Emopamil-binding protein inhibitors and uses thereof

Abstract

Provided are compounds of Formula (I), or pharmaceutically acceptable salts thereof, which are useful for the inhibition of EBP and in the treatment of a variety of EBP mediated conditions or diseases, such as multiple sclerosis.

Description

[0001] EMOPAMIL-BINDING PROTEIN INHIBITORS AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 534,658, filed on August 25, 2023. The entire contents of the foregoing application are expressly incorporated herein by reference.

[0004] FIELD OF THE INVENTION

[0005] 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 optional combination with a pharmaceutically acceptable carrier for the manufacture of pharmaceutical preparations, the use of the pharmaceutical preparations in the treatment of diseases, and methods of treating diseases comprising administering the EBP inhibitor to a warm-blooded animal, especially a human.

[0006] BACKGROUND OF THE INVENTION

[0007] Emopamil-Binding Protein (EBP) is a A8-A7 sterol isomerase enzyme which isomerizes the double bond in sterol molecules, moving the double bond from the 8-9 position to the 7-8 position. Specifically, EBP converts either zymostenol to lathosterol, or zymosterol to dehydrolathosterol, during the biosynthesis of cholesterol (Silve et al., 1996, J Biol Chem. 271 (37), 22434-22440). It has been shown that an accumulation of 8-9 unsaturated sterols activates oligodendrocyte formation and remyelination (Hubler et al., 2019, Nature 560 (7718), 372-376).

[0008] Myelin is lipid-based molecule which forms protective layers (myelin sheathes) around nerve cell axons and insulates the axons. Demyelinating diseases, or myelin-related diseases, are a result of these myelin sheathes being damaged, degraded, or reduced in thickness. The loss of the myelin sheathes disrupts the electronic signals from the brain and can lead to nerve damage, vision loss, numbness, muscle weakness, cognitive decline, loss of motor functions, and other similar symptoms. In some myelin-related diseases, such as multiple sclerosis, a subject’s immune system targets and breaks down their own myelin sheathes. The ability to repair and regenerate the myelin sheathes is key to treating these myelin-related diseases. Due to its function converting 8-9 sterols, inhibition of EBP is a potential target for activating remyelination, as its inhibition leads to an increase of these 8-9 sterol starting materials (Theodoropoulous et al, 2020, J. Am. Chem. Soc., 142, (13), 6128-6138).

[0009] In addition to its role in remyeliniation, EBP has also been shown to be a key enzyme in certain colorectal cancers due to the reduction in essential lipids such as cholesterol (Theodoropoulous et al, 2020, J. Am. Chem. Soc., 142, (13), 6128-6138).

[0010] Thus, there is a need for EBP inhibitors as potential therapeutic agents for treating diseases or disorders that are responsive to EBP inhibition.

[0011] SUMMARY OF THE INVENTION

[0012] The present disclosure provides compounds that are EBP inhibitors. In a first aspect, the present disclosure relates to compounds having the Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0013] R1is:

[0014] (1) -Z-Y;

[0015] (2) -Z-X; or

[0016] (3) Het or -Z-Het;

[0017] Y is phenyl or 5-to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one or more RY2;

[0018] X is 5- to 10-membered bicyclic carbocyclyl or 8- to 12- membered partially saturated heterocyclyl, each of which is optionally substituted by one or more RX2;

[0019] Het is 4- to 6-membered monocyclic heterocyclyl optionally substituted with one or more RH2;

[0020] Z is Ci-4alkyl optionally substituted with one or more halo or Ci-3alkoxy;

[0021] RY2, RX2, and RH2, for each occurrence, are each independently Ci-ealkyl, halo, -CN, - NR2aR2a, -C(O)R2a, -C(O)N(R2a)2, -C(O)OR2a, or OR2a, wherein the Ci-ealkyl is optionally substituted with one or more halo or Ci-3alkoxy; each R2ais independently H, Ci-ealkyl, Ci-ehaloalkyl, or Cs-ecycloalkyl;

[0022] R3is -Ci-4alkyl-phenyl, phenyl or 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one or more R4; each R4is independently halo, -OR4a, -C(O)R4a, -CN, Ci-ealkyl, Ci-ehaloalkyl, C3- ecycloalkyl, 4-to 6-membered monocyclic heterocyclyl, phenyl, or 5 or 6-membered monocyclic heteroaryl;

[0023] R4ais H or Ci-ealkyl, wherein the Ci-ealkyl is optionally substituted with one or more halo. provided that if R1is Het or -Z-Het then:

[0024] (i) Het is piperdinyl; or

[0025] (ii) R3is phenyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or -Ci-4alkyl- phenyl, provided that if R3is phenyl, pyrazolyl, or pyridinyl then at least one R4is C4- ecycloalkyl, 4-to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl

[0026] Another aspect of the disclosure relates to pharmaceutical compositions comprising compounds of Formula (I) or pharmaceutically acceptable salts thereof, and a pharmaceutical carrier.

[0027] In yet another aspect, the present disclosure provides a method of treating a disease or disorder that is responsive to inhibition of EBP in a subject comprising administering to said subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating multiple sclerosis. In some embodiments, the present disclosure provides a method for promoting myelination in a subject with a myelin-related disorder.

[0028] 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 inhibition of EBP. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder responsive to inhibition of EBP.

[0029] DETAILED DESCRIPTION OF THE INVENTION

[0030] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful in the treatment of diseases or disorders through mediation of EBP function / activity, such as multiple sclerosis or other myelin-related disorders. In some embodiments, the compounds of present disclosure are EBP inhibitors.

[0031] COMPOUNDSAND COMPOSITIONS

[0032] In a first embodiment, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables in Formula (I) are as defined in the first aspect above.

[0033] In a second embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, Z is Ci-2alkyl; and the remaining variables are as described in the first embodiment.

[0034] In a third embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, Z is -CH2-; and the remaining variables are as described in the second embodiment.

[0035] In a fourth embodiment, the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof; and the remaining variables are as described in the first, second, or third embodiment.

[0036] In a fifth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, Y is phenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted by one or two RY2; and the remaining variables are as described in the first, second, third, or fourth embodiment.

[0037] In a sixth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, Y is represented by the following formula: , each of which is optionally substituted by one or two RY2; and the remaining variables are described in the fifth embodiment.

[0038] In a seventh embodiment, for the compounds of Formula (I) or (II), or a i- Y2 pharmaceutically acceptable salt thereof, Y is represented by the following formula: R ,

[0039] described in the sixth embodiment.

[0040] In an eighth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each RY2is independently -Ci-salkyl, -NHR2a, - OR2a, or -CN, and R2ais Ci-3alkyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment. In some embodiments, the -Ci- salkyl represented by RY2is deuterated -Ci-3alkyl.

[0041] In a ninth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each RY2is independently -CH , -CD3, -CH2CH3, - NHCH3, -OCH3, or -CN; and the remaining variables are as described in the eighth embodiment.

[0042] In a tenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3is 5- to 6-membered monocyclic heteroaryl optionally substituted by one to three R4; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0043] In an eleventh embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3is pyridinyl or pyrimindinyl, each of which is optionally substituted by one to three R4; and the remaining variables are as described in the tenth embodiment.

[0044] In a twelfth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3is represented by the following formula: or , each of which is optionally substituted by one to three R4; and the remaining variables are as described in the eleventh embodiment.

[0045] In a thirteenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3is represented by the following formula: the remaining variables are as described in the twelfth embodiment.

[0046] In a fourteenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R4is independently Ci-salkyl or Ci-shaloalkyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0047] In a fifteenth embodiment, for the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, each R4is independently -CH3, -CF3, -CH2CH3, or - CF2CH3; and the remaining variables are as described in the fourteenth embodiment.

[0048] In a sixteenth embodiment, the present disclosure provides a compound of Formula

[0049] (III): or a pharmaceutically acceptable salt thereof; and the remaining variables are as described in the first, second, or third embodiment.

[0050] In a seventeenth embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, X is 5-oxa-6-azaspiro[3.4]oct-6-enyl optionally substituted with one RX2; and the remaining variables are as described in the first, second, third, or sixteenth embodiment.

[0051] In an eighteenth embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, X is represented by the formula: the remaining variables are as described in the sixteenth embodiment. In a nineteenth embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, R3is 5- to 6-membered monocyclic heteroaryl optionally substituted by one to three R4; and the remaining variables are as described in the first, second, third, sixteenth, seventeenth, or eighteenth embodiment.

[0052] In a twentieth embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, R3is pyridinyl optionally substituted by one to three R4; and the remaining variables are as described in the nineteenth embodiment.

[0053] In a twenty-first embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, R3is represented by the following formula: , which is optionally substituted by one to three R4; and the remaining variables are as described in the twentieth embodiment.

[0054] In a twenty-second embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, R3is represented by the following formula: and the remaining variables are as described in the twenty-first embodiment.

[0055] In a twenty-third embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, each R4is independently Ci-salkyl or Ci-shaloalkyl; and the remaining variables are as described in the first, second, third, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment.

[0056] In a twenty-fourth embodiment, for the compounds of Formula (I) or (III), or a pharmaceutically acceptable salt thereof, each R4is independently -CH3 or -CF3; and the remaining variables are as described in the twenty-third embodiment.

[0057] In a twenty-fifth embodiment, the present disclosure provides a compound of Formula (IVa) or (IVb):

[0058] Het z\0Het — N\ l-S-R3 O (IVb); or a pharmaceutically acceptable salt thereof; and the remaining variables are as described in the first, second, or third embodiment.

[0059] In a twenty-sixth embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, Het is tetrahydropyranyl or piperdinyl, each of which is optionally substituted by one or two RH2; and the remaining variables are as described in the first, second, third, or twenty -fifth embodiment.

[0060] In a twenty- seventh embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, Het is represented by the following formula: ^0° or , each of which is optionally substituted by one RH2; and the remaining variables are as described in the twenty-sixth embodiment.

[0061] In a twenty-eighth embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, Het is represented by the following formula: R ; and the remaining variables are as described in the twentyseventh embodiment.

[0062] In a twenty-ninth embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, each RH2is independently -C(O)R2a, and R2ais Cisalkyl; and the remaining variables are as described in the first, second, third, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment.

[0063] In a thirtieth embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, each RH2is independently -C(O)CH3; and the remaining variables are as described in the twenty-ninth embodiment.

[0064] In a thirty-first embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, R3is thiazolyl, pyrazolyl, pyridinyl, or -Ci-3alkyl- phenyl, each of which is optionally substituted with one to three R4, provided that if Het is tertahydropyranyl and R3is pyrazolyl or pyridinyl, then at least one R4is C4-6cycloalkyl, 4-to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl; and the remaining variables are as described in the first, second, third, twenty-fifth, twentysixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtieth embodiment.

[0065] In a thirty-second embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, R3is represented by the following formula: substituted with one or two R4; and the remaining variables are as described in the thirty-first embodiment. In a thirty-third embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, R3is represented by the following formula: the remaining variables are as described in the thirty-second embodiment.

[0066] In a thirty-fourth embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, each R4is independently halo, Ci-salkyl, Ci- shaloalkyl, Cs-ecycloalkyl, 4-membered monocyclic heterocyclyl, phenyl, or 6-membered monocyclic heteroaryl, provided that if Het is tetrahydropyranyl and R3is pyrazolyl or pyridinyl, then at least one R4is C4-6cycloalkyl, 4-membered monocyclic heterocyclyl, phenyl, or 6-membered monocyclic heteroaryl; and the remaining variables are as described in the first, second, third, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twentyninth, thirtieth, thirty-first, thirty-second, or thirty-third embodiment.

[0067] In a thirty-fifth embodiment, for the compounds of Formula (I), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, each R4is independently -Cl, -CH3, -CHF2, -CF3, - CH2CH3, cyclopropyl, cyclobutyl, cyclohexyl, azetidinyl, phenyl, or pyridinyl, provided that if Het is tetrahydropyranyl and R3is pyrazolyl or pyridinyl, then at least one R4is cyclobutyl, cyclohexyl, azetidinyl, phenyl, or pyridinyl; and the remaining variables are as described in the thirty-fourth embodiment.

[0068] In a thirty-sixth embodiment, the present disclosure provides a compound described herein (e.g., a compound of any one of Examples 1 to 55, or a pharmaceutically acceptable salt thereof.

[0069] In an alternative thirty-sixth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0070] 5-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2-

[0071] (tri fluoromethyl )thi azole;

[0072] 5-((6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2- (tri fluoromethyl )thi azole;

[0073] 2-cyclopropyl-5-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)thi azole;

[0074] 2-cyclopropyl-5-((6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)thi azole; 2-cyclopropyl-4-methyl-5-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-

[0075] 2-yl)sulfonyl)thiazole;

[0076] 2-chloro-4-methyl-5-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)thi azole;

[0077] 2-((3-(azetidin-l-yl)-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4- yl)-2,6-diazaspiro[3.3]heptane ;

[0078] 2-((3-cyclopropyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)- 2,6-diazaspiro[3.3]heptane;

[0079] 2-(furan-2-ylmethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane;

[0080] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((l-(methyl-d3)-lH-pyrazol-

[0081] 3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0082] 2-((lH-pyrrol-3-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)- 2,6-diazaspiro[3.3]heptane;

[0083] 2-((5 -methoxy- 1 -methyl- lH-pyrazol-4-yl)methyl)-6-((2-methyl -6- (trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0084] 2-((5-ethyl-l -methyl- IH-pyrazol -4-yl )methyl)-6-((2 -methyl-6- (trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0085] 2-((4-ethyl-lH-imidazol-2-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0086] 2-((l-methyl-lH-imidazol-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyri din-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0087] 2-((2-ethyl-lH-imidazol-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyri din-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0088] 2-methyl-4-((6-((2 -methyl -6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2, 6- diazaspiro[3.3]heptan-2-yl)methyl)oxazole;

[0089] 4-ethyl-5-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)oxazole;

[0090] 5 -methyl -4 -((6 -((2 -methyl -6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2, 6- diazaspiro[3.3]heptan-2-yl)methyl)oxazole;

[0091] N-methyl-3-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)aniline;

[0092] 1 -methyl -4-((6-((2 -methyl -6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2, 6- diazaspiro[3.3]heptan-2-yl)methyl)-lH-pyrrole-2-carbonitrile; 2-((l -ethyl-3 -methyl- IH-pyrazol -4-yl )methyl)-6-((2 -methyl-6- (trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0093] 2-((l,2-dimethyl-lH-imidazol-5-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin- 3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0094] 2-((3-ethylpyri din-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyri din-3 - yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0095] 2-((6-methoxypyridin-3-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0096] 2-((2,6-dimethylpyridin-3-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyri din-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0097] 2-((2,4-dimethylpyridin-3-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyri din-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0098] 2-((5-methoxypyridin-2-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0099] 2-((4-methyl-lH-pyrrol-3-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0100] 2-((3,5-dimethyl-lH-pyrazol-4-yl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyri din-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0101] 7-((6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan- 2-yl)methyl)-5-oxa-6-azaspiro[3.4]oct-6-ene;

