 °C for 1 hour, then the biphasic mixture was extracted with DCM (3×). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (50 - 100% 3:1 EtOAc:EtOH in heptane) to afford 3 - ((7 - (2 - oxa - 6 - azaspiro[3.3]heptan - 6 - yl) - 5 - oxa - 2 - azaspiro[3.4]octan - 2 - yl)sulfonyl) - 5 - fluorobenzonitrile as a colorless film (25 mg, 22%). LCMS m / z = 394.2 [M + H] + . 11H NMR (500 MHz, DMSO-d6): δ ppm 8.34 (broad d, J = 8.5 Hz, 1H), 8.22 (s, 1H), 8.13 - 8.10 (m, 1H), 4.56 (s, 4H), 3.89 (d, J = 9.5 Hz, 1H), 3.82 (d, J = 9.2 Hz, 1H), 3.76 (d, J = 9.5 Hz, 1H), 3.65 (d, J = 9.5 Hz, 1H), 3.50 (dd, J = 9.0, 4.4 Hz, 1H), 3.39 - 3.36 (m, 1H), 3.31 - 3.29 (m, 1H), 3.21 - 3.15 (m, 4H), 2.80 (broad s, 1H), 1.81 - 1.77 (m, 1H).

[0184] Example 29 4-(2-((3,5-Dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

Chemical Structure

[0185] 2. Synthesis of 2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one

Chemical Structure

[0186] 3.4-Synthesis of (2-((3,5-dimethylpyridin-2-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0187] Example 30 6-(2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)-2-oxa-6-azaspiro[3.3]heptane [Chemistry] Synthesis of 1,2 - Azaspiro[3.4]octan - 6 - one [Chemistry] 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 mixture was warmed to 23 °C and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was triturated with EtOAc, and a few drops of MeOH were added to obtain 2 - azaspiro[3.4]octan - 6 - one as an off - white solid as its HCl salt (721 mg, 97%), which was used without purification. 1 H NMR (500 MHz, DMSO - d6): δ ppm 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).

[0188] Synthesis of 2 - ((6 - methoxy - 2 - methylpyridin - 3 - yl)sulfonyl)-2 - azaspiro[3.4]octan - 6 - one [Chemistry] To a solution of 2-azaspiro[3.4]octan-6-one (333 mg, 2.1 mmol, HCl salt) in anhydrous DCM (10 mL) was added DIPEA (1.5 mL, 8.6 mmol) dropwise at < 5 °C and the solution was stirred for 5 min. 6-Methoxy-2-methyl-pyridine-3-sulfonyl chloride (577.1 mg, 2.60 mmol) was added and the reaction was warmed to 23 °C and stirred for 30 min. 1 M aqueous NaOH was added slowly to quench the reaction mixture. The mixture was stirred at 23 °C for 10 min and then the biphasic mixture was loaded onto a silica gel column and purified with (10 - 55% EtOAc in heptane) to give 2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-one as a white solid (190 mg, 30% yield) which was used without further purification. LCMS m / z = 311.1 [M+H] + .

[0189] 3.6 - (2 - ((6 - Methoxy - 2 - methylpyridin - 3 - yl)sulfonyl)-2 - azaspiro[3.4]octan - 6 - yl)-2 - oxa - 6 - azaspiro[3.3]heptane synthesis

Chemical Structure

[0190] Example 31 N-(4,4-Difluorocyclohexyl)-2-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine

Chemical formula

[0191] Example 32 2 - ((6 - Methoxy - 2 - methylpyridin - 3 - yl)sulfonyl)-N-(2 - methoxyethyl)-N - methyl - 2 - azaspiro[3.4]octane - 6 - amine [Chemical Structure] Following the procedure described in Example 31, 2 - ((6 - methoxy - 2 - methylpyridin - 3 - yl)sulfonyl)-N-(2 - methoxyethyl)-N - methyl - 2 - azaspiro[3.4]octane - 6 - amine was obtained as an orange oil (75 mg, 41%) from 2 - ((6 - methoxy - 2 - methylpyridin - 3 - yl)sulfonyl)-2 - azaspiro[3.4]octane - 6 - one (Example 30, Step 2) and 2 - methoxy - N - methylethanamine. LCMS m / z = 384.0 [M + H] + 1 1H NMR (500 MHz, DMSO-d6): δ ppm 8.03 (d, J = 9.2 Hz, 1H), 6.85 (d, J = 8.5 Hz, 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).

