Pyrazolyl compounds as emopamil binding protein inhibitors

Abstract

Provided herein are compounds and pharmaceutical compositions thereof for inhibiting Emopamil Binding Protein (EBP) and their use in the treatment of demyelinating diseases such as multiple sclerosis.

Description

PYRAZOLYL COMPOUNDS AS EMOPAMIL BINDING PROTEIN INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 579,111, filed on August 28, 2023, the disclosure of which is hereby incorporated by reference in its entirety.FIELD OF INVENTION

[0002] The present disclosure relates to inhibitors of Emopamil Binding Protein (EBP) useful for treating demyelinating diseases such as multiple sclerosis. Specifically, this disclosure describes compounds and compositions for inhibiting EBP, methods of treating demyelinating diseases, and methods of synthesizing these compounds.BACKGROUND OF THE DISCLOSURE

[0003] Myelin is an insulating layer, or sheath, that wraps around nerve cell axons. This lipid- rich insulating material protects the axons and makes possible the saltatory conduction, which speeds axonal electric impulse (Williamson et al., Front Cell Neurosci., 2018, 12: 424). Myelin is formed in the central nervous system (CNS) by glial cells called oligodendrocytes and in the peripheral nervous system (PNS) by glial cells called Schwann cells.

[0004] Demyelinating diseases cause damage to the myelin sheath and such diseases include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute optic neuritis, transverse myelitis, chronic inflammatory demyelinating polyneuropathy (CIDP), and Guillain- Barre syndrome. Multiple sclerosis (MS) is a complex neurological disease characterized by deterioration of CNS myelin (Ghasemi et al., Cell J., 2017, 19(1): 1-10). In the pathogenesis of MS, the myelin sheaths surrounding neuronal axons are damaged or destroyed, leading to dysfunction of propagated signals, axonal injury, neuronal loss, accumulation of lesion load, and overt neurological disabilities in patients.

[0005] The CNS has the capacity to regenerate myelin sheaths after injury through the proliferation, migration, and differentiation of a population of adult progenitor cells referred to as oligodendrocyte precursor cells (OPCs) into new myelinating oligodendrocytes to generate new myelin sheaths, or to a lesser extent, by generation of new myelin sheaths by existing oligodendrocytes (Kuhn et al., Cells, 2019, 8(11): 1424). While such endogenous remyelination by OPCs and oligodendrocytes can repair and limit the damage in early stages of MS, this process becomes inefficient during later stages of disease progression (Chari, Int Rev Neurobiol., 2007, 79: 589-620). Therefore, stimulating remyelination by enhancing the repair ofdamaged myelin to preserve neuronal function is a focus for developing new therapeutics for the treatment of MS.

[0006] Recent work established inhibition of specific cholesterol biosynthesis pathway enzymes as a functional mechanism by which many small molecules can enhance oligodendrocyte formation (Hubler et al., Nature, 2018, 560(7718): 372-376). These molecules enhanced oligodendrocyte formation by inhibiting the enzymes and causing accumulation of the 8,9-unsaturated sterol substrates of these enzymes, such as zymosterol and zymostenol.

[0007] Emopamil Binding Protein (EBP, also referred to as A8A7 isomerase, 3-beta- hydroxysteroid-Delta(8),Delta(7)-isomerase, human sterol isomerase (HSI), CDPX2, CH02, CPX, or CPXD) is the enzyme in the cholesterol biosynthesis pathway which catalyzes the conversion of zymosterol and zymostenol to dehyolathosterol and lathosterol (Silve et al., The Journal of Biological Chemistry, 1996, 271(37): 22434-22440). As such, targeting EBP is one strategy for increasing OPC differentiation. However, there exists a need for compounds and therapeutic methods capable of targeting EBP to induce differentiation of OPCs to enhance generation of new oligodendrocytes and increase myelination and / or remyelination in demyelinated lesions.

[0008] Accordingly, in one aspect, provided herein are compounds which inhibit EBP for use in treating demyelinating diseases such as multiple sclerosis.SUMMARY OF THE DISCLOSURE

[0009] Described herein, in certain embodiments, are compounds and compositions thereof for inhibiting Emopamil Binding Protein (EBP) for treating demyelinating diseases such as multiple sclerosis.

[0010] The following embodiments are encompassed.

[0011] Embodiment 1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X1is C and X2is N, or X1is N and X2is C;= is a single bond or a double bond, provided that one = is a double bond and one = is a single bond;R1is Ci-C6alkyl, C3-C6cycloalkyl, -CN, Ci-C6haloalkyl, -(Ci-C6alkylene)-O-(Ci-C6alkyl), -(Ci-Ce alkylene)-O-(Ci-C6 haloalkyl), or -(Ci-Ce alkylene)(C3-Ce cycloalkyl);L1is a bond, O, or -CH2-;Ring B is C3-C6 cycloalkyl, 6-membered heteroaryl containing 1 or 2 nitrogen atoms, or Ce-Cio aryl; each R2is independently Ci-Ce alkyl, Ci-Ce haloalkyl, halo, -O(Ci-Ce alkyl), or-O(Ci-C6haloalkyl), or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from halo and Ci-Ce haloalkyl;L2is a bond or O;Ring A is, 9- to 11-membered spiro heterocyclylene, or 8- to 10-membered bicyclic fused heterocyclylene, wherein the heterocyclylene contains 1-2 nitrogen atoms;Y1is N or CH;Y2is N or CH; x is 0, 1, or 2; y is 0 or 1; m is 0-5; each R3is independently Ci-Ce alkyl, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R3groups on the same carbon atom are taken together to form a spiro C3-C6 cycloalkyl;L3is a bond, -CH(Ra)-, -CH(Ra)CH(Ra)-, -OCH(Ra)CH(Ra)-, -CH(Ra)CH(Ra)N(Ra)-, 5- to 6-membered heterocyclylene, or -O-(4-membered heterocyclylene), wherein the heterocyclylene contains 1-2 nitrogen atoms; each Rais independently H or Ci-Ce alkyl;W is O, CH2, SO2, S(O)=NH, SO, or N(H);Z is N or CH; r is 0, 1, or 2; s is 0 or 1; each R4is independently halo, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom,or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group; and n is 0-5.

[0012] Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:

[0013] Embodiment 3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:

[0014] Embodiment 4. The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein:R1is C1-C6 alkyl, C3-C5 cycloalkyl, -CN, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(Ci-C3alkyl), -(C1-C3 alkylene)-O-(Ci-C3 haloalkyl), or -(C1-C3 alkylene)(C3-Ce cycloalkyl).

[0015] Embodiment 5. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein:R1is -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2CH2CH(CH3)2, -CH2OCH3, -CH2CH2OCH3, -CH(CH3)OCH3, -CH(CH3)CH2OCH3, -CH2CHF2, -CF3, -CHF2,

[0016] Embodiment 6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein: L1is a bond.

[0017] Embodiment 7. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein: L1is O.

[0018] Embodiment 8. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein:L1is -CH2-.

[0019] Embodiment 9. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein:Ring B is C4-C6 cycloalkyl, pyridinyl, pyrazinyl, pyrimidinyl, or phenyl.

[0020] Embodiment 10. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein:

[0021] Embodiment 11. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein: each R2is independently C1-C4 alkyl, C1-C3 haloalkyl, halo, -O(Ci-C3 alkyl), or-O(Ci-C3haloalkyl), or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from halo and C1-C3 haloalkyl.

[0022] Embodiment 12. The compound of embodiment 11, or a pharmaceutically acceptable salt thereof, wherein: each R2is independently -CF3, -CF2CH3, -CH2CHF2, -CHF2, F, Cl, Br, -OCF3, -OCHF2, -OCH3, or -C(CH3)3, or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from F or -CF3.

[0023] Embodiment 13. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein:

[0024] Embodiment 14. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein:L2is a bond.

[0025] Embodiment 15. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein:L2is O.

[0026] Embodiment 16. The compound of any one of embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein:RingY1is N or CH;Y2is N or CH; x is 0, 1, or 2; and y is 0 or 1.

[0027] Embodiment 17. The compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein:Ring A is 9- to 11 -membered spiro heterocyclylene or 8- to 10-membered bicyclic fused heterocyclylene, wherein the heterocyclylene contains 1-2 nitrogen atoms.

[0028] Embodiment 18. The compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein:

[0029] Embodiment 19. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein: m is 0.

[0030] Embodiment 20. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein: m is 1-3.

[0031] Embodiment 21. The compound of any one of embodiments 1-18 and 20, or a pharmaceutically acceptable salt thereof, wherein: each R3is independently C1-C3 alkyl, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R3groups on the same carbon atom are taken together to form a spiro C3-C5 cycloalkyl.

[0032] Embodiment 22. The compound of embodiment 21, or a pharmaceutically acceptable salt thereof, wherein: each R3is independently -CEE, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R3groups on the same carbon atom are taken together to form a spiro cyclopropyl.

[0033] Embodiment 23. The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein:

[0034] Embodiment 24. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein: L3is a bond.

[0035] Embodiment 25. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein:L3is -CH(Ra)-, -CH(Ra)CH(Ra)-, -OCH(Ra)CH(Ra)-, or -CH(Ra)CH(Ra)N(Ra)-; and each Rais independently H or C1-C3 alkyl.

[0036] Embodiment 26. The compound of embodiment 25, or a pharmaceutically acceptable salt thereof, wherein:L3is -CH2, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -OCH2CH2-, or -CH2CH2N(CH2CH3)-.

[0037] Embodiment 27. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein:L3is 5- to 6-membered heterocyclylene or -O-(4-membered heterocyclylene), wherein the heterocyclylene contains 1-2 nitrogen atoms.

[0038] Embodiment 28. The compound of embodiment 27, or a pharmaceutically acceptable salt thereof, wherein:

[0039] Embodiment 29. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein:W is O, CH2, or N(H).

[0040] Embodiment 30. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein:W is SO2, S(O)=NH, or SO.

[0041] Embodiment 31. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein:Z is N.

[0042] Embodiment 32. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein:Z is CH.

[0043] Embodiment 33. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein: r and s are each 1.

[0044] Embodiment 34. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein: r and s are each 0.

[0045] Embodiment 35. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein: r is 1; and s is 0.

[0046] Embodiment 36. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein: r is 2; and s is 1.

[0047] Embodiment 37. The compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, wherein:

[0048] Embodiment 38. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, wherein: n is 0.

[0049] Embodiment 39. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, wherein: n is 1-3.

[0050] Embodiment 40. The compound of any one of embodiments 1-37 and 39, or a pharmaceutically acceptable salt thereof, wherein: each R4is independently halo, -OH, C1-C3 alkyl, or C1-C3 haloalkyl, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom, or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group.

[0051] Embodiment 41. The compound of embodiment 40, or a pharmaceutically acceptable salt thereof, wherein: each R4is independently F, -OH, -CH3, -CH(CH3)2, or -CF3, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom, or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group.

[0052] Embodiment 42. The compound of any one of embodiments 1-41, or a pharmaceutically acceptable salt thereof, wherein:

[0053] Embodiment 43. The compound of any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-a), (I-b), or (I-c):

[0054] Embodiment 44. The compound of any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-d) or (I-e):

[0055] Embodiment 45. The compound of any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), or(I-j)whereinis 5- to 6-membered heterocyclylene andis 4-membered heterocyclylene, wherein the heterocyclylene contains 1-2 nitrogen atoms.

[0056] Embodiment 46. The compound of any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Ila) or (lib) :(Ila) (lib)

[0057] Embodiment 47. The compound of embodiment 46, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (lie):

[0058] Embodiment 48. The compound of any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Illa) or (Illb) :whereinis 9- to 11 -membered spiro heterocyclylene containing 1-2 nitrogen atoms.

[0059] Embodiment 49. The compound of any one of embodiments 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IVa) or (IVb):nitrogen atoms.

[0060] Embodiment 50. A compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

[0061] Embodiment 51. A compound selected from the compounds of Table 2 or a pharmaceutically acceptable salt thereof.

[0062] Embodiment 52. A compound selected from the compounds of Table 3 or a pharmaceutically acceptable salt thereof.

[0063] Embodiment 53. A pharmaceutical composition comprising the compound of any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0064] Embodiment 54. A method of inhibiting Emopamil Binding Protein (EBP) comprising contacting EBP with an effective amount of the compound of any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 53.

[0065] Embodiment 55. A method of remyelinating a neuronal axon comprising contacting the neuronal axon with an effective amount of the compound of any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 53.

[0066] Embodiment 56. A method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 53.

[0067] Embodiment 57. The method of embodiment 56, wherein the demyelinating disease is multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute optic neuritis, transverse myelitis, chronic inflammatory demyelinating polyneuropathy (CIDP), or Guillain- Barre syndrome.

[0068] Embodiment 58. A method of treating multiple sclerosis (MS) in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 53.DETAILED DESCRIPTION OF THE DISCLOSUREDefinitions

[0069] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. To the extent any material incorporated herein by reference is inconsistent with the express content of this disclosure, the express content controls. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless the context requires otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0070] Reference in the specification to “some embodiments”, “an embodiment”, “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the inventions.

[0071] As used herein, ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 pL” means “about 5 pL” and also“5 pL .” Generally, the term “about” includes an amount that would be expected to be within experimental error, such as for example, within 15%, 10%, or 5%.

[0072] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0073] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 10 carbon atoms (i.e., C1-C10 alkyl), 1 to 6 carbon atoms (i.e., Ci-Ce alkyl) or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3 -methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CEhjsCEE), isobutyl (i.e., -CH2CH(CH3)2), sec-butyl (i.e.,-CH(CH3)CH2CH3), and tert-butyl (i.e., -C(CH )3); and “propyl” includes n-propyl(i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0074] “Alkylene” refers to a divalent unbranched or branched saturated hydrocarbon chain. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C1-C20 alkylene), 1 to 10 carbon atoms (i.e., C1-C10 alkylene), 1 to 6 carbon atoms (i.e., Ci-Ce alkylene) or 1 to 3 carbon atoms (i.e., Ci- C3 alkylene). Examples of alkyl groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene. When an alkylene residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “C4 alkylene” includes -(CEhjsCEh- , -CH2C(CH3)2-, and-CH(CH3)CH2CH2-); and “C3 alkylene” includes -(CH2)2CH2- and -C(CH3)2-.

[0075] An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbon atoms (Ce-Cu aryl) having a single ring (e.g., phenyl or Ce aryl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons (C6-C14 aryl), and in others from 6 to 12 (C6-C12 aryl) or even 6 to 10 carbon atoms (Ce-Cio aryl) in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like.

[0076] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-C20 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-C10 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-C6 cycloalkyl). Cycloalkyl also includes “spiro cycloalkyl” when there are two positions forsubstitution on the same carbon atom. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.

[0077] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, “Ci-Ce haloalkyl” refers to a Ci-Ce alkyl which is substituted by one or more halogen atoms. A Ci haloalkyl refers to a methyl group that may be substituted by 1-3 halo groups, a C2 haloalkyl refers to an ethyl group that may be substituted by 1-5 halo groups, a C3 haloalkyl refers to a propyl group that may be substituted by 1-7 halo groups, etc. Examples of haloalkyl include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. A haloalkyl may contain one or more halo atoms that are the same (i.e., all fluoro) or a mixture of halo atoms (i.e, chloro and fluoro).

[0078] “Heteroaryl” refers to an aromatic group (e.g., a 5-14 membered ring system) having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 to 10 ring carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur within the ring. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl (i.e., thienyl).

[0079] “Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro- heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro, and may comprise one or more oxo (C=O) or N-oxide (N- O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 1 to 10 ring carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, and 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatomsindependently selected from nitrogen, sulfur and oxygen. Examples of heterocyclyl groups include dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1- dioxo-thiomorpholinyl.

[0080] “Cyano” refers to the group -CN.

[0081] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

[0082] “Hydroxy” refers to the group -OH.

[0083] “ Oxo” refers to the atom (=0) or (O).

[0084] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “phenyl” group, a divalent “heteroaryl” group, a divalent “heterocyclyl” group etc., may also be referred to as a “phenylene” group, a “heteroarylene” group, or a “heterocyclylene” group, respectively.

[0085] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not.

[0086] Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group which may or may not be replaced by a moiety other than hydrogen. The substituted group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4, or 5 substituents. In some embodiments, the substituents are selected from the functional groups provided herein.

[0087] Any compound or formula described herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as2H,3H,nC,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I and125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes, such as2H,3H,13C, and14C are incorporated, are included in this disclosure. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0088] The disclosure also includes “deuterated analogs” of compounds described herein in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. When multiple deuterium atoms are present in a compound, the deuterium atoms may be on the same portion of the molecule (for example, on a single alkyl group or on a single ring) or on different portions of the molecule (for example, on separate alkyl groups or separate rings). Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0089] “Pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0090] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluene-sulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(isopropyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the like. It is understood that reference to a particular salt, such as hydrochloride or formate, may refer to a single salt, such as monohydrochloride or monoformate, or may refer to a multiple salt, such a dihydrochloride or diformate.

[0091] The compounds disclosed herein, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. The disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0092] “ Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH-moiety and a ring=N moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. All tautomeric forms of the compounds described herein are intended to be included.

[0093] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

[0094] “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0095] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofaras any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0096] “Effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in an intended result as desired based on the disclosure herein. Effective amounts can be determined by standard pharmaceutical procedures in cell cultures or experimental animals including, without limitation, by determining the LD50 (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population).

[0097] “Therapeutically effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a subject (i.e., a human patient). The results may require multiple doses of the compound or the composition.

[0098] “Treating” or “treatment” of a disease in a subject refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For the purposes of this disclosures, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a subject. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the invention contemplate any one or more of these aspects of treatment.

[0099] As used herein, the terms “subject(s)” and “patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human, such as a primate, dog, cat, rabbit, or rodent. None of the terms require or are limited to situations characterized by the supervision (e.g., constant or intermittent) of a health care worker(e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly or a hospice worker).

[0100] As used herein, the terms “pharmaceutical composition” or “medicament” refer to a composition suitable for pharmaceutical use in a subject, e.g., as an EBP inhibitor.

[0101] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.Compounds

[0102] In one aspect, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X1is C and X2is N, or X1is N and X2is C;= is a single bond or a double bond, provided that one = is a double bond and one = is a single bond;R1is Ci-C6alkyl, C3-C6cycloalkyl, -CN, Ci-C6haloalkyl, -(Ci-C6alkylene)-O-(Ci-C6alkyl), -(Ci-Ce alkylene)-O-(Ci-Ce haloalkyl), or -(Ci-Ce alkylene)(C3-Ce cycloalkyl);L1is a bond, O, or -CH2-;Ring B is C3-C6 cycloalkyl, 6-membered heteroaryl containing 1 or 2 nitrogen atoms, or Ce-Cio aryl; each R2is independently Ci-Ce alkyl, Ci-Ce haloalkyl, halo, -O(Ci-Ce alkyl), or -O(Ci-Ce haloalkyl), or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from halo and Ci-Ce haloalkyl;L2is a bond or O;Ring A is, 9- to 11-membered spiro heterocyclylene, or 8- to 10-membered bicyclic fused heterocyclylene, wherein the heterocyclylene contains 1-2 nitrogen atoms;Y1is N or CH;Y2is N or CH; x is 0, 1, or 2; y is 0 or 1; m is 0-5; each R3is independently Ci-Ce alkyl, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R3groups on the same carbon atom are taken together to form a spiro C3-C6 cycloalkyl;L3is a bond, -CH(Ra)-, -CH(Ra)CH(Ra)-, -OCH(Ra)CH(Ra)-, -CH(Ra)CH(Ra)N(Ra)-, 5- to 6-membered heterocyclylene, or -O-(4-membered heterocyclylene), wherein the heterocyclylene contains 1-2 nitrogen atoms; each Rais independently H or Ci-Ce alkyl;W is O, CH2, SO2, S(O)=NH, SO, or N(H);Z is N or CH; r is 0, 1, or 2; s is 0 or 1; each R4is independently halo, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom, or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group; andn is 0-5.

[0103] In some embodiments, X1is C and X2is N, wherein one = is a double bond and one = is a single bond. In some embodiments, X1is N and X2is C, wherein one = is a double bond and one = is a single bond.

[0104] In some embodiments,some embodiments,

[0105] In some embodiments,some embodiments,

[0106] In some embodiments, R1is Ci-Ce alkyl, C3-C6 cycloalkyl, -CN, Ci-Ce haloalkyl, -(Ci- Ce alkylene)-O-(Ci-Ce alkyl), -(Ci-Ce alkylene)-O-(Ci-Ce haloalkyl), or -(Ci-Ce alkylene)(C3-Ce cycloalkyl). In some embodiments, R1is Ci-Ce alkyl, C3-C5 cycloalkyl, -CN, C1-C3 haloalkyl, -(Ci-C3alkylene)-O-(Ci-C3alkyl), -(C1-C3 alkylene)-O-(Ci-C3haloalkyl), or -(Ci-C3alkylene)(C3-C6 cycloalkyl).

[0107] In some embodiments, R1is Ci-Ce alkyl. In some embodiments, R1is C1-C5 alkyl. In some embodiments, R1is C1-C4 alkyl. In some embodiments, R1is Ci-C3alkyl. In some embodiments, R1is C1-C2 alkyl. In some embodiments, R1is -CH3, -CFbCHs, -CFbCFbCHs, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, or -CH2CH2CH(CH3)2.

[0108] In some embodiments, R1is C3-Ce cycloalkyl. In some embodiments, R1is C3-Cs cycloalkyl. In some embodiments, R1is C3-C4 cycloalkyl. In some embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R1is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R1is cyclopropyl. In some embodiments, R1is cyclobutyl.

[0109] In some embodiments, R1is -CN.

[0110] In some embodiments, R1is Ci-Ce haloalkyl. In some embodiments, R1is Ci-Ce haloalkyl containing 1-13 halogen atoms. In some embodiments, R1is Ci-C3haloalkyl. In some embodiments, R1is Ci-C3haloalkyl containing 1-7 halogen atoms. In some embodiments, R1is -CF3, -CHF2, -CH2F, -CC13, -CHCh, -CH2CI, -CF2CI, -CFCh, -CH2CF3, -CH2CHF2, or - CFFCCh. In some embodiments, R1is -CH2CHF2, -CF3, or -CHF2. In some embodiments, R1is -CF3. In some embodiments, R1is -CH2CHF2. In some embodiments, R1is -CHF2.

[0111] In some embodiments, R1is -(Ci-Ce alkylene)-O-(Ci-Ce alkyl). In some embodiments, R1is -(Ci-C3alkylene)-O-(Ci-C3alkyl). It is understood that -(Ci-Ce alkylene)- includes optional substitution by Ci-Ce alkyl groups such that the total number of carbon atoms is no more than 6. For example, -(Ci-Ce alkylene)- includes -(C1-C5 alkylene)- substituted by methyl, such that the total number of carbon atoms is 2-6. In some embodiments, -(Ci-Ce alkylene)- includes -(C1-C2 alkylene)- substituted by C1-C4 alkyl, such that the total number of carbon atoms is 2-6. In some embodiments, R1is -(Ci-C3alkylene)-O-(CH3), -(Ci-C3alkylene)-O- (CFbCHs), or -(Ci-C3alkylene)-O-(CH2CH2CH3). In some embodiments, R1is-CFbOCHs, - CH2CH2OCH3,-CH(CH3)OCH3, or -CH(CH3)CH2OCH3.

[0112] In some embodiments, R1is -(Ci-Ce alkylene)-O-(Ci-Ce haloalkyl). In some embodiments, R1is -(Ci-Ce alkylene)-O-(Ci-Ce haloalkyl), wherein Ci-Ce haloalkyl contains 1- 13 halogen atoms. In some embodiments, R1is -(Ci-C3alkylene)-O-(Ci-C3haloalkyl). In some embodiments, R1is -(Ci-C3alkylene)-O-(Ci-C3haloalkyl), wherein Ci-C3haloalkyl contains 1- 7 halogen atoms. It is understood that -(Ci-Ce alkylene)- includes optional substitution by Ci-Ce alkyl groups such that the total number of carbon atoms is no more than 6. For example, -(Ci-Cealkylene)- includes -(C1-C5 alkylene)- substituted by methyl, such that the total number of carbon atoms is 2-6. In some embodiments, -(Ci-Ce alkylene)- includes -(C1-C2 alkylene)- substituted by C1-C4 alkyl, such that the total number of carbon atoms is 2-6. In some embodiments, R1is -(C1-C3 alkylene)-O-(CF3), -(C1-C3 alkylene)-O-(CHF2), or -(C1-C3 alkylene)-O-(CH2F). In some embodiments, R1is -(CH2)-O-(CI-C3 haloalkyl), -(CH2CH2XO- (C1-C3 haloalkyl), or-(CH2CH2CH2)-O-(CI-C3 haloalkyl).

[0113] In some embodiments, R1is -(Ci-Ce alkylene)(C3-Ce cycloalkyl). In some embodiments, R1is -(C1-C3 alkylene)(C3-Ce cycloalkyl). It is understood that -(Ci-Ce alkylene)- includes optional substitution by Ci-Ce alkyl groups such that the total number of carbon atoms is no more than 6. For example, -(Ci-Ce alkylene)- includes -(C1-C5 alkylene)- substituted by methyl, such that the total number of carbon atoms is 2-6. In some embodiments, -(Ci-Ce alkylene)- includes -(C1-C2 alkylene)- substituted by C1-C4 alkyl, such that the total number of carbon atoms is 2-6. In some embodiments, R1is -(C1-C3 alkylene)(cyclopropyl), -(C1-C3 alkylene)(cyclobutyl), or -(C1-C3 alkylene)(cyclopentyl). In some embodiments, R1is - (CH2XC3-C6 cycloalkyl), -(CH2CH2XC3-C6 cycloalkyl), or-(CH2CH2CH2)(C3-Ce cycloalkyl). In some embodiments, R1is -(CFbXcyclopropyl), -(CFbXcyclobutyl), or -(CFbXcyclopentyl). In some embodiments, R1is -(CFbXcyclopropyl).

[0114] In some embodiments, R1is -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, - C(CH3)3,-CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2CH2CH(CH3)2, -CH2OCH3, -CH2CH2OCH3, -CH(CH3)OCH3, -CH(CH3)CH2OCH3, -CH2CHF2, -CF3, -CHF2,

[0115] In some embodiments, L1is a bond, O, or -CH2-. In some embodiments, L1is a bond. In some embodiments, L1is O. In some embodiments, L1is -CH2-.

[0116] In some embodiments, Ring B is C3-C6 cycloalkyl, 6-membered heteroaryl containing1 or 2 nitrogen atoms, or Ce-Cio aryl. In some embodiments, Ring B is C4-C6 cycloalkyl, pyridinyl, pyrazinyl, pyrimidinyl, or phenyl.

[0117] In some embodiments, Ring B is C3-C6 cycloalkyl. In some embodiments, Ring B is C4-C6 cycloalkyl. In some embodiments, Ring B is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Ring B is cyclopropyl. In some embodiments, Ring B is cyclobutyl. In some embodiments, Ring B is cyclopentyl. In some embodiments, Ring B is cyclohexyl.

[0118] In some embodiments, Ring B is 6-membered heteroaryl containing 1 or 2 nitrogen atoms. In some embodiments, Ring B is 6-membered heteroaryl containing 1 nitrogen atom. Insome embodiments, Ring B is 6-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, Ring B is pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, Ring B is

[0119] In some embodiments, Ring B is Ce-Cio aryl. In some embodiments, Ring B is Ce aryl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is Cio aryl. In some embodiments, Ring B is naphthalenyl.

[0121] In some embodiments, each R2is independently Ci-Ce alkyl, Ci-Ce haloalkyl, halo, - O(Ci-Ce alkyl), or -O(Ci-Ce haloalkyl), or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from halo and Ci-Ce haloalkyl. In some embodiments, each R2is independently C1-C4 alkyl, C1-C3 haloalkyl, halo, - O(Ci-C3alkyl), or-O(Ci-C3 haloalkyl), or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from halo and C1-C3 haloalkyl.

[0122] In some embodiments, R2is Ci-Ce alkyl. In some embodiments, R2is C1-C4 alkyl. In some embodiments, R2is methyl, ethyl, propyl, or butyl. In some embodiments, R2is isopropyl. In some embodiments, R2is -C(CH3)3.

[0123] In some embodiments, R2is Ci-Ce haloalkyl. In some embodiments, R2is Ci-Ce haloalkyl containing 1-13 halogen atoms. In some embodiments, R2is C1-C3 haloalkyl. In some embodiments, R2is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R2is-CF3, -CHF2, -CH2F, -CCh, -CHCh, -CH2C1, -CF2C1, -CFCh, -CF2CH3, -CH2CF3, -CH2CHF2, or-CH2CCh. In some embodiments, R2is -CF3, -CF2CH3, -CH2CHF2, or -CHF2.

[0124] In some embodiments, R2is halo. In some embodiments, R2is F, Cl, Br, or I. In some embodiments, R2is F, Cl, or Br. In some embodiments, R2is F. In some embodiments, R2is Cl. In some embodiments, R5is Br.

[0125] In some embodiments, R2is -O(Ci-Ce alkyl). In some embodiments, R2is -O(Ci-C3 alkyl). In some embodiments, R2is -O(CH3), -O(CH2CH3), or -O(CH2CH2CH3). In some embodiments, R2is -O(CH3). In some embodiments, R2is -O(CH2CH3),

[0126] In some embodiments, R2is -O(Ci-Ce haloalkyl). In some embodiments, R2is -O(Ci- Ce haloalkyl), wherein Ci-Ce haloalkyl contains 1-13 halogen atoms. In some embodiments, R2is-O(Ci-C3 haloalkyl). In some embodiments, R2is -O(Ci-C3 haloalkyl), wherein C1-C3 haloalkyl contains 1-7 halogen atoms. In some embodiments, R2is -OCF3, -OCHF2, -OCH2F, -OCCI3, -OCHCh, -OCH2C1, -OCF2C1, -OCFCh, -OCH2CF3, -OCH2CHF2, or -OCH2CC13. In some embodiments, R2is -OCF3 or -OCHF2. In some embodiments, R2is -OCF3. In some embodiments, R2is -OCHF2.

[0127] In some embodiments, two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from halo and Ci-Ce haloalkyl. In some embodiments, two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from halo and C1-C3 haloalkyl. In some embodiments, two R2groups on adjacent carbon atoms are taken together to form a fused phenyl optionally substituted by 1-5 groups selected from halo and C1-C3 haloalkyl. In some embodiments, two R2groups on adjacent carbon atoms are taken together to form a fused phenyl optionally substituted by 1-3 groups selected from halo and C1-C3 haloalkyl. In some embodiments, two R2groups on adjacent carbon atoms are taken together to form a fused phenyl optionally substituted by 1-2 groups selected from F and -CF3. In some embodiments, two R2groups on adjacent carbon atoms are taken together to form a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, which is optionally substituted by 1-4 groups selected from halo and C1-C3 haloalkyl. In some embodiments, two R2groups on adjacent carbon atoms are taken together to form a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, which is optionally substituted by 1-4 groups selected from F and -CF3.

[0128] In some embodiments, each R2is independently -CF3, -CF2CH3, -CH2CHF2, -CHF2, F, Cl, Br, -OCF3, -OCHF2, -OCH3, or -C(CH3)3, or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from F or -CF3.

[0130] In some embodiments, L2is a bond or O. In some embodiments, L2is a bond. In some embodiments, L2is O. -Y1Y2-^-

[0131] In some embodiments, Ring A is , wherein Y1is N or CH; Y2is N orCH; x is 0, 1, or 2; and y is 0 or 1. In some embodiments, Y1is N and Y2is N. In some embodiments, Y1is N and Y2is CH. In some embodiments, Y1is CH and Y2is N. In someembodiments, Y1is CH and Y2is CH. In some embodiments, x is 0. In some embodiments, x is1. In some embodiments, x is 2. In some embodiments, y is 0. In some embodiments, y is 1.

