Pyrazolyl compounds as emopamil binding protein inhibitors

Abstract

Provided herein are compounds and pharmaceutical compositions thereof for inhibiting emopamil binding protein (EBP), and the use of the compounds and pharmaceutical compositions thereof in the treatment of demyelinating diseases, such as multiple sclerosis.

Description

Cross-references to related applications

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

[0002] This disclosure relates to emopamivir-binding protein (EBP) inhibitors that can be used to treat demyelinating diseases such as multiple sclerosis. Specifically, this disclosure describes compounds and compositions for inhibiting EBP, methods for treating demyelinating diseases, and methods for synthesizing these compounds. Background Technology

[0003] Myelin is an insulating layer or sheath that surrounds the axons of nerve cells. This lipid-rich insulating substance protects the axons and enables skip conduction, thereby accelerating axonal electrical impulses (Williamson et al., Front Cell Neurosci., 2018, 12: 424). In the central nervous system (CNS), myelin is formed by glial cells called oligodendrocytes, and in the peripheral nervous system (PNS), by glial cells called Schwann cells.

[0004] Demyelinating diseases cause myelin sheath damage, and such diseases include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute optic neuritis, transverse myelitis, chronic inflammatory demyelinating polyneuropathy (CIDP), and Guillain-Barré syndrome. Multiple sclerosis (MS) is a complex neurological disease characterized by the degeneration of myelin sheaths in the central nervous system (CNS) (Ghasemi et al., Cell J., 2017, 19(1): 1-10). In the pathogenesis of MS, damage or destruction of the myelin sheath surrounding neuronal axons leads to dysfunction of signal transmission, axonal damage, neuronal loss, accumulation of lesion burden, and significant neurological disability in patients.

[0005] The central nervous system (CNS) possesses the ability to regenerate myelin after injury, which is achieved through the proliferation, migration, and differentiation of a population of adult progenitor cells (called oligodendrocyte precursor cells (OPCs)) into new myelin-forming oligodendrocytes to generate new myelin, or to a lesser extent through the generation of new myelin from existing oligodendrocytes (Kuhn et al., Cells, 2019, 8(11): 1424). While such endogenous myelin regeneration by OPCs and oligodendrocytes can repair and limit damage in the early stages of MS, this process becomes less efficient during later stages of disease progression (Chari, Int RevNeurobiol. 2007, 79: 589-620). Therefore, stimulating myelin regeneration to maintain neuronal function by enhancing the repair of damaged myelin is a key focus in the development of novel therapeutics for MS.

[0006] Recent studies have confirmed that inhibiting specific cholesterol biosynthesis pathway enzymes is a functional mechanism by which many small molecules enhance oligodendrocyte formation (Hubler et al., Nature, 2018, 560(7718): 372-376). These molecules enhance oligodendrocyte formation by inhibiting enzymes and leading to the accumulation of their 8,9-unsaturated sterol substrates (such as yeast sterol and dihydrozymostenol).

[0007] Emopam-binding protein (EBP, also known as Δ8Δ7 isomerase, 3-β-hydroxysteroid-Δ(8),Δ(7)-isomerase, human sterol isomerase (HSI), CDPX2, CHO2, CPX, or CPXD) is an enzyme in the cholesterol biosynthesis pathway that catalyzes the conversion of yeast sterol and dihydroyeast sterol into dehydrolanosterol and lanosterol (Silve et al., The Journal of Biological Chemistry, 1996, 271(37): 22434-22440). Therefore, targeting EBP is a strategy to increase OPC differentiation. However, compounds and therapeutic methods that can target EBP are needed to induce OPC differentiation thereby enhancing the generation of new oligodendrocytes and increasing myelin formation and / or myelin regeneration in demyelinating lesions.

[0008] Therefore, in one respect, this article provides compounds that inhibit EBP for use in the treatment of demyelinating diseases such as multiple sclerosis. Summary of the Invention

[0009] In some embodiments, this document describes compounds and compositions thereof for inhibiting emopamivir-binding protein (EBP) for the treatment of demyelinating diseases such as multiple sclerosis.

[0010] The following examples are covered.

[0011] Example 1. A compound having formula (I): (I) Or its pharmaceutically acceptable salt, wherein: X 1 It is C and X 2 Is it N, or X? 1 It is N and X 2 It is C; It is either a single bond or a double bond, depending on one condition. It is a double bond and one It is a single key; R 1 It is C1-C6 alkyl, C3-C6 cycloalkyl, -CN, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 haloalkyl), or -(C1-C6 alkylene)(C3-C6 cycloalkyl); L 1 It is a bond, O, or -CH2-; Ring B is a C3-C6 cycloalkyl group, a 6-membered heteroaryl group containing 1 or 2 nitrogen atoms, or a C6-C... 10 Aryl; Each R 2 It is independently a C1-C6 alkyl, C1-C6 haloalkyl, halogenated, -O (C1-C6 alkyl), or -O (C1-C6 haloalkyl). Or two R atoms on adjacent carbon atoms 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1 to 5 groups selected from halogenated and C1-C6 halogenated alkyl groups; L 2 It is a key or an 'O'; Ring A is , 9 to 11 spiro-heterocyclic groups, or 8 to 10 bicyclic fused heterocyclic groups, wherein the heterocyclic group contains 1 to 2 nitrogen atoms; Y 1 It is N or CH; Y 2 It is N or CH; x is 0, 1, or 2; y is 0 or 1; m is 0-5; Each R 3 It is independently a C1-C6 alkyl group. Or two Rs 3 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on the same carbon atom 3 The groups together form a spiroC3-C6 cycloalkyl group; L 3 It is a bond, -CH(R) a )-、-CH(R a )CH(R a )-、-OCH(R a )CH(R a )-、-CH(R a )CH(R a )N(R a -, 5 to 6 membered heterocyclic group or -O- (4 membered heterocyclic group), wherein the heterocyclic group contains 1 to 2 nitrogen atoms; Each R a It is independently an H or C1-C6 alkyl group; W is O, CH2, SO2, S(O)=NH, SO or N(H); Z is either N or CH; r is 0, 1, or 2; s is 0 or 1; Each R 4 It can be halogenated, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. Or two Rs 4 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on adjacent atoms 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom. Or two R atoms on the same carbon atom 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group; and n is 0-5.

[0012] Example 2. The compound as described in Example 1, or a pharmaceutically acceptable salt thereof, wherein: yes or .

[0013] Example 3. The compound as described in Example 1, or a pharmaceutically acceptable salt thereof, wherein: yes or .

[0014] Example 4. The compound as described in any one of Examples 1-3, or a pharmaceutically acceptable salt thereof, wherein: R 1 It is C1-C6 alkyl, C3-C5 cycloalkyl, -CN, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-O-(C1-C3 haloalkyl), or -(C1-C3 alkylene)(C3-C6 cycloalkyl).

[0015] Example 5. The compound as described in Example 4, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH 3. -CH2CH2CH(CH3)2, -CH2OCH3, -CH2CH2OCH3, -CH(CH3)OCH3, -CH(CH3)CH2OCH3, -CH2CHF2, -CF3, -CHF2, .

[0016] Example 6. The compound as described in any one of Examples 1-5, or a pharmaceutically acceptable salt thereof, wherein: L 1 It is a key.

[0017] Example 7. The compound as described in any one of Examples 1-5, or a pharmaceutically acceptable salt thereof, wherein: L 1 It is O.

[0018] Example 8. The compound as described in any one of Examples 1-5, or a pharmaceutically acceptable salt thereof, wherein: L 1 It is -CH2-.

[0019] Example 9. The compound as described in any one of Examples 1-8, or a pharmaceutically acceptable salt thereof, wherein: Ring B is a C4-C6 cycloalkyl, pyridyl, pyrazinyl, pyrimidinyl, or phenyl group.

[0020] Example 10. The compound as described in any one of Examples 1-9, or a pharmaceutically acceptable salt thereof, wherein: yes .

[0021] Example 11. The compound as described in any one of Examples 1-10, or a pharmaceutically acceptable salt thereof, wherein: Each R 2 It is independently a C1-C4 alkyl, C1-C3 haloalkyl, halogenated, -O (C1-C3 alkyl), or -O (C1-C3 haloalkyl). Or two R atoms on adjacent carbon atoms 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing one or two oxygen atoms, each of which is optionally substituted by one to five groups selected from halogenated and C1-C3 halogenated alkyl groups.

[0022] Example 12. The compound as described in Example 11, or a pharmaceutically acceptable salt thereof, wherein: Each R 2 Independently, it is -CF3, -CF2CH3, -CH2CHF2, -CHF2, F, Cl, Br, -OCF3, -OCHF2, -OCH3, or -C(CH3)3. Or two R atoms on adjacent carbon atoms 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing one or two oxygen atoms, each of which is optionally substituted by one to five groups selected from F or -CF3.

[0023] Example 13. The compound as described in any one of Examples 1-12, or a pharmaceutically acceptable salt thereof, wherein: yes .

[0024] Example 14. The compound as described in any one of Examples 1-13, or a pharmaceutically acceptable salt thereof, wherein: L 2 It is a key.

[0025] Example 15. The compound as described in any one of Examples 1-13, or a pharmaceutically acceptable salt thereof, wherein: L 2 It is O.

[0026] Example 16. The compound as described in any one of Examples 1-15, or a pharmaceutically acceptable salt thereof, wherein: Ring A is ; Y 1 It is N or CH; Y2 It is N or CH; x is 0, 1, or 2; and y is 0 or 1.

[0027] Example 17. The compound as described in any one of Examples 1-16, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 9- to 11-membered spiro-heterocyclic group or an 8- to 10-membered bicyclic fused-to-heterocyclic group, wherein the heterocyclic group contains 1-2 nitrogen atoms.

[0028] Example 18. The compound as described in any one of Examples 1-17, or a pharmaceutically acceptable salt thereof, wherein: yes .

[0029] Example 19. The compound as described in any one of Examples 1-18, or a pharmaceutically acceptable salt thereof, wherein: m is 0.

[0030] Example 20. The compound as described in any one of Examples 1-18, or a pharmaceutically acceptable salt thereof, wherein: m is 1-3.

[0031] Example 21. The compound as described in any one of Examples 1-18 and 20, or a pharmaceutically acceptable salt thereof, wherein: Each R 3 It is independently a C1-C3 alkyl group. Or two Rs 3 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on the same carbon atom 3 The groups together form spiroC3-C5 cycloalkyl groups.

[0032] Example 22. The compound as described in Example 21, or a pharmaceutically acceptable salt thereof, wherein: Each R 3 Independently, it is -CH3. Or two Rs 3 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on the same carbon atom 3 The groups together form a spirocyclopropyl group.

[0033] Example 23. The compound as described in any one of Examples 1-22, or a pharmaceutically acceptable salt thereof, wherein: yes .

[0034] Example 24. The compound as described in any one of Examples 1-23, or a pharmaceutically acceptable salt thereof, wherein: L 3 It is a key.

[0035] Example 25. The compound as described in any one of Examples 1-23, or a pharmaceutically acceptable salt thereof, wherein: L 3 It is -CH(R) a )-、-CH(R a )CH(R a )-、-OCH(R a )CH(R a - or -CH(R) a )CH(R a )N(R a )-;and Each R a It is independently H or C1-C3 alkyl.

[0036] Example 26. The compound as described in Example 25, or a pharmaceutically acceptable salt thereof, wherein: L 3 It is -CH2, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -OCH2CH2- or -CH2CH2N(CH2CH3)-.

[0037] Example 27. The compound as described in any one of Examples 1-23, or a pharmaceutically acceptable salt thereof, wherein: L 3 It is a 5- to 6-membered heterocyclic group or -O- (4-membered heterocyclic group), wherein the heterocyclic group contains 1-2 nitrogen atoms.

[0038] Example 28. The compound as described in Example 27, or a pharmaceutically acceptable salt thereof, wherein: L 3 yes .

[0039] Example 29. The compound as described in any one of Examples 1-28, or a pharmaceutically acceptable salt thereof, wherein: W can be O, CH2, or N(H).

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

[0041] Example 31. The compound as described in any one of Examples 1-30, or a pharmaceutically acceptable salt thereof, wherein: Z is N.

[0042] Example 32. The compound as described in any one of Examples 1-30, or a pharmaceutically acceptable salt thereof, wherein: Z is CH.

[0043] Example 33. The compound as described in any one of Examples 1-32, or a pharmaceutically acceptable salt thereof, wherein: r and s are both 1.

[0044] Example 34. The compound as described in any one of Examples 1-32, or a pharmaceutically acceptable salt thereof, wherein: r and s are both 0.

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

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

[0047] Example 37. The compound as described in any one of Examples 1-36, or a pharmaceutically acceptable salt thereof, wherein: yes .

[0048] Example 38. The compound as described in any one of Examples 1-37, or a pharmaceutically acceptable salt thereof, wherein: n is 0.

[0049] Example 39. The compound as described in any one of Examples 1-37, or a pharmaceutically acceptable salt thereof, wherein: n is 1-3.

[0050] Example 40. The compound as described in any one of Examples 1-37 and 39, or a pharmaceutically acceptable salt thereof, wherein: Each R 4 It is independently a halo, -OH, C1-C3 alkyl, or C1-C3 haloalkyl. Or two Rs 4 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on adjacent atoms 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom. Or two R atoms on the same carbon atom 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group.

[0051] Example 41. The compound as described in Example 40, or a pharmaceutically acceptable salt thereof, wherein: Each R 4 Independently, it is F, -OH, -CH3, -CH(CH3)2, or -CF3. Or two Rs 4 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on adjacent atoms 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom. Or two R atoms on the same carbon atom 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group.

[0052] Example 42. The compound as described in any one of Examples 1-41, or a pharmaceutically acceptable salt thereof, wherein: yes .

[0053] Example 43. A compound as described in any one of Examples 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (Ia), (Ib), or (Ic): .

[0054] Example 44. A compound as described in any one of Examples 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (Id) or (Ie): .

[0055] Example 45. A compound as described in any one of Examples 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il): in It is a 5- to 6-membered subheterocyclic group and It is a 4-membered heterocyclic group, wherein the heterocyclic group contains 1-2 nitrogen atoms.

[0056] Example 46. A compound as described in any one of Examples 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIa) or (IIb): .

[0057] Example 47. A compound as described in Example 46, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (IIc): .

[0058] Example 48. A compound as described in any one of Examples 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIa) or (IIIb): in It is a 9- to 11-membered spiro-heterocyclic group containing 1-2 nitrogen atoms.

[0059] Example 49. A compound as described in any one of Examples 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (IVa) or (IVb): ,in It is an 8- to 10-membered bicyclic fused heterocyclic group containing 1-2 nitrogen atoms.

[0060] Example 50. A compound selected from the compounds in Table 1 or their pharmaceutically acceptable salts.

[0061] Example 51. A compound selected from the compounds in Table 2 or their pharmaceutically acceptable salts.

[0062] Example 52. A compound selected from the compounds in Table 3 or their pharmaceutically acceptable salts.

[0063] Example 53. A pharmaceutical composition comprising a compound as described in any one of Examples 1-52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0064] Example 54. A method for inhibiting emopamiprobinding protein (EBP), the method comprising contacting EBP with an effective amount of a compound as described in any one of Examples 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Example 53.

[0065] Example 55. A method for remyelinating a neuronal axon, the method comprising contacting the neuronal axon with an effective amount of a compound as described in any one of Examples 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Example 53.

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

[0067] Example 57. The method as described in Example 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-Barré syndrome.

[0068] Example 58. A method of treating multiple sclerosis (MS) in a subject in need, the method comprising administering to the subject an effective amount of a compound as described in any one of Examples 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Example 53. Detailed Implementation definition

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. It should be understood that both the general description above and the detailed description below are exemplary and illustrative only and do not limit any of the claimed subject matter. If any material incorporated herein by reference is inconsistent with the express content of this disclosure, the express content shall prevail. In this application, the use of the singular includes the plural unless otherwise expressly stated. It must be noted that, unless the context clearly requires otherwise, the singular forms “a / an” and “the” as used in this specification and the appended claims include plural indicators. In this application, the use of “or” means “and / or” unless the context requires otherwise. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0070] In this specification, references to "some embodiments," "embodiments," "one embodiment," or "other embodiments" mean that a particular feature, structure, or characteristic described in connection with these embodiments is included in at least some, but not necessarily all, embodiments of the invention.

[0071] As used herein, ranges and quantities can be expressed as “about” a specific value or range. “About” also includes the exact quantity. Therefore, “about 5 µL” means both “about 5 µL” and “5 µL”. Typically, the term “about” includes quantities expected to be within experimental error, such as within 15%, 10%, or 5%.

[0072] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0073] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C1-C2). 20 Alkyl groups, 1 to 10 carbon atoms (i.e., C1-C1). 10Alkyl groups are alkyl groups with 1 to 6 carbon atoms (i.e., C1-C6 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, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbon atoms is named by its chemical name or identified by its molecular formula, it can encompass all positional isomers with that number of carbon atoms; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), isobutyl (i.e., -CH2CH(CH3)2), sec-butyl (i.e., -CH(CH3)CH2CH3), and tert-butyl (i.e., -C(CH3)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-C2). 20 Alkylene), 1 to 10 carbon atoms (i.e., C1-C) 10 Alkylenes, having 1 to 6 carbon atoms (i.e., C1-C6 alkylenes) or 1 to 3 carbon atoms (i.e., C1-C3 alkylenes). Examples of alkylene groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene. When an alkylene residue with a specific number of carbon atoms is named by its chemical name or identified by its molecular formula, all positional isomers with that number of carbon atoms can be covered; thus, for example, "C4 alkylene" includes -(CH2)3CH2-, -CH2C(CH3)2-, and -CH(CH3)CH2CH2-; and "C3 alkylene" includes -(CH2)2CH2- and -C(CH3)2-.

[0075] The "aryl" group has 6 to 14 carbon atoms (C6-C14). 14 An aryl group is an aromatic carbocyclic group having a single ring (e.g., phenyl or C6 aryl) or multiple fused rings (e.g., naphthyl or anthracene). In some embodiments, the aryl group contains 6-14 carbons (C6-C6). 14 Aryl), and in other embodiments, the ring portion of the group contains 6 to 12 (C6-C) groups. 12 (aryl) or 6 to 10 carbon atoms (C6-C) 10 Aryl groups. Specific aryl groups include phenyl, biphenyl, naphthyl, etc.

[0076] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings (including fused rings, bridged rings, and spirocyclic systems). The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C3-C4). 20 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C3-C4). 10 Cycloalkyl (or cycloalkyl) or 3 to 6 cyclic carbon atoms (i.e., C3-C6 cycloalkyl). Cycloalkyl also includes "spirocycloalkyl" when two substitution positions are present on the same carbon atom. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to cover any non-aromatic ring that can fused with an aryl ring, regardless of its attachment to the rest 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, "C1-C6 haloalkyl" refers to a C1-C6 alkyl group substituted with one or more halogen atoms. C1 haloalkyl refers to a methyl group that can be substituted with 1-3 halogen groups, C2 haloalkyl refers to an ethyl group that can be substituted with 1-5 halogen groups, C3 haloalkyl refers to a propyl group that can be substituted with 1-7 halogen groups, and so on. Examples of haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Haloalkyl groups may contain one or more identical halogen atoms (i.e., all fluorine) or mixtures of halogen atoms (i.e., chlorine and fluorine).

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

[0079] A "heterocyclic group" refers to a saturated or unsaturated cyclic alkyl group having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. A heterocyclic group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spiro, and can contain one or more oxo (C=O) or N-oxide (NO-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of attachment (i.e., it can be bonded by carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom that can be fused to an aryl or heteroaryl ring, regardless of its attachment to the rest of the molecule. As used herein, heterocyclic groups have 1 to 10 cyclic carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, and 1 to 5 cyclic heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms, which are independently selected from nitrogen, sulfur, and oxygen. Examples of heterocyclic groups include dioxolane, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecyclone, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0080] "Cyano" refers to the group -CN.

[0081] "Halogen" or "halo" includes fluorine, chlorine, bromine, and iodine.

[0082] "Hydroxy group" refers to the -OH group.

[0083] "Oxygenation" refers to the atom (=O) or (O).

[0084] Some commonly used alternative chemical names can be used. For example, divalent groups such as divalent "phenyl" groups, divalent "heteroaryl" groups, and divalent "heterocyclic" groups can also be called "phenylene" groups, "heteroaryl" groups, or "heterocyclic" groups, respectively.

[0085] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both the scenario in which the event or situation occurs and the scenario in which the event or situation does not occur.

[0086] Furthermore, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be substituted with hydrogen atoms other than hydrogen. The substituted group may be substituted by one or more substituents (such as, for example, 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 both the unlabeled form and the isotopically labeled form of the compound. Isotopically labeled compounds have the structures shown in the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Various isotope-labeled compounds disclosed herein, such as those containing radioactive isotopes (e.g., 2 H, 3 H, 13 C and 14 C) Those compounds incorporated herein are included. Such isotopically labeled compounds may be used in metabolic studies, reaction kinetic studies, detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution), or for the treatment of patients with radiotherapy.

[0088] This disclosure also includes “deuterated analogues” of the compounds described herein, wherein one to n hydrogen atoms attached to carbon atoms are replaced with deuterium, where n is the number of hydrogen atoms in the molecule. When multiple deuterium atoms are present in a compound, these deuterium atoms may be located in the same part of the molecule (e.g., on a single alkyl group or a single ring) or in different parts of the molecule (e.g., on separate alkyl groups or separate rings). Such compounds may exhibit increased metabolic resistance and, therefore, may be used to increase the half-life of any compound when administered to mammals, particularly humans. 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, e.g., by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0089] "Pharmaceutical acceptable" means compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0090] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" includes, for example, salts containing inorganic acids and salts containing organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt (particularly pharmaceutically acceptable addition salts) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following the conventional procedure for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines (e.g., alkylamines). Specific examples of suitable amines by way of example only include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine. It should be understood that referring to a specific salt (e.g., hydrochloride or formate) can refer to a single salt (e.g., monohydrochloride or monoformate) or a multiple salt (e.g., dihydrochloride or diformate).

[0091] The compounds disclosed herein, or their pharmaceutically acceptable salts, may contain asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomers, which may be defined as (R)- or (S)- in terms of absolute stereochemistry, or (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC).

[0092] "Tautomer" refers to alternative forms of compounds that differ in proton position, such as enol-ketone and imine-enamine tautomers, or tautomers containing heteroaryl groups attached to both the -NH- and =N-ring moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles. It is intended to include all tautomer forms of the compounds described herein.

[0093] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but with different three-dimensional structures, and these three-dimensional structures are not interchangeable. This disclosure considers various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are not mirror images of each other.

[0094] A "diastereomer" is a stereoisomer that has at least two asymmetric atoms that are not mirror images of each other.

[0095] As used herein, “pharmaceuticalally acceptable carrier” or “pharmaceuticalally acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions should be considered. Complementary active ingredients may also be incorporated into the composition.

[0096] An “effective amount” or dose of a compound or composition means the amount of the compound or composition that would produce the desired results as expected based on the disclosure herein. An effective amount can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to determining the LD50. 50 (50% lethal dose for the population) and ED 50 (The effective dose in 50% of the population).

[0097] The "therapeutic effective amount" or dose of a compound or composition refers to the amount of the compound or composition that results in a reduction or suppression of symptoms or a prolongation of survival in a subject (i.e., a human patient). Multiple doses of the compound or composition may be required to achieve the desired effect.

[0098] The term "treating" or "treatment" for a subject's disease means 1) preventing the disease from occurring in patients who are susceptible to the disease or who have not yet shown symptoms of the disease; 2) suppressing the disease or preventing its progression; or 3) improving the disease or causing its remission. As used herein, "treatment" or "treatment" is a method for obtaining a beneficial or desired outcome (including clinical outcomes). For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms caused by the disease or disorder; alleviating the severity of the disease or disorder; stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder); delaying the onset or recurrence of the disease or disorder; delaying or slowing the progression of the disease or disorder; improving the state of the disease or disorder; providing relief from the disease or disorder (whether partial or complete); reducing the dosage of one or more other agents required to treat the disease or disorder; enhancing the effect of another agent used to treat the disease or disorder; delaying the progression of the disease or disorder; improving quality of life; and / or prolonging the subject's survival. "Treatment" also encompasses reducing the pathological consequences of the disease or disorder. The method of the present invention takes into account any one or more of these therapeutic aspects.

[0099] As used herein, the terms “subject” and “patient” refer to 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 these terms require or are limited to situations characterized by supervision (e.g., continuous or intermittent) by healthcare professionals (e.g., physicians, registered nurses, nurse practitioners, physician assistants, caregivers, or hospice workers).

