Emopamil-binding protein inhibitors and uses thereof

Abstract

Provided are compounds of the 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 / 534,161, filed on August 23, 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:

[0013] °

[0014] R'-N X N-S-R30(I), or a pharmaceutically acceptable salt thereof, wherein:

[0015] R1is Het, or -Z-Het, wherein the Het is optionally substituted with one or more R2;

[0016] Z is Ci-4alkyl optionally substituted with one or more halo or Ci-3alkoxy;

[0017] Het is Cs-ecycloalkyl or 4- to 10-membered monocyclic or bicyclic heterocyclyl, , each of which is optionally substituted with R2;

[0018] R2, for each occurrence, is independently Ci-ealkyl, halo, -CN, -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;

[0019] R2ais H, Ci-ealkyl, or Cs-ecycloalkyl wherein the Ci-ealkyl is optionally substituted with one or more halo or Ci-3alkoxy;

[0020] R3is pyrazinyl or pyrimidinyl, each of which are optionally substituted with one to three R4;

[0021] R4, for each occurrence, is independently halo, -OR4a, -C(O)R2a, -CN, Ci-ealkyl, C3- ecycloalkyl, phenyl, or 5 or 6-membered monocyclic heteroaryl; or

[0022] R4ais H or Ci-ealkyl, wherein the Ci-ealkyl is optionally substituted with one or more halo.

[0023] Another aspect of the disclosure relates to pharmaceutical compositions comprising compounds of Formula (I) or pharmaceutically acceptable salts thereof, and a pharmaceutical carrier. 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.

[0024] Another aspect of the present disclosure relates to the use of at least one compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for 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.

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] 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.

[0027] COMPOUNDSAND COMPOSITIONS

[0028] 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 above.

[0029] In a second embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R3is represented by the following formula: wherein each of the formula depicted above is optionally substituted with one to three R4; and the remaining variables are as described in the first embodiment. In a third embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R3is represented by the following formula: the remaining variables are as described in the second embodiment.

[0030] In a fourth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R4, for each occurrence, is independently Ci-4alkyl, Ci-4haloalkyl, or C3-4cycloalkyl; and the remaining variables are as described in the first, second, or third embodiment.

[0031] In a fifth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R4, for each occurrence, is independently -CH3, -CH2CH3, -CF3, - CF2CH3, or cyclopropyl; and the remaining variables are as described in the fourth embodiment.

[0032] In a sixth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, Het is Cs-ecycloalkyl or 4 to 6 membered monocyclic saturated heterocyclyl, each of which is optionally substituted with one to three R2; and the remaining variables are as described in the first, second, third, fourth, or fifth embodiment.

[0033] In a seventh embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, Het is 4 to 6 membered oxygen-containing monocyclic saturated heterocyclyl or 6 to 8-membered oxygen-containing bicyclic saturated heterocyclyl, each of which is optionally substituted with one to three R2; and the remaining variables are as described in the sixth embodiment.

[0034] In an eighth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperdinyl, or 2-oxaspiro[3.3]heptanyl, each of which is optionally substituted with one to three R2; and the remaining variables are as described in the sixth embodiment.

[0035] In a ninth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R1is represented by the following formula: ; each of which is optionally substituted with one or two R2; and the remaining variables are as described in the eighth embodiment.

[0036] In a tenth embodiment, for the compounds of Formula (I), or a pharmaceutically the ninth embodiment.

[0037] In an eleventh embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R2, for each occurrence, is independently Ci-salkyl, -C(O)R2a, or OR2a, wherein the Ci-3alkyl is optionally substituted with Ci-3alkoxy; R2ais H or Ci-3alkyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0038] In a twelfth embodiment, for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R2, for each occurrence, is independently -CH3, -OH, -OCH3, or - C(O)CH3; and the remaining variables are as described in the eleventh embodiment.

[0039] In a thirteenth embodiment, the compound of the present disclosure is represented by Formula (II): or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, or 3; R1is -CH2-Het or Het, wherein the Het is optionally substituted with one or two R2;

[0040] Het is 4- to 6-membered oxygen-containing monocyclic saturated heterocyclyl, or 6 to 8-membered oxygen-containing bicyclic saturated heterocyclyl;

[0041] R4, for each occurrence, is independently Ci-3alkyl or Ci-3haloalkyl; and the remaining variables are as described in the first embodiment.

[0042] In a fourteenth embodiment, the compound of the present disclosure is represented by Formula (III): (ill); or a pharmaceutically acceptable salt thereof; and the remaining variables are as described in the thirteenth embodiment.

[0043] In a fifteenth embodiment, for the compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R4, for each occurrence, is independently -CH3 or - CF3; and the remaining variables are as described in the thirteenth or fourteenth embodiment.

[0044] In a sixteenth embodiment, for the compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, Het is tetrahydrofuranyl, tetrahydropyranyl, or 2- oxaspiro[3.3]heptanyl; and the remaining variables are as described in the thirteenth, fourteenth, or fifteenth embodiment.

[0045] In a seventeenth embodiment, for the compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, R1is represented by the following formula: described in the sixteenth embodiment.

[0046] In a eighteenth embodiment, the present disclosure provides a compound described herein (e.g., a compound of any one of Examples 1 to 47), or a pharmaceutically acceptable salt thereof.

[0047] In a ninteenth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0048] 2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane; 1-[4-[2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2,6- diazaspiro[3.3]heptan-6-yl]piperidin-l-yl]ethanone;

[0049] 6-(4-methoxycyclohexyl)-2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-

[0050] 2,6-diazaspiro[3.3]heptane;

[0051] 6-(4-methoxycyclohexyl)-2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-

[0052] 2,6-diazaspiro[3.3]heptane;

[0053] 2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane;

[0054] 2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[rac-(lR)-l-(oxan-4- yl)ethyl]-2,6-diazaspiro[3.3]heptane;

[0055] 2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6- yl)-2,6-diazaspiro[3.3]heptane;

[0056] 2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxetan-3-ylmethyl)-2,6- diazaspiro[3.3]heptane;

[0057] 6-[(3-methyloxetan-3-yl)methyl]-2-[4-methyl-2-(trifluoromethyl)pyrimidin-5- yl]sulfonyl-2,6-diazaspiro[3.3]heptane;

[0058] 2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6- ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0059] 2-[4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;

[0060] 2-[4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6-yl)-

[0061] 2,6-diazaspiro[3.3]heptane;

[0062] 2-[4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane;

[0063] 2-[4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;

[0064] 2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;

[0065] 2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6- yl)-2,6-diazaspiro[3.3]heptane;

[0066] 2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-[(lS)-l-(oxan-4-yl)ethyl]-

[0067] 2,6-diazaspiro[3.3]heptane;

[0068] 2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane; 2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(oxetan-3-ylmethyl)-2,6- diazaspiro[3.3]heptane;

[0069] 2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-[[(3S)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;

[0070] 2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-[(3-methyloxetan-3- yl)methyl]-2,6-diazaspiro[3.3]heptane;

[0071] 2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-[(lS)-l-[(3S)-oxolan-3- yl]ethyl]-2,6-diazaspiro[3.3]heptane;

[0072] 2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6- ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0073] 2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;

[0074] 2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan- 6-yl)-2,6-diazaspiro[3.3]heptane;

[0075] 2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[rac-(lR)-l-(oxan-4- yl)ethyl]-2,6-diazaspiro[3.3]heptane;

[0076] 2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane;

[0077] 2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxetan-3-ylmethyl)- 2,6-diazaspiro[3.3]heptane;

[0078] 2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[rac-(3R)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;

[0079] 2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[(3R)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;

[0080] 2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[(3S)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;

[0081] 2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan- 6-ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0082] 2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;

[0083] 2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)- 2,6-diazaspiro[3.3]heptane;

[0084] 2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-[(4-methyloxan-4- yl)methyl]-2,6-diazaspiro[3.3]heptane; 2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-(oxetan-3-ylmethyl)- 2,6-diazaspiro[3.3]heptane;

[0085] 2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-[(3-methyloxetan-3- yl)methyl]-2,6-diazaspiro[3.3]heptane;

[0086] 2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-(2- oxaspiro[3.3]heptan-6-ylmethyl)-2,6-diazaspiro[3.3]heptane;

[0087] 2-[4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;

[0088] 2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2- oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane;

[0089] 2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)- 2,6-diazaspiro[3.3]heptane;

[0090] 4-[[2-[4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2,6- diazaspiro[3.3]heptan-6-yl]methyl]oxan-4-ol;

[0091] 2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[rac-(3R)-oxolan- 3-yl]methyl]-2,6-diazaspiro[3.3]heptane;

[0092] 2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[(3 S)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;

[0093] 2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[(3R)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;

[0094] 2-[3-methyl-5-(trifluoromethyl)pyrazin-2-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane; and

[0095] 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane; or a or a pharmaceutically acceptable salt thereof.

[0096] In a twentieth 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.

[0097] In a twenty-first 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 nineteen, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the twentieth embodiment. In a twenty-second embodiment, the present disclosure provides a compound according to any one of embodiments one to nineteen, for use in the treatment of a disease or disorder mediated by EBP.

[0098] In a twenty-third embodiment, the present disclosure provides the use of a compound according to any one of embodiments one to nineteen in the manufacture of a medicament for the treatment of a disease or disorder mediated by EBP.

[0099] 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.

[0100] 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.

[0101] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0102] 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.

[0103] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. 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.

[0104] 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.

[0105] 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).

[0106] 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.

[0107] 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.

[0108] 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.

[0109] “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.

[0110] 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)-.

[0111] 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.

[0112] METHODS OF USE

[0113] 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).

[0114] 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 nineteenth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0115] 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 nineteenth 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.

[0116] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to nineteenth 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.

[0117] In certain embodiments, the EBP mediated disorder is colorectal cancer.

[0118] 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 nineteenth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0119] 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 nineteenth 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.

[0120] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to nineteenth 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.

[0121] 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”).

[0122] Relapsing multiple sclerosis (or relapsing form(s) of multiple sclerosis) includes clinically isolated syndrome, relapsing-remitting multiple sclerosis and active secondary progressive multiple sclerosis.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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 nineteenth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0128] 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 nineteenth 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.

[0129] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to nineteenth 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.

[0130] 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.

[0131] 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 nineteenth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0132] 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 nineteenth 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.

[0133] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to nineteenth 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.

[0134] In certain embodiments, the cancer is colorectal cancer.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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).

[0140] 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.

[0141] 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.

[0142] The pharmaceutical composition comprising a compound of the present disclosure is generally formulated for use as a parenteral or oral administration or alternatively suppositories.

[0143] 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. 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.

[0144] Tablets may be either film coated or enteric coated according to methods known in the art.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] DEFINITIONS

[0150] 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.

[0151] 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.

[0152] 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.

[0153] As used herein, the term “cancer” has the meaning normally accepted in the art. The term can broadly refer to abnormal cell growth.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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).

[0158] 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.

[0159] 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).

[0160] 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.

[0161] 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.

[0162] 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.

[0163] “Halogen” or “halo” may be fluorine, chlorine, bromine or iodine.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] The term “C3-6 cycloalkyl” refers to a carbocyclic ring which is fully saturated (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0169] 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.

[0170] 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.

[0171] 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). 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).

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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)).

[0178] 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.

[0179] EXEMPLIFICATION

[0180] Abbreviations:

[0181] PE = petroleum ether

[0182] EtOAc = EA = ethyl acetate

[0183] ESI = electrospray ionisation

[0184] MeOH = methanol

[0185] EtOH = ethanol

[0186] DCE = 1,2-di chloroethane

[0187] DCM = dichloromethane

[0188] CHCh = chloroform

[0189] HC1 = hydrochloric acid

[0190] H2O = water

[0191] IPA = isopropyl alcohol

[0192] LCMS = liquid chromatography mass spectrometry HFIP = hexafluoro-2-propanol

[0193] HPLC = high pressure liquid chromatography

[0194] THF = tetrahydrofuran

[0195] MeCN = ACN = acetonitrile

[0196] MgS04 = magnesium sultate

[0197] DMSO = dimetylsulfoxide

[0198] AcOH = acetic acid

[0199] TFA = tri fluoroacetic acid

[0200] DIPEA = diisopropylethyl amine

[0201] N2 = Nitrogen

[0202] NH4HCO3 = Ammonium Bicarbonate t-BuOH = tert-butanol

[0203] NH4CI = ammonium chloride

[0204] NaH = sodium hydride

[0205] Na2SO4= sodium sulfate

[0206] K2CO3 = potassium carbonate

[0207] NaHCCh = sodium bicarbonate

[0208] NaBH(0Ac)3 = STAB = sodium triacetoxyborohydride

[0209] SiCh = silicon dioxide or silica

[0210] PDA = Photo Diode Array Detection

[0211] TosMIC = toluenesulfonylmethyl isocyanide

[0212] TLC = Thin Layer Chromatography

[0213] LiHMDS = Lithium bis(trimethylsilyl)amide

[0214] DMA = dimethtyl amine

[0215] DAST = diethylaminosulfur trifluoride

[0216] DABCO = l,4-diazabicyclo[2.2.2]octane

[0217] NCS = N-Chlorosuccinimide

[0218] NBS = N-Bromosuccinimide

[0219] NIS = N-Iodosuccinimide t-BuONO = tert-Butyl nitrite ee = enantiomeric excess tR = Retention time

[0220] GENERAL METHODS LCMS instrumentation specifications:

[0221] • Agilent Technologies 1200 Series LC / MSD system: DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B mass-spectrometer.