[0192] Example 33 N-(2-Methoxyethyl)-N-methyl-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-amine

Chem.

Chem.

[0193] 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

Chem.

[0194] Example 34 4-(2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical formula

Chemical formula

[0195] Synthesis of 2.4-(2-((3-methoxy-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0196] Example 35 4-(2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

Chemical Structure

[0197] 2. Synthesis of 2.4-(2-azaspiro[3.4]octan-6-yl)morpholine

Chemical formula

[0198] 3. Synthesis of 3.4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical formula

[0199] Example 36 4-(2-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0200] Example 37 4-(2-((4-Chloro-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0201] Example 38 4-(2-((4-(difluoromethyl)-1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0202] Example 39 4-(2-((6-Methoxy-2-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0203] Example 40 4-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chem.

[0204] Example 41 4-(2-((4-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chem.

[0205] Example 42 4-(2-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical formula

[0206] Example 43 4-(2-(mesitylsulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine [ka] Synthesis of 1,4-(2-azaspiro[3.4]octan-6-yl)morpholine [ka] A solution of tert-butyl 6-morpholin-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 ice water, and then TFA (840 μL, 11.0 mmol) was added dropwise. Upon complete addition, the reaction was warmed 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 the TFA salt) as a colorless film, which was used without purification. LCMS m / z=197.1 [M+H] + .

[0207] Synthesis of 2,4-(2-(mesitylsulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine [ka] To a solution of 4-(2-azaspiro[3.4]octan-6-yl)morpholine (144 mg, 0.5 mmol, TFA salt) in anhydrous THF (1.5 mL) was added dropwise DIPEA (0.5 mL, 2.9 mmol), and DMAP (6 mg, 0.1 mmol) was added below 5 °C. After 5 minutes, 2,4,6-trimethylbenzenesulfonyl chloride (153 mg, 0.7 mmol) was added to the cooled heterogeneous solution, and the reaction was warmed to 23 °C and stirred for 30 minutes. The reaction was quenched by slowly adding 1 M aqueous NaOH, the mixture was stirred at 23 °C for 10 minutes, and then the biphasic mixture was extracted with EtOAc (3×). The combined organics were washed with saturated aqueous NaHCO3 (2×) 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 (5 - 55% of 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 (500 MHz, DMSO-d6): δ ppm 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, 6.7 Hz, 1H), 1.84 - 1.78 (m, 1H), 1.77 - 1.68 (m, 2H), 1.56 (dd, J = 12.8, 9.2 Hz, 1H), 1.42 - 1.33 (m, 1H).

[0208] Example 44 4-(2-((4-(Difluoromethoxy)phenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0209] Example 45 4-(2-((2,4-Dimethylphenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0210] Example 46 4-(2-((2,4-Difluorophenyl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0211] Example 47 4-(2-((4,6-Dimethylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical formula

[0212] Example 48 4-(2-((6-Methoxy-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical formula

[0213] Example 49 (R)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical formula

Chemical formula

[0214] 2. Synthesis of (R)-4-(2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0215] 3. Synthesis of (R)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0216] Example 50 (R)-3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile

Chemical Structure

[0217] Example 51 (S)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine

Chemical formula

Chemical formula

[0218] 2. Synthesis of tert-butyl (S)-6-morpholino-2-azaspiro[3.4]octane-2-carboxylate

Chemical Structure

[0219] 3. Synthesis of (S)-4-(2-azaspiro[3.4]octan-6-yl)morpholine

Chemical Structure

[0220] 4. Synthesis of (S)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine [Chem.] Following the same procedure as described in Step 3 of Example 49, (S)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine was obtained as a colorless film (12 mg, 6%) 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 H NMR (500 MHz, DCM-d2): δ ppm 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, 7.3 Hz, 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).