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

[0101] While various features of the invention may be described in the context of a single embodiment, these features may also be provided individually or in any suitable combination. Conversely, although the invention may be described herein in the context of a single embodiment for clarity, the invention may also be implemented in a single embodiment. compound

[0102] In one respect, this paper provides compounds having formula (I): (I) Or its pharmaceutically acceptable salt, wherein: X 1 It is C and X2 Is it N, or X? 1 It is N and X 2 It is C; It is either a single bond or a double bond, depending on one condition. It is a double bond and one It is a single key; R 1 It is C1-C6 alkyl, C3-C6 cycloalkyl, -CN, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 haloalkyl) or -(C1-C6 alkylene)(C3-C6 cycloalkyl); L 1 It is a bond, O, or -CH2-; Ring B is a C3-C6 cycloalkyl group, a 6-membered heteroaryl group containing 1 or 2 nitrogen atoms, or a C6-C... 10 Aryl; Each R 2 It is independently a C1-C6 alkyl, C1-C6 haloalkyl, halogenated, -O (C1-C6 alkyl), or -O (C1-C6 haloalkyl). Or two R atoms on adjacent carbon atoms 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1 to 5 groups selected from halogenated and C1-C6 halogenated alkyl groups; L 2 It is a key or an 'O'; Ring A is , 9 to 11 spiro-heterocyclic groups, or 8 to 10 bicyclic fused heterocyclic groups, wherein the heterocyclic group contains 1 to 2 nitrogen atoms; Y 1 It is N or CH; Y 2 It is N or CH; x is 0, 1, or 2; y is 0 or 1; m is 0-5; Each R 3 It is independently a C1-C6 alkyl group. Or two Rs 3 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on the same carbon atom 3 The groups together form a spiroC3-C6 cycloalkyl group; L 3 It is a bond, -CH(R) a )-、-CH(R a )CH(Ra )-、-OCH(R a )CH(R a )-、-CH(R a )CH(R a )N(R a -, 5 to 6 membered heterocyclic group or -O- (4 membered heterocyclic group), wherein the heterocyclic group contains 1 to 2 nitrogen atoms; Each R a It is independently an H or C1-C6 alkyl group; W is O, CH2, SO2, S(O)=NH, SO or N(H); Z is either N or CH; r is 0, 1, or 2; s is 0 or 1; Each R 4 It can be halogenated, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. Or two Rs 4 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on adjacent atoms 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom. Or two R atoms on the same carbon atom 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group; and n is 0-5.

[0103] In some embodiments, X 1 It is C and X 2 It is N, one of them It is a double bond and one It is a single key. In some embodiments, X 1 It is N and X 2 It's C, one of them. It is a double bond and one It is a single key.

[0104] In some embodiments, yes In some embodiments, yes or In some embodiments, yes In some embodiments, yes .

[0105] In some embodiments, yes In some embodiments, yes or In some embodiments, yes In some embodiments, yes .

[0106] In some embodiments, R 1 It is a C1-C6 alkyl, C3-C6 cycloalkyl, -CN, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 haloalkyl), or -(C1-C6 alkylene)(C3-C6 cycloalkyl). In some embodiments, R 1 It is C1-C6 alkyl, C3-C5 cycloalkyl, -CN, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-O-(C1-C3 haloalkyl) or -(C1-C3 alkylene)(C3-C6 cycloalkyl).

[0107] In some embodiments, R 1 It is a C1-C6 alkyl group. In some embodiments, R 1 It is a C1-C5 alkyl group. In some embodiments, R 1 It is a C1-C4 alkyl group. In some embodiments, R 1 It is a C1-C3 alkyl group. In some embodiments, R 1 It is a C1-C2 alkyl group. In some embodiments, R 1 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, or -CH2CH2CH(CH3)2.

[0108] In some embodiments, R 1 It is a C3-C6 cycloalkyl group. In some embodiments, R 1 It is a C3-C5 cycloalkyl group. In some embodiments, R 1 It is a C3-C4 cycloalkyl group. In some embodiments, R 1 It is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 It is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 1 It is cyclopropyl. In some embodiments, R 1 It is cyclobutyl.

[0109] In some embodiments, R 1 Yes - CN.

[0110] In some embodiments, R 1 It is a C1-C6 haloalkyl group. In some embodiments, R 1 It is a C1-C6 haloalkyl group containing 1-13 halogen atoms. In some embodiments, R 1 It is a C1-C3 haloalkyl group. In some embodiments, R 1 It is a C1-C3 haloalkyl group containing 1-7 halogen atoms. In some embodiments, R 1 It is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 1 It is -CH2CHF2, -CF3, or -CHF2. In some embodiments, R 1 It is -CF3. In some embodiments, R 1 It is -CH2CHF2. In some embodiments, R 1 It is -CHF2.

[0111] In some embodiments, R 1 It is -(C1-C6 alkylene)-O-(C1-C6 alkyl). In some embodiments, R 1 It is -(C1-C3 alkylene)-O-(C1-C3 alkyl). It should be understood that -(C1-C6 alkylene)- includes optional substitutions with C1-C6 alkyl groups, such that the total number of carbon atoms does not exceed 6. For example, -(C1-C6 alkylene)- includes -(C1-C5 alkylene)- substituted with methyl, such that the total number of carbon atoms is 2-6. In some embodiments, -(C1-C6 alkylene)- includes -(C1-C2 alkylene)- substituted with C1-C4 alkyl, such that the total number of carbon atoms is 2-6. In some embodiments, R 1 It is -(C1-C3 alkylene)-O-(CH3), -(C1-C3 alkylene)-O-(CH2CH3), or -(C1-C3 alkylene)-O-(CH2CH2CH3). In some embodiments, R 1 Is -CH2OCH3, -CH2CH2OCH3, -CH(CH3)OCH3 or -CH(CH3)CH2OCH3.

[0112] In some embodiments, R 1 It is -(C1-C6 alkylene)-O-(C1-C6 haloalkyl). In some embodiments, R 1It is -(C1-C6 alkylene)-O-(C1-C6 haloalkyl), wherein the C1-C6 haloalkyl contains 1-13 halogen atoms. In some embodiments, R 1 It is -(C1-C3 alkylene)-O-(C1-C3 haloalkyl). In some embodiments, R 1 It is -(C1-C3 alkylene)-O-(C1-C3 haloalkyl), wherein the C1-C3 haloalkyl contains 1-7 halogen atoms. It should be understood that -(C1-C6 alkylene)- includes optional substitutions with C1-C6 alkyl groups, such that the total number of carbon atoms does not exceed 6. For example, -(C1-C6 alkylene)- includes -(C1-C5 alkylene)- substituted with methyl, such that the total number of carbon atoms is 2-6. In some embodiments, -(C1-C6 alkylene)- includes -(C1-C2 alkylene)- substituted with C1-C4 alkyl, such that the total number of carbon atoms is 2-6. In some embodiments, R 1 It is -(C1-C3 alkylene)-O-(CF3), -(C1-C3 alkylene)-O-(CHF2), or -(C1-C3 alkylene)-O-(CH2F). In some embodiments, R 1 It is -(CH2)-O-(C1-C3 haloalkyl), -(CH2CH2)-O-(C1-C3 haloalkyl) or -(CH2CH2CH2)-O-(C1-C3 haloalkyl).

[0113] In some embodiments, R 1 It is -(C1-C6 alkylene)(C3-C6 cycloalkyl). In some embodiments, R 1 It is -(C1-C3 alkylene)(C3-C6 cycloalkyl). It should be understood that -(C1-C6 alkylene)- includes optional substitutions with C1-C6 alkyl groups, such that the total number of carbon atoms does not exceed 6. For example, -(C1-C6 alkylene)- includes -(C1-C5 alkylene)- substituted with methyl, such that the total number of carbon atoms is 2-6. In some embodiments, -(C1-C6 alkylene)- includes -(C1-C2 alkylene)- substituted with C1-C4 alkyl, such that the total number of carbon atoms is 2-6. In some embodiments, R 1 It is -(C1-C3 alkylene)(cyclopropyl), -(C1-C3 alkylene)(cyclobutyl), or -(C1-C3 alkylene)(cyclopentyl). In some embodiments, R 1 It is -(CH2)(C3-C6 cycloalkyl), -(CH2CH2)(C3-C6 cycloalkyl), or -(CH2CH2CH2)(C3-C6 cycloalkyl). In some embodiments, R 1It is -(CH2)(cyclopropyl), -(CH2)(cyclobutyl), or -(CH2)(cyclopentyl). In some embodiments, R 1 It is -(CH2)(cyclopropyl).

[0114] In some embodiments, R 1 is -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH 3. -CH2CH2CH(CH3)2, -CH2OCH3, -CH2CH2OCH3, -CH(CH3)OCH3, -CH(CH3)CH2OCH3, -CH2CHF2, -CF3, -CHF2, .

[0115] In some embodiments, L 1 It is a bond, O, or -CH2-. In some embodiments, L 1 It is a key. In some embodiments, L 1 It is O. In some embodiments, L 1 It is -CH2-.

[0116] In some embodiments, ring B is a C3-C6 cycloalkyl group, a 6-membered heteroaryl group containing one or two nitrogen atoms, or a C6-C6 cycloalkyl group. 10 Aryl group. In some embodiments, ring B is a C4-C6 cycloalkyl, pyridyl, pyrazinyl, pyrimidinyl, or phenyl group.

[0117] In some embodiments, ring B is a C3-C6 cycloalkyl group. In some embodiments, ring B is a C4-C6 cycloalkyl group. 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 a 6-membered heteroaryl group containing one or two nitrogen atoms. In some embodiments, ring B is a 6-membered heteroaryl group containing one nitrogen atom. In some embodiments, ring B is a 6-membered heteroaryl group containing two nitrogen atoms. In some embodiments, ring B is pyridyl, pyrazinyl, or pyrimidinyl. In some embodiments, ring B is... or .

[0119] In some embodiments, ring B is C6-C. 10 Aryl. In some embodiments, ring B is C6 aryl. In some embodiments, ring B is phenyl. In some embodiments, ring B is C6 aryl. 10Aryl. In some embodiments, ring B is naphthyl.

[0120] In some embodiments, yes: .

[0121] In some embodiments, each R 2 Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, halogenated, -O (C1-C6 alkyl), or -O (C1-C6 haloalkyl), or two Rs on adjacent carbon atoms. 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing one or two oxygen atoms, each of which is optionally substituted by one to five groups selected from halogenated and C1-C6 halogenated alkyl groups. In some embodiments, each R 2 Independently, it is a C1-C4 alkyl, C1-C3 haloalkyl, halogenated, -O (C1-C3 alkyl), or -O (C1-C3 haloalkyl), or two Rs on adjacent carbon atoms. 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing one or two oxygen atoms, each of which is optionally substituted by one to five groups selected from halogenated and C1-C3 halogenated alkyl groups.

[0122] In some embodiments, R 2 It is a C1-C6 alkyl group. In some embodiments, R 2 It is a C1-C4 alkyl group. In some embodiments, R 2 It is methyl, ethyl, propyl, or butyl. In some embodiments, R 2 It is isopropyl. In some embodiments, R 2 It is -C(CH3)3.

[0123] In some embodiments, R 2 It is a C1-C6 haloalkyl group. In some embodiments, R 2 It is a C1-C6 haloalkyl group containing 1-13 halogen atoms. In some embodiments, R 2 It is a C1-C3 haloalkyl group. In some embodiments, R 2 It is a C1-C3 haloalkyl group containing 1-7 halogen atoms. In some embodiments, R 2 It is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CF2CH3, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 2 It is -CF3, -CF2CH3, -CH2CHF2, or -CHF2.

[0124] In some embodiments, R 2 It is halogenated. In some embodiments, R 2 The city is F, Cl, Br or I. In some embodiments, R 2 It is F, Cl, or Br. In some embodiments, R 2 It is F. In some embodiments, R 2 It is Cl. In some embodiments, R 5 It is Br.

[0125] In some embodiments, R 2 It is -O (C1-C6 alkyl). In some embodiments, R 2 It is -O (C1-C3 alkyl). In some embodiments, R 2 It is -O(CH3), -O(CH2CH3), or -O(CH2CH2CH3). In some embodiments, R 2 It is -O(CH3). In some embodiments, R 2 It is -O(CH2CH3).

[0126] In some embodiments, R 2 It is -O (C1-C6 haloalkyl). In some embodiments, R 2 It is -O (C1-C6 haloalkyl), wherein the C1-C6 haloalkyl contains 1-13 halogen atoms. In some embodiments, R 2 It is -O (C1-C3 haloalkyl). In some embodiments, R 2 It is -O (C1-C3 haloalkyl), wherein the C1-C3 haloalkyl contains 1-7 halogen atoms. In some embodiments, R 2 It is -OCF3, -OCHF2, -OCH2F, -OCCl3, -OCHCl2, -OCH2Cl, -OCF2Cl, -OCFCl2, -OCH2CF3, -OCH2CHF2, or -OCH2CCl3. In some embodiments, R 2 It is -OCF3 or -OCHF2. In some embodiments, R 2 Yes -OCF3. In some embodiments, R 2 Yes, it is -OCHF2.

[0127] In some embodiments, the two R atoms on adjacent carbon atoms 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing one or two oxygen atoms, each of which is optionally substituted by one to five groups selected from halogenated and C1-C6 halogenated alkyl groups. In some embodiments, the two R groups on adjacent carbon atoms 2The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing one or two oxygen atoms, each of which is optionally substituted by one to five groups selected from halogenated and C1-C3 halogenated alkyl groups. In some embodiments, the two R groups on adjacent carbon atoms 2 The groups together form a fused phenyl group optionally substituted with 1-5 groups selected from halogenated and C1-C3 halogenated alkyl groups. In some embodiments, the two R groups on adjacent carbon atoms 2 The groups together form a fused phenyl group optionally substituted with 1-3 groups selected from halogenated and C1-C3 halogenated alkyl groups. In some embodiments, the two R groups on adjacent carbon atoms 2 The groups together form a fused phenyl group optionally substituted with 1-2 groups selected from F and -CF3. In some embodiments, the two R groups on adjacent carbon atoms... 2 The groups together form a fused 5-membered heterocyclic group containing one or two oxygen atoms, which is optionally substituted by one to four groups selected from halogenated and C1-C3 halogenated alkyl groups. In some embodiments, the two R groups on adjacent carbon atoms... 2 The groups together form a fused 5-membered heterocyclic group containing 1 or 2 oxygen atoms, which is optionally substituted by 1 to 4 groups selected from F and -CF3.

[0128] In some embodiments, each R 2 Independently, it is -CF3, -CF2CH3, -CH2CHF2, -CHF2, F, Cl, Br, -OCF3, -OCHF2, -OCH3, or -C(CH3)3, or two R atoms on adjacent carbon atoms. 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing one or two oxygen atoms, each of which is optionally substituted by one to five groups selected from F or -CF3.

[0129] In some embodiments, yes: .

[0130] In some embodiments, L 2 It is a key or an O. In some embodiments, L 2 It is a key. In some embodiments, L 2 It is O.

[0131] In some embodiments, ring A is , where Y1 Is it N or CH; Y 2 It is N or CH; x is 0, 1, or 2; and y is 0 or 1. In some embodiments, Y 1 It is N and Y 2 It is N. In some embodiments, Y 1 It is N and Y 2 It is CH. In some embodiments, Y 1 It is CH and Y 2 It is N. In some embodiments, Y 1 It is CH and Y 2 It is CH. In some embodiments, x is 0. In some embodiments, x is 1. 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 a 9- to 11-membered spiro-heterocyclic sub-group or an 8- to 10-membered bicyclic fused-to-heterocyclic sub-group, wherein the sub-heterocyclic group contains 1-2 nitrogen atoms. In some embodiments, ring A is a 9- to 11-membered spiro-heterocyclic sub-group containing 1-2 nitrogen atoms. In some embodiments, ring A is a 9- to 11-membered spiro-heterocyclic sub-group containing 1 nitrogen atom. In some embodiments, ring A is a 9- to 11-membered spiro-heterocyclic sub-group containing 2 nitrogen atoms. In some embodiments, ring A is an 8- to 10-membered bicyclic fused-to-heterocyclic sub-group containing 1-2 nitrogen atoms. In some embodiments, ring A is an 8- to 10-membered bicyclic fused-to-heterocyclic sub-group containing 1 nitrogen atom. In some embodiments, ring A is an 8- to 10-membered bicyclic fused-to-heterocyclic sub-group containing 2 nitrogen atoms.

[0133] In some embodiments, yes: It should be understood that when —(R) 3 ) m When drawing across two rings, any ring or both rings can be represented by m R's. 3 Group substitution.

[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 R 3It is independently a C1-C6 alkyl group, or two R groups. 3 The groups together form a bridging -CH2- or -CH2CH2- group, or two R groups on the same carbon atom. 3 The groups together form a spiroC3-C6 cycloalkyl group. In some embodiments, each R 3 It is independently a C1-C3 alkyl group, or two R groups. 3 The groups together form a bridging -CH2- or -CH2CH2- group, or two R groups on the same carbon atom. 3 The groups together form spiroC3-C5 cycloalkyl groups.

[0136] In some embodiments, R 3 It is a C1-C6 alkyl group. In some embodiments, R 3 It is a C1-C3 alkyl group. In some embodiments, R3 is methyl, ethyl, n-propyl, or isopropyl. 3 It is methyl, ethyl, or isopropyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is isopropyl.

[0137] In some embodiments, two R 3 The groups together form a bridging -CH2- or -CH2CH2- group. In some embodiments, the two R groups... 3 The groups together form a bridging -CH2- group. In some embodiments, the two R groups... 3 The groups together form a bridging -CH2CH2- group.

[0138] In some embodiments, two R atoms on the same carbon atom 3 The groups together form a spiroC3-C6 cycloalkyl group. In some embodiments, the two R groups on the same carbon atom... 3 The groups together form a spiroC3-C5 cycloalkyl group. In some embodiments, the two R groups on the same carbon atom... 3 The groups together form a spiropropyl, cyclobutyl, or cyclopentyl group. In some embodiments, the two R groups on the same carbon atom... 3 The groups together form a spirocyclopropyl group. In some embodiments, the two R groups on the same carbon atom... 3 The groups together form a spirocyclic butyl group.

[0139] In some embodiments, each R 3 It is -CH3 on its own, or two Rs. 3 The groups together form a bridging -CH2- or -CH2CH2- group, or two R groups on the same carbon atom. 3 The groups together form a spirocyclopropyl group.

[0140] In some embodiments, yes: .

[0141] In some embodiments, L 3 It is a bond, -CH(R) a )-、-CH(R a )CH(R a )-、-OCH(R a )CH(R a )-、-CH(R a )CH(R a )N(R a -, 5 to 6-membered heterocyclic groups or -O- (4-membered heterocyclic groups), wherein the heterocyclic group contains 1 to 2 nitrogen atoms, and each R a It is independently H or C1-C6 alkyl.

[0142] In some embodiments, L 3 It is a key.

[0143] In some embodiments, L 3 It is -CH(R) a )-、-CH(R a )CH(R a )-、-OCH(R a )CH(R a - or -CH(R) a )CH(R a )N(R a In some embodiments, each R a Independently, it is H or C1-C3 alkyl. In some embodiments, each R a Independently, it is H, methyl, ethyl, or propyl. In some embodiments, each R a Independently, it is H or methyl. In some embodiments, L 3 It is -CH2, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -OCH2CH2- or -CH2CH2N(CH2CH3)-.

[0144] In some embodiments, L 3 It is a 5- to 6-membered heterocyclic group or -O- (4-membered heterocyclic group), wherein the heterocyclic group contains 1-2 nitrogen atoms.

[0145] In some embodiments, L 3 It is a 5- to 6-membered subheterocyclic group containing 1-2 nitrogen atoms. In some embodiments, L 3 It is a 5- to 6-membered subheterocyclic group containing one nitrogen atom. In some embodiments, L 3 It is a 5- to 6-membered subheterocyclic group containing 2 nitrogen atoms. In some embodiments, L 3 It is a 5-membered subheterocyclic group containing 1-2 nitrogen atoms. In some embodiments, L 3 It is a 5-membered subheterocyclic group containing one nitrogen atom. In some embodiments, L 3 It is a 5-membered subheterocyclic group containing 2 nitrogen atoms. In some embodiments, L 3 It is a 6-membered subheterocyclic group containing 1-2 nitrogen atoms. In some embodiments, L 3 It is a 6-membered subheterocyclic group containing one nitrogen atom. In some embodiments, L 3 It is a 6-membered subheterocyclic group containing 2 nitrogen atoms. In some embodiments, L 3 It is pyridinealkyl, piperidinyl or piperazineyl.

[0146] In some embodiments, L 3 It is -O-(4-membered heterocyclic group), wherein the heterocyclic group contains 1-2 nitrogen atoms. In some embodiments, L 3 It is -O- (4-membered heterocyclic group), wherein the heterocyclic group contains one nitrogen atom. In some embodiments, L 3 It is -O- (4-membered heterocyclic group), wherein the heterocyclic group contains 2 nitrogen atoms. In some embodiments, L 3 It is -O-(diazepine) or -O-(diazepine).

[0147] In some embodiments, L 3 yes: .

[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 SO2, S(O)=NH, or SO. In some embodiments, W is O. In some embodiments, W is CH2. In some embodiments, W is SO2. 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.

[0153] In some embodiments, yes: It should be understood that when —(R) 4 ) n When drawing across two rings, any ring or both rings can be represented by n R's. 4 Group substitution.

[0154] In some embodiments, each R 4 It is independently a halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or two R groups. 4 The groups together form a bridging -CH2- or -CH2CH2- group, or two R groups on adjacent atoms. 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom, or two R groups on the same carbon atom. 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group. In some embodiments, each R 4 It is independently a halo, -OH, C1-C3 alkyl or C1-C3 haloalkyl, or two R 4 The groups together form a bridging -CH2- or -CH2CH2- group, or two R groups on adjacent atoms. 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom, or two R groups on the same carbon atom. 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group. In some embodiments, each R 4 It can be F, -OH, -CH3, -CH(CH3)2 or -CF3 independently, or two Rs. 4 The groups together form a bridging -CH2- or -CH2CH2- group, or two R groups on adjacent atoms. 4The groups together form a fused 5-membered heterocyclic group containing one oxygen atom, or two R groups on the same carbon atom. 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group.

[0155] In some embodiments, R 4 It is halogenated. In some embodiments, R 4 It is F, Cl, Br, or I. In some embodiments, R 4 It is F, Cl, or Br. In some embodiments, R 4 It is F or Cl. In some embodiments, R 4 It is F. In some embodiments, R 4 It is Cl.

[0156] In some embodiments, R 4 It is -OH.

[0157] In some embodiments, R 4 It is a C1-C6 alkyl group. In some embodiments, R 4 It is a C1-C3 alkyl group. In some embodiments, R 4 It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R4 6 It is methyl, ethyl, or isopropyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is isopropyl.

[0158] In some embodiments, R 4 It is a C1-C6 haloalkyl group. In some embodiments, R 4 It is a C1-C6 haloalkyl group containing 1-13 halogen atoms. In some embodiments, R 4 It is a C1-C3 haloalkyl group. In some embodiments, R 4 It is a C1-C3 haloalkyl group containing 1-7 halogen atoms. In some embodiments, R 4 It is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 4 It is -CF3.

[0159] In some embodiments, two R 4 The groups together form a bridging -CH2- or -CH2CH2- group. In some embodiments, the two R groups... 4 The groups together form a bridging -CH2- group. In some embodiments, the two R groups...4 The groups together form a bridging -CH2CH2- group.

[0160] In some embodiments, two R atoms on adjacent atoms 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom.

[0161] In some embodiments, two R atoms on the same carbon atom 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group. In some embodiments, the two R groups on the same carbon atom... 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom. In some embodiments, the two R groups on the same carbon atom... 4 The groups together form a spiro-4-membered heterocyclic group containing one 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.

[0163] In some embodiments, yes: .

[0164] In some embodiments, the compound having formula (I) is a compound having formula (Ia), (Ib), or (Ic): Among them, ring A, ring B, and X 1 X 2 L 2 L 3 R 1 R 2 R 3 R 4 Z, W, m, n, r, s and As described in formula (I).

[0165] In some embodiments, a compound having formula (I) is a compound having formula (Id) or (Ie): Among them, ring A, ring B, and X 1X 2 L 1 L 3 R 1 R 2 R 3 R 4 Z, W, m, n, r, s and As described in formula (I).

[0166] In some embodiments, the compound having formula (I) is a compound having formula (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il): Among them, ring A, ring B, and X 1 X 2 L 1 L 2 R 1 R 2 R 3 R 4 R a Z, W, m, n, r, s and As described in equation (I); where It is a 5- to 6-membered subheterocyclic group; and among which It is a 4-membered subheterocyclic group containing 1-2 nitrogen atoms.

[0167] In some embodiments, a compound having formula (I) is a compound having formula (IIa) or (IIb): Where X 1 X 2 Y 1 Y 2 R 1 R 2 R 3 R 4 Z, W, m, n, r, s and As described in formula (I).

[0168] In some embodiments, a compound having formula (I) is a compound having formula (IIc): Where R 1 R 2 R 3 R 4 m and n are as described in equation (I).