[0222] • Agilent Technologies 1260 Infinity LC / MSD system: DAD\ELSD Alltech 3300 and Agilent LC\MSD G6120B mass-spectrometer.

[0223] • Agilent Technologies 1260 Infinity II LC / MSD system: DAD\ELSD G7102A 1290 Infinity II and Agilent LC\MSD G6120B mass-spectrometer.

[0224] • Agilent 1260 Series LC / MSD system: DAD\ELSD and Agilent LC\MSD (G6120B) mass-spectrometer.

[0225] • UHPLC Agilent 1290 Series LC / MSD system: DAD\ELSD and Agilent LC\MSD (G6125B) mass-spectrometer.

[0226] HPLC analytical method specifications:

[0227] • 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

[0228] • Column Temperature, 60 C

[0229] • Injection volume 0.5 pL

[0230] • Modifier: Formic acid 0.1% (v / v) cone.

[0231] • 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.

[0232] • UV scan: 207-223 nm, 246-262 nm, 272-288 nm

[0233] QC Analysis LC / MS method conditions:

[0234] Ammonium hydroxide (basic pH) conditions

[0235] MS mode: MS:ESI+ scan range 165-650 daltons

[0236] PDA: 200-400 nm scan range

[0237] Column: Waters ACQUITY UPLC BEH C18 2.1x50 mm, 1.7 pm; Part No. 186002350 Modifier: Ammonium hydroxide 0.2% (v / v) cone.

[0238] 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. Trifluoroacetic acid (acidic pH) conditions

[0239] MS mode: MS:ESI+ scan range 165-650 daltons

[0240] PDA: 200-400 nm scan range

[0241] Column: Waters ACQUITY UPLC BEH C18 2.1x50 mm, 1.7 gm; Part No. 186002350

[0242] Modifier: Trifluoroacetic acid 0.1% (v / v) cone.

[0243] 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.

[0244] General prep HPLC conditions:

[0245] Ammonium hydroxide (basic pH) conditions

[0246] Flow rate: 30 mL / min

[0247] MS mode: MS:ESI+ scan range 165-650 daltons

[0248] PDA: 200-400 nm scan range

[0249] Column: Waters XSELECT CSH C18 PREP 19x100 mm, 5 gm; Part No. 186005421 Modifier: 0.2% Ammonium hydroxide (v / v) cone.

[0250] 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.

[0251] Flow rate: 50 mL / min

[0252] MS mode: MS:ESI+ scan range 165-650 daltons

[0253] PDA: 200-400 nm scan range

[0254] Column: Waters XSELECT CSH C18 PREP 30x100 mm, 5 gm; Part No. 186005425 Modifier: 0.2% NH4OH (v / v) cone.

[0255] 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.

[0256] Flow rate, 60 mL / min

[0257] MS mode: MS:ESI+ scan range 165-650 daltons

[0258] PDA: 200-400 nm scan range

[0259] Column: Waters XSELECT CSH C18 PREP 30x50 mm, 5 pm; Part No. 186005423 Modifier: 0.2% NH4OH (v / v) cone. 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.

[0260] Trifluoroacetic acid (acidic pH) conditions

[0261] Flow rate, 30 mL / min

[0262] MS mode: MS:ESI+ scan range 165-650 daltons

[0263] PDA: 200-400 nm scan range

[0264] Column: Waters Sunfire OBD C18 PREP 19x100 mm, 5 pm; Part No. 186002567

[0265] Modifier: 0.1% Trifluoroacetic acid (v / v) cone.

[0266] 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.

[0267] Flow rate, 50 mL / min

[0268] MS mode: MS:ESI+ scan range 165-650 daltons

[0269] PDA: 200-400 nm scan range

[0270] Column: Waters Sunfire OBD C18 PREP 30x100 mm, 5 pm; Part No. 186002572

[0271] Modifier: 0.1% Trifluoroacetic acid (v / v) cone.

[0272] 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.

[0273] Flow rate, 60 mL / min

[0274] MS mode: MS:ESI+ scan range 165-650 daltons

[0275] PDA: 200-400 nm scan range

[0276] Column: Waters Sunfire OBD C18 PREP 30x50 mm, 5 pm; Part No. 186002570

[0277] Modifier: 0.1% Trifluoroacetic acid (v / v) cone.

[0278] 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.

[0279] Example 1 : 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro [3.3] heptane 1. Synthesis of 5-(benzylthio)-4-methyl-2-(trijluoromethyl)pyrimidine

[0280] 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 h 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% yield) as a yellow oil. LCMS m / z = 285.0 [M+H]+.XH NMR (400 MHz, CDCI3): 6 ppm 8.50 (s, 1H), 7.36-7.29 (m, 5H), 4.23 (s, 2H), 2.58 (s, 3H).

[0281] 2. Synthesis of 4-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride

[0282] 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 light yellow oil which was not purified further. H NMR (400 MHz, CDCI3): 8 ppm 9.36 (s, 1H), 2.33 (s, 3H).

[0283] 3. Synthesis of 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-

[0284] ( tetrahydro-2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0285] 4-Methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride (114.39 mg, 438.91 pmol) was added to a solution of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (80 mg, 365.76 pmol, Hydrochloride) and DIPEA (47.27 mg, 365.76 pmol, 63.71 pL) in DCM (3 mL) at 0°C. The mixture was stirred at 20 °C for 2 h under N2. The reaction mixture was concentrated in vacuum and purified by pre-HPLC (Column: Welch Xtimate C18 150*25mm*5um, Condition: water (NH4HCO3)-ACN, 30%~60%, Flow Rate (mL / min): 25) to give the desired compound (36 mg, 24% yield) as a yellow oil. LCMS m / z = 407.1 [M+H]+. 'H NMR (400 MHz, CDCI3): 5 ppm 9.18 (s, 1H), 4.12 (s, 4H), 3.94 (d, J =11.6 Hz, 2H), 3.38-3.31 (m, 5H), 2.90 (s, 3H), 2.18 (br s, 1H), 1.62-1.58 (m, 3H), 1.33-1.30 (m, 2H).

[0286] Example 2: l-(4-(6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)piperidin-l-yl)ethan-l-one

[0287] 1. Synthesis of tert-butyl 6-((4-methyl-2-(trijluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[ 3.3 ]heptane-2-carboxylate

[0288] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg, 756.58 pmol) and DIPEA (293.35 mg, 2.27 mmol) in DCM (5 mL) was added 4-methyl-2 (trifhioromethyl)pyrimidine-5-sulfonyl chloride (197.18 mg, 756.58 pmol) in DCM (ImL) dropwise over 5 minutes at 0~5 °C. The mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (10 mL), extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude was purified by flash silica gel chromatography (MeOH in DCM = 2%-6%) to give the desired compound (260 mg, 615.50 pmol, 81.4% yield) as a white solid.JH NMR (400 MHz, CDC13): 8 ppm 9.18 (s, 1H), 4.23 (s, 4H), 4.16-4.14 (m, 4H), 2.90 (s, 3H), 1.42 (s, 9H).

[0289] 2. Synthesis of 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[ 3.3 ] heptane

[0290] To a solution of tert-butyl 6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (230 mg, 544.48 pmol) in HFIP (7.98 g, 47.49 mmol, 5 mL) was added TFA (744.50 mg, 6.53 mmol, 0.5 mL), then the mixture was stirred at 25 °C for 12 h under N2. The mixture was concentrated in vacuo to give the desired compound (200 mg, crude, TFA salt) as colorless oil. LCMS m / z = 323.1 [M+H]+. 'HNMR (400 MHz, CDCI3): 5 ppm 8.66 (s, 1H), 4.31-4.29 (m, 4H), 4.25-4.23 (m, 4H), 2.45 (s, 3H).

[0291] 3. Synthesis of l-(4-(6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2, 6- diazaspiro [ 3.3 ]heptan-2-yl)piperidin-l-yl)ethan-l-one

[0292] To a solution of 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane (100 mg, 229.72 pmol, Trifluoroacetate) and l-acetylpiperidin-4-one (64.86 mg, 459.43 pmol, 56.59 pL) in MeOH (5 mL) was added Sodium cyanob oranui de (43.31 mg, 689.15 pmol) under N2. The mixture was stirred at 20°C for 12 h. The mixture was concentrated in vacuo and purified by prep-HPLC (Column: Boston Prime C18 150*30mm*5um, Condition: water (NH4HCO3)-ACN, 25%~55%, Flow Rate (ml / min): 25) to give the desired compound (36.9 mg, 82.5 pmol, 35.9% yield) as a light-yellow solid. LCMS m / z = 448.1 [M+H]+. 'HNMR (400 MHz, CDC13): 8 ppm 9.18 (s, 1H), 4.22 (d, J = 12.8 Hz, 1H), 4.12 (s, 4H), 3.71 (d, J =13.6 Hz, 1H), 3.33 (s, 3H), 3.12-3.05 (m, 1H), 2.90 (s, 3H), 2.20- 2.18 (m, 1H), 2.07 (s, 3H), 1.72-1.58 (m, 4H), 1.21-1.18 (m, 2H).

[0293] Examples 3 and 4: 2-((ls,4s)-4-methoxycyclohexyl)-6-((4-methyl-2-

[0294] (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 2-((lr,4r)-4- methoxycyclohexyl)-6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane

[0295] Rac-2-(4-methoxycyclohexyl)-6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane was obtained from 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 4-methoxycyclohexan-l-one, following a similar procedure described in Example 2 (step 3). The two diastereomers were purified and separated by prep-HPLC (Welch Xtimate C18 150*25mm*5pm, 37%~65%, Condition: water (NH4HCO3)-ACN, Flow Rate (mL / min): 25) to give:

[0296] 2-((ls,4s)-4-methoxycyclohexyl)-6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)- 2,6-diazaspiro[3.3]heptane (50.26 mg, 115.7 pmol, 9.8% yield). LCMS m / z = 435.1 [M+H]+.1H NMR (400 MHz, CDCI3): 6 ppm 9.18 (s, 1H), 4.10 (s, 4H), 3.33 (s, 3H), 3.30 (s, 4H), 3.12- 3.05 (m, 1H), 2.90 (s, 3H), 2.04-2.00 (m, 2H), 1.95-1.88 (m, 1H), 1.75-1.72 (m, 2H), 1.21-1.11 (m, 2H), 1.04-0.94 (m, 2H), and

[0297] 2-((lr,4r)-4-methoxycyclohexyl)-6-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)- 2,6-diazaspiro[3.3]heptane (75.5 mg, 173.78 pmol, 14.7% yield). LCMS m / z = 435.1 [M+H]+.1HNMR (400 MHz, CDCI3): 6 ppm 9.18 (s, 1H), 4.09 (s, 4H), 3.33-3.29 (m, 1H), 3.27 (s, 7H), 2.90 (s, 3H), 1.98-1.96 (m, 1H), 1.85-1.79 (m, 2H), 1.42-1.34 (m, 6H) as white solids.

[0298] Stereochemistry of the final compounds was chosen arbitrarily.

[0299] Example 5: 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydro-2H- pyran-4-yl)methyl)-2,6-diazaspiro [3.3] heptane

[0300] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (72 mg, 37.4% yield) from 2-((4-methyl- 2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and tetrahydro-2H- pyran-4-carbaldehyde, following a similar procedure to that described in Example 2 (step 3). LCMS m / z = 421.1 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 ppm 9.18 (s, 1H), 4.10 (s, 4H), 3.95-3.91 (m, 2H), 3.37-3.31 (m, 2H), 3.30 (s, 4H), 2.90 (s, 3H), 2.27 (d, J=6.8 Hz, 2H), 1.59- 1.58 (m, 2H), 1.52-1.47 (m, 1H), 1.29-1.19 (m, 2H).