[0221] Example 52 (S)-3-Fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile [Chem.] Following the same procedure as described in Step 3 of Example 49, (S)-3-fluoro-5-((6-morpholino-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile was obtained as a colorless film (14 mg, 11%) from (S)-4-(2-azaspiro[3.4]octan-6-yl)morpholine (Example 51, Step 3) and 3-cyano-5-fluoro-benzenesulfonyl chloride, provided that the product was not further purified by HPLC. LCMS m / z = 380.2 [M+H] + . 11H NMR (500 MHz, DMSO-d6): δ ppm 8.33 (br d, J = 8.5 Hz, 1H), 8.16 (s, 1H), 8.05 (br d, J = 7.9 Hz, 1H), 3.71 - 3.68 (m, 2H), 3.67 - 3.62 (m, 2H), 3.51 (t, J = 4.4 Hz, 4H), 2.41 - 2.34 (m, 1H), 2.32 - 2.18 (m, 4H), 1.74 (dd, J = 13.0, 7.2 Hz, 1H), 1.69 - 1.59 (m, 2H), 1.54 - 1.48 (m, 1H), 1.40 (dd, J = 13.0, 8.7 Hz, 1H), 1.34 - 1.27 (m, 1H).

[0222] Example 53 2-(Mesitylsulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane [Chemical formula] 1. Synthesis of tert-butyl 7-morpholino-5-oxa-2-azaspiro[3.4]octane-2-carboxylate [Chemical formula] A solution of tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (692 mg, 3.05 mmol) in anhydrous DCM (50 mL) was added dropwise with morpholine (0.8 mL, 9.2 mmol) and TEA (480 μL, 3.4 mmol) at 23 °C. After 15 minutes, AcOH (440 μL, 7.3 mmol) was added dropwise to the reaction mixture to adjust the pH to about 5 - 6. Upon completion of the addition, the reaction was stirred at 23 °C for 30 minutes, and then NaBH(OAc)3 (5.33 g, 25.2 mmol) was added portionwise. The reaction was stirred at 23 °C for 19 hours (additional anhydrous DCM (50 mL) was added to the thick white paste to assist stirring), and then quenched by slowly adding saturated aqueous ammonium chloride solution. The mixture was stirred at 23 °C for 15 minutes, and then the biphasic mixture was extracted with DCM (3×). The combined organic extracts were washed with brine (2×) and then dried over anhydrous magnesium sulfate. The mixture was filtered and evaporated under reduced pressure to obtain tert-butyl (7S)-7-morpholino-5-oxa-2-azaspiro[3.4]octane-2-carboxylate, which was used without purification. LCMS m / z = 299.1 [M+H] + .

[0223] Synthesis of 2.7-Morpholino-5-oxa-2-azaspiro[3.4]octane

Chemical Structure

[0224] Synthesis of 3.2-(Mesitylsulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane [Chemical formula] To a solution of 7-morpholino-5-oxa-2-azaspiro[3.4]octane (143 mg, 0.5 mmol, TFA salt) in anhydrous THF (1.5 mL), DIPEA (460 μL, 2.6 mmol) was added dropwise, and DMAP (6 mg, 0.1 mmol) was added below 5 °C. After 5 minutes, 2,4,6-trimethylbenzenesulfonyl chloride (147 mg, 0.7 mmol) was added to the cooled heterogeneous solution, and the reaction mixture was warmed to 23 °C and stirred for 30 minutes. The reaction was quenched by slowly adding 1 M aqueous NaOH solution, the mixture was stirred at 23 °C for 10 minutes, and then the biphasic mixture was extracted with EtOAc (3×). The combined organic layers were washed with saturated aqueous NaHCO3 solution (2×), 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 (10 - 70% of 3:1 EtOAc:EtOH in heptane) to obtain 2-(mesitylsulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane as a colorless film (66 mg, 36%). LCMS m / z = 381.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ ppm 7.08 (s, 2H), 3.82 (dd, J = 8.5, 6.7 Hz, 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, 2.4 Hz, 2H), 2.31 - 2.24 (m, 6H), 2.02 - 1.97 (m, 1H).