[0169] In some embodiments, the compound having formula (I) is a compound having formula (IIIa) or (IIIb): Where X 1 X 2 R 1 R 2 R 3 R 4 Z, W, m, n, r, s and As described in equation (I); and where It is a 9- to 11-membered spiro-heterocyclic group containing 1-2 nitrogen atoms.

[0170] In some embodiments, the compound having formula (I) is a compound having formula (IVa) or (IVb): Where X 1 X 2 R 1 R 2 R 3 R 4 Z, W, m, n, r, s and As described in equation (I); and where It is an 8- to 10-membered bicyclic fused heterocyclic group containing 1-2 nitrogen atoms.

[0171] In the description herein, it should be understood that each description, variation, embodiment, or aspect of a part can be combined with each description, variation, embodiment, or aspect of other parts, as if each combination described were specifically and individually listed. For example, each description, variation, embodiment, or aspect of ring A of formula (I) provided herein can be combined with X 1 X 2 Y 1 Y 2 R 1 R 2 R 3 R 4 R a L 1 L 2 L 3Each description, variation, embodiment, or aspect combination of W, Z, ring B, x, y, m, r, s, and n is described as if each combination and every combination were specifically and individually listed. It should also be understood that all descriptions, variations, embodiments, or aspects of equation (I) are equivalent to and described equally to the other equations detailed herein, as if each description, variation, embodiment, or aspect were individually and individually listed to apply to all equations. For example, all descriptions, variations, embodiments, or aspects of equation (I) are equally applicable where applicable to any equation as detailed herein, such as equations (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IVa), and (IVb), and are described equally as if each description, variation, embodiment, or aspect were individually and separately listed to apply to all equations.

[0172] In some embodiments, compounds selected from the following are provided: compounds in Table 1 or pharmaceutically acceptable salts thereof. Although some compounds described in this disclosure (including those in Table 1) are presented as specific stereoisomers and / or in non-stereochemical forms, it should be understood that any or all stereochemical forms of any of the compounds disclosed herein (including those in Table 1) are described herein, including any enantiomers or diastereomers and any tautomers or other forms. Similarly, although some compounds described in this disclosure are presented as specific salts, it should be understood that any pharmaceutically acceptable salt of any of the compounds disclosed herein is described herein. It should be further understood that although some compounds described in this disclosure are presented as specific salts, free forms of the compounds disclosed herein are also described herein. Table 1. "&1" indicates that the absolute stereochemistry is undetermined; "abs" indicates that the absolute stereochemistry is determined. Or its pharmaceutically acceptable salt.

[0173] This document also provides for compounds selected from the following: compounds in Table 2 or their pharmaceutically acceptable salts. Although some compounds described in this disclosure (including those in Table 2) are presented in specific stereoisomers and / or in non-stereochemical forms, it should be understood that this document describes any or all stereochemical forms of any of the compounds disclosed (including those in Table 2), including any enantiomers or diastereomers and any tautomers or other forms. Table 2. Or its pharmaceutically acceptable salt.

[0174] This document also provides for compounds selected from the following: compounds in Table 3 or their pharmaceutically acceptable salts. Although some compounds described in this disclosure (including those in Table 3) are presented in a particular stereoisomer and / or in a non-stereochemical form, it should be understood that this document describes any or all stereochemical forms of any of the compounds disclosed (including those in Table 3), including any enantiomer or diastereomer form and any tautomer or other form. Table 3.

[0175] It should be understood that, in this specification, combinations of substituents and / or variables of the indicated formula are permitted only if such contributions result in a stable compound.

[0176] Furthermore, all compounds disclosed herein that exist in the form of free bases or acids (e.g., compounds having formula (I)) can be converted into their pharmaceutically acceptable salts by methods known to those skilled in the art through treatment with a suitable inorganic or organic base or acid. Salts of compounds can be converted into their free base or acid forms using standard techniques. Synthesis method

[0177] In a further aspect, this document provides methods for preparing compounds having formula (I) or pharmaceutically acceptable salts thereof. This document also provides intermediate compounds that can be used to prepare compounds having formula (I) or pharmaceutically acceptable salts thereof.

[0178] Intermediate compounds that can be used to prepare compounds having formula (I) (e.g., intermediates having formula A) can be prepared as shown in Scheme 1. Option 1. Where R 1 and R 2 As described for equation (I), and -N(R')(R”) represents ring A.

[0179] Starting compound A-1 can react with an amine of formula A-2 to form a compound having formula A-3. These compounds having formula A-3 can then be treated with Lawson's reagent to give a compound having formula A-4. Treatment of the compound having formula A-4 with hydrazine hydrate provides a compound having formula A-5. These compounds having formula A-5 can then be coupled with a compound having formula A-6, for example, using copper(II) acetate, to give an intermediate having formula A.

[0180] Piperazinyl-pyrazole compounds having formula B can be prepared according to the general reaction shown in Scheme 2. Option 2. Where R 1 and R 2 As stated for equation (I), and -N(R) a (R) b ) represents the part with equation (I). .

[0181] Compounds having formula B-1 can be treated with an acid (e.g., TFA) to obtain compounds having formula B-2, and these compounds having formula B-2 can then be alkylated to give compounds having formula B. For example, compounds having formula B-2 can be alkylated with 2-chloroacetaldehyde, followed by the use of a coupling agent (e.g., NaBH(OAc)3) and HN(R) a (R) b Reductive coupling. Alternatively, compounds having formula B-2 can be alkylated with amine-based alkyl chlorides to provide compounds having formula B-2.

[0182] Piperazinylamino-pyrazole compounds having formula C can be prepared according to the general reaction shown in Scheme 3. Option 3. Where R 1 and R 2 As described for equation (I), and -N(R')(R”) represents optionally with L 3And a ring A containing Z-part coupling with formula (I).

[0183] Compounds having formula C-1 can be coupled with amines having formula C-2 under palladium-catalyzed coupling conditions to give compounds having formula C.

[0184] Piperazinylaminoisopropylpyrazole compounds having formula D can be prepared according to the general reaction shown in Scheme 4. Option 4. Where R 2 As described for equation (I), and -N(R')(R”) represents optionally with L 3 And a ring A containing Z-part coupling with formula (I).

[0185] Compounds having formula D-1 can be arylated, for example, by coupling with a compound having formula D-2 using Cu(OAc)2 to give compounds having formula D-3. These compounds having formula D-3 can then be alkylated using D-4 under Pd-catalyzed reaction conditions, followed by Pt-catalyzed hydrogenation to give compounds having formula D-5. Next, the Pd-catalyzed coupling of the compound having formula D-5 with an amine having formula D-6 yields a compound having formula D.

[0186] The synthesis of additional intermediates that can be used to prepare compounds having formula (I) is outlined in Scheme 5. Option 5. Where R 1 As described for formula (I).

[0187] Compounds having formula E-1 can be treated with compounds having formula E-2 in the presence of an alkoxide to obtain compounds having formula E-3. These compounds having formula E-3 can then be treated with hydrazine hydrate to produce compounds having formula E-4. Subsequent treatment with PtO2 and an acid (e.g., HCl) yields compounds having formula E-5, which can then be reacted with Boc2O to provide compounds having formula E.

[0188] Intermediates having formula E can be used to prepare pyrazole-piperidinyl compounds having formula F, as shown in Scheme 6. Option 6. Where R 1 and R 2 As stated for equation (I), and R c Represents the part with formula (I) .

[0189] Compounds having formula E can be arylated with compounds having formula F-1, for example, using Cu(OAc)2, to give compounds having formula F-2. Deprotection with an acid (e.g., TFA) then yields compounds having formula F-3, which can then be alkylated to give compounds having formula F. For example, compounds having formula F-3 can be reductively coupled with an aldehyde using a coupling agent (e.g., NaBH(OAc)3) to provide compounds having formula F. Alternatively, compounds having formula F-3 can be treated with alkyl chlorides to provide compounds having formula F.

[0190] It should be understood that the synthetic methods disclosed herein can be modified by selecting appropriate reagents and starting materials to obtain the various compounds disclosed herein.

[0191] All compounds of formula (I) or any variant thereof existing in free base or acid form as described herein can be converted into their pharmaceutically acceptable salts by methods known to those skilled in the art through treatment with a suitable inorganic or organic base or acid. Salts of the compounds disclosed herein can be converted into their free base or acid forms using standard techniques. Pharmaceutical Composition

[0192] In another aspect, this document provides pharmaceutical compositions having a compound of formula (I) or a pharmaceutically acceptable salt thereof. Therefore, this 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 this disclosure are available in forms suitable for oral, buccal, sublingual, parenteral (subcutaneous, intramuscular, intravenous, or intrathecal), nasal, topical, vaginal, rectal, intracerebral, intradermal, intravitreal, intraosseous, intraperitoneal, intraperitoneal, or inhalation administration. The pharmaceutical compositions of this disclosure comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0193] The compounds described herein can be used to prepare pharmaceutical compositions by combining the compounds as active ingredients with pharmaceutically acceptable excipients. Some examples of materials that can be used 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 astragalus gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; diols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffer solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic and compatible substances used in pharmaceutical formulations. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0194] The composition may also contain wetting agents, emulsifiers and lubricants, such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, releasing agents, coating agents, sweeteners, flavoring agents and aroma agents, preservatives and antioxidants.

[0195] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbate palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0196] Pharmaceutical compositions can be readily available in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0197] In some embodiments, the pharmaceutical compositions disclosed herein comprise excipients selected from the group consisting of cyclodextrins, liposomes, micelle forming agents (e.g., bile acids), and polymer carriers (e.g., polyesters and polyanhydrides); and compounds having formula (I) or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition imparts oral bioavailability to compounds having formula (I) or pharmaceutically acceptable salts thereof.

[0198] The pharmaceutical compositions disclosed herein, suitable for oral administration, may be in the form of capsules, pouches, pills, tablets, lozenges (using a flavoring matrix, typically sucrose and gum arabic or astragalus gum), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as soft lozenges (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic), and / or as mouthwashes, etc., each form containing a predetermined amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient. Compounds having formula (I) or pharmaceutically acceptable salts thereof may also be administered as large pills, licks, or pastes.

[0199] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) disclosed herein for oral administration, 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 starch, lactose, sucrose, glucose, mannitol, and / or silica; binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; humectants, such as glycerin; disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; solution blockers, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol, glyceryl monostearate, and nonionic surfactants; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffer. Excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol can also be used as fillers in soft-shell and hard-shell gelatin capsules.

[0200] Tablets can be prepared by compression or molding (optionally with one or more excipients). Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared in a suitable machine using a mixture of powdered compounds wetted with an inert liquid diluent.

[0201] The tablets and other solid dosage forms (e.g., sugar-coated pills, capsules, pellets, and granules) of the pharmaceutical compositions disclosed herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may also be formulated using, for example, different proportions of hydroxypropyl methylcellulose to provide a slow or controlled release of the active ingredient therein to deliver a desired release profile, other polymer matrices, liposomes, and / or microspheres. They may be formulated for rapid release, for example, by lyophilization. They may be sterilized, for example, by filtering through a bacterial trap filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be immediately dissolved in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain a light-blocking agent and may be compositions that, optionally in a delayed manner, release only or preferentially one or more active ingredients in a portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. The active ingredient may also be in a microencapsulated form and, where appropriate, may contain one or more of the excipients described above.

[0202] Liquid dosage forms for oral administration of compounds having formula (I) or pharmaceutically acceptable salts thereof include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents (such as water or other solvents), solubilizers, and emulsifiers commonly used in the art, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuran methanol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.

[0203] In addition to inert diluents, oral compositions may also include excipients such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents, and preservatives.

[0204] In addition to containing active compounds, suspensions may also contain suspending agents such as isostearyl alcohol ethoxylate, polyoxyethylene sorbitol and dehydrated sorbitol, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and astragalus gum, and mixtures thereof.

[0205] The pharmaceutical compositions disclosed herein for rectal or vaginal administration may be presented as suppositories prepared by mixing one or more of the disclosed compounds with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates, and being solid at room temperature but liquid at body temperature, and thus melting in the rectal or vaginal cavity to release the active compound.

[0206] Dosage forms for topical or transdermal application of the compounds disclosed herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compound (i.e., a compound having 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 that may be required.

[0207] In addition to compounds having formula (I) or pharmaceutically acceptable salts thereof, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, astragalus gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0208] In addition to compounds having formula (I) or their pharmaceutically acceptable salts, powders and sprays may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. Sprays may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0209] The pharmaceutical compositions disclosed herein suitable for parenteral administration comprise one or more compounds of formula (I) or pharmaceutically acceptable salts thereof in combination with one or more pharmaceutically acceptable reagents: sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders, which can be reconstituted immediately prior to use in sterile injectable solutions or dispersions, which may contain sugars, alcohols, antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0210] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Appropriate flowability can be maintained, for example, by using a coating material (e.g., lecithin), by maintaining the desired particle size in the case of a dispersion, and by using a surfactant.

[0211] Pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenylsorbic acid, etc.) can ensure the inhibition of microbial activity against the subject compound. It is also desirable to include isotonic agents such as sugars and sodium chloride in the composition. Additionally, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0212] In some cases, to prolong the action of a drug, it is desirable to slow down its absorption via subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, absorption of parenterally administered drug forms can be delayed by dissolving or suspending the drug in an oily medium.

[0213] Injectable reservoir formulations are prepared by forming microcapsule matrices of the subject compound within a biodegradable polymer, such as poly(lactide-polyglycolic acid). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable reservoir formulations are also prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions. Treatment

[0214] Compounds having formula (I) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising compounds having formula (I) or pharmaceutically acceptable salts thereof, may be used in the administration and treatment methods provided herein. These compounds and pharmaceutical compositions may also be used in in vitro methods, such as administering the compound or pharmaceutical composition to cells for screening purposes and / or for quality control assays.

[0215] In some embodiments, this document provides a method for inhibiting emopamiprobinding protein (EBP), which includes contacting an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein, with the EBP.

[0216] In some embodiments, compounds having formula (I) or pharmaceutically acceptable salts thereof inhibit 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, compounds having formula (I) inhibit 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%, 90%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%-100%, 80%-100%, 85%-100%, 90%, 10%, 10%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 90%, 10%, 10%, 10%, 80%, 85%, 90%, 10%, 10%, 10%, 10%, 80%, 85%, 90%, 0%-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, compounds having formula (I) or pharmaceutically acceptable salts thereof are used at IC50 concentrations of less than about 10 µM, such as about 9 µM, 8 µM, 7 µM, 6 µM, 5 µM, 4 µM, 3 µM, 2 µM, 1 µM, or 0.5 µM. 50Combine with EBP. In some embodiments, a compound having formula (I) or a pharmaceutically acceptable salt thereof is present in amounts of about 0.01 µM to about 5 µM, about 0.01 µM to about 4 µM, about 0.01 µM to about 3 µM, about 0.01 µM to about 2 µM, about 0.01 µM to about 1 µM, about 0.01 µM to about 0.05 µM, about 0.1 µM to about 5 µM, about 0.1 µM to about 4 µM, about 0.1 µM to about 3 µM, about 0.1 µM to about 2 µM, about 0.1 µM to about 1 µM, about 0.5 µM to about 5 µM, about 0.5 µM to about 4 µM, about 0.5 µM to about 3 µM, about 0.5 µM to about 2 µM, about 0.5 µM to about 1 µM, about 1 µM to about 5 µM, about 1 µM to about 4 µM, about 1 µM to about 3 µM, about 1 µM to about 2 µM, about 2 µM to about 5 µM ICs of approximately µM, approximately 2 µM to approximately 4 µM, approximately 2 µM to approximately 3 µM, approximately 3 µM to approximately 5 µM, approximately 3 µM to approximately 4 µM, or approximately 4 µM to approximately 5 µM 50Combined with EBP. In some embodiments, a compound having formula (I) or a pharmaceutically acceptable salt thereof is used in amounts from about 0.01 µM to about 1 µM, from about 0.01 µM to about 0.9 µM, from about 0.01 µM to about 0.8 µM, from about 0.01 µM to about 0.7 µM, from about 0.01 µM to about 0.6 µM, from about 0.01 µM to about 0.5 µM, from about 0.01 µM to about 0.4 µM, from about 0.01 µM to about 0.3 µM, from about 0.01 µM to about 0.2 µM, from about 0.01 µM to about 0.1 µM, from about 0.1 µM to about 1 µM, from about 0.1 µM to about 0.9 µM, from about 0.1 µM to about 0.8 µM, from about 0.1 µM to about 0.7 µM, from about 0.1 µM to about 0.6 µM, from about 0.1 µM to about 0.5 µM, from about 0.1 µM to about 0.4 µM. µM, about 0.1 µM to about 0.3 µM, about 0.1 µM to about 0.2 µM, about 0.2 µM to about 1 µM, about 0.2 µM to about 0.9 µM, about 0.2 µM to about 0.8 µM, about 0.2 µM to about 0.7 µM, about 0.2 µM to about 0.6 µM, about 0.2 µM to about 0.5 µM, about 0.2 µM to about 0.4 µM, about 0.2 µM to about 0.3 µM, about 0.3 µM to about 1 µM, about 0.3 µM to about 0.9 µM, about 0.3 µM to about 0.8 µM, about 0.3 µM to about 0.7 µM, about 0.3 µM to about 0.6 µM, about 0.3 µM to about 0.5 µM, about 0.3 µM to about 0.4 µM, about 0.4 µM to about 1 µM, about 0.4 µM to about 0.9 µM µM, about 0.4 µM to about 0.8 µM, about 0.4 µM to about 0.7 µM, about 0.4 µM to about 0.6 µM, about 0.4 µM to about 0.5 µM, about 0.5 µM to about 1 µM, about 0.5 µM to about 0.9 µM, about 0.5 µM to about 0.8 µM, about 0.5 µM to about 0.7 µM, about 0.5 µM to about 0.6 µM, about 0.6 µM to about 1 µM, about 0.6 µM to about 0.9 µM, about 0.6 µM to about 0.8 µM, about 0.6 µM to about 0.7 µM, about 0.7 µM to about 1 µM, about 0.7 µM to about 0.9 µM, about 0.7 µM to about 0.8 µM, about 0.8 µM to about 1 µM, about 0.8 µM to about 0.9 µM, or about 0.9 µM to about 1 µM IC 50 Combine with EBP.

[0218] In some cases, increased EBP inhibition may be associated with increased human Ether-à-go-go-related gene (hERG) toxicity. Therefore, in some embodiments disclosed herein, compounds having formula (I) or pharmaceutically acceptable salts thereof inhibit EBP and promote low hERG toxicity. In some embodiments, compounds having formula (I) or pharmaceutically acceptable salts thereof are used at IC50 concentrations of less than about 30 µM, such as about 25 µM, 20 µM, 15 µM, 10 µM, 5 µM, 2 µM, or 1 µM. 50 Combine with hERG. In some embodiments, a compound having formula (I) or a pharmaceutically acceptable salt thereof is present in amounts from about 0.05 µM to about 30 µM, for example, from about 0.05 µM to about 25 µM, from about 0.05 µM to about 20 µM, from about 0.05 µM to about 15 µM, from about 0.05 µM to about 10 µM, from about 0.05 µM to about 5 µM, from about 0.05 µM to about 2 µM, from about 0.05 µM to about 1 µM, from about 1 µM to about 30 µM, for example, from about 1 µM to about 25 µM, from about 1 µM to about 20 µM, from about 1 µM to about 15 µM, from about 1 µM to about 10 µM, from about 1 µM to about 5 µM, from about 1 µM to about 2 µM, from about 5 µM to about 30 µM, from about 5 µM to about 25 µM, from about 5 µM to about 20 µM, from about 5 µM to about 15 µM, from about 5 µM to about 10 µM, from about 10 µM to about 30 µM. ICs of approximately 10 µM to approximately 25 µM, approximately 10 µM to approximately 20 µM, approximately 10 µM to approximately 15 µM, approximately 15 µM to approximately 30 µM, approximately 15 µM to approximately 25 µM, approximately 15 µM to approximately 20 µM, approximately 20 µM to approximately 30 µM, or approximately 20 µM to approximately 25 µM 50 Combine with hERG.

[0219] In some embodiments, a compound having formula (I) or a pharmaceutically acceptable salt thereof can stimulate myelin regeneration of neuronal axons. In some embodiments, a compound having formula (I) or a pharmaceutically acceptable salt thereof stimulates myelin regeneration 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 having formula (I) The compounds stimulate myelin regeneration in neuronal axons at rates of approximately 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%, and 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, neuronal axons are artificial, such as those used in laboratory settings (i.e., cell culture). In some embodiments, neuronal axons are endogenous (i.e., naturally present in the body of a subject, such as a subject with multiple sclerosis (MS)). In some embodiments, myelin regeneration of neuronal axons is achieved by oligodendrocyte precursor cells (OPCs), which repair and limit MS-related damage. In some embodiments, administration of a compound having formula (I) or a salt thereof to a subject with multiple sclerosis (MS) stimulates myelin regeneration to enhance the repair of damaged myelin and protect neuronal function.

[0221] In one aspect, this document provides a method for treating demyelinating diseases, the method comprising administering to a subject an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides a method for preventing demyelinating diseases in a subject in need, the method comprising administering to the subject an effective amount of a compound having 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-Barré syndrome.

[0222] In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need reduces the severity of demyelinating disease in that subject. In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need stabilizes demyelinating disease (e.g., prevents or delays disease progression). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need delays the onset or recurrence of demyelinating disease. In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need slows the progression of demyelinating disease. In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need prevents recurrence of demyelinating disease. In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need reduces the dosage of one or more other drugs required for treating demyelinating disease. In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need enhances the effect of another drug used to treat demyelinating disease. In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need delays the progression of demyelinating diseases. In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need improves the quality of life of a subject with demyelinating diseases. In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need prolongs the survival of a subject with demyelinating diseases.

[0223] In some aspects, this document provides methods for delaying the progression of demyelinating diseases in subjects, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides methods for stabilizing demyelinating diseases in subjects, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method prevents the progression of demyelinating diseases. In some embodiments, the method delays the progression of demyelinating diseases.

[0224] In another aspect, this article provides a method for delaying the onset or recurrence of demyelinating diseases in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0225] In a further aspect, this document provides a method for reducing the dose of one or more other drugs required for treating demyelinating diseases in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides a method for enhancing the effect of another drug for treating demyelinating diseases in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0226] This article also provides a method for delaying the progression of demyelinating diseases in subjects, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method improves the quality of life of subjects with demyelinating diseases. In some embodiments, the method prolongs the survival of subjects with demyelinating diseases.

[0227] In some respects, this document provides compounds having formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of demyelinating diseases. In other respects, this document provides compounds having formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of medicaments for the treatment of demyelinating diseases.

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

[0229] In some embodiments, the type of multiple sclerosis (MS) is relapsing-remitting MS, in which an individual with MS will experience episodes of new or worsening symptoms, referred to as relapses. In some embodiments, the type of multiple sclerosis (MS) is primary progressive MS, in which an individual with MS will experience symptom exacerbations and / or symptom accumulation without remission periods. In some embodiments, the type of multiple sclerosis (MS) is secondary progressive MS, in which an individual with MS experiences nerve damage or loss, leading to an overall worsening of the disease.

[0230] In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need reduces the severity of multiple sclerosis (MS) in that subject (e.g., loss of myelin sheath coating of brain and spinal nerves, development of perineurotic plaques in brain and spinal nerves, neuroinflammation). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need stabilizes multiple sclerosis (MS) (e.g., prevents or delays the progression of MS). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need delays the onset or relapse of multiple sclerosis (MS). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need slows the progression of multiple sclerosis (MS). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need prevents the relapse of multiple sclerosis (MS). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need reduces the dose of one or more other drugs required for the treatment of multiple sclerosis (MS). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need enhances the effects of other drugs used to treat multiple sclerosis (MS). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need delays the progression of multiple sclerosis (MS). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need improves the quality of life of a subject with multiple sclerosis (MS). In some embodiments, administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof to a subject in need prolongs the survival of a subject with multiple sclerosis (MS).

[0231] In some aspects, this document provides methods for slowing the progression of multiple sclerosis (MS) in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides methods for stabilizing multiple sclerosis (MS) in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof. 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, this article provides a method for delaying the onset or recurrence of multiple sclerosis (MS) in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0233] In a further aspect, this document provides a method for reducing the dosage of one or more other drugs required for treating multiple sclerosis (MS) in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides a method for enhancing the effect of another drug for treating multiple sclerosis (MS) in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0234] This article also provides a method for delaying the progression of multiple sclerosis (MS) in a subject, the method comprising administering to the subject a compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method improves the quality of life of a subject with multiple sclerosis (MS). In some embodiments, the method prolongs the survival of a subject with multiple sclerosis (MS).