[0132] In some embodiments, Ring A is 9- to 11 -membered spiro heterocyclylene, or 8- to 10- membered bicyclic fused heterocyclylene, wherein the heterocyclylene contains 1-2 nitrogen atoms. In some embodiments, Ring A is 9- to 11 -membered spiro heterocyclylene containing 1- 2 nitrogen atoms. In some embodiments, Ring A is 9- to 11 -membered spiro heterocyclylene containing 1 nitrogen atom. In some embodiments, Ring A is 9- to 11 -membered spiro heterocyclylene containing 2 nitrogen atoms. In some embodiments, Ring A is 8- to 10- membered bicyclic fused heterocyclylene containing 1-2 nitrogen atoms. In some embodiments, Ring A is 8- to 10-membered bicyclic fused heterocyclylene containing 1 nitrogen atom. In some embodiments, Ring A is 8- to 10-membered bicyclic fused heterocyclylene containing 2 nitrogen atoms.— (R3)m is drawn across two rings, either ring or both rings can be substituted with m R3groups.

[0134] In some embodiments, m is 0-5. In some embodiments, m is 0. In some embodiments, m is 1-3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0135] In some embodiments, each R3is independently Ci-Ce alkyl, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R3groups on the same carbon atom are taken together to form a spiro C3-C6 cycloalkyl. In some embodiments, each R3is independently C1-C3 alkyl, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R3groups on the same carbon atom are taken together to form a spiro C3-C5 cycloalkyl.

[0136] In some embodiments, R3is Ci-Ce alkyl. In some embodiments, R3is C1-C3 alkyl. In some embodiments, R3is methyl, ethyl, w-propyl, or isopropyl. In some embodiments, R3is methyl, ethyl, or isopropyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl.

[0137] In some embodiments, two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group. In some embodiments, two R3groups are taken together to form a bridging - CH2-group. In some embodiments, two R3groups are taken together to form a bridging - CH2CH2- group.

[0138] In some embodiments, two R3groups on the same carbon atom are taken together to form a spiro C3-C6 cycloalkyl. In some embodiments, two R3groups on the same carbon atom are taken together to form a spiro C3-C5 cycloalkyl. In some embodiments, two R3groups on the same carbon atom are taken together to form a spiro cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, two R3groups on the same carbon atom are taken together to form a spiro cyclopropyl. In some embodiments, two R3groups on the same carbon atom are taken together to form a spiro cyclobutyl.

[0139] In some embodiments, each R3is independently -CH3, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R3groups on the same carbon atom are taken together to form a spiro cyclopropyl.

[0141] In some embodiments, L3is a bond, -CH(Ra)-, -CH(Ra)CH(Ra)-, -OCH(Ra)CH(Ra)-, -CH(Ra)CH(Ra)N(Ra)-, 5- to 6-membered heterocyclylene, or -O-(4-membered heterocyclylene), wherein the heterocyclylene contains 1-2 nitrogen atoms, and each Rais independently H or Ci-Ce alkyl.

[0142] In some embodiments, L3is a bond.

[0143] In some embodiments, L3is -CH(Ra)-, -CH(Ra)CH(Ra)-, -OCH(Ra)CH(Ra)-, or -CH(Ra)CH(Ra)N(Ra)-. In some embodiments, each Rais independently H or C1-C3 alkyl. In some embodiments, each Rais independently H, methyl, ethyl, or propyl. In some embodiments, each Rais independently H or methyl. In some embodiments, L3is -CH2, - CH2CH2-, -CH(CH3)CH2-,-CH2CH(CH3)-, -OCH2CH2-, or -CH2CH2N(CH2CH3)-.

[0144] In some embodiments, L3is 5- to 6-membered heterocyclylene or -O-(4-membered heterocyclylene), wherein the heterocyclylene contains 1-2 nitrogen atoms.

[0145] In some embodiments, L3is 5- to 6-membered heterocyclylene containing 1-2 nitrogen atoms. In some embodiments, L3is 5- to 6-membered heterocyclylene containing 1 nitrogen atom. In some embodiments, L3is 5- to 6-membered heterocyclylene containing 2 nitrogen atoms. In some embodiments, L3is 5-membered heterocyclylene containing 1-2 nitrogen atoms. In some embodiments, L3is 5-membered heterocyclylene containing 1 nitrogen atom. In some embodiments, L3is 5-membered heterocyclylene containing 2 nitrogen atoms. In some embodiments, L3is 6-membered heterocyclylene containing 1-2 nitrogen atoms. In someembodiments, L3is 6-membered heterocyclylene containing 1 nitrogen atom. In some embodiments, L3is 6-membered heterocyclylene containing 2 nitrogen atoms. In some embodiments, L3is pyrrolidinylene, piperidinylene, or piperazinylene.

[0146] In some embodiments, L3is -O-(4-membered heterocyclylene), wherein the heterocyclylene contains 1-2 nitrogen atoms. In some embodiments, L3is -O-(4-membered heterocyclylene), wherein the heterocyclylene contains 1 nitrogen atom. In some embodiments, L3is -O-(4-membered heterocyclylene), wherein the heterocyclylene contains 2 nitrogen atoms. In some embodiments, L3is -O-(azetidinylene) or -O-(diazetidinylene).

[0147] In some embodiments, L3is:

[0148] In some embodiments, W is O, CH2, SO2, S(O)=NH, SO, or N(H). In some embodiments, W is O, CH2, or N(H). In some embodiments, W is is SO2, S(O)=NH, or SO. In some embodiments, W is O. In some embodiments, W is CH2. In some embodiments, W isSO2. In some embodiments, W is S(O)=NH. In some embodiments, W is SO. In some embodiments, W is N(H).

[0149] In some embodiments, Z is N or CH. In some embodiments, Z is N. In some embodiments, Z is CH.

[0150] In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2.

[0151] In some embodiments, s is 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1.

[0152] In some embodiments, r and s are each 1. In some embodiments, r and s are each 0. In some embodiments, r is 1 and s is 0. In some embodiments, r is 2 and s is 1.understood that when — (R4)n is drawn across two rings, either ring or both rings can be substituted with n R4groups.

[0154] In some embodiments, each R4is independently halo, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom, or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group. In some embodiments, each R4is independently halo, -OH, C1-C3 alkyl, or C1-C3 haloalkyl, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5 -membered heterocyclyl containing 1 oxygen atom, or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group. In some embodiments, each R4is independently F, -OH, -CH3, -CH(CH3)2, or -CF3, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom, or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group.

[0155] In some embodiments, R4is halo. In some embodiments, R4is F, Cl, Br, or I. In some embodiments, R4is F, Cl, or Br. In some embodiments, R4is F or Cl. In some embodiments, R4is F. In some embodiments, R4is Cl.

[0156] In some embodiments, R4is -OH.

[0157] In some embodiments, R4is Ci-Ce alkyl. In some embodiments, R4is C1-C3 alkyl. In some embodiments, R4is methyl, ethyl, w-propyl, or isopropyl. In some embodiments, R46is methyl, ethyl, or isopropyl. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is isopropyl.

[0158] In some embodiments, R4is Ci-Ce haloalkyl. In some embodiments, R4is Ci-Ce haloalkyl containing 1-13 halogen atoms. In some embodiments, R4is C1-C3 haloalkyl. In some embodiments, R4is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R4is -CF3, -CHF2, -CH2F, -CCI3, -CHCh, -CH2CI, -CF2CI, -CFCh, -CH2CF3, -CH2CHF2, or - CH2CCI3. In some embodiments, R4is -CF3.

[0159] In some embodiments, two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group. In some embodiments, two R4groups are taken together to form a bridging - CH2- group. In some embodiments, two R4groups are taken together to form a bridging - CH2CH2- group.

[0160] In some embodiments, two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom.

[0161] In some embodiments, two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group. In some embodiments, two R4groups on the same carbon atom are taken together to form a spiro 4- membered heterocyclyl containing 1 oxygen atom. In some embodiments, two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 SO2 group.

[0162] In some embodiments, n is 0-5. In some embodiments, n is 0. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0164] In some embodiments, the compound of Formula (I) is a compound of Formula (I-a),(I-b), or (I-c):wherein Ring A, Ring B, X1, X2, L2, L3, R1, R2, R3, R4, Z, W, m, n, r, s, and = are as described for Formula (I).

[0165] In some embodiments, the compound of Formula (I) is a compound of Formula (I-d) orwherein Ring A, Ring B, X1, X2, L1, L3, R1, R2, R3, R4, Z, W, m, n, r, s, and = are as described for Formula (I).

[0166] In some embodiments, the compound of Formula (I) is a compound of Formula (I-f),(I-g), (I-h), (I-i), (I-j), (I-k), or (1-1):wherein Ring A, Ring B, X1, X2, L1, L2, R1, R2, R3, R4, Ra, Z, W, m, n, r, s, and = are as described for Formula (I); whereinis 5- to 6-membered heterocyclylene; and whereinis 4-membered heterocyclylene containing 1-2 nitrogen atoms.

[0167] In some embodiments, the compound of Formula (I) is a compound of Formula (Ila) or (lib):wherein X1, X2, Y1, Y2, R1, R2, R3, R4, Z, W, m, n, r, s, and = are as described for Formula(I).

[0168] In some embodiments, the compound of Formula (I) is a compound of Formula (lie):wherein R1, R2, R3, R4, m, and n are as described for Formula (I).

[0169] In some embodiments, the compound of Formula (I) is a compound of Formula (Illa) or (Illb):whereinfor Formula (I); and whereinis 9- to 11 -membered spiro heterocyclylene containing 1-2 nitrogen atoms.

[0170] In some embodiments, the compound of Formula (I) is a compound of Formula (IVa) or (IVb):wherein X1, X2, R1, R2, R3, R4, Z, W, m, n, r, s, and = are as described for Formula (I); and wherein ^ZZCZZ”^ js8- to 10-membered bicyclic fused heterocyclylene containing 1-2 nitrogen atoms.

[0171] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety may be combined with every description, variation, embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment, or aspect provided herein with respect to Ring A of Formula (I) may be combined with every description, variation, embodiment, or aspect of X1, X2, Y1, Y2, R1, R2, R3, R4, Ra, L1, L2, L3, W, Z, Ring B, x, y, m, r, s, and n, the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments, or aspects of Formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments, or aspects of Formula (I), where applicable, apply equally to any of the formulae as detailed herein, such as Formulae (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (Lg), (Lh), (Li), (I-j), (Lk), (1-1), (Ila), (lib), (lie), (Illa), (Illb), (IVa), and (IVb), are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae.

[0172] In some embodiments, provided is a compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. Although certain compounds described in the present disclosure, including in Table 1, are presented as specific stereoisomers and / or in a nonstereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 1, are herein described. Similarly, although certain compounds described in the present disclosure are presented as specific salts, it is understood that any pharmaceutically acceptable salt of any of the compounds of the present disclosure are herein described. It is further understood that although certain compoundsdescribed in the present disclosure are presented as specific salts, the free form of the compounds of the present disclosure are also herein described.Table 1.“&1” denotes that the absolute stereochemistry was not determined; “abs” denotes that the absolute stereochemistry was determined or a pharmaceutically acceptable salt thereof.

[0173] Also provided herein is a compound selected from the compounds in Table 2 or a pharmaceutically acceptable salt thereof. Although certain compounds described in the present disclosure, including in Table 2, are presented as specific stereoisomers and / or in a nonstereochemical form, it is understood that any or all stereochemical forms, including anyenantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 2, are herein described.Table 2.or a pharmaceutically acceptable salt thereof.

[0174] Also provided herein is a compound selected from the compounds in Table 3 or a pharmaceutically acceptable salt thereof. Although certain compounds described in the presentdisclosure, including in Table 3, are presented as specific stereoisomers and / or in a nonstereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 3, are herein described.Table 3.

[0175] It is understood that in the present description, combinations of substituents and / or variables of the depicted formulae are permissible only if such contributions result in stable compounds.

[0176] Furthermore, all compounds disclosed herein, such as compounds of Formula (I), that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds can be converted to their free base or acid form by standard techniques.Methods of Synthesis

[0177] In a further aspect, provided herein are methods of preparing compounds of Formula (I) or pharmaceutically acceptable salts thereof. Also provided herein are intermediate compounds useful for preparing compounds of Formula (I) or pharmaceutically acceptable salts thereof.

[0178] Intermediate compounds, such as intermediates of Formula A, useful for preparing compounds of Formula (I) can be prepared as shown in Scheme 1.Scheme 1.wherein R1and R2are as described for Formula (I), and -N(R’)(R”) represents Ring A.

[0179] Starting compounds A-l can be reacted with amines of Formula A-2 to form compounds of Formula A-3, which can then be treated with Lawesson’s reagent to afford compounds of Formula A-4. Treatment of compounds of Formula A-4 with hydrazine hydrate provides compounds of Formula A-5, which can then be coupled with compounds of Formula A-6 using, for example copper(II) acetate, to afford intermediates of Formula A.

[0180] Piperazinyl-pyrazole compounds of Formula B may be prepared according to the general reactions shown in Scheme 2.Scheme 2.baseB-1wherein R1and R2are as described for Formula (I), and -N(Ra)(Rb) represents the moiety

[0181] Compounds of Formula B-l can be treated with an acid, such as TFA, to afford compounds of Formula B-2, which can then be alkylated to give compounds of Formula B. For example, compounds of Formula B-2 can be alkylated with 2-chloroacetaldehyde followed by reductive coupling with HN(Ra)(Rb) using a coupling agent such as NaBH(OAc)3.Alternatively, compounds of Formula B-2 can be alkylated with an amine-based alkylchloride to provide compounds of Formula B-2.

[0182] Piperazinyl amino-pyrazole compounds of Formula C may be prepared according to the general reaction shown in Scheme 3.Scheme 3.wherein R1and R2are as described for Formula (I), and -N(R’)(R”) represents Ring A optionally coupled to L3and the Z-containing moiety of Formula (I).

[0183] Compounds of Formula C-1 can be coupled with amines of Formula C-2 under palladium-catalyzed coupling conditions to afford compounds of Formula C.

[0184] Piperazinyl amino isopropyl-pyrazole compounds of Formula D may be prepared according to the general reactions shown in Scheme 4.Scheme 4.wherein R2is as described for Formula (I), and -N(R’)(R”) represents Ring A optionally coupled to L3and the Z-containing moiety of Formula (I).

[0185] Compounds of Formula D-l can be arylated by coupling with compounds of Formula D-2 using, for example, Cu(OAc)2, to give compounds of Formula D-3, which can then be alkylated using D-4 under Pd-catalyzed reaction conditions, followed by Pt-catalyzed hydrogenation, to give compounds of Formula D-5. Next, Pd-catalyzed coupling of compounds of Formula D-5 with amines of Formula D-6 affords compounds of Formula D.

[0186] The synthesis of additional intermediates useful for the preparation of compounds of Formula (I) is outlined in Scheme 5.Scheme 5.wherein R1is as described for Formula (I).

[0187] Compounds of Formula E-l can be treated with compound of Formula E-2 in the presence of an alkoxide to afford compounds of Formula E-3, which can then be treated with hydrazine hydrate to yield compounds of Formula E-4. Subsequent treatment with PtCh and an acid (such as HC1) affords compounds of Formula E-5, which can then be reacted with BOC2O to provide compounds of Formula E.

[0188] Intermediates of Formula E can be used to prepare pyrazole-piperidinyl compounds of Formula F as shown in Scheme 6.Scheme 6.wherein R1and R2are as described for Formula (I), and Rcrepresents the moietyFormula (I).

[0189] Compounds of Formula E can be arylated with compounds of Formula F-l using, for example, Cu(OAc)2, to give compounds of Formula F-2. Subsequent deprotection with an acid, such as TFA, affords compounds of Formula F-3, which can then be alkylated to afford compounds of Formula F. For example, compounds of Formula F-3 can be reductively coupled with an aldehyde using a coupling agent such as NaBH(OAc)3 to provide compounds of Formula F. Alternatively, compounds of Formula F-3 can be treated with an alkylchloride to provide compounds of Formula F.

[0190] It is understood that the synthetic processes disclosed herein may be modified to arrive at various compounds of the present disclosure by selection of appropriate reagents and starting materials.

[0191] All compounds of Formula (I) or any variation thereof as described herein which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the disclosure can be converted to their free base or acid form by standard techniques.Pharmaceutical Compositions

[0192] In another aspect, provided herein are pharmaceutical compositions of the compounds of Formula (I) or a pharmaceutically acceptable salt thereof. Thus, the present disclosure includes pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Pharmaceutical compositions according to the disclosure may take a form suitable for oral, buccal, sublingual, parenteral (subcutaneous, intramuscular, intravenous, or intrathecal), nasal, topical, vaginal, rectal, intracerebral, intradermal, intravitreal, intraosseous infusion, intraperitoneal, or inhalation administration. Pharmaceutical compositions of the presentdisclosure comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0193] A compound described herein can be used in the preparation of a pharmaceutical composition by combining the compound as an active ingredient with a pharmaceutically acceptable excipient. Some examples of materials which can serve as pharmaceutically acceptable excipients include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; surfactants, such as polysorbate 80 (i.e., Tween 80); powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found in, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21sted. (2005), which is incorporated herein by reference.

[0194] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0195] Examples of pharmaceutically-acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

[0196] The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.Generally, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

[0197] In certain embodiments, a pharmaceutical composition of the present disclosure comprises an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, e.g., bile acids and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition renders orally bioavailable a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0198] Pharmaceutical compositions of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules or as a solution or a suspension in an aqueous or non-aqueous liquid or as an oil-in-water or water-in-oil liquid emulsion or as an elixir or syrup or as pastilles (using an inert base, such as gelatin and glycerin or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as an active ingredient. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, may also be administered as a bolus, electuary, or paste.

[0199] In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate and non-ionic surfactants; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0200] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin orhydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made in a suitable machine in which a mixture of the powdered compound is moistened with an inert liquid diluent.

[0201] The tablets and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0202] Liquid dosage forms for oral administration of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

[0203] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0204] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth and mixtures thereof.

[0205] Pharmaceutical compositions of the disclosure for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0206] Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) may be mixed under sterile conditions with a pharmaceutically- acceptable carrier and with any preservatives, buffers or propellants which may be required.

[0207] The ointments, pastes, creams, and gels may contain, in addition to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

[0208] Powders and sprays can contain, in addition to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0209] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0210] Examples of suitable aqueous and nonaqueous carriers, which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils, such as olive oil and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[0211] The pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action ofmicroorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenyl sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0212] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0213] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.Methods of Treatment

[0214] Compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising compounds of Formula (I), or a pharmaceutically acceptable salt thereof, may be used in methods of administration and treatment as provided herein. The compounds and pharmaceutical compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or pharmaceutical composition to cells for screening purposes and / or for conducting quality control assays.

[0215] In some embodiments, provided herein is a method of inhibiting Emopamil Binding Protein (EBP) comprising contacting either an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein, with EBP.

[0216] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, inhibits the activity of EBP by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, a compound of formula (I) inhibits the activity of EBP by about 1-100%, 5-100%,10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 5- 95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5- 35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0217] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, binds EBP with an ICso of less than about 10 pM, such as about 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, or 0.5 pM. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, binds EBP with an ICso from about 0.01 pM to about 5 pM, from about 0.01 pM to about 4 pM, from about 0.01 pM to about 3 pM, from about 0.01 pM to about 2 pM, from about 0.01 pM to about 1 pM, from about 0.01 pM to about 0.05 pM, from about 0.1 pM to about 5 pM, from about 0.1 pM to about 4 pM, from about 0.1 pM to about 3 pM, from about 0.1 pM to about 2 pM, from about 0.1 pM to about 1 pM, from about 0.5 pM to about 5 pM, from about 0.5 pM to about 4 pM, from about 0.5 pM to about 3 pM, from about 0.5 pM to about 2 pM, from about 0.5 pM to about 1 pM, from about 1 pM to about 5 pM, from about 1 pM to about 4 pM, from about 1 pM to about 3 pM, from about 1 pM to about 2 pM, from about 2 pM to about 5 pM, from about 2 pM to about 4 pM, from about 2 pM to about 3 pM, from about 3 pM to about 5 pM, from about 3 pM to about 4 pM, or from about 4 pM to about 5 pM. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, binds EBP with an ICso from about 0.01 pM to about 1 pM, from about 0.01 pM to about 0.9 pM, from about 0.01 pM to about 0.8 pM, from about 0.01 pM to about 0.7 pM, from about 0.01 pM to about 0.6 pM, from about 0.01 pM to about 0.5 pM, from about 0.01 pM to about 0.4 pM, from about 0.01 pM to about 0.3 pM, from about 0.01 pM to about 0.2 pM, from about 0.01 pM to about 0.1 pM, from about 0.1 pM to about 1 pM, from about 0.1 pM to about 0.9 pM, from about 0.1 pM to about 0.8 pM, from about 0.1 pM to about 0.7 pM, from about 0.1 pM to about 0.6 pM, from about 0.1 pM to about 0.5 pM, from about 0.1 pM to about 0.4 pM, from about 0.1 pM to about 0.3 pM, from about 0.1 pM to about 0.2 pM, from about 0.2 pM to about 1 pM, from about 0.2 pM to about 0.9 pM, from about 0.2 pM to about 0.8 pM, from about 0.2 pM to about 0.7 pM, from about 0.2 pM to about 0.6 pM, from about 0.2 pM to about 0.5 pM, from about 0.2 pM to about 0.4 pM, from about 0.2 pM to about 0.3 pM, from about 0.3 pM to about 1 pM, from about 0.3 pM to about 0.9 pM, from about 0.3 pM to about 0.8 pM, from about 0.3 pM to about 0.7 pM, from about 0.3 pM to about 0.6 pM, from about 0.3 pM to about 0.5 pM, from about 0.3 pM to about 0.4 pM, from about 0.4 pM to about 1 pM, from about 0.4 pM to about 0.9 pM, from about 0.4 pM to about 0.8 pM, from about 0.4 pM to about 0.7 pM, from about 0.4 pM to about 0.6 pM, from about 0.4 pM to about 0.5 pM, from about 0.5 pM to about 1 pM, from about 0.5pM to about 0.9 pM, from about 0.5 pM to about 0.8 pM, from about 0.5 pM to about 0.7 pM, from about 0.5 pM to about 0.6 pM, from about 0.6 pM to about 1 pM, from about 0.6 pM to about 0.9 pM, from about 0.6 pM to about 0.8 pM, from about 0.6 pM to about 0.7 pM, from about 0.7 pM to about 1 pM, from about 0.7 pM to about 0.9 pM, from about 0.7 pM to about 0.8 pM, from about 0.8 pM to about 1 pM, from about 0.8 pM to about 0.9 pM, or from about 0.9 pM to about 1 pM.

[0218] In some instances, increased inhibition of EBP can be associated with increased human Ether-a-go-go-Related Gene (hERG) toxicity. Accordingly, in some embodiments of the present disclosure, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, inhibits EBP and promotes low hERG toxicity. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, binds hERG with an ICso of less than about 30 pM, such as about 25 pM, 20 pM, 15 pM, 10 pM, 5 pM, 2 pM, or 1 pM. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, binds hERG with an ICso from about 0.05 pM to about 30 pM, such as from about 0.05 pM to about 25 pM, from about 0.05 pM to about 20 pM, from about 0.05 pM to about 15 pM, from about 0.05 pM to about 10 pM, from about 0.05 pM to about 5 pM, from about 0.05 pM to about 2 pM, from about 0.05 pM to about 1 pM, from about 1 pM to about 30 pM, such as from about 1 pM to about 25 pM, from about 1 pM to about 20 pM, from about 1 pM to about 15 pM, from about 1 pM to about 10 pM, from about 1 pM to about 5 pM, from about 1 pM to about 2 pM, from about 5 pM to about 30 pM, from about 5 pM to about 25 pM, from about 5 pM to about 20 pM, from about 5 pM to about 15 pM, from about 5 pM to about 10 pM, from about 10 pM to about 30 pM, from about 10 pM to about 25 pM, from about 10 pM to about 20 pM, from about 10 pM to about 15 pM, from about 15 pM to about 30 pM, from about 15 pM to about 25 pM, from about 15 pM to about 20 pM, from about 20 pM to about 30 pM, or from about 20 pM to about 25 pM.

[0219] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, stimulates remyelination of neuronal axons. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, stimulates remyelination of neuronal axons by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, a compound of formula (I) stimulates remyelination of neuronal axons by about 1-100%, 5-100%, 10-100%, 15-100%, 20- 100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65- 100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5- 80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5- 20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0220] In some embodiments, the neuronal axons are artificial, such as those used in a laboratory setting (i.e., cell culture). In some embodiments, the neuronal axons are endogenous (i.e., naturally occuring inside a subject, such as a subject having multiple sclerosis (MS)). In some embodiments, remyelination of neuronal axons is achieved by oligodendrocyte precursor cells (OPCs), which repair and limit the damage associated with MS. In some embodiments, administering a compound of Formula (I), or a salt thereof, to a subject having multiple sclerosis (MS) stimulates remyelination to enhance the repair of damaged myelin and to preserve neuronal function.

[0221] In one aspect, provided herein is a method for treating a demyelinating disease, comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for preventing a demyelinating in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I). In some embodiments, the demyelinating disease is multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute optic neuritis, transverse myelitis, chronic inflammatory demyelinating polyneuropathy (CIDP), or Guillain-Barre syndrome.

[0222] In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof diminishes the extent of the demyelinating disease in the subject. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof stabilizes the demyelinating disease (for example, prevents or delays the worsening of the disease). In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof delays the occurrence or recurrence of the demyelinating disease. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof slows the progression of the demyelinating disease. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof prevents relapse of the demyelinating disease. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof decreases the dose of one or more other medications required to treat the demyelinating disease. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof enhances the effect of another medication used to treat the demyelinating disease. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof delays the progression of the demyelinating disease. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, to a subject in need thereof increases the quality of life of the subject having the demyelinating disease. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof prolongs survival of a subject having the demyelinating disease.

[0223] In some aspects, provided herein is a method of slowing progression of a demyelinating disease in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, provided herein is a method of stabilizing a demyelinating disease in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the method prevents the progression of the demyelinating disease. In some embodiments, the method delays the progression of the demyelinating disease.

[0224] In another aspect, provided herein is a method of delaying the occurrence or recurrence of a demyelinating disease in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0225] In further aspects, provided herein is a method of decreasing the dose of one or more other medications required to treat the demyelinating disease in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, provided herein is a method of enhancing the effect of another medication used to treat the demyelinating disease in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0226] Also provided here is a method of delaying the progression of the demyelinating disease in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the method increases the quality of life of the subject having the demyelinating disease. In some embodiments, the method prolongs survival of the subject having the demyelinating disease.

[0227] In some aspects, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a demyelinating disease. In other aspects, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of medicament for treating a demyelinating disease.

[0228] In another aspect, provided herein is a method for treating multiple sclerosis (MS) with EBP inhibition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for preventing multiple sclerosis (MS) in a subject inneed thereof, comprising administering to the subject an effective amount of a compound of Formula (I).

[0229] In some embodiments, the type of multiple sclerosis (MS) is relapsing remitting MS, in which an individual having MS will have episodes of new or worsening symptoms, known as relapses. In some embodiments, the type of multiple sclerosis (MS) is primary progressive MS, in which an individual having MS will experience worsening symptoms and / or accumulating symptoms and with no periods of remission. In some embodiments, the type of multiple sclerosis (MS) is secondary progressive MS, in which an individual having MS experiences nerve damage or loss, leading to a general worsening of the disease.

[0230] In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof diminishes the extent of the disease multiple sclerosis (MS) (for example, loss of myelin coating of brain and spinal cord nerves, development of plaque around brain and spinal cord nerves, neuroinflammation) in the subject. In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof stabilizes the disease multiple sclerosis (MS) (for example, prevents or delays the worsening of MS). In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof delays the occurrence or recurrence of the disease multiple sclerosis (MS). In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof slows the progression of the disease multiple sclerosis (MS). In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof prevents relapse of the disease multiple sclerosis (MS). In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof decreases the dose of one or more other medications required to treat the disease multiple sclerosis (MS). In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof enhances the effect of another medication used to treat the disease multiple sclerosis (MS). In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof delays the progression of the disease multiple sclerosis (MS). In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof increases the quality of life of the subject having the disease multiple sclerosis (MS). In some embodiments, administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof prolongs survival of a subject having the disease multiple sclerosis (MS).

[0231] In some aspects, provided herein is a method of slowing progression of multiple sclerosis (MS) in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, provided herein is a method of stabilizing multiple sclerosis (MS) in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the method prevents the progression of multiple sclerosis (MS). In some embodiments, the method delays the progression of multiple sclerosis (MS).

[0232] In another aspect, provided herein is a method of delaying the occurrence or recurrence of multiple sclerosis (MS) in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0233] In further aspects, provided herein is a method of decreasing the dose of one or more other medications required to treat the disease multiple sclerosis (MS) in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, provided herein is a method of enhancing the effect of another medication used to treat multiple sclerosis (MS) in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0234] Also provided here is a method of delaying the progression of the disease multiple sclerosis (MS) in a subject, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the method increases the quality of life of the subject having multiple sclerosis (MS). In some embodiments, the method prolongs survival of the subject having multiple sclerosis (MS).

[0235] In some aspects, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis (MS). In other aspects, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of medicament for treating multiple sclerosis (MS).Dosing and Method of Administration

[0236] The phrases “parenteral administration” and “administered parenterally” as used herein mean modes of administration other than enteral and topical administration, usually by injection and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0237] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0238] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intraci stemally and topically, as by powders, ointments or drops, including buccally and sublingually.

[0239] Regardless of the route of administration selected, the compounds of the present disclosure, or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0240] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.

[0241] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present disclosure employed or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated and like factors well known in the medical arts. A daily, weekly or monthly dosage (or other time interval) can be used.

[0242] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and then gradually increasing the dosage until the desired effect is achieved.

[0243] In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect (e.g., inhibit necrosis). Such an effective dose will generally depend upon the factors described above. Generally, doses of the compounds of this disclosure for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kg of body weight per day. Preferablythe daily dosage will range from 0.001 to 50 mg of compound per kg of body weight and even more preferably from 0.01 to 10 mg of compound per kg of body weight.

[0244] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

[0245] When the compounds of the present disclosure are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (such as 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0246] The compounds of the present application or the pharmaceutical compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in certain embodiments, may also be continuous.

[0247] When administered orally, the total daily dosage for a human subject may be between about 1 mg and 1,000 mg, between about 1,000-2,000 mg / day, between about 10-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day or between about 100-150 mg / day.

[0248] The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 20 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day or between about 15 to 150 mg / day.

[0249] In certain embodiments, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50 or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week or once per week.

[0250] In certain embodiments, a compound or pharmaceutical preparation is administered orally. In certain embodiments, the compound or pharmaceutical preparation is administered intravenously. Alternative routes of administration include sublingual, intramuscular and transdermal administrations.

[0251] The preparations of the present disclosure may be given orally, parenterally, topically, or rectally. They are, of course, given in forms suitable for each administration route. For example, they are administered in tablets or capsule form; by injection, inhalation, eye lotion, ointment, suppository, infusion, inhalation, etc.; topical by lotion or ointment; and rectal by suppositories. In certain embodiments, the administration is oral.Kits / Article of Manufacture

[0252] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more compounds, compositions, or methods described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[0253] A kit typically includes labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[0254] In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[0255] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.EXAMPLES

[0256] The examples and preparations provided below further illustrate and exemplify the compounds of the present disclosure and methods for testing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples.

[0257] The chemical reactions in the Examples described can be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds of this disclosure are deemed to be within the scope of this disclosure. For example, the synthesis of non-exemplified compounds according to the present disclosure can be performed by modifications apparent to those skilled in the art, for example by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modification of reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.

[0258] The following abbreviations may be relevant for the application.AbbreviationsACN acetonitrile aq aqueousCDI 1 , 1 '-carbonyl diimidazoleCV column volume(s)DAST diethylaminosulfur trifluorideDCE di chloroethaneDCM dichloromethaneDIAD diisopropyl azodi carb oxy lateDIEA, DIPEA N,N-DiisopropylethylamineDMF dimethylformamideDMP Dess-Martin periodinaneDMS dimethyl sulfideDMSO dimethylsulfoxideEA, EtOAc ethylacetateEt2O di ethyl etherEtOH ethanol h, hr hour(s)HBTU 3-[bis(dimethylamino)methyliumyl]-3J / -benzotriazol-l-oxide hexafluorophosphateHPLC high-performance liquid chromatographyLCMS liquid chromatography-mass spectrometryLiHMDS, LHMDS lithium HexamethyldisilazideMeOD-d4 deuterated methanol (CD3OD)MeOH methanol min. minute(s)MW micro waveNIS N-iodosuccinimideNMP N -methyl -2-py rroli donePd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)PdC12(dppf) [1, l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloridePd PEPPSI-IPENT dichlorofl, 3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II)PE petroleum etherRT, rt room temperature sat. saturatedSGC Silica Gel Chromatography tBu tert-butyl tBuXPhos Pd G3 [(2-di-tert-butylphosphino-2 ',4 6 ' -tri i sopropyl- 1 , 1 '-biphenyl)-2-(2 '- amino- 1 , 1 '-biphenyl)] palladium(II) methanesulfonateTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuran xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneSynthetic ExamplesExample SI. Synthesis of l-(5-Methyl-l-Phenyl-Pyrazol-3-yl)-4-(Tetrahydropyran-4- ylmethyl) Piperazine (Compound 1).