[0225] Example 54 2-((4-(Difluoromethoxy)phenyl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane [Chemical formula] 1. Synthesis of tert-butyl 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

Chem.

[0226] 2. Synthesis of 7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

Chem.

[0227] 3. Synthesis of 2-((4-(difluoromethoxy)phenyl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

Chem.

[0228] Example 55 2-((1,3-Dimethyl-1H-pyrazol-5-yl)sulfonyl)-7-(4-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]octane

Chemical Structure

[0229] Example 56 2 - ((6 - Methoxy - 2 - methylpyridin - 3 - yl)sulfonyl)-7-(4 - methylpiperidin - 1 - yl)-5 - oxa - 2 - azaspiro[3.4]octane

Chemical Structure

[0230] Example 57 (R)-2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

Chemical Structure

Chemical Structure

[0231] 2. Synthesis of tert-Butyl (R)-7-Morpholino-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

Chemical Structure

[0232] 3. Synthesis of (R)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

Chemical formula

[0233] 4. Synthesis of (R)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

Chemical formula

[0234] Example 58 (R)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-7-morpholino-5-oxa-2-azaspiro[3.4]octane

Chemical formula

[0235] Example 59 3 - ((7 - ((4,4 - Difluorocyclohexyl)(methyl)amino)-5 - oxa - 2 - azaspiro[3.4]octan - 2 - yl)sulfonyl)-4 - fluorobenzonitrile [Chemical Structure] A mixture of 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) n (63 mg, 2.1 mmol) in MeOH (3 mL) was adjusted to pH = 6 using AcOH. NaBH3CN (65.85 mg, 1.05 mmol) was added and the reaction mixture was stirred at 20 °C for 14 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC ((column: Boston Prime C18 150 × 30 mm × 5 μm, conditions: water (NH3 . H2O + NH4HCO3)-MeCN, 45% - 75%, flow rate (mL / min): 25)) to give 3 - ((7 - ((4,4 - Difluorocyclohexyl)(methyl)amino)-5 - oxa - 2 - azaspiro[3.4]octan - 2 - yl)sulfonyl)-4 - fluorobenzonitrile (40 mg, 43%) as a white solid. LCMS m / z = 444.2 [M + H] + . 11H NMR (400 MHz, MeOH-d4): δ ppm 8.24 (dd, J = 6.4, 2.0 Hz, 1H), 8.15 - 8.10 (m, 1H), 7.61 (t, J = 9.6 Hz, 1H), 4.07 - 4.04 (m, 1H), 4.00 - 3.83 (m, 4H), 3.57 (t, J = 8.0 Hz, 1H), 3.41 - 3.34 (m, 1H), 2.59 (t, J = 11.6 Hz, 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).

[0236] Examples 60 and 61 (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

Chemical Structure

[0237] 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 as an off-white solid (13 mg, 24%). LCMS m / z = 420.2 [M+H] + . 11H NMR (500 MHz, DMSO-d6): δ ppm 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, 1H), 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).

[0238] 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 as an off-white solid (14 mg, 27%). LCMS m / z = 420.2 [M+H] + . 1 1H NMR (500 MHz, DMSO-d6): δ ppm 8.45 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 3.79 - 3.73 (m, 3H), 3.72 - 3.69 (m, 1H), 3.52 (t, J = 4.6 Hz, 4H), 2.83 (s, 3H), 2.46 - 2.41 (m, 1H), 2.38 - 2.27 (m, 4H), 1.96 (dd, J = 12.8, 7.3 Hz, 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). The stereochemistry of the isomers was arbitrarily assigned.

[0239] Examples 62 and 63: (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 [Chemistry] 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 30×250 mm, 5 μm column with 30% MeOH in CO2, flow rate: 100 mL / min; ABPR 120 bar; MBPR 40 psi, column temperature 40 °C to obtain the following.