[0301] Example 6 : Rac-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(l-

[0302] (tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro [3.3] heptane

[0303] Rac-2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(l-(tetrahydro-2H-pyran-4- yl)ethyl)-2,6-diazaspiro[3.3]heptane was obtained (70 mg, 35% yield) from 2-((4-methyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and l-(tetrahydro-2H- pyran-4-yl)ethan-l-one, following a similar procedure to that described in Example 2 (step 3). LCMS m / z = 435.1 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 9.18 (s, 1H), 4.10 (s, 4H), 4.00-3.96 (m, 2H), 3.39-3.27 (m, 6H), 2.90 (s, 3H), 2.03-2.01 (m, 1H), 1.55-1.31 (m, 5H), 0.81 (d, J=6.4 Hz, 3H).

[0304] Example 7 : 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(2- oxaspiro [3.3] heptan-6-yl)-2,6-diazaspiro [3.3] heptane

[0305] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6- diazaspiro[3.3]heptane was obtained (56 mg, 29.2% yield) from 2-((4-methyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and 2- oxaspiro[3.3]heptan-6-one, following a similar procedure to that described in Example 2 (step 3). LCMS m / z = 419.1 [M+H]+.XH NMR (400 MHz, CDCI3): 6 ppm 9.18 (s, 1H), 4.65 (s, 2H), 4.59 (s, 2H), 4.09 (s, 4H), 3.23 (s, 4H), 2.90 (s, 3H), 2.85-2.78 (m, 1H), 2.29-2.23 (m, 2H), 1.95-1.90 (m, 2H).

[0306] Example 8: 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(oxetan-3- ylmethyl)-2,6-diazaspiro[3.3]heptane

[0307] 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6- diazaspiro[3.3]heptane was obtained (35 mg, 38.9% yield) from 2-((4-methyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and oxetane-3- carbaldehyde, following a similar procedure to that described in Example 2 (step 3). LCMS m / z = 393.1 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 9.17 (s, 1H), 4.76-4.73 (m, 2H), 4.35 (t, J=6.0 Hz, 2H), 4.09 (s, 4H), 3.30 (s, 4H), 2.97-2.92 (m, 1H), 2.90 (s, 3H), 2.70 (d, J=7.6 Hz, 2H).

[0308] Example 9: 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((3- methyloxetan-3-yl)methyl)-2,6-diazaspiro [3.3] heptane 2-((4-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((3-methyloxetan-3-yl)methyl)- 2,6-diazaspiro[3.3]heptane was obtained (36 mg, 32.2% yield) from 2-((4-methyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 3-methyloxetane-3- carbaldehyde, following a similar procedure to that described in Example 2 (step 3). LCMS m / z = 407.1 [M+H]+. 'HNMR (400 MHz, CDC13): 8 ppm 9.18 (s, 1H), 4.38 (d, J=5.6 Hz, 2H), 4.29 (d, J=5.6 Hz, 2H), 4.11 (s, 4H), 3.39 (s, 4H), 2.90 (s, 3H), 2.61 (s, 2H), 1.25 (s, 3H).

[0309] Example 10 : 2-((2-oxaspiro [3.3] heptan-6-yl)methyl)-6-((4-methyl-2-

[0310] (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0311] 1. Synthesis of (2-oxaspiro[3.3]heptan-6-yl)methyl 4-methylbenzenesulfonate

[0312] 4-Methylbenzenesulfonyl chloride (327.2 mg, 1.72 mmol) , TEA (394.75 mg, 3.90 mmol, 543.74 uL) and DMAP (19.06 mg, 156.04 umol) were added to a solution of 2- oxaspiro[3.3]heptan-6-ylmethanol (200 mg, 1.56 mmol) in DCM (3 mL). The mixture was stirred at 20 °C for 16 h. The mixture was quenched with aq. NH4CI (10 mL) and extracted with EtOAc (5 mL x3). The combined layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under vacuum to give the crude, which was purified by Flash column (Petroleum ether / EtOAc = 5 / 1 to 3 / 1) to give the product 2-oxaspiro[3.3]heptan- 6-ylmethyl 4-methylbenzenesulfonate (230 mg, 814.58 umol, 52.2% yield) as colorless oil. LCMS m / z = 283.2 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 ppm 7.72 - 7.84 (m, 2 H), 7.35 (d, J=7.87 Hz, 2 H), 4.64 (s, 2 H), 4.53 (s, 1 H), 4.46 - 4.49 (m, 1 H), 3.91 (d, J=6.08 Hz, 2 H), 2.46 (s, 3 H), 2.36 - 2.44 (m, 1 H), 2.26 - 2.34 (m, 2 H), 1.91 - 1.99 (m, 2 H).

[0313] 2. Synthesis of 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((4-methyl-2- ( tr ifluorome thy l)pyrimidin-5-y I) sulfonyl) -2, 6-diazaspiro[ 3.3 ] heptane

[0314] To a solution of 2-[[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2,6- diazaspiro[3.3]heptane (150 mg, 389.32 umol, TFA) and K2CO3 (161.43 mg, 1.17mmol) in ACN (5 mL) was added 2-oxaspiro[3.3]heptan-6-ylmethyl 4- methylbenzenesulfonate (219.85 mg, 778.65 umol) in portions and the resulting mixture was stirred at 80°C for 16 h. The mixture was filtered and concentrated in vacuo. The crude residue was purified by prep-HPLC (Column: Cl 8-1 150*30mm*5um; Condition: water( NH4HCO3)-ACN; Begin B: 25 ; End B: 55; Flow Rate (ml / min): 25) to give 6-[[4-methyl-2- (tri fluoromethyl )pyrimidin-5-yl]methyl]-2-(2-oxaspiro[3.3]heptan-6-ylmethyl)-2, 6- diazaspiro[3.3]heptane (20 mg, 52.3 umol, 13.4% yield) as white solid. LCMS m / z = 383.2 [M+H]+. 'H NMR (400 MHz, CDCI3): 8 ppm 8.63 (s, 1H), 4.70 (s, 2H), 4.56 (s, 2H), 3.59 (s, 2H), 3.33 (s, 4H), 3.25 (s, 4H), 2.60 (s, 3H), 2.36 - 2.27 (m, 4H), 2.13 - 2.01 (m, 1H), 1.87 - 1.79 (m, 2H).

[0315] Example 11 : 2-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2,6-diazaspiro [3.3] heptane

[0316] 1. Synthesis of 4-bromo-2-(trifluoromethyl)pyrimidin-5-amine NBS (14.19 g, 79.71 mmol) was added to a solution of 2-(trifluoromethyl)pyrimidin-5-amine (10 g, 61.31 mmol) in ACN (100 mL). The mixture was stirred at 20 °C for 16 h under nitrogen. The solvent was evaporated, and the residue partitioned in water (10 mL) and ethyl acetate (80 mL). The layers were separated, and the aqueous layer 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 material 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, 59.31% yield) as brown oil. LCMS m / z = 243.9 [M+H]+. 'HNMR (400 MHz, CDC13): 5 8.18 (s, 1H), 4.55 (br s, 2H).

[0317] 2. Synthesis of 2-(trifluoromethyl)-4-vinylpyrimidin-5-amine dioxane / H2O

[0318] 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) were added under nitrogen 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). The mixture was stirred at 90°C for 3 h. 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, 26.4 mmol, 74.4% yield) as yellow liquid. LCMS m / z = 190.1 [M+H]+. ‘H NMR (400 MHz, CDCI3): 8 ppm 8.25 (s, 1H), 6.85-6.73 (m, 1H), 6.64-6.56 (m, 1H), 5.82-5.79 (m, 1H).

[0319] 3. Synthesis of 4-ethyl-2-(trijluoromethyl)pyrimidin-5-amine Pd / C (2.64 g, 2.48 mmol, 10% purity) was added under H2 atmosphere to a solution of 2- (trifluoromethyl)-4-vinylpyrimidin-5-amine (4.7 g, 24.85 mmol) in THF (30 mL). The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 12 h. The reaction mixture was filtered and concentrated to give the desired compound (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]+.JH NMR (500 MHz, CDCI3): 8 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).

[0320] 4. Synthesis of 5-bromo-4-ethyl-2-(trifluoromethyl)pyrimidine

[0321] To a solution of 4-ethyl-2-(trifluoromethyl)pyrimidin-5-amine (1.5 g, 7.85 mmol) in ACN (20 mL) was added CuBr2 (2.63 g, 11.77 mmol, 551.15 pL) and t-BuONO (1.21 g, 11.77 mmol, 1.38 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 purified by flash column (EtOAc in petroleum ether = 0% ~5%) to give the desired compound (870 mg, 43.5% yield) as colorless oil. LCMS m / z = 256.9 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 3.03 (q, J=7.6 Hz, 2H), 1.36 (t, J=7.6 Hz, 3H).

[0322] 5. Synthesis of 5-(benzylthio)-4-ethyl-2-(trijluoromethyl)pyrimidine

[0323] To a solution of 5-bromo-4-ethyl-2-(trifluoromethyl)pyrimidine (870 mg, 3.41 mmol) and BnSH (420 mg, 3.38 mmol, 396.98 pL) in dioxane (10 mL) was added DIPEA (1.32 g, 10.23 mmol, 1.78 mL) and Pd(t-Bu3P)2 (261.50 mg, 511.69 pmol). The reaction mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (30 mL) and 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 to give the desired compound (1 g, crude) as a yellow oil. LCMS m / z = 256.9 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 8.50 (s, 1H), 7.35-7.32 (m, 5H), 4.22 (s, 2H), 2.90 (q, J=7.6 Hz, 2H), 1.33-1.28 (m, 3H).

[0324] 6. Synthesis of 4-ethyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride

[0325] SO2CI2 (3.17 g, 23.46 mmol, 1.90 mL) Was added at 0 °C to a solution of 5-(benzylthio)-4- ethyl-2-(trifluoromethyl)pyrimidine (1 g, 3.35 mmol) in DCM (10 mL) and water (2 mL). The mixture was stirred at 0 °C for 1 h under N2. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 5). The combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired compound (500 mg, crude) as yellow oil.1HNMR (400 MHz, CDCI3): 6 ppm 9.15 (s, 1H), 3.21 (q, J=7.2 Hz, 2H), 1.37-1.32 (m, 3H).

[0326] 7. Synthesis of tert-butyl 6-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[ 3.3 ]heptane-2-carboxylate

[0327] DIPEA (705.85 mg, 5.46 mmol, 951.28 pL) and 4-ethyl-2-(trifluoromethyl)pyrimidine-5- sulfonyl chloride(500 mg, 1.82 mmol) were added to a solution of tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate (397.03 mg, 2.00 mmol) in DCM (10 mL). The mixture was stirred at 0 °C for 1 hour and was then filtered and concentrated in vacuo. The crude material was purified by flash column (EtOAc in petroleum ether from 0% to 30%) to give the desired compound (580 mg, 73.0% yield) as a yellow solid. LCMS m / z = 381.2 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 ppm 9.20 (s, 1H), 4.15 (s, 4H), 4.07 (s, 4H), 3.21 (q, J=7.6 Hz, 2H), 1.44 (s, 9H), 1.43-1.25 (m, 3H). 8. Synthesis of 2-((4-ethyl-2-(trijluoromethyl)pyrimidin-5-yl)sulfonyl)-2, 6-

[0328] TFA (454.57 mg, 3.99 mmol, 305.28 pL) was added to a solution of tert-butyl 6-((4-ethyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane-2-carboxylate (580 mg, 1.33 mmol) in HFIP (8 mL). The mixture was stirred for 14 h. and then concentrated to give the desired compound (600 mg, crude, TFA salt) as a yellow oil. LCMS m / z = 337.1 [M+H]+. ‘H NMR (400 MHz, CDCI3): 6 ppm 9.19 (s, 1H), 4.33 (s, 4H), 4.24 (s, 4H), 3.18 (q, J=7.6 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).