[0259] Compound 1 was prepared as outlined below.

[0260] Step 1. Synthesis of tert-butyl 4-(3-oxobutanoyl) piperazine-l-carboxylate.

[0261] A mixture of tert-butyl piperazine-l-carboxylate (6.0 g, 32.2 mmol) and tert-butyl acetoacetate (5.61 g, 35.4 mmol) in toluene (100 mL) was heated at 100°C for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 330 g silica gel column @200mL / min, eluting with 0-30% acetone in petroleum ether) to afford the desired product tert-butyl 4-(3 -oxobutanoyl) piperazine-l- carboxylate (8.4 g, yield 93%) as a yellow oil.

[0262] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C; LC purity: 96.32% (214 nm), Mass: found peak 293.3 (M+23) at 1.039 min.

[0263] ‘H NMR (500 MHz, CDC13) 5 3.63-3.59 (m, 2H), 3.58 (s, 2H), 3.46-3.42 (m, 4H), 3.41-3.36 (m, 2H), 2.28 (s, 3H), 1.47 (s, 9H) ppm.

[0264] Step 2. Synthesis of tert-butyl 4-(3-oxobutanethioyl) piperazine-l-carboxylate.Lawesson's reagent(0.5 eq) toluene, 75°c, 16h

[0265] To a solution of tert-butyl 4-(3 -oxobutanoyl) piperazine-l-carboxylate (4.0 g, 14.8 mmol) in toluene (100 mL) was added Lawesson's reagent (2.99 g, 7.4 mmol) and the mixture was heated at 75°C for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 330 g silica gel column@200mL / min, eluting with 10-65% ethyl acetate in petroleum ether) to afford the desired crude product tert-butyl 4-(3 -oxobutanethioyl) piperazine- 1 -carboxylate (2.33 g) as a brown oil.

[0266] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA);Gradient: 5% increase to 95%B within 1.3min, 95%B for 1.7min; Flow Rate: 2mL / min;Column: SunFire, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 78.09% (214 nm), Mass: found peak 287.2 (M+1) at 1.744 min; LC purity: 20.64% (214 nm) Mass: found peak 287.1 (M+1) at 1.975 min.

[0267] Step 3. Synthesis of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl) piperazine-1- carboxylate.

[0268] To a solution of tert-butyl 4-(3 -oxobutanethioyl) piperazine- 1 -carboxylate (2.33 g, 8.14 mmol) in toluene (60 mL) was added hydrazine monohydrate (1.21 mL, 24.4 mmol) and the mixture was stirred at 70°C for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 120 g silica gel column @100mL / min, eluting with 0-6% MeOH in DCM) to afford the desired product tertbutyl 4-(5-methyl-lH-pyrazol-3-yl) piperazine- 1 -carboxylate (1.59 g, yield 38.6% over 2 steps) as a yellow solid. LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 96.86% (214 nm), Mass: found peak 267.3 (M+1) at 1.022 min.

[0269] 'H NMR (400 MHz, CDCh) 5 5.52 (s, 1H), 3.54 (t, J = 4.8 Hz, 4H), 3.14 (t, J = 4.8 Hz, 4H), 2.25 (s, 3H), 1.48 (s, 9H) ppm.

[0270] Step 4. Synthesis of tert-butyl 4-(5-methyl-l-phenyl-pyrazol-3-yl) piperazine-1- carboxylate.Boc

[0271] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl) piperazine- 1 -carboxylate (0.6 g, 2.25mmol) in dichloromethane (30 mL) was added phenylboronic acid (561 mg, 4.51 mmol),anhydrous copper acetate (614 mg, 3.38 mmol), pyridine (0.363 mL, 4.51 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 64 h. The mixture was filtered. The filtrate was purified by flash chromatography (Biotage, 120 g silica gel column @100 mL / min, eluting with 0-30% ethyl acetate in petroleum ether) to afford the desired product tert-butyl 4-(5-methyl-l-phenyl-pyrazol-3-yl) piperazine- 1 -carboxylate (0.54 g, yield 70%) as a yellow solid.

[0272] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 100% (214 nm), Mass: found peak 343.4 (M+l) at 1.395 min.

[0273] Step 5. Synthesis of l-(5-methyl-l-phenyl-pyrazol-3-yl) piperazine.

[0274] To a solution of tert-butyl 4-(5-methyl-l-phenyl-pyrazol-3-yl) piperazine-1- carboxylate (0.62 g, 1.81 mmol) in dichloromethane (15 mL) was added TFA (3 mL, 40.4 mmol). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (20 mL), neutralized with potassium carbonate to pH=8, extracted with dichloromethane (30 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product l-(5-methyl-l-phenyl-pyrazol- 3-yl) piperazine (420 mg, yield 92%) as a yellow solid.

[0275] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 96.07% (214 nm) Mass: found peak 243.3 (M+l) at 0.928 min.

[0276] Step 6. Synthesis of l-(5-methyl-l-phenyl-pyrazol-3-yl)-4-(tetrahydropyran-4- ylmethyl) piperazine (Compound 1).

[0277] To a solution of l-(5-methyl-l-phenyl-pyrazol-3-yl) piperazine (0.15 g, 0.619 mmol) in 1,2-dichloroethane (8 mL) was added tetrahydropyran-4-carbaldehyde (84.8 mg, 0.743 mmol), follow by Sodium triacetoxyborohydride (0.262 g, 1.24 mmol), 4A molecular sieve (0.5 g) and acetic acid (2 drops). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered. The filtrate was treated with MeOH (2 mL), concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product l-(5-methyl-l-phenyl-pyrazol-3-yl)- 4-(tetrahydropyran-4-ylmethyl) piperazine (126.5 mg, yield 60%) as a white solid.

[0278] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Gradient: 5% increase to 95%B within 1.3min, 95%B for 1.7min O.Olmin; Flow Rate: 1.8mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm), Mass: found peak 341.3 (M+l) at 1.813 min.

[0279] 'H NMR (400 MHz, DMSO-d6) 5 7.52-7.42 (m, 4H), 7.33-7.27 (m, 1H), 5.84 (s, 1H), 3.82 (dd, J = 11.2, 2.8 Hz, 2H), 3.28 (td, J = 11.6, 1.6 Hz, 2H), 3.11 (t, J = 4.8 Hz, 4H), 2.43 (t, J = 4.8 Hz, 4H), 2.28 (s, 3H), 2.16 (d, J = 7.6 Hz, 2H), 1.82-1.71 (m, 1H), 1.61 (d, J = 11.2 Hz, 2H), 1.12 (qd, J = 12.0, 4.0 Hz, 2H) ppm.Example S2. Synthesis of 4-[2-[4-[5-methyl-l-(2-naphthyl) pyrazol-3-yl] piperazin-1- yl] ethyl] morpholine (Compound 2)

[0280] Compound 2 was prepared as outlined below.

[0281] Step 1. Synthesis of tert-butyl 4-[5-methyl-l-(2-naphthyl) pyrazol-3-yl] piperazine-l-carboxylate.Boc

[0282] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl) piperazine-l-carboxylate (0.2 g, 0.751 mmol) in dichloromethane (10 mL) was added 2-naphthylboronic acid (264 mg, 1.5 mmol), anhydrous copper acetate (205 mg, 1.13 mmol), pyridine (0.121 mL, 1.5 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 24h. The mixture was filtered. The filtrate was purified by flash chromatography (Biotage, 40 g silica gel column @50 mL / min, eluting with 5-40% ethyl acetate in petroleum ether) to afford the desired product tert-butyl 4- [5 -methyl- 1 -(2 -naphthyl) pyrazol-3-yl] piperazine-l-carboxylate (160 mg, yield 54.3%) as a yellow oil.

[0283] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 100% (214 nm), Mass: found peak 393.3 (M+l) at 1.503 min.

[0284] Step 2. Synthesis of l-[5-methyl-l-(2-naphthyl) pyrazol-3-yl] piperazine.Boc

[0285] To a solution of tert-butyl 4-[5-methyl-l-(2-naphthyl) pyrazol-3-yl] piperazine-1- carboxylate (0.24 g, 0.611 mmol) in dichloromethane (10 mL) was added TFA (2 mL, 26.9 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL), neutralized with potassium carbonate to pH=8, extracted with dichloromethane (20 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product l-[5-methyl-l-(2-naphthyl) pyrazol-3-yl] piperazine (157 mg, yield 84.9%) as a yellow solid.

[0286] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA);Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm;Column Temperature: 40 °C; LC purity: 96.72% (214 nm), Mass: found peak 293.2 (M+l) at 1.073 min.

[0287] Step 3. Synthesis of 4-[2-[4-[5-methyl-l-(2-naphthyl) pyrazol-3-yl] piperazin-1- yl] ethyl] morpholine (Compound 2).

[0288] To a solution of l-[5-methyl-l-(2-naphthyl) pyrazol-3-yl] piperazine (130 mg, 0.445 mmol), potassium carbonate (184 mg, 1.33 mmol) and KI (10 mg, 0.06 mmol) in 95% ethanol (10 mL) was added 4-(2-chloroethyl) morpholine hydrochloride (99 mg, 0.534 mmol). The reaction was stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[4-[5- methyl-l-(2-naphthyl) pyrazol-3-yl] piperazin- 1 -yl]ethyl] morpholine (63 mg, yield 34.9%) as a white solid.

[0289] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Gradient: 5% increase to 95%B within 1.3min, 95%B for 1.7min O.Olmin; Flow Rate: 1.8mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm), Mass: found peak 406.3 (M+l) at 1.751 min.

[0290] 'H NMR (400 MHz, DMSO-d6) 5 8.03-7.92 (m, 4H), 7.70 (dd, J = 8.8, 2.0 Hz, 1H), 7.58-7.49 (m, 2H), 5.90 (s, 1H), 3.56 (t, J = 4.8 Hz, 4H), 3.14 (t, J = 4.4 Hz, 4H), 2.56-2.51 (m, 3H), 2.48-2.32 (m, 12H) ppm.Example S3. Synthesis of l-(5-methyl-l-phenyl-pyrazol-3-yl)-4-(2-tetrahydropyran-4- ylethyl) piperazine (Compound 3).

[0291] Compound 3 was prepared as outlined below.

[0292] To a solution of l-(5-methyl-l-phenyl-pyrazol-3-yl) piperazine (0.14 g, 0.578 mmol) in 1,2-dichloroethane (8 mL) was added 2-tetrahydropyran-4-ylacetaldehyde (88.9 mg, 0.693 mmol), follow by sodium triacetoxyborohydride (0.245 g, 1.16 mmol), 4A molecular sieve (0.5 g) and acetic acid (2 drops). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered. The filtrate was treated with MeOH (2 mL), concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product l-(5-methyl-l-phenyl-pyrazol-3-yl)- 4-(2-tetrahydropyran-4-ylethyl) piperazine (95 mg, yield 46.4%) as a white solid.

[0293] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Gradient: 5% increase to 95%B within 1.3min, 95%B for 1.7min O.Olmin; Flow Rate: 1.8mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm), Mass: found peak 355.3 (M+l) at 1.794 min.

[0294] 'H NMR (400 MHz, DMSO-d6) 5 7.50-7.42 (m, 4H), 7.34-7.26 (m, 1H), 5.84 (s, 1H), 3.81 (dd, J = 10.4, 3.2 Hz, 2H), 3.26 (td, J = 11.6, 1.6 Hz, 2H), 3.11 (t, J = 4.4 Hz, 4H), 2.44 (d, J = 4.8 Hz, 4H), 2.32 (t, J = 7.2 Hz, 2H), 2.28 (s, 3H), 1.60-1.45 (m, 3H), 1.39 (dd, J = 14.8, 7.2 Hz, 2H), 1.22-1.08 (m, 2H) ppm.Example S4. Synthesis of 4-(5-methyl-l-phenyl-pyrazol-3-yl)-l-(tetrahydropyan-4- ylmethyl) piperidine (Compound 4).

[0295] Compound 4 was prepared as outlined below.

[0296] Step 1. Synthesis of l-(4-Pyridinyl)-l,3-butanedione.

[0297] To a 500 mL flask with sodium methoxide (715 mg, 13.2 mmol) and anhydrous ether (15 mL) was sequentially added ethyl pyridine-4-carboxylate (2.0 g, 13.2 mmol), and a solution of acetone (3.84 g, 66.2 mmol) in ether (15 mL). The suspension was stirred at reflux for 6 h, cooled, and filtered. The isolated solid was washed with ether and dissolved in water (40 mL). Glacial acetic acid (5.2 mL) was added, and the mixture was extracted with chloroform (40 mL x 2). The organic extracts were dried over anhydrous Sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA= 1 : 1) to afford the desired product l-(4-pyridinyl)- 1,3 -butanedi one (1.55 g, yield 72%) as a brown solid.

[0298] LCMS method: Mobile Phase: A: water (0.01% TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3min, 95%B for 0.7min; Flow Rate: 2.2mL / min; Column: Chromolith Fast gradient RP-18e, 50mm*3mm; Column Temperature: 40 °C; LC purity: 100% (214 nm), Mass: found peak 164.1(M+1) at 0.791 min.

[0299] Step 2. Synthesis of 4-(3-methyl-lH-pyrazol-5-yl) pyridine.

[0300] l-(4-Pyridinyl)-l,3-butanedione (1.55 g, 9.5 mmol) was suspended in ethanol (10 mL), hydrazinium hydroxide (476 mg, 9.5 mmol) was added and the mixture was stirred at 85°C for 48 h. The reaction mixture was diluted with saturated Sodium bicarbonate solution (pH 7-8) and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo to afford the desired product 4-(3-methyl-lH-pyrazol-5-yl) pyridine (1.2 g, 79.4%) as beige solid.

[0301] LCMS method: Mobile Phase: A: water (0.01% TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3min, 95%B for 0.7min; Flow Rate: 2.2mL / min; Column: Chromolith Fast gradient RP-18e, 50mm*3mm; Column Temperature: 40 °C; LC purity: 90% (214 nm), Mass: found peak 160.1 (M+l) at 0.303 min.

[0302] Step 3. Synthesis of 4-(3-methyl-lH-pyrazol-5-yl) piperidine hydrochloride.

[0303] 4-(3-methyl-lH-pyrazol-5-yl) pyridine (1.1 g, 6.91 mmol) was dissolved in ethanol (30 mL), hydrochloric acid solution (1 M, 13.8 mL, 1.38 mmol) was added and the mixture was hydrogenated with platinum oxide hydrate (80% Pt, 150 mg) at atmospheric pressure and room temperature for 16 h. The reaction mixture was filtered and concentrated in vacuo to afford the desired product 4-(3-methyl-lH-pyrazol-5-yl) piperidine hydrochloride (1.0 g, yield 71.7%) as a yellow solid.

[0304] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Mobile phase: water (10 mM ammonium hydrogen carbonate) (A) / Acetonitrile (B); Gradient from 10 to 95% of B in 1.5min at 1.8mL / min; Column: X-BRIDGE C18, 4.6x50 mm, 3.5 pm; Temperature: 50 °C; LC purity: 90% (214 nm), Mass: found peak 166.1(M+1) at 0.592 min.

[0305] Step 4. Synthesis of tert-butyl 4-(3-methyl-lH-pyrazol-5-yl) piperidine-1- carboxylate.BOC2Q(1 .0 eq)N-N / — \ NaHCO3(3 o eq)II ) — \ H T - - - — Boc\ / dioxane, H2O RT 2h / HCI

[0306] 4-(3-methyl-lH-pyrazol-5-yl)piperidine hydrochloride (1.0 g, 6.6 mmol) was dissolved in water (10 mL). Sodium bicarbonate (1.68 g, 20 mmol) and di-tertbutyldicarbonate (1.45 g, 6.6 mmol) in dioxane (15 mL) were added and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (PE: EA= 3: 1) to afford the desired product tert-butyl 4- (3-methyl-lH-pyrazol-5-yl) piperidine- 1 -carboxylate (900 mg, yield 43.2%) as a colorless oil.

[0307] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Mobile phase: water (10 mM ammonium hydrogen carbonate) (A) / Acetonitrile(B); Gradient from 10 to 95% of B in 1.5min at 1.8mL / min; Column: X-BRIDGE C18, 4.6x50 mm, 3.5 pm; Temperature: 50 °C; LC purity: 77% (214 nm), Mass: found peak 210.2 (M-55)+at 1.690 min.

[0308] Step 5. Synthesis of tert-butyl 4-(5-methyl-l-phenyl-pyrazol-3-yl)piperidine-l- carboxylate.

[0309] Tert-butyl 4-(3 -methyl- lH-pyrazol-5-yl)piperidine-l -carboxylate (980 mg, 3.7 mmol), phenylboronic acid (980 mg, 7.4 mmol), anhydrous copper acetate (1.34 g, 7.4 mmol) and molecular sieves 4 A was suspended in anhydrous dichloromethane (30 mL). Pyridine (584 mg, 7.4 mmol) was added and the mixture was stirred at ambient temperature for 48h. The reaction mixture was concentrated in vacuo to dryness and purified by prep-HPLC (water / ammonium hydrogen carbonate / acetonitrile) to afford the desired product tert-butyl 4-(5-methyl-l-phenyl- pyrazol-3-yl)piperidine-l -carboxylate (420 mg, yield 48%) as a yellow oil.

[0310] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA); Gradient: 5%B increase to 95%B within 1.3min, 95%B for 1.2 min; Flow Rate: 2.2mL / min; Column: Chromolith Fast gradient RP-18e, 50mm*3mm; Column Temperature: 40 °C; LC purity: 95.53% (214 nm), Mass: found peak 342.2 (M-55)+at 1.374 min.

[0311] Step 6. Synthesis of 4-(5-methyl-l-phenyl-pyrazol-3-yl) piperidine.

[0312] Hydrogen chloride solution (4.0 M in dioxane, 5.0 mL) was added to tert-butyl 4-(5- methyl-1 phenyl-pyrazol-3-yl) piperidine- 1 -carboxylate (600 mg, 1.76 mmol) in 1,4-dioxane (10 mL) and stirred for 2 h at ambient temperature. The reaction was concentrated in vacuo. The saturated Sodium bicarbonate solution was added to adjust to pH 7-8 and extracted with dichloromethane (50 mL x 2). The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo to afford the desired product 4-(5-methyl-l-phenyl-pyrazol- 3-yl) piperidine (380 mg, yield 89.6%) as yellow oil.

[0313] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA);Gradient: 5%B increase to 95%B within 1.3min, 95%B for 1.2 min; Flow Rate: 2.2mL / min;Column: Chromolith Fast gradient RP-18e, 50mm*3mm; Column Temperature: 50 °C; LC purity: 98.27% (214 nm), Mass: found peak 242.3 (M+H)+ at 0.863 min.

[0314] Step 7. Synthesis of 4-(5-methyl-l-phenyl-pyrazol-3-yl)-l-(tetrahydropyan-4- ylmethyl) piperidine (Compound 4).

[0315] A solution of 4-(5-methyl-l-phenyl-pyrazol-3-yl) piperidine (100 mg, 0.41 mmol), tetrahydropyran-4-carbaldehyde (47.3 mg, 0.41 mmol) and sodium triacetoxyborohydride (176 mg, 8.3 mmol) in 1,2-di chloroethane (5 mL) was stirred for overnight at room temperature. The reaction mixture was filtered, and concentrated in vacuo. The residue was purified by prep- HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-(5- methyl-l-phenyl-pyrazol-3-yl)-l-(tetrahydropyan-4-ylmethyl) piperidine (71.6 mg, yield 50.9%) as a yellow oil.

[0316] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA); Gradient: 5% increase to 95%B within 1.3min, 95% B for 1.7min; Flow rate: 2mL / min;Column: Sunfire, 50*4.6mm, 3.5pm; Column temperature: 50 °C; LC purity: 100% (214 nm), Mass: found peak 340.2 (M+l) at 1.359 min.

[0317] 'H NMR (400 MHz, DMSO-d6) d 7.49 (d, J = 4.4 Hz, 4H), 7.42-7.31 (m, 1H), 6.13 (s, 1H), 3.82 (dd, J = 11.2, 2.8 Hz, 2H), 3.32-3.24 (m, 2H), 2.87 (d, J = 11.2 Hz, 2H), 2.53 (s, 1H), 2.30 (s, 3H), 2.14 (d, J = 6.8 Hz, 2H), 1.96 (t, J = 11.2 Hz, 2H), 1.85(d, J = 11.6 Hz, 2H) 1.78- 1.72 (m, 1H), 1.59-1.58 (m, 4H), 1.19-1.03 (m, 2H) ppm.Example S5. Synthesis of 4-(5-methyl-l-phenyl-pyrazol-3-yl)-l-(2-tetrahydropyran-4- ylethyl) piperidine (Compound 5).

[0318] Compound 5 was prepared as outlined below.

[0319] A solution of 4-(5-methyl-l-phenyl-pyrazol-3-yl) piperidine (90 mg, 0.37 mmol), 2- (tetrahydro-2H-pyran-4-yl) acetaldehyde (47.3 mg, 0.41 mmol) and sodium triacetoxyborohydride (158 mg, 0.74 mmol) in 1,2-dichloroethane (5 mL) was stirred for overnight at room temperature. The reaction mixture was filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-(5-methyl-l-phenyl-pyrazol-3-yl)-l-(2-tetrahydropyran-4-ylethyl) piperidine (42.7 mg, yield 32.4 %) as a yellow solid.

[0320] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA); Gradient: 5% increase to 95%B within 1.3min, 95% B for 1.7min; Flow rate: 2mL / min;Column: Sunfire, 50*4.6mm, 3.5pm; Column temperature: 50 °C; LC purity: 100% (214 nm), found peak 354.3 (M+H)+ at 1.388 min.

[0321] 'H NMR (400 MHz, DMSO-d6) d 7.49 (d, J = 4.4 Hz, 4H), 7.42-7.31 (m, 1H), 6.13 (s, 1H), 3.82 (dd, J = 10.8, 3.2 Hz, 2H), 3.32-3.24 (m, 2H), 2.9 (d, J = 11.6 Hz, 2H), 2.53 (s, 1H), 2.32-2.80 (m, 5H), 1.96 (t, J = 11.6 Hz, 2H), 1.85 (d, J = 11.2 Hz, 2H), 1.60-1.40 (m, 5H), 1.35 (m, 2H), 1.20-1.13 (m ,2H) ppm.Example S6. Synthesis of 4-[2-[4-[l-[4-fluoro-3-(trifluoromethoxy) phenyl] -5-methyl- pyrazol-3-yl] piperazin-l-yl] ethyl] morpholine (Compound 6).

[0322] Compound 6 was prepared as outlined below.

[0323] Step 1. Sythesis of 2-[4-fluoro-3-(trifluoromethoxy) phenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane.

[0324] Under argon atmosphere, a mixture of 4-bromo-l-fluoro-2-(trifluorom ethoxy) benzene (1.5 g, 5.79 mmol), l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.47 g, 5.79 mmol), PdC12(dppf) (315 mg, 0.386 mmol) and potassium acetate (1.14 g, 11.6 mmol) in 1,4-dioxane (30 mL) was stirred at 80 °C for 16h. The reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 80 g silica gel column @100 mL / min, eluting with 0-5% ethyl acetate in petroleum ether) to afford the desired product 2- [4-fluoro-3 -(trifluoromethoxy) phenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (910 mg, yield 63.1%) as a yellow oil.

[0325] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2 min at 2.2 mL / min; Column: HALO C18 2.7 pm 4.6*30 mm; Column Temperature: 40 °C; LC purity: 81.98% (214 nm) Mass: found peak 307.1 (M+l) at 1.582 min. 'H NMR (400 MHz, CDCh) 57.75-7.68 (m, 2H), 7.18 (dd, J = 10.0, 8.4 Hz, 1H), 1.34 (s, 12H) ppm.

[0326] Step 2. Synthesis of [4-fluoro-3-(trifluoromethoxy) phenyl] boronic acid.

[0327] To a stirred solution of 2-[4-fluoro-3-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (850 mg, 2.78 mmol) in tetrahydrofuran (20 mL) and water (5 mL) was added a Sodium periodate (1.78 g, 8.33 mmol). After stirring at room temperature for 30 min, HC1 aqueous (2.78 mL, 2.78 mmol) was added and stirred for an additional 16h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL*3). The organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product [4-fluoro-3 -(trifluoromethoxy) phenyl] boronic acid (576 mg, yield 85.6%) as yellow solid. LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; FlowRate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 92.47% (214 nm) Mass: no ms peak, at 1.876 min.

[0328] Step 3. Synthesis of tert-butyl 4-[l-[4-fluoro-3-(trifluoromethoxy) phenyl]-5-

[0329] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl) piperazine- 1 -carboxylate (100 mg, 0.375 mmol) in chloroform (20 mL) was added [4-fluoro-3 -(trifluoromethoxy) phenyl] boronic acid (109 mg, 0.488 mmol), anhydrous copper acetate (136 mg, 0.751 mmol), pyridine (0.15 mL, 1.88 mmol) and molecular sieves 4 A. The reaction mixture was stirred at 40 °C for 24h. The mixture was filtered. The filtrate was purified by flash chromatography (Biotage, 80g silica gel column @100mL / min, eluting with 0-30% ethyl acetate in petroleum ether) to afford the desired product tert-butyl 4-[l-[4-fluoro-3 -(trifluoromethoxy) phenyl]-5-methyl-pyrazol-3- yl] piperazine- 1 -carboxylate (160 mg, yield 91.1%) as a yellow solid.

[0330] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2 min at 2.2 mL / min; Column: HALO C18 2.7 pm 4.6*30 mm; Column Temperature: 40 °C; LC purity: 95.04% (214 nm) Mass: found peak 445.3 (M+l) at 1.527 min. 'H NMR (400 MHz, CDCh) 5 7.44-7.40 (m, 1H), 7.39-7.34 (m, 1H), 7.28-7.22 (m, 1H), 5.71 (s, 1H), 3.55 (t, J = 5.2 Hz, 4H), 3.20 (t, J = 5.2 Hz, 4H), 2.31 (s, 3H), 1.49 (s, 9H) ppm.

[0331] Step 4. Synthesis of l-[l-[4-fluoro-3-(trifluoromethoxy) phenyl]-5-methyl-pyrazol- 3-yl] piperazine.

[0332] To a solution of tert-butyl 4-[l-[4-fluoro-3 -(trifluoromethoxy) phenyl]-5-methyl- pyrazol-3-yl] piperazine- 1 -carboxylate (160 mg, 0.36 mmol) in di chloromethane (10 mL) wasadded TFA (2 mL, 26.9 mmol). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (20 mL), neutralized with potassium carbonate to pH=9, extracted with dichloromethane (20 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product 1 -[ 1 -[4- fluoro-3 -(trifluoromethoxy) phenyl]-5-methyl-pyrazol-3-yl] piperazine (120 mg, yield 92.2%) as a yellow oil.

[0333] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 95.22% (214 nm) Mass: found peak 345.1 (M+l) at 1.989 min.

[0334] Step 5. Synthesis of 4-[2-[4-[l-[4-fluoro-3-(trifluoromethoxy) phenyl]-5-methyl- pyrazol-3-yl] piperazin-l-yl] ethyl] morpholine (Compound 6).

[0335] To a solution of l-[l-[4-fluoro-3 -(trifluoromethoxy) phenyl]-5-methyl-pyrazol-3-yl] piperazine (120 mg, 0.349 mmol), potassium carbonate (193 mg, 1.39 mmol) and KI (58 mg, 0.349 mmol) in 95% ethanol (10 mL) was added 4-(2-chloroethyl) morpholine hydrochloride (97 mg, 0.523 mmol). The reaction was stirred at 90°C for 16h. The reaction was filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium carbonate / water / acetonitrile) to afford the desired product 4-[2-[4-[l-[4-fluoro-3- (trifluoromethoxy) phenyl]-5-methyl-pyrazol-3-yl] piperazin-l-yl] ethyl] morpholine (134.7 mg, yield 84.5%) as a yellow solid.

[0336] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 458.1 (M+l) at 2.029 min. 'H NMR (400 MHz, CD3OD) 5 7.60-7.55 (m, 1H), 7.54-7.44 (m, 2H), 5.87 (s, 1H), 3.72 (t, J = 4.8 Hz, 4H), 3.26 (t, J = 4.8 Hz, 4H), 2.66 (t, J = 4.8 Hz, 4H), 2.63-2.58 (m, 4H), 2.54 (t, J = 4.8 Hz, 4H), 2.31 (s, 3H) ppm.Example S7. Synthesis of 4-[2-[l-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl] pyrrolidin-3-yl] oxyethyl] morpholine (Compound 7).

[0337] Compound 7 was prepared as outlined below.

[0338] Step 1. Synthesis of l-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl] pyr rolidin-3-ol.

[0339] Under argon atmosphere, a mixture of 3-bromo-5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazole 500 mg, 1.56 mmol), tert-butyl 2,6-diazaspiro-[3.3]-heptane-2-carboxylate (203 mg, 2.34 mmol), tBuXPhos Pd G3 (124 mg, 0.156 mmol) and sodium tert-butoxide (449 mg, 4.67 mmol) in 1,4-dioxane (20 mL) was stirred 100 °C for 16h. The reaction mixture was directly purified by flash chromatography (Biotage, 120 g silica gel column @100 mL / min, eluting with 0-80% ethyl acetate in petroleum ether) to afford the desired product l-[5-methyl-l- [4-(trifluoromethoxy) phenyl]pyrazol-3-yl]pyrrolidin-3-ol (97 mg, yield 17.9%) as a yellow oil.

[0340] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C; LC purity: 93.81% (214 nm) Mass: found peak 328.2 (M+l) at 1.164 min.

[0341] Step 2. Synthesis of 4-[2-[l-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl] pyrrolidin-3-yl] oxyethyl] morpholine (Compound 7).

[0342] To a solution of l-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]pyrrolidin-3- ol (97 mg, 0.296 mmol) in dry DMF (9 mL) was added sodium hydride (60%, 237 mg, 5.93 mmol). The reaction was stirred at 60°C for 2h. The reaction was cooled and 4-(2- chloroethyl)morpholine hydrochloride (165 mg, 0.889 mmol) was added and stirred at 80 °C for 16h. The reaction was cooled to room temperature, quenched with water (5 mL), extracted with DCM (20 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[l-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl] pyrrolidin-3-yl] oxyethyl] morpholine (53.9 mg, yield 41.3%) as a yellow oil.

[0343] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column:X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 441.1 (M+l) at 2.059 min. 'H NMR (400 MHz, CD3OD) 5 7.59-7.54(m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 5.68 (s, 1H), 4.23-4.18 (m, 1H), 3.72-3.63 (m, 6H), 3.50-3.34 (m, 4H), 2.62 (t, J = 5.6 Hz, 2H), 2.54 (t, J = 4.4 Hz, 4H), 2.30 (s, 3H), 2.15-2.07 (m, 2H) ppm.Example S8. Synthesis of 4-[(7S,8aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-7-yl]morpholine (Compound 8).

[0344] Compound 8 was prepared as outlined below.

[0345] Step 1. Synthesis of methyl (2S,4R)-l-[2-(tert-butoxycarbonylamino)acetyl]-4- hydroxy-pyrrolidine-2-carboxylate.