[0235] In some respects, this document provides compounds having formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of multiple sclerosis (MS). In other respects, this document provides compounds having formula (I) or pharmaceutically acceptable salts thereof for use in the manufacture of medicaments for the treatment of multiple sclerosis (MS). Dosage and administration method

[0236] As used in this article, the phrases “extragastric administration” and “post-gastric administration” refer to administration methods other than intestinal and local administration, usually by injection, and including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0237] As used in this article, the phrases “systemic administration,” “administered via the whole body,” “administered via the periphery,” and “administered via the periphery” refer to administration of a compound, drug, or other material into the patient’s whole body, rather than administration directly to the central nervous system, and thus to its metabolism and other similar processes, such as subcutaneous administration.

[0238] These compounds can be administered to humans and other animals for treatment via any suitable route of administration, including oral, nasal (e.g., via spray), rectal, vaginal, parenteral, intracerebrospinal, and topical (e.g., via powder, ointment, or drops), including buccal and sublingual administration.

[0239] Regardless of the chosen route of administration, the compounds or pharmaceutical compositions disclosed herein shall be formulated into a pharmaceutically acceptable dosage form using conventional methods known to those skilled in the art.

[0240] The actual dosage level of the active ingredient in the pharmaceutical composition disclosed herein can be altered to obtain an amount of active ingredient that effectively achieves the desired therapeutic response without toxicity to the patient, for a specific patient, composition, and administration method.

[0241] The chosen dose level will depend on a variety of factors, including the activity of the specific compound disclosed herein or its esters, salts or amides, the route of administration, the time of administration, the excretion or metabolic rate of the specific compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound used, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical field. Daily, weekly or monthly doses (or other time intervals) may be used.

[0242] A physician or veterinarian with ordinary skills in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can begin administering the disclosed compound used in the pharmaceutical composition at a level below that required to achieve the desired therapeutic effect, and then gradually increase the dose until the desired effect is achieved.

[0243] Generally, a suitable daily dose of the compounds disclosed herein will be the amount of the lowest dose of the compound that effectively produces a therapeutic effect (e.g., inhibition of necrosis). Such an effective dose will generally depend on the factors described above. Typically, when used for the indicated effect, the dose range of the compounds disclosed herein for a patient will be from about 0.0001 to about 100 mg / kg body weight / day. Preferably, the daily dose range will be from 0.001 to 50 mg of compound / kg body weight, and even more preferably from 0.01 to 10 mg of compound / kg body weight.

[0244] If necessary, the effective daily dose of the active compound can be administered throughout the day in two, three, four, five, six or more sub-dose at appropriate intervals, optionally in unit dosage form.

[0245] When the compounds disclosed herein are administered to humans and animals as medicines, they may be given on their own or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (e.g., 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0246] The compounds or pharmaceutical compositions thereof of this application may be administered once, twice, three or four times daily using any of the suitable modes described above. Furthermore, the administration of the compound or treatment may last for several days; for example, for a treatment cycle, treatment typically lasts at least 7, 14, or 28 days. Treatment cycles are well known and often alternate with rest periods of approximately 1 to 28 days, typically approximately 7 or 14 days (between cycles). In some embodiments, treatment cycles may also be continuous.

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

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

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

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

[0251] The formulations disclosed herein can be administered orally, parenterally, topically, or rectally. Of course, the formulations are administered in a form suitable for each route of administration. For example, they are administered in tablet or capsule form; by injection, inhalation, eye wash, ointment, suppository, infusion, or other methods; topically by wash or ointment; and rectally by suppository. In some embodiments, administration is oral. reagent kits / products

[0252] In some embodiments, kits and articles thereof are disclosed herein for use with one or more compounds, compositions, or methods described herein. Such kits include carriers, packages, or containers that are partitioned to contain one or more containers, such as vials, tubes, etc., each containing one of the individual elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the container is formed of various materials, such as glass or plastic.

[0253] Kits typically include a label listing the contents and / or instructions for use, as well as a package insert containing the instructions for use. A set of instructions may also be included.

[0254] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when the letters, numbers, or other characters forming the label are affixed, molded, or etched into the container itself; the label is associated with the container when it is present within a vessel or carrier that also contains the container, for example, as a packaging instruction. In one embodiment, the label is used to indicate that the contents will be used for a specific therapeutic application. The label also indicates the direction of use of the contents, as described herein.

[0255] In some embodiments, the pharmaceutical composition is contained in a packaging or dispenser device that holds one or more unit dosage forms containing the compounds provided herein. The packaging may contain, for example, metal or plastic foil, such as blister packs. In one embodiment, the packaging or dispenser device is accompanied by instructions for use. In one embodiment, the packaging or dispenser is also accompanied by a notification associated with the container in a form specified by a government agency, indicating the manufacture, use, or sale of the pharmaceutical preparation, reflecting the agency's approval of the form of the drug for human or veterinary use. For example, such notification may be a label or approved product insert approved by the U.S. Food and Drug Administration for use in a drug. In one embodiment, a composition containing the compounds provided herein, formulated in a compatible pharmaceutical carrier, is also prepared, placed in an appropriate container, and labeled for the treatment of a specified condition. Example

[0256] The examples and preparation methods provided below further illustrate and demonstrate the compounds disclosed herein and methods for testing such compounds. It should be understood that the scope of this disclosure is not in any way limited by the scope of the examples provided below.

[0257] The chemical reactions described in the examples are readily adaptable to the preparation of a variety of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are considered to be within the scope of this disclosure. For example, the synthesis of non-exemplary compounds according to this disclosure can be carried out by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art besides those described, or by conventional modifications to the reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of the other compounds disclosed herein.

[0258] The following abbreviations may be used in connection with this application. abbreviation Synthesis Example Example S1. Synthesis of 1-(5-methyl-1-phenyl-pyrazol-3-yl)-4-(tetrahydropyran-4-ylmethyl)piperazine (compound 1).

[0259] Compound 1 was prepared as described below.

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

[0261] A mixture of piperazine-1-carboxylate tert-butyl ester (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 under vacuum. The residue was purified by rapid chromatography (Biotage, 330 g silica gel column @ 200 mL / min, eluting with 0-30% acetone in petroleum ether) to give the desired product, 4-(3-oxobutyryl)piperazine-1-carboxylate tert-butyl ester (8.4 g, 93% yield), as a yellow oil.

[0262] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 96.32% (214 nm); mass: peak found at 1.039 min at 293.3 (M+23).

[0263] 1 H NMR (500 MHz, CDCl3) δ 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-1-carboxylate.

[0265] Lawson's reagent (2.99 g, 7.4 mmol) was added to a solution of 4-(3-oxobutyryl)piperazine-1-carboxylate (4.0 g, 14.8 mmol) in toluene (100 mL), and the mixture was heated at 75°C for 16 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 330 g silica gel column @ 200 mL / min, eluted with 10%–65% ethyl acetate in petroleum ether) to give the desired crude product, 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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2 mL / min; Column: SunFire, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 78.09% (214 nm); mass: peak observed at 1.744 min at 287.2 (M). +1 ); LC purity: 20.64% (214 nm), mass: peak found at 1.975 min at 287.1 (M+1).

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

[0268] A solution of tert-butyl piperazine-1-carboxylate (2.33 g, 8.14 mmol) in toluene (60 mL) was mixed with hydrazine monohydrate (1.21 mL, 24.4 mmol) and stirred at 70°C for 16 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 120 g silica gel column @ 100 mL / min, eluted with 0-6% MeOH in DCM) to give the desired product, tert-butyl piperazine-1-carboxylate (1.59 g, 2-step yield 38.6%), as a yellow solid. LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALOC18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 96.86% (214 nm); mass: peak found at 1.022 min at 267.3 (M+1).

[0269] 1 H NMR (400 MHz, CDCl3) δ 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-1-phenyl-pyrazol-3-yl)piperazine-1-carboxylate.

[0271] To a solution of 4-(5-methyl-1H-pyrazole-3-yl)piperazin-1-carboxylate tert-butyl ester (0.6 g, 2.25 mmol) in dichloromethane (30 mL), phenylboronic acid (561 mg, 4.51 mmol), anhydrous copper acetate (614 mg, 3.38 mmol), pyridine (0.363 mL, 4.51 mmol), and a 4 Å molecular sieve were added. The reaction mixture was stirred at room temperature for 64 h. The mixture was filtered. The filtrate was purified by rapid chromatography (Bytazy Corporation, 120 g silica gel column @ 100 mL / min, eluted with 0-30% ethyl acetate in petroleum ether) to give the desired product, 4-(5-methyl-1-phenyl-pyrazole-3-yl)piperazin-1-carboxylate tert-butyl ester (0.54 g, 70% yield), as a yellow solid.

[0272] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 100% (214 nm); mass: peak found at 1.395 min at 343.4 (M+1).

[0273] Step 5. Synthesis of 1-(5-methyl-1-phenyl-pyrazol-3-yl)piperazine.

[0274] TFA (3 mL, 40.4 mmol) was added to a solution of 0.62 g (1.81 mmol) of 4-(5-methyl-1-phenyl-pyrazol-3-yl)piperazine-1-carboxylic acid tert-butyl ester in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water (20 mL), neutralized to pH 8 with potassium carbonate, and then concentrated with dichloromethane (30 mL). 3) Extraction, drying with sodium sulfate, filtration and vacuum concentration to obtain the desired product 1-(5-methyl-1-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% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 96.07% (214 nm); mass: peak found at 0.928 min at 243.3 (M+1).

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

[0277] To a solution of 1-(5-methyl-1-phenyl-pyrazol-3-yl)piperazine (0.15 g, 0.619 mmol) in 1,2-dichloroethane (8 mL), tetrahydropyran-4-carboxaldehyde (84.8 mg, 0.743 mmol) was added, followed 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) and concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 1-(5-methyl-1-phenyl-pyrazol-3-yl)-4-(tetrahydropyran-4-ylmethyl)piperazine (126.5 mg, 60% yield) as a white solid.

[0278] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 5% B increased to 95% B over 1.3 min, 95% B sustained for 1.7 min, then 0.01 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.813 min at 341.3 (M+1).

[0279] 1 H NMR (400 MHz, DMSO-d6) δ 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-1-(2-naphthyl)pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 2)

[0280] Compound 2 was prepared as described below.

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

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

[0283] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 100% (214 nm); mass: peak found at 1.503 min at 393.3 (M+1).

[0284] Step 2. Synthesis of 1-[5-methyl-1-(2-naphthyl)pyrazol-3-yl]piperazine.

[0285] TFA (2 mL, 26.9 mmol) was added to a solution of tert-butyl piperazine-1-carboxylate (0.24 g, 0.611 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water (10 mL), neutralized to pH 8 with potassium carbonate, and then concentrated with dichloromethane (20 mL). 3) Extraction, drying with sodium sulfate, filtration and vacuum concentration to obtain the desired product 1-[5-methyl-1-(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% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 96.72% (214 nm); mass: peak found at 1.073 min at 293.2 (M+1).

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

[0288] 4-(2-chloroethyl)morpholine hydrochloride (99 mg, 0.534 mmol) was added to a solution of 1-[5-methyl-1-(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). The reaction mixture was stirred at 90°C for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 4-[2-[4-[5-methyl-1-(2-naphthyl)pyrazol-3-yl]piperazine-1-yl]ethyl]morpholine (63 mg, 34.9% yield) as a white solid.

[0289] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 5% B increased to 95% B over 1.3 min, 95% B sustained for 1.7 min, then 0.01 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.751 min at 406.3 (M+1).

[0290] 1H NMR (400 MHz, DMSO-d6) δ 8.03-7.92 (m, 4H), 7.70 (dd, J = 8.8, 2.0Hz, 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 1-(5-methyl-1-phenyl-pyrazol-3-yl)-4-(2-tetrahydropyran-4-ylethyl)piperazine (compound 3).

[0291] Compound 3 was prepared as described below.

[0292] To a solution of 1-(5-methyl-1-phenyl-pyrazol-3-yl)piperazine (0.14 g, 0.578 mmol) in 1,2-dichloroethane (8 mL), 2-tetrahydropyran-4-ylacetaldehyde (88.9 mg, 0.693 mmol) was added, followed by sodium triacetoxyborohydride (0.245 g, 1.16 mmol), 4 Å 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) and concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 1-(5-methyl-1-phenyl-pyrazol-3-yl)-4-(2-tetrahydropyran-4-ylethyl)piperazine (95 mg, 46.4% yield) as a white solid.

[0293] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 5% B increased to 95% B over 1.3 min, 95% B sustained for 1.7 min, then 0.01 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.794 min at 355.3 (M+1).

[0294] 1H NMR (400 MHz, DMSO-d6) δ 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-1-phenyl-pyrazol-3-yl)-1-(tetrahydropyran-4-ylmethyl)piperidine (compound 4).

[0295] Compound 4 was prepared as described below.

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

[0297] A solution of ethyl pyridine-4-carboxylate (2.0 g, 13.2 mmol) and acetone (3.84 g, 66.2 mmol) in ether (15 mL) was added sequentially to a 500 mL flask containing sodium methoxide (715 mg, 13.2 mmol) and anhydrous diethyl ether (15 mL). The suspension was stirred under reflux for 6 h, cooled, and filtered. The separated solid was washed with diethyl 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 extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 1:1) to give the desired product 1-(4-pyridyl)-1,3-butanedione (1.55 g, 72% yield) as a brown solid.

[0298] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 0.7 min; Flow rate: 2.2 mL / min; Column: Chromolith Fast gradient RP-18e, 50 mm 3 mm; column temperature: 40°C; LC purity: 100% (214 nm); mass: peak found at 0.791 min at 164.1 (M+1).

[0299] Step 2. Synthesis of 4-(3-methyl-1H-pyrazol-5-yl)pyridine.

[0300] 1-(4-pyridyl)-1,3-butanedione (1.55 g, 9.5 mmol) was suspended in ethanol (10 mL), hydrazine 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 under vacuum to give the desired product, 4-(3-methyl-1H-pyrazol-5-yl)pyridine (1.2 g, 79.4%), as a beige solid.

[0301] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 0.7 min; Flow rate: 2.2 mL / min; Column: Chromolith Fast gradient RP-18e, 50 mm 3 mm; column temperature: 40°C; LC purity: 90% (214 nm); mass: peak found at 0.303 min 160.1 (M+1).

[0302] Step 3. Synthesis of 4-(3-methyl-1H-pyrazol-5-yl)piperidine hydrochloride.

[0303] 4-(3-methyl-1H-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 hydrated platinum oxide (80% Pt, 150 mg) at ambient pressure and room temperature for 16 h. The reaction mixture was filtered and concentrated under vacuum to give the desired product, 4-(3-methyl-1H-pyrazol-5-yl)piperidine hydrochloride (1.0 g, 71.7% yield), as a yellow solid.

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

[0305] Step 4. Synthesis of tert-butyl 4-(3-methyl-1H-pyrazol-5-yl)piperidine-1-carboxylate.

[0306] 4-(3-methyl-1H-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-tert-butyl dicarbonate (1.45 g, 6.6 mmol) were added to dioxane (15 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (PE:EA = 3:1) to give the desired product, 4-(3-methyl-1H-pyrazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (900 mg, yield 43.2%), as a colorless oil.

[0307] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Mobile phase: water (10 mM ammonium bicarbonate) (A) / acetonitrile (B); from 10% to 95% B in a gradient of 1.8 mL / min over 1.5 min; Column: X-BRIDGE C18, 4.6 x 50 mm, 3.5 µm; Temperature: 50°C; LC purity: 77% (214 nm); Mass: peak observed at 1.690 min at 210.2 (M-55). + .

[0308] Step 5. Synthesis of tert-butyl 4-(5-methyl-1-phenyl-pyrazol-3-yl)piperidine-1-carboxylate.

[0309] 4-(3-methyl-1H-pyrazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (980 mg, 3.7 mmol), phenylboronic acid (980 mg, 7.4 mmol), anhydrous copper acetate (1.34 g, 7.4 mmol), and 4A molecular sieve were suspended in anhydrous dichloromethane (30 mL). Pyridine (584 mg, 7.4 mmol) was added, and the mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated to dryness under vacuum and purified by preparative HPLC (water / ammonium bicarbonate / acetonitrile) to give the desired product, 4-(5-methyl-1-phenyl-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester (420 mg, 48% yield), as a yellow oil.

[0310] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 1.2 min; Flow rate: 2.2 mL / min; Column: Chromolith Fast gradient RP-18e, 50 mm 3 mm; column temperature: 40°C; LC purity: 95.53% (214 nm); mass: peak observed at 1.374 min at 342.2 (M-55). + .

[0311] Step 6. Synthesis of 4-(5-methyl-1-phenyl-pyrazol-3-yl)piperidine.

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

[0313] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 1.2 min; Flow rate: 2.2 mL / min; Column: Chromolith Fast gradient RP-18e, 50 mm 3 mm; column temperature: 50°C; LC purity: 98.27% (214 nm); mass: peak 242.3(M+H)+ was found at 0.863 min.

[0314] Step 7. Synthesis of 4-(5-methyl-1-phenyl-pyrazol-3-yl)-1-(tetrahydropyran-4-ylmethyl)piperidine (compound 4).

[0315] A solution of 4-(5-methyl-1-phenyl-pyrazol-3-yl)piperidine (100 mg, 0.41 mmol), tetrahydropyran-4-carboxaldehyde (47.3 mg, 0.41 mmol), and sodium triacetoxyborohydride (176 mg, 8.3 mmol) in 1,2-dichloroethane (5 mL) was stirred overnight at room temperature. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 4-(5-methyl-1-phenyl-pyrazol-3-yl)-1-(tetrahydropyran-4-ylmethyl)piperidine (71.6 mg, 50.9% yield) as a yellow oil.

[0316] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2 mL / min; Column: Sunfire, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.359 min at 340.2 (M+1).

[0317] 1H 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-1-phenyl-pyrazol-3-yl)-1-(2-tetrahydropyran-4-ylethyl)piperidine (compound 5).

[0318] Compound 5 was prepared as described below.

[0319] A solution of 4-(5-methyl-1-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 overnight at room temperature. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 4-(5-methyl-1-phenyl-pyrazol-3-yl)-1-(2-tetrahydropyran-4-ylethyl)piperidine (42.7 mg, 32.4% yield) as a yellow solid.

[0320] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2 mL / min; Column: Sunfire, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm), peak 354.3 (M+H)+ was observed at 1.388 min.

[0321] 1H 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-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-methyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 6).

[0322] Compound 6 was prepared as described below.

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

[0324] Under an argon atmosphere, a mixture of 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene (1.5 g, 5.79 mmol), 1,3,2-dioxane-2-yl)-1,3,2-dioxane (1.47 g, 5.79 mmol), PdCl2(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 16 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy, 80 g silica column @ 100 mL / min, eluted with 0-5% ethyl acetate in petroleum ether) to give the desired product 2-[4-fluoro-3-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxane (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% B at 2.2 mL / min over 1.2 min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 81.98% (214 nm); mass: peak found at 1.582 min at 307.1 (M+1). 1 H NMR (400 MHz, CDCl3) δ7.75-7.68 (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] Sodium periodate (1.78 g, 8.33 mmol) was added to a stirred solution of 2-[4-fluoro-3-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxane-1,3,2-dioxane-3-pyrocyclopentaborane (850 mg, 2.78 mmol) in tetrahydrofuran (20 mL) and water (5 mL). After stirring at room temperature for 30 min, an aqueous solution of HCl (2.78 mL, 2.78 mmol) was added and stirring was continued for 16 h. The reaction mixture was diluted with water (20 mL) and diluted with EtOAc (50 mL). 3) Extraction. The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the desired product, [4-fluoro-3-(trifluoromethoxy)phenyl]boronic acid (576 mg, yield 85.6%), as a yellow solid. LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; 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-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-methyl-pyrazol-3-yl]piperazine-1-carboxylate.

[0329] To a solution of tert-butyl piperazine-1-carboxylate (100 mg, 0.375 mmol) in chloroform (20 mL), [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 a 4 Å molecular sieve were added. The reaction mixture was stirred at 40°C for 24 h. The mixture was then filtered. The filtrate was purified by rapid chromatography (Bytazy Corporation, 80 g silica column @ 100 mL / min, eluted with 0-30% ethyl acetate in petroleum ether) to give the desired product, tert-butyl 4-[1-[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% B at 2.2 mL / min over 1.2 min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 95.04% (214 nm); mass: peak found at 1.527 min at 445.3 (M+1). 1 H NMR (400 MHz, CDCl3) δ 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 1-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-methyl-pyrazol-3-yl]piperazine.

[0332] TFA (2 mL, 26.9 mmol) was added to a solution of tert-butyl piperazine-1-carboxylate (160 mg, 0.36 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water (20 mL), neutralized to pH = 9 with potassium carbonate, and then concentrated with dichloromethane (20 mL). 3) Extraction, drying with sodium sulfate, filtration and vacuum concentration to obtain the desired product 1-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-methyl-pyrazol-3-yl]piperazine (120 mg, yield 92.2%), which is a yellow oil.

[0333] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 95.22% (214 nm); mass: peak found at 1.989 min at 345.1 (M+1).

[0334] Step 5. Synthesis of 4-[2-[4-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-methyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 6).

[0335] Add 4-(2-chloroethyl)morpholine hydrochloride (97 mg, 0.523 mmol) to a solution of 1-[1-[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). Stir the reaction at 90°C for 16 h. Filter the reaction mixture. Concentrate the filtrate under vacuum. Purify the residue by preparative HPLC (ammonium carbonate / water / acetonitrile) to give the desired product 4-[2-[4-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-methyl-pyrazol-3-yl]piperazine-1-yl]ethyl]morpholine (134.7 mg, 84.5% yield) as a yellow solid.

[0336] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 2.029 min at 458.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 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-[1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]pyrrolidine-3-yl]oxyethyl]morpholine (compound 7).

[0337] Compound 7 was prepared as described below.

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

[0339] Under an argon atmosphere, a mixture of 3-bromo-5-methyl-1-[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 at 100°C for 16 h. The reaction mixture was purified directly by rapid chromatography (Bytazy, 120 g silica column @ 100 mL / min, eluted with 0-80% ethyl acetate in petroleum ether) to give the desired product 1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]pyrrolidine-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% B at 2.2 mL / min over 1.2 min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 93.81% (214 nm); mass: peak found at 1.164 min at 328.2 (M+1).

[0341] Step 2. Synthesis of 4-[2-[1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]pyrrolidine-3-yl]oxyethyl]morpholine (compound 7).

[0342] Sodium hydride (60%, 237 mg, 5.93 mmol) was added to a solution of 1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]pyrrolidine-3-ol (97 mg, 0.296 mmol) in dry DMF (9 mL). The reaction was stirred at 60°C for 2 h. The reaction was cooled and 4-(2-chloroethyl)morpholine hydrochloride (165 mg, 0.889 mmol) was added, and the mixture was stirred at 80°C for 16 h. The reaction was cooled to room temperature, quenched with water (5 mL), and then quenched with DCM (20 mL). 3) Extraction, drying with sodium sulfate, filtration, and vacuum concentration. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to obtain the desired product 4-[2-[1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]pyrrolidine-3-yl]oxyethyl]morpholine (53.9 mg, yield 41.3%), which was a yellow oil.

[0343] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 2.059 min at 441.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-yl]morpholine (compound 8).

[0344] Compound 8 was prepared as described below.

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

[0346] L-4-hydroxyproline methyl ester hydrochloride (3 g, 16.5 mmol) was added 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, and the resulting suspension was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (750 mL), water (100 mL), and brine (100 mL). 4) Wash, dry with sodium sulfate, filter and concentrate under vacuum. Purify the residue by rapid chromatography (Bytazy, 80 g silica gel column @ 75 mL / min, eluting with 0-50% acetone in petroleum ether) to give the desired (2S,4R)-1-[2-(tert-butoxycarbonylamino)acetyl]-4-hydroxy-pyrrolidine-2-carboxylate (4.0 g, 79.6% yield) as a yellow solid.

[0347] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 99.42% (214 nm); mass: peak found at 1.567 min 325.1 (M+23)+. 1 H NMR (400 MHz, DMSO-d6) δ6.86 (t, J = 5.6 Hz, 1H), 3.48-3.39 (m, 1H), 4.30 (t, J = 8.0 Hz, 1H), 3.84-3.72 (m, 1H), 3.67-3.55 (m, 5H), 3.52-3.40 (m, 2H), 2.13-2.05 (m, 1H), 1.92-1.84 (m, 1H), 1.38 (s, 9H) ppm.

[0348] Step 2. Synthesis of (7R,8aS)-7-hydroxy-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione.

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

[0350] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak 171 (M+1) was found at 0.349 min. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 2.4 Hz, 1H), 5.11 (d, J = 2.8 Hz, 1H), 4.36-4.26 (m, 2H), 4.04 (dd, J =16.8, 1.2 Hz, 1H), 3.56-3.46 (m, 2H), 3.22 (d, J = 12.4 Hz, 1H), 2.08-2.01(m, 1H), 1.93-1.85 (m, 1H) ppm.

[0351] Step 3. Synthesis of (7R,8aS)-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine-7-ol.