[0102] 2-((l-methyl-lH-pyrazol -4-yl )methyl)-6-((2-methyl-6-(trifluoromethyl)pyri din-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0103] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(pyrimidin-5-ylmethyl)-2,6- diazaspiro[3.3]heptane;

[0104] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((2-methylpyrimidin-5- yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0105] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(pyridin-3-ylmethyl)-2,6- diazaspiro[3.3]heptane;

[0106] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(pyridin-2-ylmethyl)-2,6- diazaspiro[3.3]heptane;

[0107] 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(pyridin-4-ylmethyl)-2,6- diazaspiro[3.3]heptane;

[0108] 2-((l-methyl-lH-pyrazol-3-yl)methyl)-6-((4-methyl-2-(trifluoromethyl)pyrimidin-5- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-((l-methyl-lH-pyrazol- 3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0109] 2-((6-( 1 , 1 -difluoroethyl)-2-methylpyri din-3 -yl)sulfonyl)-6-(( 1 -methyl- lH-pyrazol-3 - yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0110] 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((l-methyl-lH-pyrazol- 3-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0111] 2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((l-methyl-lH- pyrazol-4-yl)methyl)-2,6-diazaspiro[3.3]heptane;

[0112] 2-((l-methyl-3 -phenyl- lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2, 6- diazaspiro[3.3]heptane;

[0113] 2-((l-methyl-3-(pyridin-3-yl)-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4- yl)-2,6-diazaspiro[3.3]heptane;

[0114] 2-((l-methyl-3-(pyridin-4-yl)-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4- yl)-2,6-diazaspiro[3.3]heptane;

[0115] 2-((3-cyclohexyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-

[0116] 2,6-diazaspiro[3.3]heptane;

[0117] 2-((3-cyclobutyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-

[0118] 2,6-diazaspiro[3.3]heptane;

[0119] 1-(4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan- 2-yl)piperidin- 1 -yl)ethan- 1 -one;

[0120] 2-(tetrahydro-2H-pyran-4-yl)-6-((4-(trifluoromethoxy)phenyl)sulfonyl)-2,6- diazaspiro[3.3]heptane;

[0121] 2-(phenethylsulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane; rac-2-((l-phenylpropan-2-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane;

[0122] 2-((l-methoxycyclohexyl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyri din-3- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0123] 2-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-6- (trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0124] 2-((6-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane;

[0125] 2-((2-methyl-6-(perfluoroethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-

[0126] 2,6-diazaspiro[3.3]heptane; or a or a pharmaceutically acceptable salt thereof. In a thirty-seventh embodiment, the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof.

[0127] In a thirty-eighth embodiment, the present disclosure provides a method of treating a disease or disorder mediated by EBP comprising administering to a subject an effective amount of a compound according to any one of embodiments one to thirty-six, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the thirty-seventh embodiment.

[0128] The present disclosure also provides a compound according to any one of embodiments one to thirty-six, for use in the treatment of a disease or disorder mediated by EBP.

[0129] In some embodiments, the present disclosure provides the use of a compound according to any one of embodiments one to thirty-six in the manufacture of a medicament for the treatment of a disease or disorder mediated by EBP.

[0130] The compounds and intermediates described herein may be isolated and used as the compound per se. Alternatively, when a moiety is present that is capable of forming a salt, the compound or intermediate may be isolated and used as its corresponding salt. As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound described herein. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds described herein and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0131] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids or organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfornate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandi sulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

[0132] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0133] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0134] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

[0135] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0136] The salts can be synthesized by conventional chemical methods from a compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0137] Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed. In one embodiment, the present disclosure provides deuterated compounds described herein or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de-acetone, de- DMSO.

[0138] It will be recognized by those skilled in the art that the compounds of the present invention may contain chiral centers and as such may exist in different stereoisomeric forms. As used herein, the term “an optical isomer” or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound.

[0139] “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 term “racemic” or “rac” is used to designate a racemic mixture where appropriate. When designating the stereochemistry for the compounds of the present invention, a single stereoisomer with known relative and absolute configuration of the two chiral centers is designated using the conventional RS system (e.g., (15,25)). “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the respective retention times for the corresponding enantiomers / diastereomers via chiral HPLC.

[0140] Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0141] Unless specified otherwise, the compounds of the present disclosure are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-stereoi somers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAKR™ and CHIRALCELR™ available from DAICEL Corp, using the appropriate solvent or mixture of solvents to achieve good separation). If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0142] METHODS OF USE

[0143] 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 10% decrease in EBP activity as measured by a given assay such as the bioassay described in the examples and known in the art).

[0144] In certain embodiments, the present disclosure provides a method of treating a disease or disorder responsive to inhibition of EBP activity (referred herein as “EBP mediated disease or disorder” or “disease or disorder mediated by EBP”) in a subject in need of the treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to thirty-fifth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0145] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a EBP mediated disorder or disease in a subject in need of the treatment.

[0146] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of a EBP mediated disorder or disease in a subject in need of the treatment.

[0147] In certain embodiments, the EBP mediated disorder is colorectal cancer.

[0148] In certain embodiments, the present disclosure provides a method of treating an autoimmune disease in a subject in need of the treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0149] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an autoimmune disease in a subject in need of the treatment.

[0150] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease in a subject in need of the treatment.

[0151] In certain embodiments, the autoimmune disease is multiple sclerosis (MS). The compounds of the present disclosure can be used for treating all stages of MS, including relapsing multiple sclerosis (or relapsing form(s) of multiple sclerosis), relapsing-remitting multiple sclerosis, primary progress multiple sclerosis, secondary progressive multiple sclerosis and clinically isolated syndrome (hereinafter “CIS”).

[0152] Relapsing multiple sclerosis (or relapsing form(s) of multiple sclerosis) includes clinically isolated syndrome, relapsing-remitting multiple sclerosis and active secondary progressive multiple sclerosis.

[0153] Relapsing-remitting multiple sclerosis is a stage of MS characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave problems, the latter in about 40% of attacks and being more common the longer a person has had the disease. This describes the initial course of 80% of individuals with multiple sclerosis.

[0154] Secondary progressive multiple sclerosis occurs in around 65% of those with initial relapsing-remitting multiple sclerosis, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The most common length of time between disease onset and conversion from relapsing-remitting to secondary progressive multiple sclerosis is 19 years.

[0155] Primary progressive multiple sclerosis is characterized by the same symptoms of secondary progressive multiple sclerosis, i.e., progressive neurologic decline between acute attacks without any definite periods of remission, without the prior relapsing-remitting stage.

[0156] CIS is a first episode of neurologic symptoms caused by inflammation and demyelination in the central nervous system. The episode, which by definition must last for at least 24 hours, is characteristic of multiple sclerosis but does not yet meet the criteria for a diagnosis of MS because people who experience a CIS may or may not go on to develop MS. When CIS is accompanied by lesions on a brain MRI (magnetic resonance imaging) that are similar to those seen in MS, the person has a high likelihood of a second episode of neurologic symptoms and diagnosis of relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on a brain MRI, the person has a much lower likelihood of developing MS.

[0157] In certain embodiments, the present disclosure provides a method of promoting myelination in a subject with a myelin-related disease or disorder in a subject in need of the treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0158] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for promoting myelination in a subject with a myelin-related disease or disorder in a subject in need of the treatment.

[0159] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in promoting myelination in a subject with a myelin-related disease or disorder in a subject in need of the treatment.

[0160] In certain embodiments, the myelin-related disease or disorder is selected from multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophies, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), acute disseminated encephalomyelitis (ADEM), central pontine myelolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, transverse myelitis, amylotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Komzweig syndrome, Marchiafava-Bignami syndrome, autism, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillian-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy and radiation-induced demyelination, for example, neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophies, neonatal white matter injury, age-related dementia, and schizophrenia.

[0161] In certain embodiments, the present disclosure provides a method of treating cancer in a subject in need of the treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0162] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer in a subject in need of the treatment.

[0163] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to thirty-sixth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need of the treatment.

[0164] In certain embodiments, the cancer is colorectal cancer.

[0165] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a mammal. In certain embodiments, the subject is a primate. In certain embodiments, the subject is a human.

[0166] As used herein, an “effective amount” and a “therapeutically effective amount” can used interchangeably. It means an amount effective for treating or lessening the severity of one or more of the diseases, disorders or conditions as recited herein. In some embodiments, the effective dose can be between 10 pg and 500 mg.

[0167] The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders or conditions recited above.

[0168] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered parenterally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically or intranasally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered systemically.

[0169] The compounds of the present invention can be used as a pharmaceutical composition (e.g., a compound of the present invention and at least one pharmaceutically acceptable carrier). As used herein, the term “pharmaceutically acceptable carrier” includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. For purposes of this disclosure, solvates and hydrates are considered pharmaceutical compositions comprising a compound of the present invention and a solvent (i.e., solvate) or water (i.e., hydrate).

[0170] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

[0171] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0172] The pharmaceutical composition comprising a compound of the present disclosure is generally formulated for use as a parenteral or oral administration or alternatively suppositories. For example, the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

[0173] Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavors and sweeteners.

[0174] Tablets may be either film coated or enteric coated according to methods known in the art.

[0175] Suitable compositions for oral administration include a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0176] The parenteral compositions (e.g, intravenous (IV) formulation) are aqueous isotonic solutions or suspensions. The parenteral compositions may be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.

[0177] The compound of the present disclosure or pharmaceutical composition thereof for use in a subject (e.g., human) is typically administered orally or parenterally at a therapeutic dose. When administered intravenously via infusion, the dosage may depend upon the infusion rate at which an IV formulation is administered. In general, the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, pharmacist, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

[0178] The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10-3 molar and 10-9 molar concentrations.

[0179] DEFINITIONS

[0180] As used herein, a “patient,” “subject” or “individual” are used interchangeably and refer to either a human or non-human animal. The term includes mammals such as humans. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. Preferably, the subject is a human. As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0181] As used herein, the term “treat”, “treating” or “treatment” of any disease, condition or disorder, refers to the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to obtaining desired pharmacological and / or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, condition or disorder; ameliorating or improving a clinical symptom, complications or indicator associated with the disease, condition or disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or disorder; or eliminating the disease, condition or disorder. In certain embodiments, the effect can be to prevent the onset of the symptoms or complications of the disease, condition or disorder.

[0182] As used herein, the term “cancer” has the meaning normally accepted in the art. The term can broadly refer to abnormal cell growth.

[0183] As used herein, the term “autoimmune disease” has the meaning normally accepted the art. The term can broadly refer to a disease where the host’s immune system targets or attacks normal or healthy tissue of the host.

[0184] As used herein, the term “myelination” has the meaning normally accepted in the art. The term can broadly mean the process by which myelin is produced.

[0185] As used herein, the term “myelin-related disease or disorder”, “demyelinating disorder”, or “demyelation disorder” has the meaning normally accepted in the art. These terms can broadly refer to diseases or disorders which involve damage to myelin.

[0186] As used herein, a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (preferably, a human).

[0187] As used herein, the phrase “optionally substituted” is used interchangeably with the phrase “substituted or un substituted.” In general the term “optionally substituted” refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety. The term “Ci-4alkyl” refers to an alkyl having 1 to 4 carbon atoms. The terms “Ci-3alkyl” and “Ci-2alkyl” are to be construed accordingly. Representative examples of “Ci-4alkyl” include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, secbutyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy have the same definition as above. When indicated as being “optionally substituted”, the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls).

[0188] As used herein, the term “alkoxy” refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e. a — O— C1-4 alkyl group wherein C1-4 alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy and the like. Preferably, alkoxy groups have about 1-4 carbons, more preferably about 1-2 carbons. The term “ C1-2 alkoxy” is to be construed accordingly.

[0189] As used herein, the term “C1-4 alkoxyCi-4 alkyl” refers to a Ci-4allkyl group as defined herein, wherein at least of the hydrogen atoms is replaced by an Ci-4alkoxy. The Ci-4alkoxyCi- 4 alkyl group is connected through the rest of the molecule described herein through the alkyl group.

[0190] The number of carbon atoms in a group is specified herein by the prefix “Cx-xx”, wherein x and xx are integers. For example, “C1-3 alkyl” is an alkyl group which has from 1 to 3 carbon atoms.

[0191] “Halogen” or “halo” may be fluorine, chlorine, bromine or iodine.

[0192] As used herein, the term “halo-substituted-Ci-4alkyl” or “ Ci-4haloalkyl” refers to a Ci- 4alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The Ci-4haloalkyl group can be monohalo-Ci-4alkyl, dihalo-Ci-4alkyl or polyhalo-Ci-4 alkyl including perhalo-Ci-4alkyl. A monohalo-Ci-4alkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihalo-Ci-4alkyl and polyhalo-Ci-4alkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhalo-Ci-4alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. Non-limiting examples of Ci-4haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, di chloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and di chloropropyl. A perhalo-Ci-4alkyl group refers to a Ci-4alkyl group having all hydrogen atoms replaced with halo atoms.

[0193] The term “aryl” refers to an aromatic carbocyclic single ring or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0194] The term “heteroaryl” refers to a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some instances, nitrogen atoms in a 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 mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, furanyl, oxadiazolyl, thiophenyl, and the like. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include pyrazolopyridinyl, pyrazolopyridinyl, benzotriazolyl, imidazopyridinyl, and indoyl.

[0195] The term “carbocyclic ring” or “carbocyclyl” refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring and may exist as a single ring, bicyclic ring (including fused, spiral or bridged carbocyclic rings) or a spiral ring. Bi-cyclic carbocyclyl groups include, e.g., unsaturated carbocyclic radicals fused to another unsaturated carbocyclic radical, cycloalkyl, or aryl, such as, for example, 2,3-dihydroindenyl, decahydronaphthal enyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless specified otherwise, the carbocyclic ring generally contains 4- to 10- ring members.

[0196] The term “C3-6 cycloalkyl” refers to a carbocyclic ring which is fully saturated (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0197] The term “heterocycle” or “heterocyclyl” refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. A heterocyclyl group may be mono- or bicyclic (e.g., a bridged, fused, or spiro bicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and piperdinyl. Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as, for example, tetrahydro-3H-[l,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 a 8 to 10 membered bicyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 8 to 10 membered bicyclic saturated heterocyclyl group.