[0346] To a mixture of N-(tert-butoxycarbonyl)glycine (2.89 g, 16.5 mmol), DIEA (8.21 mL, 49.6 mmol) and HBTU (6.26 g, 16.5 mmol) in 75 mL DMF at 0°C, L-4-hydroxyproline methyl ester hydrochloride (3 g, 16.5 mmol) was added and the suspension thus obtained was stirred at room temperature for 16h. The reaction mixture was diluted with EtOAc (750 mL), washed withwater (100 mL) and brine (100 mL*4), dried over Sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 80 g silica gel column @75 mL / min, eluting with 0-50% acetone in petroleum ether) to afford the desired methyl (2S,4R)-1- [2-(tert-butoxycarbonylamino)acetyl]-4-hydroxy-pyrrolidine-2-carboxylate (4.0 g, yield 79.6%) as a yellow solid.

[0347] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 99.42% (214 nm) Mass: found peak 325.1 (M+23)+ at 1.567 min. 'HNMR (400 MHz, DMSO-d6) 5 6.86 (t, J = 5.6 Hz, IH), 3.48-3.39 (m, IH), 4.30 (t, J = 8.0 Hz, IH), 3.84-3.72 (m, IH), 3.67-3.55 (m, 5H), 3.52-3.40 (m, 2H), 2.13-2.05 (m, IH), 1.92-1.84 (m, IH), 1.38 (s, 9H) ppm.

[0348] Step 2. Synthesis of (7R,8aS)-7-hydroxy-2,3,6,7,8,8a-hexahydropyrrolo[l,2- a]pyrazine-l, 4-dione.

[0349] To a solution of methyl (2S,4R)-l-[2-(tert-butoxycarbonylamino)acetyl]-4-hydroxy- pyrrolidine-2-carboxylate (700 mg, 2.32 mmol) in methanol (10 mL), was added a solution of HC1 in dioxane (4 M, 8 mL, 32 mmol). The reaction was stirred at room temperature for Ih and concentrated in vacuo under reduced pressure below 40 °C. The residue was dissolved in MeOH (40 mL), treated slowly dropwise with DIPEA until the pH was stable at 9-10. Another DIPEA (0.575 mL, 3.47 mmol) was added and stirred at room temperature for 16h. The reaction was concentrated in vacuo. The residue was diluted with chloroform (30 mL) and stirred at reflux for 2h, then cooled to room temperature for 2h and overnight at 4°C. The solid was filtered, washed with cold chloroform and Et2O to afford desired product (7R,8aS)-7-hydroxy-2,3,6,7,8,8a- hexahydropyrrolo[l,2-a]pyrazine- 1,4-dione (0.3 g, yield 76.1%) as a white solid.

[0350] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 171 (M+l) at 0.349 min. ‘HNMR (400 MHz, DMSO-d6) 5 8.08 (d, J = 2.4 Hz, IH), 5.11 (d, J = 2.8 Hz, IH), 4.36-4.26 (m, 2H), 4.04 (dd, J = 16.8, 1.2 Hz, IH), 3.56-3.46 (m, 2H), 3.22 (d, J = 12.4 Hz, IH), 2.08-2.01 (m, IH), 1.93-1.85 (m, IH) ppm.

[0351] Step 3. Synthesis of (7R,8aS)-l,2,3,4,6,7,8,8a-octahydropyrrolo[l,2-a]pyrazin-7-ol.

[0352] To a solution of (7R,8aS)-7-hydroxy-2,3,6,7,8,8a-hexahydropyrrolo[l,2-a]pyrazine-I, 4-dione (1.45 g, 8.52 mmol) in tetrahydrofuran (50 mL), was added a solution of LiAIT in tetrahydrofuran (1.0 M, 50 mL, 50 mmol). The reaction was stirred at 60 °C for 3h, then stirred at room temperature for 16h. The reaction was cooled to 0 °C, quenched with water (1.9 g), 15% NaOH aqueous (1.9 g) and water (5.7 g), diluted with tetrahydrofuran (50 mL), stirred for 15 min, filtered, and concentrated in vacuo to afford the desired product (7R,8aS)-l,2,3,4,6,7,8,8a- octahydropyrrolo[l,2-a]pyrazin-7-ol (680 mg, yield 56.1%) as a yellow oil.

[0353] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B with 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; Mass: found peak 143 (M+l) at 0.367 min. ‘H NMR (500 MHz, DMSO-d6) 5 4.70 (s, 1H), 4.16-4.09 (m, 1H), 3.22 (dd, J = 9.0, 7.0 Hz, 1H), 2.88 (dd, J = 11.5, 2.5 Hz, 1H), 2.78-2.72 (m, 2H), 2.56-2.50 (m, 1H), 2.17 (dd, J =I I.5, 10.0 Hz, 1H), 2.09-1.98 (m, 2H), 1.88 (dd, J = 9.0, 5.5 Hz, 1H), 1.50-1.41 (m, 2H) ppm.

[0354] Step 4. Synthesis of (7R,8aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol- 3-yl]-3,4,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-7-ol.

[0355] A mixture of 3-bromo-5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazole (300 mg, 0.934 mmol), (7R,8aS)-l,2,3,4,6,7,8,8a-octahydropyrrolo[l,2-a]pyrazin-7-ol (159 mg, 1.12 mmol), tBuXPhos Pd G3 (74 mg, 0.0934 mmol) and sodium tert-butoxide (269 mg, 2.8 mmol) in 1,4-di oxane (15 mL) was stirred 100 °C for 16h under argon atmosphere. The reaction was cooled to room temperature and directly purified by flash chromatography (Biotage, 40 g silica gel column @75 mL / min, eluting with 0-20% MeOH in DCM) to afford the desired product (7R,8aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-lH- pyrrolo[l,2-a]pyrazin-7-ol (84 mg, yield 23.9%) as a brown solid.

[0356] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column:X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 90.87% (214 nm) Mass: found peak 383.1 (M+l) at 1.885 min.

[0357] Step 5. Synthesis of [(7R,8aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol- 3-yl]-3,4,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-7-yl] 4-methylbenzenesulfonate.

[0358] To a solution of (7R,8aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- 3,4,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-7-ol (84 mg, 0.22 mmol), DMAP (81 mg, 0.66 mmol) and triethylamine (67 mg, 0.66 mmol) in dichloromethane (15 mL) was added 4- methylbenzenesulfonyl chloride (126 mg, 0.66 mmol). The reaction was stirred at room temperature for 16h. The reaction was diluted with di chloromethane (50 mL), washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 25 g silica gel column @75 mL / min, eluting with 0- 20% MeOH in DCM) to afford the desired product [(7R,8aS)-2-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-7-yl] 4-methylbenzenesulfonate (90 mg, yield 72.3%) as a brown solid.

[0359] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 94.66% (214 nm) Mass: found peak 537.1 (M+l) at 2.262 min.

[0360] Step 6. Synthesis of 4-[(7S,8aS)-2-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin- 7-yl]morpholine (Compound 8).

[0361] To a solution of [(7R,8aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- 3,4,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-7-yl] 4-methylbenzenesulfonate (85 mg, 0.158 mmol) and DIPEA (102 mg, 0.792 mmol) in l-methylpyrrolidin-2-one (3 mL) was added morpholine (41.4 mg, 0.475 mmol). The reaction was treated with microwave reactor and stirred at 120 °C for Ih. The reaction was cooled to room temperature and directly purified by prep- HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4- [(7S,8aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-lH- pyrrolo[l,2-a]pyrazin-7-yl]morpholine (44.3 mg, yield 61.9%) as a yellow solid.

[0362] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column:X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50°C; LC purity: 100% (214 nm) Mass: found peak 452.1 (M+l) at 2.054 min. ‘H NMR (400 MHz, CD3OD) 5 7.59-7.54 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 5.86 (s, 1H), 3.81 (dd, J = 12.0, 2.0 Hz, 1H), 3.71 (t, J = 4.4 Hz, 4H), 3.67-3.61 (m, 1H), 3.21 (dd, J = 10.4, 2.4 Hz, 1H), 3.07-2.98 (m, 2H), 2.92 (qd, J = 11.6, 3.2 Hz, 1H), 2.62 (dd, J = 11.2, 10.8 Hz, 1H), 2.54 (t, J = 4.0 Hz, 4H), 2.40-2.27 (m, 6H), 2.10- 2.02 (m, 1H), 1.59-1.49 (m, 1H) ppm.Example S9. Synthesis of 4-[2-[3-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]- 3, 6-diazabicyclo [3.1.1] heptan-6-yl] ethyl] morpholine (Compound 9).

[0363] Compound 9 was prepared as outlined below.

[0364] Step 1. Synthesis of tert-butyl 3-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate.

[0365] To a solution of 3-bromo-5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazole (100 mg, 0.31mmol), sodium t-butoxide (90 mg, 0.93 mmol), methanesulfonato (2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'-amino-l,l'-biphenyl-2-yl)palladium(II) (25 mg, 0.031 mmol) in 1,4-dioxane (6 mL) was added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (93 mg, 0.47 mmol). The reaction was stirred at 100 °C in tube for 16h. The mixture was then filtered and the filtrate was washed with water (10 mL) and extracted by EtOAc (10 mL X 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give tert-butyl 3-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate (75 mg, 54.9% yield) as a yellow oil.

[0366] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C. LC purity: 76 % (214 nm); Mass: found peak 439.3 (M + H) at 2.16 min.

[0367] Step 2. Synthesis of 3-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-3, 6-diazabicyclo-[3.1.1]-heptane.

[0368] To a solution of tert-butyl 3-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]- 3, 6- diazabicyclo-[3.1.1]-heptane-6-carboxylate (75 mg, 0.171 mmol) in dichloromethane (6 mL) was added TFA (2.5mL). The reaction mixture was stirred at room temperature for Ih. The mixture was neutralized with saturated potassium carbonate solution (5 mL) and extracted with dichloromethane (10 mL X 3). Combined DCM layers were dried over sodium sulfate and filtered. The filtrate was concentrated to dryness to give 3-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-3, 6-diazabicyclo-[3.1.1]-heptane (57 mg, crude) as a yellow oil.

[0369] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 78 % (214 nm); Mass: found peak 339.2 (M + H) at 1.55 min.

[0370] Step 3. Synthesis of 4-[2-[3-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl]-3, 6-diazabicyclo [3.1.1] heptan-6-yl] ethyl] morpholine (Compound 9).

[0371] To a solution of 3-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-3, 6- diazabicyclo [3.1.1] heptane (57 mg, 0.168 mmol), potassium carbonate (70 mg, 0.505 mmol) and KI (28 mg, 0.168 mmol) in 95% ethanol / water (5 mL / 0.5 mL) was added 4-(2- chloroethyl) morpholine (38 mg, 0.253 mmol). The reaction mixture was stirred at 90 °C for 16h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[3-[5-methyl-l-[4- (trifluorom ethoxy) phenyl] pyrazol-3-yl]-3, 6-diazabicyclo [3.1.1] heptan-6-yl] ethyl] morpholine (47.8 mg, yield: 62.8%) as a yellow oil.

[0372] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 99 % (214 nm); Mass: found peak 452.2 (M + H) at 2.00 min.

[0373] 'H NMR (400 MHz, CD3OD): 5 7.60-7.56 (m, 2H), 7.40 (d, J = 8.4 Hz, 2H), 5.76 (s, 1H), 3.76 (d, J = 5.6 Hz, 2H), 3.69-3.61 (m, 6H), 3.39 (d, J = 11.6 Hz, 2H), 2.65 (t, J = 7.2 Hz, 3H), 2.51-2.42 (m, 6H), 2.30 (s, 3H), 1.73 (d, J = 8.4 Hz, 1H) ppm.Example S10. Synthesis of 4-[2-[5-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]- 2, 5-diazabicyclo [2.2.1] heptan-2-yl] ethyl] morpholine (Compound 10).

[0374] Compound 10 was prepared as outlined below.

[0375] Step 1. Synthesis of 4-[2-[5-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl] -2, 5-diazabicyclo [2.2.1] heptan-2-yl] ethyl] morpholine.

[0376] To a solution of 3-bromo-5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazole (100 mg, 0.31mmol), sodium t-butoxide (90 mg, 0.93 mmol), methanesulfonato(2-di-t-butylphosphino- 2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-amino-l,r-biphenyl-2-yl)palladium(II) (25 mg, 0.031 mmol) in 1,4-dioxane (4 mL) was added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (93 mg, 0.47 mmol). The reaction was stirred at 100 °C in tube for 16h. The reaction mixture was filtered, and the filtrate was washed with water (10 mL) and extracted by EtOAc (10 mL X 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 4-[2-[5-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-2,5- diazabicyclo [2.2.1] heptan-2-yl] ethyl] morpholine (120 mg, 85.3% yield

[0377] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C. LC purity: 100 % (214 nm); Mass: found peak 439.3 (M + H) at 2.15 min.

[0378] Step 2. Synthesis of 2-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-2, 5-diazabicyclo [2.2.1] heptane.

[0379] To a solution of tert-butyl 5-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]- 2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (120 mg, 0.274 mmol) in dichloromethane (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for Ih. The mixture was neutralized with saturated potassium carbonate solution (5 mL) and extracted with dichloromethane (10 mL X 3). Combined DCM layers were dried over sodium sulfate and filtered. The filtrate was concentrated to dryness to give 2-[5-methyl-l-[4-(trifluoromethoxy)phenyl] pyrazol-3-yl]-2, 5-diazabicyclo [2.2.1] heptane (92 mg, crude). The crude is used directly in the next step.

[0380] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column:X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 93 % (214 nm);Mass: found peak 339.1 (M + H) at 1.94 min.

[0381] Step 3. Synthesis of 4-[2-[5-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl]-2, 5-diazabicyclo [2.2.1] heptan-2-yl] ethyl] morpholine (Compound 10).

[0382] To a solution of 2-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-2, 5- diazabicyclo [2.2.1] heptane (92 mg, 0.27 mmol), potassium carbonate (113 mg, 0.816 mmol) and KI (45 mg, 0.27 mmol) in 95% ethanol / water (5 mL / 0.5 mL) was added 4-(2-chloroethyl) morpholine (61 mg, 0.408 mmol). The reaction was stirred at 90 °C for 16h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[5-[5-methyl-l-[4-(trifhioromethoxy) phenyl] pyrazol-3-yl]-2, 5- diazabicyclo [2.2.1] heptan-2-yl] ethyl] morpholine (83.5 mg, yield 68%) as a yellow oil.

[0383] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN; Gradient: 10% increase to 95%B within 1.5min; Flow Rate: 1.8 mL / min; Column: X- Bridge: C18, 3.5pm, 4.6*50mm; Column Temperature: 50 °C; LC purity: 99 % (214 nm); Mass: found peak 452.1 (M + H) at 1.92 min.

[0384] 'H NMR (400 MHz, CD3OD): 5 7.54-7.58 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.72 (s, 1H), 4.18 (s, 1H), 3.69 (t, J = 4.4 Hz, 5H), 3.51 (d, J = 10.0 Hz, 1H), 3.35 (d, J = 2.0 Hz, 1H), 2.96 (t, J = 8.4 Hz, 1H), 2.77 (t, J = 7.6 Hz, 3H), 2.48-2.52 (m, 6H), 2.30 (s, 3H), 1.94 (dd, J = 20 Hz, 9.6 Hz, 2H) ppm.Example Sil. Synthesis of 4-[2-[4-[l-(2, 2-difluoro-l,3-benzodioxol-5-yl)-5-isopropyl- pyrazol-3-yl] piperazin-l-yl] ethyl] morpholine (Compound 11).

[0385] Compound 11 was prepared as outlined below.

[0386] Step 1. Synthesis of 3,5-dibromo-l-(2, 2-difluoro-l, 3-benzodioxol-5-yl) pyrazole.

[0387] To a solution of 3,5-dibromo-lH-pyrazole (0.2 g, 0.885 mmol) in dichloromethane (10 mL) was added (2,2-difluoro-l,3-benzodioxol-5-yl) boronic acid (215 mg, 1.06 mmol), anhydrous copper acetate (482 mg, 2.66 mmol), pyridine (0.356 mL, 4.43 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 16h. The mixture was filtered. The filtrate was purified by silica column chromatography (petroleum ether: ethyl acetate = 10 / 1) to afford the desired product 3, 5-dibromo-l-(2, 2-difluoro-l, 3-benzodioxol-5- yl) pyrazole (338 mg, yield: 93%) as a yellow oil.

[0388] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: 5% increase to 95%B in 1.0 min; Flow Rate: 2.2 mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C. LC purity: 93 % (214 nm); Mass: found peak 382.9 (M + H) at 1.48 min.

[0389] Step 2. Synthesis of 3-bromo-l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5-isopropenyl- pyrazole.

[0390] To a solution of 3,5-dibromo-l-(2,2-difluoro-l,3-benzodioxol-5-yl) pyrazole (338 mg, 0.82 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (124 mg, 0.741 mmol) in 1,4-dioxane (5 mL) was added Sodium carbonate (174 mg, 1.65 mmol) and PdC12(dppf) dichloromethane complex (67.2 mg, 0.082 mmol) under argon atmosphere. The reaction mixture was stirred at 80 °C for 16h. The mixture was filtered. The filtrate was purified by flash chromatography (Biotage, 25g silica gel column @40mL / min, eluting with 30% ethyl acetate in petroleum ether) to afford the desired product 3-bromo-l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)- 5-isopropenyl-pyrazole (91 mg, yield: 29.6%) as a colorless oil.

[0391] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN; Gradient: 10% increase to 95%B within 1.5min; Flow Rate: 1.8 mL / min; Column: X- Bridge: C18, 3.5pm, 4.6*50mm; Column Temperature: 50 °C; LC purity: 92 % (214 nm); Mass: found peak 343.0 (M + H) at 2.25 min.

[0392] Step 3. Synthesis of 3-bromo-l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5-isopropyl- pyrazole.

[0393] To a solution of 3-bromo-l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5-isopropenyl- pyrazole (91 mg, 0.24 mmol) in 2 mL THF was added platinum dioxide (10 mg) in one portion. The mixture was stirred at room temperature under H2 atmosphere for Ih. The mixture was filtered, and the filtrate was concentrated to dryness to give 3 -bromo- 1 -(2, 2-difluoro-l, 3- benzodioxol-5-yl)-5-isopropyl-pyrazole (91 mg, crude). The crude was used directly in the next step without purification.

[0394] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 85 % (214 nm); Mass: found peak 345.0(M + H) at 2.27 min.

[0395] Step 4. Synthesis of tert-butyl 4-[l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5- isopropyl-pyrazol-3-yl] piperazine-l-carboxylate.

[0396] Under argon atmosphere, a mixture of 3-bromo-l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)- 5-isopropyl-pyrazole (91 mg, 0.26 mmol), tert-butyl piperazine- 1 -carboxylate (98 mg, 0.53 mmol), Pd PEPPSI-IPENT (10 mg, 0.01 mmol) and sodipm; 2-methylpropan-2-olate (76 mg, 0.79 mmol) in THF (2 mL) in a sealed tube was stirred at 60 °C for 16h. Then concentrated and purified by SGC (petroleum ether: ethyl acetate = 1 : 1) to afford the product tert-butyl 4-[l-(2,2-difluoro-l, 3-benzodioxol-5-yl)-5-isopropyl-pyrazol-3-yl] piperazine- 1 -carboxylate (61 mg, 43.7%) as a yellow solid.

[0397] LCMS method: Column: HALO C18 2.7pm 4.6*30mm. Mobile phase: Water (0.01%TFA) (A) / ACN (0.01% TFA) (B). Elution program: Gradient from 5 to 95% of B in l.Omin at 2.2 mL / min. Temperature: 40°C. LC purity: 85% (214 nm), Mass: found peak 451.3 (M+l) at 1.55 min.

[0398] Step 5. Synthesis of l-[l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5-isopropyl-pyrazol-3-yl] piperazine.

[0399] To a solution of tert-butyl 4-[l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5-isopropyl- pyrazol-3-yl] piperazine-l-carboxylate (104 mg, 0.22 mmol) in dichloromethane (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for Ih. The mixture was neutralized with saturated potassium carbonate solution (5 mL) and extracted with dichloromethane (10 mL X 3). Combined DCM layers were dried over sodium sulfate and filtered. The filtrate was concentrated to dryness to give 1 -[ 1 -(2, 2-difluoro-l, 3-benzodioxol-5- yl)-5-isopropyl-pyrazol-3-yl] piperazine (78 mg, crude). The crude was used directly in the next step.

[0400] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column:X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 89 % (214 nm);Mass: found peak 351.1 (M + H) at 2.11 min.

[0401] Step 6. Synthesis of 4-[2-[4-[l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5-isopropyl- pyrazol-3-yl] piperazin-l-yl] ethyl] morpholine (Compound 11).

[0402] To a solution of 1 -[ l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5-isopropyl-pyrazol-3-yl] piperazine (78 mg, 0.22 mmol), potassium carbonate (154 mg, 1.11 mmol) and KI (37 mg, 0.22 mmol) in ethanol / water (5 mL / 0.5 mL) was added 4-(2-chloroethyl) morpholine (50 mg, 0.33 mmol). The reaction was stirred at 90 °C for 16h, then cooled down and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[4-[l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)- 5-isopropyl-pyrazol-3-yl] piperazin-l-yl] ethyl]morpholine (63 mg, yield 61.1%) as a yellow solid.

[0403] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN; Gradient: 10% increase to 95%B within 1.5min; Flow Rate: 1.8 mL / min; Column: X- Bridge: C18, 3.5pm, 4.6*50mm; Column Temperature: 50 °C; LC purity: 100 % (214 nm); Mass: found peak 464.1 (M + H) at 2.05 min.

[0404] 'H NMR (400 MHz, CD3OD): 5 7.34 (dd, J = 4.0 Hz, 1.6 Hz, 2H), 7.22 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 5.88 (s, 1H), 3.72 (t, J = 4.4 Hz, 4H), 3.26 (t, J = 4.4 Hz, 4H), 2.91-2.98 (m, 1H), 2.69 (t, J = 4.8 Hz, 4H), 2.62-2.65 (m, 4H), 2.56 (s, 4H), 1.20 (s, 3H), 1.18 (s, 3H) ppm.Example S12. Synthesis of 4-[2-[4-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]morpholine (Compound 12).Synthesis 1

[0405] Compound 12 was prepared as outlined below.

[0406] Step 1. Synthesis of tert-butyl 4-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol- 3-yl] piperazine-l-carboxylate.Boc

[0407] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl) piperazine-l-carboxylate (0.2 g, 0.75 mmol) in chloroform (10 mL) was added [4-(trifluoromethyl) phenyl] boronic acid (214 mg, 1.13 mmol), anhydrous copper acetate (273 mg, 1.5 mmol), pyridine (0.3 mL, 3.75 mmol) and molecular sieves 4 A. The reaction mixture was stirred at 40 °C for 16h. The mixture was filtered. The filtrate was purified by silica column chromatography (petroleum ether: ethyl acetate = 4 / 1) to afford the desired product tert-butyl 4-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazine-l-carboxylate (1.39 g, yield: 75.2%) as a yellow solid.

[0408] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 99 % (214 nm); Mass: found peak 411.1 (M + H) at 2.27 min.

[0409] Step 2. Synthesis of l-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazine.

[0410] To a solution of tert-butyl 4-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazine-l-carboxylate (1.39 g, 3.39 mmol) in dichloromethane (30 mL) was added 2, 2, 2- trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for Ih. The mixture was neutralized with saturated potassium carbonate solution (5 mL) and extracted with dichloromethane (10 mL X 3). Combined DCM layers were dried over sodium sulfate and filtered. The filtrate was concentrated to dryness to give l-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazine (1.05 g, crude). The crude was used directly in the next step.

[0411] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA);Gradient: 5% increase to 95%B in 1.0 min; Flow Rate: 2.2 mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C. LC purity: 84% (214 nm) Mass: found peak 311.3 (M+l) + at 0.99 min.

[0412] Step 3. Synthesis of 4-[2-[4-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazin-l-yl] ethyl] morpholine (Compound 12).

[0413] To a solution of l-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazine (1.05 g, 3.38 mmol), potassium carbonate (1.4 g, 10.2 mmol) and KI (0.562 g, 3.38 mmol) in 95% ethanol / water (90 mL / 10 mL) was added 4-(2-chloroethyl) morpholine (1.01 g, 6.77 mmol). The reaction was stirred at 95°C for 16h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[4-[5- methyl-l-[4-(trifluorom ethyl) phenyl] pyrazol-3-yl] piperazin-l-yl] ethyl] morpholine (1.04 g, yield: 72%) as a yellow solid.

[0414] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 99 % (214 nm); Mass: found peak 424.2 (M + H) at 2.01 min.

[0415] 'H NMR (400 MHz, CD3OD): 5 7.79 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 5.91 (s, 1H), 3.72 (t, J = 4.8 Hz, 4H), 3.29 (t, J = 4.8 Hz, 4H), 2.70 (t, J = 4.8 Hz, 4H), 2.63-2.65 (m, 4H), 2.56 (s, 4H), 2.38 (s, 3H) ppm.Synthesis 2

[0416] Compound 12 was prepared as outlined below.

[0417] Step 1. Synthesis of tert-butyl 4-(3-oxobutanoyl)piperazine-l-carboxylate.

[0418] To a solution of tert-butyl 3-oxobutanoate (11.2 g, 70.8 mmol) in toluene (150 mL) was added tert-butyl piperazine- 1 -carboxylate (12.0g, 64.4 mmol) and the mixture was stirred at 100°C overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 330 g silica gel column @100mL / min, eluting with 0-35% MeOH in DCM) to afford the desired product tert-butyl 4-(3- oxobutanoyl)piperazine-l -carboxylate (13.9 g, yield 72.6%) as a transparent oil.

[0419] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 215.1 (M-56)+ at 1.30 min.

[0420] Step 2. Synthesis of tert-butyl 4-(3-oxobutanethioyl)piperazine-l-carboxylate.Lawesson's reagent(0.5 eq) toluene, 75°c 16h

[0421] To a solution of tert-butyl 4-(3-oxobutanoyl)piperazine-l -carboxylate (16.9 g, 60.6 mmol) in toluene (200 mL) was added Lawesson's reagent (12.3 g, 30.3 mmol) and the mixture was heated at 75°C overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 330 g silica gel column @200mL / min, eluting with 10-65% ethyl acetate in petroleum ether for 8 CV) to afford tertbutyl 4-(3-oxobutanethioyl)piperazine-l -carboxylate (9.1g, yield 38.4%) as a brown oil.

[0422] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 73.32% (254 nm) Mass: found peak 287.0 (M+l) at 1.51 min.

[0423] Step 3. Synthesis of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl)piperazine-l- carboxylate.,

[0424] To a solution of tert-butyl 4-(3-oxobutanethioyl)piperazine-l -carboxylate (9.1 g, 23.3 mmol) in toluene (200 mL) was added hydrazine monohydrate (4.65 mL, 95.9 mmol) and the mixture was stirred at 70°C overnight. The mixture was cooled to room temperature andconcentrated in vacuo. The residue was purified by flash chromatography (Biotage, 120 g silica gel column @100mL / min, eluting with 0-6% MeOH in DCM) to afford the desired product tertbutyl 4-(5-methyl-lH-pyrazol-3-yl)piperazine-l-carboxylate (4.35 g, yield 69.0%) as a yellow solid.

[0425] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 73.32% (254 nm) Mass: found peak 287.0 (M+l) at 1.51 min. LC purity: 98.33% (254 nm) Mass: found peak 267.1 (M+l) at 1.33 min.

[0426] Step 4. Synthesis of tert-butyl 4-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl] piperazine-l-carboxylate.

[0427] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl)piperazine-l-carboxylate (5 g, 18.8 mmol) in chloroform (500 mL) was added [4-(trifluoromethoxy)phenyl]boronic acid (7.28 g, 37.5 mmol), anhydrous copper acetate (6.82 g, 37.5 mmol), pyridine (7.42 g, 93.9 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 24h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 25 g silica gel column @70mL / min, eluting with 10-50% di chloromethane in petroleum ether) to afford the desired product tert-butyl 4-[5-methyl-l-[4- (trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-l -carboxylate (4.1 g, yield 53.2%) as a white solid.

[0428] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA);Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min;Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C. LC purity: 100% (214 nm) Mass: found peak 411.2 (M + 1) + at 2.258 min.

[0429] Step 5. Synthesis of l-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl] piperazine.I l l

[0430] To a solution of tert-butyl 4-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl]piperazine-l -carboxylate (2.6 g, 6.33 mmol) in dichloromethane (20 mL) was added 2,2,2- trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for Ih. The reaction mixture was concentrated in vacuo. The residue was diluted with water (5 mL), neutralized with potassium carbonate to pH=8, extracted with dichloromethane (5 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo to afford l-[5-methyl-l-[4- (trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (2.1 g, crude). The crude product was used directely in the next step.

[0431] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min;Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C. LC purity: 100% (214 nm) Mass: found peak 311.2 (M + 1) + at 1.663 min.

[0432] Step 6. Synthesis of 4-[2-[4-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]morpholine (Compound 12).

[0433] To a solution of l-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (3.4 g, 11 mmol), potassium carbonate (7.57 g, 54.8 mmol) and KI (1.82 g, 11 mmol) in 95% ethanol (30 mL) was added 4-(2-chloroethyl)morpholine (2.4 g, 16.4 mmol). The reaction was stirred at 95 °C for 16h. The reaction was cooled to room temperature, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[4-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]morpholine (2.16 g, yield: 46.6%) as a white solid.

[0434] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 99.56 % (214 nm); Mass: found peak 424.2 (M + H) at 1.790 min.

[0435] 'H NMR (400 MHz, CDCh) 5 7.67 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 5.73 (s, 1H), 3.77-3.54 (m, 4H), 3.36-3.19 (m, 4H), 2.66-2.59 (m, 4H), 2.57 (s, 4H), 2.50 (s, 4H), 2.36 (s, 3H) ppm.Example S13. Synthesis of 4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl] cyclohexoxy] ethyl] morpholine (Compound 13).

[0436] Compound 13 was prepared as outlined below.

[0437] Step 1. Synthesis of tert-butyl 4-(2-morpholinoethoxy) piperidine-l-carboxylate.Boc

[0438] To a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (1.0 g, 5 mmol) in THF (20 mL) was added sodium hydride (1.19 g, 50 mmol). The reaction mixture was stirred at room temperature for 2h. Then N-(2-Chloroethyl) morpholine hydrochloride (925 mg, 5 mmol) was added. The mixture was stirred at reflux overnight. The mixture was purified by prep-HPLC (ammonium hydrogen carbonate) to afford the desired product tert-butyl 4-(2- morpholinoethoxy) piperidine-l-carboxylate (500 mg, yield: 32%) as a white solid.

[0439] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 95% (214 nm), Mass: found peak 315.2 (M+l) at 1.861 min.

[0440] Step 2. Synthesis of 4- [2-(4-piperidyloxy)ethyl] morpholine.

[0441] To a solution of tert-butyl 4-(2-morpholinoethoxy) piperidine-l-carboxylate (500 mg, 1.59 mmol) in 1,4-dioxane (10 mL) was added HC1 (8 mL, 4 mol / L in dioxane). The mixture was stirred for 3h at room temperature. The residue was concentrated to afford the desired product 4-[2-(4-piperidyloxy)ethyl]morpholine (300 mg, yield 88%) as a yellow oil.

[0442] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 99% (214 nm), Mass: found peak 215.1 (M+l) at 0.179 min.

[0443] Step 3. Synthesis of 4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl] cyclohexoxy] ethyl] morpholine (Compound 13).

[0444] To a solution of 3-iodo-5-methyl-l-[4-(trifluoromethoxy) phenyl]pyrazole (50 mg, 0.13 mmol) in dry 1,4-dioxane (3 mL) was added 4-[2-(4-piperidyloxy)ethyl]morpholine (58 mg, 0.27 mmol), Pd-PEPPSI-ipent (10.7 mg, 0.01 mmol), sodium tert-butoxide (39 mg, 0.4 mmol) in a microwave tube. The reaction mixture was stirred at 100 °C for 24h. The mixture was filtered. The filtrate was purified by prep-HPLC (ammonium hydrogen carbonate) to afford the desired product 4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl]cyclohexoxy] ethyl]morpholine (11.7 mg, yield 19%) as a colorless oil.

[0445] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 98% (214 nm), Mass: found peak 455.2 (M+l) at 2.108 min.