[0240] 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 as an off-white solid (21 mg, 26%). LCMS m / z = 420.2 [M+H] + . 1 H NMR (500 MHz, MeOH-d4): δ ppm 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 = 4.6 Hz, 4H), 2.75 (s, 3H), 2.61 - 2.54 (m, 1H), 2.51 - 2.43 (m, 4H), 2.12 (dd, J = 7.3, 12.8 Hz, 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).

[0241] Peak 2, (S)-4-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine and (R)-4-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.4]octan-6-yl)morpholine as an off-white solid (22 mg, 28%). LCMS m / z = 420.2 [M+H] + 1 H NMR(500MHz,MeOH-d4):δppm9.05(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). The stereochemistry of the isomers was arbitrarily assigned.

[0242] Examples 64 and 65: (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

Chemical formula

[0243] 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 as an off-white solid (51 mg, 28%). LCMS m / z = 386.1 [M+H] + . 1 H NMR(500MHz,MeOH-d4):δppm8.21(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). <l

[0244] 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 as an off-white solid (55 mg, 31%). LCMS m / z = 386.1 [M+H] + . 1 H NMR(500MHz,MeOH-d4):δppm8.21(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). The stereochemistry of the isomers was arbitrarily assigned.

[0245] Examples 66 and 67: (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 [Chemical formula] 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 30×250 mm, 5 μm column with 40% MeOH and 0.1% DEA in CO2, flow rate: 100 mL / min; ABPR 120 bar; MBPR 40 psi; column temperature 40 °C to obtain the following compounds, which were concentrated to dryness and then lyophilized.

[0246] 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 as a yellowish-brown oil (95 mg, 34%). LCMS m / z = 355.2 [M+H] + . 11H NMR (500 MHz, DMSO-d6): δ ppm 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, 7.0 Hz, 1H), 1.75 - 1.68 (m, 2H), 1.64 - 1.57 (m, 1H), 1.48 (dd, J = 13.0, 8.7 Hz, 1H), 1.39 - 1.29 (m, 1H).

[0247] 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 as a yellowish-brown oily substance (68 mg, 24%). LCMS m / z = 355.2 [M + H] + . 1 1H NMR (500 MHz, DMSO-d6): δ ppm 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, 7.0 Hz, 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). The stereochemistry of the isomers was arbitrarily assigned.

[0248] Example 68 6-(2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-6-azaspiro[3.3]heptane

Chemical Structure

[0249] Example 69 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine

Chemical Structure

[0250] Example 70 2 - ((6 - (1,1 - Difluoroethyl) - 2 - methylpyridin - 3 - yl)sulfonyl) - N - (2 - oxaspiro[3.3]heptan - 6 - yl) - 2 - diazaspiro[3.3]heptan - 6 - amine

Chemical Structure

[0251] Example 71 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine

Chemical formula

[0252] Example 72 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

Chemical formula

[0253] Example 73 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine [Chemical formula] According to the procedure described in Example 59, 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine (55 mg, 53%) was obtained from 2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-one (100 mg, 302.7 μmol) and (CH2O) n(70.3 mg, 2.0 mmol). LCMS m / z = 402.1 [M+H] + . 1 HNMR (400 MHz, CDCl3): δ ppm 8.27 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.64 (t, J = 6.4 Hz, 2H), 4.56 (t, J = 6.4 Hz, 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).

[0254] Example 74 2 - ((6 - (1,1 - Difluoroethyl)-2 - methylpyridin - 3 - yl)sulfonyl)-N - methyl - N - (2 - oxaspiro[3.3]heptan - 6 - yl)-2 - diazaspiro[3.3]heptan - 6 - amine

Chemical Structure

[0255] Example 75 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine

Chem.

[0256] Example 76 2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine

Chem.