[0198] As used herein the term “spiral” ring means a two-ring system wherein both rings share one common atom. Examples of spiral rings include, 2-oxa-6-azaspiro[3.3]heptanyl and the like.

[0199] The term “fused” ring refers to two ring systems share two adjacent ring atoms. Fused heterocycles have at least one the ring systems contain a ring atom that is a heteroatom selected from O, N and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0200] As used herein the term “bridged” refers to a 5 to 10 membered cyclic moiety connected at two non-adjacent ring atoms (e.g. 5-oxabicyclo[2.1.1]hexane).

[0201] The phrase “pharmaceutically acceptable” indicates that the substance, composition or dosage form must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0202] Unless specified otherwise, the term “compounds of the present disclosure” refers to compounds of Formula (I), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). When a moiety is present that is capable of forming a salt, then salts are included as well, in particular pharmaceutically acceptable salts.

[0203] As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and 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 intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

[0204] It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0205] In one embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in free form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in salt form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in acid addition salt form. In a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable salt form. In yet a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in free form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in acid addition salt form. In yet a 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.

[0206] Compounds of the present disclosure may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma- Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally 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, including supplements (also available via the Beilstein online database)).

[0207] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions.

[0208] EXEMPLIFICATION

[0209] Abbreviations:

[0210] PE = petroleum ether

[0211] EtOAc = EA = ethyl acetate ESI = electrospray ionisation MeOH = methanol EtOH = ethanol

[0212] DCE = 1,2-di chloroethane

[0213] DCM = dichloromethane

[0214] CHCI3 = chloroform

[0215] HC1 = hydrochloric acid

[0216] H2O = water

[0217] IPA = isopropyl alcohol

[0218] LCMS = liquid chromatography mass spectrometry

[0219] HFIP = hexafluoro-2-propanol

[0220] HPLC = high pressure liquid chromatography

[0221] THF = tetrahydrofuran

[0222] MeCN = ACN = acetonitrile

[0223] MgSO4 = magnesium sultate

[0224] DMSO = dimetylsulfoxide

[0225] AcOH = acetic acid

[0226] TFA = tri fluoroacetic acid

[0227] DIPEA = diisopropylethyl amine

[0228] N2 = Nitrogen

[0229] NH4HCO3 = Ammonium Bicarbonate t-BuOH = tert-butanol

[0230] NH4CI = ammonium chloride

[0231] NaH = sodium hydride

[0232] Na2SO4= sodium sulfate

[0233] K2CO3 = potassium carbonate

[0234] NaHCCE = sodium bicarbonate

[0235] NaBH(0Ac)3 = STAB = sodium triacetoxyborohydride

[0236] SiCE = silicon dioxide or silica

[0237] PDA = Photo Diode Array Detection

[0238] TosMIC = toluenesulfonylmethyl isocyanide

[0239] TLC = Thin Layer Chromatography

[0240] LiHMDS = Lithium bis(trimethylsilyl)amide

[0241] DMA = dimethtyl amine

[0242] DAST = diethylaminosulfur trifluoride

[0243] DABCO = l,4-diazabicyclo[2.2.2]octane NCS = N-Chlorosuccinimide

[0244] NBS = N-Bromosuccinimide

[0245] NIS = N-Iodosuccinimide t-BuONO = tert-Butyl nitrite ee = enantiomeric excess tR = Retention time

[0246] Rf = Response factor

[0247] GENERAL METHODS

[0248] GENERAL METHODS

[0249] LCMS instrumentation specifications:

[0250] • Agilent Technologies 1200 Series LC / MSD system: DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B mass-spectrometer.

[0251] • Agilent Technologies 1260 Infinity LC / MSD system: DAD\ELSD Alltech 3300 and Agilent LC\MSD G6120B mass-spectrometer.

[0252] • Agilent Technologies 1260 Infinity II LC / MSD system: DAD\ELSD G7102A 1290 Infinity II and Agilent LC\MSD G6120B mass-spectrometer.

[0253] • Agilent 1260 Series LC / MSD system: DAD\ELSD and Agilent LC\MSD (G6120B) mass-spectrometer.

[0254] • UHPLC Agilent 1290 Series LC / MSD system: DAD\ELSD and Agilent LC\MSD (G6125B) mass-spectrometer.

[0255] HPLC analytical method specifications:

[0256] • Column: Agilent Poroshell 120 SB-C18 4.6 x 30mm 2.7 pm, with UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6 x 5mm 2.7 pm

[0257] • Column Temperature, 60 C

[0258] • Injection volume 0.5 pL

[0259] • Modifier: Formic acid 0.1% (v / v) cone.

[0260] • Method: 99% water / 1% MeCN (initial conditions), HOLD initial conditions for 0.1 min, linear gradient to 0% water / 100% MeCN at 1.5min, HOLD 0% water / 100% MeCN to 1.73 min, linear gradient to 99% water / 1% MeCN at 1.74 min. Flow rate, 3.0 mL / min.

[0261] • UV scan: 207-223 nm, 246-262 nm, 272-288 nm

[0262] QC Analysis LC / MS method conditions:

[0263] Ammonium hydroxide (basic pH) conditions

[0264] MS mode: MS:ESI+ scan range 165-650 daltons

[0265] PDA: 200-400 nm scan range

[0266] Column: Waters ACQUITY UPLC BEH C18 2.1x50 mm, 1.7 gm; Part No. 186002350

[0267] Modifier: Ammonium hydroxide 0.2% (v / v) cone.

[0268] Method: 95% water / 5% MeCN (initial conditions) linear gradient to 5% water / 95% MeCN at 3.75 min, HOLD 5% water / 95% MeCN to 4 min. Flow rate, 0.8 mL / min.

[0269] Trifluoroacetic acid (acidic pH) conditions

[0270] MS mode: MS:ESI+ scan range 165-650 daltons

[0271] PDA: 200-400 nm scan range

[0272] Column: Waters ACQUITY UPLC BEH C18 2.1x50 mm, 1.7 gm; Part No. 186002350 Modifier: Trifluoroacetic acid 0.1% (v / v) cone.

[0273] Method: 95% water / 5% MeCN (initial conditions) linear gradient to 5% water / 95% MeCN at 3.75 min, HOLD 5% water / 95% MeCN to 4 min. Flow rate, 0.8 mL / min.

[0274] General prep HPLC conditions:

[0275] Ammonium hydroxide (basic pH) conditions

[0276] Flow rate: 30 mL / min

[0277] MS mode: MS:ESI+ scan range 165-650 daltons

[0278] PDA: 200-400 nm scan range

[0279] Column: Waters XSELECT CSH C18 PREP 19x100 mm, 5 gm; Part No. 186005421 Modifier: 0.2% Ammonium hydroxide (v / v) cone.

[0280] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, ramp to 5% water / 95% MeCN at 8.5 min, HOLD 5% water / 95% MeCN to 10 min.

[0281] Flow rate: 50 mL / min MS mode: MS:ESI+ scan range 165-650 daltons

[0282] PDA: 200-400 nm scan range

[0283] Column: Waters XSELECT CSH C18 PREP 30x100 mm, 5 gm; Part No. 186005425

[0284] Modifier: 0.2% NEUOH (v / v) cone.

[0285] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, ramp to 5% water / 95% MeCN at 8.5min, HOLD 5% water / 95% MeCN to 10 min.

[0286] Flow rate, 60 mL / min

[0287] MS mode: MS:ESI+ scan range 165-650 daltons

[0288] PDA: 200-400 nm scan range

[0289] Column: Waters XSELECT CSH C18 PREP 30x50 mm, 5 gm; Part No. 186005423

[0290] Modifier: 0.2% NH4OH (v / v) cone.

[0291] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, ramp to 5% water / 95% MeCN at 8.5min, HOLD 5% water / 95% MeCN to 10 min.

[0292] Trifluoroacetic acid (acidic pH) conditions

[0293] Flow rate, 30 mL / min

[0294] MS mode: MS:ESI+ scan range 165-650 daltons

[0295] PDA: 200-400 nm scan range

[0296] Column: Waters Sunfire OBD C18 PREP 19x100 mm, 5 pm; Part No. 186002567

[0297] Modifier: 0.1% Trifluoroacetic acid (v / v) cone.

[0298] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, ramp to 5% water / 95% MeCN at 8.5 min, HOLD 5% water / 95% MeCN to 10 min.

[0299] Flow rate, 50 mL / min

[0300] MS mode: MS:ESI+ scan range 165-650 daltons

[0301] PDA: 200-400 nm scan range

[0302] Column: Waters Sunfire OBD C18 PREP 30x100 mm, 5 pm; Part No. 186002572

[0303] Modifier: 0.1% Trifluoroacetic acid (v / v) cone.

[0304] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, ramp to 5% water / 95% MeCN at 8.5 min, HOLD 5% water / 95% MeCN to 10 min.

[0305] Flow rate, 60 mL / min MS mode: MS:ESI+ scan range 165-650 daltons

[0306] PDA: 200-400 nm scan range

[0307] Column: Waters Sunfire OBD C18 PREP 30x50 mm, 5 gm; Part No. 186002570

[0308] Modifier: 0.1% Trifluoroacetic acid (v / v) cone.

[0309] Method: A% water / B% MeCN (initial conditions) linear gradient to A% water / B% MeCN at 8 min, ramp to 5% water / 95% MeCN at 8.5 min, HOLD 5% water / 95% MeCN to 10 min.

[0310] Example 1 : 5-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro [3.3] heptan-2-yl)sulfonyl)-2- (trifluoromethyl)thiazole

[0311] DIPEA (274.31 mg, 2.12 mmol) was added to a vial containing 2-tetrahydropyran-4-yl-2,6- diazaspiro[3.3]heptane (80 mg, 438.93 umol, HC1 salt) in anhydrous dichloromethane (2 mL). After 5 minutes, 2-(trifluoromethyl)thiazole-5-sulfonyl chloride (84.96 mg, 337.64 umol) was added and the reaction stirred for 3 hours. The reaction was quenched with water and extracted three times with dichloromethane. The organic extractions were pooled then washed with NaHCOs (sat, aq.) and water. Crude material was purified by column chromatography with 0 - 100%: {EtOAc:EtOH (3: 1) with 0.2%NH3OH} in EtOH to afford the desired compound (98 mg. 73%). LCMS m / z = 398.2 [M+H]+. 'H NMR (500 MHz, CDC13) 8 8.25 (d, 1H, J=1.2 Hz), 3.84 (s, 2H), 3.75 (s, 2H), 3.61 (br s, 4H), 2.51 (br t, 1H, J=7.5 Hz), 2.0-2.3 (m, 6H), 1.94 (br d, 2H, .7=8,5 Hz).

[0312] Example 2: 5-((6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)-2-(trifluoromethyl)thiazole

[0313] 5-((6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)-2-

[0314] (trifluoromethyl )thiazole was obtained (50 mg, yield 43.6%) from 2-((tetrahydro-2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptane and 2-(trifluoromethyl)thiazole-5-sulfonyl chloride, following a similar procedure to that described in Example 1. LCMS m / z = 412.2 [M+H]+. 'H NMR (500 MHz, CDC13): 8 8.25 (d, 1H, J=1.2 Hz), 3.90 (s, 4H), 3.85 (br dd, 2H, J=2.9, 11.1 Hz), 3.26 (dt, 2H, J=1.8, 11.8 Hz), 3.13 (s, 4H), 2.17 (d, 2H, .7=7,0 Hz), 1.4-1.6 (m, 3H), 1.0- 1.2 (m, 2H).

[0315] Example 3: 2-cyclopropyl-5-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)thiazole

[0316] 2-cyclopropyl-5-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)thiazole was obtained (116 mg, 99.1%) from 2-tetrahydropyran-4-yl-2,6- diazaspiro[3.3]heptane and 2-cyclopropylthiazole-5-sulfonyl chloride following a similar procedure to that described in Example 1. LCMS m / z = 370.3 [M+H]+. 'H NMR (500 MHz, CDCI3): 6 7.91 (s, 1H), 3.77 (s, 2H), 3.68 (s, 2H), 3.61 (br s, 3H), 3.5-3.6 (m, 1H), 2.5-2.6 (m, 1H), 2.48 (s, 1H), 2.3-2.4 (m, 1H), 2.0-2.3 (m, 6H), 1.8-2.0 (m, 3H), 1.1-1.3 (m, 5H).

[0317] Example 4 : 2-cyclopropyl-5-((6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6- diazaspiro[3.3]heptan-2-yl)sulfonyl)thiazole

[0318] 2-cyclopropyl-5-((6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)thiazole was obtained (49 mg, yield 51.5%) from 2-((tetrahydro-2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptane and 2-cyclopropylthiazole-5-sulfonyl chloride, following a similar procedure to that described in Example 1. LCMS m / z = 384.3 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 7.99 (s, 1H), 3.8-4.0 (m, 7H), 3.33 (dt, 2H, J=2.0, 11.8 Hz), 3.18 (s, 4H), 2.3-2.4 (m, 1H), 2.24 (d, 2H, J=7.0 Hz), 1.4-1.6 (m, 3H), 1.1-1.3 (m, 5H). Example 5: 2-cyclopropyl-4-methyl-5-((6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)sulfonyl)thiazole

[0319] 2-cyclopropyl-4-methyl-5-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)thiazole was obtained (75 mg, 57.9%) from 2-tetrahydropyran-4-yl-2,6- diazaspiro[3.3]heptane and 2-cyclopropyl-4-methylthiazole-5-sulfonyl chloride following a similar procedure to that described in Example 1. LCMS m / z = 384.3 [M+H]+. 'H NMR (500 MHz, CDC13): 8 3.78 (s, 2H), 3.68 (s, 2H), 3.61 (br t, 4H, J=4.3 Hz), 2.52 (s, 4H), 2.1-2.3 (m, 7H), 1.8-2.0 (m, 2H), 1.1-1.2 (m, 2H), 1.0-1.1 (m, 2H).

[0320] Example 6: 2-chloro-4-methyl-5-((6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl)sulfonyl)thiazole

[0321] 2-chloro-4-methyl-5-((6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)thiazole was obtained (80 mg, 12.9%) from 2-tetrahydropyran-4-yl-2,6- diazaspiro[3.3]heptane and 2-chloro-4-methylthiazole-5-sulfonyl chloride following a similar procedure to that described in Example 1. LCMS m / z = 378.2 [M+H]+. 'H NMR (400 MHz, MeOD): 5 3.97 (s, 4H), 3.9-3.9 (m, 2H), 3.32 (br s, 2H), 3.30 (s, 3H), 2.61 (s, 3H), 2.2-2.3 (m, 1H), 1.6-1.7 (m, 2H), 1.1-1.3 (m, 2H).