[0352] A solution of LiAlH4 in tetrahydrofuran (1.0 M, 50 mL, 50 mmol) was added to a solution of (7R,8aS)-7-hydroxy-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (1.45 g, 8.52 mmol) in tetrahydrofuran (50 mL). The reaction was stirred at 60°C for 3 h, and then stirred at room temperature for 16 h. The reaction was cooled to 0°C, quenched with water (1.9 g), 15% NaOH aqueous solution (1.9 g), and water (5.7 g), diluted with tetrahydrofuran (50 mL), stirred for 15 min, filtered, and concentrated under vacuum to obtain the desired product (7R,8aS)-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazin-7-ol (680 mg, yield 56.1%), which was a yellow oil.

[0353] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; mass: peak 143 (M+1) was observed at 0.367 min. 1H NMR (500 MHz, DMSO-d6) δ 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 = 11.5, 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-ol.

[0355] A mixture of 3-bromo-5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (300 mg, 0.934 mmol), (7R,8aS)-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-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-dioxane (15 mL) was stirred at 100°C for 16 h under an argon atmosphere. The reaction was cooled to room temperature and purified directly by rapid chromatography (Bytazy, 40 g silica column @ 75 mL / min, eluted with 0-20% MeOH in DCM) to give the desired product (7R,8aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-ol (84 mg, 23.9% yield) as a brown solid.

[0356] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 90.87% (214 nm); mass: peak found at 1.885 min at 383.1 (M+1).

[0357] Step 5. Synthesis of [(7R,8aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-yl]4-methylbenzenesulfonate.

[0358] 4-Methylbenzenesulfonyl chloride (126 mg, 0.66 mmol) was added to a solution of (7R,8aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-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). The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 25 g silica column @ 75 mL / min, eluted with 0-20% MeOH in DCM) to give the desired product [(7R,8aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-yl]4-methylbenzenesulfonate (90 mg, 72.3% yield) as a brown solid.

[0359] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 94.66% (214 nm); mass: peak found at 2.262 min at 537.1 (M+1).

[0360] Step 6. Synthesis of 4-[(7S,8aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-yl]morpholine (compound 8).

[0361] Morpholine (41.4 mg, 0.475 mmol) was added to a solution of [(7R,8aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-yl]4-methylbenzenesulfonate (85 mg, 0.158 mmol) and DIPEA (102 mg, 0.792 mmol) in 1-methylpyrrolidone-2-one (3 mL). The reaction was treated in a microwave reactor and stirred at 120°C for 1 h. The reaction was cooled to room temperature and purified directly by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 4-[(7S,8aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-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 bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 2.054 min at 452.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,6-diazabicyclo[3.1.1]hept-6-yl]ethyl]morpholine (compound 9).

[0363] Compound 9 was prepared as described below.

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

[0365] To a solution of 3-bromo-5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (100 mg, 0.31 mmol), sodium tert-butoxide (90 mg, 0.93 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (25 mg, 0.031 mmol) in 1,4-dioxane (6 mL), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (93 mg, 0.47 mmol) was added. The reaction was stirred in a tube at 100°C for 16 h. The mixture was then filtered, and the filtrate was washed with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (75 mg, yield 54.9%) as a yellow oil.

[0366] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C. LC purity: 76% (214 nm); mass: peak found at 2.16 min at 439.3 (M + H).

[0367] Step 2. Synthesis of 3-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,6-diazabicyclo-[3.1.1]-heptane.

[0368] TFA (2.5 mL) was added to a solution of tert-butyl 3-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,6-diazabicyclo-[3.1.1]-heptane-6-carboxylate (75 mg, 0.171 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated potassium carbonate solution (5 mL) and extracted with dichloromethane (10 mL x 3). The combined DCM layers were dried over sodium sulfate and filtered. The filtrate was concentrated to dryness to give 3-[5-methyl-1-[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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 78% (214 nm); mass: peak found at 1.55 min at 339.2 (M + H).

[0370] Step 3. Synthesis of 4-[2-[3-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,6-diazabicyclo[3.1.1]hept-6-yl]ethyl]morpholine (compound 9).

[0371] Add 4-(2-chloroethyl)morpholine (38 mg, 0.253 mmol) to a solution of 3-[5-methyl-1-[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). Stir the reaction mixture at 90°C for 16 h. Cool the reaction mixture to room temperature and filter. Concentrate the filtrate under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to obtain the desired product 4-[2-[3-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-3,6-diazabicyclo[3.1.1]hept-6-yl]ethyl]morpholine (47.8 mg, yield: 62.8%), which was a yellow oil.

[0372] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 99% (214 nm); mass: peak found at 2.00 min at 452.2 (M + H).

[0373] 1 H NMR (400 MHz, CD3OD): δ 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 = 11.6Hz, 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl]morpholine (compound 10).

[0374] Compound 10 was prepared as described below.

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

[0376] To a solution of 3-bromo-5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (100 mg, 0.31 mmol), sodium tert-butoxide (90 mg, 0.93 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (25 mg, 0.031 mmol) in 1,4-dioxane (4 mL), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (93 mg, 0.47 mmol) was added. The reaction mixture was stirred in a tube at 100°C for 16 h. The reaction mixture was filtered, and the filtrate was washed with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-2,5-diazabicyclo[2.2.1]hept-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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C. LC purity: 100% (214 nm); mass: peak found at 2.15 min at 439.3 (M + H).

[0378] Step 2. Synthesis of 2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-2,5-diazabicyclo[2.2.1]heptane.

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

[0380] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 93% (214 nm); mass: peak found at 1.94 min at 339.1 (M + H).

[0381] Step 3. Synthesis of 4-[2-[5-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl]morpholine (compound 10).

[0382] Add 4-(2-chloroethyl)morpholine (61 mg, 0.408 mmol) to a solution of 2-[5-methyl-1-[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). Stir the reaction mixture at 90°C for 16 h. Cool the reaction mixture to room temperature and filter. Concentrate the filtrate under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to obtain the desired product 4-[2-[5-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl]morpholine (83.5 mg, yield 68%), which was a yellow oil.

[0383] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.8 mL / min; Column: X-Bridge: C18, 3.5 µm, 4.6 50 mm; column temperature: 50°C; LC purity: 99% (214 nm); mass: peak found at 1.92 min at 452.1 (M + H).

[0384] 1 H NMR (400 MHz, CD3OD): δ 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 S11. Synthesis of 4-[2-[4-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-isopropyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 11).

[0385] Compound 11 was prepared as described below.

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

[0387] A solution of 3,5-dibromo-1H-pyrazole (0.2 g, 0.885 mmol) in dichloromethane (10 mL) was supplemented with (2,2-difluoro-1,3-benzodioxane-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 a 4 Å molecular sieve. The reaction mixture was stirred at room temperature for 16 h. The mixture was filtered. The filtrate was purified by silica column chromatography (petroleum ether: ethyl acetate = 10 / 1) to give the desired product, 3,5-dibromo-1-(2,2-difluoro-1,3-benzodioxane-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% to 95% B over 1.0 min; Flow rate: 2.2 mL / min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C. LC purity: 93% (214 nm); mass: peak found at 1.48 min at 382.9 (M + H).

[0389] Step 2. Synthesis of 3-bromo-1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-isopropenyl-pyrazole.

[0390] Under an argon atmosphere, sodium carbonate (174 mg, 1.65 mmol) and a PdCl2(dppf)dichloromethane complex (67.2 mg, 0.082 mmol) were added to a solution of 3,5-dibromo-1-(2,2-difluoro-1,3-benzodioxane-5-yl)pyrazole (338 mg, 0.82 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxane (124 mg, 0.741 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at 80°C for 16 h. The mixture was then filtered. The filtrate was purified by rapid chromatography (Bytazy, 25 g silica column @ 40 mL / min, eluted with 30% ethyl acetate in petroleum ether) to give the desired product 3-bromo-1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-isopropenyl-pyrazole (91 mg, yield: 29.6%) as a colorless oil.

[0391] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.8 mL / min; Column: X-Bridge: C18, 3.5 µm, 4.6 50 mm; column temperature: 50°C; LC purity: 92% (214 nm); mass: peak found at 2.25 min at 343.0 (M + H).

[0392] Step 3. Synthesis of 3-bromo-1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-isopropylpyrazole.

[0393] Platinum dioxide (10 mg) was added in a single addition to a solution of 3-bromo-1-(2,2-difluoro-1,3-benzodioxopenten-5-yl)-5-isopropylpyrazole (91 mg, 0.24 mmol) in 2 mL of THF. The mixture was stirred at room temperature under a H2 atmosphere for 1 h. The mixture was filtered, and the filtrate was concentrated to dryness to give 3-bromo-1-(2,2-difluoro-1,3-benzodioxopenten-5-yl)-5-isopropylpyrazole (91 mg, crude). The crude product was used directly in the next step without purification.

[0394] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 85% (214 nm); mass: peak found at 2.27 min at 345.0 (M + H).

[0395] Step 4. Synthesis of tert-butyl piperazine-1-carboxylate.

[0396] Under an argon atmosphere, a mixture of 3-bromo-1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-isopropylpyrazole (91 mg, 0.26 mmol), tert-butyl piperazine-1-carboxylate (98 mg, 0.53 mmol), PdPEPPSI-IPENT (10 mg, 0.01 mmol), and sodium 2-methylpropionic acid (76 mg, 0.79 mmol) in THF (2 mL) was stirred at 60°C for 16 h in a sealed tube. The mixture was then concentrated and purified by SGC (petroleum ether: ethyl acetate = 1:1) to give the product 4-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-isopropylpyrazole-3-yl]piperazine-1-carboxylate (61 mg, 43.7%) as a yellow solid.

[0397] LCMS method: Column: HALO C18 2.7 µm 4.6 30 mm. Mobile phase: Water (0.01% TFA) (A) / ACN (0.01% TFA) (B). Elution program: from 5% to 95% B in a gradient of 2.2 mL / min over 1.0 min. Temperature: 40°C. LC purity: 85% (214 nm), mass: peak observed at 1.55 min at 451.3 (M+1).

[0398] Step 5. Synthesis of 1-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-isopropyl-pyrazol-3-yl]piperazine.

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

[0400] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 89% (214 nm); mass: peak found at 2.11 min at 351.1 (M + H).

[0401] Step 6. Synthesis of 4-[2-[4-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-isopropyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 11).

[0402] To a solution of 1-[1-(2,2-difluoro-1,3-benzodioxane-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), 4-(2-chloroethyl)morpholine (50 mg, 0.33 mmol) was added. The reaction was stirred at 90°C for 16 h, then cooled and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 4-[2-[4-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-isopropyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (63 mg, yield 61.1%) as a yellow solid.

[0403] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.8 mL / min; Column: X-Bridge: C18, 3.5 µm, 4.6 50 mm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 2.05 min at 464.1 (M + H).

[0404] 1H NMR (400 MHz, CD3OD): δ 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-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 12). Synthesis 1

[0405] Compound 12 was prepared as described below.

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

[0407] To a solution of 4-(5-methyl-1H-pyrazol-3-yl)piperazine-1-carboxylate tert-butyl ester (0.2 g, 0.75 mmol) in chloroform (10 mL), [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 a 4 Å molecular sieve were added. The reaction mixture was stirred at 40°C for 16 h. The mixture was filtered. The filtrate was purified by silica column chromatography (petroleum ether: ethyl acetate = 4 / 1) to give the desired product, 4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-1-carboxylate tert-butyl ester (1.39 g, yield: 75.2%), as a yellow solid.

[0408] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 99% (214 nm); mass: peak 411.1 (M + H) was observed at 2.27 min.

[0409] Step 2. Synthesis of 1-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine.

[0410] Add 10 mL of 2,2,2-trifluoroacetic acid to a solution of 1.39 g (3.39 mmol) of 4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-1-carboxylic acid tert-butyl ester in dichloromethane (30 mL). Stir the reaction mixture at room temperature for 1 h. Neutralize the mixture with saturated potassium carbonate solution (5 mL) and extract with dichloromethane (10 mL x 3). Dry the combined DCM layers with sodium sulfate and filter. Concentrate the filtrate to dryness to give 1-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (1.05 g, crude). Use the crude product directly in the next step.

[0411] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% to 95% B over 1.0 min; Flow rate: 2.2 mL / min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C. LC purity: 84% (214 nm), mass: peak 311.3 (M+1)+ was observed at 0.99 min.

[0412] Step 3. Synthesis of 4-[2-[4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 12).

[0413] 4-(2-chloroethyl)morpholine (1.01 g, 6.77 mmol) was added to a solution of 1-[5-methyl-1-[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). The reaction was stirred at 95°C for 16 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 4-[2-[4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-1-yl]ethyl]morpholine (1.04 g, yield: 72%) as a yellow solid.

[0414] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 99% (214 nm); mass: peak found at 2.01 min at 424.2 (M + H).

[0415] 1 H NMR (400 MHz, CD3OD): δ 7.79 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8Hz, 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 described below.

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

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

[0419] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak 215.1 (M-56)+ was observed at 1.30 min.

[0420] Step 2. Synthesis of tert-butyl 4-(3-oxobutanethioyl)piperazine-1-carboxylate.

[0421] Lawson's reagent (12.3 g, 30.3 mmol) was added to a solution of 4-(3-oxobutyryl)piperazine-1-carboxylate (16.9 g, 60.6 mmol) in toluene (200 mL), and the mixture was heated at 75°C overnight. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 330 g silica gel column @ 200 mL / min, eluted with 10%–65% ethyl acetate in petroleum ether for 8 CV) to give 4-(3-oxobutanethioyl)piperazine-1-carboxylate (9.1 g, 38.4% yield) as a brown oil.

[0422] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 73.32% (254 nm); mass: peak found at 1.51 min at 287.0 (M+1).

[0423] Step 3. Synthesis of tert-butyl 4-(5-methyl-1H-pyrazol-3-yl)piperazine-1-carboxylate.

[0424] To a solution of tert-butyl piperazine-1-carboxylate (9.1 g, 23.3 mmol) in toluene (200 mL), hydrazine monohydrate (4.65 mL, 95.9 mmol) was added, and the mixture was stirred overnight at 70°C. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 120 g silica gel column @ 100 mL / min, eluted with 0-6% MeOH in DCM) to give the desired product, tert-butyl piperazine-1-carboxylate (4.35 g, 69.0% yield), as a yellow solid.

[0425] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 73.32% (254 nm), mass: peak observed at 1.51 min at 287.0 (M+1). LC purity: 98.33% (254 nm), mass: peak observed at 1.33 min at 267.1 (M+1).

[0426] Step 4. Synthesis of tert-butyl 4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-1-carboxylate.

[0427] To a solution of 4-(5-methyl-1H-pyrazol-3-yl)piperazine-1-carboxylate tert-butyl ester (5 g, 18.8 mmol) in chloroform (500 mL), [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 a 4 Å molecular sieve were added. The reaction mixture was stirred at room temperature for 24 h. The mixture was filtered and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 25 g silica gel column @ 70 mL / min, eluted with 10%–50% dichloromethane in petroleum ether) to give the desired product, 4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-1-carboxylate tert-butyl ester (4.1 g, 53.2% yield), as a white solid.

[0428] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C. LC purity: 100% (214 nm), mass: peak found at 2.258 min at 411.2 (M + 1) +.

[0429] Step 5. Synthesis of 1-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine.

[0430] Add 2,2,2-trifluoroacetic acid (10 mL) to a solution of 2.6 g (6.33 mmol) of 4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-1-carboxylic acid tert-butyl ester (2.6 g, 6.33 mmol) in dichloromethane (20 mL). Stir the reaction mixture at room temperature for 1 h. Concentrate the reaction mixture under vacuum. Dilute the residue with water (5 mL), neutralize with potassium carbonate to pH = 8, and concentrate with dichloromethane (5 mL). 3) Extraction, drying with sodium sulfate, filtration, and vacuum concentration to obtain 1-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (2.1 g, crude product). The crude product was used directly in the next step.

[0431] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C. LC purity: 100% (214 nm), mass: peak found at 1.663 min 311.2 (M + 1) +.

[0432] Step 6. Synthesis of 4-[2-[4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 12).

[0433] 4-(2-chloroethyl)morpholine (2.4 g, 16.4 mmol) was added to a solution of 1-[5-methyl-1-[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). The reaction was stirred at 95°C for 16 h. The reaction was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 4-[2-[4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-1-yl]ethyl]morpholine (2.16 g, yield: 46.6%) as a white solid.

[0434] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 99.56% (214 nm); mass: peak found at 1.790 min at 424.2 (M + H).

[0435] 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5Hz, 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]cyclohexyloxy]ethyl]morpholine (compound 13).

[0436] Compound 13 was prepared as described below.

[0437] Step 1. Synthesis of tert-butyl 4-(2-morpholinoethoxy)piperidine-1-carboxylic acid.

[0438] Sodium hydride (1.19 g, 50 mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 5 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 2 h. Then N-(2-chloroethyl)morpholine hydrochloride (925 mg, 5 mmol) was added. The mixture was stirred under reflux overnight. The mixture was purified by preparative HPLC (ammonium bicarbonate) to give the desired product, tert-butyl 4-(2-morpholinoethoxy)piperidine-1-carboxylate (500 mg, yield: 32%), as a white solid.

[0439] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 95% (214 nm); mass: peak found at 1.861 min at 315.2 (M+1).

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

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

[0442] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 99% (214 nm); mass: peak found at 0.179 min at 215.1 (M+1).

[0443] Step 3. Synthesis of 4-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]cyclohexyloxy]ethyl]morpholine (compound 13).

[0444] In a microwave-safe tube, 4-[2-(4-piperidinyloxy)ethyl]morpholine (58 mg, 0.27 mmol), Pd-PEPPSI-ipent (10.7 mg, 0.01 mmol), and sodium tert-butoxide (39 mg, 0.4 mmol) were added to a solution of 3-iodo-5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]cyclohexyloxy]ethyl]morpholine (11.7 mg, 19% yield). The reaction mixture was stirred at 100°C for 24 h. The mixture was filtered. The filtrate was purified by preparative HPLC (ammonium bicarbonate) to give the desired product 4-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]cyclohexyloxy]ethyl]morpholine (11.7 mg, 19% yield) as a colorless oil.

[0445] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 98% (214 nm); mass: peak found at 2.108 min at 455.2 (M+1).

[0446] 1 H NMR (400 MHz, MeOD-d4) δ 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 1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4-(1-tetrahydropyran-4-ylazacyclobutane-3-yl)oxy-piperidine (compound 14).

[0447] Compound 14 was prepared as described below.

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

[0449] A mixture of pyridine-4-ol (0.824 g, 8.66 mmol), tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (1.0 g, 5.77 mmol), triphenylphosphine (1.82 g, 6.93 mmol), and diisopropyl azodicarbonate (1.4 g, 6.93 mmol) in THF (20 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 50°C for 16 h under a nitrogen atmosphere. The reaction mixture was quenched by adding water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20 / 1 to 5 / 1) to give the desired product, tert-butyl 3-(4-pyridyloxy)azacyclobutane-1-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% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 70% (214 nm); mass: peak found at 0.871 min 251.2 (M+1).

[0451] Step 2. Synthesis of tert-butyl 3-(4-piperidinoxy)azacyclobutane-1-carboxylate.

[0452] Under a hydrogen atmosphere, a mixture of tert-butyl 3-(4-pyridinyloxy)azacyclobutane-1-carboxylate (500 mg, 2 mmol), platinum dioxide (200 mg, 40% w / w), and p-toluenesulfonic acid (688 mg, 4 mmol) in ethanol (30 mL) was stirred overnight. The mixture was then filtered and concentrated to give the desired product, tert-butyl 3-(4-piperidinyloxy)azacyclobutane-1-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% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 50% (214 nm); mass: peak found at 0.87 min at 257.4 (M+1).

[0454] Step 3. Synthesis of tert-butyl 3-[[1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4-piperidinyl]oxy]azacyclobutane-1-carboxylic acid.

[0455] Under an argon atmosphere, a mixture of 3-bromo-5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (300 mg, 0.92 mmol), tert-butyl 3-(4-piperidinyloxy)azacyclobutane-1-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) was stirred at 60°C for 16 h. The mixture was then concentrated and purified by SGC (petroleum ether: ethyl acetate = 2:1) to give the desired product (160 mg, 35.1%).

[0456] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 98% (214 nm); mass: peak found at 2.293 min at 497.3 (M+1).

[0457] Step 4. Synthesis of 4-(azacyclobutane-3-yloxy)-1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperidine.

[0458] TFA (3 mL) was added to a solution of 3-[[1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4-piperidinyl]oxy]azacyclobutane-1-carboxylic acid tert-butyl ester (160 mg, 0.3 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated to remove the 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 give the desired product 4-(azacyclobutane-3-yloxy)-1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperidine (127 mg, 99.4% yield) as a yellow oil.

[0459] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 86% (214 nm); mass: peak found at 1.075 min at 397.2 (M+1).

[0460] Step 5. Synthesis of 1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4-(1-tetrahydropyran-4-ylazacyclobutane-3-yl)oxy-piperidine (compound 14).

[0461] 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 a 4 Å molecular sieve were added to a solution of 4-(azacyclobutan-3-yloxy)-1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyran-3-yl]-4-(1-tetrahydropyran-4-ylazacyclobutan-3-yl)oxy-piperidine (96.5 mg, 62.7% yield). The reaction mixture was stirred at room temperature for 24 h. The mixture was filtered. The filtrate was purified by preparative HPLC (ammonium bicarbonate) to give the desired product 1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyran-3-yl]-4-(1-tetrahydropyran-4-ylazacyclobutan-3-yl)oxy-piperidine as a yellow oil.

[0462] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 99% (214 nm); mass: peak found at 2.096 min at 481.2 (M+1).

[0463] 1 H NMR (400 MHz, MeOD-d4) δ 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-2-tetrahydropyran-4-yl-2,7-diazaspiro[3.5]nonane (compound 15).

[0464] Compound 15 was prepared as described below.

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

[0466] In a microwave-safe tube, tert-butyl 2,7-diazaspiro[3,5]nonane-2-carboxylate (61.5 mg, 0.27 mmol), (2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (21.6 mg, 0.027 mmol), and sodium tert-butoxide (78 mg, 0.81 mmol) were added to a solution of 3-iodo-5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (100 mg, 0.27 mmol) in dry 1,4-dioxane (3 mL). The reaction mixture was stirred at 100°C for 24 h. The mixture was then filtered. The reaction mixture was purified by SGC (PE:EA = 1:1) to give the desired product, tert-butyl 7-[5-methyl-1-[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% B at 2.2 mL / min over 1.2 min; column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 76% (214 nm); mass: peak found at 1.510 min at 467.3 (M+1).

[0467] Step 2. Synthesis of tert-butyl 2,2-dimethyl-4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-carboxylate.

[0468] A solution of tert-butyl 7-[5-methyl-1-[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 2 h. The mixture was concentrated to remove the solvent, and potassium carbonate was added to pH = 10. It was extracted with DCM and dried over sodium sulfate. It was concentrated under vacuum to give the desired product, tert-butyl 2,2-dimethyl-4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-carboxylate (60 mg, 92.8% yield), as a yellow oil.

[0469] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 66% (214 nm); mass: peak found at 1.077 min at 367.3 (M+1).

[0470] Step 3. Synthesis of 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-2-tetrahydropyran-4-yl-2,7-diazaspiro[3.5]nonane (compound 15).

[0471] Tetrahydropyran-4-one (22 mg, 0.22 mmol), sodium triacetoxyborohydride (139 mg, 0.65 mmol), acetic acid (0.01 mL, 0.22 mmol), and a 4 Å molecular sieve were added to a solution of 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyran-3-yl]-2,7-diazaspiro[3.5]nonane (33.5 mg, 34.1% yield) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 24 h. The mixture was filtered. The filtrate was purified by preparative HPLC (ammonium bicarbonate) to give the desired product, 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyran-3-yl]-2-tetrahydropyran-4-yl-2,7-diazaspiro[3.5]nonane, as a yellow solid.

[0472] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 93% (214 nm); mass: peak found at 2.144 min at 451.2 (M+1).

[0473] 1H NMR (400 MHz, MeOD-d4) δ 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 16).

[0474] Compound 16 was prepared as described below.

[0475] Step 1. Synthesis of 3,5-dibromo-1-[4-(trifluoromethoxy)phenyl]pyrazole.

[0476] Under an argon atmosphere, a mixture of 3,5-dibromo-1H-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 room temperature for 16 h. The reaction mixture was then concentrated and purified by SGC (PE:DCM = 2:1) to give the desired product, 3,5-dibromo-1-[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% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 95% (214 nm); mass: peak found at 1.493 min at 387.0 (M+1).

[0478] Step 2. Synthesis of 3-bromo-5-isopropenyl-1-[4-(trifluoromethoxy)phenyl]pyrazole.

[0479] Under an argon atmosphere, a mixture of 3,5-dibromo-1-[4-(trifluoromethoxy)phenyl]pyrazole (150 mg, 0.382 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane (64.3 mg, 0.382 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) 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 16 h. The reaction mixture was then concentrated and purified by SGC (petroleum ether: ethyl acetate = 1:1) to give the desired product 3-bromo-5-isopropenyl-1-[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% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 67% (214 nm); mass: peak found at 1.511 min at 347.1 (M+1).