[0446] 'H NMR (400 MHz, MeOD-d4) 5 7.59-7.50 (m, 2H), 7.42-7.35 (m, 2H), 5.83 (d, J = 0.4 Hz, 1H), 3.68 (dt, J = 9.6, 5.2 Hz, 6H), 3.60-3.44 (m, 3H), 2.95 (ddd, J = 12.8, 9.6, 3.2 Hz, 2H), 2.60 (t, J = 5.6 Hz, 2H), 2.56 (d, J = 4.2 Hz, 4H), 2.33-2.22 (m, 3H), 2.03-1.90 (m, 2H), 1.69-1.55 (m, 2H) ppm.Example S14. Synthesis of l-[5-methyl-l-[4 (trifluoromethoxy) phenyl]pyrazol-3-yl]-4-(l- tetrahydropyran-4-ylazetidin-3-yl)oxy-piperidine (Compound 14).

[0447] Compound 14 was prepared as outlined below.

[0448] Step 1. Synthesis of tert-butyl 3-(4-pyridyloxy)azetidine-l-carboxylate.,

[0449] A mixture of pyridin-4-ol (0.824 g, 8.66 mmol), tert-butyl 3-hydroxyazetidine-l- carboxylate (1.0 g 5.77 mmol), triphenylphosphine (1.82 g, 6.93 mmol) and diisopropylazodicarboxylate (1.4 g, 6.93 mmol) in THF (20 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 50°C for 16h under nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a reside, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=20 / l to 5 / 1) to afford the desired product tertbutyl 3 -(4-pyridyloxy)azetidine-l -carboxylate (500 mg, 34.6%).

[0450] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 70% (214 nm), Mass: found peak 251.2 (M+l) at 0.871 min.

[0451] Step 2. Synthesis of tert-butyl 3-(4-piperidyloxy)azetidine-l-carboxylate.

[0452] Under hydrogen atmosphere, a mixture of tert-butyl 3-(4-pyridyloxy)azetidine-l- carboxylate (500 mg, 2 mmol), platinum dioxide (200 mg, 40%w / w), p-toluenesulfonic acid (688 mg, 4 mmol) in ethanol (30 mL) was stirred overnight. Then the mixture was filtered, and concentrated to afford the desired product tert-butyl 3 -(4-piperidyloxy)azetidine-l -carboxylate (400 mg, 78.1%) as a yellow oil.

[0453] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 50% (214 nm), Mass: found peak 257.4 (M+l) at 0.87 min.

[0454] Step 3. Synthesis of tert-butyl 3-[[l-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-4-piperidyl] oxy] azetidine-l-carboxylate.

[0455] Under argon atmosphere, a mixture of 3-bromo-5-methyl-l-[4- (trifluoromethoxy)phenyl] pyrazole (300 mg, 0.92 mmol), tert-butyl 3-(4- piperidyloxy)azetidine-l -carboxylate (471 mg, 1.84 mmol), Pd-PEPPSI-IPent catalyst (26.8 mg, 2.76e-5 mol) and sodium tert-butoxide (442 mg, 4.6 mmol) in anhydrous THF (10 mL) in a sealed tube was stirred at 60 °C for 16h. Then the mixture was concentrated and purified by SGC (petroleum ether: ethyl acetate =2: 1) to afford the desired product (160 mg, 35.1%)

[0456] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 98% (214 nm), Mass: found peak 497.3 (M+l) at 2.293 min.

[0457] Step 4. Synthesis of 4-(azetidin-3-yloxy)-l-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl] piperidine.

[0458] To a solution of tert-butyl 3-[[l-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl]-4-piperidyl] oxy] azetidine- 1 -carboxylate (160 mg, 0.3 mmol) in dichloromethane (10 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 2h, then concentrated to remove solvent, and potassium carbonate was added to pH=10. The product was extracted with DCM and dried over sodium sulfate. The organic layer was concentrated to afford the desired product 4-(azetidin-3-yloxy)-l-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl] piperidine (127 mg, yield 99.4 %) as a yellow oil.

[0459] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 86% (214 nm), Mass: found peak 397.2 (M+l) at 1.075 min.

[0460] Step 5. Synthesis of l-[5-methyl-l-[4 (trifluoromethoxy) phenyl]pyrazol-3-yl]-4-(l- tetrahydropyran-4-ylazetidin-3-yl)oxy-piperidine (Compound 14).

[0461] To a solution of 4-(azetidin-3-yloxy)-l-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl] piperidine (127 mg, 0.32 mmol) in methanol (10 mL) was added tetrahydropyran- 4-one (64.1 mg, 0.64 mmol), sodium triacetoxyborohydride (204 mg, 0.96 mmol), acetic acid (0.2 mL, 0.22 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 24h. The mixture was filtered. The filtrate was purified by prep-HPLC (ammonium hydrogen carbonate) to afford the desired product l-[5-methyl-l-[4 (trifluoromethoxy) phenyl]pyrazol-3-yl]-4-(l-tetrahydropyran-4-ylazetidin-3-yl)oxy-piperidine (96.5 mg, yield 62.7 %) as a yellow oil.

[0462] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 99% (214 nm), Mass: found peak 481.2 (M+l) at 2.096 min.

[0463] 'H NMR (400 MHz, MeOD-d4) 5 7.56 (d, J = 9.2 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 5.85 (s, 1H), 4.34-4.24 (m, 1H), 3.95 (d, J = 9.6 Hz, 2H), 3.67 (dd, J = 8.4, 6.4 Hz, 2H), 3.57 (d, J = 14.2 Hz, 3H), 3.43-3.37 (m, 2H), 3.03-2.91 (m, 4H), 2.39-2.27 (m, 4H), 1.92 (s, 2H), 1.73 (d, J = 11.2 Hz, 2H), 1.62 (d, J = 9.5 Hz, 2H), 1.37-1.19 (m, 2H) ppm.Example S15. Synthesis of 7-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-2- tetrahydropyran-4-yl-2,7-diazaspiro [3.5] nonane (Compound 15).

[0464] Compound 15 was prepared as outlined below.

[0465] Step 1. Synthesis of tert-butyl 7-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-2,7-diazaspiro [3.5] nonane-2-carboxylate.

[0466] To a solution of 3-iodo-5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazole(100 mg, 0.27 mmol) in dry 1,4-dioxane (3 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-2- carboxylate (61.5 mg, 0.27 mmol), methanesulfonate (2-di-t-butylphosphino-2',4',6'-tri-i-propyl- l,T-biphenyl)(2'-amino-l,r-biphenyl-2-yl)palladium(II) (21.6 mg, 0.027 mmol), and sodium tert-butoxide (78 mg, 0.81 mmol) in a microwave tube. The reaction mixture was stirred at 100 °C for 24h. The mixture was filtered. The reaction mixture was purified by SGC (PE: EA= 1 : 1) to afford the desired product tert-butyl 7-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl]-2,7-diazaspiro [3.5] nonane-2-carboxylate (80 mg, yield: 63.1%) as a yellow oil. LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 76% (214 nm), Mass: found peak 467.3 (M+l) at 1.510 min.

[0467] Step 2. Synthesis of tert-butyl 2,2-dimethyl-4-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]piperazine-l-carboxylate.

[0468] A solution of tert-butyl 7-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-2,7- diazaspiro [3.5] nonane-2-carboxylate (80 mg, 0.27 mmol) in dichloromethane (10 mL) was stirred for 2h. The mixture was concentrated to remove solvent, and potassium carbonate was added to pH=10. It was extracted with DCM and dried over sodium sulfate. It was concentrated in vacuo to afford the desired product tert-butyl 2,2-dimethyl-4-[5-methyl-l-[4- (trifluoromethoxy) phenyl] pyrazol-3-yl]piperazine-l -carboxylate (60 mg, yield 92.8 %) as a yellow oil.

[0469] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 66% (214 nm), Mass: found peak 367.3 (M+l) at 1.077 min.

[0470] Step 3. Synthesis of 7-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-2- tetrahydropyran-4-yl-2,7-diazaspiro [3.5] nonane (Compound 15).

[0471] To a solution of 7-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]-2,7- diazaspiro [3.5] nonane (80 mg, 0.22mmol) in 1,2-di chloroethane (5 mL) was added tetrahydropyran-4-one (22 mg, 0.22 mmol), sodium triacetoxyborohydride (139 mg, 0.65 mmol), acetic acid (0.01 mL, 0.22 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 24h. The mixture was filtered. The filtrate was purified by prep- HPLC (ammonium hydrogen carbonate) to afford the desired product 7-[5-methyl-l-[4- (trifluoromethoxy) phenyl] pyrazol-3-yl]-2-tetrahydropyran-4-yl-2,7-diazaspiro [3.5] nonane (33.5 mg, yield 34.1%) as a yellow solid.

[0472] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 93% (214 nm), Mass: found peak 451.2 (M+l) at 2.144 min.

[0473] 'H NMR (400 MHz, MeOD-d4) 5 7.54 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H),5.84 (s, 1H), 3.97 (d, J = 9.6 Hz, 2H), 3.38 (t, J = 11.6 Hz, 4H), 3.17 (d, J = 4.8 Hz, 6H), 2.67 (s,1H), 2.28 (s, 3H), 1.90-1.75 (m, 6H), 1.32 (d, J = 12.0 Hz, 2H) ppm.Example S16. Synthesis of 4-[2-[4-[5-isopropyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]morpholine (Compound 16).

[0474] Compound 16 was prepared as outlined below.

[0475] Step 1. Synthesis of 3,5-dibromo-l-[4-(trifluoromethoxy)phenyl] pyrazole.CHCI3, RT, o / n

[0476] Under argon atmosphere, a mixture of 3,5-dibromo-lH-pyrazole (200 mg, 0.88 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (365 mg, 1.77 mmol), copper acetate (322 mg, 1.77 mmol) and Pyridine (280 mg, 3.54 mmol) in chloroform (10 mL) was stirred at RT for 16h.Then the reaction mixture was concentrated and purified by SGC (PE:DCM = 2: 1) to afford the desired product 3,5-dibromo-l-[4-(trifluoromethoxy)phenyl] pyrazole (150 mg, 44%) as a colorless oil.

[0477] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 95% (214 nm); Mass: found peak 387.0 (M+l) at 1.493 min.

[0478] Step 2. Synthesis of 3-bromo-5-isopropenyl-l-[4- (trifluoromethoxy)phenyl]pyrazole.dioxane / H2O(10:1 )

[0479] Under argon atmosphere, a mixture of 3,5-dibromo-l-[4-(trifluoromethoxy)phenyl] pyrazole (150 mg, 0.382 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (64.3 mg, 0.382 mmol), l,l'-bis(diphenylphosphino) ferrocene-Palladium(II)dichloride dichloromethane complex (31.2 mg, 0.038 mmol) and sodium carbonate (38.5 mg, 0.4 mmol) in anhydrous dioxane / water (10 / 2 mL) was stirred at 80 °C for 16h. Then the reaction mixture was concentrated and purified by SGC (petroleum : ethyl acetate=l : 1) to afford the desired product 3- bromo-5-isopropenyl-l-[4-(trifluoromethoxy)phenyl]pyrazole (100 mg, 71.3%) as a colorless oil.

[0480] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 67% (214 nm); Mass: found peak 347.1 (M+l) at 1.511 min.

[0481] Step 3. Synthesis of 3-bromo-5-isopropyl-l-[4-(trifluoromethoxy)phenyl] pyrazole.

[0482] Under hydrogen atmosphere, a mixture of 3-bromo-5-isopropenyl-l-[4- (trifluoromethoxy)phenyl]pyrazole (90 mg, 0.01 mmol), PtO2 (30 mg, i / i, 30%) in THF (5 mL) was stirred at RT for 2h. Then the reaction mixture was filtered and concentrated to afford the desired product 3-bromo-5-isopropyl-l-[4-(trifluoromethoxy)phenyl] pyrazole (80 mg, 88%).

[0483] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN; Gradient: 5% increase to 95%B within 1.3min, 95%B for 1.7min; Flow Rate: 1.8 mL / min; Column: X-Bridge C18, 3.5pm, 4.6*50mm; Column Temperature: 50 °C; LC purity: 66% (214 nm) Mass: found peak 349.1 (M+l) at 2.089 min.

[0484] Step 4. Synthesis of tert-butyl 4-[5-isopropyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-l-carboxylate.BocTHF, 60°c, o / n

[0485] Under argon atmosphere, a mixture of 3-bromo-5-isopropyl-l-[4- (trifluoromethoxy)phenyl]pyrazole (80 mg, 0.22 mmol), tert-butyl 2,2-dimethylpiperazine-l- carboxylate(84 mg, 0.45 mmol), Pd PEPPSI IPENT (5 mg, 0.006 mmol) and sodium tert- butoxide (65 mg, 0.6 mmol) in anhydrous THF (2 mL) in a sealed tube was stirred at 60 °C for 16h. Then the reaction mixture was concentrated and purified by SGC (petroleum ether: ethyl acetate=l : 1) to afford the product tert-butyl 4-[5-isopropyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-l -carboxylate (50 mg, 46.2%) as a yellow solid.

[0486] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 100% (214 nm), Mass: found peak 455.3 (M+l) at 1.562 min.

[0487] Step 5. Synthesis of tert-butyl 4-[5-isopropyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-l-carboxylate.

[0488] To a solution of tert-butyl 4-[5-isopropyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazine-l -carboxylate (40 mg, 0.088 mmol) in di chloromethane (6 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2h. Then the reaction mixture was concentrated to remove solvent, and potassium carbonate was added to pH=10. The product was extracted with DCM and dried over sodium sulfate. The mixture was concentrated to afford the desired product tert-butyl 4-[5-isopropyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazine-l -carboxylate (35 mg, yield 70 %) as a yellow oil.

[0489] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm;Column Temperature: 40 °C; LC purity: 81% (214 nm), Mass: found peak 355.3 (M+l) at 1.072 min.

[0490] Step 6. Synthesis of 4-[2-[4-[5-isopropyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]morpholine (Compound 16).

[0491] To a solution of l-[5-isopropyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (30 mg, 0.084 mmol), potassium carbonate (58 mg, 0.42 mmol) and KI (14 mg, 0.084 mmol) in 95% ethanol (5 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (23 mg, 0.127 mmol). The reaction was stirred at 95 °C for 16h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford 4-[2-[4-[5-isopropyl- l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-l-yl]ethyl]morpholine (9.0 mg, yield 22.5%) as a yellow solid.

[0492] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate), B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 96% (214 nm), Mass: found peak 468.2 (M+l) at 2.115 min.

[0493] 'H NMR (400 MHz, MeOD-d4) 5 7.56-7.51 (m, 2H), 7.44 (d, J = 8.8 Hz, 2H), 5.90 (s, 1H), 3.78-3.66 (m, 4H), 3.28-3.20 (m, 4H), 2.98 (dt, J = 13.6, 6.8 Hz, 1H), 2.70-2.64 (m, 4H), 2.63-2.58 (m, 4H), 2.55 (s, 4H), 1.20 (d, J = 6.8 Hz, 6H) ppm.Example S17. Synthesis of l-imino-4-[2-[4-[5-methyl-l-[4-(tr ifluoromethoxy)phenyl] pyrazol-3-yl] piperazin- 1-yl] ethyl] - 1 ,4-t h iazina ne 1 -oxide (Compound 17).

[0494] Compound 17 was prepared as outlined below.

[0495] Step 1. Synthesis of tert-butyl thiomorpholine-4-carboxylate.

[0496] To a solution of thiomorpholine (500 mg, 4.85 mmol) and TEA (1.47 g, 14.6 mmol) in DCM (40 mL) was added di -tert-butyl di carb onate (1.27 g, 5.82 mmol). The reaction mixture was stirred at room temperature for 16h. The mixture was directly purified by flash chromatography (Biotage, 80g silica gel column @100mL / min, eluting with 3-45% ethyl acetate in petroleum ether) to afford the desired product tert-butyl thiomorpholine-4-carboxylate (927 mg, yield 94%) as a white solid.

[0497] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.3 min 95%B for 1.7min at 2.0 mL / min; Column: HALO C18 3.5pm 4.6*50mm; Column Temperature: 50 °C; LC purity: 97% (214 nm) Mass: found peak 226.3 (M+23) at 1.266min.

[0498] Step 2. Synthesis of tert-butyl l-oxo-l,4-thiazinane-4-carboxylate.

[0499] At 0 °C, to a solution of tert-butyl thiomorpholine-4-carboxylate (827 mg, 4.07 mmol) in 50 mL EtOAc, 25 mL MeOH and 25 mL water was added sodium periodate (870 mg, 4.07 mmol) portion wise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was diluted with brine, extracted with DCM (4*50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified via silica gel chromatography to afford the desired product tert-butyl l-oxo-l,4-thiazinane-4-carboxylate (800 mg, yield 89.7%) as a white solid. LCMS method: Mobile Phase: A: water (0.01% TFA) B: Acetonitrile (0.01% TFA); Gradient: from 5 to 95% of B in 1.3min 95%B for 1.7min at2.0mL / min; Column: HALO C18 3.5pm 4.6*50mm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 242.2 (M+23)+ at 0.934 min.

[0500] Step 3. Synthesis of tert-butyl 1-benzyloxy-carbonylimino- l-oxo-l,4-thiazinane-4- carboxylate.benzyl carbamate(2.5eq) rhodium(ll) acetate dimer(0.05eqMgO(4eq), DCMRT 48 h

[0501] A mixture of tert-butyl l-oxo-l,4-thiazinane-4-carboxylate (700 mg, 3.19 mmol), benzyl carbamate (1.21 g, 7.98 mmol), phenyl-13 -iodanediyl diacetate (2.06 g, 6.38 mmol), MgO (515 mg, 12.8 mmol), and [Rh(OAc)2]2 (70 mg, 0.160 mmol) in DCM (10 mL) was stirred at room temperature for 4 days. The reaction mixture was filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography to afford the desired product tert-butyl 1- benzyloxy-carbonylimino- l-oxo-l,4-thiazinane-4-carboxylate (620 mg, yield 52.7%) as a yellow solid.

[0502] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.3min 95%B for 1.7min at 2.0mL / min; Column: HALO C18 3.5pm 4.6*50mm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 369.2(M+1) at 1.250 min.

[0503] Step 4. Synthesis of benzyl N-(l-oxo-l,4-thiazinan-l-ylidene) carbamate.O N-Cbz

[0504] To a solution of tert-butyl 1 -benzyl oxy carbonylimino- 1 -oxo- l,4-thiazinane-4- carboxylate (620 mg, 1.68 mmol) in dichloromethane (20 mL) was added TFA (3 mL, 40.4 mmol). The reaction was stirred at room temperature for 4h. The reaction mixture was concentrated in vacuo to afford the desired product benzyl N-(l-oxo-l,4-thiazinan-l-ylidene) carbamate as TFA salt (660 mg, yield 100%) as a white solid.

[0505] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C; LC purity: 97.91% (214 nm), Mass: found peak 269.2 (M+l)+, at 0.867 min.

[0506] Step 5. Synthesis of benzyl N-[4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy)phenyl] pyrazol-3-yl]piperazin-l-yl]ethyl]-l-oxo-l,4-thiazinan-l-ylidene]carbamate.

[0507] A mixture of l-(2-chloroethyl)-4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazine (150 mg, 0.386 mmol), benzyl N-(l-oxo-l,4-thiazinan-l-ylidene)carbamate TFA salt (221 mg, 0.579 mmol) and DIPEA (249mg, 1.93 mmol) in NMP (3 mL) was treated with microwave reactor and stirred at 160°C for 3h. The reaction was cooled to room temperature and directly purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product benzyl N-[4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy)phenyl] pyrazol-3- yl]piperazin-l-yl]ethyl]-l-oxo-l,4-thiazinan-l-ylidene]carbamate (110 mg, yield 45.3%) as a white solid.

[0508] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 98.68% (214 nm) Mass: found peak 621.3 (M+l) at 1.148 min.

[0509] Step 6. Synthesis of l-imino-4-[2-[4-[5-methyl-l-[4-(tr ifluoromethoxy)phenyl] pyrazol-3-yl] piperazin- 1-yl] ethyl] - 1 ,4-t h iazina ne 1 -oxide (Compo

[0510] Under H2 atmosphere, a mixture of benzyl N-[4-[2-[4-[5-methyl-l-[4- (trifluorom ethoxy) phenyl]pyrazol-3-yl]piperazin- 1 -yl]ethyl]- 1 -oxo- 1 ,4-thiazinan- 1 - ylidene]carbamate (100 mg, 0.068 mmol) and Pd / C (10%, 20 mg) in methanol (50 mL) was stirred at room temperature for 3h. The reaction was filtered. The filtrate was concentrated in vacuo to afford the desired product l-imino-4-[2-[4-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-l-yl]ethyl]-l,4-thiazinane 1-oxide (67.3 mg, yield 85.9%) as a yellow solid.

[0511] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 487.1 (M+l) at 1.861 min.

[0512] 'H NMR (400 MHz, CD3OD) 5 7.57-7.52 (m, 2H), 7.39 (d, J = 8.8 Hz, 2H), 5.84 (s, 1H), 3.25 (t, J = 4.8 Hz, 4H), 3.20-2.94 (m, 8H), 2.74 (t, J = 6.4 Hz, 2H), 2.67 (t, J = 4.4 Hz, 4H), 2.61 (t, J = 6.4 Hz, 2H), 2.29 (s, 3H) ppm.Example S18. Synthesis of 9-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3- tetrahydropyran-4-yl-3-azaspiro[5.5] undecane (Compound 18).

[0513] Compound 18 was prepared as outlined below.

[0514] Step 1. Synthesis of tert-butyl 9-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl] oxy-3-azaspiro [5.5] undecane-3-carboxylate.

[0515] To a solution of 5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-ol (100 mg, 0.387 mmol), tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (209 mg, 0.775 mmol) and triphenylphosphane (203 mg, 0.775 mmol) in THF (15 mL) were add DIAD (157 mg, 0.775 mmol) at 0 °C. The reaction was stirred at RT under the protection of Argon for 16h. LCMS showed the reaction was complete. The mixture was concentrated and purified by flashchromatography (Biotage, 50 g silica gel column @80mL / min, eluting with 50%-100% ethyl acetate in petroleum ether for 30 min) to afford tert-butyl 9-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3-azaspiro[5.5]undecane-3-carboxylate (150 mg, 75.1%) as a colorless oil.

[0516] LCMS method: Column: X Bridge C18 (4.6x 50 mm, 3.5pm); Mobile phase: Water (10 mM ammonium hydrogen carbonate) (A) / ACN (B); Elution program: Gradient from 5% to 95% of B in 1.5 min at 1.5 mL / minTemperature: 50 °C; LC purity: 98.8% (214 nm) Mass: found peak 510.2 (M+l) at 2.441 min.

[0517] Step 2. Synthesis of 9-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy- 3-azaspiro [5.5] undecane.

[0518] To a solution of tert-butyl 9-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]oxy-3-azaspiro[5.5]undecane-3-carboxylate (30 mg, 0.0589 mmol) in dichloromethane (5 mL) was added TFA (336 mg, 1.18 mmol), The reaction mixture was stirred at RT for 2h. The mixture was concentrated and was diluted with DCM (50 mL). The organic mixture was washed with potassium carbonate (aq) and then aq NaCl solution. The organic layer was dried and concentrated to afford 9-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3- azaspiro[5.5]undecane (100 mg, 69.2%) as a colorless oil.

[0519] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN; Gradient: from 5% increase to 95%B within 1.4 min, 95%B for 1.6 min. Flow Rate: 1.8 mL / min; Column: X Bridge C18, 4.6*50mm, 3.5pm; Column Temperature: 45 °C; LC purity: 83.4% (214 nm) Mass: found peak 409.9 (M+l) at 1.845 min.

[0520] Step 3. Synthesis of 9-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy- 3-tetrahydropyran-4-yl-3-azaspiro[5.5] undecane (Compound 18).

[0521] To a solution of 9-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3- azaspiro[5.5]undecane (85 mg, 0.208 mmol), tetrahydropyran-4-one (41.6 mg, 0.415 mmol) andsodium triacetoxyborohydride (132 mg, 0.623 mmol) in 1,2-di chloroethane (10 mL) were add acetic acid (125 mg, 2.08 mmol). The reaction was stirred at RT for 16h. LCMS showed the reaction was complete. The mixture was concentrated and purified by prep-HPLC to afford 9-[5- methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3-tetrahydropyran-4-yl-3-azaspiro[5.5] undecane (16.5 mg, 14.6%) as a colorless oil.

[0522] LCMS method: Column: Sun fire, 50*4.6mm, 3.5pm; Mobile phase: A: Water (0.01%TFA) B: ACN (0.01%TFA); Elution program: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min Flow Rate: 2 mL / min; Temperature: 50°C; LC purity: 91.0% (214 nm) Mass: found peak 494.0 (M+l) at 1.650 min.

[0523] 'H NMR (400 MHz, CDCh) 5 7.46 (d, J = 9.2 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.65 (s, 1H), 4.53 (t, J = 4.4 Hz, 1H), 4.01 (t, J = 8.0, 2H), 3.37 (t, J = 11.2 Hz, 2H), 2.48-2.56 (m, 4H), 2.30 (s, 3H), 1.91 (d, J = 5.6 Hz, 2H), 1.81 (d, J = 11.2 Hz, 2H), 1.60-1.71 (m, 8H), 1.49 (s, 2H), 1.26 (d, J = 11.2 Hz, 3H).Example S19. Synthesis of 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-2- tetrahydropyran-4-yl-2-azaspiro[3.5] nonane (Compound 19).

[0524] Compound 19 was prepared as outlined below.

[0526] To a round bottom flask were add isopropyl 3-oxobutanoate (2.0 g, 13.9 mmol), hydrazine hydrochloride (998 mg, 14.6 mmol) and propan-2-ol (25 mL). The mixture was stirred at 90 °C for 16h, and LCMS showed the reaction was complete. The solution was concentrated and EtOAc (200 mL) was added to the mixture. The organic phase was washedwith IN solution of sodium hydrogen carbonate, dried over sodium sulfate and concentrated to dryness to afford 3-isopropoxy-5-methyl-lH-pyrazole (850mg, 38.5%) as a colorless oil.

[0527] LCMS method: Mobile Phase: Water (0.01%TFA) (A) / ACN (0.01%TFA) (B); Gradient: 5% to 95% of B in 1.0 min at 2.2 mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C; LC purity: 88.0% (214 nm) Mass: found peak 141.3 (M+l) at 0.963 min.

[0528] Step 2. Synthesis of 3-isopropoxy-5-methyl-l-[4-(trifluoromethoxy)phenyl].

[0529] A suspension 3-isopropoxy-5-methyl-lH-pyrazole (800 mg, 5.71 mmol), [4- (trifluoromethoxy)phenyl]boronic acid (3.53 g, 17.1 mmol), pyridine (2.26 g, 28.5 mmol), copper(II) acetate (3.11 mg, 17.1 mmol) in di chloromethane (50 mL) was stirred at RT for 48h under the protection of Argon. LCMS showed the reaction was complete, the mixture was filtered, and the filter cake was washed with di chloromethane (30 mL). The DCM solution was concentrated, and purified by flash chromatography (Biotage, 100 g silica gel column @100mL / min, eluting with 10%-60% ethyl acetate in petroleum ether for 30 min) to afford 3- isopropoxy-5-methyl-l-[4-(trifluoromethoxy)phenyl] (700 mg, 40.0%) as a colorless oil.

[0530] LCMS method: Mobile Phase: water (10 mM ammonium hydrogen carbonate) (A) / ACN (B); Gradient: from 5% to 95% of B ini.5 min at 1.5 mL / min; Column: X BRIGE C18 (4.6x 50 mm, 3.5pm); Column Temperature: 50 °C; LC purity: 98.0% (214 nm) Mass: found peak 301.1 (M+l) at 2.237 min.

[0531] Step 3. Synthesis of 5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-ol.

[0532] To a screw-cap vial were add 3-isopropoxy-5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazole (670 mg, 2.23 mmol), hydrogen bromide (3.61 g, 17.9 mmol) and acetic acid (3 mL). The reaction was stirred at 140 °C under the protection of Argonfor 3h. LCMS showed the reaction was complete. The mixture was concentrated and diluted with ethyl acetate (100 mL), which was washed with sodium bicarbonate solution and aq NaCl solution. Then the organic solution was concentrated and purified by flash chromatography (Biotage, 50 g silica gel column @90mL / min, eluting with 10%-30% EtOAc in PE for 30 min) to afford 5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-ol (430 mg, 73.4%) as awhite solid.

[0533] LCMS method: Column: HALO C18 2.7pm 4.6*30mm; Mobile phase: Water (0.01%TFA) (A) / ACN (0.01%TFA) (B); Elution program: Gradient from 5% to 95% of B in 1.0 min at 2.2 mL / min; Temperature: 40°C; LC purity: 98.4% (214 nm) Mass: found peak 259.2 (M+l) at 1.204 min.

[0534] Step 4. Synthesis of tert-butyl 9-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol- 3-yl] oxy-3-azaspiro [5.5] undecane-3-carboxylate.

[0535] To a solution of 5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-ol (30 mg, 0.116 mmol), tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (56.1 mg, 0.232 mmol) and triphenylphosphane (61 mg, 0.232 mmol) in THF (5 mL) were added DIAD (47 mg, 0.232 mmol) at 0 °C. The reaction was stirred at RT under the protection of Argon for 16h. LCMS showed the reaction was complete. The mixture was concentrated and which was purified by flash chromatography (Biotage, 50 g silica gel column @80mL / min to afford tert-butyl 9-[5- methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3-azaspiro[5.5]undecane-3-carboxylate (30 mg, 52.9%) as a colorless oil.

[0536] LCMS method: Column: X Bridge C18 (4.6x 50 mm, 3.5pm); Mobile phase: water (10 mM ammonium hydrogen carbonate) (A) / ACN (B); Elution program: Gradient from 5% to 95% of B ini.5 min at 1.5 mL / min. Temperature: 50 °C; LC purity: 98.7% (214 nm) Mass: found peak 426.1 (M-56+l)+ at 2.364 min.

[0537] Step 5. Synthesis of 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy- 2-azaspiro [3.5] nonane.

[0538] To a solution of tert-butyl 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]oxy-2-azaspiro[3.5]nonane-2-carboxylate (180 mg, 0.374 mmol) in dichloromethane (5 mL) was added TFA (852 mg, 0.748 mmol), The reaction mixture was stirred at RT for 2h. The mixture was concentrated, diluted with DCM (50mL) and washed with aq potassium carbonate. Then the solution was washed with aq NaCl solution, dried over sodium sulfate and concentrated to afford 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-2- azaspiro[3.5]nonane (110 mg, 69.6%) as a colorless oil.

[0539] LCMS method: Mobile Phase: water (10 mM ammonium hydrogen carbonate) (A) / ACN (B); Gradient: from 10% to 95% of B in 1.5 min at 1.8 mL / min; Column: X-BRIDGE Cl 8 (4.6x 50 mm, 3.5pm); Column Temperature: 50 °C; LC purity: 87.3% (214 nm) Mass: found peak 382.1 (M+l) at 1.907 min.

[0540] Step 6. Synthesis of 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-2-tetrahydropyran-4-yl-2-azaspiro[3.5] nonane (Compound 19).

[0541] To a suspension of 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-2- azaspiro[3.5]nonane (110 mg, 0.288 mmol), tetrahydropyran-4-one (57.8 mg, 0.577 mmol) and sodium triacetoxyborohydride (183 mg, 0.865 mmol) in 1,2-di chloroethane (10 mL) was added acetic acid (173 mg, 2.88 mmol). The reaction was stirred at RT for 16h. LCMS showed the reaction was complete. The mixture was concentrated and purified by prep-HPLC to afford 7-[5- methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-2-tetrahydropyran-4-yl-2-azaspiro[3.5] nonane (28.3 mg, 20.4%) as a colorless oil.

[0542] LCMS method: Column: Sun fire, 50*4.6mm, 3.5pm; Mobile phase: A: Water (0.01%TFA) B: ACN (0.01%TFA); Elution program: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min Flow Rate : 2 mL / min; Temperature: 50°C; LC purity: 97.0% (214 nm) Mass: found peak 466.0 (M+l) at 1.610 min.

[0543] 'H NMR (500 MHz, CDCh) 5 7.43-7.46 (m, 2H), 7.26-7.28 (m, 2H), 5.64 (s, 1H), 4.53 (d, J = 7.0 Hz, 1H), 3.94-3.97 (m, 2H), 3.33-3.38 (m, 2H), 2.97 (d, J = 19.5 Hz, 4H), 2.30 (s, 3H), 2.22 (d, J = 9.0 Hz, 1H), 1.96 (d, J = 10.0 Hz, 4H), 1.55-1.65 (m, 6H), 1.30-1.37 (m, 2H).Example S20. Synthesis of 2-[5-methyl-l-[4-(trifluoro-methoxy)phenyl]pyrazol-3-yl]oxy-7- tetrahydropyran-4-yl-7-azaspiro[3.5]nonane (Compound 20).