[0322] Example 7: 2-((3-(azetidin-l-yl)-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro [3.3] heptane

[0323] 1. Synthesis of 2-((3-bromo-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro- 2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0324] To a vial containing 2-tetrahydropyran-4-yl-2,6-diazaspiro[3.3]heptane hydrochloride (328 mg, 1.5 mmol) in anhydrous dichloromethane (5 mL) was added DIPEA (1.2 mL, 6.9 mmol) carefully dropwise at < 5 °C. After 5 minutes, 5-bromo-2-methyl-pyrazole-3-sulfonyl chloride (503 mg, 1.9 mmol) was added carefully to the cold solution. Upon complete addition of sulfonyl chloride, the reaction was warmed to 23 °C. After 30 minutes, the reaction was carefully quenched with slow addition of aqueous 1 M sodium hydroxide solution. The mixture was stirred at 23 °C for 20 minutes, then the biphasic mixture was extracted three times with dichloromethane. The organic extractions were pooled then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (40-85% 3: 1 ethyl acetate: ethanol in heptane.) The desired fractions were pooled then concentrated under reduced pressure to afford a white solid as 2-((3-bromo-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro[3.3]heptane (316 mg, 52%) that was used without further purification. LCMS m / z = 405.2 [M+H]+. 'H NMR (500 MHz, CD2CI2): 8 (ppm)= 6.74 (s, 1H), 4.05 (s, 3H), 3.94 (s, 4H), 3.88 - 3.82 (m, 2H), 3.33 - 3.26 (m, 2H), 3.17 (s, 4H), 2.14 - 2.03 (m, 1H), 1.58 - 1.53 (m, 2H), 1.24 - 1.14 (m, 2H).

[0325] 2. Synthesis of 2-((3-(azetidin-l-yl)-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-

[0326] ( tetrahydro-2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane A vial containing 2-((3-bromo-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran- 4-yl)-2,6-diazaspiro[3.3]heptane (72 mg, 179 umol), azetidine (0.04 mL, 593 umol), BrettPhos Pd G3 (48 mg, 53 umol), and sodium tert-butoxide (77 mg, 803 umol) in anhydrous dioxane (1 mL) was degassed and backfilled with nitrogen. (Repeated evacuation and nitrogen backfill three times.) The heterogeneous reaction mixture was carefully heated to 90 °C and monitored with LCMS. After 19 hours, the heterogeneous reaction was cooled to room temperature then carefully partitioned between water and dichloromethane. The aqueous layer was extracted two additional times with dichloromethane. The organic extractions were pooled then washed once saturated aqueous sodium chloride solution, then the organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (60-100% 3: 1 ethyl acetate: ethanol in heptane.) The desired fractions were pooled then concentrated under reduced pressure to afford a colorless film that was dissolved in DMSO and few drops of water then filtered. The homogeneous solution was submitted for mass directed reverse phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 pm, 30 mm x 100 mm column with mobile phase H2O (A) and MeCN (B) and a gradient of 5 - 35 % B (0.2% NH4OH final v / v % modifier) with flow rate at 30 mL / min. The desired fractions were pooled then concentrated under reduced pressure to afford a colorless film as 2-((3- (azetidin-l-yl)-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane (14 mg, 20 % yield). LCMS m / z = 382.4 [M+H]+. 'H NMR (500 MHz, CD2CI2): 8 (ppm) = 5.95 (s, 1H), 3.92 - 3.87 (m, 8H), 3.86 - 3.82 (m, 5H), 3.36 - 3.18 (m, 6H), 2.38 - 2.32 (m, 2H), 2.19 (br s, 1H), 1.57 (br d, J = 12.5 Hz, 2H), 1.29 - 1.19 (m, 2H).

[0327] Example 8: 2-((3-cyclopropyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro [3.3] heptane

[0328] 2-((3-cyclopropyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane was obtained (48.2 mg, 100%) as a yellow oil, from 2-tetrahydropyran-

[0329] 4-yl-2,6-diazaspiro[3.3]heptane hydrochloride and 5-cyclopropyl-2-methyl-pyrazole-3- sulfonyl chloride, following a similar procedure to that described in Example 1. LCMS m / z = 367.2 [M+H]+, Rf= 0.51 min.

[0330] Example 9: 2-(furan-2-ylmethyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-

[0331] 2,6-diazaspiro [3.3] heptane

[0332] 1. Synthesis of tert-butyl 6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-

[0333] 2, 6-diazaspiro[ 3.3 ]heptane-2-carboxylate

[0334] DIPEA (21.63 g, 167.39 mmol, 29.16 mL) was added to a vial containing tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate (7.5 g, 31.95 mmol, Hydrochloride) in anhydrous dichloromethane (200 mL) . After 5 minutes, 2-methyl-6- (trifluoromethyl)pyridine-3-sulfonyl chloride (6.91 g, 26.63 mmol) was added. Upon complete addition of sulfonyl chloride, the reaction was stirred at RT. After 3 hours, the reaction was carefully quenched with water. The solution was extracted three times with dichloromethane. The organic extractions were pooled then washed with NaHCCh (sat, aq.) and water. The material was purified by recrystallization from MeOH / Water to afford the desired compound (23.96g, 83.5%). LCMS m / z = 422.1 [M+H]+. 'H NMR (500 MHz, CHLOROFORM-tZ) 5 ppm 8.29 (d, . / =7.94 Hz, 1 H), 7.59 (d, J=8.24 Hz, 1 H), 4.02 (s, 4 H), 3.97 (s, 4 H), 2.83 (s, 3 H), 1.35 (s, 9 H).

[0335] 2. Synthesis of tert-butyl 6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-

[0336] 2, 6-diazaspiro[ 3.3 ]heptane-2-carboxylate tert-Butyl 2-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane-6- carboxylate (1 g, 2.37 mmol) was dissolved in acetonitrile (7 mL) and p-toluenesulfonic acid monohydrate (902.73 mg, 4.75 mmol) was added. The reaction was stirred at RT for 2 hr. The thick white solid was filtered, and the filter cake rinsed with acetonitrile to afford the desired compound in quantitative yield as a TsOH salt. LCMS m / z = 322.1 [M+H]+.JH NMR (500 MHz, DMSO-i / ,) 8 ppm 8.44 - 8.58 (m, 3 H), 8.04 (d, J=8.24 Hz, 1 H), 7.56 (d, J=7.94 Hz, 2 H), 7.19 (d, .7=7.94 Hz, 2 H), 4.14 - 4.20 (m, 8 H), 2.87 (s, 3 H), 2.35 (s, 3 H).

[0337] 3. Synthesis of 2-(furan-2-ylmethyl)-6-( (2-methyl-6-(trifluoromethyl)pyridin-3- yl) sulfonyl) -2, 6-diazaspiro[ 3.3 ] heptane

[0338] To a mixture of tert-butyl 6-((2-methyl-6-(trifluorom ethyl )pyri din-3 -yl)sulfonyl)-2, 6- diazaspiro[3.3]heptane-2-carboxylate) TsOH salt (35 mg, 70.9 pmol), furan-2-carbaldehyde (8.2 pL, 99 pmol) and DIEA (27 pL, 156 pmol) in 1ml 1,2-di chloroethane was added tetramethylammonium triacetoxyborohydride (75 mg, 354 pmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduce pressure and the residue was mixed with ammonium hydroxide (1ml of 5% solution in MeOH). The resulting mixture was evaporated under reduce pressure and the residue was dissolved in DMSO (appr. 1 ml up to 100 mg of product). The solution was neutralized with acetic acid, filtered, and submitted for mass directed reverse phase HPLC purification, by HPLC Purification was performed using Agilent 1260 Infinity systems equipped with DAD and mass-detector. Waters Sunfire C18 OBD Prep Column, 100 A, 5 pm, 19 mm * 100 mm with SunFire Cl 8 Prep Guard Cartridge, 100 A, 10 pm, 19 mm x 10 mm was used, deionized water (phase A) and acetonitrile (phase B) were used as an eluent with a gradient of 5 - 35 % B to afford the desired compound (11.9 mg, 41.2%). LCMS m / z = 402.0 [M+H]+. 'H NMR (DMSO-d6, 500 MHz): 6 (ppm) 8.42 (d, J=8.2 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.51 (d, J=1.9 Hz, 1H), 6.33 (t, J=2.5, 2.5 Hz, 1H), 6.17 (d, J=3.1 Hz, 1H), 3.97 (s, 4H), 3.42 (s, 2H), 3.21 (s, 4H), 2.79 (s, 3H)

[0339] Examples 10 - 34: The Examples 10 - 34 in Table A were prepared using a similar method described in Example 9 (step 3) from either the TsOH or TFA salt of 2-((2-methyl-6- (trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and the corresponding aldehyde. Table A

[0340] Example 35: 2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-(pyridin-3- ylmethyl)-2,6-diazaspiro [3.3] heptane

[0341] To a suspension of 2-((2-methyl-6-(trifluorom ethyl )pyri din-3 -yl)sulfonyl)-2, 6- diazaspiro[3.3]heptane trifluoroacetate salt (59 mg, 140 umol) and potassium carbonate (56 mg, 410 umol) in DMF was added 3 -(chi orom ethyl )pyri dine hydrochloride (276 mg, 160 umol) . The reaction mixture was stirred at 80 °C for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organics were evaporated, and the residue purified by liquid chromatography using a Waters XSelect CSH Cl 8, 5 pm, 30 mm x 100 mm column with mobile phase H2O (A) and MeCN (B) and a gradient of 5 - 70 % B (0.2% NH4OH final v / v % modifier) with flow rate at 30 mL / min. The desired fractions were pooled then concentrated under reduced pressure to afford the desired compound (31 mg, 56%) as a yellow solid. LCMS m / z = 413.2 [M+H]+. Rf= 1.22 min.

[0342] Examples 36-37:

[0343] Examples 36-37 in Table B were prepared using a similar method described in Example 35 from the TFA salt of 2-((2 -methyl-6-(trifluorom ethyl )pyri din-3 -yl)sulfonyl)-2, 6- diazaspiro[3.3]heptane and the corresponding halide.

[0344] Table B

[0345]

[0346] Example 38: 2-((l-methyl-lH-pyrazol-3-yl)methyl)-6-((4-methyl-2-

[0347] (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0348] 1. Synthesis of 5-(benzylthio)-4-methyl-2-(trifluoromethyl)pyrimidine

[0349] To a solution of 5-bromo-4-methyl-2-(trifluoromethyl)pyrimidine (590 mg, 2.45 mmol) and BnSH (550 mg, 4.43 mmol, 519.85 uL) in Dioxane (15 mL) was added DIPEA (949.18 mg, 7.34 mmol, 1.28 mL) and Pd(tBusP) (187.66 mg, 367.21 umol). The reaction mixture was stirred at 100 °C for 12 hr under a nitrogen atmosphere. The mixture was diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (EtOAc in petroleum ether = 0~2%) to give the desired compound (620 mg, 89% ) as a yellow oil. LCMS m / z = 285.0 [M+H]+.JH NMR (400 MHz, CDC13): 8 ppm 8.50 (s, 1H), 7.36-7.29 (m, 5H), 4.23 (s, 2H), 2.58 (s, 3H).

[0350] 2. Synthesis of 4-methyl-2-(trijluoromethyl)pyrimidine-5-sulfonyl chloride

[0351] To a solution of 5-(benzylthio)-4-methyl-2-(trifluoromethyl)pyrimidine (110 mg, 386.92 pmol) in DCM (5 mL) and water (1 mL) was added a solution of SO2CI2 (365.55 mg, 2.71 mmol, 219.55 pL) in DCM (1 mL) dropwise over 5 minutes at 0~5 °C. The mixture was stirred at 0~5 °C for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired compound (81.8 mg, crude) as a yellow oil which was not purified further. 'H NMR (400 MHz, CDCI3): 6 ppm 9.36 (s, 1H), 2.33 (s, 3H).

[0352] 3. Synthesis of tert-butyl 6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-

[0353] To a solution of 4-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride (232.40 mg, 959.25 umol, 0.5 Oxalate) and DIPEA (371.92 mg, 2.88 mmol, 501.24 uL) in DCM (5 mL) was added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (250 mg, 959.25 umol) at 0 °C. The mixture was stirred at 0 °C under N2 for 2 hours. The mixture was concentrated to give the residue, which was purified by silica gel chromatography (EtOAc in Petroleum ether from 0 % to 30 %) to give the desired compound (288 mg, 681.78 umol, 71%) as a colorless oil. LCMS m / z = 367.0 [M+H]+.JH NMR (400 MHz, CDCI3): 8 ppm 9.18 (s, 1 H), 4.15 (s, 4 H), 4.06 (s, 4 H), 2.90 (s, 3 H), 1.43 (s, 9 H).

[0354] 4. Synthesis of 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro [ 3.3 ] heptane

[0355] To a solution of tert-butyl 6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (70 mg, 165.71 umol) in HFIP (2 mL) was added TFA (56.68 mg, 497.13 umol) at 20 °C under N2, the mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The product was used for next step without further purification. The desired compound (72 mg, crude, TFA salt) was obtained as a light yellow solid. LCMS m / z = 323.0 [M+H]+.JH NMR (400 MHz, CDCI3) 8 ppm 9.18 (s, 1 H), 4.36-4.21 (m, 8 H), 2.89 (s, 3 H).

[0356] 5. Synthesis of 2-((l-methyl-lH-pyrazol-3-yl)methyl)-6-((4-methyl-2-

[0357] To a solution of 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane (72 mg, 165.40 umol, TFA salt) (Adjust pH to 6-7 with triethylamine) in MeOH (2 mL) was added NaBHiCN (41.58 mg, 661.58 umol) and 1-methyl-lH-pyrazole- 3-carbaldehyde (36.42 mg, 330.79 umol). The mixture was stirred at 20°C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 21%-51%, l lmin). The desired compound (25.84 mg, 59.66 umol, 36.1% yield) was obtained as a white solid. LCMS m / z = 417.1 [M+H]+. 'HNMR (400 MHz, CDCI3) 6 ppm 9.17 (s, 1H), 7.27 (d, J=2.0 Hz, 1H), 6.10 (d, J=2.0 Hz, 1H), 4.10 (s, 4H), 3.85 (s, 3H), 3.57 (s, 2H), 3.39 (s, 4H), 2.89 (s, 3H).