[0329] 9. Synthesis of 2-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane 2-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane (200 mg, 445.09 pmol, TFA salt) and tetrahydro-4H-pyran-4-one (66.84 mg, 667.63 pmol, 61.66 pL) in MeOH (5 mL) was added TEA to pH = 5~6. Then NaBHsCN (83.91 mg, 1.34 mmol) was then added, and the mixture stirred at 20 °C for 1 h. The mixture was concentrated and purified by pre-HPLC (Column: Boston Prime C18 150*30 mm*5 pm, Condition: water (NH3.H2O+NH4HCO3)-ACN, 40%~70%, Flow Rate (mL / min): 25) to give the desired compound (85 mg, 43.9% yield) as a white solid. LCMS m / z = 421.1 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 9.19 (s, 1H), 4.12 (s, 4H), 3.98-3.92 (m, 2H), 3.39-3.34 (m, 2H), 3.32 (s, 4H), 3.25-3.18 (m, 2H), 2.21-2.12 (m, 1H), 1.60-1.58 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 1.36-1.25 (m, 2H).

[0330] Example 12: 2-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(2- oxaspiro [3.3] heptan-6-yl)-2,6-diazaspiro [3.3] heptane

[0331] 2-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)-2,6- diazaspiro[3.3]heptane was obtained (44 mg, 23% yield) from 2-((4-ethyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and 2- oxaspiro[3.3]heptan-6-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 433.1 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 ppm 9.18 (s, 1H), 4.65 (s, 2H), 4.59 (s, 2H), 4.08 (s, 4H), 3.24-3.17 (m, 6H), 2.84-2.81 (m, 1H), 2.29-2.24 (m, 2H), 1.94-1.93 (m, 2H), 1.39 (t, J=7.6 Hz, 3H).

[0332] Example 13: 2-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydro-2H- pyran-4-yl)methyl)-2,6-diazaspiro [3.3] heptane

[0333] 2-((4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (190 mg, 39% yield) from 2-((4-ethyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and tetrahydro-2H- pyran-4-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 435.1 [M+H]+. *HNMR (500 MHz, CDC13): 8 ppm 4.08 (s, 4H), 3.95-3.90 (m, 2H), 3.37-3.29 (m, 6H), 2.90 (s, 6H), 2.27 (d, J = 6.5 Hz, 2H), 1.58-1.55 (m, 3H), 1.28-1.21 (m, 2H).

[0334] Example 14: 2-((4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-

[0335] (tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro [3.3] heptane . Synthesis of 4-cyclopropyl-2-(trijluoromethyl )pyrimidin-5-amine toluene / H2O

[0336] To a solution of cyclopropylboronic acid (2.84 g, 33.06 mmol) and 4-bromo-2- (trifluoromethyl)pyrimidin-5-amine (2 g, 8.26 mmol) in toluene (30 mL) and water (10 mL) was added SPhos (169.64 mg, 413.23 pmol), K3PO4 (5.26 g, 24.79 mmol) and Pd2(dba)s (256.64 mg, 247.94 umol) in turn at 20 °C, the mixture was stirred at 80 °C for 12 hours. The mixture was filtered and 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 (1.2 g, 71.47% yield) as a light-yellow oil. LCMS m / z = 204.1 [M+H]+. *HNMR (400 MHz, CDCI3): 8 ppm 8.09 (s, 1H), 1.88-1.81 (m, 1H), 1.24-1.20 (m, 2H), 1.14-1.09 (m, 2H).

[0337] 2. Synthesis of 5-bromo-4-cyclopropyl-2-(trifluoromethyl)pyrimidine

[0338] To a solution of 4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-amine (1.2 g, 5.91 mmol) in CH3CN (50 mL) was added CuBr2(1.98 g, 8.86 mmol, 414.86 uL) and t-BuONO (913.63 mg, 8.86 mmol, 1.05 mL) in turn slowly. The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with Water(150mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the residue, which was purified by silica gel chromatography (EtOAc in Petroleum ether from 0% to 10%) to give the desired compound (1.1 g, 69.7% yield) as light-yellow oil. LCMS m / z = 268.6 [M+H]+.

[0339] 3. Synthesis of 5-(benzylthio)-4-cyclopropyl-2-(trifluoromethyl)pyrimidine To a solution of BnBr (774.97 mg, 4.53 mmol, 538.92 pL) and 5-bromo-4-cyclopropyl-2- (trifluoromethyl)pyrimidine (1.1 g, 4.12 mmol) in DMF (25 mL) and water (0.5 mL) was added K2CO3 (2.28 g, 16.48 mmol) and thiourea (470.33 mg, 6.18 mmol) in turn at 20 °C. The mixture was stirred at 100 °C for 8 hours. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3), the combined organic layers were dried over ISfeSCh, filtered and concentrated to give the residue, which was purified by silica gel chromatography (EtOAc in Petroleum ether from 0 % to 10 %) to give the desired compound (1 g, 78.2% yield) as a lightyellow oil. LCMS m / z = 311.0 [M+H]+. 'H NMR (400 MHz, CDCI3): 8 ppm 8.42 (s, 1H), 7.30- 7.28 (m, 5H), 4.16 (s, 2H), 2.56-2.42 (m, 1H), 1.29-1.26 (m, 2H), 1.19-1.14 (m, 2H).

[0340] 4. Synthesis of 4-cyclopropyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride

[0341] To a 0 °C solution of 5-(benzylthio)-4-cyclopropyl-2-(trifluoromethyl)pyrimidine (250 mg, 805.58 pmol) in DCM (10 mL) and water (2 mL) was added a solution of sulfuryl chloride (761.10 mg, 5.64 mmol, 457.12 pL) in DCM (0.5 mL). The reaction mixture was stirred at 0- 5 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired compound (200 mg, crude) as a yellow oil.1H NMR (400 MHz, CDCI3): 6 ppm 9.24 (s, 1H), 1.94-1.87 (m, 1H), 1.65-1.61 (m, 2H), 1.57-1.54 (m, 2H).

[0342] 5. Synthesis of 2-(( 4-cyclopropyl-2-(trijluoromethyl )pyrimidin-5-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0343] 2-((4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained (90 mg, 28% yield over 2 steps) from 4-cyclopropyl-2-

[0344] (trifluoromethyl)pyrimidine-5-sulfonyl chloride and tert-butyl 2,6-diazaspiro[3.3]heptane-2- carboxylate, following a similar procedure to that described in Example 11 (steps 7 and 8). LCMS m / z = 349.0 [M+H]+.

[0345] 6. Synthesis of 2-(( 4-cyclopropyl-2-(trijluoromethyl )pyrimidin-5-yl)sulfonyl)-6-

[0346] (tetrahydro-2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0347] 2-((4-Cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)- 2,6-diazaspiro[3.3]heptane was obtained (21.9 mg, 28.7% yield) from 2-((4-cyclopropyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and tetrahydro-4H- pyran-4-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 433.1 [M+H]+.XH NMR (400 MHz, MeOD): 5 ppm 9.13 (s, 1H), 4.09 (s, 4H), 3.95-3.87 (m, 2H), 3.41-3.33 (m, 6H), 3.03-2.91 (m, 1H), 2.31-2.20 (m, 1H), 1.73-1.61 (m, 2H), 1.46- 1.36 (m, 4H), 1.27-1.15 (m, 2H).

[0348] Example 15: 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(tetrahydro-

[0349] 2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0350] 1. Synthesis of 5-bromo-4-methylpyrimidine-2-carbonitrile

[0351] 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 pL) 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% yield) as a yellow solid. LCMS m / z = 197.7 [M+H]+.1H NMR (400 MHz, CDC13): 5 ppm 8.80 (s, 1H), 2.70 (s, 3H).

[0352] 2. Synthesis of l-(5-bromo-4-methylpyrimidin-2-yl)ethan-l-one

[0353] 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% yield) 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). . Synthesis of 5-bromo-2-( 1, l-dijluoroethyl)-4-methylpyrimidine

[0354] 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 Na2SO4, filtered and concentrated under reduced pressure to give the desired product (1.7 g, 6.45 mmol, 96.4% yield) as a brown oil. LCMS m / z = 236.5 [M+H]+. *HNMR (400 MHz, CDCI3): 8 ppm 8.79 (s, 1H), 2.71 (s, 3H), 2.05 (t, J = 18.8 Hz, 3H). . Synthesis 5-(benzylthio)-2-( 1, 1 -difluoroethyl) -4 -methylpyrimidine

[0355] 5-(benzylthio)-2-(l,l-difluoroethyl)-4-methylpyrimidine was obtained (470 mg, 36% yield) from 5-bromo-2-(l,l-difluoroethyl)-4-methylpyrimidine, following a similar procedure to that described in Example 14 (step 3).1H NMR (400 MHz, CDCh): 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).

[0356] 5. Synthesis 2-(l,l-dijluoroethyl)-4-methylpyrimidine-5-sulfonyl chloride

[0357] 2-(l,l-Difluoroethyl)-4-methylpyrimidine-5-sulfonyl chloride was obtained (180 mg, crude) from 5-(benzylthio)-2-(l,l-difluoroethyl)-4-methylpyrimidine, following a similar procedure to that described in Example 14 (step 4). LCMS m / z = 256.9 [M+H]+. 'H NMR (400 MHz, CDCh): 6 ppm 9.30 (s, 1H), 3.07 (s, 3H), 2.12-2.06 (m, 3H).

[0358] 6. Synthesis 2-((2-(l, l-difluoroethyl)-4-methylpyrimidin-5-yl )sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0359] 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained (105 mg, 33% yield over 2 steps) from 2-(l,l-difluoroethyl)-4-methylpyrimidine-5- sulfonyl chloride and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, following a similar procedure to that described in Example 11 (steps 7 and 8).1H NMR (400 MHz, CDCh): 8 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).

[0360] 7. Synthesis of 2-((2-(l, l-dijluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(tetrahydro-

[0361] 2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0362] 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane was obtained (9.1 mg, 32.7% yield) from 2-((2-(l,l-difluoroethyl)-4- methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and tetrahydro-4H-pyran-4-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 403.1 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 ppm 9.13 (s, 1H), 4.09 (s, 4H), 3.97-3.91 (m, 2H), 3.38 - 3.28 (m, 6H), 2.88 (s, 3H), 2.18-2.15 (m, 1H), 2.07 (t, J = 18.8 Hz, 3H), 1.62-1.60 (m, 2H), 1.36-1.24 (m, 2H).

[0363] Example 16: 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(2- oxaspiro [3.3] heptan-6-yl)-2,6-diazaspiro [3.3] heptane

[0364] 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)- 2,6-diazaspiro[3.3]heptane was obtained (24.7 mg, 25.5% yield) from 2-((2-(l,l- difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 2- oxaspiro[3.3]heptan-6-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 414.3 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 9.12 (s, 1H), 4.64 (s, 2H), 4.59 (s, 2H), 4.06 (s, 4H), 3.25 (br s, 4H), 2.93-2.75 (m, 4H), 2.34-2.20 (m, 2H), 2.07 (t, J=18.6 Hz, 3H), 1.99-1.85 (m, 2 H).

[0365] Example 17: Rac-2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(2- oxaspiro [3.3] heptan-6-yl)-2,6-diazaspiro [3.3] heptane

[0366] Rac-2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6- yl)-2,6-diazaspiro[3.3]heptane was obtained (20.6 mg, 20.2% yield) from 2-((2-(l,l- difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 1- (tetrahydro-2H-pyran-4-yl)ethan-l-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 431.1 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 9.13 (s, 1H), 4.09 (br s, 4H), 4.01-3.95 (m, 2H), 3.69-3.00 (m, 6H), 2.87 (s, 3H), 2.18-1.96 (m, 4H), 1.54-1.29 (m, 5H), 1.11-0.62 (m, 3H).

[0367] Example 18: 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-((tetrahydro- 2H-pyran-4-yl)methyl)-2,6-diazaspiro [3.3] heptane

[0368] 2-((2-(l,l-Difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (14.6 mg, 25.4% yield) from 2-((2-(l,l- difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and tetrahydro-

[0369] 2H-pyran-4-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 417.1 [M+H]+. 'HNMR (400 MHz, CDCI3): 6 ppm 9.06 (s, 1H), 4.00 (s, 4H), 3.89-3.84 (m, 2H), 3.31-3.22 (m, 6H), 2.81 (s, 3H), 2.22-2.19 (m, 2H), 2.00 (t, J = 18.8 Hz, 3H), 1.49-1.43 (m, 3H), 1.23-1.15 (m, 2H).