[0544] Compound 20 was prepared as outlined below.

[0545] Step 1. Synthesis of tert-butyl 2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol- 3-yl]oxy-7-azaspiro[3.5]nonane-7-carboxylate.

[0546] To a solution of 5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-ol (50 mg, 0.194 mmol), tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (93.5 mg, 0.387 mmol) and triphenylphosphine (102 mg, 0.387 mmol) in THF (8 mL) was added DIAD (78.3 mg, 0.387 mmol) at 0 °C. The reaction was stirred at RT under the protection of Argon for 16h. LCMS showed the reaction was complete. The mixture was concentrated and purified by flash chromatography (Biotage, 50 g silica gel column @70mL / min, eluting with 10%-60% ethyl acetate in petroleum ether for 30 min) to afford tert-butyl 2-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-7-azaspiro[3.5]nonane-7-carboxylate (30 mg, 14.8%) as a colorless oil.

[0547] LCMS method: Column: X-Bridge C18 (4.6x 50 mm, 3.5pm); Mobile phase: water (10 mM ammonium hydrogen carbonate) (A) / ACN (B); Elution program: Gradient from 10% to 95% of B in 1.5 min at 1.8 mL / min; Temperature: 50°C; LC purity: 92.3% (214 nm) Mass: found peak 426.1 (M-56+l)+ at 2.374 min.

[0548] Step 2. Synthesis of 2-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl]oxy- 7-azaspiro [3.5] nonane.

[0549] To a solution of tert-butyl 2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]oxy-7-azaspiro[3.5]nonane-7-carboxylate (40 mg, 0.0831 mmol) in dichloromethane (3 mL) was added TFA (189 mg, 1.66 mmol). The reaction mixture was stirred at RT for 2h. The mixture was concentrated, diluted with DCM (50 mL), washed with aq potassium carbonate. Then the solution was washed with aq NaCl solution, dried and concentrated to afford 2-[5- methyl-l-[4-(trifluorom ethoxy) phenyl]pyrazol-3-yl]oxy-7-azaspiro[3.5]nonane (20 mg, 32.8%) as a colorless oil.

[0550] LCMS method: Mobile Phase: water (10 mM ammonium hydrogen carbonate) (A) / ACN (B); Gradient: from 5% to 95% of B in 1.5 min at 1.5 mL / min; Column: X-BRIDGE Cl 8 (4.6x 50 mm, 3.5pm); Column Temperature: 50 °C; LC purity: 52.0% (214 nm) Mass: found peak 382.1 (M+l) at 2.086 min.

[0551] Step 3. Synthesis of 2-[5-methyl-l-[4-(trifluoro-methoxy)phenyl]pyrazol-3-yl]oxy-7-tetrahydropyran-4-yl-7-azaspiro [3.5] nonane (Compound 20).

[0552] To a suspension of 2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-7- azaspiro[3.5]nonane (20 mg, 0.0524 mmol), tetrahydropyran-4-one (10.5 mg, 0.105 mmol) and sodium triacetoxyborohydride (33.3 mg, 0.157 mmol) in 1,2-dichloroethane (5 mL) was add acetic acid (173 mg, 2.88 mmol). The reaction was stirred at RT for 48h. LCMS showed the reaction was complete. The mixture was concentrated and purified by prep-HPLC to afford 2-[5-methyl- l-[4-(trifluoro-methoxy)phenyl]pyrazol-3-yl]oxy-7-tetrahydropyran-4-yl-7- azaspiro[3.5]nonane (17.5 mg, 71.7%) as a colorless oil.

[0553] LCMS method: Column: X-BRIDGE Cl 8 (4.6x 50 mm, 3.5pm); Mobile phase: water (10 mM ammonium hydrogen carbonate) (A) / ACN (B); Elution program: Gradient from 10% to 95% of B in 1.5 min at 1.8 mL / min; Temperature: 50°C; LC purity: 100% (214 nm) Mass: found peak 466.1 (M+l) at 2.146 min.

[0554] 'H NMR (400 MHz, CD3OD) 5 7.54-7.56 (m, 2H), 7.43 (d, J = 8.4 Hz, 2H), 5.74 (s, 1H), 4.84 (t, J = 6.8 Hz, 1H), 3.98-4.02 (m, 2H), 3.40 (t, J = 7.6 Hz, 2H), 2.48-2.58 (m, 4H), 2.38-2.45 (m, 3H), 2.31 (s, 3H), 1.82-1.92 (m, 4H), 1.69 -1.72(m, 4H), 1.55-1.60 (m, 2H).Example S21. Synthesis of 4-[2-[4-[l-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl- pyrazol-3-yl]piperazin-l-yl]ethyl]morpholine (Compound 21).

[0555] Compound 21 was prepared as outlined below.

[0556] Step 1. Synthesis of tert-butyl 4-[l-[3-(difluoromethoxy)-4-fluoro-phenyl]-5- methyl-pyrazol-3-yl]piperazine-l-carboxylate.

[0557] A suspension of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl)piperazine-l-carboxylate (200 mg, 0.751 mmol), [3-(difluoromethoxy)-4-fluoro-phenyl]boronic acid (309 mg, 1.50 mmol), pyridine (297 mg, 3.75 mmol), copper(II) acetate (409 mg, 2.25 mmol) in chloroform (25 mL) was stirred at 40°C for 16h under the atmosphere of O2. LCMS showed the reaction was complete, the mixture was filtered, and the filter cake was washed with dichloromethane (50 mL), The filtrate was concentrated, and purified by flash chromatography (Biotage, 50 g silica gel column @80mL / min, eluting with 0%-40% ethyl acetate in petroleum ether for 30 min) to afford tert-butyl 4-[l-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazine- 1-carboxylate (190 mg, 59.3%) as a white solid.

[0558] LCMS method: Mobile Phase: water (10 mM ammonium hydrogen carbonate) (A) / ACN (B), Gradient: from 5% to 95% of B ini.5 min at 1.5 mL / min, Column: X Bridge C18 (4.6x 50 mm, 3.5pm), Column Temperature: 50 °C, LC purity: 100% (254 nm) Mass: found peak 427.1 (M+l) at 2.179 min.

[0559] Step 2. Synthesis of l-[l-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-pyrazol- 3-yl] piperazine.

[0560] To a solution of tert-butyl 4-[l-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl- pyrazol-3-yl]piperazine- 1-carboxylate (190 mg, 0.446 mmol) in dichloromethane (8 mL) was added TFA (508 mg, 4.46 mmol). The reaction mixture was stirred at RT for 2h. The mixture concentrated, diluted with DCM (50 mL) and washed with aq. potassium carbonate. Then the organic solution was washed with aq. NaCl solution, dried and concentrated to afford 1 -[ 1 -[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazine (110 mg, 56.4%) as a colorless oil.

[0561] LCMS method: Mobile Phase: Water (0.01%TFA) (A) / ACN (0.01%TFA) (B), Gradient: from 5% to 95% of B in 1.0 min at 2.2 mL / min, Column: HALO C18 2.7pm 4.6*30mm, Column Temperature: 40 °C, LC purity: 74.6% (214 nm) Mass: found peak 327.5 (M+l) at 0.954 min.

[0562] Step 3. Synthesis of 4-[2-[4-[l-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl- pyrazol-3-yl]piperazin-l-yl]ethyl]morpholine (Compound 21).

[0563] To a solution of l-[l-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-pyrazol-3- yl]piperazine (110 mg, 0.337 mmol) in ethanol / water (10 mL / 0.5 mL) were added 4-(2- chloroethyl)morpholine;hydrochloride (94.1 mg, 0.506 mmol), KI (56.0 mg, 0.337 mmol) and potassium carbonate (140 mg, 1.01 mmol). The reaction mixture was stirred at 90 °C for 16h under the protection of Argon, then the mixture was concentrated and diluted with methanol. The mixture was filtered, and the filter cake washed with MeOH (5 mL), then the filtrate was concentrated and purified by HPLC to afford 4-[2-[4-[l-[3-(difluoromethoxy)-4-fluoro-phenyl]- 5-methyl-pyrazol-3-yl]piperazin-l-yl]ethyl]morpholine (40.3 mg, yield 27.2% ) as a white solid.

[0564] LCMS method: Mobile Phase: WATER (10 mM ammonium hydrogen carbonate) (A) / ACN (B), Gradient: from 5% to 95% of B ini.5 min at 1.5 mL / min, Column: X Bridge C18 (4.6x 50 mm, 3.5pm), Column Temperature: 50 °C, LC purity: 100% (214 nm) Mass: found peak 440.2 (M+l) at 1.900 min.

[0565] 'H NMR (400 MHz, CDCh) 5 7.35 (dt, J = 2.4 Hz, 7.2 Hz, 1H), 7.28 (t, J = 1.2 Hz, 1H), 7.23 (dt, J = 9.6 Hz, 18.8 Hz, 1H), 6.40-6.76 (m, 1H), 3.69-3.74 (m, 8H), 5.68 (s, 1H), 3.71 (t, J = 4.4 Hz, 4H), 3.25 (t, J = 5.2 Hz, 4H), 2.61 (t, J = 4.8 Hz, 4H), 2.56 (dt, J = 4.8 Hz, 10.8 Hz, 4H), 2.50 (t, J = 4.0 Hz, 4H), 2.28 (s, 3H).Example S22. Synthesis of 5-[4-(2-morpholinoethyl)piperazin-l-yl]-2-[4- (trifluoromethoxy)phenyl] pyrazole-3-carbonitrile (Compound 22) and 5-[4-(2-morpholinoethyl)piperazin-l-yl]-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxamide (Compound a3).

[0566] Compounds 22 and a3 were prepared as outlined below.

[0567] Step 1. Synthesis of trimethyl-[2-(pyrazol-l-ylmethoxy)ethyl]silane.THF 0 C-RT, 16 h

[0568] Sodium hydride (1.29 g, 32.3 mmol) was added portion-wise to IH-pyrazole (2 g, 29.4 mmol) in THF (50 mL) at 21 °C over a period of 15 minutes. The resulting solution was stirred at 21 °C for 1 h. The mixture was cooled to 0 °C and (2-(chloromethoxy)ethyl)trimethylsilane (6.7 mL, 32.3 mmol) was added and the mixture was stirred for 16 h at room temperature. The reaction mixture was quenched by the addition of brine (150 mL) and extracted with EtOAc (3 x 100 mL). The organic phases were combined, dried over sodium sulfate and the volatiles removed under reduced pressure. Purification by flash chromatography 2-30% acetone in petroleum ether to afford trimethyl-[2-(pyrazol-l-ylmethoxy)ethyl]silane (360 mg, 61.0% yield) as a yellow solid.

[0569] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: 5% increase to 95%B in 1.0 min; Flow Rate: 2.2 mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C; LC purity: 96.47% (214 nm) Mass: found peak 199.2 (M+l) at 1.305 min.

[0570] Step 2. Synthesis of l-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carbonitrile.

[0571] Lithium magnesium 2,2,6,6-tetramethylpiperidin-l-ide dichloride (13.1 mL, 13.1 mmol) was added dropwise to trimethyl-[2-(pyrazol-l-ylmethoxy)ethyl]silane (2 g, 10.1 mmol) in THF (30 mL) at 21 °C under nitrogen. The resulting suspension was stirred at 21 °C for 1 h and then cooled to 5 °C. p-tolylsulfonyl-formonitrile (2.38 g, 13.1 mmol) was added and the mixture stirred for 45 minutes. The reaction was quenched by the addition of brine and extracted with EtOAc (200 mL). The organic layer was dried and concentrated in vacuo to crude material. The crude product was purified by flash silica chromatography, elution gradient 5 to 40% acetone in petroleum ether to afford l-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carbonitrile (1.5 g, 52.8%) as a colorless liquid.

[0572] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 66.12% (254 nm) Mass: found peak 199.0 (M+l) at 2.018 min.

[0573] Step 3. Synthesis of 5-iodo-2-(2-trimethylsilylethoxymethyl)pyrazole-3- carbonitrile. M (2 eq)(SEMh _ ^NC^_NCgH18CI2MgN.Li (1 .5 eq) THF, -16 °c, 2 h

[0574] Lithium magnesium 2,2,6,6-tetramethylpiperidin-l-ide dichloride (12.1 mL, 12.1 mmol) was added dropwise over 15 minutes to 2-(2 -trimethylsilylethoxymethyl) pyrazole-3- carbonitrile (1.8 g, 8.06 mmol) in THF (40 mL) at -16°C under nitrogen. The resulting solution was stirred at-16°C for 1 h. Iodine (818 mg, 3.22 mmol) was added and the mixture stirred for 1 h. The reaction was quenched by the addition of brine, extracted with EtOAc (2 x 100 mL), dried and concentrated in vacuo to crude material. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in isohexane. Pure fractions were concentrated in vacuo to dryness to afford ethyl 5-iodo-2-(2- trimethylsilylethoxymethyl)pyrazole-3-carbonitrile (1.8 g, 47.9%) as a colorless liquid.

[0575] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min;Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 61.34% (214 nm) Mass: found peak 470.1 (M+l) at 2.013 min.

[0576] Step 4. Synthesis of 3-iodo-lH-pyrazole-5-carbonitrile.

[0577] Under argon atmosphere, a mixture of 5-iodo-2-(2 -trimethylsilylethoxymethyl) pyrazole-3 -carbonitrile (2 g, 5.73 mmol) in anhydrous ethanol (15 mL) was treated with IN HC1 (15 mL). The mixture was stirred at 90 °C for 3h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL), neutralized with sodium bicarbonate to pH=8, extracted with EtOAc (100 mL*3), dried over sodium sulfate, filtered, and concentrated, then purified by flash chromatography 2-20% MeOH in DCM to afford 3-iodo-lH-pyrazole-5- carbonitrile (1.2 g, 77.5% yield) as a yellow solid.

[0578] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min;Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 80.97% (214 nm), Mass: found peak 220.0 (M+l) at 1.638 min.

[0579] Step 5. Synthesis of 5-iodo-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carbonitrile.

[0580] To a solution of 3-iodo-lH-pyrazole-5-carbonitrile (300 mg, 1.37 mmol) in dichloromethane (20 mL) was added [4-(trifluoromethoxy)phenyl]boronic acid (564 mg, 2.74 mmol), pyridine (542 mg, 6.85 mmol) and Copper (II) acetate (498 mg, 2.74 mmol). The reaction mixture was stirred at RT for 16h. The mixture was concentrated, finally purified by flash chromatography (Biotage, 40 g silica gel column @70 mL / min, eluting with 0-40% dichloromethane in petroleum ether for 30 min) to afford 5-iodo-2-[4- (trifluoromethoxy)phenyl]pyrazole-3-carbonitrile (310 mg, 50.6%) as a white solid.

[0581] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 84.72% (214 nm) Mass: found peak 380.0 (M+l) at 2.160 min.

[0582] Step 6. Synthesis of tert-butyl 4-[5-cyano-l-[4-(trifluoromethoxy)phenyl]indazol- 3-yl] piperazine- 1-carboxylate. p . (0.1 eq) Pd2(dba)3 Xantphosjf^Seq) Cs2CO3dioxane, 80uc, in tube

[0583] Under argon atmosphere, a mixture of 3-iodo-l-[4-(trifluoromethoxy)phenyl] indazole- 5-carbonitrile (50 mg, 0.132 mmol), tert-butyl piperazine- 1 -carboxylate (37 mg, 0.2 mmol), xantphos (15 mg, 0.026 mmol), Pd2(dba)3 (12 mg, 0.013 mmol) and cesium carbonate (130 mg, 0.4 mmol) in anhydrous 1,4-di oxane (3 mL) in a sealed tube was stirred at 80 °C for 16h, filtered, and concentrated, then purified by flash chromatography 0-20% ethyl acetate in petroleum ether to afford tert-butyl 4-[5-cyano-l-[4-(trifluoromethoxy)phenyl]indazol-3- yl]piperazine-l -carboxylate (40 mg, 55.7% yield) as a yellow oil.

[0584] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 80.28% (214 nm) Mass: found peak 382.2 (M-55)+at 2.297 min.

[0585] Step 7. Synthesis of 5-piperazin-l-yl-2-[4-(trifluoromethoxy)phenyl] pyrazole-3- carbonitrile.

[0586] To a solution of tert-butyl 4-[5-cyano-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazine-l -carboxylate (40 mg, 0.09 mmol) in di chloromethane (3 mL) was added TFA (0.3 mL). The reaction mixture was stirred at room temperature for Ih. The reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL), neutralized with potassium carbonate to pH=8, extracted with dichloromethane (10 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-piperazin-l-yl-2-[4-(trifluoromethoxy)phenyl] pyrazole-3 -carbonitrile (30 mg, yield 77.5%) as a yellow oil.

[0587] Gradient: 5% increase to 95%B in 1.0 min; Flow Rate: 2.2 mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C; LC purity: 79.68% (214 nm) Mass: found peak 338.2 (M+l) at 1.066 min.

[0588] Step 8. Synthesis of 5-[4-(2-morpholinoethyl)piperazin-l-yl]-2-[4- (trifluoromethoxy)phenyl] pyrazole-3-carbonitrile (Compound 22) and 5-[4-(2- morpholinoethyl)piperazin-l-yl]-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxamide (Compound a3).

[0589] To a solution of 5-piperazin-l-yl-2-[4-(trifluoromethoxy)phenyl]pyrazole-3- carbonitrile (25 mg, 0.074 mmol), potassium carbonate (52 mg, 0.37 mmol) and KI (12 mg, 0.074 mmol) in 95% ethanol (3 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (21 mg, 0.111 mmol). The reaction was stirred at 90 °C for 16h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford 5-[4-(2- morpholinoethyl)piperazin-l-yl]-2-[4-(trifluoromethoxy)phenyl] pyrazole-3 -carbonitrile (6.6 mg, yield 19.6%) as a white solid and 5-[4-(2-morpholinoethyl)piperazin-l-yl]-2-[4- (trifluoromethoxy)phenyl]pyrazole-3-carboxamide (6.6 mg, yield 11.9%) as a yellow oil.

[0590] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C.

[0591] Compound 22: LC purity: 99.07% (214 nm) Mass: found peak 451.1 (M+l) at 2.065 min. 'H NMR (400 MHz, MeOD-d4) 5 7.84-7.78 (m, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.75 (s, 1H), 3.70 (t, J = 4.8 Hz, 4H), 3.32 (t, J = 4.8 Hz, 4H), 2.65 (J = 4.8 Hz, 4H), 2.61-2.57 (m, 4H), 2.58 (t, J = 4.8 Hz, 4H) ppm.

[0592] Compound a3: LC purity: 93.82% (214 nm) Mass: found peak 468.9 (M+l) at 1.555 min.XH NMR (400 MHz, MeOD-d4) 5 7.54-7.50 (m, 2H), 7.35 (d, J= 8.5 Hz, 2H), 6.45 (s, 1H), 3.72(t, J=4.8 Hz, 4H), 3.32 (t, J=4.8 Hz, 4H), 2.68 (t, J = 4.8 Hz, 4H), 3.34-3.29 (m, 4H), 2.60 (t, J=4.8 Hz, 4H) ppm.Example S23. Synthesis of 4-[2-[4-[l-(2,2-difluoro-l,3-benzodioxol-5-yl)-5-methyl-pyrazol- 3-yl]piperazin-l-yl]ethyl]morpholine (Compound 23).Synthesis 1

[0593] Compound 23 was prepared as outlined below.

[0594] Step 1. Synthesis of tert-butyl 4-[l-(2,2-difluoro-l,3-benzodioxol-5-yl)-5-methyl- pyrazol-3-yl]piperazine-l-carboxylate.

[0595] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl)piperazine-l-carboxylate (0.2 g, 0.751 mmol), anhydrous copper acetate (273 mg, 1.5 mmol), and pyridine (0.302 mL, 3.75 mmol) in dichloromethane (5 mL) was added (2,2-difluorobenzo [d][l,3]dioxol-5-yl)boronic acid (227 mg, 1.13 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 16h. The mixture was filtered. The filtrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford the desired product tert-butyl 4-[ 1 -(2,2-difluoro- 1 ,3 -benzodi oxol-5-yl)-5-methyl-pyrazol-3 -yl]piperazine- 1 -carboxylate (206 mg, yield 64.9%) as a yellow solid.

[0596] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA);Gradient: 5% increase to 95%B in 1.0 min; Flow Rate: 2.2 mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C; LC purity: 99 % (214 nm); Mass: found peak 423.3 (M + H) at 1.49 min.

[0597] Step 2. Synthesis of l-[l-(2,2-difluoro-l,3-benzodioxol-5-yl)-5-methyl-pyrazol-3- yl] piperazine.

[0598] To a solution of tert-butyl 4-[l-(2,2-difluoro-l,3-benzodioxol-5-yl)-5-methyl-pyrazol- 3 -yl]piperazine-l -carboxylate (206 mg, 0.488 mmol) in 3mL dichloromethane was added TFA (1 mL). The mixture was stirred at room temperature for Ih. The reaction was quenched with saturated potassium carbonate (3mL) and extracted with dichloromethane (10 mL X 3). The organic layer was dried over sodium sulfate, and the organic phase was concentrated to dryness to give l-[l-(2,2-difluoro-l,3-benzodioxol-5-yl)-5-methyl-pyrazol-3-yl]piperazine (155 mg, crude) as a yellow solid.

[0599] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 98 % (214 nm); Mass: found peak 323.2 (M + H) at 1.56 min.

[0600] Step 3. Synthesis of 4-[2-[4-[l-(2,2-difluoro-l,3-benzodioxol-5-yl)-5-methyl- pyrazol-3-yl]piperazin-l-yl]ethyl]morpholine (Compound 23).

[0601] To a solution of l-[l-(2,2-difluoro-l,3-benzodioxol-5-yl)-5-methyl-pyrazol-3- yl]piperazine (115 mg, 0.481 mmol), potassium carbonate (199 mg, 1.44 mmol) and KI (79.8 mg, 0.481 mmol) in 95% ethanol / water (lOmL / I mL) was added 4-(2-chloroethyl)morpholine (10.8 mg, 0.721 mmol). The reaction was stirred at 90 °C for 16h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / CFLCN) to afford the desired product 4- [2- [4- [ 1 -(2,2-difluoro- 1 ,3 -benzodi oxol-5-yl)-5-methyl-pyrazol-3 -yl]piperazin- 1 - yl]ethyl]morpholine (141.4 mg, yield 67.4%) as a white solid.

[0602] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column:X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 99 % (214 nm);Mass: found peak 436.2 (M + H) at 1.96 min.

[0603] 'H NMR (400MHz, CDCh): 5 7.22 (d, J = 3.2 Hz, 1H), 7.08-7.13 (m, 2H), 5.71 (s,1H), 3.73 (t, J = 4.8 Hz, 4H), 3.27 (t, J = 4.8 Hz, 4H), 2.63 (t, J = 4.8 Hz, 4H), 2.56-2.60 (m,4H), 2.52-2.55 (m, 4H) ppm.Synthesis 2

[0604] Compound 23 was prepared as outlined below.

[0605] Step 1. Synthesis of tert-butyl 4-(3-oxobutanoyl) piperazine-l-carboxylate.

[0606] A mixture of tert-butyl piperazine-l-carboxylate (30.0 g, 0.161mol) and tert-butyl acetoacetate (28.0 g, 0.177mol) in toluene (300 mL) was heated at 100°C overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 330 g silica gel column @200mL / min, eluting with 0-60% acetone in petroleum ether for 8 CV) to afford tert-butyl 4-(3 -oxobutanoyl) piperazine-l- carboxylate (43.0 g, 96.6% yield) as a transparent oil.

[0607] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C. LC purity: 97.84% (214 nm) Mass: found peak 215.3 (M-55)+at 1.48 min.

[0608] Step 2. Synthesis of tert-butyl 4-(3-oxobutanethioyl) piperazine-l-carboxylate.

[0609] To a solution of tert-butyl 4-(3-oxobutanoyl)piperazine-l -carboxylate (43.0 g, 0.156mol) in toluene (400 mL) was added Lawesson's reagent (31.5 g, 0.078mol) and the mixture was heated at 75°C overnight. The mixture was cooled to room temperature andconcentrated in vacuo. The residue was purified by flash chromatography (Biotage, 330 g silica gel column @200mL / min, eluting with 10-65% ethyl acetate in petroleum ether for 8 CV) to afford tert-butyl 4-(3 -oxobutanethioyl) piperazine- 1 -carboxylate (20.1g, yield 39.5%) as a yellow solid.

[0610] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min;Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C. LC purity: 87.59% (254 nm) Mass: found peak 287.3 (M+l) at 1.65 min.

[0611] Step 3. Synthesis of tert-butyl 4-[l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5-methyl- pyrazol-3-yl]piperazine-l-carboxylate.

[0612] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl)piperazine-l-carboxylate (3 g, 11.3 mmol) in chloroform (300 mL) was added (2, 2-difluoro-l, 3-benzodioxol-5-yl)boronic acid (4.64 g, 22.5 mmol), anhydrous copper acetate (4.09 g, 22.5 mmol), pyridine (4.45 g, 56.3 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 24h. The mixture was filtered, and concentrated in vacuo The residue was purified by flash chromatography (Biotage, 25 g silica gel column @70mL / min, eluting with 10-50% di chloromethane in petroleum ether) to afford the desired product tert-butyl 4-[l-(2, 2-difluoro- 1, 3-benzodioxol-5-yl)-5-methyl-pyrazol-3-yl]piperazine-l-carboxylate (3.0 g, yield 63%) as a white solid.

[0613] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C. LC purity: 97.73% (214 nm) Mass: found peak 422.9 (M + 1)+ at 2.036 min.

[0614] Step 4. Synthesis of l-[l-(2, 2-difluoro-l, 3-benzodioxol-5-yl)-5-methyl-pyrazol-3- yl] piperazine.

[0615] To a solution oftert-butyl 4-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl]piperazine-l -carboxylate (3 g, 11.26 mmol) in di chloromethane (20 mL) was added 2,2,2- trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for Ih. Thereaction mixture was concentrated in vacuo. The residue was diluted with water (5 mL), neutralized with potassium carbonate to pH=8, extracted with dichloromethane (5 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo to afford l-[l-(2,2-difluoro-l,3- benzodioxol-5-yl)-5-methyl-pyrazol-3-yl]piperazine (2.5 g, crude). The crude product was used directly in the next step.

[0616] LCMS method: Mobile Phase: A: Water (0.01% TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C. LC purity: 100% (214 nm) Mass: found peak 323.2 (M + 1)+ at 1.644 min.

[0617] Step 5. Synthesis of 4-[2-[4-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]morpholine.

[0618] To a solution of l-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (3.4 g, 11 mmol), potassium carbonate (7.57 g, 54.8 mmol) and KI (1.82 g, 11 mmol) in 95% ethanol (30 mL) was added 4-(2-chloroethyl)morpholine (2.4 g, 16.4 mmol). The reaction was stirred at 95 °C for 16h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[4-[5-methyl-l-[4- (trifluoromethyl)phenyl]pyrazol-3-yl]piperazin-l-yl]ethyl]morpholine (2.18 g, yield: 64.6%) as a white solid.

[0619] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 99.56 % (214 nm); Mass: found peak 436.2 (M + H) at 1.758 min.

[0620] 'H NMR (400 MHz, CDCh) 5 7.21 (d, J = 1.3 Hz, 1H), 7.11-7.08 (m, 2H), 5.68 (s, 1H), 3.76-3.66 (m, 4H), 3.35-3.16 (m, 4H), 2.65-2.60 (m, 4H), 2.58 (s, 4H), 2.51 (s, 4H), 2.27 (s, 3H) ppm.Example S24. Synthesis of 4-[2-[4-[l-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl- pyrazol-3-yl]piperazin-l-yl]ethyl]morpholine (Compound 24).

[0621] Compound 24 was prepared as outlined below.

[0622] Step 1. Synthesis of tert-butyl 4-[l-(4-fluoro-3-formyl-phenyl)-5-methyl-pyrazol-3- yl] piperazine-l-carboxylate.

[0623] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl)piperazine-l-carboxylate (0.1 g, 0.375 mmol), anhydrous copper acetate (0.136 g, 0.751 mmol), and pyridine (0.151 mL, 1.88 mmol) in chloroform (5 mL) were added (4-fluoro-3-formyl-phenyl)boronic acid (94.6 mg, 0.563 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 16h. The mixture was filtered. The filtrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford the desired product tert-butyl 4-[l-(4-fluoro-3- formyl-phenyl)-5-methyl-pyrazol-3-yl]piperazine-l-carboxylate (100 mg, yield 68.6%) as a yellow solid.

[0624] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: CH3CN (0.01%TFA);Gradient: 5% increase to 95%B in 1.0 min; Flow Rate: 2.2 mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C; LC purity: 95 % (214 nm); Mass: found peak 389.3 (M + H) at 1.36 min.

[0625] 'H NMR (400MHz, CDCh): 5 10.39 (s, 1H), 7.90 (dd, J = 6.0, 2.8 Hz, 1H), 7.74-7.79 (m, 1H), 7.28 (d, J = 18.4 Hz, 1H), 5.74 (s, 1H), 3.57 (t, J = 4.8 Hz, 4H), 3.22 (t, J = 5.2 Hz, 4H), 2.34 (s, 3H), 1.50 (s, 9H) ppm.

[0626] Step 2. Synthesis of tert-butyl 4-[l-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl- pyrazol-3-yl]piperazine-l-carboxylate.

[0627] At -78 °C, a solution of tert-butyl 4-[l-(4-fluoro-3-formyl-phenyl)-5-methyl-pyrazol-3- yl]piperazine-l -carboxylate (80 mg, 0.206 mmol) in 1 mL DCM was added DAST (0.5 mL, 4.12 mmol) dropwise. The mixture was stirred at -78 °C for 1 h, then warmed to room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated sodium bicarbonate solution (3 mL) and extracted with dichloromethane (3x3 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give tert-butyl 4-[l-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3- yl]piperazine-l -carboxylate (65 mg, 76.9% yield) as a colorless oil.

[0628] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: CH3CN; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X- Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 96 % (214 nm); Mass: found peak 411.2 (M + H) at 2.15 min.

[0629] Step 3. Synthesis of l-[l-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3- yl] piperazine.Boc

[0630] To a solution of tert-butyl 4-[l-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3 -yl]piperazine-l -carboxylate (73 mg, 0.178 mmol) in dichloromethane (1.5 mL) was addedTFA (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated potassium carbonate (5 mL). The resulting mixture was extracted with dichloromethane (10 mL* 3). The combined DCM layers were dried over sodium sulfate, filtered, and concentrated to dryness to give l-[l-[3-(difhioromethyl)-4-fluoro-phenyl]-5- methyl-pyrazol-3-yl]piperazine (55 mg, crude) as a yellow solid.

[0631] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 95 % (214 nm); Mass: found peak 323.2 (M + H) at 1.49 min.

[0632] Step 4. Synthesis of 4-[2-[4-[l-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl- pyrazol-3-yl]piperazin-l-yl]ethyl]morpholine (Compound 24).

[0633] To a solution of l-[l-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3- yl]piperazine (55 mg, 0.177 mmol), potassium carbonate (73.5 mg, 0.532 mmol) and KI (29.4 mg, 0.177 mmol) in 95% ethanol / water (10 mL / I mL) was added 4-(2-chloroethyl)morpholine (39.8 mg, 0.266 mmol). The reaction was stirred at 90 °C for 16h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / CHiCN) to afford the desired product 4- [2-[4-[l-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazin-l- yl]ethyl]morpholine (28.4 mg, yield 37.8%) as a yellow solid.

[0634] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 5%B increase to 95%B within 1.5 min, 95%B for 1.5 min, back to 5%B within O.Olmin. Flow Rate: 1.8mL / min; Column: Sunfire C18 ,4.6*50mm, 3.5pm; Oven Temperature: 50 °C; LC purity: 99 % (214 nm); Mass: found peak 423.9 (M + H) at 1.71 min.