[0358] Example 39: 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-((l-methyl- lH-pyrazol-3-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0359] 1. Synthesis of 5-bromo-4-methylpyrimidine-2-carbonitrile A mixture of 5-bromo-2-chloro-4-methylpyrimidine (2 g, 9.64 mmol), NaCN (500.81 mg, 10.22 mmol) and DABCO (400.12 mg, 3.57 mmol, 392.28 L) in DMSO (40 mL) and H2O (40 mL) was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 14 hours under nitrogen. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 100 / 1 to 10 / 1) to give the desired compound (1.76 g, 8.00 mmol, 83) as a yellow solid. LCMS m / z = 197.7 [M+H]+.1H NMR (400 MHz, CDCI3): 8 ppm 8.80 (s, 1H), 2.70 (s, 3H).

[0360] 2. Synthesis of l-(5-bromo-4-methylpyrimidin-2-yl)ethan-l-one

[0361] MeMgBr (3 M, 8.00 mL) was added to a -40 °C solution of 5-bromo-4-methylpyrimidine-2- carbonitrile (1.76 g, 8.00 mmol, 90% purity) in THF (40 mL). The material was stirred at -40 °C for 6 hrs. Water (50 ml) was added followed by enough 2M HC1 to make the reaction mixture pH = 2 at 25 °C with stirring for 2 hours. The reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The material was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=100 / l to 9 / 1) to give the desired compound (1.08 g, 56.5%) as a lightyellow solid. LCMS m / z = 216.7 [M+H]+. *H NMR (400 MHz, CDCI3): 6 ppm 8.86 (s, 1H), 2.76 (s, 3H), 2.74 (s, 3H).

[0362] 3. Synthesis of 5-bromo-2-( 1, l-difluoroethyl)-4-methylpyrimidine

[0363] A solution of l-(5-bromo-4-methylpyrimidin-2-yl)ethan-l-one (1.6 g, 6.70 mmol) in DAST (8.79 g, 54.51 mmol, 7.20 mL) was stirred at 60 °C for 4 hours. The reaction was quenched with saturated NaHCCL aq. until pH = 7, then extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over ISfeSCL, filtered, and concentrated under reduced pressure to give the desired product (1.7 g, 6.45 mmol, 96.4%) as a brown oil. LCMS m / z = 236.5 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 8.79 (s, 1H), 2.71 (s, 3H), 2.05 (t, J = 18.8 Hz, 3H).

[0364] 4. Synthesis of 5-(benzylthio)-2-(l , l-dijluoroethyl)-4-methylpyrimidine

[0365] To a solution of BnBr (1.43 g, 8.35 mmol, 992.10 pL), K2CO3 (2.60 g, 18.79 mmol), Cui (79.54 mg, 417.64 pmol) and thiourea (635.83 mg, 8.35 mmol) in DMF (20 mL) and H2O (1 mL) was degassed and purged with N2. The mixture was stirred at 25 °C for 60 minutes, and 5-bromo-2-(l,l-difluoroethyl)-4-m ethylpyrimidine (1.1 g, 4.18 mmol) was added. The mixture was stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=100 / l to 3 / 1) to give the desired product (470 mg, 1.51 mmol, 36.1%) as a light yellow solid.XH NMR (400 MHz, CDCI3): 6 ppm 8.48 (s, 1H), 7.33 - 7.27 (m, 5H), 4.17 (s, 2H), 2.56 (s, 3H), 2.02 (t, J = 18.8 Hz, 3H).

[0366] 5. Synthesis of 2-(l, l-difluoroethyl)-4-methylpyrimidine-5-sulfonyl chloride

[0367] To a solution of 5-(benzylthio)-2-(l,l-difluoroethyl)-4-methylpyrimidine (200 mg, 642.09 pmol) in DCM (10 mL) and H2O (1 mL) was added dropwise at 0 °C. After addition, and then SO2CI2 (606.64 mg, 4.49 mmol, 449.36 pL) in DCM (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched by addition H2O (5 mL) at 0 °C, and then diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product (180 mg, crude) as a yellow oil, which was used for next step without further purification. LCMS m / z = 256.9 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 ppm 9.30 (s, 1H), 3.07 (s, 3H), 2.12-2.06 (m, 3H).

[0368] 6. Synthesis of tert-butyl 6-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5- yl) sulfonyl) -2, 6-diazaspiro[ 3.3 ]heptane-2-carboxylate

[0369] To a solution of 2-(l,l-difluoroethyl)-4-methylpyrimidine-5-sulfonyl chloride (160 mg, 623.40 pmol) in DCM (10 mL) was added DIPEA (322.28 mg, 2.49 mmol, 434.34 pL) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (359.45 mg, 1.25 mmol). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiCL, Petroleum ether / ethyl acetate = 100 / 0 to 3 / 1) to give the desired product (95 mg, 204.32 umol, 32.8%) as a light yellow solid. LCMS m / z = 362.8 [M+H]+. ' H NMR (400 MHz, CDCI3) 8 ppm 9.13 (s, 1H), 4.12 (s, 4H), 4.05 (s, 4H), 2.88 (s, 3H), 2.07 (t, J = 18.4 Hz 3H), 1.43 (s, 9H).

[0370] 7. Synthesis of 2-((2-(l, l-dijluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0371] To a solution of tert-butyl 6-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (95 mg, 204.32 pmol) in HFIP (8 mL) was added TFA (69.89 mg, 612.97 pmol, 45.38 pL). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the desired product (105 mg, crude, TFA salt) as a yellowish solid, which was used for next step without further purification. 'HNMR 00 MHz, CDCI3) 6 ppm 9.14 (s, 1H), 4.33 (br s, 4H), 4.23 (s, 4H), 2.86 (s, 3H), 2.07 (t, J = 18.8 Hz, 3H). 8. Synthesis of 2-((2-(l, l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-((l- methyl-lH-pyrazol-3-yl)methyl)-2, 6-diazaspiro[ 3.3 ] heptane

[0372] 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-((l-methyl-lH-pyrazol-3- yl)methyl)-2,6-diazaspiro[3.3]heptane (21.29 mg, 22%) was obtained from 2-((2-(l,l- difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane following a similar procedure to that described in Example 38 (step 5). LCMS m / z = 413.1 [M+H]+. 'H NMR (400 MHz, CDC13) 8 ppm 9.12 (s, 1H), 7.29-7.26 (m, 1H), 6.11 (d, J = 2.0 Hz, 1H), 4.07 (s, 4H), 3.85 (s, 3H), 3.57 (s, 2H), 3.39 (s, 4H), 2.86 (s, 3H), 2.07 (t, J = 18.4 Hz, 3H).

[0373] Example 40: 2-((6-(l,l-difluoroethyl)-2-methylpyridin-3-yl)sulfonyl)-6-((l-methyl-lH- pyrazol-3-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0374] 1. Synthesis of l-(5-bromo-6-methylpyridin-2-yl)ethan-l-one

[0375] To a solution of 3-bromo-2,6-dimethylpyridine (10 g, 39.85 mmol) in toluene (200 mL) was added n-BuLi (2.5 M, 17.54 mL) at -78 °C under a nitrogen atmosphere. After stirring for Ihr, DMA (10.42 g, 119.56 mmol, 11.12 mL) was added, the mixture was stirred at -78 °C for Ihr and slowly warmed to 20 °C. The reaction was poured into saturated aqueous ammonium chloride solution, and extraction and liquid separation. The extract was purified by silica gel chromatography (Petroleum ether / EtOAc = 1 / 0 to 8 / 1) to give the desired compound (8.1 g, 37.84 mmol, 95%) as a yellow solid. ' H NMR (400 MHz, CDC13) 6 ppm 7.92 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 2.72 (s, 3H), 2.69 (s, 3H).

[0376] 2. Synthesis of 3-bromo-6-( 1, 1 -difluoroethyl) -2 -methylpyridine

[0377] A solution of l-(5-bromo-6-methylpyridin-2-yl)ethan-l-one (8.1 g, 37.84 mmol) in DAST (36.60 g, 227.06 mmol, 30 mL) was stirred at 60 °C for 4 hours. The reaction was quenched with saturated NaHCCL aq. until pH = 7, and it was extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by silica gel chromatography (Petroleum ether / EtOAc = 20 / 1 to 10 / 1) to give the desired compound (4.5 g, 19.06 mmol, 50.4%) as a colorless oil. LCMS m / z = 236.0 [M+H]+. 'HNMR (400 MHz, CDCI3) 5 ppm: 7.89 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 2.69 (s, 3H), 2.00 (t, J=18.4 Hz, 3H).

[0378] 3. Synthesis of 2-(l, l-difluoroethyl)-4-methylpyrimidine-5-sulfonyl chloride

[0379] 2-(l,l-difluoroethyl)-4-methylpyrimidine-5-sulfonyl chloride (650 mg, crude) was obtained from 3-bromo-6-(l,l-difluoroethyl)-2-methylpyridine following a similar procedure to that described in Example 39 (steps 4 and 5). LCMS m / z = 256.1 [M+H]+. 'H NMR (400 MHz, CDCI3) 8 ppm 8.44 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 3.05 (s, 3H), 2.05 (t, J=18.8 Hz, 3H).

[0380] 4. Synthesis of 2-(( 6-( 1, l-difluoroethyl)-2-methylpyridin-3-yl )sulfonyl)-6-( (1- methyl-lH-pyrazol-3-yl)methyl)-2, 6-diazaspiro[ 3.3 ] heptane

[0381] 2-((6-( 1 , 1 -difluoroethyl)-2-methylpyri din-3 -yl)sulfonyl)-6-(( 1 -methyl- lH-pyrazol-3 - yl)methyl)-2,6-diazaspiro[3.3]heptane (64 mg) was obtained from 2-(l,l-difluoroethyl)-4- methylpyrimidine-5-sulfonyl chloride following a similar procedure to that described in Example 39 (steps 6-8). LCMS m / z = 412.1 [M+H]+. *HNMR (400 MHz, CDCI3) 8 ppm 8.27 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 4.00 (s, 4H), 3.86 (s, 3H), 3.41 (s, 2H), 3.27 (s, 4H), 2.85 (s, 3H), 2.01 (t, J=18.4 Hz, 3H).

[0382] Example 41 : 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((l-methyl- lH-pyrazol-3-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0383] 1. Synthesis of 2, 4-dimethyl-6-(trijluoromethyl )pyridin-3-amine

[0384] To a solution of 2,4-dibromo-6-(trifluoromethyl)pyridin-3-amine (1 g, 3.13 mmol) in dioxane (15 mL) and water (1.5 mL) was added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (935.59 mg, 15.63 mmol), K2CO3 (1.73 g, 12.50 mmol) and Pd(dppf)C12 (255.28 mg, 312.59 pmol) at 25 °C under N2. The mixture was stirred at 100 °C for 16 hr under N2. The mixture was filtered and diluted with water (20 mL), extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (EtOAc in petroleum ether = from 0% to 70%) to give the desired compound (430 mg, 2.26 mmol, 72.3%) as a yellow solid. LCMS m / z = 191.0 [M+H]+. ' H NMR (500 MHz, CHLOROFORM-d) 5 ppm 7.26 (s, 1H), 3.86 (s, 2H), 2.47 (s, 3H), 2.21 (s, 3H).

[0385] 2. Synthesis of 2, 4-dimethyl-6-(trifluoromethyl )pyridine-3-sulfonyl chloride

[0386] Thionyl chloride (2 mL) was added over 10 min to water (12 mL), while the temperature was maintained 0-7 °C, then the solution was stirred at 15 °C for 12hr. CuCI (1.56 mg, 15.78 pmol) was added, and the reaction cooled to -3 °C. In separate flask, a solution of 2,4-dimethyl-6- (trifluoromethyl)pyridin-3-amine (150 mg, 788.79 pmol) in HCI (12 M, 1 mL) at -5 °C was added dropwise to a solution of NaNCL (58.23 mg, 844.00 pmol) in water (0.6 mL) while maintaining temperature -5 to 0° C. When the addition was complete, this solution was then added to the precooled thionyl chloride solution and stirred at -2 °C for 10 min, then at 0 °C for 75 min. The reaction was added water H2O (30 mL) and extracted with DCM (50 mL x 5), dried over anhydrous ISfeSCU, filtered, and concentrated to give the desired compound (70 mg, crude) as a yellow oil which was used directly in the next reaction.

[0387] 3. Synthesis of 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((l- methyl-lH-pyrazol-3-yl)methyl)-2, 6-diazaspiro[ 3.3 ] heptane

[0388] 2-((2,4-dimethyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-6-((l-methyl-lH-pyrazol-3- yl)methyl)-2,6-diazaspiro[3.3]heptane (18.5 mg) was obtained from 2,4-dimethyl-6- (trifluoromethyl)pyridine-3-sulfonyl chloride following a similar procedure to that described in Example 39 (steps 6-8). LCMS m / z = 430.1 [M+H]+. 'H NMR (400 MHz, MeOD) 5 ppm 7.67 (s, 1H), 7.50 (s, 1H), 7.38 (s, 1H), 4.02 (s, 4H), 3.84 (s, 3H), 3.47 (s, 2H), 3.36 (s, 4H), 2.87 (s, 3H), 2.73 (s, 3H). Example 42: 2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((l- methyl-lH-pyrazol-4-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0389] 1. Synthesis of 4-bromo-2-(trifluoromethyl)pyrimidin-5-amine ACN

[0390] To a solution of trifluoromethyl)pyrimidin-5-amine (10 g, 61.31 mmol) in ACN (100 mL) was added NBS (14.19 g, 79.71 mmol). The mixture was stirred at 20 °C for 16 h under nitrogen. The solvent was evaporated and the residue was partitioned in water (10 mL) and ethyl acetate (80 mL). The layers were separated, and the aqueous layer was extracted (80 mL x 2) with ethyl acetate. The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude was purified by silica gel chromatography (Ethyl acetate in Petroleum ether from 0% to 20%) to give the desired compound (8.8 g, 36.36 mmol, 59.3%) as a brown oil. LCMS m / z = 243.9 [M+H]+.JH NMR (500 MHz, CDC13) 8 ppm 8.18 (s, 1H), 4.55 (br s, 2H).

[0391] 2. Synthesis of 2-(trifluoromethyl)-4-vinylpyrimidin-5-amine

[0392] F N~ Pd(dppf)CI2, K2CO3F N~

[0393] Dioxane, H2O

[0394] To a solution of 4-bromo-2-(trifluoromethyl)pyrimidin-5-amine (8.6 g, 35.54 mmol) in dioxane (150 mL) and water (30 mL) was added 4,4,5,5-tetramethyl-2-vinyl-l,3,2- dioxaborolane (10.95 g, 71.08 mmol, 12.06 mL), Pd(dppf)C12 (2.60 g, 3.55 mmol) and K2CO3 (14.73 g, 106.61 mmol) under N2. The mixture was stirred at 90 °C for 3 hr. The reaction mixture was filtered and extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether / EtOAc = 1 / 0 to 1 / 1) to give the desired compound (5 g, 26.44 mmol, 74.4%) as a yellow oil. LCMS m / z = 190.1 [M+H]+. 'HNMR (400 MHz, CDC13) 8 ppm 8.25 (s, 1H), 6.85-6.73 (m, 1H), 6.64-6.56 (m, 1H), 5.82- 5.79 (m, 1H).