[0257] Example 77 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine

Chemical Structure

[0258] Example 78 2 - ((4 - Methyl - 2 - (trifluoromethyl)pyrimidin - 5 - yl)sulfonyl)-N-(2 - oxaspiro[3.3]heptan - 6 - yl)-2 - azaspiro[3.3]heptan - 6 - amine

Chemical Structure

[0259] Example 79 2 - ((4 - Methyl - 2 - (trifluoromethyl)pyridin - 5 - yl)sulfonyl)-N-((tetrahydro - 2H - pyran - 4 - yl)methyl)-2 - azaspiro[3.3]heptan - 6 - amine [Chemistry] 2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine (13 mg, 17%) was obtained from 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) according to the procedure described in Step 4 of Example 16. LCMS m / z = 435.1 [M+H] + . 1 HNMR(400MHz,CDCl3): δ ppm 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).

[0260] Example 80 N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine [Chemistry] According to the procedure described in Step 4 of Example 16, 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%) was obtained from 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). LCMS m / z = 435.1 [M+H] + . 1 HNMR(400MHz,CDCl3):δppm9.18(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).

[0261] Example 81 N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine

Chemical formula

[0262] Example 82 N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-2-azaspiro[3.3]heptan-6-amine

Chemical Structure

[0263] Example 83 N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine

Chem.

[0264] Assay EBP Functional Assay The EBP immunoaffinity (IA) LC-MS assay measures the potency of small molecule inhibitors of EBP by quantifying concentration-dependent changes in the 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 the source of the EBP enzyme. The enzyme was incubated with small molecule inhibitors at various concentrations for 30 minutes. Subsequently, deuterated EBP substrate, timosterol-d5 (Avanti Polar Lipids, catalog number 700068P-1mg), was added and the plate was incubated at 37 °C for 4 hours. Finally, the sterol isomers were extracted and injected into the LC-APCI MRM MS. The MRM transitions used for the quantification of timosterol and dihydrolathosterol (substrate and product of the EBP enzyme reaction, respectively) are 372.3-203.2, CE30, and DP80 in positive ion mode. The conversion ratio from timosterol-d5 to dehydro-lathosterol-d5 was used to derive the IC 50 curve. Tacin-1 (1’-[(4-methoxyphenyl)sulfonyl]-4-methyl-1,4’-bipiperidine, CAS 792927-06-1) was used as a reference small molecule inhibitor. [Chemical formula]

[0265] Data on the conversion ratio versus compound concentration were fitted to the following four-parameter logistic model to generate the IC 50 curve: [Mathematical formula]

[0266] Data for the examples [Table 1]

Claims

1. A compound represented by formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein X is O, CH ２ , or a bond, R １ and R ２ are each independently selected from H, C １～６ alkyl, C １～３ haloalkyl, C ３～８ cycloalkyl, Het and -Z-Het, where said C １－６ alkyl, C ３～８ cycloalkyl and Het are each optionally substituted with one or more R ４ with the proviso that at least one of R １ and R ２ is not H, or or R １ and R ２ together with the N atom to which they are attached form a 4- to 7-membered monocyclic heterocycle or a 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more R ４ and Z is one or more Rs ４ Optionally replaced C １－４ is alkyl, Het is a 4- to 6-membered monocyclic heterocyclyl or a 6- to 8-membered bicyclic heterocyclyl, each of which is optionally substituted with R ４ and is optionally substituted with Each R ４ is independently OR ４ａ , halo, C １～３ alkyl, C １～３ haloalkyl, and a 4- to 7-membered monocyclic heterocycle, and is selected from R ４ａ is selected from H, C １～３ alkyl, and C １～３ haloalkyl, and R ３ is phenyl, a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, or a 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 with one or more substituents R ５ and is substituted with Each R ５ is independently selected from C １～３ alkyl, C １～３ haloalkyl, OR ５ａ , cyano, and halo R ５ａ is selected from H, C １～３ alkyl and C ３～６ cycloalkyl, wherein said C １～３ alkyl is optionally substituted with one or more halos, However, R １ and R ２ wherein they, together with the N atom to which they are attached, do not form an unsubstituted pyrrolidine, an unsubstituted piperidine, or 4-methylpiperazine, the compound, or a pharmaceutically acceptable salt thereof.