[0481] Step 3. Synthesis of 3-bromo-5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazole.

[0482] Under a hydrogen atmosphere, a mixture of 3-bromo-5-isopropenyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (90 mg, 0.01 mmol) and PtO2 (30 mg, w / w, 30%) in THF (5 mL) was stirred at room temperature for 2 h. The reaction mixture was then filtered and concentrated to give the desired product 3-bromo-5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (80 mg, 88%).

[0483] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 3.5 µm, 4.6 μm. 50 mm; column temperature: 50°C; LC purity: 66% (214 nm); mass: peak found at 2.089 min at 349.1 (M+1).

[0484] Step 4. Synthesis of tert-butyl 4-[5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-carboxylate.

[0485] Under an argon atmosphere, a mixture of 3-bromo-5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (80 mg, 0.22 mmol), tert-butyl 2,2-dimethylpiperazine-1-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) was stirred at 60°C for 16 h. The reaction mixture was then concentrated and purified by SGC (petroleum ether: ethyl acetate = 1:1) to give the product 4-[5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazole-3-yl]piperazine-1-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% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 100% (214 nm); mass: peak found at 1.562 min at 455.3 (M+1).

[0487] Step 5. Synthesis of tert-butyl 4-[5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-carboxylate.

[0488] TFA (2 mL) was added to a solution of 4-[5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazole-3-yl]piperazine-1-carboxylate tert-butyl ester (40 mg, 0.088 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated to remove the 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 give the desired product, 4-[5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazole-3-yl]piperazine-1-carboxylate tert-butyl ester (35 mg, 70% yield), as a yellow oil.

[0489] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 81% (214 nm); mass: peak found at 1.072 min at 355.3 (M+1).

[0490] Step 6. Synthesis of 4-[2-[4-[5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 16).

[0491] 4-(2-chloroethyl)morpholine hydrochloride (23 mg, 0.127 mmol) was added to a solution of 1-[5-isopropyl-1-[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). The reaction mixture was stirred at 95°C for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give 4-[2-[4-[5-isopropyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-yl]ethyl]morpholine (9.0 mg, 22.5% yield) as a yellow solid.

[0492] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 96% (214 nm); mass: peak found at 2.115 min at 468.2 (M+1).

[0493] 1 H NMR (400 MHz, MeOD-d4) δ 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 1-imino-4-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1,4-thiazine 1-oxide (compound 17).

[0494] Compound 17 was prepared as described below.

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

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

[0497] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.0 mL / min over 1.3 min, with 95% B maintained for 1.7 min; Column: HALO C18 3.5 µm 4.6 50 mm; column temperature: 50°C; LC purity: 97% (214 nm); mass: peak found at 1.266 min at 226.3 (M+23).

[0498] Step 2. Synthesis of tert-butyl 1-oxo-1,4-thiazinane-4-carboxylate.

[0499] Sodium periodate (870 mg, 4.07 mmol) was added fractionally 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 at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was diluted with brine and subjected to DCM (4... Extracted (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography to give the desired product, tert-butyl 1-oxo-1,4-thiazinane-4-carboxylate (800 mg, 89.7% yield), as a white solid. LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.0 mL / min over 1.3 min, with 95% B held for 1.7 min; Column: HALO C18 3.5 µm 4.6 50 mm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak 242.2 (M+23)+ was found at 0.934 min.

[0500] Step 3. Synthesis of tert-butyl 1-benzyloxy-carbonylimino-1-oxo-1,4-thiazine-4-carboxylate.

[0501] A mixture of tert-butyl 1-oxo-1,4-thiazinane-4-carboxylate (700 mg, 3.19 mmol), benzyl carbamate (1.21 g, 7.98 mmol), phenyl-1,3-iodoalkyldiacetate (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 under vacuum. The residue was purified by silica gel chromatography to give tert-butyl 1-benzyloxy-carbonylimino-1-oxo-1,4-thiazinane-4-carboxylate (620 mg, 52.7% yield) as the desired yellow solid.

[0502] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.0 mL / min over 1.3 min, with 95% B maintained for 1.7 min; Column: HALO C18 3.5 µm 4.6 50 mm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.250 min at 369.2 (M+1).

[0503] Step 4. Synthesis of N-(1-oxo-1,4-thiazinane-1-yl)carbamate benzyl ester.

[0504] TFA (3 mL, 40.4 mmol) was added to a solution of 1-benzyloxycarbonylimino-1-oxo-1,4-thiazinane-4-carboxylic acid tert-butyl ester (620 mg, 1.68 mmol) in dichloromethane (20 mL). The reaction was stirred at room temperature for 4 h. The reaction mixture was concentrated under vacuum to give the desired product N-(1-oxo-1,4-thiazinane-1-yl)carbamate as a white solid as a TFA salt (660 mg, 100% yield).

[0505] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 97.91% (214 nm); mass: peak observed at 0.867 min at 269.2 (M+1). + .

[0506] Step 5. Synthesis of N-[4-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1-oxo-1,4-thiazinane-1-yl]carbamate benzyl ester.

[0507] A mixture of 1-(2-chloroethyl)-4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (150 mg, 0.386 mmol), N-(1-oxo-1,4-thiazinyl-1-yl)carbamate TFA salt (221 mg, 0.579 mmol) and DIPEA (249 mg, 1.93 mmol) in NMP (3 mL) was treated with a microwave reactor and stirred at 160°C for 3 h. The reaction was cooled to room temperature and purified directly by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product N-[4-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1-oxo-1,4-thiazinane-1-yl]carbamate (110 mg, yield 45.3%) as a white solid.

[0508] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 98.68% (214 nm); mass: peak found at 1.148 min at 621.3 (M+1).

[0509] Step 6. Synthesis of 1-imino-4-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1,4-thiazine 1-oxide (compound 17).

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

[0511] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.861 min at 487.1 (M+1).

[0512] 1 H NMR (400 MHz, CD3OD) δ 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 = 6.4Hz, 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3-tetrahydropyran-4-yl-3-azaspiro[5.5]undecane (compound 18).

[0513] Compound 18 was prepared as described below.

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

[0515] DIAD (157 mg, 0.775 mmol) was added to a solution of 5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole-3-ol (100 mg, 0.387 mmol), 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (209 mg, 0.775 mmol), and triphenylphosphine (203 mg, 0.775 mmol) in THF (15 mL) at 0°C. The reaction was stirred at room temperature under argon protection for 16 h. LCMS showed that the reaction was complete. The mixture was concentrated and purified by rapid chromatography (Bytazy, 50 g silica column @ 80 mL / min, eluted with 50%-100% ethyl acetate in petroleum ether for 30 min) to give tert-butyl 9-[5-methyl-1-[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 (4.6 x 50 mm, 3.5 µm); Mobile phase: Water (10 mM ammonium bicarbonate) (A) / ACN (B); Elution program: from 5% to 95% B in a gradient of 1.5 mL / min over 1.5 min; Temperature: 50°C; LC purity: 98.8% (214 nm); Mass: peak found at 2.441 min at 510.2 (M+1).

[0517] Step 2. Synthesis of 9-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3-azaspiro[5.5]undecane.

[0518] TFA (336 mg, 1.18 mmol) was added to a solution of tert-butyl 9-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3-azaspiro[5.5]undecane-3-carboxylate (30 mg, 0.0589 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and diluted with DCM (50 mL). The organic mixture was washed with potassium carbonate (aqueous) and then with an aqueous NaCl solution. The organic layer was dried and concentrated to give 9-[5-methyl-1-[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 bicarbonate), B: ACN; Gradient: 5% B increased to 95% B over 1.4 min, with 95% B maintained for 1.6 min. Flow rate: 1.8 mL / min; Column: X Bridge C18, 4.6 50 mm, 3.5 µm; column temperature: 45°C; LC purity: 83.4% (214 nm); mass: peak found at 1.845 min at 409.9 (M+1).

[0520] Step 3. Synthesis of 9-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3-tetrahydropyran-4-yl-3-azaspiro[5.5]undecane (compound 18).

[0521] Acetic acid (125 mg, 2.08 mmol) was added to a solution of 9-[5-methyl-1-[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), and sodium triacetoxyborohydride (132 mg, 0.623 mmol) in 1,2-dichloroethane (10 mL). The reaction was stirred at room temperature for 16 h. LCMS showed that the reaction was complete. The mixture was concentrated and purified by preparative HPLC to give 9-[5-methyl-1-[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 Methodology: Column: Sunfire, 50 4.6 mm, 3.5 µm; Mobile phase: A: water (0.01% TFA), B: ACN (0.01% TFA); Elution program: 5% to 95% B in 1.3 min, 95% B for 1.7 min; Flow rate: 2 mL / min; Temperature: 50°C; LC purity: 91.0% (214 nm); Mass: peak found at 1.650 min at 494.0 (M+1).

[0523] 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 9.2 Hz, 2H), 7.28 (d, J = 8.0Hz, 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-2-tetrahydropyran-4-yl-2-azaspiro[3.5]nonane (compound 19).

[0524] Compound 19 was prepared as described below.

[0525] Step 1. Synthesis of 3-isopropoxy-5-methyl-1H-pyrazole.

[0526] Isopropyl 3-oxobutyrate (2.0 g, 13.9 mmol), hydrazine hydrochloride (998 mg, 14.6 mmol), and propan-2-ol (25 mL) were added to a round-bottom flask. The mixture was stirred at 90°C for 16 h, and LC-MS showed that the reaction was complete. The solution was concentrated, and EtOAc (200 mL) was added to the mixture. The organic phase was washed with 1 N sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness to give 3-isopropoxy-5-methyl-1H-pyrazole (850 mg, 38.5%) as a colorless oil.

[0527] LCMS method: Mobile phase: Water (0.01% TFA) (A) / ACN (0.01% TFA) (B); Gradient: From 5% to 95% B at 2.2 mL / min over 1.0 min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 88.0% (214 nm); mass: peak found at 0.963 min at 141.3 (M+1).

[0528] Step 2. Synthesis of 3-isopropoxy-5-methyl-1-[4-(trifluoromethoxy)phenyl].

[0529] A suspension of 3-isopropoxy-5-methyl-1H-pyrazole (800 mg, 5.71 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (3.53 g, 17.1 mmol), pyridine (2.26 g, 28.5 mmol), and copper(II) acetate (3.11 mg, 17.1 mmol) in dichloromethane (50 mL) was stirred at room temperature for 48 h under argon protection. LCMS showed that the reaction was complete. The mixture was filtered, and the filter cake was washed with dichloromethane (30 mL). The DCM solution was concentrated and purified by rapid chromatography (Bytazy, 100 g silica gel column @ 100 mL / min, eluted with 10%-60% ethyl acetate in petroleum ether for 30 min) to give 3-isopropoxy-5-methyl-1-[4-(trifluoromethoxy)phenyl] (700 mg, 40.0%) as a colorless oil.

[0530] LCMS method: Mobile phase: water (10 mM ammonium bicarbonate) (A) / ACN (B); Gradient: from 5% to 95% B at 1.5 mL / min over 1.5 min; Column: X BRIGE C18 (4.6 x 50 mm, 3.5 µm); Column temperature: 50°C; LC purity: 98.0% (214 nm); Mass: peak found at 2.237 min at 301.1 (M+1).

[0531] Step 3. Synthesis of 5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole-3-ol.

[0532] 3-Isopropoxy-5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (670 mg, 2.23 mmol), hydrogen bromide (3.61 g, 17.9 mmol), and acetic acid (3 mL) were added to a screw-top vial. The reaction was stirred at 140°C under argon protection for 3 h. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with ethyl acetate (100 mL), and washed with sodium bicarbonate solution and aqueous NaCl solution. The organic solution was then concentrated and purified by rapid chromatography (Bytazy, 50 g silica gel column @ 90 mL / min, eluted with 10%–30% EtOAc in PE for 30 min) to give 5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole-3-ol (430 mg, 73.4%) as a white solid.

[0533] LCMS method: Column: HALO C18 2.7 µm 4.6 30 mm; Mobile phase: water (0.01% TFA) (A) / ACN (0.01% TFA) (B); Elution program: from 5% to 95% B in a gradient of 2.2 mL / min over 1.0 min; Temperature: 40°C; LC purity: 98.4% (214 nm); Mass: peak found at 1.204 min at 259.2 (M+1).

[0534] Step 4. Synthesis of tert-butyl 9-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3-azaspiro[5.5]undecane-3-carboxylate.

[0535] DIAD (47 mg, 0.232 mmol) was added to a solution of 5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-ol (30 mg, 0.116 mmol), 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (56.1 mg, 0.232 mmol), and triphenylphosphine (61 mg, 0.232 mmol) in THF (5 mL) at 0°C. The reaction was stirred at room temperature under argon protection for 16 h. LCMS showed that the reaction was complete. The mixture was concentrated and purified by rapid chromatography (Bytazy, 50 g silica gel column @ 80 mL / min) to give 9-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (30 mg, 52.9%) as a colorless oil.

[0536] LCMS method: Column: X Bridge C18 (4.6 x 50 mm, 3.5 µm); Mobile phase: Water (10 mM ammonium bicarbonate) (A) / ACN (B); Elution program: from 5% to 95% B in a gradient of 1.5 mL / min over 1.5 min. Temperature: 50°C; LC purity: 98.7% (214 nm); Mass: peak found at 2.364 min at 426.1 (M-56+1)+.

[0537] Step 5. Synthesis of 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-2-azaspiro[3.5]nonane.

[0538] TFA (852 mg, 0.748 mmol) was added to a solution of tert-butyl 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-2-azaspiro[3.5]nonane-2-carboxylate (180 mg, 0.374 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, diluted with DCM (50 mL), and washed with aqueous potassium carbonate. The solution was then washed with aqueous NaCl solution, dried over sodium sulfate, and concentrated to give 7-[5-methyl-1-[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 bicarbonate) (A) / ACN (B); Gradient: from 10% to 95% B at 1.8 mL / min over 1.5 min; Column: X-BRIDGE C18 (4.6 x 50 mm, 3.5 µm); Column temperature: 50°C; LC purity: 87.3% (214 nm); Mass: peak found at 1.907 min at 382.1 (M+1).

[0540] Step 6. Synthesis of 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-2-tetrahydropyran-4-yl-2-azaspiro[3.5]nonane (compound 19).

[0541] Acetic acid (173 mg, 2.88 mmol) was added to a suspension of 7-[5-methyl-1-[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-dichloroethane (10 mL). The reaction was stirred at room temperature for 16 h. LCMS showed that the reaction was complete. The mixture was concentrated and purified by preparative HPLC to give 7-[5-methyl-1-[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 Methodology: Column: Sunfire, 50 4.6 mm, 3.5 µm; Mobile phase: A: water (0.01% TFA), B: ACN (0.01% TFA); Elution program: 5% to 95% B in 1.3 min, 95% B for 1.7 min; Flow rate: 2 mL / min; Temperature: 50°C; LC purity: 97.0% (214 nm); Mass: peak found at 1.610 min at 466.0 (M+1).

[0543] 1 H NMR (500 MHz, CDCl3) δ 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-1-[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 described below.

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

[0546] DIAD (78.3 mg, 0.387 mmol) was added to a solution of 5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole-3-ol (50 mg, 0.194 mmol), 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (93.5 mg, 0.387 mmol), and triphenylphosphine (102 mg, 0.387 mmol) in THF (8 mL) at 0°C. The reaction was stirred at room temperature under argon protection for 16 h. LCMS showed that the reaction was complete. The mixture was concentrated and purified by rapid chromatography (Bytazy, 50 g silica column @ 70 mL / min, eluted with 10%-60% ethyl acetate in petroleum ether for 30 min) to give tert-butyl 2-[5-methyl-1-[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 (4.6 x 50 mm, 3.5 µm); Mobile phase: Water (10 mM ammonium bicarbonate) (A) / ACN (B); Elution program: from 10% to 95% B in a gradient of 1.8 mL / min over 1.5 min; Temperature: 50°C; LC purity: 92.3% (214 nm); Mass: peak found at 2.374 min at 426.1 (M-56+1)+.

[0548] Step 2. Synthesis of 2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-7-azaspiro[3.5]nonane.

[0549] TFA (189 mg, 1.66 mmol) was added to a solution of tert-butyl 2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]oxy-7-azaspiro[3.5]nonane-7-carboxylate (40 mg, 0.0831 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, diluted with DCM (50 mL), and washed with aqueous potassium carbonate. The solution was then washed with aqueous NaCl solution, dried, and concentrated to give 2-[5-methyl-1-[4-(trifluoromethoxy)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 bicarbonate) (A) / ACN (B); Gradient: from 5% to 95% B at 1.5 mL / min over 1.5 min; Column: X-BRIDGE C18 (4.6 x 50 mm, 3.5 µm); Column temperature: 50°C; LC purity: 52.0% (214 nm); Mass: peak found at 2.086 min at 382.1 (M+1).

[0551] Step 3. Synthesis of 2-[5-methyl-1-[4-(trifluoro-methoxy)phenyl]pyrazol-3-yl]oxy-7-tetrahydropyran-4-yl-7-azaspiro[3.5]nonane (compound 20).

[0552] Acetic acid (173 mg, 2.88 mmol) was added to a suspension of 2-[5-methyl-1-[4-(trifluoro-methoxy)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). The reaction was stirred at room temperature for 48 h. LCMS showed that the reaction was complete. The mixture was concentrated and purified by preparative HPLC to give 2-[5-methyl-1-[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 C18 (4.6 x 50 mm, 3.5 µm); Mobile phase: Water (10 mM ammonium bicarbonate) (A) / ACN (B); Elution program: from 10% to 95% B in a gradient of 1.8 mL / min over 1.5 min; Temperature: 50°C; LC purity: 100% (214 nm); Mass: peak found at 2.146 min at 466.1 (M+1).

[0554] 1H NMR (400 MHz, CD3OD) δ 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 = 7.6Hz, 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-[1-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 21).

[0555] Compound 21 was prepared as described below.

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

[0557] A suspension of tert-butyl 4-(5-methyl-1H-pyrazol-3-yl)piperazine-1-carboxylate (200 mg, 0.751 mmol), [3-(difluoromethoxy)-4-fluoro-phenyl]boronic acid (309 mg, 1.50 mmol), pyridine (297 mg, 3.75 mmol), and copper(II) acetate (409 mg, 2.25 mmol) in chloroform (25 mL) was stirred at 40°C for 16 h under an O2 atmosphere. LCMS showed that 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 rapid chromatography (Bytazy Corporation, 50 g silica column @ 80 mL / min, eluted with 0%-40% ethyl acetate in petroleum ether for 30 min) to give tert-butyl 4-[1-[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 bicarbonate) (A) / ACN (B), gradient: from 5% to 95% B at 1.5 mL / min over 1.5 min, column: X Bridge C18 (4.6 x 50 mm, 3.5 µm), column temperature: 50°C, LC purity: 100% (254 nm), mass: peak found at 2.179 min at 427.1 (M+1).

[0559] Step 2. Synthesis of 1-[1-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazine.

[0560] TFA (508 mg, 4.46 mmol) was added to a solution of tert-butyl piperazine-1-carboxylate (190 mg, 0.446 mmol) in dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, diluted with DCM (50 mL), and washed with aqueous potassium carbonate. The organic solution was then washed with aqueous NaCl solution, dried, and concentrated to give 1-[1-[3-(difluoromethoxy)-4-fluorophenyl]-5-methylpyrazol-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% B at 2.2 mL / min over 1.0 min; Column: HALO C18 2.7 µm 4.6 30 mm, column temperature: 40°C, LC purity: 74.6% (214 nm), mass: peak found at 0.954 min at 327.5 (M+1).

[0562] Step 3. Synthesis of 4-[2-[4-[1-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 21).

[0563] To a solution of 1-[1-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazine (110 mg, 0.337 mmol) in ethanol / water (10 mL / 0.5 mL), 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) were added. The reaction mixture was stirred at 90°C for 16 h under argon protection, then the mixture was concentrated and diluted with methanol. The mixture was filtered, and the filter cake was washed with MeOH (5 mL). The filtrate was then concentrated and purified by HPLC to give 4-[2-[4-[1-[3-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (40.3 mg, yield 27.2%) as a white solid.

[0564] LCMS method: Mobile phase: water (10 mM ammonium bicarbonate) (A) / ACN (B), gradient: from 5% to 95% B at 1.5 mL / min over 1.5 min, column: X Bridge C18 (4.6 x 50 mm, 3.5 µm), column temperature: 50°C, LC purity: 100% (214 nm), mass: peak found at 1.900 min at 440.2 (M+1).

[0565] 1 H NMR (400 MHz, CDCl3) δ 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-1-yl]-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxylonitrile (compound 22) and 5-[4-(2-morpholinoethyl)piperazin-1-yl]-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxamide (compound a3).

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

[0567] Step 1. Synthesis of trimethyl-[2-(pyrazol-1-ylmethoxy)ethyl]silane.

[0568] Sodium hydride (1.29 g, 32.3 mmol) was added in portions over 15 minutes to 1H-pyrazole (2 g, 29.4 mmol) in THF (50 mL). 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. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding brine (150 mL) and extracted with EtOAc (3 x 100 mL). The organic phases were combined, dried over sodium sulfate, and volatiles were removed under reduced pressure. The solution was purified by rapid chromatography (in petroleum ether, 2%–30% acetone) to give trimethyl-[2-(pyrazole-1-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% to 95% B over 1.0 min; Flow rate: 2.2 mL / min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 96.47% (214 nm); mass: peak found at 199.2 (M+1) at 1.305 min.

[0570] Step 2. Synthesis of 1-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxynitrile.

[0571] 2,2,6,6-Tetramethylpiperidin-1-yllithium magnesium dichloride (13.1 mL, 13.1 mmol) was added dropwise to trimethyl-[2-(pyrazol-1-ylmethoxy)ethyl]silane (2 g, 10.1 mmol) in THF (30 mL) under nitrogen atmosphere at 21°C. The resulting suspension was stirred at 21°C for 1 h and then cooled to 5°C. p-Toluenesulfonylformonitrile (2.38 g, 13.1 mmol) was added and the mixture was stirred for 45 min. The reaction was quenched by adding brine and extracted with EtOAc (200 mL). The organic layer was dried and concentrated under vacuum to crude material. The crude product was purified by rapid silica gel chromatography (elution gradient of 5% to 40% acetone in petroleum ether) to give 1,2-(2-trimethylsilylethoxymethyl)pyrazol-3-formonitrile (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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 66.12% (254 nm); mass: peak found at 2.018 min 199.0 (M+1).

[0573] Step 3. Synthesis of 5-iodo-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxynitrile.

[0574] 2,2,6,6-Tetramethylpiperidin-1-yllithium magnesium dichloride (12.1 mL, 12.1 mmol) was added dropwise over 15 minutes to 2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxynitrile (1.8 g, 8.06 mmol) in THF (40 mL). The resulting solution was stirred at -16°C for 1 h. Iodine (818 mg, 3.22 mmol) was added and the mixture was stirred for 1 h. The reaction was quenched by adding brine, extracted with EtOAc (2 x 100 mL), dried, and concentrated under vacuum to the crude material. The crude product was purified by rapid silica gel chromatography (elution gradient of 0 to 40% EtOAc in isohexane). The pure fraction was concentrated to dryness under vacuum to obtain ethyl 5-iodo-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 61.34% (214 nm); mass: peak found at 2.013 min at 470.1 (M+1).

[0576] Step 4. Synthesis of 3-iodo-1H-pyrazole-5-carboxynitrile.

[0577] Under an argon atmosphere, a mixture of 5-iodo-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxynitrile (2 g, 5.73 mmol) in anhydrous ethanol (15 mL) was treated with 1 N HCl (15 mL). The mixture was stirred at 90°C for 3 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water (10 mL), neutralized to pH = 8 with sodium bicarbonate, and then treated with EtOAc (100 mL). 3) Extraction, drying with sodium sulfate, filtration and concentration, followed by purification by rapid chromatography (2%-20% MeOH in DCM) to give 3-iodo-1H-pyrazole-5-carboxynitrile as a yellow solid (1.2 g, 77.5% yield).

[0578] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 80.97% (214 nm); mass: peak found at 1.638 min at 220.0 (M+1).

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

[0580] A solution of 3-iodo-1H-pyrazole-5-carboxynitrile (300 mg, 1.37 mmol) in dichloromethane (20 mL) was supplemented with [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 room temperature for 16 h. The mixture was concentrated and finally purified by rapid chromatography (Bytazy Corporation, 40 g silica gel column @ 70 mL / min, eluted with 0-40% dichloromethane in petroleum ether for 30 min) to give 5-iodo-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxynitrile (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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 84.72% (214 nm); mass: peak found at 2.160 min at 380.0 (M+1).

[0582] Step 6. Synthesis of tert-butyl 4-[5-cyano-1-[4-(trifluoromethoxy)phenyl]indazole-3-yl]piperazine-1-carboxylate.