[0395] 3. Synthesis of 4-ethyl-2-(trifluoromethyl)pyrimidin-5-amine

[0396] To a solution of 2-(trifluoromethyl)-4-vinylpyrimidin-5-amine (4.7 g, 24.85 mmol) in THF (30 mL) was added Pd / C (2.64 g, 2.48 mmol, 10% purity) under H2 atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (15 PSI) at 25 °C for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give compound 5 (4.2 g, crude) as a yellow-green liquid. The reaction mixture was used in next step without further purification. LCMS m / z = 192.1 [M+H]+. ' H NMR (500 MHz, CDCI3) 6 ppm 8.14 (s, 1H), 4.00 (s, 2H), 2.73 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.5 Hz, 3H).

[0397] 4. Synthesis of 4-bromo-6-ethyl-2-(trifluoromethyl)pyrimidin-5-amine

[0398] To a solution of 4-ethyl-2-(trifluoromethyl)pyrimidin-5-amine (4.4 g, 23.02 mmol) in ACN (40 mL) was added NBS (4.51 g, 25.32 mmol). The mixture was stirred at room temperature for 12 hr under nitrogen. Solvent was evaporated, the residue was partitioned in water (100 mL) and EtO Ac (100 mL), the layer was separated, and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 0-30% ethyl acetate in Petroleum ether to afford the desired compound (3.55 g, 13.15 mmol, 57.1%) as a yellow oil. LCMS m / z = 270.0 [M+H]+. 'H NMR (400 MHz, CDCI3) 6 ppm 4.56-4.34 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 1.36 (t, J=7.6 Hz, 3H).

[0399] 5. Synthesis of 4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-amine

[0400] To a solution of 4-bromo-6-ethyl-2-(trifluoromethyl)pyrimidin-5-amine (3.55 g, 13.15 mmol) in dioxane (35 mL) and water (3.5 mL) was added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (4.95 g, 39.44 mmol, 5.51 mL), Pd(dppf)C12 (961.88 mg, 1.31 mmol) and K2CO3 (4.54 g, 32.86 mmol) under N2. The mixture was stirred at 90 °C for 3 hr. The reaction mixture was filtered and extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether / EtOAc = 100 / 1 to 3 / 1) to give the desired compound (2.47 g, 12.04 mmol, 91.6%) as a yellow solid. LCMS m / z = 206.1 [M+H]+. 'H NMR (500 MHz, CDCI3) 8 ppm 3.60 (br s, 2H), 2.72 (q, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.34 (t, J=7.5 Hz, 3H).

[0401] 6. Synthesis of 5-bromo-4-ethyl-6-methyl-2-(trijluoromethyl)pyrimidine

[0402] To a solution of 4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-amine (2.5 g, 12.0 mmol) in CH3CN (20 mL) was added CuBi2 (4.0 g, 18.0 mmol, 845.5 pL) and t-BuONO (1.86 g, 18.0 mmol, 2.0 mL) in sequence under N2. The reaction mixture was stirred at 15 °C for 30 min. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc in petroleum ether = 0% ~5%) to give the desired compound (2.75 g, 10.22 mmol, 84.9%) as a colorless oil. LCMS m / z = 269.0 [M+H]+. 'H NMR (500 MHz, CDC13) 5 ppm 3.03 (q, J=7.5 Hz, 2H), 2.73 (s, 3H), 1.33 (t, J=7.5 Hz, 3H).

[0403] 7. Synthesis of 4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride

[0404] 4-Ethyl-6-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride (1.1 g crude) was obtained from 5-bromo-4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidine following a similar procedure to that described in Example 39 (steps 4 and 5).XH NMR (400 MHz, CDCI3) 6 ppm 3.41 (q, J=7.6 Hz, 2H), 3.07 (s, 3H), 1.43 (t, J=7.6 Hz, 3H).

[0405] 8. Synthesis of 2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-

[0406] 6-((l -methyl- lH-pyrazol-4-yl)methyl)-2, 6-diazaspiro[ 3.3 ] heptane

[0407] 2-((4-Ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((l-methyl-lH-pyrazol- 4-yl)methyl)-2,6-diazaspiro[3.3]heptane (55.2 mg) was obtained from 4-ethyl-6-methyl-2- (trifluoromethyl)pyrimidine-5-sulfonyl chloride following a similar procedure to that described in Example 39 (steps 6-8). LCMS m / z = 445.1 [M+H]+. 'H NMR (500 MHz, CDC13) 8 ppm 7.34 (s, 1H), 7.23 (s, 1H), 4.07 (s, 4H), 3.86 (s, 3H), 3.43 (s, 2H), 3.30 (s, 4H), 3.22 (q, J=7.5 Hz, 2H), 2.89 (s, 3H), 1.33 (t, J=7.5 Hz, 3H).

[0408] Example 43: 2-((l-methyl-3-phenyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-

[0409] 4-yl)-2,6-diazaspiro [3.3] heptane

[0410] 1. Synthesis of l-methyl-3-phenyl-lH-pyrazole dioxane, H2O To a solution of 3-bromo-l-methyl-lH-pyrazole (3 g, 18.63 mmol, 1.89 mL) in dioxane (50 mL) and water (10 mL) was added phenylboronic acid (4.54 g, 37.27 mmol), Pd(dppf)C12 (1.36 g, 1.86 mmol) and K2CO3 (7.73 g, 55.90 mmol) under N2. The mixture was stirred at 100 °C for 14 hr. The reaction mixture was filtered and extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc from 0% to 50%) to give the desired compound (3 g, crude) as yellow liquid. LCMS m / z = 159.2 [M+H]+. *HNMR (500 MHz, CDCI3) 8 ppm 7.71-7.67 (m, 2H), 7.31-7.26 (m, 3H), 7.21-7.15 (m, 1H), 6.43 (d, J=2.0 Hz, 1H), 3.85 (s, 3H).

[0411] 2. Synthesis of lithium l-methyl-3-phenyl-lH-pyrazole-5-sulfmate

[0412] To a solution of l-methyl-3-phenyl-lH-pyrazole (1 g, 6.32 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 3.03 mL) at -65 °C under N2. The mixture was stirred at 0 °C for Ihr and then cooled to -70 °C. Excess sulfur dioxide was bubbled to the mixture for 10 min, while maintaining the temperature below -65 °C. The reaction was stirred at -65 °C for Ihr and was then allowed to warm to 25 °C. The reaction was concentrated to give the desired compound (1 g, crude) as a white solid.1H NMR (500 MHz, DMSO-d6) 5 ppm 7.79-7.76 (m, 2H), 7.40- 7.33 (m, 3H), 6.68 (d, J=2.0 Hz, 1H), 3.88 (s, 3H).

[0413] 3. Synthesis of l-methyl-3-phenyl-lH-pyrazole-5-sulfonyl chloride

[0414] A solution of lithium l-methyl-3-phenyl-lH-pyrazole-5-sulfmate (1 g, 4.38 mmol) was added to a biphasic mixture of DCM (5 mL) and water (5 mL). NCS (585.15 mg, 4.38 mmol) was added portion-wise with vigorous stirring. The reaction mixture was stirred further for 30 min at 0 °C. The organic layer was separated, and the aqueous layer was extracted with DCM (30 mL x 5). The combine organic layer was dried over sodium sulfate and evaporated under vacuum to give the desired compound (1 g, crude) as a yellow oil. LCMS m / z = 257.2 [M+H]+.

[0415] 4. Synthesis of 2-((l -methyl-3-phenyl-lH-pyrazol-5-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0416] 2-((l-Methyl-3-phenyl-lH-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained from l-methyl-3 -phenyl- lH-pyrazole-5-sulfonyl chloride following a similar procedure to that described in Example 38 (steps 3 and 4). LCMS m / z = 319.1 [M+H]+.JH NMR (400 MHz, MeOD) 5 ppm 7.85-7.80 (m, 2H), 7.44-7.33 (m, 3H), 7.24 (s, 1H), 4.20 (s, 3H), 4.13 (s, 8H).

[0417] 5. Synthesis of 2-((l-methyl-3-phenyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro- 2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0418] To a solution of 2-((l-methyl-3-phenyl-lH-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (180 mg, 417.24 pmol, TFA salt) and tetrahydro-4H-pyran-4-one (83.54 mg, 834.48 pmol, 77.07 pL) in MeOH (5 mL) was added TEA to pH = 5~6. Then NaBH3CN (131.10 mg, 2.09 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 2h. The mixture was concentrated and purified by prep-HPLC (Column: Boston Prime C18 150*30 mm*5 pm, Condition: water (NH3.H2O+NH4HCO3)-ACN, 37%~67%, Flow Rate (mL / min): 25) to give the desired compound (117.9 mg, 298.13 pmol, 71.4%) as a white solid. LCMS m / z = 403.2 [M+H]+. 'H NMR (400 MHz, CDC13) 8 ppm 7.81-7.77 (m, 2H), 7.47-7.34 (m, 3H), 7.06 (s, 1H), 4.15 (s, 3H), 4.00 (s, 4H), 3.97-3.91 (m, 2H), 3.37-3.25 (m, 6H), 2.16 (br s, 1H), 1.60 (br s, 2H), 1.37-1.24 (m, 2H).

[0419] Example 44: 2-((l-methyl-3-(pyridin-3-yl)-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro [3.3] heptane

[0420] 1. Synthesis of tert-butyl 6-((3-bromo-l-methyl-lH-pyrazol-5-yl)sulfonyl)-2,6- diazaspiro[ 3.3 ]heptane-2-carboxylate

[0421] To a solution of 3-bromo-l-methyl-lH-pyrazole-5-sulfonyl chloride and DIEA (896.45 mg, 6.94 mmol, 1.21 mL) in DCM (15mL) was slowly added tert-butyl 2,6-diazaspiro[3.3]heptane- 2-carboxylate in DCM (2 mL) at 0 °C. The mixture was stirred for 1 hr at 25 °C. The mixture was added water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (10 mL) and dried by Na2SO4. The residue was purified by silica gel chromatography (EtOAc in petroleum ether from 5% to 40%, Flow Rate (mL / min): 30) to give the desired compound (600 mg, crude) as white solid. LCMS m / z = 365.0 [M+H]+.JH NMR (400 MHz, CDC13) 8 ppm 6.75 (s, 1H), 4.05 (s, 3H), 4.01 (s, 8H), 1.42 (s, 9H).

[0422] 2. Synthesis of 2-((3-bromo-l-methyl-lH-pyrazol-5-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0423] To a solution of tert-butyl 6-((3-bromo-l-methyl-lH-pyrazol-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (600 mg, 1.42 mmol) in HFIP (10 mL) was added TFA (811.92 mg, 7.12 mmol, 545.28 pL). The mixture was stirred for 4 hr at 25 °C. The mixture was added water (30 mL), extracted with DCM (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired compound (710 mg, crude, TFA salt) as a white solid. LCMS m / z = 321.0 [M+H]+. 'H NMR (500 MHz, MeOD) 5 ppm 5.32 (s, 1H), 2.62 (s, 4H), 2.53 (s, 4H), 2.46 (s, 3H). 3. Synthesis of 2-((3-bromo-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro- 2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0424] 2-((3-Bromo-l -methyl- lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2, 6- diazaspiro[3.3]heptane (450 mg) was obtained from 2-((3-bromo-l-methyl-lH-pyrazol-5- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane following a similar procedure to that described in Example 43 (step 5). LCMS m / z = 405.2 [M+H]+. ‘HNMR (400 MHz, CDCI3) 6 ppm 6.76 (s, 1H), 4.06 (s, 3H), 4.00-3.96 (m, 2H), 3.49 (s, 8H), 3.45-3.41 (m, 1H), 3.37-3.30 (m, 2H), 1.94- 1.87 (m, 2H), 1.68-1.65 (m, 2H).

[0425] 4. Synthesis of 2-((l-methyl-3-(pyridin-3-yl)-lH-pyrazol-5-yl)sulfonyl)-6-

[0426] ( tetrahydro-2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0427] 2-((l-Methyl-3-(pyridin-3-yl)-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane (40 mg) was obtained from 2-((3-bromo-l-methyl-lH-pyrazol-5- yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3 ,3]heptane and pyri din-3 -ylboronic acid following a similar procedure to that described in Example 43 (step 1). LCMS m / z = 404.2 [M+H]+. 'HNMR (400 MHz, CDC13) 8 ppm 9.04-8.98 (m, 1H), 8.60 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.09-8.05 (m, 1H), 7.38-7.34 (m, 1H), 7.10 (s, 1H), 4.15 (s, 3H), 4.01 (s, 4H), 3.94- 3.90 (m, 2H), 3.36-3.29 (m, 2H), 3.25 (s, 4H), 2.17-2.08 (m, 1H), 1.56-1.55 (m, 2H), 1.33-1.22 (m, 2H).

[0428] Example 45: 2-((l-methyl-3-(pyridin-4-yl)-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro [3.3] heptane

[0429] 2-((l-methyl-3-(pyridin-4-yl)-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane was obtained from 2-((3-bromo-l-methyl-lH-pyrazol-5-yl)sulfonyl)- 6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane and pyridin-4-ylboronic acid following a similar procedure to that described in Example 43 (step 1). LCMS m / z = 404.2 [M+H]+. 'H NMR (400 MHz, CDC13) 8 ppm 8.67 (d, J=6.4 Hz, 2H), 7.68-7.65 (m, 2H), 7.15 (s, 1H), 4.16 (s, 3H), 4.01 (s, 4H), 3.96-3.90 (m, 2H), 3.37-3.29 (m, 2H), 3.26 (s, 4H), 2.18- 2.09 (m, 1H), 1.58 (d, J=13.2 Hz, 2H), 1.34-1.23 (m, 2H).

[0430] Example 46: 2-((3-cyclohexyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro [3.3] heptane

[0431] 1. Synthesis of 2-((3-( cyclohex- l-en-l-yl)-l -methyl- lH-pyrazol-5-yl )sulfonyl)-6- ( tetrahydro-2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0432] 2-((3 -(cyclohex- 1 -en- 1 -yl)- 1 -methyl- lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4- yl)-2,6-diazaspiro[3.3]heptane (130 mg) was obtained from 2-((3 -bromo- 1 -methyl- 1H- pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3 ,3]heptane and 2- (cyclohex-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane following a similar procedure to that described in Experiment 43 (stepl). LCMS m / z = 407.2 [M+H]+. 'H NMR (400 MHz, CDCI3) 6 ppm 6.76 (s, 1H), 6.36-6.32 (m, 1H), 4.05(s, 3H), 3.95-3.92 (m, 6H), 3.36-3.30 (m, 2H), 3.28-3.24 (m, 1H), 3.23-3.20 (m, 4H), 2.22-2.17 (m, 2H), 2.17-2.06 (m, 2H), 1.79-1.73 (m, 2H), 1.68-1.64 (m, 2H), 1.62-1.57 (m, 2H), 1.32-1.27 (m, 2H).