[0370] Example 19: 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(oxetan-3- ylmethyl)-2,6-diazaspiro[3.3]heptane

[0371] 2-((2-(l,l-Difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6- diazaspiro[3.3]heptane was obtained (6.2 mg, 21.8% yield) from 2-((2-(l,l-difhroroethyl)-4- methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and oxetane-3-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 389.1 [M+H]+. 'HNMR (400 MHz, CDCI3): 6 ppm 9.12 (s, 1H), 4.76-4.72 (m, 2H), 4.35 (t, J = 6.0 Hz, 2H), 4.06 (s, 4H), 3.29 (s, 4H), 2.98-2.90 (m, 1H), 2.87 (s, 3H), 2.69 (d, J = 7.2 Hz, 2H), 2.07 (t, J = 18.4 Hz, 3H).

[0372] Example 20: Rac-2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-

[0373] ((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0374] Rac-2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (22.7 mg, 23.9% yield) from 2-((2-(l, 1- difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and tetrahydrofuran-3-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 403.1 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 ppm 9.13 (s, 1H), 4.09 (s, 4H), 3.86-3.78 (m, 2H), 3.75-3.67 (m, 1H), 3.55-3.15 (m, 5H), 2.87 (s, 3H), 2.58-2.31 (m, 2H), 2.26-2.14 (m, 1H), 2.07 (t, J = 18.4 Hz, 3H), 2.01-1.86 (m, 1H), 1.53-1.48 (m, 1H).

[0375] Example 21: 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-((3- methyloxetan-3-yl)methyl)-2,6-diazaspiro [3.3] heptane

[0376] 2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-((3-methyloxetan-3-yl)methyl)- 2,6-diazaspiro[3.3]heptane was obtained (10.7 mg, 11.3% yield) from 2-((2-(l,l- difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 3- m ethyl ox etane-3-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 403.1 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 9.13 (s, 1H), 4.39 (d, J = 5.6 Hz, 2H), 4.30 (d, J = 6.0Hz, 2H), 4.09 (s, 4H), 3.62-3.20 (m, 4H), 2.87 (s, 3H), 2.79- 2.49 (m, 2H), 2.07 (t, J = 18.4Hz, 3H), 1.27 (s, 3H).

[0377] Example 22: Rac-2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(l- (tetrahydrofuran-3-yl)ethyl)-2,6-diazaspiro [3.3] heptane

[0378] Rac-2-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-6-(l-(tetrahydrofuran-3- yl)ethyl)-2,6-diazaspiro[3.3]heptane was obtained (17.2 mg, 35.4% yield) from 2-((2-(l,l- difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and l-(oxetan-3- yl)ethan-l-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 417.1 [M+H]+. *HNMR (400 MHz, CDC13): 8 ppm 9.13 (s, 1H), 4.08 (s, 4H), 3.76-3.67 (m, 3H), 3.55-3.26 (m, 5H), 2.87 (s, 3H), 2.16-2.13 (m, 2H), 2.07 (t, J = 18.4 Hz, 3H), 1.99- 1.84 (m, 1H), 1.56-1.53 (m, 1H), 1.00-0.77 (m, 3H).

[0379] Example 23: 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((2-(l,l-difluoroethyl)-4- methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro [3.3] heptane

[0380] 2-((2-Oxaspiro[3.3]heptan-6-yl)methyl)-6-((2-(l,l-difluoroethyl)-4-methylpyrimidin-5- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained (18.6 mg, 18.2% yield) from 2-((2-(l , 1 - difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and (2- oxaspiro[3.3]heptan-6-yl)methanol, following a similar procedure to that described in Example 10 (steps 1 and 2). LCMS m / z = 429.1 [M+H]+. *HNMR (400 MHz, CDCI3): 6 ppm 9.12 (s, 1H), 4.69 (s, 2H), 4.55 (s, 2H), 4.07 (s, 4H), 3.29 (br s, 4H), 2.87 (s, 3H), 2.44-2.23 (m, 4H), 2.12-2.02 (m, 4H), 1.89-1.77 (m, 2H).

[0381] Example 24: 2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(tetrahydro-

[0382] 2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane . Synthesis 4, 6-dibromo-2-(trifluoromethyl)pyrimidin-5-amine To a solution of 2-(trifluoromethyl)pyrimidin-5-amine (2.5 g, 15.33 mmol) in ACN (40 mL) was added NBS (6.00 g, 33.72 mmol) at 20 °C, the mixture was stirred at 40 °C for 12 hours. The mixture was concentrated to give a crude residue, which was purified by silica gel chromatography (Petroleum ether / EtOAc from 0% to 30 %) to give the desired compound (2.5 g, 50.83% yield) as light-yellow solid. LCMS m / z = 321.7 [M+H]+.

[0383] 2. Synthesis 4, 6-dimethyl-2-(trifluoromethyl )pyrimidin-5-amine

[0384] Pd(dppf)C12 (570.05 mg, 779.08 umol) and K2CO3 (2.69 g, 19.48 mmol) were added to a solution of 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (7.82 g, 31.16 mmol, 8.71 mL) and 4,6-dibromo-2-(trifluoromethyl)pyrimidin-5-amine (2.5 g, 7.79 mmol) in Dioxane (100 mL) and water (20 mL). The mixture was stirred at 80 °C for 12 hours under N2. 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 (1.4 g, 94% yield) as a lightyellow solid. LCMS m / z = 192.1 [M+H]+. 'H NMR (400 MHz, CDCI3): 8 ppm 4.04-3.50 (m, 2H), 2.46 (s, 6H). . Synthesis 4, 6-dimethyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride

[0385] 4,6-dimethyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride was obtained (600 mg, crude) from 4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-amine (1.4g, 7.32 mmol) following a similar three step procedure to that described in Example 14 (steps 2, 3 and 4). 'H NMR (400 MHz, CDCI3): 6 ppm 3.07 (s, 6H).

[0386] 4. Synthesis 2-((4, 6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl )sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0387] 2-((4,6-Dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained (150 mg, 31% yield over 2 steps) from 4,6-dimethyl-2-(trifluoromethyl)pyrimidine- 5-sulfonyl chloride and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, following a similar procedure to that described in Example 11 (steps 7 and 8). LCMS m / z = 337.0 [M+H]+. 'HNMR (400 MHz, MeOD): 5 ppm 4.26 (s, 4H), 4.24 (s, 4H), 2.90 (s, 6H). . Synthesis 2-((4, 6-dimethyl-2-(trijluoromethyl)pyrimidin-5-yl ) sulfonyl) -6-( tetrahydro- 2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0388] 2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)- 2,6-diazaspiro[3.3]heptane was obtained (18.3 mg, 65.3% yield) from 2-((4,6-dimethyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and tetrahydro-4H- pyran-4-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 421.1 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 4.10 (s, 4H), 3.95-3.87 (m, 2H), 3.41-3.33 (m, 6H), 2.89 (s, 6H), 2.19-2.35 (m, 1H), 1.67 (dd, J=12.4 Hz, 1.6 Hz, 2H), 1.31- 1.14 (m, 2H).

[0389] Example 25: 2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(2- oxaspiro [3.3] heptan-6-yl)-2,6-diazaspiro [3.3] heptane

[0390] 2-((4,6-Dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan-6-yl)- 2,6-diazaspiro[3.3]heptane was obtained (17.7 mg, 61.3% yield) from 2-((4,6-dimethyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and 2- oxaspiro[3.3]heptan-6-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 433.0 [M+H]+. 'H NMR (400 MHz, MeOD): 5 ppm 4.66 (s, 2H), 4.59 (s, 2H), 4.08 (s, 4H), 3.31 (s, 4H), 2.97-2.91 (m, 1H), 2.88 (s, 6H), 2.35-2.27 (m, 2H), 2.01- 1.93 (m, 2H).

[0391] Example 26: Rac-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(l- (tetrahydro-2H-pyran-4-yl)ethyl)-2,6-diazaspiro [3.3] heptane

[0392] Rac-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(l-(tetrahydro-2H-pyran- 4-yl)ethyl)-2,6-diazaspiro[3.3]heptane was obtained (20.3 mg, 63.7% yield) from 2-((4,6- dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 1- (tetrahydro-2H-pyran-4-yl)ethan-l-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 449.1 [M+H]+. ' H NMR (400 MHz, MeOD): 5 ppm 4.09 (s, 4H), 3.97-3.75 (m, 2H), 3.44-3.32 (m, 6H), 2.89 (s, 6H), 2.20-2.09 (m, 1H), 1.71-1.59 (m, 1H), 1.53-1.29 (m, 4H), 0.85 (d, J = 6.4 Hz, 3H).

[0393] Example 27 : 2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-

[0394] ((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro [3.3] heptane

[0395] 2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (17.7 mg, 61.3% yield) from 2-((4,6- dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and tetrahydro-2H-pyran-4-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 433.0 [M+H]+. ' H NMR (400 MHz, MeOD): 5 ppm 4.66 (s, 2H), 4.59 (s, 2H), 4.08 (s, 4H), 3.31 (s, 4H), 2.97-2.91 (m, 1H), 2.88 (s, 6H), 2.35-2.27 (m, 2H), 2.01-1.93 (m, 2H).

[0396] Example 28: 2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(oxetan-3- ylmethyl)-2,6-diazaspiro[3.3]heptane

[0397] 2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(oxetan-3-ylmethyl)-2,6- diazaspiro[3.3]heptane was obtained (13.3 mg, 49.0% yield) from 2-((4,6-dimethyl-2- (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and oxetane-3- carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 407.1 [M+H]+. 'H NMR (400 MHz, MeOD): 5 ppm 4.78-4.73 (m, 2H), 4.37 (t, J = 6.0 Hz, 2H), 4.08 (s, 4H), 3.37 (s, 4H), 2.96-3.06 (m, 1H), 2.88 (s, 6H), 2.76 (d, J = 7.2 Hz, 2H).

[0398] Example 29: Rac-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-

[0399] ((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0400] Rac-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (13.0 mg, 45.7% yield) from 2-((4,6- dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and tetrahydrofuran-3-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 421.1 [M+H]+. 'H NMR (400 MHz, MeOD): 5 ppm 4.15 (s, 4H), 3.97-3.59 (m, 7H), 3.45-3.41 (m, 1H), 2.89 (s, 6H), 2.84-2.58 (m, 2H), 2.36-2.23 (m, 1H), 2.12- 1.98 (m, 1H), 1.64-1.50 (m, 1H).

[0401] Examples 30 and 31: (S)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-

[0402] ((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane and (R)-2-((4,6-dimethyl-2-

[0403] (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6- diazaspiro[3.3]heptane

[0404] Rac-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro[3.3]heptane (350 mg, 832.44 pmol) was separated by SFC (Column: Phenomenex Lux Cellulose-4 250*30mm*5pm; Mobile Phase: from 15% to 15% of 0.1%NH3H2O IP A; Flow Rate (mL / min): 60; Column temp: 40 °C) to give:

[0405] (S)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro[3.3]heptane (118 mg, 33.7% yield). LCMS m / z = 421.1 [M+H]+.JH NMR (500 MHz, MeOD): 5 ppm 4.09 (s, 4H), 3.83-3.79 (m, 2H), 3.74-3.69 (m, 1H), 3.42-3.39 (m, 1H), 3.33 (br s, 4H), 2.90 (s, 6H), 2.41-2.37 (m, 2H), 2.21-2.15 (m, 1H), 2.01-1.95 (m, 1H), 1.54-1.51 (m, 1H), and

[0406] (R)-2-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro[3.3]heptane (85 mg, 24.3% yield). LCMS m / z = 421.1 [M+H]+.JH NMR (500 MHz, MeOD): 5 ppm 4.09 (s, 4H), 3.83-3.79 (m, 2H), 3.74-3.69 (m, 1H), 3.42-3.39 (m, 1H), 3.32 (s, 4H), 2.90 (s, 6H), 2.39 (d, J=7.5 Hz, 2H), 2.20-2.15 (m, 1H), 2.01-1.96 (m, 1H), 1.54-1.49 (m, 1H). Both as white solids.

[0407] The stereochemistry of these isomers was assigned arbitrarily.