[0635] 'H NMR (400MHz, CDCh): 5 7.68 (dd, J = 6.0, 2.4 Hz, 1H), 7.62-7.66 (m, 1H), 7.37 (t, J = 9.6 Hz, 1H), 7.05(t, J = 54.4 Hz, 1H), 5.86 (s, 1H), 3.71 (t, J = 4.8 Hz, 4H), 2.66 (t, J = 4.8 Hz, 4H), 2.59-2.62 (m, 4H), 2.54 (s, 4H), 2.29 (s, 3H) ppmExample S25. Synthesis of 4-[(7R,9aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol- 3-yl]-l,3,4,6,7,8,9,9a-octahydropyrido [l,2-a]pyrazin-7-yl]morpholine (Compound 25).

[0636] Compound 25 was prepared as outlined below.

[0637] Step 1. Synthesis of methyl (2S, 5S)-5-hydroxypiperidine-2-carboxylate.

[0638] Under argon atmosphere, a mixture of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (500 mg, 3.44 mmol), thionyl chloride (615 mg, 5.17 mmol) in MeOH (20 mL) was stirred at 65 °C for 2h. The reaction was cooled to room temperature, diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 25 g silica gel column @75 mL / min, eluting with 0-40% acetone in petroleum ether) to afford the desired product methyl (2S, 5S)-5-hydroxypiperidine-2-carboxylate (540 mg, yield 98.5%) as a colorless oil.

[0639] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: from 10 to 95% of B in 1.5 min at 1.8 mL / min; Column: X-BRIDGE C18 3.5 pm 4.6*50 mm; Column Temperature: 50 °C; Mass: found peak 160 (M + H) at 0.399 mm.

[0640] Step 2. Synthesis of methyl (2S, 5S)-5-hydroxypiperidine-2-carboxylate.

[0641] Under argon atmosphere, a mixture of methyl (2S,5S)-5-hydroxypiperidine-2- carboxylate (540 mg, 3.39 mmol), potassium carbonate (1.41 g, 10.2 mmol), tertbutoxycarbonyl tert-butyl carbonate (830 mg, 3.78 mmol) in THF / water (20 mL / 5 mL) was stirred at room temperature for 16h. The reaction was cooled to room temperature, diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 25 g silica gel column @75 mL / min, eluting with 0-40% acetone in petroleum ether) to afford the desired product methyl (2S, 5S)-5-hydroxypiperidine-2-carboxylate (800 mg, yield 90.9%) as a colorless oil.

[0642] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: from 10 to 95% of B in 1.5 min at 1.8 mL / min; Column: X-BRIDGE C18 3.5 pm 4.6*50 mm; Column Temperature: 50 °C; LC purity: 100% (214 nm); Mass: found peak 160 (M -100) + at 1.061 min.

[0643] Step 3. Synthesis of 1-tert-butyl 2-methyl (2S)-5-oxopiperidine-l,2-dicarboxylate

[0644] To a solution of 01 -tert-butyl O2-methyl (2S, 5S)-5-hydroxypiperidine-l, 2- dicarboxylate (700 mg, 2.7 mmol) in DCM (30 mL) at 0 °C was added DMP (2.29 g, 5.4 mmol). The reaction mixture was stirred at this temperature for Ih. The reaction was diluted with DCM (30 mL), washed with 5% Na2S20s aqueous (20 mL) and 5% sodium bicarbonate aqueous (20 mL), dried over Sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 25g silica gel column @75mL / min, eluting with 0-45% ethyl acetate in petroleum ether) to afford the desired product 1-tert-butyl 2-methyl (2S)-5- oxopiperidine-l,2-dicarboxylate (500 mg, yield 70%) as a yellow oil.

[0645] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: no peak Mass: found peak 158.3 (M- 100)+ at 1.111 min.

[0646] Step 4. Synthesis of 1-tert-butyl 2-methyl (2S)-5-morpholinopiperidine-l,2- dicarboxylate.

[0647] Under argon atmosphere, a mixture of Ol-tert-butyl O2-methyl (2S)-5-oxopiperidine- 1,2-dicarboxylate (50 mg, 0.194 mmol), acetic acid (0.09 mmol, 5.8 mg), morpholine (58.4 mg, 0.389 mmol) and sodium triacetoxyborohydride (124 mg, 0.583 mmol) in DCE (5 mL) was stirred at RT for 16h. The reaction mixture was filtered and diluted with water (5 mL), then extracted with ethyl acetate (20 mL*3), dried over sodium sulfate, filtered, and concentrated, finally purified by flash chromatography 2-30% ethyl acetate in petroleum ether to afford Ol- tert-butyl O2-methyl (2S)-5-morpholinopiperidine-l,2-dicarboxylate (50 mg, 78.3% yield) as a yellow solid.

[0648] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 329.2(M+1) at 1.1850 min.

[0649] Step 5. Synthesis of methyl (2S)-5-morpholinopiperidine-2-carboxylate.

[0650] To a solution of Ol-tert-butyl O2-methyl (2S)-5-morpholinopiperidine-l, 2- dicarboxylate (579 mg, 1.76 mmol) in 1,4-dioxane (10 mL) was added a solution of HCI / dioxane (4 M, 5 mL, 20 mmol). The reaction was stirred at room temperature for 2h. The reaction was concentrated in vacuo. The residue was washed with EtOAc (20 mL), dried in vacuo to afford the desired product methyl (2S)-5-morpholinopiperidine-2-carboxylate (270 mg, 67.1% yield) as a white solid.

[0651] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2 min at 2.2 mL / min; Column: HALO C18 2.7 pm 4.6*30 mm; Column Temperature: 40 °C; LC purity: 100% (214nm); Mass: 229.1 [M-100]+ at 1.358 min.

[0652] Step 6. Synthesis of methyl l-[2-(l, 3-dioxoisoindolin-2-yl) ethyl]-4-morpholino- piperidine-2-carboxylate.

[0653] To a cooled (0 °C) solution of 2-(2-hydroxyethyl) isoindoline-1, 3-dione (192 mg, 1.0 mmol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (334 mg, 1.18 mmol) under argon atmosphere. After 10 min 2,6-lutidine (127 mg, 1.18 mmol) and after another lOmin a solution of methyl 4-morpholinopiperidine-2-carboxylate (270 mg, 1.18 mmol) and TEA (120 mg, 1.18 mmol) in DCM (5 mL) were added. The reaction mixture was stirred at room temperature for 16h. The residue was diluted with water (10 mL), extracted with dichloromethane (20 mL x 3), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (dichloromethane: methanol = 10 / 1) to give methyl l-[2-(l, 3-dioxoisoindolin-2-yl) ethyl]-4-morpholino-piperidine-2-carboxylate (250 mg, 49.5% yield) as a yellow oil.

[0654] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA); Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C. LC purity: 94.33% (214 nm); Mass: found peak 402.2 (M + H) at 0.855 min.

[0655] Step 7. Synthesis of (9aS)-7-morpholino-2,3,4,6,7,8,9,9a-octahydropyrido[l,2- a]pyrazin-l-one.

[0656] To a solution of methyl (2S)-l-[2-(l,3-dioxoisoindolin-2-yl)ethyl]-5-morpholino- piperidine-2-carboxylate (250 mg, 0.623 mmol) in methanol (15 mL) was added NELNEh water (70 mg , 1.37 mmol). The reaction mixture was stirred at room temperature for 16h. The reaction mixture was concentrated in vacuo. The residue was dissolved with dichloromethane (30 mL), filtered, and concentrated in vacuo to afford (9aS)-7-morpholino-2,3,4,6,7,8,9,9a- octahydropyrido[l,2-a]pyrazin-l-one (130 mg, crude). The crude was used directly in the next step.

[0657] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 89% (214 nm); Mass: found peak 240.1 (M + H) at 1.23 min.

[0658] Step 8. Synthesis of 4-[(9aS)-2,3,4,6,7,8,9,9a-octahydro-lH-pyrido[l,2-a]pyrazin-7-yl]morpholine.

[0659] At 0 °C, to a solution of (9aS)-7-morpholino-2,3,4,6,7,8,9,9a-octahydropyrido[l,2- a]pyrazin-l-one (130 mg, 1.6 mmol) in THF (20 mL) was added LiAlLL (5.4 mL, 5.4 mmol) under Argon atmosphere. The reaction was stirred at 60 °C for 3h. The reaction mixture was cooled to 0 °C, then 10 drops of water was added. 5 minutes later, 10 drops of 15% NaOH were added to the mixture slowly, then 30 drops of water were added. The solution was dried over sodium sulfate, filtered, and concentrated to dryness to give 4-[(9aS)-2,3,4,6,7,8,9,9a-octahydro- lH-pyrido[l,2-a]pyrazin-7-yl]morpholine (130 mg, crude) as a yellow solid.

[0660] 'H NMR (400 MHz, CDCh): 5 3.73 (t, J = 4.4 Hz, 4H), 2.85-2.99 (m, 4H), 2.78 (td, J = 12.0, 2.4 Hz, 1H), 2.52-2.57 (m, 4H), 2.29-2.36 (m, 1H), 2.07-2.17 (m, 2H), 1.82-1.92 (m, 2H), 1.59-1.68 (m, 2H), 1.18-1.27 (m, 2H) ppm.

[0661] Step 9. Synthesis of 4-[(7R,9aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-l,3,4,6,7,8,9,9a-octahydropyrido [l,2-a]pyrazin-7- yljmorp

[0662] Under argon atmosphere, a mixture of 3-bromo-5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazole (247 mg, 0.67 mmol), 4-(2,3,4,6,7,8,9,9a-octahydro-lH-pyrido[l,2-a]pyrazin- 7-yl)morpholine (162 mg, 0.72 mmol), tBuXPhos Pd G3 (61.1 mg, 0.076 mmol) and sodium tert-butoxide (222 mg, 2.3 mmol) in 1,4-dioxane (16 mL) was stirred 100 °C for 16h. The reaction mixture was directly purified by flash chromatography (Biotage, 25g silica gel column @75mL / min, eluting with 0-10% MeOH in DCM) to afford the crude product, which was further purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 25-P1 4-[(7R,9aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- l,3,4,6,7,8,9,9a-octahydropyrido [l,2-a]pyrazin-7-yl]morpholine (36.5 mg, yield 10%) as a yellow solid and product 25-P2 4-[(7S,9aS)-2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-7-yl]morpholine (2.3 mg, yield 0.6%) as a yellow solid.

[0663] 25-P1: LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 97.62% (214 nm) Mass: found peak 465.9 (M+l) at 1.747 min.

[0664] 25-P1:1H NMR (400 MHz, CDCh) 5 7.39 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 4.8 Hz, 2H), 5.63 (s, 1H), 3.64 (s, 4H), 3.54 (d, J = 11.8 Hz, 2H), 3.02 (d, J = 10.2 Hz, 1H), 2.88 (t, J = 11.8 Hz, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.53 (s, 4H), 2.41 (dt, J = 20.7, 11.1 Hz, 3H), 2.23 (s, 3H), 1.95 (t, J = 10.5 Hz, 3H), 1.72 (s, 1H), 1.33-1.15 (m, 2H) ppm.

[0665] 25-P2: LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 465.9 (M+l) at 1.907 min.

[0666] 25-P2:1H NMR (400 MHz, CDCh) 5 7.39 (d, J = 8.9 Hz, 2H), 7.20 (d, J = 5.8 Hz, 2H), 5.62 (s, 1H), 3.69 (s, 4H), 3.45 (dd, J = 21.0, 11.8 Hz, 2H), 2.95 (d, J = 10.6 Hz, 2H), 2.73- 2.58 (m, 2H), 2.52 (s, 4H), 2.26 (d, J = 12.7 Hz, 1H), 2.23 (s, 2H), 2.14 (d, J = 7.9 Hz, 2H), 1.99-1.87 (m, 2H), 1.43-1.28 (m, 3H) ppm.Example S26. Synthesis of 4-[2-[7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- 4,7-diazaspiro[2.5]octan-4-yl]ethyl]morpholine (Compound 26).

[0667] Compound 26 was prepared as outlined below.

[0668] Step 1. Synthesis of tert-butyl 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol- 3-yl]-4,7-diazaspiro [2.5] octane-4-carboxylate.

[0669] Under argon atmosphere, a mixture of 3-bromo-5-methyl-l-[4-(trifluoromethoxy) phenyl]pyrazole (300 mg, 0.934 mmol), tert-butyl 4,7-diazaspiro[2.5] octane-4-carboxylate (298 mg, 1.4 mmol), tBuXPhos Pd G3 (74 mg, 0.0934 mmol) and sodium tert-butoxide (269 mg, 2.8mmol) in 1,4-di oxane (18 mL) was stirred 100 °C for 16h. The reaction mixture was directly purified by flash chromatography (Biotage, 25g silica gel column @75mL / min, eluting with 0- 10% EA in PE) to afford the desired product tert-butyl 7-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate (160 mg, yield 34.7%) as a yellow solid.

[0670] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA) Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min;Column: Sunfire C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 91.72% (214 nm) Mass: found peak 453.2 (M+l) at 2.146 min.

[0671] Step 2. Synthesis of 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7- diazaspiro [2.5] octane.

[0672] A mixture of tert-butyl 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7- diazaspiro[2.5]octane-4-carboxylate (160 mg, 0.354 mmol) and TFA (1.5 mL, 19.6 mmol) in di chloromethane (10 mL) was stirred at room temperature for 2h. The reaction was concentrated in vacuo. The residue was diluted with water (10 mL), neutralized with potassium carbonate to pH=9, extracted with dichloromethane (20 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product 7-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5] octane (124 mg, yield 91.6%) as a yellow oil.

[0673] Step 3. Synthesis of 4-[2-[7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]-4,7-diazaspiro [2.5] octan-4-yl] ethyl] morpholine (Compound 26).

[0674] To a solution of 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7- diazaspiro [2.5]octane (50 mg, 0.142 mmol), potassium carbonate (98 mg, 0.71 mmol) and KI (24 mg, 0.142 mmol) in 95% ethanol (10 mL) was added 4-(2-chloroethyl)morpholinehydrochloride (40 mg, 0.213 mmol). The reaction was stirred at 95 °C for 16h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / Water / acetonitrile) to afford the desired product 4-[2-[7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7- diazaspiro[2.5]octan-4-yl]ethyl]morpholine (13.3 mg, yield 20.1%) as a yellow oil.

[0675] LCMS: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 5% increase to 95%B within 1.3 min; Flow Rate: 1.7 mL / min; Column:X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 45 °C; LC purity: 100% (214 nm) Mass: found peak 466.3 (M+l) at 1.902 min.

[0676] 'H NMR (400 MHz, CDCh) 5 7.48-7.42 (m, 2H), 7.30-7.24 (m, 2H), 5.69 (s, 1H), 3.71 (t, J = 4.4 Hz, 4H), 3.23-3.12 (m, 4H), 3.01 (s, 2H), 2.91 (t, J = 7.2 Hz, 2H), 2.53-2.40 (m, 6H), 2.30 (s, 3H), 0.76-0.69 (m, 2H), 0.61-0.56 (m, 2H) ppm.Example S27. Synthesis of 4-[2-[7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- 4,7-diazaspiro[2.5]octan-4-yl]ethyl]-l,4-thiazinane 1,1-dioxide (Compound 27).

[0677] Compound 27 was prepared as outlined below.

[0678] Step 1. Synthesis of 4-(2-chloroethyl)-7-[5-methyl-l-[4- (trifluoromethoxy)phenyl] pyrazol-3-yl]-4,7-diazaspiro [2.5] octane.

[0679] A mixture of 7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7- diazaspiro[2.5] octane (124 mg, 0.352 mmol), 2-chloroacetaldehyde (40% aqueous, 138 mg, 0.704 mmol) and acetic acid (10.6 mg, 0.176 mmol) in methanol (8 mL) was stirred at room temperature for 0.5h. The reaction was cooled to 0 °C, sodium cyanoborohydride (44 mg, 0.704 mmol) was added and stirred at room temperature for 8h. The reaction mixture was diluted with water (20 mL), extracted with dichloromethane (20 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 25 g silica gel column @75mL / min, eluting with 0-5% methanol in di chloromethane) to afford thedesired product 4-(2-chloroethyl)-7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7- diazaspiro[2.5]octane (110 mg, yield 55.6%) as a yellow oil.

[0680] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 5% increase to 95%B within 1.3 min; Flow Rate: 1.8 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 73.78% (214 nm) Mass: found peak 414.9 (M+l) at 2.055 min.

[0681] Step 2. Synthesis of 4-[2-[7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]-4,7-diazaspiro[2.5]octan-4-yl]ethyl]-l,4-thiazinane 1,1-dioxide (Compound 27).

[0682] A mixture of 4-(2-chloroethyl)-7-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]-4,7-diazaspiro[2.5]octane (110 mg, 0.265 mmol), 1,4-thiazinane 1,1-dioxide (72 mg, 0.53 mmol) and N-ethyl-N-isopropyl-propan-2-amine (103 mg, 0.795 mmol) in 1-methylpyrrolidin- 2-one (3 mL) was treated with microwave reactor and stirred at 160 °C for 2h. The reaction was cooled to room temperature, directly purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[7-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]octan-4-yl]ethyl]-l,4-thiazinane 1,1- dioxide (16.5 mg, yield 12.1%) as a brown solid.

[0683] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 5% increase to 95%B within 1.3 min; Flow Rate: 1.7 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 45 °C; LC purity: 100% (214 nm) Mass: found peak 514.2 (M+l) at 1.837 min.

[0684] 'H NMR (400 MHz, CDCh) 5 7.48-7.42 (m, 2H), 7.30-7.25 (m, 2H), 5.69 (s, 1H), 3.25- 3.08 (M, 4H), 3.07-2.95 (m, 10H), 2.93-2.82 (m, 2H), 2.66-2.53 (m, 2H), 2.30 (s, 3H), 0.79-0.55 (m, 4H) ppm.Example S28. Synthesis of 2,2-difluoro-4-[2-[4-[5-methyl-l-[4- (trifluoromethoxy)phenyl] pyrazol-3-yl] piperazin- 1-yl] ethyl] morpholine (Compound 28).

[0685] Compound 28 was prepared as outlined below.

[0686] Step 1. Synthesis of 2-(dibenzylamino)ethanol.

[0687] To a solution of 2-(benzylamino)ethanol (9.39 mL, 66.1 mmol) in acetonitrile (300 mL) and potassium carbonate (18.3 g, 132 mmol) was added benzyl bromide (11.8 mL, 99.2 mmol). The reaction mixture was stirred at 80 °C for 1.5 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 330 g silica gel column @100mL / min, eluting with 0-10% methanol in di chloromethane) to afford the desired product 2-(dibenzylamino)ethanol (15 g, yield 94%) as a colorless oil.

[0688] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA) Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min;Column: Sunfire C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 242.2 (M+l) at 1.233 min.

[0689] Step 2. Synthesis of 2-[2-(dibenzylamino)ethoxy]-2,2-difluoro-acetic acid.

[0690] At 0 °C, to a solution of 2-(dibenzylamino)ethanol (3.0 g, 12.4 mmol) and sodium chloro-2,2-difluoro-acetic acid (1.9 g, 12.4 mmol) in THF (25 mL) was added sodium hydride (60%, 1.24 g, 31.1 mmol). The reaction mixture was stirred at 75 °C for 16h. The mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with diethyl ether (30 mL*2). The mixture solution was separated and the aqueous layer was adjusted to pH 6 with 6 N HC1. The mixture was extracted with EtOAc (50 mL*3), dried over sodiumsulfate, filtered, and concentrated in vacuo to afford the desired product 2-[2- (dibenzylamino)ethoxy]-2,2-difluoro-acetic acid (3.5 g, yield 80.9%) as a yellow solid.

[0691] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA) Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min;Column: Sunfire C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 96.37% (214 nm) Mass: found peak 336.2 (M+l) at 1.383 min.

[0692] Step 3. Synthesis of methyl 2-[2-(dibenzylamino)ethoxy]-2,2-difluoro-acetate.

[0693] To a solution of 2-[2-(dibenzylamino)ethoxy]-2,2-difluoro-acetic acid (0.5 g, 1.49 mmol) in toluene (18 mL) and methanol (4 mL) was added (trimethyl silyl) diazomethane (2 M in hexane, 0.82 mL, 1.64 mmol). The reaction mixture was stirred at room temperature for 15 min and quenched with acetic acid (0.5 mL). The mixture was concentrated in vacuo to afford the desired product methyl 2-[2-(dibenzylamino)ethoxy]-2,2-difluoro-acetate (0.5 g, yield 45.6%) as a yellow oil.

[0694] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA) Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: Sunfire C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 45.57% (214 nm) Mass: found peak 350.2 (M+l) at 1.553 min.

[0695] Step 4. Synthesis of 4-benzyl-2, 2-difluoro-morpholin-3-one.

[0696] Under H2 atmosphere, a mixture of methyl 2-[2-(dibenzylamino)ethoxy]-2,2-difluoro- acetate (3.13 g, 8.96 mmol) and Pd / C (10%, 300 mg) in ethanol (150 mL) was stirred at room temperature for 16h. The reaction was filtered and concentrated in vacuo to afford the desired product 4-benzyl-2, 2-difluoro-morpholin-3-one (1.86 g, yield 87.2%) as a white solid.

[0697] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA) Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: Sunfire C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 95.45% (214 nm) Mass: found peak 228.1 (M+l) at 1.635 min.

[0698] Step 5. Synthesis of 4-benzyl-2, 2-difluoro-morpholine.

[0699] To a solution of 4-benzyl-2, 2-difluoro-morpholin-3-one (1.8 g, 7.92 mmol) in THF (80 mL) was added a solution of boron dimethyl sulfide complex (2 M in THF, 20 mL, 40 mmol). The reaction was stirred at 55 °C for 6h, then, room temperature for 16h. The reaction was quenched with water slowly, acidified with HC1 aqueous to pH=l and stirred at room temperature for Ih. The mixture was neutralized with sodium bicarbonate, extracted with EtOAc (100 mL*3). The organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 40 g silica gel column @75mL / min, eluting with 0-10% MeOH in DCM) to afford the desired product 4-benzyl-2, 2-difluoro-morpholine (700 mg, yield 40.4%) as a yellow oil.

[0700] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA) Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min; Column: Sunfire C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 95.45% (214 nm) Mass: found peak 228.1 (M+l) at 1.635 min. LC purity: 97.48% (214 nm) Mass: found peak 214.2 (M+l) at 1.752 min.

[0701] Step 6. Synthesis of tert-butyl 2,2-difluoromorpholine-4-carboxylate.Boc

[0702] Under H2 atmosphere, a mixture of 4-benzyl-2, 2-difluoro-morpholine (0.7 g, 3.28 mmol), BOC2O (0.86 g, 3.94 mmol) and Pd(OH)2 / C (20%, 450 mg) in ethyl acetate (60 mL) was stirred at room temperature for 16 h. The reaction was filtered and concentrated under reduced pressure to afford the desired product tert-butyl 2,2-difluoromorpholine-4-carboxylate (700 mg, yield 95.5%) as a colorless oil.

[0703] 'H NMR (400 MHz, CDCI3) 54.05 (t, J = 4.8 Hz, 2H), 3.71 (t, J = 8.0 Hz, 2H), 3.54 (t, J = 4.8 Hz, 2H), 1.48 (s, 9H) ppm.

[0704] Step 7. Synthesis of 2,2-difluoromorpholine TFA salt.

[0705] A mixture of tert-butyl 2,2-difluoromorpholine-4-carboxylate (200 mg, 0.896 mmol) and TFA (2 mL, 26.1 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2h. The reaction was concentrated in vacuo to afford the desired product 2,2-difluoromorpholine TFA salt (160 mg, yield 75.3%) as a brown solid.

[0706] 'H NMR (400 MHz, MeOD-d4) 3 4.27 - 4.20 (m, 2H), 3.58 (t, J= 7.5 Hz, 2H), 3.35 - 3.29 (m, 2H) ppm.

[0707] Step 8. Synthesis of 2,2-difluoro-4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy)phenyl] pyrazol-3-yl] piperazin- 1-yl] ethyl] morpholine (Compound 28).

[0708] A mixture of l-(2-chloroethyl)-4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazine (80 mg, 0.206 mmol), 2,2-difluoromorpholine 2,2,2-trifluoroacetic acid (98 mg, 0.412 mmol) and N-ethyl-N-isopropyl-propan-2-amine (160 mg, 1.23 mmol) in 1- methylpyrrolidin-2-one (3 mL) was treated with microwave reactor and stirred at 160 °C for 2h. The reaction was cooled to room temperature, directly purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 2,2-difluoro-4-[2-[4-[5- methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-l-yl]ethyl]morpholine (36.1 mg, yield 36.9%) as a yellow solid.

[0709] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 5% increase to 95%B within 1.3 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 45 °C; LC purity: 100% (214 nm) Mass: found peak 476.1 (M+l) at 2.031 min.

[0710] 'H NMR (400 MHz, CDC13) 5 7.49-7.43 (m, 2H), 7.27 (d, J = 8.8 Hz, 2H), 5.70 (s, 1H), 4.08-4.03 (m, 2H), 3.26 (t, J = 4.8 Hz, 4H), 2.82 (t, J = 7.2 Hz, 2H), 2.69-2.55 (m, 10H), 2.30 (s, 3H) ppm.Example S29. Synthesis of 5-[2-[4-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazin-l-yl] ethyl]-l,3,3a,4,6,6a-hexahydrofuro[3,4-c] pyrrole (Compound 29).

[0711] Compound 29 was prepared as outlined below.

[0712] Step 1. Synthesis of tert-butyl 4-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazine-l-carboxylate.

[0713] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl) piperazine-l-carboxylate (200 mg, 0.75 mmol) in DCM (20 mL) was added [4-(trifluoromethyl) phenyl] boronic acid (285 mg, 1.5 mmol), Copper (II) acetate (409 mg, 2.25 mmol), pyridine (297 mg, 3.75 mmol) and molecular sieves 4A. The reaction mixture was stirred at room temperature for 48h. The mixture was filtered and purified by flash chromatography (PE / DCM=1 / 1) to afford desired product tertbutyl 4-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazine-l-carboxylate (160 mg, yield 52%) as a yellow oil.

[0714] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 5% increase to 95%B within 1.4 min; 95% B for 1.6 min; Flow Rate: 1.8 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 45 °C; LC purity: 96% (214 nm) Mass: found peak 411.2 (M+l) at 2.097 min.

[0715] Step 2. Synthesis of l-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl] piperazine.

[0716] A solution of tert-butyl 4-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl]piperazine-l -carboxylate (160 mg, 0.39 mmol) in dichloromethane (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2h, then concentrated in vacuo. The residue was diluted with water (10 mL), neutralized with potassium carbonate to pH=8, extracted with di chloromethane (10 mL*3), dried over sodium sulfate, filtered, and concentratedin vacuo to afford l-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (130 mg, yield 95.6%) as a yellow oil.

[0717] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA);Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 2.0 mL / min;Column: SUNFIRE C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 311.2 (M+l) at 1.391 min.

[0718] Step 3. Synthesis of l-(2-chloroethyl)-4-[5-methyl-l-[4-(trifluoromethyl)phenyl] pyrazol-3-yl] piperazine.

[0719] Under argon atmosphere, a mixture of l-[5-methyl-l-[4-(trifluoromethyl)phenyl] pyrazol-3-yl]piperazine (140 mg, 0.451 mmol), acetic acid (13.5 mg, 0.226 mmol), 2- chloroacetaldehyde (177 mg, 0.902 mmol) and sodium cyanoborohydride (56 mg, 0.91 mmol) in methanol (6 mL) was stirred at RT for 16h. Then the mixture was filtered and concentrated in vacuo. The residue was diluted with water (10 mL), neutralized with sodium bicarbonate to pH = 8, extracted with dichloromethane (10 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo to afford l-(2-chloroethyl)-4-[5-methyl-l-[4- (trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (100 mg, yield 59.5%) as a yellow oil.

[0720] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: 5% increase to 95%B in 1.0 min; Flow Rate: 2.2 mL / min; Column: HALO C18 2.7pm 4.6*30mm; Column Temperature: 40 °C.

[0721] Step 4. Synthesis of 5-[2-[4-[5-methyl-l-[4-(trifluoromethyl) phenyl] pyrazol-3-yl] piperazin-l-yl] ethyl]-l,3,3a,4,6,6a-hexahydrofuro[3,4-c] pyrrole (Compound 29).

[0722] To a solution of l-(2-chloroethyl)-4-[5-methyl-l-[4-(trifluoromethyl)phenyl]pyrazol-3- yl]piperazine (50 mg, 0.134 mmol), 3,3a,4,5,6,6a-hexahydro-lH-furo[3,4-c]pyrrole (30 mg, 0.268 mmol) and DIPEA (87 mg, 0.671 mmol) in NMP (1.5 mL) stirred at 160 °C for 2h in MW. The reaction was cooled to room temperature and directly purified by prep-HPLC (NH4HCO4 / water / acetonitrile) to afford the desired product 5-[2-[4-[5-methyl-l-[4- (trifluoromethyl) phenyl] pyrazol-3-yl] piperazin-l-yl] ethyl]-l,3,3a,4,6,6a-hexahydrofuro[3,4- c] pyrrole (30.2 mg, yield: 50.1%) as a brown solid.

[0723] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B:ACN; Gradient: 5% increase to 95%B within 1.3min, 95%B for 1.7min; Flow Rate: 1.8 mL / min; Column: X-Bridge C18, 3.5pm, 4.6*50mm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 450.3 (M+l) at 1.830 min.

[0724] 'H NMR (400 MHz, CDCh) 5 7.67 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 5.73 (s, 1H), 3.76 (s, 2H), 3.59 (d, J = 7.4 Hz, 2H), 3.30- 3.25 (m, 4H), 2.79 (s, 4H), 2.64-2.56 (m, 8H), 2.36 (s, 5H) ppm.Example S30. Synthesis of 5-[2-[4-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl] piperazin-l-yl] ethyl]-l,3,3a,4,6,6a-hexahydrofuro [3,4-c] pyrrole (Compound 30).

[0725] Compound 30 was prepared as outlined below.

[0726] Step 1. Synthesis of tert-butyl 4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol- 3-yl] piperazine- 1-carboxylate.

[0727] Under Oxygen atmosphere, a mixture of tert-butyl 4-(5-methyl-lH-pyrazol-3- yl)piperazine- 1-carboxylate (1.0 g, 3.75 mmol), [4-(trifluoromethoxy) phenyl ]b or onic acid (1.55 g, 7.51 mmol), copper (II) acetate (1.36 g, 7.51 mmol) and pyridine (1.2 g, 15 mmol) in di chloromethane (20 mL) was stirred at RT for 16h. Then concentrated and purified by flash chromatography (PE: EA = 3: 1) to afford the desired product tert-butyl 4-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine- 1-carboxylate (800 mg, 46.8%) as a yellow solid.

[0728] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: ACN (0.01%TFA); Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min. Flow Rate: 2.0mL / min Column: Sunfire C18, 4.6*50mm, 3.5pm; Column Temperature: 50 °C. LC purity: 99.3% (214 nm), Mass: found peak 427.2 (M+l) at 2.090 min.

[0729] Step 2. Synthesis of l-[5-ethyl-l-[4-(trifluoromethyl) phenyl]pyrazol-3- yl] piperazine.

[0730] To a solution of tert-butyl 4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazine-l -carboxylate (1.5 g, 3.52 mmol) in DCM (30 mL) was added TFA (8 mL). The reaction mixture was stirred at room temperature for 2h. Then the mixture was concentrated and neutralized with a solution of potassium carbonate to pH=10. The resulting mixture was extracted with DCM and dried over sodium sulfate and filtered. The filtrate was concentrated to afford the desired product l-[5-ethyl-l-[4-(trifluoromethyl) phenyl]pyrazol-3-yl]piperazine (1.1 g, yield: 95.8%) as a yellow oil.

[0731] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: ACN (0.01%TFA); Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min. Flow Rate: 2.0mL / min; Column: Sunfire C18, 4.6*50mm, 3.5pm; Column Temperature: 50 °C. LC purity: 93% (214 nm), Mass: found peak 327.2 (M+l) at 1.406 min.

[0732] Step 3. Synthesis of l-(2-chloroethyl)-4-[5-methyl-l-[4-(tr ifluoromethoxy)phenyl] pyrazol-3-yl] piperazine.