[0433] 2. Synthesis of 2-((3-cyclohexyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-

[0434] ( tetrahydro-2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0435] To a solution of 2-((3-(cyclohex-l-en-l-yl)-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6- (tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (130 mg, 319.77 pmol) in MeOH (10 mL) was added Pd / C (50 mg, 46.98 pmol, 10% purity) at 20 °C under N2. Then the mixture was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20 °C for 16 hr. The mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Column: Phenomenex Gemini-NX 150*30mm*5um, Condition: water (NH4HCO3)-ACN, 37%~65%, Flow Rate (mL / min): 25) to afford the desired compound (42 mg, 102.80 pmol, 32.1%) as a yellow solid. LCMS m / z = 409.2 [M+H]+. 'H NMR (400 MHz, CDCI3) 8 ppm 6.56 (s, 1H), 4.03 (s, 3H), 3.93-3.91 (m, 6 H), 3.33 (t, J=11.2 Hz, 2H), 3.21 (s, 4H), 2.66-2.60 (m, 1H), 2.14-2.12 (m, 1H), 1.97-1.92 (m, 2H), 1.81-1.80 (m, 2H), 1.76- 1.70 (m, 2H), 1.59-1.57 (m, 2H), 1.40-1.32 (m, 4H), 1.29-1.23 (m, 2H).

[0436] Example 47: 2-((3-cyclobutyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro [3.3] heptane

[0437] 1. Synthesis of 3-cyclobutyl-l-methyl-lH-pyrazole-5-sulfonyl chloride Thionyl chloride (6.12 g, 51.41 mmol, 3.75 mL) was added to water (10 mL) over 10 min, while the temperature was maintained 0-5 °C, then the solution was stirred at 20 °C for 12 hr. CuCl (32.74 mg, 330.67 pmol) was added, and the mixture was cooled to -3 °C. In another flask, a solution of 3-cyclobutyl-l-methyl-lH-pyrazol-5-amine (500 mg, 3.31 mmol) in HC1 (12 M, 3.12 mL) at -5 °C was added dropwise to the solution of NaNCL (250.96 mg, 3.64 mmol) in water (0.5 mL) while maintaining temperature -5 to 0 °C for 1 hr. When the addition was complete, this solution was added to the precooled thionyl chloride solution and stirred at -2 °C for 10 min, then at 0 °C for 75 min. The mixture was extracted with DCM (30 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated to give the desired compound (300 mg, crude) as yellow oil.JH NMR (400 MHz, CDC13) 5 ppm 6.08 (s, 1H), 3.78 (s, 3H), 3.52-3.43 (m, 1H), 2.32-2.30 (m, 2H), 2.18-2.13 (m, 2H), 1.91-1.86 (m, 2H).

[0438] 2. Synthesis of 2 -( (3-cyclobutyl-l-methyl-lH-pyrazol-5-yl )sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0439] 2-((3-cyclobutyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (60 mg crude) was obtained from 3-cyclobutyl-l-methyl-lH-pyrazole-5-sulfonyl chloride following a similar procedure to that described in Example 38 (steps 3,4). LCMS m / z = 297.1 [M+H]+.

[0440] 3. Synthesis of 2 -( (3-cyclobutyl-l-methyl-lH-pyrazol-5-yl )sulfonyl)-6-

[0441] ( tetrahydro-2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0442] 2-((3-Cyclobutyl-l-methyl-lH-pyrazol-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane was obtained (21 mg) from 2-((3-cyclobutyl-l-methyl-lH-pyrazol-5- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane following a similar procedure to that described in Example 43 (step 5). LCMS m / z = 381.1 [M+H]+. *HNMR (400 MHz, CDC13) 8 ppm 6.62 (s, 1H), 4.03 (s, 3H), 3.94 (s, 4H), 3.92-3.90 (m, 2H), 3.57-3.48 (m, 1H), 3.36-3.29 (m, 2H), 3.22 (s, 4H), 2.38-2.33 (m, 2H), 2.20-2.12 (m, 2H), 2.06-1.89 (m, 2H), 1.59-1.56 (m, 3H), 1.32-1.22 (m, 2H).

[0443] Example 48: l-(4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)piperidin-l-yl)ethan-l-one

[0444] 1. Synthesis of 2-bromo-6-(difluoromethyl)pyridin-3-amine

[0445] To a solution of 6-(difluoromethyl)pyridin-3-amine (550 mg, 3.82 mmol) in CH3CN (20 mL) was added NBS (679.23 mg, 3.82 mmol) at 0 °C. The mixture was stirred for 20 min at 0 °C under N2. The reaction mixture was concentrated in vacuo. The crude was purified by silica gel chromatography (EtOAc in petroleum ether from 10% to 30%) to afford the desired compound (760 mg, 3.41 mmol, 89.3%) as white solid. 'H NMR (500 MHz, CDCI3) 6 ppm 7.40 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.52 (t, J=55.5 Hz, 1H), 4.38 (br s, 2H).

[0446] 2. Synthesis of 6-(difluoromethyl)-2-ethylpyridin-3-amine

[0447] 6-(Difluoromethyl)-2-ethylpyri din-3 -amine was obtained (800 mg, crude) from 2-bromo-6- (difluoromethyl)pyri din-3 -amine following a similar procedure to that described in Example 42 (steps 2,3). LCMS m / z = 173.1 [M+H]+. *H NMR (400 MHz, CDC13) 8 ppm 7.30 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.56 (t, J=56.0 Hz, 1H), 3.82 (br s, 2H), 2.71 (q, J=7.6 Hz, 2H), 1.31 (t, J=7.6 Hz, 3H).

[0448] 3. Synthesis of 6-(difluoromethyl)-2-ethylpyridine-3-sulfonyl chloride

[0449] 6-(Difluoromethyl)-2-ethylpyridine-3-sulfonyl chloride (320 mg crude) was obtained from 6- (difluoromethyl)-2-ethylpyri din-3 -amine following a similar procedure to that described in Example 41 (step 2). 'HNMR (500 MHz, CDC13) 8 ppm 8.48 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 6.67 (t, J=55.0 Hz, 1H), 3.38 (q, J=7.5 Hz, 2H), 1.43 (t, J=7.5 Hz, 3H).

[0450] 4. Synthesis of 6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2- azaspiro[ 3.3 ] heptane

[0451] 6-((6-(Difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptane (700 mg crude) was obtained from 6-(difluoromethyl)-2-ethylpyridine-3 -sulfonyl chloride following a similar procedure to that described in Experiment 38 (steps 3,4). LCMS m / z = 318.1 [M+H]+. 'H NMR (400 MHz, MeOD) 5 ppm 8.42 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 6.75 (t, J=55.2 Hz, 1H), 4.24 (s, 4H), 4.14 (s, 4H), 3.18 (q, J=7.2 Hz, 1H), 1.33 (t, J=7.6 Hz, 3H).

[0452] 5. Synthesis of l-(4-(6-((6-(difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6- diazaspiro[ 3.3 ]heptan-2-yl)piperidin-l-yl)ethan-l-one l-(4-(6-((6-(Difluoromethyl)-2-ethylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptan-2- yl)piperidin-l-yl)ethan-l-one (55 mg) was obtained from 6-((6-(Difluoromethyl)-2- ethylpyridin-3-yl)sulfonyl)-2-azaspiro[3.3]heptane and l-acetylpiperidin-4-one following a similar procedure to that described in Experiment 43 (step 5). LCMS m / z = 443.2 [M+H]+. 'H NMR (400 MHz, CDCI3) 6 ppm 8.32 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 6.63 (t, J=55.2 Hz, 1H), 4.23-4.17 (m, 1H), 4.01 (s, 4H), 3.71-3.66 (m, 1H), 3.28 (s, 4H), 3.17 (q, J=7.6 Hz, 2H), 3.11-3.04 (m, 1H), 2.91-2.84 (m, 1H), 2.19-2.13 (m, 1H), 2.06 (s, 3H), 1.65-1.60 (m, 2H), 1.34 (t, J=7.6 Hz, 3H), 1.25-1.12 (m, 2H). Example 49: 2-(tetrahydro-2H-pyran-4-yl)-6-((4-(trifluoromethoxy)phenyl)sulfonyl)-

[0453] 2,6-diazaspiro [3.3] heptane

[0454] 1. Synthesis of 2-(tetrahydro-2H-pyran-4-yl)-6-((4-

[0455] (trifluoromethoxy)phenyl) sulfonyl) -2, 6-diazaspiro[ 3.3 ] heptane

[0456] To a mixture of 4-(trifluoromethoxy)benzenesulfonyl chloride (28.7 mg, 110 mmol) in DCM (1 mL) was added DIPEA (4 eq.) at 0 °C. 2-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane (25.5 mg, 100 mmol) was slowly added to the reaction solution. The reaction was then warmed to RT and stirred for 16 hr. The reaction mixture was concentrated in vacuo and the crude product purified by prep-HPLC (Column: Phenomenex Gemini-NX 150*30mm*5um, Condition: water (NH4HCO3)-ACN, 37%~65%, Flow Rate (mL / min): 25) to afford the desired compound (42 mg, 102.80 pmol, 32.1%) as a yellow solid. LCMS m / z = 407.0 [M+H]+. Rf= 0.57 min.

[0457] Example 50: 2-(phenethylsulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane

[0458] 2-(Phenethylsulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3 ,3]heptane was obtained (57 mg, 99%) from 2-phenyl ethane- 1 -sulfonyl chloride following a similar procedure to that described in Experiment 49 (step 1). LCMS m / z = 351.1 [M+H]+. Rf = 0.52 min.

[0459] Example 51 : rac-2-((l-phenylpropan-2-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane rac- 2-((l-Phenylpropan-2-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane (60 mg, 100%) was obtained from l-phenylpropane-2-sulfonyl chloride following a similar procedure to that described in Experiment 49 (step 1). LCMS m / z = 365.1 [M+H]+. Rf= 0.56 min.

[0460] Example 52 : 2-((l-methoxycyclohexyl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyridin-

[0461] 3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0462] 3. Synthesis of 1-methoxycyclohexane-l-carbaldehyde

[0463] — O Dess-Martin Periodinane

[0464] HC) [ JDCM water

[0465] To a solution of (1 -methoxy cyclohexyl )m ethanol (400 mg, 2.77 mmol) in DCM (10 mL) was added Dess-Martin Periodinane (1.76 g, 4.16 mmol) and water (0.05 mL) at 0 °C. The reaction was stirred at 0 °C for 1 hr then warmed to 20 °C and stirred for an additional 1 hr. The mixture was quenched by slow addition of saturated aqueous sodium bicarbonate solution (20 mL) and saturated aqueous sodium thiosulfate (20 mL). The mixture was extracted with DCM (50 mL x 3). The combined organic layers were pooled and dried over anhydrous sodium sulfate. After filtration and concentration under vacuum, the colorless oil was taken directly onto the next step.

[0466] 4. Synthesis of 2-((l-methoxycyclohexyl)methyl)-6-((2-methyl-6-

[0467] (trifluoromethyl)pyridin-3-yl)sulfonyl)-2, 6-diazaspiro[ 3.3 ] heptane A solution of 2-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane (120 mg, 0.28 mmol, TFA salt) and crude 1 -methoxycyclohexane- 1-carbaldehyde (180 mg, 1.27 mmol) in MeOH (10 mL) was adjusted pH 7-8 by TEA, then the pH was adjusted to pH 5-6 with acetic acid. The mixture was stirred for 0.5 h at 20 °C, then sodium cyanoborohydride (52 mg, 0.83 mmol) was carefully added to the mixture. After 1 hour, the mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Column: Phenomenex Gemini NX 150 * 30mm, 5pm, Condition: Water ( TMLHCOsj-ACN, 50%~83%, Flow Rate (mL / min): 25) to give 2-((l -methoxy cyclohexyl)methyl)-6-((2-methyl-6-(trifluoromethyl)pyri din-3 - yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (65 mg, 53 %) as a yellow oil. LCMS m / z = 448.2 [M+H]+. 'H NMR (500 MHz, MeOD) 5 (ppm): 8.45 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 4.02 (s, 4H), 3.39 (s, 4H), 3.13 (s, 3H), 2.86 (s, 3H), 2.45 (s, 2H), 1.68-1.65 (m, 2H), 1.56-1.41 (m, 6H), 1.27-1.22 (m, 2H).

[0468] Example 53 : 2-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-6-

[0469] (trifluoromethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0470] 1. Synthesis of (4-methoxytetrahydro-2H-pyran-4-yl)methanol

[0471] [(1 R,4S)-7,7-dimethyl-2-oxo-norbornan-1 -yl]methanesulfonic acid

[0472] MeOH

[0473] To a solution of l,6-dioxaspiro[2.5]octane (300 mg, 2.63 mmol) in MeOH (10 mL) was added [(lR,4S)-7,7-dimethyl-2-oxo-norbornan-l-yl]methanesulfonic acid (30 mg, 0.13 mmol) at 20 °C. After 2 hours, the mixture was concentrated to give (4-methoxytetrahydro-2H-pyran- 4-yl)methanol (300 mg, crude) as a colorless oil. 'H NMR (500 MHz, CDCh) 8 (ppm): 3.80- 3.69 (m, 6H), 3.24 (s, 3H), 1.77-1.75 (m, 2H), 1.60-1.54 (m, 2H).

[0474] 2. Synthesis of 4-methoxytetrahydro-2H-pyran-4-carbaldehyde Dess-Martin Periodinane — O

[0475] DCM water

[0476] To a solution of (4-methoxytetrahydro-2H-pyran-4-yl)methanol (300 mg, 2.05 mmol) in DCM (10 mL) was added Dess-Martin Periodinane (1.22 g, 2.87 mmol, 1.02 mL) and water (0.01 mL) at 0 °C. The reaction was stirred at 0 °C for 1 hr and stirred at 20 °C for 1 hr. The mixture was quenched by slow addition of saturated aqueous sodium bicarbonate solution (20 mL) and saturated aqueous sodium thiosulfate (20 mL). The mixture was extracted with DCM (50 mL x 3). The combined organic layers were pooled and dried over anhydrous sodium sulfate. After filtration and concentration under vacuum, the colorless oil (100 mg, crude) was taken directly onto the next step.