[0408] Example 32: 2-((2-oxaspiro [3.3] heptan-6-yl)methyl)-6-((4,6-dimethyl-2-

[0409] (trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0410] 2-((2-Oxaspiro[3.3]heptan-6-yl)methyl)-6-((4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained (41.8 mg, 30.2% yield) from 2-((2-(l, 1 - difluoroethyl)-4-methylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and (2- oxaspiro[3.3]heptan-6-yl)methanol, following a similar procedure to that described in Example 10 (steps 1 and 2). LCMS m / z = 447.1 [M+H]+. ‘HNMR (400 MHz, CDC13): 8 ppm 4.69 (s, 2H), 4.55 (s, 2H), 4.07 (s, 4H), 3.28 (s, 4H), 2.90 (s, 6H), 2.35-2.27 (m, 4H), 2.09-2.00 (m, 1H), 1.85-1.78 (m, 2H).

[0411] Example 33: 2-((2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-

[0412] (tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro [3.3] heptane . Synthesis 5-bromo-4, 6-dimethylpyrimidin-2-ol

[0413] To a solution of 4,6-dimethylpyrimidin-2-ol (10.91 g, 87.85 mmol) in CHCI3 (300 mL) was added NBS (9.38 g, 52.71 mmol) with stirring at 0 °C and the reaction stirred for 30 minutes. More NBS (6.25 g, 35.14 mmol) was then added and the mixture was stirred at 0°C for an additional 2 hours. The reaction mixture was filtered and the solution was concentrated to dryness. The crude product was purified by silica gel chromatography eluted with DCM in EtOAc from 0% to 1 / 1 to give the desired compound (11.48 g, 57.9% yield) as a white solid. LCMS m / z = 202.7 [M+H]+. 'H NMR (400 MHz, CDCI3): 8 ppm 2.53 (s, 6H).

[0414] 2. Synthesis 5-bromo-2-chloro-4, 6-dimethylpyrimidine

[0415] To a solution of 5-bromo-4,6-dimethylpyrimidin-2-ol (12 g, 59.10 mmol) in DMF (432.00 mg, 5.91 mmol, 457.63 uL) was added POCI3 (49.35 g, 321.85 mmol, 30.00 mL) at 20 °C. The mixture was stirred at 100 °C for 12 hours. After concentrating the mixture, the residue was quenched with sat.NaHCCh (300 ml) and extracted with DCM (100 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the residue, which was purified by silica gel chromatography (Petroleum ether in EtOAc from 0% to 10 %) to give the desired compound (11.64 g, 53.3% yield) as light-yellow solid. LCMS m / z = 222.8 [M+H]+.XH NMR (400 MHz, CDCI3): 6 ppm 2.62 (s, 6H).

[0416] 3. Synthesis 5-bromo-4, 6-dimethylpyrimidine-2-carbonitrile

[0417] To a mixture of 5-bromo-2-chloro-4, 6-dimethylpyrimidine (12 g, 54.18 mmol) and DABCO (2.25 g, 20.05 mmol, 2.20 mL) in DMSO (120 mL) and water (120 mL) was added NaCN (2.84 g, 57.95 mmol) and the reaction stirred for 14h. The reaction mixture was diluted with H2O (500 mL) and extracted with ethyl acetate (200 mL x 3). The ethyl acetate layers were combined, washed with brine (250 mL), dried over Na2SO4, filtered and concentrated. The residue was purified with silica-gel chromatography (Petroleum ether / EtOAc from 1 / 0 to 10 / 1) to give the desired compound (7 g, 61% yield) as a yellow solid. 'H NMR (400 MHz, CDCI3): 5 ppm 2.69 (s, 6H).

[0418] 4. Synthesis l-(5-bromo-4, 6-dimethylpyrimidin-2-yl)ethan-l-one

[0419] To a solution of 5-bromo-4,6-dimethylpyrimidine-2-carbonitrile (7 g, 33.01 mmol) in THF (100 mL) was added MeMgBr (3 M, 33.01 mL) at -40 °C under N2. The mixture was stirred at -40 °C for 6 hr. Water (100 ml) was added, followed by enough 2N HC1 to make the reaction mixture pH= 2 at 25 °C. This solution was then stirred for 2 hr. The reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (50 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 silica gel chromatography (Petroleum ether / Ethyl acetate=100 / l to 9 / 1) to give the desired compound (4.1 g, 48.9% yield) as a yellow solid. LCMS m / z = 228.9 [M+H]+.XH NMR (400 MHz, CDCI3): 8 ppm 2.74 (s, 3H), 2.73 (s, 6H). . Synthesis 5-bromo-2-( 1, 1 -difluoroethyl) -4, 6-dimethylpyrimidine To a solution of l-(5-bromo-4,6-dimethylpyrimidin-2-yl)ethan-l-one (4 g, 15.72 mmol) in anhydrous DCM (10 mL) was added DAST (12.67 g, 78.58 mmol, 10.38 mL) at 20 °C. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched by saturated ammonium chloride (100 mL), and extracted with DCM (50 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 silica gel chromatography (Petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the desired compound (3.6 g, 73% yield) as a yellow oil. LCMS m / z = 250.9 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 2.70 (s, 6H), 2.03 (t, J=18.4 Hz, 3H).

[0420] 6. Synthesis 2-( 1, l-difluoroethyl)-4, 6-dimethylpyrimidine-5-sulfonyl chloride

[0421] 2-(l,l-Difluoroethyl)-4,6-dimethylpyrimidine-5-sulfonyl chloride was obtained (708 mg, crude) from 5-bromo-2-(l,l-difluoroethyl)-4,6-dimethylpyrimidine (2.2 g, 7.01 mmol) following a similar procedure to that described in Example 14 (steps 3 and 4).1H NMR (400 MHz, CDCI3): 6 ppm 3.04 (s, 6H), 2.06 (t, J=18.8 Hz, 3H).

[0422] 7. Synthesis 2-((2-(l, 1 -difluoroethyl) -4, 6-dimethylpyrimidin-5-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0423] 2-((2-(l,l-Difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained (300mg, crude) from 2-(l,l-difluoroethyl)-4,6-dimethylpyrimidine-5-sulfonyl chloride and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, following a similar procedure to that described in Example 11 (steps 7 and 8). LCMS m / z = 333.1 [M+H]+.

[0424] 8. Synthesis 2-((2-(l, 1 -difluoroethyl) -4, 6-dimethylpyrimidin-5-yl)sulfonyl)-6-(tetrahydro- 2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0425] 2-((2-(l,l-Difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4- yl)-2,6-diazaspiro[3.3]heptane was obtained (30.6 mg, 51.5% yield) from 2-((2-(l,l- difhroroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and tetrahydro-4H-pyran-4-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 417.1 [M+H]+.XH NMR (400 MHz, CDCI3): 6 ppm 4.07 (s, 4H), 3.97- 3.91 (m, 2H), 3.38-3.32 (m, 2H), 3.31 (s, 4H), 2.88 (s, 6H), 2.21-2.11 (m, 1H), 2.04 (t, J=18.4 Hz, 3H), 1.65-1.60 (m, 2H), 1.36-1.23 (m, 2H).

[0426] Example 34: 2-((2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-

[0427] ((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro [3.3] heptane

[0428] 2-((2-(l,l-Difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (34.6 mg, 56.1% yield) from 2-((2-(l,l- difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and tetrahydro-2H-pyran-4-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 431.1 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 4.05 (s, 4H), 3.93 (br dd, J = 10.8, 3.2 Hz, 2H), 3.39-3.31 (m, 2H), 3.30 (s, 4H), 2.88 (s, 6H), 2.27 (br d, J = 6.4 Hz, 2H), 2.04 (t, J = 18.4 Hz, 3H), 1.58-1.53 (m, 2H), 1.52-1.44 (m, 1H), 1.31- 1.16 (m, 2H).

[0429] Example 35: 2-((2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-((4- methyltetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane 2-((2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-((4-methyltetrahydro-2H- pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (32.9 mg, 43.7% yield) from 2- ((2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 4-methyltetrahydro-2H-pyran-4-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 445.3 [M+H]+. *HNMR (400 MHz, CDC13): 8 ppm 4.08 (br s, 4H), 3.74-3.66 (m, 2H), 3.64-3.53 (m, 2H), 3.39 (br s, 4H), 2.90 (s, 6H), 2.26 (br s, 2H), 2.07 (t, J = 18.8 Hz, 3H), 1.56-1.40 (m, 2H), 1.32-1.16 (m, 2H), 0.98 (br s, 3H).

[0430] Example 36: 2-((2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-(oxetan-3- ylmethyl)-2,6-diazaspiro[3.3]heptane

[0431] 2-((2-(l, l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-(ox etan-3 -ylmethyl)-2, 6- diazaspiro[3.3]heptane was obtained (13.4 mg, 44.2% yield) from 2-((2-(l,l-difhroroethyl)- 4,6-dimethylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and oxetane-3-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 403.1 [M+H]+. 'HNMR (400 MHz, CDCI3): 6 ppm 4.77-4.72 (m, 2H), 4.36 (t, J=6.0 Hz, 2H), 4.05 (s, 4H), 3.32 (br s, 4H), 2.91-3.02 (m, 1H), 2.88 (s, 6H), 2.72 (br d, J=7.2 Hz, 2H), 2.04 (t, J=18.4 Hz, 3H).

[0432] Example 37 : 2-((2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-((3- methyloxetan-3-yl)methyl)-2,6-diazaspiro [3.3] heptane

[0433] 2-((2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-6-((3-methyl ox etan-3- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (32.8 mg, 54.9% yield) from 2-((2-(l, 1- difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 3- m ethyl ox etane-3-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 417.1 [M+H]+. 'HNMR (400 MHz, CDCI3): 6 ppm 4.39 (d, J=6.0 Hz, 2H), 4.29 (d, J=6.0 Hz, 2H), 4.06 (s, 4H), 3.38 (s, 4H), 2.88 (s, 6H), 2.60 (s, 2H), 2.04 (t, J=18.4 Hz, 3H), 1.25 (s, 3H).

[0434] Example 38: 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((2-(l,l-difluoroethyl)-4,6- dimethylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane

[0435] 2-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-((2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained (15.8 mg, 20.9% yield) from 2-((2-(l , 1 - difluoroethyl)-4,6-dimethylpyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and (2- oxaspiro[3.3]heptan-6-yl)methanol, following a similar procedure to that described in Example 10 (steps 1 and 2). LCMS m / z = 443.1 [M+H]+. *HNMR (400 MHz, CDC13): 8 ppm 4.71 (s, 2H), 4.58 (s, 2H), 4.07 (s, 4H), 3.30 (br s, 4H), 2.90 (s, 6H), 2.43-2.28 (m, 4H), 2.06 (t, J = 18.6 Hz, 4H), 1.89-1.79 (m, 2H).

[0436] Example 39: 2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6- (tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro [3.3] heptane

[0437] 1. Synthesis 4-bromo-6-ethyl-2-(trifluoromethyl )pyrimidin-5 -amine

[0438] 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 h under nitrogen. The acetonitrile was evaporated and the residue was partitioned in water (100 mL) and EtOAc (100 mL). The layers were 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, with 0-30% ethyl acetate in Petroleum ether to afford the desired compound (3.55 g, 57.1% yield) as yellow oil. LCMS m / z = 270.0 [M+H]+. ‘H NMR (400 MHz, CDC13): 8 ppm 4.56-4.34 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 1.36 (t, J=7.6 Hz, 3H).

[0439] 2. Synthesis 4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-amine

[0440] 2,4,6-Trimethyl-l,3,5,2,4,6-trioxatriborinane (4.95 g, 39.44 mmol, 5.51 mL) was added 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). Pd(dppf)C12 (961.88 mg, 1.31 mmol) and K2CO3 (4.54 g, 32.86 mmol) were then added and the mixture was stirred at 90 °C for 3 h. The reaction mixture was filtered and extracted with DCM (100 mL x 3) and 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, 91.6% yield) as yellow solid. LCMS m / z = 206.1 [M+H]+. 'HNMR (500 MHz, CDCI3): 6 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).