[0583] Under an argon atmosphere, in a sealed tube, a mixture of 3-iodo-1-[4-(trifluoromethoxy)phenyl]indazole-5-carboxylonitrile (50 mg, 0.132 mmol), piperazine-1-carboxylate tert-butyl ester (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-dioxane (3 mL) was stirred at 80°C for 16 h, filtered, concentrated, and then purified by rapid chromatography (0-20% ethyl acetate in petroleum ether) to give 4-[5-cyano-1-[4-(trifluoromethoxy)phenyl]indazole-3-yl]piperazine-1-carboxylate tert-butyl ester (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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 80.28% (214 nm); mass: peak observed at 2.297 min at 382.2 (M-55). + .

[0585] Step 7. Synthesis of 5-piperazin-1-yl-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxylonitrile.

[0586] TFA (0.3 mL) was added to a solution of 4-[5-cyano-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.09 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water (10 mL), neutralized to pH = 8 with potassium carbonate, and then concentrated with dichloromethane (10 mL). 3) Extraction, drying with sodium sulfate, filtration and vacuum concentration to obtain 5-piperazin-1-yl-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxylonitrile (30 mg, yield 77.5%), which is a yellow oil.

[0587] Gradient: 5% to 95% B over 1.0 min; Flow rate: 2.2 mL / min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 79.68% (214 nm); mass: peak found at 1.066 min at 338.2 (M+1).

[0588] Step 8. Synthesis of 5-[4-(2-morpholinoethyl)piperazin-1-yl]-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxynitrile (compound 22) and 5-[4-(2-morpholinoethyl)piperazin-1-yl]-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxamide (compound a3).

[0589] Add 4-(2-chloroethyl)morpholine hydrochloride (21 mg, 0.111 mmol) to a solution of 5-piperazin-1-yl-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxylonitrile (25 mg, 0.074 mmol), potassium carbonate (52 mg, 0.37 mmol), and KI (12 mg, 0.074 mmol) in 95% ethanol (3 mL). Stir the reaction mixture at 90°C for 16 h. Cool the reaction mixture to room temperature and filter. Concentrate the filtrate under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give 5-[4-(2-morpholinoethyl)piperazin-1-yl]-2-[4-(trifluoromethoxy)phenyl]pyrazole-3-carboxynitrile (6.6 mg, yield 19.6%) as a white solid; and 5-[4-(2-morpholinoethyl)piperazin-1-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 bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C.

[0591] Compound 22: LC purity: 99.07% (214 nm), mass: peak found at 2.065 min at 451.1 (M+1). 1 HNMR (400 MHz, MeOD-d4) δ 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 = 4.8Hz, 4H), 2.61-2.57 (m, 4H), 2.58 (t, J = 4.8Hz, 4H) ppm.

[0592] Compound a3: LC purity: 93.82% (214 nm), mass: peak found at 1.555 min at 468.9 (M+1). 1HNMR (400 MHz, MeOD-d4) δ 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-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-methyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 23). Synthesis 1

[0593] Compound 23 was prepared as described below.

[0594] Step 1. Synthesis of tert-butyl piperazine-1-carboxylate.

[0595] To a solution of tert-butyl piperazine-1-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), (227 mg, 1.13 mmol) boric acid and a 4 Å molecular sieve were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was then filtered. The filtrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the desired product, 4-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-methyl-pyrazol-3-yl]piperazine-1-carboxylic acid tert-butyl ester (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% to 95% B over 1.0 min; Flow rate: 2.2 mL / min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 99% (214 nm); mass: peak 423.3 (M + H) was observed at 1.49 min.

[0597] Step 2. Synthesis of 1-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-methyl-pyrazol-3-yl]piperazine.

[0598] TFA (1 mL) was added to a solution of tert-butyl piperazine-1-carboxylate (206 mg, 0.488 mmol) in 3 mL of dichloromethane. The mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated potassium carbonate (3 mL) 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 1-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-methylpyrazol-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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 98% (214 nm); mass: peak found at 1.56 min at 323.2 (M + H).

[0600] Step 3. Synthesis of 4-[2-[4-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-methyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 23).

[0601] Add 4-(2-chloroethyl)morpholine (10.8 mg, 0.721 mmol) to a solution of 1-[1-(2,2-difluoro-1,3-benzodioxane-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 (10 mL / 1 mL). Stir the reaction mixture at 90°C for 16 h. Cool the reaction mixture to room temperature and filter. Concentrate the filtrate under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / CH3CN) to give the desired product 4-[2-[4-[1-(2,2-difluoro-1,3-benzodioxane-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 bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 99% (214 nm); mass: peak found at 1.96 min at 436.2 (M + H).

[0603] 1 H NMR (400MHz, CDCl3): δ 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 described below.

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

[0606] A mixture of piperazine-1-carboxylate tert-butyl ester (30.0 g, 0.161 mol) and tert-butyl acetoacetate (28.0 g, 0.177 mol) in toluene (300 mL) was heated overnight at 100°C. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 330 g silica column @ 200 mL / min, eluting with 0-60% acetone in petroleum ether 8 CV) to give 4-(3-oxobutyryl)piperazine-1-carboxylate tert-butyl ester (43.0 g, 96.6% yield) as a clear oil.

[0607] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C. LC purity: 97.84% (214 nm), mass: peak observed at 1.48 min at 215.3 (M-55). + .

[0608] Step 2. Synthesis of tert-butyl 4-(3-oxobutanethioyl)piperazine-1-carboxylate.

[0609] Lawson's reagent (31.5 g, 0.078 mol) was added to a solution of 4-(3-oxobutyryl)piperazine-1-carboxylate (43.0 g, 0.156 mol) in toluene (400 mL), and the mixture was heated at 75°C overnight. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 330 g silica gel column @ 200 mL / min, eluted with 10%-65% ethyl acetate in petroleum ether 8 CV) to give 4-(3-oxobutanethioyl)piperazine-1-carboxylate (20.1 g, yield 39.5%) as a yellow solid.

[0610] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C. LC purity: 87.59% (254 nm), mass: peak observed at 1.65 min at 287.3 (M+1).

[0611] Step 3. Synthesis of tert-butyl piperazine-1-carboxylate.

[0612] To a solution of tert-butyl piperazine-1-carboxylate (3 g, 11.3 mmol) in chloroform (300 mL), (2,2-difluoro-1,3-benzodioxane-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 4 Å molecular sieve were added. The reaction mixture was stirred at room temperature for 24 h. The mixture was filtered and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 25 g silica column @ 70 mL / min, eluted with 10%-50% dichloromethane in petroleum ether) to give the desired product, 4-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-methyl-pyrazol-3-yl]piperazine-1-carboxylic acid tert-butyl ester (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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C. LC purity: 97.73% (214 nm), mass: peak found at 2.036 min at 422.9 (M + 1)+.

[0614] Step 4. Synthesis of 1-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-methyl-pyrazol-3-yl]piperazine.

[0615] Add 10 mL of 2,2,2-trifluoroacetic acid to a solution of tert-butyl piperazine-1-carboxylate (3 g, 11.26 mmol) in dichloromethane (20 mL). Stir the reaction mixture at room temperature for 1 h. Concentrate the reaction mixture under vacuum. Dilute the residue with water (5 mL), neutralize with potassium carbonate to pH = 8, and then concentrate with dichloromethane (5 mL). 3) Extraction, drying with sodium sulfate, filtration, and vacuum concentration to obtain 1-[1-(2,2-difluoro-1,3-benzodioxane-5-yl)-5-methyl-pyrazol-3-yl]piperazine (2.5 g, crude product). 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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C. LC purity: 100% (214 nm), mass: peak found at 1.644 min at 323.2 (M + 1)+.

[0617] Step 5. Synthesis of 4-[2-[4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine.

[0618] 4-(2-chloroethyl)morpholine (2.4 g, 16.4 mmol) was added to a solution of 1-[5-methyl-1-[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). The reaction was stirred at 95°C for 16 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 4-[2-[4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-1-yl]ethyl]morpholine (2.18 g, yield: 64.6%) as a white solid.

[0619] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 99.56% (214 nm); mass: peak found at 1.758 min at 436.2 (M + H).

[0620] 1H NMR (400 MHz, CDCl3) δ 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-[1-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 24).

[0621] Compound 24 was prepared as described below.

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

[0623] To a solution of 4-(5-methyl-1H-pyrazol-3-yl)piperazin-1-carboxylate tert-butyl ester (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), (4-fluoro-3-formyl-phenyl)boronic acid (94.6 mg, 0.563 mmol) and a 4 Å molecular sieve were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was filtered. The filtrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the desired product, 4-[1-(4-fluoro-3-formyl-phenyl)-5-methyl-pyrazol-3-yl]piperazin-1-carboxylate tert-butyl ester (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% to 95% B over 1.0 min; Flow rate: 2.2 mL / min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 95% (214 nm); mass: peak 389.3 (M + H) was observed at 1.36 min.

[0625] 1H NMR (400MHz, CDCl3): δ 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-[1-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazine-1-carboxylate.

[0627] At -78°C, DAST (0.5 mL, 4.12 mmol) was added dropwise to a solution of 4-[1-(4-fluoro-3-formyl-phenyl)-5-methyl-pyrazole-3-yl]piperazine-1-carboxylate (80 mg, 0.206 mmol) in 1 mL of DCM. The mixture was stirred at -78°C for 1 h, then heated 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 (3 x 3 mL). The combined organic layers were 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-[1-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazole-3-yl]piperazine-1-carboxylate (65 mg, 76.9% yield) as a colorless oil.

[0628] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: CH3CN; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 96% (214 nm); mass: peak 411.2 (M + H) was observed at 2.15 min.

[0629] Step 3. Synthesis of 1-[1-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazine.

[0630] TFA (0.5 mL) was added to a solution of tert-butyl piperazine-1-carboxylate (73 mg, 0.178 mmol) in dichloromethane (1.5 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 then rinsed with dichloromethane (10 mL). 3) Extraction. The combined DCM layers were dried over sodium sulfate, filtered and concentrated to dryness to give 1-[1-[3-(difluoromethyl)-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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 95% (214 nm); mass: peak found at 1.49 min at 323.2 (M + H).

[0632] Step 4. Synthesis of 4-[2-[4-[1-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 24).

[0633] Add 4-(2-chloroethyl)morpholine (39.8 mg, 0.266 mmol) to a solution of 1-[1-[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 / 1 mL). Stir the reaction at 90°C for 16 h. Cool the reaction to room temperature and filter. Concentrate the filtrate under vacuum. Purify the residue by preparative HPLC (ammonium bicarbonate / water / CH3CN) to give the desired product 4-[2-[4-[1-[3-(difluoromethyl)-4-fluoro-phenyl]-5-methyl-pyrazol-3-yl]piperazine-1-yl]ethyl]morpholine (28.4 mg, 37.8% yield) as a yellow solid.

[0634] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 5% B increased to 95% B over 1.5 min, 95% B maintained for 1.5 min, then returned to 5% B over 0.01 min. Flow rate: 1.8 mL / min; Column: Sunfire C18, 4.6 50 mm, 3.5 µm; Oven temperature: 50°C; LC purity: 99% (214 nm); Mass: Peak found at 1.71 min at 423.9 (M + H).

[0635] 1 H NMR (400MHz, CDCl3): δ 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) ppm Example S25. Synthesis of 4-[(7R,9aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-1,3,4,6,7,8,9,9a-octahydropyridino[1,2-a]pyrazin-7-yl]morpholine (compound 25).

[0636] Compound 25 was prepared as described below.

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

[0638] Under an argon atmosphere, a mixture of (2S,5S)-5-hydroxypiperidin-2-carboxylic acid (500 mg, 3.44 mmol) and thionyl chloride (615 mg, 5.17 mmol) in MeOH (20 mL) was stirred at 65°C for 2 h. The reaction was cooled to room temperature, diluted with EtOAc (50 mL), and then diluted with water (10 mL) and brine (10 mL). 3) Wash, dry with sodium sulfate, filter and concentrate under vacuum. Purify the residue by rapid chromatography (Bytazy, 25 g silica column @ 75 mL / min, eluting with 0-40% acetone in petroleum ether) to obtain the desired product (2S,5S)-5-hydroxypiperidine-2-carboxylate (540 mg, 98.5% yield) as a colorless oil.

[0639] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: from 10% to 95% B at 1.8 mL / min over 1.5 min; Column: X-BRIDGE C18 3.5 µm 4.6 50 mm; column temperature: 50°C; mass: peak 160 (M + H) was observed at 0.399 min.

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

[0641] Under an argon atmosphere, a mixture of methyl (2S,5S)-5-hydroxypiperidin-2-carboxylate (540 mg, 3.39 mmol), potassium carbonate (1.41 g, 10.2 mmol), and tert-butoxycarbonyl tert-butyl carbonate (830 mg, 3.78 mmol) in THF / water (20 mL / 5 mL) was stirred at room temperature for 16 h. The reaction was cooled to room temperature, diluted with EtOAc (50 mL), and then diluted with water (10 mL) and brine (10 mL). 3) Wash, dry with sodium sulfate, filter and concentrate under vacuum. The residue was purified by rapid chromatography (Bytazy, 25 g silica column @ 75 mL / min, eluting with 0-40% acetone in petroleum ether) to give the desired product (2S, 5S)-5-hydroxypiperidine-2-carboxylate (800 mg, 90.9% yield) as a colorless oil.

[0642] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: from 10% to 95% B at 1.8 mL / min over 1.5 min; Column: X-BRIDGE C18 3.5 µm 4.6 50 mm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak 160 (M -100)+ was observed at 1.061 min.

[0643] Step 3. Synthesis of (2S)-5-oxopiperidinium-1,2-dicarboxylic acid 1-tert-butyl-2-methyl ester

[0644] DMP (2.29 g, 5.4 mmol) was added to a solution of (2S,5S)-5-hydroxypiperidine-1,2-dicarboxylic acid O1-tert-butyl O2-methyl ester (700 mg, 2.7 mmol) in DCM (30 mL) at 0°C. The reaction mixture was stirred at this temperature for 1 h. The reaction mixture was diluted with DCM (30 mL), washed with 5% Na2S2O3 aqueous solution (20 mL) and 5% sodium bicarbonate aqueous solution (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 25 g silica gel column @ 75 mL / min, eluted with 0-45% ethyl acetate in petroleum ether) to give the desired product (2S)-5-oxopiperidinidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (500 mg, 70% yield) as a yellow oil.

[0645] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: no peak; mass: peak found at 1.111 min 158.3 (M-100)+.

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

[0647] Under an argon atmosphere, a mixture of (2S)-5-oxopiperidinium-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (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 a DCE (5 mL) was stirred at room temperature for 16 h. The reaction mixture was filtered and diluted with water (5 mL), then with ethyl acetate (20 mL). 3) Extraction, drying with sodium sulfate, filtration and concentration, and finally purification by rapid chromatography (2%-30% ethyl acetate in petroleum ether) to obtain (2S)-5-morpholinopiperidine-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.1850 min at 329.2 (M+1).

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

[0650] A solution of HCl / dioxane (4 M, 5 mL, 20 mmol) was added to a solution of (2S)-5-morpholinopiperidine-1,2-dicarboxylic acid O1-tert-butylO2-methyl ester (579 mg, 1.76 mmol) in 1,4-dioxane (10 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated under vacuum. The residue was washed with EtOAc (20 mL) and dried under vacuum to give the desired product (2S)-5-morpholinopiperidine-2-carboxylic acid methyl ester (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% B at 2.2 mL / min over 1.2 min; Column: HALO C18 2.7 µm 4.6 30 mm; column temperature: 40°C; LC purity: 100% (214 nm); mass: 229.1 [M-100]+ at 1.358 min.

[0652] Step 6. Synthesis of methyl 1-[2-(1,3-dioxoisoindoline-2-yl)ethyl]-4-morpholino-piperidine-2-carboxylate.

[0653] Under an argon atmosphere, trifluoromethanesulfonic anhydride (334 mg, 1.18 mmol) was added to a cooled (0°C) solution of 2-(2-hydroxyethyl)isoindoline-1,3-dione (192 mg, 1.0 mmol) in DCM (10 mL). After 10 min, 2,6-dimethylpyridine (127 mg, 1.18 mmol) was added, followed by a solution of methyl 4-morpholinopiperidine-2-carboxylate (270 mg, 1.18 mmol) and TEA (120 mg, 1.18 mmol) in DCM (5 mL) after another 10 min. The reaction mixture was stirred at room temperature for 16 h. The residue was diluted with water (10 mL), extracted with dichloromethane (20 mL x 3), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography (dichloromethane: methanol = 10 / 1) to give methyl 1-[2-(1,3-dioxoisoindoline-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% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C. LC purity: 94.33% (214 nm); mass: peak found at 0.855 min at 402.2 (M + H).

[0655] Step 7. Synthesis of (9aS)-7-morpholino-2,3,4,6,7,8,9,9a-octahydropyridino[1,2-a]pyrazin-1-one.

[0656] To a solution of (2S)-1-[2-(1,3-dioxoisoindoline-2-yl)ethyl]-5-morpholino-piperidine-2-carboxylate (250 mg, 0.623 mmol) in methanol (15 mL), NH₂NH₂·water (70 mg, 1.37 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (30 mL), filtered, and concentrated under vacuum to give (9aS)-7-morpholino-2,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-1-one (130 mg, crude). The crude product was used directly in the next step.

[0657] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 89% (214 nm); mass: peak found at 1.23 min at 240.1 (M + H).

[0658] Step 8. Synthesis of 4-[(9aS)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-yl]morpholine.

[0659] Under an argon atmosphere at 0°C, LiAlH4 (5.4 mL, 5.4 mmol) was added to a solution of (9aS)-7-morpholino-2,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-1-one (130 mg, 1.6 mmol) in THF (20 mL). The reaction was stirred at 60°C for 3 h. The reaction mixture was cooled to 0°C, and then 10 drops of water were added. After 5 minutes, 10 drops of 15% NaOH were slowly added to the mixture, followed by 30 drops of water. 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-1H-pyrido[1,2-a]pyrazin-7-yl]morpholine (130 mg, crude) as a yellow solid.

[0660] 1 H NMR (400 MHz, CDCl3): δ 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-1,3,4,6,7,8,9,9a-octahydropyridino[1,2-a]pyrazin-7-yl]morpholine (compound 25).

[0662] Under an argon atmosphere, a mixture of 3-bromo-5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazole (247 mg, 0.67 mmol), 4-(2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-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 at 100°C for 16 h. The reaction mixture was purified directly by rapid chromatography (Bytazy, 25 g silica column @ 75 mL / min, eluted with 0-10% MeOH in DCM) to obtain a crude product. This crude product was further purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to obtain the desired product 25-P1 4-[(7R,9aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-1,3,4,6,7,8,9,9a-octahydropyridino[1,2-a]pyrazin-7-yl]morpholine (36.5 mg, 10% yield) as a yellow solid, and product 25-P2 as a yellow solid. 4-[(7S,9aS)-2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-7-yl]morpholine (2.3 mg, yield 0.6%).

[0663] 25-P1: LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 97.62% (214 nm); mass: peak found at 1.747 min at 465.9 (M+1).

[0664] 25-P1: 1H NMR (400 MHz, CDCl3) δ 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 = 10.5Hz, 3H), 1.72 (s, 1H), 1.33-1.15 (m, 2H) ppm.

[0665] 25-P2: LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.907 min at 465.9 (M+1).

[0666] 25-P2: 1 H NMR (400 MHz, CDCl3) δ 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]oct-4-yl]ethyl]morpholine (compound 26).

[0667] Compound 26 was prepared as described below.

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

[0669] Under an argon atmosphere, a mixture of 3-bromo-5-methyl-1-[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, 2.8 mmol) in 1,4-dioxane (18 mL) was stirred at 100°C for 16 h. The reaction mixture was purified directly by rapid chromatography (Bytazy, 25 g silica column @ 75 mL / min, eluted with 0-10% EA in PE) to give the desired product, tert-butyl 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]octane-4-carboxylate (160 mg, 34.7% yield), as a yellow solid.

[0670] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: Sunfire C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 91.72% (214 nm); mass: peak found at 2.146 min at 453.2 (M+1).

[0671] Step 2. Synthesis of 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]octane.

[0672] A mixture of tert-butyl 7-[5-methyl-1-[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 dichloromethane (10 mL) was stirred at room temperature for 2 h. The reaction was concentrated under vacuum. The residue was diluted with water (10 mL), neutralized to pH = 9 with potassium carbonate, and then dissolved in dichloromethane (20 mL). 3) Extraction, drying with sodium sulfate, filtration and vacuum concentration to obtain the desired product 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]octane (124 mg, yield 91.6%), which is a yellow oil.

[0673] Step 3. Synthesis of 4-[2-[7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]oct-4-yl]ethyl]morpholine (compound 26).

[0674] Add 4-(2-chloroethyl)morpholine hydrochloride (40 mg, 0.213 mmol) to a solution of 7-[5-methyl-1-[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). Stir the reaction at 95°C for 16 h. Cool the reaction to room temperature and filter. Concentrate the filtrate under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to obtain the desired product 4-[2-[7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]oct-4-yl]ethyl]morpholine (13.3 mg, yield 20.1%), which was a yellow oil.

[0675] LCMS: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 5% to 95% B over 1.3 min; Flow rate: 1.7 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 45°C; LC purity: 100% (214 nm); mass: peak found at 1.902 min at 466.3 (M+1).

[0676] 1H NMR (400 MHz, CDCl3) δ 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]oct-4-yl]ethyl]-1,4-thiazine 1,1-dioxide (compound 27).

[0677] Compound 27 was prepared as described below.

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

[0679] A mixture of 7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]octane (124 mg, 0.352 mmol), 2-chloroacetaldehyde (40% aqueous solution, 138 mg, 0.704 mmol), and acetic acid (10.6 mg, 0.176 mmol) in methanol (8 mL) was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0°C, sodium cyanoborohydride (44 mg, 0.704 mmol) was added, and the mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with water (20 mL) and then with dichloromethane (20 mL). 3) Extraction, drying with sodium sulfate, filtration, and vacuum concentration. The residue was purified by rapid chromatography (Bytazy, 25 g silica gel column @ 75 mL / min, eluting with 0-5% methanol in dichloromethane) to give the desired product 4-(2-chloroethyl)-7-[5-methyl-1-[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 bicarbonate), B: acetonitrile; Gradient: 5% to 95% B over 1.3 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 73.78% (214 nm); mass: peak found at 2.055 min at 414.9 (M+1).

[0681] Step 2. Synthesis of 4-[2-[7-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-4,7-diazaspiro[2.5]oct-4-yl]ethyl]-1,4-thiazine 1,1-dioxide (compound 27).

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

[0683] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 5% to 95% B over 1.3 min; Flow rate: 1.7 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 45°C; LC purity: 100% (214 nm); mass: peak found at 1.837 min 514.2 (M+1).

[0684] 1H NMR (400 MHz, CDCl3) δ 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 28).

[0685] Compound 28 was prepared as described below.

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

[0687] Benzyl bromide (11.8 mL, 99.2 mmol) was added 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). 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 under vacuum. The residue was purified by rapid chromatography (Bytazy Corporation, 330 g silica gel column @ 100 mL / min, eluted with 0-10% methanol in dichloromethane) to give the desired product 2-(dibenzylamino)ethanol (15 g, 94% yield) as a colorless oil.

[0688] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: Sunfire C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.233 min at 242.2 (M+1).

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

[0690] Sodium hydride (60%, 1.24 g, 31.1 mmol) was added to a solution of 2-(dibenzylamino)ethanol (3.0 g, 12.4 mmol) and sodium chloro-2,2-difluoroacetate (1.9 g, 12.4 mmol) in THF (25 mL) at 0°C. The reaction mixture was stirred at 75°C for 16 h. The mixture was cooled to room temperature and diluted with water (20 mL). The mixture was then diluted with diethyl ether (30 mL). 2) Extraction. Separate the mixed solutions and adjust the pH of the aqueous layer to 6 with 6 N HCl. Extract the mixture with EtOAc (50 mL). 3) Extraction, drying with sodium sulfate, filtration and vacuum concentration to obtain the desired product 2-[2-(dibenzylamino)ethoxy]-2,2-difluoroacetic 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 increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: Sunfire C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 96.37% (214 nm); mass: peak found at 1.383 min at 336.2 (M+1).

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

[0693] Add (trimethylsilyl)diazomethane (2 M, 0.82 mL, 1.64 mmol in hexane) 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). Stir the reaction mixture at room temperature for 15 min and quench with acetic acid (0.5 mL). Concentrate the mixture under vacuum to give the desired product, methyl 2-[2-(dibenzylamino)ethoxy]-2,2-difluoro-acetate (0.5 g, 45.6% yield), as a yellow oil.

[0694] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: Sunfire C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 45.57% (214 nm); mass: peak found at 1.553 min at 350.2 (M+1).