[0477] 3. Synthesis of 2-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)-6-((2-methyl-6- (trijluoromethyl)pyridin-3-yl)sulfonyl)-2, 6-diazaspiro[ 3.3 ] heptane

[0478] A solution of 2-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane (100 mg, 0.23 mmol, TFA salt) and 4-methoxytetrahydro-2H-pyran-4-carbaldehyde (90 mg, 0.62 mmol) in MeOH (10 mL) was adjusted pH 7-8 by TEA, then the pH was adjusted to pH 5-6 with acetic acid. The mixture was stirred for 0.5 hr at 20 °C, then sodium cyanoborohydride (43 mg, 0.69 mmol) was carefully added to the mixture. After 1 hour, the mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Column: Boston Green ODS 150 x 30mm, 5pm, Condition: Water (FA)-ACN, 8%~38%, Flow Rate (mL / min): 25) to give the desired compound (16 mg, 16 %) as a yellow oil. LCMS m / z = 450.2 [M+H]+. 'H NMR (400 MHz, MeOD) 5 (ppm): 8.46 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 4.09-4.07 (m, 6H), 3.75-3.58 (m, 9H), 3.19 (s, 2H), 2.87 (s, 3H), 1.70-1.67 (m, 2H), 1.57-1.49 (m, 2H). Example 54: 2-((6-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane

[0479] 1. Synthesis of 2-((6-methoxypyridin-3-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)~

[0480] 2, 6-diazaspiro[ 3.3 ] heptane

[0481] To a solution of 2-tetrahydropyran-4-yl-2,6-diazaspiro[3.3]heptane (120 mg, 0.41 mmol, TFA salt) and DIPEA (0.21 mL, 1.2 mmol) in DCM (10 mL) was added 6-methoxypyridine-3 - sulfonyl chloride (92 mg, 0.44 mmol) at 0 °C then warmed to 20 °C. After 1 hour, the mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Welch Xtimate Cl 8 150 x 25mm, 5um, Condition: Water (NH4HCO3)-ACN, Flow Rate (mL / min): 25) to give 2-((6-methoxypyridin-3-yl)sulfonyl)-6- (tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (78 mg, 54 %) as a white solid. LCMS m / z = 354.1 [M+H]+. 'H NMR (400 MHz, CDC13) 8 (ppm): 8.63-8.62 (m, 1H), 7.94 (dd, Jy=8.8Hz, .A=2.4Hz, 1H), 6.88-6.86 (m, 1H), 4.03 (s, 3H), 3.94-3.89 (m, 2H),3.86 (s, 4H), 3.35-3.28 (m, 2H), 3.18 (s, 4H), 2.10 (m, 1H), 1.57-1.54 (m, 2H), 1.30-1.21 (m, 2H).

[0482] Example 55: 2-((2-methyl-6-(perfluoroethyl)pyridin-3-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro [3.3] heptane 1. Synthesis of tert-butyl 6-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-2,6- diazaspiro[ 3.3 ]heptane-2-carboxylate

[0483] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.0 g, 3.5 mmol, oxalate salt) in DCM (20 mL) was added DIPEA (2.3 mL, 13 mmol) at 0 °C, then 6-(difluoromethyl)- 2-ethyl-pyridine-3 -sulfonyl chloride (630 mg, 2.46 mmol) was added to the mixture. The mixture was stirred for 1 hr at 20 °C under N2, then the mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column (ethyl acetate in petroleum ether from 10% to 30%) to give tert-butyl 6-((6-chl oro-2 - methylpyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (700 mg, 41 %) as a white solid. LCMS m / z = 388.1 [M+H]+.

[0484] 2. Synthesis of tert-butyl 6-((2-methyl-6-(perfluoroethyl)pyridin-3-yl)sulfonyl)-

[0485] 2, 6-diazaspiro[ 3.3 ]heptane-2-carboxylate

[0486] To a solution of tert-butyl 6-((6-chl oro-2 -methylpyri din-3 -yl)sulfonyl)-2, 6- diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.26 mmol) and Cu (65 mg, 1.0 mmol) in DMSO (5 mL) was added l,l,l,2,2-pentafhioro-2-iodo-ethane (0.3 mL, 2.6 mmol). The mixture was heated in the microwave for 2 hr at 130 °C, then the mixture was filtered. The filtrate was purified by prep-HPLC (Column: Boston Green ODS 150 x 30mm, 5um, Condition: Water (FA)- ACN, 54%~84%, Flow Rate (mL / min): 25) to give tert-butyl 6-((2- methyl-6-(perfluoroethyl)pyridin-3-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (17 mg, 14 %) as a white solid. LCMS m / z = 472.2 [M+H]+.

[0487] 3. Synthesis of 2-((2-methyl-6-(perfluoroethyl)pyridin-3-yl)sulfonyl)-2,6- diazaspiro[ 3.3 ] heptane 2, 2, 2-trifluoroacetate

[0488] To a solution of tert-butyl 6-((2-methyl-6-(perfluoroethyl)pyridin-3-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (20 mg, 0.04 mmol) in HFIP (2 mL) was added TFA (16 uL, 0.2 mmol). The mixture was stirred for 2 hr at 20 °C, then the mixture was concentrated in vacuo to afford 2-((2-methyl-6-(perfluoroethyl)pyridin-3-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane 2,2,2-trifluoroacetate (15 mg, crude) as a light yellow oil. LCMS m / z = 372.1 [M+H]+.

[0489] 4. Synthesis of 2-((2-methyl-6-(perjluoroethyl)pyridin-3-yl)sulfonyl)-6-

[0490] (tetrahydro-2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0491] A solution of 2-((2-methyl-6-(perfluoroethyl)pyridin-3-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane 2,2,2-trifluoroacetate (15 mg, 0.03 mmol) and tetrahydropyran-4-one (6 uL, 62 pmol) in MeOH (2 mL) was adjusted pH 7-8 by TEA, then the pH was adjusted to pH 5-6 by acetic acid. The mixture was stirred for 0.5 hr at 20 °C, then sodium cyanoborohydride (6 mg, 0.09 mmol) was carefully added to the mixture. After 4 hours, the mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Column: Boston Green ODS 150 x 30mm, 5um, Condition: Water (FA)-ACN, 13%~43%, Flow Rate (mL / min): 25) to give the desired compound (7 mg, 53%) as a yellow solid. LCMS m / z = 456.2 [M+H]+.1H NMR (500, MeOD) 5 (ppm): 8.48 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 4.10 (s, 4H), 3.96-3.93 (m, 2H), 3.64 (s, 4H), 3.38-3.33 (m, 2H), 2.87 (s, 3H), 2.60-2.55 (m, 1H), 1.75-1.72 (m, 2H), 1.32- 1.24 (m, 2H). ASSAYS

[0492] EBP [3H]ifenprodil scintillation proximity assay (SPA)

[0493] Expi293F cells overexpressing EBP-FLAG were lysed using MPER buffer. Lysates were rocked at 4 °C for 1 h then centrifuged at 15k g for 15 min at 4 °C to remove the insoluble material. The supernatant was mixed with anti-FLAG antibody and rocked overnight at 4 °C. Then, anti-mouse PVT scintillation beads were resuspended in assay buffer and added to the cell supernatant. The mixture was rocked for 3 hours at 4 °C then the beads were pelleted at 870 g for 10 min at 4 °C. The supernatant was discarded, and the beads were washed by rocking at 4 °C for 15 min in assay buffer. After washing a total of three times the beads were resuspended to a final concentration of 20 mg beads / mL in assay buffer and stored in aliquots at -80 °C until use.

[0494] Compounds were serial-diluted in DMSO and 40 nL / well were transferred to 384 well plates using an Echo acoustic dispenser. DMSO and 10 mM Tasin-1 were used as positive and negative controls, respectively. SPA beads were diluted to 2% v / v in assay buffer and incubated with 20 nM3H-ifenprodil for 20 minutes. Then 40 pL of bead mixture per well were added to the plate. The plates were rocked on an orbital shaker for 2 h then read in a Microbeta microplate counter (Perkin Elmer) with a read time of 1 min per well. Data were analyzed by plotting the percent-of-control (POC, Eq 1) signal versus compound concentration and fit using a 4-parameter fit to generate IC50 curves.

[0495] Eq 1 : POC = (well read - Tasin-1 read) / (DMSO read - Tasin-1 read) x 100%

[0496] DATA FOR EXAMPLES

[0497] + means >100nM to <500 nM; ++ means >30nM to <100 nM; +++ means >15 to <30 nM; ++++ means <15 nM; NT means not tested

Claims

CLAIMSWhat is claimed is:

1. A compound represented by Formula (I):°R1-N X N-S-R30(I), or a pharmaceutically acceptable salt thereof, wherein:R1is:(1) -Z-Y;(2) -Z-X; or(3) Het or -Z-Het;Y is phenyl or 5-to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one or more RY2;X is 5- to 10-membered bicyclic carbocyclyl or 8- to 12- membered partially saturated heterocyclyl, each of which is optionally substituted by one or more RX2;Het is 4- to 6-membered monocyclic heterocyclyl optionally substituted with one or more RH2;Z is Ci-4alkyl optionally substituted with one or more halo or Ci-3alkoxy;RY2RX2ancj RH2,or eac occurrence,areeach independently Ci-ealkyl, halo, -CN, -NR2aR2a, -C(O)R2a, -C(O)N(R2a)2, -C(O)OR2a, or OR2a, wherein the Ci-6alkyl is optionally substituted with one or more halo or Ci-3alkoxy; each R2ais independently H, Ci-ealkyl, Ci-ehaloalkyl, or Cs-ecycloalkyl;R3is -Ci-4alkyl-phenyl, phenyl or 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by one or more R4; each R4is independently halo, -OR4a, -C(O)R4a, -CN, Ci-ealkyl, Ci-ehaloalkyl, Cs-ecycloalkyl, 4-to 6-membered monocyclic heterocyclyl, phenyl, or 5 or 6- membered monocyclic heteroaryl;R4ais H or Ci-ealkyl, wherein the Ci-ealkyl is optionally substituted with one or more halo. provided that if R1is Het or -Z-Het then:(i) Het is piperdinyl; or(ii) R3is phenyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or -Ci-4alkyl-phenyl, provided that if R3is phenyl, pyrazolyl, or pyridinyl then atleast one R4is C4-6cycloalkyl, 4-to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is Ci-2alkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Z is -CH2-.

4. The compound of any one of claims 1-3, wherein the compound is represented byFormula II:or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted by one or two RY2.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Y is represented by the following formula:each of which is optionally substituted by one or two RY2.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Y is represented by the following formula:

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each RY2is independently -Ci-3alkyl, -NHR2a, -OR2a, or -CN, and R2ais Ci-3alkyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein each RY2is independently -CH3, -CD3, -CH2CH3, -NHCH3, -OCH3, or -CN.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R3is 5- to 6-membered monocyclic heteroaryl optionally substituted by one to three R4.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R3is pyridinyl or pyrimindinyl, each of which is optionally substituted by one to three R4.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R3each of which is optionally substituted by one to three R4.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R3is represented by the following formula:

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein each R4is independently Ci-salkyl or Ci-shaloalkyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein each R4is independently -CH3, -CF3, -CH2CH3, or -CF2CH3.

16. The compound of any one of claims 1-3, wherein the compound is represented by Formula III:or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1-3 or 16, or a pharmaceutically acceptable salt thereof, wherein X is 5-oxa-6-azaspiro[3.4]oct-6-enyl optionally substituted with one or two RX2.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein X is represented by the formula:

19. The compound of any one of claims 1-3 or 16-18, or a pharmaceutically acceptable salt thereof, wherein R3is 5- to 6-membered monocyclic heteroaryl optionally substituted by one to three R4.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R3is pyridinyl optionally substituted by one to three R4.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R3is represented by the following formula:, which is optionally substituted by one to three R4.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R3is represented by the following formula:

23. The compound of any one of claims 1-3 or 16-22, or a pharmaceutically acceptable salt thereof, wherein each R4is independently Ci-salkyl or Ci-shaloalkyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein each R4is independently -CH? or -CF3.

25. The compound of any one of claims 1-3, wherein the compound is represented by Formula IVa or IVb:or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1-3 or 25, or a pharmaceutically acceptable salt thereof, wherein Het is tetrahydropyranyl or piperdinyl, each of which is optionally substituted by one or two RH2.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein Het is represented by the following formula:, each of which is optionally substituted by one RH2.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein Het is represented by the following formula:

29. The compound of any one of claims 1-3 or 25-28, or a pharmaceutically acceptable salt thereof, wherein each RH2is independently -C(O)R2a, and R2ais Ci-salkyl.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein each RH2is independently -C(O)CH3.

31. The compound of any one of claims 1-3 or 25-30, or a pharmaceutically acceptable salt thereof, wherein R3is thiazolyl, pyrazolyl, pyridinyl, or -Ci-3alkyl-phenyl, each of which is optionally substituted with one to three R4, provided that if Het is tertahydropyranyl and R3is pyrazolyl or pyridinyl, then at least one R4is C4- ecycloalkyl, 4-to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R3, each of which is optionally substituted with one or two R4.

33. The compound of 32, or a pharmaceutically acceptable salt thereof, wherein R3is represented by the following formula:

34. The compound of any one of claims 1-3 or 25-33, or a pharmaceutically acceptable salt thereof, wherein each R4is independently halo, Ci-salkyl, Ci-shaloalkyl, C3- ecycloalkyl, 4-membered monocyclic heterocyclyl, phenyl, or 6-membered monocyclic heteroaryl, provided that if Het is tetrahydropyranyl and R3is pyrazolyl or pyridinyl, then at least one R4is C4-6cycloalkyl, 4-membered monocyclic heterocyclyl, phenyl, or 6-membered monocyclic heteroaryl.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein each R4is independently -Cl, -CH3, -CHF2, -CF3, -CH2CH3, cyclopropyl, cyclobutyl, cyclohexyl, azetidinyl, phenyl, or pyridinyl, provided that if Het is tetrahydropyranyl and R3is pyrazolyl or pyridinyl, then at least one R4is cyclobutyl, cyclohexyl, azetidinyl, phenyl, or pyridinyl.

36. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is any one of examples 1-55.

37. A pharmaceutical composition comprising a compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

38. A method of treating a disease mediated by Emopamil-Binding Protein comprising administering to a subject an effective amount of a compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 37.

39. A method of treating an autoimmune disease in a subject comprising administering to the subject an effective amount of a compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 37.

40. The method of claim 39, wherein said autoimmune disease is multiple sclerosis.

41. The method of claim 40, wherein said compound or pharmaceutical composition repairs or forms new myelin sheaths in said subject.

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