[0733] To a solution of l-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (1.1 g, 3.37 mmol) in methanol (20 mL) was added sodium cyanoborohydride (424 mg, 6.74 mmol), 2-chloroacetaldehyde (530 mg, 6.74 mmol) and acetic acid (100 mg, 1.7 mmol). The reaction mixture was stirred at room temperature for 16h. The mixture was quenched by water (5 mL) and extracted by dichloromethane (10 mL X 3). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to afford the desired product l-(2- chloroethyl)-4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl] piperazine (1.0 g, 75%) as a colorless oil.

[0734] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: ACN (0.01%TFA); Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min. Flow Rate: 2.0mL / min; Column: Sunfire C18, 4.6*50mm, 3.5pm; Column Temperature: 50 °C. LC purity: 96% (214 nm) Mass: found peak 389.2 (M+l) at 1.454 min.

[0735] Step 4. Synthesis of 5-[2-[4-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3- yl] piperazin-l-yl] ethyl]-l,3,3a,4,6,6a-hexahydrofuro [3,4-c] pyrrole (Compound 30).

[0736] To a mixture of l-(2-chloroethyl)-4-[5-methyl-l-[4-(trifluoromethoxy)phenyl] pyrazol- 3-yl]piperazine (50 mg, 0.13 mmol) in NMP (3 mL) was added 3,3a,4,5,6,6a-hexahydro-lH- furo[3,4-c]pyrrole hydrochloride (25.5 mg, 0.26 mmol) and N-ethyl-N-isopropyl-propan-2- amine (0.11 mL, 0.64 mmol). The reaction mixture was stirred at 140 °C in microwave reactor for 2h. The mixture was purified by prep-HPLC (ammonium hydrogen carbonate / acetonitrile) to afford the desired product 5-[2-[4-[5-methyl-l-[4-(trifluoromethoxy) phenyl] pyrazol-3-yl] piperazin- 1-yl] ethyl]-l,3,3a,4,6,6a-hexahydrofuro [3,4-c] pyrrole (26.5 mg, 44.3%) as a yellow solid.

[0737] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN; Gradient: 5%B increase to 95%B within 1.3min, 95%B for 1.7min; Flow Rate: 1.8 mL / min; Column: X-Bridge C18, 3.5pm, 4.6*50mm; Column Temperature: 45 °C; LC purity: 100% (214 nm) Mass: found peak 466.1 (M+l) at 1.828 min.

[0738] 'H NMR (400 MHz, CDCh) 5 7.46 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 5.70 (s, 1H), 3.78 - 3.71 (m, 2H), 3.60 (d, J = 8.4 Hz, 2H), 3.30 - 3.22 (m, 4H), 2.84 (s, 4H), 2.69 - 2.57 (m, 8H), 2.36 (d, J = 5.2 Hz, 2H), 2.30 (s, 3H) ppm.Example S31. Synthesis of 6-[2-[4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]-2-oxa-6-azaspiro[3.3]heptane (Compound 31).

[0739] Compound 31 was prepared as outlined below.

[0740] To a mixture of l-(2-chloroethyl)-4-[5-methyl-l-[4-(trifluoromethoxy)phenyl] pyrazol- 3-yl] piperazine (50 mg, 0.13 mmol) in NMP (3 mL) was added 2-oxa-6-azaspiro[3.3]heptane hydrochloride (35 mg, 0.26 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.11 mL, 0.64 mmol). The reaction mixture was stirred at 140 °C in microwave reactor for 2h. The mixture was purified by prep-HPLC (ammonium hydrogen carbonate / acetonitrile) to afford the desired product 6-[2-[4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-l-yl]ethyl]-2- oxa-6-azaspiro[3.3]heptane (24.7 mg, 42.5%) as a yellow oil.

[0741] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN; Gradient: 5%B increase to 95%B within 1.3min, 95%B for 1.7min; Flow Rate: 1.8mL / min; Column: X-Bridge C18, 3.5pm, 4.6*50mm; Column Temperature: 45 °C; LC purity: 96% (214 nm); Mass: found peak 452.1 (M+l) at 1.743 min.

[0742] 'H NMR (400 MHz, CDCh) 5 7.46 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 5.70 (s, 1H), 3.78 - 3.71 (m, 2H), 3.60 (d, J = 8.4 Hz, 2H), 3.30 - 3.22 (m, 4H), 2.84 (s, 4H), 2.69 - 2.57 (m, 8H), 2.36 (d, J = 5.2 Hz, 2H), 2.30 (s, 3H) ppm.Example S32. Synthesis of 4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]-2-(trifluoromethyl)morpholine (Compound 32).

[0743] Compound 32 was prepared as outlined below.

[0744] To a mixture of l-(2-chloroethyl)-4-[5-methyl-l-[4-(trifluoromethoxy)phenyl] pyrazol- 3-yl]piperazine (50 mg, 0.13 mmol) in NMP (3 mL) was added 2-(trifluoromethyl)morpholine hydrochloride(49.3 mg, 0.26 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.11 mL, 0.64 mmol). The reaction mixture was stirred at 160 °C in microwave reactor for 4h. The mixture was purified by prep-HPLC (ammonium hydrogen carbonate / acetonitrile) to afford the desired product 4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-l-yl]ethyl]-2- (trifhioromethyl)morpholine (7.9 mg, 12.1%) as a yellow oil.

[0745] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN; Gradient: 5%B increase to 95%B within 1.3min, 95%B for 1.7min; Flow Rate: 1.8 mL / min; Column: X-Bridge C18, 3.5pm, 4.6*50mm; Column Temperature: 45 °C; LC purity: 98% (214 nm) Mass: found peak 508.1 (M+l) at 2.039 min.

[0746] 'H NMR (400 MHz, CDCh) 5 7.49 - 7.42 (m, 2H), 7.27 (d, J = 6.0 Hz, 2H), 5.70 (s, 1H), 4.03 - 3.87 (m, 2H), 3.71 (td, J = 11.6, 2.4 Hz, 1H), 3.32 - 3.20 (m, 4H), 2.99 (d, J = 11.2 Hz, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.66-2.54 (m, 8H), 2.33 - 2.26 (m, 4H), 2.21 (t, J = 10.8 Hz, 1H) ppm.Example S33. Synthesis of 4-[2-[4-[5-(l-methoxyethyl)-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl] piperazin-l-yl]ethyl]morpholine (Compound 33).

[0747] Compound 33 was prepared as outlined below.

[0748] Step 1. Synthesis of tert-butyl 4-methoxy-3-oxo-pentanoate.THF, 0 C-rt, 24h

[0749] To a solution of 2-methoxypropanoic acid (1.05 g, 10.1 mmol) in THF (30 mL) at 0°C was added di(imidazol-l-yl) methanone (1.8 g, 11.1 mmol) and the mixture was stirred at room temperature for 24h. In a separate flask, 2M isopropylmagnesium chloride in THF (16.6 mL, 33.3 mmol) was added dropwise to a solution of 3-tert-butoxy-3-oxo-propanoic acid (2.42 g, 15.1 mmol) in THF (30 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2h. Then, this solution was added dropwise to the acyl imidazole solution at 0°C and the resulting mixture was allowed to warm up to room temperature and stirred 16h. The mixture was quenched by addition of 10 % aqueous citric acid (100 mL) and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (acetone / petroleum ether = 1 : 4) to afford tert-butyl 4-methoxy-3-oxo-pentanoate (1.84 g, yield: 83.9%) as a yellow oil.

[0750] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN; Gradient: 5%B increase to 95%B within 1.3min,95%B for 1.7min; Flow Rate: 1.8 mL / min; Column: X-Bridge C18,3.5pm,4.6*50mm; Column Temperature: 45 °C. LC purity: 93% (254 nm) Mass: found peak 147.1 (M - 55)+ at 1.628 min.

[0751] Step 2. Synthesis of tert-butyl 4-(4-methoxy-3-oxo-pentanoyl)piperazine-l- carboxylate.

[0752] A mixture of tert-butyl 4-m ethoxy-3 -oxo-pentanoate (1.9 g, 9.4 mmol) and tert-butyl piperazine- 1 -carboxylate (1.92 g, 10.3 mmol) in toluene (40 mL) was heated at 100°C for 16h.The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography eluting with 0-30% acetone in petroleum ether to afford tertbutyl 4-(4-methoxy-3-oxo-pentanoyl)piperazine-l -carboxylate (2.6 g, 78.5% yield) as a yellow oil.

[0753] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN Gradient: 5%B increase to 95%B within 1.3min,95%B for 1.7min; Flow Rate: 1.8 mL / min; Column: X bridge C18,3.5pm,4.6*50mm; Column Temperature:45 °C; LC purity: 92.86% (254 nm) Mass: found peak 315.2 (M -55)+at 1.452 min.

[0754] Step 3. Synthesis of tert-butyl 4-(6-methyl-3-oxo-heptanethioyl)piperazine-l- carboxylate. Lawesson's reagent_ (°5 eq) _ toluene, 75°c 16h

[0755] To a solution of tert-butyl 4-(6-methyl-3-oxo-heptanoyl)piperazine-l -carboxylate (2.6 g, 7.65 mmol) in toluene (40 mL) was added Lawesson's reagent (1.55 g, 3.82 mmol) and the mixture was stirred at 75°C for 16h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography eluting with 10-65% ethyl acetate in petroleum ether to afford tert-butyl 4-(6-methyl-3-oxo-heptanethioyl)piperazine- 1-carboxylate (1.7 g, yield 46.2%) as a yellow oil.

[0756] LCMS method: Mobile Phase: A: Water (10 mM ammonium hydrogen carbonate) B: ACN Gradient: 5%B increase to 95%B within 1.3min,95%B for 1.7min; Flow Rate: 1.8 mL / min; Column: X-Bridge C18,3.5pm,4.6*50mm; Column Temperature:45 °C; LC purity: 71.68% (214 nm) Mass: found peak 343.2 (M + H) at 2.015 min.

[0757] Step 4. Synthesis of tert-butyl 4-[5-(l-methoxyethyl)-lH-pyrazol-3-yl]piperazine- 1-carboxylate. Boc

[0758] To a solution of tert-butyl 4-(4-methoxy-3-oxo-pentanethioyl)piperazine-l -carboxylate (1.2 g, 3.63 mmol) in toluene (50 mL) was added NH2NH2 water (560 mg, 11 mmol) and the mixture was stirred at 75°C for 16h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, 80 g silica gel column @100mL / min, eluting with 10-65% ethyl acetate in petroleum ether for 10 CV) to afford tert-butyl 4-[5-(l-methoxyethyl)-lH-pyrazol-3-yl]piperazine-l-carboxylate (1g, yield 88.7%) as a white solid.

[0759] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: ACN (0.01%TFA); Gradient: 5%B increase to 95%B within 1.5 min, 95%B for 1.5 min. Flow Rate: 2.0mL / min; Column: Poroshell 120 EC-C18,4.6*50mm, 4pm; Column Temperature: 50 °C. LC purity: 100% (214 nm) Mass: found peak 311.1 (M+H) + at 1.566 min.

[0760] Step 5. Synthesis of tert-butyl 4-[5-butyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- y 1] piperazine-l-carboxylate.

[0761] To a solution of tert-butyl 4-[5-(l-methoxyethyl)-lH-pyrazol-3-yl]piperazine-l- carboxylate (1.0 g, 3.2 mmol) in chloroform (50 mL) was added [4- (trifluoromethoxy)phenyl]boronic acid (1.35 g, 6.44 mmol), anhydrous copper acetate (1.17 g, 6.44 mmol), pyridine (1.3 mL, 16.1 mmol) and molecular sieves 4 A. The reaction mixture was stirred at room temperature for 24h. The mixture was filtered. The filtrate was purified by flash chromatography (Biotage, 40 g silica gel column @70mL / min, eluting with 10-50% di chloromethane in petroleum ether) to afford the desired product tert-butyl 4-[5-butyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-l -carboxylate (600 mg, yield 36.8%) as a white solid.

[0762] LCMS method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01% TFA);Gradient: 5% increase to 95%B within 1.5 min, 95%B for 1.5 min; Flow Rate: 2.0 mL / min;Column: Poroshell 120 EC-C18, 4.6*50mm, 4pm; Column Temperature: 50 °C. LC purity: 97.76% (214 nm) Mass: found peak 471.0 (M + 1) + at 2.179 min.

[0763] Step 6. Synthesis of l-[5-(l-methoxyethyl)-l-[4-(trifluoromethoxy)phenyl]pyrazol- 3-yl] piperazine.

[0764] To a solution of tert-butyl 4-[5-(l-methoxyethyl)-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-l -carboxylate (100 mg, 0.213 mmol) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for Ih. The reaction mixture was concentrated in vacuo. The residue was diluted with water (5 mL), neutralized with potassium carbonate to pH=8, extracted with dichloromethane (5 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo toafford l-[5-(l-methoxyethyl)-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (78 mg, crude). The crude product was used directly in the next step.

[0765] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA);Gradient: from 5 to 95% of B in 1.2 min at 2.2mL / min; Column: HALO Cl 8, 2.7pm, 4.6*30mm; Column Temperature: 40 °C. LC purity: 86% (214nm); Mass: 409.3 (M+l) at 1.043 min.

[0766] Step 7. Synthesis of 4-[2-[4-[5-(l-methoxyethyl)-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl] piperazin-l-yl]ethyl]morpholine (Compound 33).

[0767] To a solution of l-[5-(l-methoxyethyl)-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazine (100 mg, 0.27 mmol), potassium carbonate (188 mg, 1.36 mmol) and KI (45 mg, 0.27 mmol) in 95% ethanol (5 mL) was added 4-(2-chloroethyl)morpholine (80.8 mg, 0.54 mmol). The reaction was stirred at 95 °C for 16h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[2-[4-[5-( 1 - methoxyethyl)-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl] piperazin- l-yl]ethyl]morpholine (51.7 mg, yield: 39.6%) as a white solid.

[0768] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 1.8 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 99.09 % (214 nm); Mass: found peak 484.2 (M + H) at 1.837 min.

[0769] ‘H NMR (400 MHz, CDCh) 5 7.52 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.29 (s, 2H), 5.92 (s, 1H), 4.37 (q, J = 6.5 Hz, 1H), 3.76 - 3.68 (m, 4H), 3.29 (s, 4H), 3.24 (s, 3H), 2.68 - 2.46 (m, 12H), 1.45 (d, J = 6.5 Hz, 3H) ppm.Example S34. Synthesis of 4-[[2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-8-yl]methyl]morpholine (Compound 34).

[0770] Compound 34 was prepared as outlined below.

[0771] Step 1. Synthesis of dimethyl pyridine-2,4-dicarboxylate.

[0772] To a solution of pyridine-2,4-dicarboxylic acid (2.0 g, 12 mmol) in MeOH (50 mL) was added thionyl chloride (4.3 mL, 60 mmol) at 0 °C. Then the mixture was stirred at 60 °C for 16h. The mixture was concentrated and purified by SGC (petroleum ether: ethyl acetate=l : 1) to afford the desired product dimethyl pyridine-2,4-dicarboxylate (1.4 g , yield 59.9%) as a yellow solid.

[0773] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 95% (214 nm) Mass: found peak 196.2 (M+l) at 0.947 min.

[0774] Step 2. Synthesis of dimethyl piperidine-2,4-dicarboxylate.

[0775] Under hydrogen, to a solution of dimethyl pyridine-2,4-dicarboxylate (1.4 g, 0.5 mmol) in acetic acid (50 mL) was added platinum dioxide (210 mg, 15%w / w). The reaction mixture was stirred at rt for 16h. The mixture was filtered. The filtrate was concentrated to afford the desired product dimethyl piperidine-2,4-dicarboxylate (1.44 g, yield 99.8%) as a colorless oil.

[0776] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA);Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 100% (214 nm) Mass: found peak 202.1 (M+l) at 0.198 min.

[0777] Step 3. Synthesis of dimethyl l-[2-(l,3-dioxoisoindolin-2-yl)ethyl]piperidine-2,5- dicarboxylate.

[0778] A stirred mixture of DCM (20 mL), N-(2-hydroxyethyl)phthalimide (2.0 g, 10.4 mmol) and 2,6-lutidine (1.62 mL, 13.9 mmol ) was cooled to 0 °C. Maintaining the temperature below 15 °C, trifluoromethanesulfonicanhydride (2.34 mL, 13.9 mmol) was added slowly over Ih. The resulting mixture was stirred at rt for 2h, then washed sequentially with water (10 mL), 2N HC1 (10 mL) and water (10 mL) to yield a solution of 2-(l,3-dioxoisoindolin-2-yl)ethyl trifluoromethanesulfonate. At 20-25 °C, a separate reaction vessel was charged with DCM (10 mL), water and sodium carbonate (3.69 g, 34.8 mmol). After stirring for 15 minutes, dimethyl piperidine-2,5-dicarboxylate (1.4 g, 6.96 mmol) in DCM (10 mL) was added, and the mixture was stirred for 16h. The organic layer was separated and crystallized by DCM to afford dimethyl l-[2-(l,3-dioxoisoindolin-2-yl)ethyl]piperidine-2,5-dicarboxylate (2.6 g , yield 99.8%) as a yellow solid.

[0779] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; LC purity: 100% (254 nm) Mass: found peak 375.3 (M+l) at 1.17 min.

[0780] Step 4. Synthesis of methyl l-oxo-2,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazine- 8-carboxylate.

[0781] A solution of dimethyl l-[2-(l,3-dioxoisoindolin-2-yl)ethyl]piperidine-2,4- dicarboxylate (2.6 g, 6.94 mmol) and hydrazine hydrate solution (0.7 mL, 13.9 mmol) in MeOH (20 mL) was stirred for 16h at rt. The organic layer was separated and crystallized by DCM (10 mL). The filtrate was concentrated to afford the desired product methyl l-oxo-2,3,4,6,7,8,9,9a- octahydropyrido[l,2-a]pyrazine-8-carboxylate (1.3 g , yield 88.2%) as a yellow solid.

[0782] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA);Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm;Column Temperature: 40 °C; Mass: found peak 213.1 (M+l) at 0.1 min.

[0783] Step 5. Synthesis of 2,3,4,6,7,8,9,9a-octahydro-lH-pyrido[l,2-a]pyrazin-8- ylmethanol.

[0784] At 0 °C, to a solution of methyl l-oxo-2,3,4,6,7,8,9,9a-octahydropyrido[l,2- a]pyrazine-8-carboxylate (383 mg, 1.6 mmol) in tetrahydrofuran (20 mL) was added LiAlH4 (18.8 mL, 18.8 mmol) under Ar atomosphere. The reaction was stirred at 60 °C for 3h, then were added 20 drops of water and 20 drops of 15% NaOH to the mixture slowly. Then were added 60 drops of water, the organic phase was separated and dried over sodium sulfate, filtered, and concentrated to dryness to afford 2,3,4,6,7,8,9,9a-octahydro-lH-pyrido[l,2-a]pyrazin-8- ylmethanol (800 mg, crude) as a yellow oil.

[0785] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA); Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm; Column Temperature: 40 °C; Mass: found peak 171.3 (M + H) at 0.233 min.

[0786] Step 6. Synthesis of [2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-8-yl]methanol.

[0787] To a solution of 3-bromo-5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazole (100 mg, 0.31 mmol) in dry 1,4-dioxane (3 mL) was added 2,3,4,6,7,8,9,9a-octahydro-lH-pyrido[l,2- a]pyrazin-8-ylmethanol (106 mg, 0.62 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladipm;dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (26 mg, 0.01 mmol), and sodium tert-butoxide (90 mg, 0.9 mmol) in a microwave tube. The reaction mixture was stirred at 100 °C for 24h. The mixture was filtered. The filtrate was purified by SGC (DCM:MeOH=20: l) to afford the desired product [2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-8- yl]methanol (50 mg, yield 39%) as a colorless oil.

[0788] LCMS method: Mobile Phase: A: Water (0.01%TFA) B: Acetonitrile (0.01%TFA);Gradient: from 5 to 95% of B in 1.2min at 2.2mL / min; Column: HALO C18, 2.7pm, 4.6*30mm;Column Temperature: 40 °C; LC purity: 92% (214 nm) Mass: found peak 411.3 (M+l) at 1.13 min.

[0789] Step 7. Synthesis of 2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazine-8-carbaldehyde.

[0790] To a solution of [2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-8-yl]methanol (50 mg, 0.12 mmol) and DIPEA (78 mg, 0.61 mmol) in DCM (5 mL) at 0 °C was added dropwise pyridine sulfur trioxide (96 mg, 0.61 mmol) in DMSO (1 mL). The reaction mixture was stirred at this temperature for 16h. The reaction was diluted with DCM (30 mL), washed with 5% Na2SOs aqueous (20 mL) and 5% sodium bicarbonate aqueous (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Then the crude product was diluted with EtOAc (20 mL), washed with saturated sodium chloride (lOmL x 3) dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product 2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-l,3,4,6,7,8,9,9a- octahydropyrido[l,2-a]pyrazine-8-carbaldehyde (40 mg, yield 78.1%) as a yellow solid.

[0791] LCMS method: Column: HALO C18 2.7pm 4.6*30mm Mobile phase: water (0.01%TFA) (A) / ACN (0.01%TFA) (B) Elution program: Gradient from 5 to 95% of B in l.Omin at 2.2.mL / min Temperature: 40°C LC purity: 40% (214nm); Mass: 409.3 [M + 1]+ at 1.011 min.

[0792] Step 8. Synthesis of 4-[[2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-8-yl]methyl]morpholine (Compound 34).

[0793] To a solution of 2-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazine-8-carbaldehyde (40 mg, 0.0979 mmol) in methanol (5 mL) was added sodium triacetoxyborohydride (62.3 mg, 0.294 mmol), morpholine (17.1 mg, 0.196 mmol), a drop of acetic acid and 4A molecular sieves. The reaction mixture was stirred at room temperature for 16h. The mixture was quenched with water (5 mL) and extracted with dichloromethane (10 mL X 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (ammonium hydrogen carbonate / water / acetonitrile) to afford the desired product 4-[[2-[5-methyl-l-[4- (trifluoromethoxy)phenyl]pyrazol-3-yl]-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-8- yl]methyl]morpholine (4.9 mg, yield 10.2%) as a colorless oil.

[0794] LCMS method: Mobile Phase: A: water (10 mM ammonium hydrogen carbonate) B: Acetonitrile; Gradient: 10% increase to 95%B within 1.5 min; Flow Rate: 1.5 mL / min; Column: X-Bridge C18, 50*4.6mm, 3.5pm; Column Temperature: 50 °C; LC purity: 100% (214 nm) Mass: found peak 480.2 (M+l) at 2.121 min.

[0795] 'H NMR (400 MHz, CDCh) 5 7.49 - 7.43 (m, 2H), 7.28 (s, 2H), 5.70 (s, 1H), 3.79 - 3.67 (m, 4H), 3.61 (dd, J = 20.0, 12.4 Hz, 2H), 3.06 - 2.80 (m, 3H), 2.58 (m, 1H), 2.40 (s, 5H), 2.30 (s, 3H), 2.18 (d, J = 7.2 Hz, 2H), 2.14 - 1.99 (m, 2H), 1.77 (t, J = 14.8 Hz, 2H), 1.29 (d, J = 26.4 Hz, 2H).Example S35. Synthesis of 4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]morpholine (Compound 35).

[0796] Compound 35 was prepared as outlined below.

[0797] Step 1. Synthesis of tert-butyl 4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol- 3-yl] piperazine- 1-carboxylate.Boc

[0798] To a solution of tert-butyl 4-(5-methyl-lH-pyrazol-3-yl)piperazine-l-carboxylate (150 mg, 0.563 mmol), [4-(trifluoromethyl)phenyl]boronic acid (232 mg, 1.13 mmol) and Cu(OAc)2 (224 mg, 1.13 mmol) in DCM (10 mL) was added dry pyridine (89 mg, 1.13 mmol). The mixture was stirred at rt for 16h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (PE / EA=3 / 1) to afford the desired product tertbutyl 4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-l-carboxylate (157 mg, yield 62.8%) as a yellow solid.

[0799] LCMS Method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA; Gradient: 5%B increase to 95%B within l.Omin; Flow Rate: 2.2 mL / min; Column: Sunfire,4.6*30 mm, 2.7 pm; Column Temperature: 40 °C; LC purity: 96.4% (214 nm), Mass: found peak 427.2(M+H) at 1.526 min.

[0800] Step 2. Synthesis of l-[5-methyl-l-[4-(trifluoro-methoxy)phenyl] pyrazol-3- yl] piperazine.Boc

[0801] A solution of tert-butyl 4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazine-l -carboxylate (157 mg, 0.368 mmol) and TFA (420 mg, 3.68 mmol) in DCM (10 mL) was stirred at rt for Ih. The reaction mixture was concentrated in vacuo. The residue was diluted with water (20 mL), neutralized with potassium carbonate to pH=8, extracted with dichloromethane (30 mL*3), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product l-[5-methyl-l-[4-(trifluoro-methoxy)phenyl] pyrazol-3-yl]piperazine (110 mg, yield 61.1%) as a yellow oil.

[0802] LCMS Method: Mobile Phase: A: Water (0.01%TFA), B: Acetonitrile (0.01%TFA); Gradient: 5%B increase to 95%B within l.Omin; Flow Rate: 2.2mL / min; Column: Sunfire,4.6*30 mm, 2.7 pm; Column Temperature: 40 °C; LC purity: 100.0% (214 nm), Mass: found peak 327.2(M+H) at 1.036 min.

[0803] Step 3. Synthesis of 4-[2-[4-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3- yl]piperazin-l-yl]ethyl]morpholine (Compound 35).

[0804] To a solution of l-[5-methyl-l-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (118 mg, 0.362 mmol), potassium carbonate (150 mg, 1.08 mmol), and KI (60 mg, 0.362 mmol) ...

Claims

CLAIMS1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X1is C and X2is N, or X1is N and X2is C;= is a single bond or a double bond, provided that one = is a double bond and one = is a single bond;R1is Ci-C6alkyl, C3-C6cycloalkyl, -CN, Ci-C6haloalkyl, -(Ci-C6alkylene)-O-(Ci-C6alkyl),-(Ci-Ce alkylene)-O-(Ci-Ce haloalkyl), or -(Ci-Ce alkylene)(C3-Ce cycloalkyl);L1is a bond, O, or -CH2-;Ring B is C3-C6 cycloalkyl, 6-membered heteroaryl containing 1 or 2 nitrogen atoms, or Ce-Cio aryl; each R2is independently Ci-Ce alkyl, Ci-Ce haloalkyl, halo, -O(Ci-Ce alkyl), or -O(Ci-C6haloalkyl), or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from halo and Ci-Ce haloalkyl;L2is a bond or O;Ring A is, 9- to 11-membered spiro heterocyclylene, or 8- to 10-membered bicyclic fused heterocyclylene, wherein the heterocyclylene contains 1-2 nitrogen atoms;Y1is N or CH;Y2is N or CH; x is 0, 1, or 2; y is 0 or 1; m is 0-5; each R3is independently Ci-Ce alkyl, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R3groups on the same carbon atom are taken together to form a spiro C3-C6 cycloalkyl;L3is a bond, -CH(Ra)-, -CH(Ra)CH(Ra)-, -OCH(Ra)CH(Ra)-, -CH(Ra)CH(Ra)N(Ra)-, 5- to 6-membered heterocyclylene, or -O-(4-membered heterocyclylene), wherein the heterocyclylene contains 1-2 nitrogen atoms; each Rais independently H or Ci-Ce alkyl;W is O, CH2, SO2, S(O)=NH, SO, or N(H);Z is N or CH; r is 0, 1, or 2; s is 0 or 1; each R4is independently halo, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom, or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group; and n is 0-5.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein:R1is Ci-C6alkyl, C3-C5 cycloalkyl, -CN, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(Ci-C3alkyl), -(C1-C3 alkylene)-O-(Ci-C3 haloalkyl), or -(C1-C3 alkylene)(C3-Ce cycloalkyl).

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein:R1is -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2CH2CH(CH3)2, -CH2OCH3, -CH2CH2OCH3, -CH(CH3)OCH3, -CH(CH3)CH2OCH3, -CH2CHF2, -CF3, -CHF2,6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein:L1is a bond.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein:L1is O.

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein:L1is -CH2-.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein:Ring B is C4-C6 cycloalkyl, pyridinyl, pyrazinyl, pyrimidinyl, or phenyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein:

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein: each R2is independently C1-C4 alkyl, C1-C3 haloalkyl, halo, -O(Ci-C3 alkyl), or-O(Ci-C3haloalkyl), or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from halo and C1-C3 haloalkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: each R2is independently -CF3, -CF2CH3, -CH2CHF2, -CHF2, F, Cl, Br, -OCF3, -OCHF2, -OCH3, or -C(CH3)3, or two R2groups on adjacent carbon atoms are taken together to form a fused phenyl or a fused 5-membered heterocyclyl containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1-5 groups selected from F or -CF3.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein:

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein:L2is a bond.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein:L2is O.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein:Y1is N or CH;Y2is N or CH; x is 0, 1, or 2; and y is 0 or 1.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein:Ring A is 9- to 11 -membered spiro heterocyclylene or 8- to 10-membered bicyclic fused heterocyclylene, wherein the heterocyclylene contains 1-2 nitrogen atoms.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein:

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein: m is 0.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein: m is 1-3.

21. The compound of any one of claims 1-18 and 20, or a pharmaceutically acceptable salt thereof, wherein: each R3is independently C1-C3 alkyl, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R3groups on the same carbon atom are taken together to form a spiro C3-C5 cycloalkyl.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein: each R3is independently -CH3, or two R3groups are taken together to form a bridging -CH2- or -CH2CH2- group,or two R3groups on the same carbon atom are taken together to form a spiro cyclopropyl.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein:

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein:L3is a bond.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein:L3is -CH(Ra)-, -CH(Ra)CH(Ra)-, -OCH(Ra)CH(Ra)-, or -CH(Ra)CH(Ra)N(Ra)-; and each Rais independently H or C1-C3 alkyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein:L3is -CH2, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -OCH2CH2-, or -CH2CH2N(CH2CH3)-.

27. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein:L3is 5- to 6-membered heterocyclylene or -0-(4-membered heterocyclylene), wherein the heterocyclylene contains 1-2 nitrogen atoms.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein:

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein:W is O, CH2, or N(H).

30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein:W is SO2, S(O)=NH, or SO.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein:Z is N.

32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein:Z is CH.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein: r and s are each 1.

34. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein: r and s are each 0.

35. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein: r is 1; and s is 0.

36. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein: r is 2; and s is 1.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein:

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein: n is 0.

39. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein: n is 1-3.

40. The compound of any one of claims 1-37 and 39, or a pharmaceutically acceptable salt thereof, wherein: each R4is independently halo, -OH, C1-C3 alkyl, or C1-C3 haloalkyl, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom, or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein: each R4is independently F, -OH, -CH3, -CH(CH3)2, or -CF3, or two R4groups are taken together to form a bridging -CH2- or -CH2CH2- group, or two R4groups on adjacent atoms are taken together to form a fused 5-membered heterocyclyl containing 1 oxygen atom, or two R4groups on the same carbon atom are taken together to form a spiro 4-membered heterocyclyl containing 1 oxygen atom or SO2 group.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein:

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-a), (I-b), or (I-c):

44. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-d) or (I-e):

45. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), or (1-1):heterocyclylene, wherein the heterocyclylene contains 1-2 nitrogen atoms.

46. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Ila) or (lib):

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (lie):

48. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Illa) or (Illb):whereinis 9- to 11 -membered spiro heterocyclylene containing 1-2 nitrogen atoms.

49. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IVa) or (IVb):nitrogen atoms.

50. A compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

51. A compound selected from the compounds of Table 2 or a pharmaceutically acceptable salt thereof.

52. A compound selected from the compounds of Table 3 or a pharmaceutically acceptable salt thereof.

53. A pharmaceutical composition comprising the compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

54. A method of inhibiting Emopamil Binding Protein (EBP) comprising contacting EBP with an effective amount of the compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 53.

55. A method of remyelinating a neuronal axon comprising contacting the neuronal axon with an effective amount of the compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 53.

56. A method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 53.

57. The method of claim 56, wherein the demyelinating disease is multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute optic neuritis, transverse myelitis, chronic inflammatory demyelinating polyneuropathy (CIDP), or Guillain-Barre syndrome.

58. A method of treating multiple sclerosis (MS) in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 53.

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