[0441] 3. Synthesis 4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride

[0442] 4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride was obtained (L I g, crude) from 4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-amine (2.47 g, 12.04 mmol) following a similar procedure to that described in Example 14 (steps 2, 3 and 4). LCMS m / z = 269.0 [M+H]+. ‘H NMR (500 MHz, CDCI3): 6 ppm 3.03 (q, J=7.5 Hz, 2H), 2.73 (s, 3H), 1.33 (t, J=7.5 Hz, 3H). 4. Synthesis 2-(( 4-ethyl-6-methyl-2-(trifhioromethyl)pyrimidin-5-yl )sulfonyl)-6-(tetrahydro- 2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0443] To a solution of 2-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane (51.14 mg, 173.21 umol, TFA salt) in DCM (2 mL) was added DIEA (67.16 mg, 519.62 umol, 90.51 uL) and 4- ethyl-6-methyl-2-(trifluoromethyl)pyrimidine-5-sulfonyl chloride (50 mg, 173.21 umol) at 0 °C. Then the mixture was stirred at 20 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure, and the residue purified by prep-HPLC (column: Waters xbridge 150*25mm 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-60%, l lmin). Sch-124-1 (9.62 mg, 10.6% yield) was obtained as a white solid. LCMS m / z = 435.1 [M+H]+. 'H NMR (500 MHz, CDC13): 8 ppm 4.09 (s, 4H), 3.96-3.92 (m, 2H), 3.38-3.32 (m, 2H), 3.32- 3.28 (m, 4H), 3.23 (q, J=7.5 Hz, 2H), 2.91 (s, 3H), 2.18-2.11 (m, 1H), 1.61-1.58 (m, 2H), 1.35 (t, J=7.5 Hz, 3H), 1.32-1.24 (m, 2H).

[0444] Example 40: 2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(2- oxaspiro [3.3] heptan-6-yl)-2,6-diazaspiro [3.3] heptane

[0445] 1. Synthesis 2-(( 4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl )sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane 2-((4-Ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained (1.8 g, crude, TFA salt) from 4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidine-5- sulfonyl chloride and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, following a similar procedure to that described in Example 11 (steps 7 and 8). LCMS m / z = 350.9 [M+H]+.

[0446] 2. Synthesis 2-(( 4-ethyl-6-methyl-2-(trifhioromethyl)pyrimidin-5-yl )sulfonyl)-6-(2- oxaspiro[ 3.3 ]heptan-6-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0447] 2-((4-Ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-(2-oxaspiro[3.3]heptan- 6-yl)-2,6-diazaspiro[3.3]heptane was obtained (36 mg, 39% yield) from 2-((4-Ethyl-6-methyl- 2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and 2- oxaspiro[3.3]heptan-6-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 447.1 [M+H]+. 'H NMR (500 MHz, CDC13): 8 ppm 4.65 (s, 2H), 4.59 (s, 2H), 4.06 (s, 4H), 3.25-3.20 (m, 6H), 2.90 (s, 3H), 2.83-2.77 (m, 1H), 2.28-2.24 (m, 2H), 1.94-1.93 (m, 2H), 1.34 (t, J=7.5 Hz, 3H).

[0448] Example 41 : 2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6- ((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro [3.3] heptane

[0449] 2-((4-ethyl-6-methyl-2-(tri fluoromethyl )pyrimidin-5-yl)sulfonyl)-6-((tetrahydro-2H-pyran-4- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (86.5 mg, 37% yield) from 2-((4-Ethyl-6- methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and tetrahydro-2H-pyran-4-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 449.1 [M+H]+. 'H NMR (500 MHz, CDCI3): 6 ppm 4.09 (s, 4H), 3.96-3.92 (m, 2H), 3.38-3.32 (m, 3H), 3.31 (s, 3H), 3.27-3.21 (m, 2H), 2.91 (s, 3H), 2.28 (d, J=7.0 Hz, 2H), 1.60-1.55 (m, 2H), 1.55-1.47 (m, 1H), 1.35 (t, J=7.5 Hz, 3H), 1.30-1.20 (m, 2H). Example 42: 4-((6-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol

[0450] 1. Synthesis of 4-((6-(( 4-ethyl-6-methyl-2-(trijluoromethyl )pyrimidin-5-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ]heptan-2-yl)methyl)tetrahydro-2H-pyran-4-ol

[0451] To a solution of 2-((4-Ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane (150 mg, 323.01 pmol, TFA salt) and l,6-dioxaspiro[2.5]octane (55.30 mg, 484.51 pmol) in MeOH (10 mL) was added TEA (98.06 mg, 969.03 pmol, 135.06 pL) and the mixture was stirred for 6 h at 80 °C. The mixture was concentrated in vacuo and the residue purified by prep-HPLC (Column: Welch Xtimate C18 150*25mm*5pm, Condition: water (NH4HCO3)-ACN, 33%~63%, Flow Rate (mL / min): 25) to give the desired compound (76 mg, 50.6% yield) as a white solid. LCMS m / z = 465.1 [M+H]+. 'HNMR (400 MHz, CDC13): 5 ppm 4.09 (s, 4H), 3.76-3.73 (m, 4H), 3.49 (s, 4H), 3.23 (q, J=7.2 Hz, 2H), 2.91 (s, 3H), 2.83 (s, 1H), 2.40 (s, 2H), 1.57-1.49 (m, 2H), 1.37-1.33 (m, 5H).

[0452] Example 43: Rac- 2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6- ((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro[3.3]heptane

[0453] Rac- 2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro[3.3]heptane was obtained (102.3 mg, 36% yield) from 2-((4-Ethyl- 6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane and tetrahydrofuran-3-carbaldehyde, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 435.2 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 4.08 (s, 4H), 3.85-3.78 (m, 2H), 3.75-3.67 (m, 1H), 3.45-3.38 (m, 1H), 3.32 (s, 4H), 3.23 (q, J=7.2 Hz, 2H), 2.91 (s, 3H), 2.40 (d, J=7.2 Hz, 2H), 2.23-2.12 (m, 1H), 2.02-1.93 (m, 1H), 1.55-1.48 (m, 1H), 1.35 (t, J=7.2 Hz, 3H).

[0454] Examples 44 and 45: (S)-2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5- yl)sulfonyl)-6-((tetrahydrofuran-3-yl)methyl)-2,6-diazaspiro [3.3] heptane and (R)-2-((4- ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro [3.3] heptane

[0455] Rac- 2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro[3.3]heptane (350 mg, 832.44 pmol) was separated by SFC (ColummDAICEL CHIRALPAK AD(250mm*30mm,10um); Mobile Phase: from 0 to 10% of 0.1% NH3.H2O ETOH; Flow Rate (mL / min): 80; Column temp: 35°C) to give:

[0456] (S)-2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro[3.3]heptane (30.9 mg, 34.4% yield). LCMS m / z = 435.2 [M+H]+. 'HNMR (400 MHz, CDCI3): 6 ppm 4.09 (s, 4H), 3.84-3.79 (m, 2H), 3.74-3.68 (m, 1H), 3.46- 3.19 (m, 7H), 2.90 (s, 3H), 2.54-2.32 (m, 2H), 2.26-2.12 (m, 1H), 2.04-1.92 (m, 1H), 1.55-1.50 (m, 1H), 1.35 (t, J = 7.6 Hz, 3H). and

[0457] (R)-2-((4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)-6-((tetrahydrofuran-3- yl)methyl)-2,6-diazaspiro[3.3]heptane (19.5 mg, 21.6% yield). LCMS m / z = 435.2 [M+H]+. 'HNMR (400 MHz, CDCI3): 6 ppm 4.09 (s, 4H), 3.84-3.79 (m, 2H), 3.74-3.68 (m, 1H), 3.45- 3.27 (m, 5H), 3.26-3.22 (m, 2H), 2.90 (s, 3H), 2.49-2.35 (m, 2H), 2.25-2.16 (m, 1H), 2.04-1.94 (m, 1H), 1.55-1.48 (m, 1H), 1.35 (t, J = 7.6 Hz, 3H).

[0458] The stereochemistry of these isomers was assigned arbitrarily.

[0459] Example 46: 2-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)sulfonyl)-6-((tetrahydro-2H- pyran-4-yl)methyl)-2,6-diazaspiro [3.3] heptane

[0460] 1. Synthesis of 5-chloro-3-methylpyrazin-2-amine

[0461] To a solution of 3-methylpyrazin-2-amine (10 g, 91.63 mmol) in DCM (100 mL) was added NCS (12.24 g, 91.63 mmol) slowly at 0 °C, the mixture was stirred at 20 °C for 2 hours. The mixture was diluted with water (250 mL) and extracted with DCM (100 mL x 3), the combined organic layers dried over anhydrous sodium sulfate, filtered and 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 (11 g, 83.6% yield) as a yellow solid. LCMS m / z = 144.0 [M- / -Bu+H] , 'H NMR (400 MHz, CDC13): 8 ppm 7.89 (s, 1H), 4.52 (br s, 2H), 2.39 (s, 3H).

[0462] 2. Synthesis of 5-chloro-3-methylpyrazine-2 -sulfonyl chloride

[0463] 5-Chloro-3-methylpyrazine-2-sulfonyl chloride was obtained (3.0 g, crude) from 5-chloro-3- methylpyrazin-2-amine (11 g, 76.62 mmol) following a similar procedure to that described in Example 14 (steps 2, 3 and 4). 'H NMR (400 MHz, CDCI3): 6 ppm 8.55 (s, 1H), 3.00 (s, 3H).

[0464] 3. Synthesis of tert-butyl 6-((5-chloro-3-methylpyrazin-2-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ]heptane-2-carboxylate tert-butyl 6-((5-chloro-3-methylpyrazin-2-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate was obtained (1.4 g, 27.2% yield) from 5-Chloro-3-methylpyrazine-2-sulfonyl chloride and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, following a similar procedure to that described in Example 11 (step 7). LCMS m / z = 333.0 [M+H]+. 'H NMR (400 MHz, CDC13): 8 ppm 8.35 (s, 1H), 4.39 (s, 4H), 4.11 (s, 4H), 2.86 (s, 3H), 1.44 (s, 9H).

[0465] 4. Synthesis of tert-butyl 6-((5-amino-3-methylpyrazin-2-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ]heptane-2-carboxylate

[0466] A solution of tert-butyl 6-((5-chloro-3-methylpyrazin-2-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (700 mg, 1.80 mmol) in NH3 H2O (1.5 mL, 28% purity) and DMSO (10 mL) was stirred at 80 °C for 12 hours. The mixture was concentrated to give the residue, which was purified by silica gel chromatography (EtOAc in Petroleum ether from 0% to 50 %) to give the desired compound (700 mg, crude) as a yellow oil. LCMS m / z = 370.1 [M+H]+. 'H NMR (400 MHz, CDCI3): 6 ppm 7.71 (s, 1H), 5.55-5.24 (m, 2H), 4.27 (s, 4H), 4.05 (s, 4H), 2.65 (s, 3H), 1.42 (s, 9H).

[0467] 5. Synthesis of tert-butyl 6-((5-iodo-3-methylpyrazin-2-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ]heptane-2-carboxylate

[0468] To a solution of tert-butyl 6-((5-amino-3-methylpyrazin-2-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (700 mg, 1.89 mmol), Cui (51.55 mg, 270.68 pmol) and CH2I2(L01 g, 3.79 mmol, 305.25 uL) in THF (20 mL) was added t-BuONO (390.78 mg, 3.79 mmol, 450.72 pL) at 0 °C, and the mixture stirred at 60 °C for 12 hours. The mixture was diluted with water (50 ml) and extracted with EtOAc (20ml x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and 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 (450 mg, 49.5% yield) as a yellow solid. LCMS m / z = 424.9 [M-L Bu+H]+. 'HNMR (400 MHz, CDCh): 6 ppm 8.61 (s, 1H), 4.39 (s, 4H), 4.11 (s, 4H), 2.84 (s, 3H), 1.44 (s, 9H).

[0469] 6. Synthesis of tert-butyl 6-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)sulfonyl)-2,6- diazaspiro[ 3.3 ]heptane-2-carboxylate

[0470] To a solution of tert-butyl 6-((5-iodo-3-methylpyrazin-2-yl)sulfonyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (200 mg, 416.39 pmol) in DMF (0.7 mL) was added diphenyl(trifluoromethyl)sulfanium trifluoromethanesulfonate (336.73 mg, 832.78 pmol) and copper (52.92 mg, 832.78 pmol) at 20 °C. The mixture was stirred at 60 °C for 12 hours. The reaction mixture was filtered and concentrated to give the residue, which was purified by silica gel chromatography (EtOAc in Petroleum ether from 0% to 50%) to give the desired compound (120 mg, 68.2% yield) as a white solid. LCMS m / z = 367.0 [M-LBu+H]+. 'H NMR (400 MHz, CDCh): 8 ppm 8.73 (s, 1H), 4.46 (s, 4H), 4.18 (s, 4H), 2.98 (s, 3H), 1.47 (s, 9H).