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

[0696] Under a 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 16 h. The reaction was filtered and concentrated under vacuum to give the desired product, 4-benzyl-2,2-difluoro-morpholin-3-one (1.86 g, 87.2% yield), as a white solid.

[0697] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: Sunfire C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 95.45% (214 nm); mass: peak found at 1.635 min at 228.1 (M+1).

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

[0699] A solution of boron dimethyl sulfide complex (2 M, 20 mL, 40 mmol in THF) was added to a solution of 4-benzyl-2,2-difluoro-morpholino-3-one (1.8 g, 7.92 mmol) in THF (80 mL). The reaction was stirred at 55°C for 6 h, then at room temperature for 16 h. The reaction was slowly quenched with water, acidified with aqueous HCl to pH = 1, and stirred at room temperature for 1 h. The mixture was neutralized with sodium bicarbonate and then with EtOAc (100 mL). 3) Extraction. The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (Bytazy, 40 g silica gel column @ 75 mL / min, eluted with 0-10% MeOH in DCM) to give the desired product 4-benzyl-2,2-difluoromorpholine (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 increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: Sunfire C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 95.45% (214 nm), mass: peak found at 1.635 min at 228.1 (M+1). LC purity: 97.48% (214 nm), mass: peak found at 1.752 min at 214.2 (M+1).

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

[0702] Under a H2 atmosphere, a mixture of 4-benzyl-2,2-difluoromorpholine (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 give the desired product, tert-butyl 2,2-difluoromorpholine-4-carboxylate (700 mg, 95.5% yield), as a colorless oil.

[0703] 1 H NMR (400 MHz, CDCl3) δ 4.05 (t, J = 4.8 Hz, 2H), 3.71 (t, J = 8.0Hz, 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] The 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 2 h. The reaction was concentrated under vacuum to give the desired product, 2,2-difluoromorpholine TFA salt (160 mg, 75.3% yield), as a brown solid.

[0706] 1H NMR (400 MHz, MeOD-d4) δ 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 28).

[0708] A mixture of 1-(2-chloroethyl)-4-[5-methyl-1-[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-prop-2-amine (160 mg, 1.23 mmol) in 1-methylpyrrolidone (3 mL) was treated in a microwave reactor and stirred at 160°C for 2 h. The reaction was cooled to room temperature and purified directly by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 2,2-difluoro-4-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-yl]ethyl]morpholine (36.1 mg, 36.9% yield) as a yellow solid.

[0709] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 5% to 95% B over 1.3 min; Flow rate: 1.5 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 45°C; LC purity: 100% (214 nm); mass: peak found at 2.031 min at 476.1 (M+1).

[0710] 1 H NMR (400 MHz, CDCl3) δ 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 = 7.2Hz, 2H), 2.69-2.55 (m, 10H), 2.30 (s, 3H) ppm. Example S29. Synthesis of 5-[2-[4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrole (compound 29).

[0711] Compound 29 was prepared as described below.

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

[0713] To a solution of 4-(5-methyl-1H-pyrazol-3-yl)piperazine-1-carboxylate tert-butyl ester (200 mg, 0.75 mmol) in DCM (20 mL), [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 a 4 Å molecular sieve were added. The reaction mixture was stirred at room temperature for 48 h. The mixture was filtered and purified by rapid chromatography (PE / DCM = 1 / 1) to give the desired product, 4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine-1-carboxylate tert-butyl ester (160 mg, 52% yield), as a yellow oil.

[0714] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 5% B increased to 95% B over 1.4 min; 95% B sustained for 1.6 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 45°C; LC purity: 96% (214 nm); mass: peak found at 2.097 min at 411.2 (M+1).

[0715] Step 2. Synthesis of 1-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine.

[0716] TFA (1 mL) was added to a solution of tert-butyl piperazine-1-carboxylate (160 mg, 0.39 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was diluted with water (10 mL), neutralized to pH = 8 with potassium carbonate, and then concentrated with dichloromethane (10 mL). 3) Extraction, drying with sodium sulfate, filtration and vacuum concentration to obtain 1-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (130 mg, yield 95.6%), which is a yellow oil.

[0717] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 2.0 mL / min; Column: SUNFIRE C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.391 min at 311.2 (M+1).

[0718] Step 3. Synthesis of 1-(2-chloroethyl)-4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine.

[0719] Under an argon atmosphere, a mixture of 1-[5-methyl-1-[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 room temperature for 16 h. The mixture was then filtered and concentrated under vacuum. The residue was diluted with water (10 mL), neutralized to pH = 8 with sodium bicarbonate, and then concentrated with dichloromethane (10 mL). 3) Extraction, drying with sodium sulfate, filtration and vacuum concentration to obtain 1-(2-chloroethyl)-4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (100 mg, yield 59.5%), which is a yellow oil.

[0720] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: 5% to 95% B over 1.0 min; Flow rate: 2.2 mL / min; Column: HALO C18 2.7 µm 4.6 30 mm; Column temperature: 40°C.

[0721] Step 4. Synthesis of 5-[2-[4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrole (compound 29).

[0722] A solution of 1-(2-chloroethyl)-4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine (50 mg, 0.134 mmol), 3,3a,4,5,6,6a-hexahydro-1H-furano[3,4-c]pyrrole (30 mg, 0.268 mmol) and DIPEA (87 mg, 0.671 mmol) in NMP (1.5 mL) was stirred in a microwave at 160°C for 2 h. The reaction was cooled to room temperature and purified directly by preparative HPLC (NH4HCO4 / water / acetonitrile) to obtain the desired product 5-[2-[4-[5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrole (30.2 mg, yield: 50.1%), which was a brown solid.

[0723] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 5% B increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 3.5 µm, 4.6 μm. 50 mm; column temperature: 50°C; LC purity: 100% (214 nm); mass: peak found at 1.830 min at 450.3 (M+1).

[0724] 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5Hz, 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrole (compound 30).

[0725] Compound 30 was prepared as described below.

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

[0727] Under an oxygen atmosphere, a mixture of tert-butyl 4-(5-methyl-1H-pyrazol-3-yl)piperazine-1-carboxylate (1.0 g, 3.75 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (1.55 g, 7.51 mmol), copper(II) acetate (1.36 g, 7.51 mmol), and pyridine (1.2 g, 15 mmol) in dichloromethane (20 mL) was stirred at room temperature for 16 h. The mixture was then concentrated and purified by rapid chromatography (PE:EA = 3:1) to give the desired product, tert-butyl 4-[5-methyl-1-[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 increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min. Flow rate: 2.0 mL / min; Column: Sunfire C18, 4.6 50 mm, 3.5 µm; column temperature: 50°C. LC purity: 99.3% (214 nm), mass: peak found at 2.090 min at 427.2 (M+1).

[0729] Step 2. Synthesis of 1-[5-ethyl-1-[4-(trifluoromethyl)phenyl]pyrazol-3-yl]piperazine.

[0730] TFA (8 mL) was added to a solution of tert-butyl piperazine-1-carboxylate (1.5 g, 3.52 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was then concentrated and neutralized to pH = 10 with a solution of potassium carbonate. The resulting mixture was extracted with DCM, dried over sodium sulfate, and filtered. The filtrate was concentrated to give the desired product 1-[5-ethyl-1-[4-(trifluoromethyl)phenyl]pyrazine-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 increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min. Flow rate: 2.0 mL / min; Column: Sunfire C18, 4.6 50 mm, 3.5 µm; column temperature: 50°C. LC purity: 93% (214 nm), mass: peak observed at 1.406 min at 327.2 (M+1).

[0732] Step 3. Synthesis of 1-(2-chloroethyl)-4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine.

[0733] Sodium cyanoborohydride (424 mg, 6.74 mmol), 2-chloroacetaldehyde (530 mg, 6.74 mmol), and acetic acid (100 mg, 1.7 mmol) were added to a solution of 1-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (1.1 g, 3.37 mmol) in methanol (20 mL). The reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with water (5 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated to give the desired product 1-(2-chloroethyl)-4-[5-methyl-1-[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 increased to 95% B over 1.3 min, with 95% B maintained for 1.7 min. Flow rate: 2.0 mL / min; Column: Sunfire C18, 4.6 50 mm, 3.5 µm; column temperature: 50°C. LC purity: 96% (214 nm), mass: peak found at 1.454 min at 389.2 (M+1).

[0735] Step 4. Synthesis of 5-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrole (compound 30).

[0736] Add 3,3a,4,5,6,6a-hexahydro-1H-furano[3,4-c]pyrrole hydrochloride (25.5 mg, 0.26 mmol) and N-ethyl-N-isopropyl-propyl-2-amine (0.11 mL, 0.64 mmol) to a mixture of 1-(2-chloroethyl)-4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (50 mg, 0.13 mmol) in NMP (3 mL). Stir the reaction mixture in a microwave reactor at 140°C for 2 h. The mixture was purified by preparative HPLC (ammonium bicarbonate / acetonitrile) to obtain the desired product 5-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrole (26.5 mg, 44.3%) as a yellow solid.

[0737] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 1.7 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 3.5 µm, 4.6 50 mm; column temperature: 45°C; LC purity: 100% (214 nm); mass: peak found at 1.828 min at 466.1 (M+1).

[0738] 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8Hz, 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-2-oxa-6-azaspiro[3.3]heptane (compound 31).

[0739] Compound 31 was prepared as described below.

[0740] Add 2-oxa-6-azaspiro[3.3]heptane hydrochloride (35 mg, 0.26 mmol) and N-ethyl-N-isopropyl-prop-2-amine (0.11 mL, 0.64 mmol) to a mixture of 1-(2-chloroethyl)-4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (50 mg, 0.13 mmol) in NMP (3 mL). Stir the reaction mixture in a microwave reactor at 140°C for 2 h. Purify the mixture by preparative HPLC (ammonium bicarbonate / acetonitrile) to the desired product 6-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-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 bicarbonate), B: ACN; Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 1.7 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 3.5 µm, 4.6 50 mm; column temperature: 45°C; LC purity: 96% (214 nm); mass: peak found at 1.743 min at 452.1 (M+1).

[0742] 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8Hz, 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-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]-2-(trifluoromethyl)morpholine (compound 32).

[0743] Compound 32 was prepared as described below.

[0744] To a mixture of 1-(2-chloroethyl)-4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (50 mg, 0.13 mmol) in NMP (3 mL), 2-(trifluoromethyl)morpholine hydrochloride (49.3 mg, 0.26 mmol) and N-ethyl-N-isopropyl-prop-2-amine (0.11 mL, 0.64 mmol) were added. The reaction mixture was stirred in a microwave reactor at 160°C for 4 h. The mixture was purified by preparative HPLC (ammonium bicarbonate / acetonitrile) to give the desired product 4-[2-[4-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-yl]ethyl]-2-(trifluoromethyl)morpholine (7.9 mg, 12.1%) as a yellow oil.

[0745] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 1.7 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 3.5 µm, 4.6 50 mm; column temperature: 45°C; LC purity: 98% (214 nm); mass: peak found at 2.039 min 508.1 (M+1).

[0746] 1H NMR (400 MHz, CDCl3) δ 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-(1-methoxyethyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 33).

[0747] Compound 33 was prepared as described below.

[0748] Step 1. Synthesis of tert-butyl 4-methoxy-3-oxo-valerate.

[0749] Di(imidazol-1-yl) ketone (1.8 g, 11.1 mmol) was added to a solution of 2-methoxypropionic acid (1.05 g, 10.1 mmol) in THF (30 mL) at 0°C, and the mixture was stirred at room temperature for 24 h. In a separate flask, 2 M isopropyl magnesium chloride (16.6 mL, 33.3 mmol) in THF was added dropwise to a solution of 3-tert-butoxy-3-oxopropionic acid (2.42 g, 15.1 mmol) in THF (30 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 h. This solution was then added dropwise to an acylimidazole solution at 0°C, and the resulting mixture was heated to room temperature and stirred for 16 h. The mixture was quenched by adding 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 under vacuum. The residue was purified by silica gel rapid column chromatography (acetone / petroleum ether = 1:4) to give tert-butyl 4-methoxy-3-oxo-valerate as a yellow oil (1.84 g, yield: 83.9%).

[0750] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 1.7 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 3.5 µm, 4.6 50 mm; column temperature: 45°C. LC purity: 93% (254 nm), mass: peak found at 147.1 (M - 55)+ at 1.628 min.

[0751] Step 2. Synthesis of tert-butyl 4-(4-methoxy-3-oxo-pentanoyl)piperazine-1-carboxylate.

[0752] A mixture of tert-butyl 4-methoxy-3-oxo-valerate (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 16 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by rapid chromatography (eluting with 0-30% acetone in petroleum ether) to give tert-butyl 4-(4-methoxy-3-oxo-valerate)piperazine-1-carboxylate (2.6 g, 78.5% yield) as a yellow oil.

[0753] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 1.7 min; Flow rate: 1.8 mL / min; Column: X-bridge C18, 3.5 µm, 4.6 μm. 50 mm; column temperature: 45°C; LC purity: 92.86% (254 nm); mass: peak observed at 1.452 min at 315.2 (M -55). + .

[0754] Step 3. Synthesis of tert-butyl 4-(6-methyl-3-oxo-heptanethioyl)piperazine-1-carboxylate.

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

[0756] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: ACN; Gradient: 5% B increased to 95% B over 1.3 min, 95% B maintained for 1.7 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 3.5 µm, 4.6 μm. 50 mm; column temperature: 45°C; LC purity: 71.68% (214 nm); mass: peak found at 2.015 min at 343.2 (M + H).

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

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

[0759] LCMS method: Mobile phase: A: water (0.01% TFA), B: ACN (0.01% TFA); Gradient: 5% B increased to 95% B over 1.5 min, with 95% B maintained for 1.5 min. Flow rate: 2.0 mL / min; Column: Poroshell 120 EC-C18, 4.6 50 mm, 4 µm; column temperature: 50°C. LC purity: 100% (214 nm), mass: peak 311.1 (M+H)+ was observed at 1.566 min.

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

[0761] To a solution of 4-[5-(1-methoxyethyl)-1H-pyrazole-3-yl]piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 3.2 mmol) in chloroform (50 mL), [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 a 4 Å molecular sieve were added. The reaction mixture was stirred at room temperature for 24 h. The mixture was filtered. The filtrate was purified by rapid chromatography (Bytazy Corporation, 40 g silica gel column @ 70 mL / min, eluted with 10%–50% dichloromethane in petroleum ether) to give the desired product, 4-[5-butyl-1-[4-(trifluoromethoxy)phenyl]pyrazole-3-yl]piperazine-1-carboxylic acid tert-butyl ester (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% B increased to 95% B over 1.5 min, 95% B maintained for 1.5 min; Flow rate: 2.0 mL / min; Column: Poroshell 120 EC-C18, 4.6 50 mm, 4 µm; column temperature: 50°C. LC purity: 97.76% (214 nm), mass: peak found at 2.179 min at 471.0 (M+1)+.

[0763] Step 6. Synthesis of 1-[5-(1-methoxyethyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine.

[0764] Add 2,2,2-trifluoroacetic acid (1 mL) to a solution of tert-butyl 4-[5-(1-methoxyethyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-carboxylate (100 mg, 0.213 mmol) in dichloromethane (5 mL). Stir the reaction mixture at room temperature for 1 h. Concentrate the reaction mixture under vacuum. Dilute the residue with water (5 mL), neutralize with potassium carbonate to pH = 8, and then concentrate with dichloromethane (5 mL). 3) Extraction, drying with sodium sulfate, filtration, and vacuum concentration were performed to obtain 1-[5-(1-methoxyethyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine (78 mg, crude product). 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% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C. LC purity: 86% (214 nm); mass: 409.3 (M+1) at 1.043 min.

[0766] Step 7. Synthesis of 4-[2-[4-[5-(1-methoxyethyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazin-1-yl]ethyl]morpholine (compound 33).

[0767] 4-(2-chloroethyl)morpholine (80.8 mg, 0.54 mmol) was added to a solution of 1-[5-(1-methoxyethyl)-1-[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). The reaction was stirred at 95°C for 16 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (ammonium bicarbonate / water / acetonitrile) to give the desired product 4-[2-[4-[5-(1-methoxyethyl)-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]piperazine-1-yl]ethyl]morpholine (51.7 mg, yield: 39.6%) as a white solid.

[0768] LCMS method: Mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile; Gradient: 5% B increased to 95% B over 1.3 min, 95% B sustained for 1.7 min; Flow rate: 1.8 mL / min; Column: X-Bridge C18, 50 4.6 mm, 3.5 µm; column temperature: 50°C; LC purity: 99.09% (214 nm); mass: peak found at 1.837 min at 484.2 (M + H).

[0769] 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.2Hz, 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 = 6.5Hz, 3H) ppm. Example S34. Synthesis of 4-[[2-[5-methyl-1-[4-(trifluoromethoxy)phenyl]pyrazol-3-yl]-1,3,4,6,7,8,9,9a-octahydropyridino[1,2-a]pyrazin-8-yl]methyl]morpholine (compound 34).

[0770] Compound 34 was prepared as described below.

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

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

[0773] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 95% (214 nm); mass: peak found at 0.947 min at 196.2 (M+1).

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

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

[0776] LCMS method: Mobile phase: A: water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient: from 5% to 95% B at 2.2 mL / min over 1.2 min; Column: HALO C18, 2.7 µm, 4.6 30 mm; column temperature: 40°C; LC purity: 100% (214 nm); mass: peak found at 0.198 min 202.1 (M+1).

[0777] Step 3. Synthesis of dimethyl 1-[2-(1,3-dioxoisoindoline-2-yl)ethyl]piperidine-2,5-dicarboxylic acid.

[0778] A stirred mixture of DCM (20 mL), N-(2-hydroxyethyl)phthalimide (2.0 g, 10.4 mmol), and 2,6-dimethylpyridine (1.62 mL, 13.9 mmol) was cooled to 0°C. While maintaining the temperature below 15°C, trifluoromethanesulfonic anhydride (2.34 mL, 13.9 mmol) was slowly added over 1 h. The resulting mixture was stirred at room temperature for 2 h, then washed sequentially with water (10 mL), 2 N HCl (10 mL), and water (10 mL) to produce a solution of 2-(1,3-dioxoisoindoline-2-yl)ethyltrifluoromethanesulfonate. DCM (10 mL), water, and sodium carbonate (3.69 g, 34.8 mmol) were added to separate reaction vessels at 20–25°C. After stirring for 15 minutes, dimethyl piperidine-2,5-dica...

Claims

1. A compound having formula (I): (I) Or its pharmaceutically acceptable salt, wherein: X 1 It is C and X 2 Is it N, or X? 1 It is N and X 2 It is C; It is either a single bond or a double bond, depending on one condition. It is a double bond and one It is a single key; R 1 It is C1-C6 alkyl, C3-C6 cycloalkyl, -CN, C1-C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 haloalkyl), or -(C1-C6 alkylene)(C3-C6 cycloalkyl); L 1 It is a bond, O, or -CH2-; Ring B is a C3-C6 cycloalkyl group, a 6-membered heteroaryl group containing 1 or 2 nitrogen atoms, or a C6-C... 10 Aryl; Each R 2 It is independently a C1-C6 alkyl, C1-C6 haloalkyl, halogenated, -O (C1-C6 alkyl), or -O (C1-C6 haloalkyl). Or two R atoms on adjacent carbon atoms 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing 1 or 2 oxygen atoms, each of which is optionally substituted by 1 to 5 groups selected from halogenated and C1-C6 halogenated alkyl groups; L 2 It is a key or an 'O'; Ring A is , 9 to 11 spiro-heterocyclic groups, or 8 to 10 bicyclic fused heterocyclic groups, wherein the heterocyclic group contains 1 to 2 nitrogen atoms; Y 1 It is N or CH; Y 2 It is N or CH; x is 0, 1, or 2; y is 0 or 1; m is 0-5; Each R 3 It is independently a C1-C6 alkyl group. Or two Rs 3 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on the same carbon atom 3 The groups together form a spiroC3-C6 cycloalkyl group; L 3 It is a bond, -CH(R) a )-、-CH(R a )CH(R a )-、-OCH(R a )CH(R a )-、-CH(R a )CH(R a )N(R a -, 5 to 6 membered heterocyclic group or -O- (4 membered heterocyclic group), wherein the heterocyclic group contains 1 to 2 nitrogen atoms; Each R a It is independently an H or C1-C6 alkyl group; W is O, CH2, SO2, S(O)=NH, SO or N(H); Z is either N or CH; r is 0, 1, or 2; s is 0 or 1; Each R 4 It can be halogenated, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. Or two Rs 4 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on adjacent atoms 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom. Or two R atoms on the same carbon atom 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group; and n is 0-5.

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

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

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein: R 1 It is C1-C6 alkyl, C3-C5 cycloalkyl, -CN, C1-C3 haloalkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-O-(C1-C3 haloalkyl), or -(C1-C3 alkylene)(C3-C6 cycloalkyl).

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -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: L 1 It is a key.

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

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

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

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein: yes 。 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein: Each R 2 It is independently a C1-C4 alkyl, C1-C3 haloalkyl, halogenated, -O (C1-C3 alkyl), or -O (C1-C3 haloalkyl). Or two R atoms on adjacent carbon atoms 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing one or two oxygen atoms, each of which is optionally substituted by one to five groups selected from halogenated and C1-C3 halogenated alkyl groups.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: Each R 2 Independently, it is -CF3, -CF2CH3, -CH2CHF2, -CHF2, F, Cl, Br, -OCF3, -OCHF2, -OCH3, or -C(CH3)3. Or two R atoms on adjacent carbon atoms 2 The groups together form a fused phenyl group or a fused 5-membered heterocyclic group containing one or two oxygen atoms, each of which is optionally substituted by one to five groups selected from F or -CF3.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein: yes 。 14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein: L 2 It is a key.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein: L 2 It is O.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein: Ring A is ; Y 1 It is N or CH; Y 2 It is 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 a 9- to 11-membered spiro-heterocyclic group or an 8- to 10-membered bicyclic fused-to-heterocyclic group, wherein the heterocyclic group contains 1-2 nitrogen atoms.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein: yes 。 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 R 3 It is independently a C1-C3 alkyl group. Or two Rs 3 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on the same carbon atom 3 The groups together form spiroC3-C5 cycloalkyl groups.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein: Each R 3 Independently, it is -CH3. Or two Rs 3 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on the same carbon atom 3 The groups together form a spirocyclopropyl group.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein: yes 。 24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein: L 3 It is a key.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein: L 3 It is -CH(R) a )-、-CH(R a )CH(R a )-、-OCH(R a )CH(R a - or -CH(R) a )CH(R a )N(R a )-;and Each R a It is independently H or C1-C3 alkyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein: L 3 It is -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: L 3 It is a 5- to 6-membered heterocyclic group or -O- (4-membered heterocyclic group), wherein the heterocyclic group contains 1-2 nitrogen atoms.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein: L 3 yes .

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein: W can be 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 both 1.

34. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein: r and s are both 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: yes 。 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 R 4 It is independently a halo, -OH, C1-C3 alkyl, or C1-C3 haloalkyl. Or two Rs 4 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on adjacent atoms 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom. Or two R atoms on the same carbon atom 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein: Each R 4 Independently, it is F, -OH, -CH3, -CH(CH3)2, or -CF3. Or two Rs 4 The groups together form bridging -CH2- or -CH2CH2- groups. Or two R atoms on adjacent atoms 4 The groups together form a fused 5-membered heterocyclic group containing one oxygen atom. Or two R atoms on the same carbon atom 4 The groups together form a spiro-4-membered heterocyclic group containing one oxygen atom or an SO2 group.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein: yes 。 43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ia), (Ib), or (Ic): 。 44. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (Id) or (Ie): 。 45. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il): in It is a 5- to 6-membered subheterocyclic group and It is a 4-membered heterocyclic group, wherein the heterocyclic group contains 1-2 nitrogen atoms.

46. ​​The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIa) or (IIb): 。 47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (IIc): 。 48. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIa) or (IIIb): in It is a 9- to 11-membered spiro-heterocyclic group containing 1-2 nitrogen atoms.

49. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IVa) or (IVb): ,in It is an 8- to 10-membered bicyclic fused heterocyclic group containing 1-2 nitrogen atoms.

50. A compound selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof.

51. A compound selected from the compounds in Table 2 or pharmaceutically acceptable salts thereof.

52. A compound selected from the compounds in Table 3 or pharmaceutically acceptable salts thereof.

53. A pharmaceutical composition comprising a compound as described in any one of claims 1-52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

54. A method for inhibiting emopamiprobinding protein (EBP), the method comprising contacting EBP with an effective amount of a compound as described in any one of claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 53.

55. A method for remyelinating a neuronal axon, the method comprising contacting the neuronal axon with an effective amount of a compound as described in any one of claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 53.

56. A method of treating a demyelinating disease in a subject in need, the method comprising administering to the subject an effective amount of a compound as described in any one of claims 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in 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-Barré syndrome.

58. A method of treating multiple sclerosis (MS) in a subject in need, the method 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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