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

3. R ３ is phenyl, pyridinyl, pyrimidinyl, or pyrazole, each of which is optionally substituted with 1 to 3 R ５ groups, and the compound according to claim 2, or a pharmaceutically acceptable salt thereof.

4. R ３ is given by the following formula: 【Chemical 2】 represented by, each of the above formulas having 1 to 3 Rs ５ The compound according to claim 2, or a pharmaceutically acceptable salt thereof, optionally substituted by

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

6. R １ and R ２ together with the nitrogen atom to which they are attached form the following formula: [Chemical Formula 3] forms a group represented by, each of the above formulas being optionally substituted by one or two R ４ The compound according to claim 5, or a pharmaceutically acceptable salt thereof, which is optionally substituted by

7. R １ is C alkyl optionally substituted by H or one to three R ４ groups １～３ and is R ２ is C １～３ alkyl, C ３～６ cycloalkyl, Het, or -Z-Het, wherein said C １～３ alkyl, C ３～６ cycloalkyl, and Het is a saturated 4- to 6-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from oxygen and nitrogen, at least one of said heteroatoms being oxygen, and said saturated 4- to 6-membered monocyclic heterocycle is optionally substituted with 1 to 3 R ４ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is optionally substituted with

8. Het is selected from tetrahydropyran and oxetane, each of which is optionally substituted with 1 to 2 R ４ The compound according to claim 7, or a pharmaceutically acceptable salt thereof, which is optionally substituted with

9. The compound is of formula (II) 【Chemical Formula 4】 The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, represented by

10. R ３ is given by the following formula: [Chemical Formula 5] The compound according to claim 9, or a pharmaceutically acceptable salt thereof, represented by

11. R ５ is, for each occurrence, independently selected from C １～３ alkyl, C １～３ haloalkyl, and OR ５ａ the compound according to claim 9 or 10, or a pharmaceutically acceptable salt thereof.

12. R ５ is, for each occurrence, -CH ３ , -CF ３ , -CF ２ CH ３ , -CH(CH ３ ), ２ and -OCHF ２ independently selected from, the compound according to claim 11, or a pharmaceutically acceptable salt thereof.

13. R １ and R ２ together with the nitrogen atom to which they are attached form the following formula: 【Chemical Formula 6】 The compound according to any one of claims 9 to 12, or a pharmaceutically acceptable salt thereof, forming a group represented by

14. R １ is H or -CH ３ and R ２ is of the following formula 【Chemical Formula 7】 represented by, each of the above formulas having one or two Rs ４ optionally substituted with, a compound according to any one of claims 9 to 12, or a pharmaceutically acceptable salt thereof.

15. R １ is H, and R ２ is represented by the following formula 【Chemical 8】 represented by, each of the above formulas having one or two Rs ４ The compound according to any one of claims 9 to 12, or a pharmaceutically acceptable salt thereof, optionally substituted by.

16. R ２ is represented by the following formula 【Chemical Formula 9】 The compound according to claim 14, or a pharmaceutically acceptable salt thereof, represented by

17. R ２ is represented by the following formula 【Chemical Formula 10】 The compound according to claim 15, or a pharmaceutically acceptable salt thereof, represented by

18. R ４ is, for each occurrence, C １～３ alkyl, and a 4- to 7-membered monocyclic heterocyclic ring, independently selected from the compound according to any one of claims 9 to 17, or a pharmaceutically acceptable salt thereof.

19. R ４ is, for each occurrence, -CH ３ and tetrahydropyran, independently selected from, the compound according to claim 18, or a pharmaceutically acceptable salt thereof.

20. The compound is of formula (III) or (IV): 【Chemical 11】 The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, represented by

21. The compound is of formula (IIIA), (IIIB), (IVA), or (IVA): 【Chemical 12】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof, represented by

22. R ３ is represented by the following formula 【Chemical 13】 The compound according to claim 20 or 21, or a pharmaceutically acceptable salt thereof, represented by

23. R ５ is, for each occurrence, independently selected from halo, cyano, C １～２ alkyl, C １～２ haloalkyl, and OR ５ａ wherein R ５ａ is C １～２ alkyl or C １～２ haloalkyl, a compound according to any one of claims 20 to 22, or a pharmaceutically acceptable salt thereof.