[0471] 7. Synthesis of 2-( (3-methyl-5-(trifluoromethyl)pyrazin-2-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0472] TFA (97.17 mg, 852.23 pmol, 65.26 pL) was added at 20 °C to a solution of tert-butyl 6-((3- methyl-5-(trifluoromethyl)pyrazin-2-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (120 mg, 284.08 umol) in HFIPA (5 mL). The mixture was stirred at 20 °C for 20 minutes. The mixture was concentrated to give the desired compound (120 mg, crude, TFA salt) as a white solid. LCMS m / z = 323.0 [M+H]+. 8. Synthesis of 2-( (3-methyl-5-(trifluoromethyl)pyrazin-2-yl)sulfonyl)-6-(tetrahydro-2H- pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0473] 2-((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)sulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6- diazaspiro[3.3]heptane was obtained (63.5 mg, 56.0 % yield) from 2-((3-methyl-5- (trifluoromethyl)pyrazin-2-yl)sulfonyl)-2,6-diazaspiro[3 ,3]heptane and tetrahydro-4H-pyran- 4-one, following a similar procedure to that described in Example 11 (step 9). LCMS m / z = 407.0 [M+H]+. ‘H NMR (400 MHz, CDC13): 8 ppm 8.69 (s, 1H), 4.40 (s, 4H), 3.98-3.95 (m, 2H), 3.43 (s, 4H), 3.38-3.33 (m, 2H), 2.95 (s, 3H), 2.27-2.14 (m, 1H), 1.63-1.59 (m, 2H), 1.41- 1.26 (m, 2H).

[0474] Example 47 : 2-((3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl)sulfonyl)-6-(tetrahydro-

[0475] 2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptane

[0476] 1. Synthesis of 5-chloro-3-cyclopropylpyrazin-2-amine , , dioxane / H2O

[0477] 5-Chloro-3-cyclopropylpyrazin-2-amine was obtained (5.0 g, 60.5 % yield) from 3-bromo-5- chloropyrazin-2-amine and cyclopropylboronic acid, following a similar procedure to that described in Example 14 (step 1). LCMS m / z = 234.8 [M+H]+.

[0478] 2. Synthesis of 5-chloro-3-cyclopropylpyrazine-2-sulfonyl chloride

[0479] 5-chloro-3-cyclopropylpyrazine-2-sulfonyl chloride was obtained (2.7 g, crude) from 5- Chi oro-3 -cy cl opropylpyrazin-2-amine (6 g, 35.4 mmol) following a similar procedure to that described in Example 14 (steps 2, 3 and 4). 'HNMR (400 MHz, CDC13): 8 ppm 8.29 (s, 1H), 2.99-2.78 (m, 1H), 1.30-1.23 (m, 4H).

[0480] 3. Synthesis of tert-butyl 6-((5-chloro-3-cyclopropylpyrazin-2-yl)sulfonyl)-2, 6- diazaspiro[ 3.3 ]heptane-2-carboxylate

[0481] Tert-butyl 6-((5-chloro-3-cyclopropylpyrazin-2-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate was obtained (600 mg, 36.6% yield) from of 5-chloro-3-cyclopropylpyrazine-2- sulfonyl chloride and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, following a similar procedure to that described in Example 11 (step 7). LCMS m / z = 359.1 [M-t-Bu+H]+. 'HNMR (400 MHz, CDCI3): 6 ppm 8.19 (s, 1H), 4.40 (s, 4H), 4.11 (s, 4H), 2.91-2.76 (m, 1H), 1.44 (s, 9H), 1.28-1.24 (m, 4H).

[0482] 4. Synthesis of 2-( (3-cyclopropyl-5-(trifluoromethyl )pyrazin-2-yl )sulfonyl)-2, 6- diazaspiro[ 3.3 ] heptane

[0483] 2-((3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane was obtained (80 mg, crude, TFA salt) from tert-butyl 6-((5-chloro-3-cyclopropylpyrazin-2- yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (500 mg, 1.21 mmol) following a similar procedure to that described in Example 46 (steps 4-7). LCMS m / z = 349.0 [M+H]+.

[0484] 5. Synthesis of 2-( (3-cyclopropyl-5-(trifluoromethyl )pyrazin-2-yl )sulfonyl)-6-(tetrahydro- 2H-pyran-4-yl)-2, 6-diazaspiro[ 3.3 ] heptane

[0485] Tetrahydro-4H-pyran-4-one (80 mg, 173.40 pmol, TFA) and 2-((3-cyclopropyl-5- (trifluoromethyl)pyrazin-2-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane (43.40 mg, 433.50 umol, 40.04 pL) were dissolved in MeOH (2 mL). NaBHjCN (54.48 mg, 867.00 pmol) was added at 20 °C and the mixture stirred at 20 °C for 2 hours. The mixture was concentrated to give the residue, which was purified by prep-HPLC (Column: Waters xbridge 150*25mm lOum; Condition: water (NH4HCO3)-ACN; Begin B: 26; End B: 56; Gradient Time (min) 8; 100%B Hold Time (min) 2 Flow Rate (mL / min) 30) to afford the desired compound (11.86 mg, 12.65% yield) as a white solid. LCMS m / z = 433.1 [M+H]+. 'HNMR (400 MHz, CDC13): 8 ppm 8.54 (s, 1H), 4.41 (s, 4H), 3.98-3.95 (m, 2H), 3.42-3.34 (m, 6H), 2.92-2.87 (m, 1H), 2.22-2.16 (m, 1H), 1.66-1.62 (m, 2H), 1.39-1.29 (m, 6H).

[0486] ASSAYS

[0487] EBP [3H]ifenprodil scintillation proximity assay (SPA)

[0488] 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.

[0489] 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.

[0490] Eq 1 : POC = (well read - Tasin-1 read) / (DMSO read - Tasin-1 read) x 100%

[0491] DATA FOR EXAMPLES + means >100nM to <500 nM; ++ means >30nM to <100 nM; +++ means >15 to <30 nM;

[0492] ++++ means <15 nM

Claims

CLAIMSWhat is claimed is:

1. A compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is Het, or -Z-Het, wherein the Het is optionally substituted with one or more R2;Z is Ci-4alkyl optionally substituted with one or more halo or Ci-3alkoxy;Het is Cs-ecycloalkyl or 4- to 10-membered monocyclic or bicyclic heterocyclyl, , each of which is optionally substituted with R2;R2, for each occurrence, is independently Ci-ealkyl, halo, -CN, -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;R2ais H, Ci-ealkyl, or Cs-ecycloalkyl wherein the Ci-ealkyl is optionally substituted with one or more halo or Ci-3alkoxy;R3is pyrazinyl or pyrimidinyl, each of which are optionally substituted with one to three R4;R4, for each occurrence, is independently halo, -OR4a, -C(O)R2a, -CN, Ci- ealkyl, Cs-ecycloalkyl, phenyl, or 5 or 6-membered monocyclic heteroaryl; orR4ais H or Ci-ealkyl, wherein the Ci-ealkyl is optionally substituted with one or more halo.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3is represented by the following formula:wherein each of the formula depicted above is optionally substituted with one to three R4.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R3is represented by the following formula:

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R4, for each occurrence, is independently Ci-4alkyl, Ci-4haloalkyl, or C3- 4cycloalkyl.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R4, for each occurrence, is independently -CH3, -CH2CH3, -CF3, -CF2CH3, or cyclopropyl.

6. The compound of any one claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Het is Cs-ecycloalkyl or 4 to 6 membered monocyclic saturated heterocyclyl, each of which is optionally substituted with one to three R2.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Het is 4 to 6 membered oxygen-containing monocyclic saturated heterocyclyl or 6 to 8-membered oxy gen-containing bicyclic saturated heterocyclyl, each of which is optionally substituted with one to three R2.

8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Het is cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperdinyl, or 2- oxaspiro[3.3]heptanyl, each of which is optionally substituted with one or two R2.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R1is represented by the following formula:optionally substituted with one or two R2.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R1is11. The compounds of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein:R2, for each occurrence, is independently Ci-3alkyl, -C(O)R2a, or OR2a, wherein the Ci-3alkyl is optionally substituted with Ci-3alkoxy;R2ais H or Ci-3alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R2, for each occurrence, is independently -CH3, -OH, -OCH3, or -C(O)CH3.

13. The compound of claim 1, wherein the compound is represented by Formula II:or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, or 3;R1is -CH2-Het or Het, wherein the Het is optionally substituted with one or two R2;Het is 4- to 6-membered oxygen-containing monocyclic saturated heterocyclyl, or 6 to 8-membered oxygen-containing bicyclic saturated heterocyclyl;R4, for each occurrence, is independently Ci-3alkyl or Ci-3haloalkyl.

14. The compound of claim 13, wherein the compound is represented by Formula III:(ill); or a pharmaceutically acceptable salt thereof.

15. The compound of claim 13 or 14, or a pharmaceutically acceptable salt thereof, wherein R4, for each occurrence, is independently -CH3 or -CF3.

16. The compound of any one of claims 13 to 15, or a pharmaceutically acceptable salt thereof, wherein Het is tetrahydrofuranyl, tetrahydropyranyl, or 2-oxaspiro[3.3]heptanyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R1is represented by the following formula:

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;1-[4-[2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2,6- diazaspiro[3.3]heptan-6-yl]piperidin-l-yl]ethanone;6-(4-methoxycyclohexyl)-2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2,6-diazaspiro[3.3]heptane;6-(4-methoxycyclohexyl)-2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl- 2,6-diazaspiro[3.3]heptane;2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane;2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[rac-(lR)-l-(oxan-4- yl)ethyl]-2,6-diazaspiro[3.3]heptane;2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6- yl)-2,6-diazaspiro[3.3]heptane;2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxetan-3-ylmethyl)-2,6- diazaspiro[3.3]heptane;6-[(3-methyloxetan-3-yl)methyl]-2-[4-methyl-2-(trifluoromethyl)pyrimidin-5- yl]sulfonyl-2,6-diazaspiro[3.3]heptane;2-[4-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6- ylmethyl)-2,6-diazaspiro[3.3]heptane;2-[4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;2-[4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6-yl)- 2,6-diazaspiro[3.3]heptane;2-[4-ethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane;2-[4-cyclopropyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6- yl)-2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-[(lS)-l-(oxan-4-yl)ethyl]- 2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(oxetan-3-ylmethyl)-2,6- diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-[[(3S)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-[(3-methyloxetan-3- yl)methyl]-2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-[(lS)-l-[(3S)-oxolan-3- yl]ethyl]-2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4-methylpyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan-6- ylmethyl)-2,6-diazaspiro[3.3]heptane;2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan- 6-yl)-2,6-diazaspiro[3.3]heptane;2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[rac-(lR)-l-(oxan-4- yl)ethyl]-2,6-diazaspiro[3.3]heptane;2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane;2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane;2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[rac-(3R)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[(3R)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[(3S)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;2-[4,6-dimethyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2-oxaspiro[3.3]heptan- 6-ylmethyl)-2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-[(4-methyloxan-4- yl)methyl]-2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-(oxetan-3-ylmethyl)-2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-[(3-methyloxetan-3- yl)methyl]-2,6-diazaspiro[3.3]heptane;2-[2-(l,l-difluoroethyl)-4,6-dimethylpyrimidin-5-yl]sulfonyl-6-(2- oxaspiro[3.3]heptan-6-ylmethyl)-2,6-diazaspiro[3.3]heptane;2-[4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane;2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(2- oxaspiro[3.3]heptan-6-yl)-2,6-diazaspiro[3.3]heptane;2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-(oxan-4-ylmethyl)- 2,6-diazaspiro[3.3]heptane;4-[[2-[4-ethyl-6-methyl-2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-2,6- diazaspiro[3.3]heptan-6-yl]methyl]oxan-4-ol;2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[rac-(3R)-oxolan- 3-yl]methyl]-2,6-diazaspiro[3.3]heptane;2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[(3 S)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;2-[4-ethyl-6-m ethyl -2-(trifluoromethyl)pyrimidin-5-yl]sulfonyl-6-[[(3R)-oxolan-3- yl]methyl]-2,6-diazaspiro[3.3]heptane;2-[3-methyl-5-(trifluoromethyl)pyrazin-2-yl]sulfonyl-6-(oxan-4-ylmethyl)-2,6- diazaspiro[3.3]heptane; or2-[3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]sulfonyl-6-(oxan-4-yl)-2,6- diazaspiro[3.3]heptane; or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. 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 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

21. 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 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

22. The method of claim 21, wherein said autoimmune disease is multiple sclerosis.

23. The method of claim 22, wherein said compound or pharmaceutical composition repairs or forms new myelin sheaths in said subject.

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