24. R ５ is, for each occurrence, independently selected from F, Cl, cyano, -CH ３ , -CF ３ , -CHF ２ , -OCH ３ , and -OCHF ２ and is the compound according to claim 23, or a pharmaceutically acceptable salt thereof.

25. R １ and R ２ together with the nitrogen atom to which they are attached form the following formula: 【Chemical Formula 14】 The compound according to any one of claims 20 to 24, or a pharmaceutically acceptable salt thereof, forming a group represented by

26. R １ is H or C １～３ alkyl, and R ２ is C １～３ alkyl, C ３～６ cycloalkyl, -Z-Het, or Het, each of which is optionally substituted with one to three R ４ and is a compound according to any one of claims 20 to 25, or a pharmaceutically acceptable salt thereof.

27. R １ is H or -CH ３ and R ２ is C ４ alkyl optionally substituted with one R １～３ or the following formula: 【Chemical Formula 15】 represented by, each of the above formulas being optionally substituted with one or two R ４ The compound according to claim 26, or a pharmaceutically acceptable salt thereof, which is optionally substituted with

28. R １ is H or -CH ３ and R ２ is of the formula: 【Chemical 16】 The compound according to claim 27, or a pharmaceutically acceptable salt thereof, represented by

29. R ４ is, for each occurrence, independently selected from OR ４ａ , halo, and C １～３ alkyl, and R ４ａ is C １～３ alkyl, a compound according to any one of claims 20 to 28, or a pharmaceutically acceptable salt thereof.

30. R ４ is, for each occurrence, a halo, -CH ３ , and -OCH ３ independently selected from, the compound according to claim 29, or a pharmaceutically acceptable salt thereof.

31. The compound is 6-(2-((6-(1,1-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-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]heptane-6-amine; 2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine; 6-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 4-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)morpholine; 6-(2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptan-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]heptan-6-amine; 2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; 4-(2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)morpholine; 2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-ylmethyl)-2-azaspiro[3.3]heptan-6-amine; 2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-((3-methyloxetan-3-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; 2-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.5]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 6-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-6-azaspiro[3.3]heptane; 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-6-azaspiro[3.3]heptane; 6-(2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2-oxa-6-azaspiro[3.3]heptane; 2-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridine-3-sulfonamide; 4-(2-((3-isopropyl-1-methyl-1H-pyrazol-5-yl)sulfonyl)-2-azaspiro[3.3]heptan-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]heptan-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]octan-2-yl)sulfonyl)-4-fluorobenzonitrile; 4-Fluoro-3-((7-((tetrahydro-2H-pyran-4-yl)amino)-5-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)benzonitrile; 3-((7-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)-5-oxa-2-azaspiro[3.4]octan-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]octan-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]heptan-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]heptan-6-amine; 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-2-diazaspiro[3.3]heptan-6-amine; 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; 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; 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((6-(1,1-Difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-N-methyl-N-(2-oxaspiro[3.3]heptan-6-yl)-2-diazaspiro[3.3]heptan-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]heptan-6-amine; 2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((4-Methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-2-azaspiro[3.3]heptan-6-amine; 2-((4-Methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine; N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-2-azaspiro[3.3]heptan-6-amine; N-Methyl-2-((4-methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-6-amine; The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from N-methyl-2-((4-methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-amine; N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(oxetan-3-yl)-2-azaspiro[3.3]heptan-6-amine; N-methyl-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)-2-azaspiro[3.3]heptan-6-amine; N-methyl-2-((4-methyl-2-(trifluoromethyl)pyridin-5-yl)sulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-azaspiro[3.3]heptan-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 an emopamil-binding protein, comprising administering an effective amount of the compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 32, to a subject.

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

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

36. The method according to claim 35, wherein the compound or the pharmaceutical composition repairs or forms a new myelin sheath in the subject.

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