Compounds and uses thereof

Abstract

To provide compounds useful in the treatment of neurological disorders.SOLUTION: For example, compounds represented by the following formula are shown. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders.SELECTED DRAWING: Figure 1A

Description

[Background technology]

[0001] An incomplete understanding of the molecular perturbations that cause disease, as well as a limited availability of robust model systems, contribute to the failure to develop successful disease-modifying therapies for common and progressive neurological disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Progress has been made on many fronts in identifying drugs that can slow the progression of these disorders. However, current therapies for many, if not all, of these diseases provide little relief. Therefore, there is a need to develop therapies that can alter the course of neurodegenerative diseases. More generally, better methods and compositions are needed for the treatment of neurodegenerative diseases to improve the quality of life of those suffering from such diseases. Summary of the Invention

[0002] The present disclosure provides compounds of the structure of Formula I:

[0003] [ka] or a pharmaceutically acceptable salt thereof, wherein B is absent or has the following structure:

[0004] [ka] The dashed lines represent optional double bonds; Het is —C(O)NH— or optionally substituted C2-C9 heteroaryl; m is 0 or 1, n is 0, 1, or 2; o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; p, p', r, and r' are independently 0 or 1; X 1 and X 2 are each independently N or CR 6 and L 1-O-, -SO2-, NR 2 , optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkenylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C6-C 10 aryl, or an optionally substituted C2-C9 heterocycle; L 2 is absent, -O-, -SO2-, NR 2 , or -CR 2 R 3 - and R 1 is hydrogen, amino, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C-C 10 arylC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heterocycle, or optionally substituted C2-C9 heterocycleC1-C6 alkyl; R 2 and R 3 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or together with the carbon to which they are attached form a carbonyl or an optionally substituted C3-C7 cycloalkyl; Each R 4 are independently halogen, hydroxyl, optionally substituted C-C alkyl, optionally substituted C-C heteroalkyl, or two R 4 together with the carbon to which they are attached form a carbonyl or an optionally substituted C3-C7 cycloalkyl; R 5 optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10Aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocycle, optionally substituted C6-C 10 arylC1-C6 alkyl, optionally substituted C2-C9 heterocycleC1-C6 alkyl, or optionally substituted C2-C9 heteroarylC1-C6 alkyl; Each R 6 are independently hydrogen, halogen, hydroxy, optionally substituted C1-C6 heteroalkyl, or optionally substituted C1-C6 alkyl.

[0005] In some embodiments, B is absent.

[0006] In some embodiments, B has the structure of formula Ib:

[0007] [ka] It has.

[0008] In some embodiments, X 1 is N and X 2 is CR 6 In some embodiments, o is 0, 1, or 2. In some embodiments, R 4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R 4 together with the carbon to which they are attached form a carbonyl. 6 is hydrogen. In some embodiments, R 6 is halogen (e.g., fluoro). In some embodiments, R 6is an optionally substituted C1-C6 alkyl (e.g., methyl). In some embodiments, the dashed line represents an optional double bond. In some embodiments, both dashed lines represent a single bond. In some embodiments, p is 1 and r is 1. In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, B has the following structure:

[0009] [ka] It has.

[0010] In some embodiments, X 1 is CR 6 and X 2 is N. In some embodiments, o is 0, 1, or 2. In some embodiments, R 4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R 4 together with the carbon to which they are attached form a carbonyl. 6 is hydrogen. In some embodiments, R 6 is halogen (e.g., fluoro). In some embodiments, R 6 is an optionally substituted C1-C6 alkyl (e.g., methyl). In some embodiments, the dashed line represents an optional double bond. In some embodiments, the dashed line represents a single bond. In some embodiments, p is 1 and r is 1. In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, B has the following structure:

[0011] [ka] It has.

[0012] In some embodiments, X 1 is N and X 2 is N. In some embodiments, o is 0, 1, or 2. In some embodiments, R 4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R 4 together with the carbon to which they are attached form a carbonyl. In some embodiments, the dashed line represents an optional double bond. In some embodiments, the dashed line represents a single bond. In some embodiments, p is 1 and r is 1. In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, p is 1 and r is 2. In some embodiments, B has the following structure:

[0013] [ka] It has.

[0014] In some embodiments, X 1 is CR 6 and X 2 is CR 6 In some embodiments, o is 0, 1, or 2. In some embodiments, R 4 is halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., methyl), or two R 4 together with the carbon to which they are attached form a carbonyl. In some embodiments, the dashed line represents an optional double bond. In some embodiments, the dashed line represents a single bond. In some embodiments, p is 1 and r is 1. In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, B is the structure

[0015] [ka] It has.

[0016] In some embodiments, B has the structure of formula Ic:

[0017] [ka] It has.

[0018] In some embodiments, X 1 is N and X 2 is N. In some embodiments, o is 0. In some embodiments, p, p', r, and r' are 0. In some embodiments, p and r are each 1, and p' and r' are 0. In some embodiments, B has the following structure:

[0019] [ka] It has.

[0020] In some embodiments, B has the structure of formula Id:

[0021] [ka] It has.

[0022] In some embodiments, X 1 is N and X 2 is N. In some embodiments, o is 0. In some embodiments, B has the following structure:

[0023] [ka] It has.

[0024] In some embodiments, B has the structure of formula Ie:

[0025] [ka] It has.

[0026] In some embodiments, X 1 is N and X 2 is N. In some embodiments, o is 0. In some embodiments, B has the following structure:

[0027] [ka] It has.

[0028] In some embodiments, B has the structure of formula If:

[0029] [ka] It has.

[0030] In embodiments of any of the foregoing compounds, Het is —C(O)NH—, or

[0031] [ka] is In the formula, X 3 is O or S.

[0032] In some embodiments, Het is -C(O)NH-.

[0033] In some embodiments, Het

[0034] [ka] is.

[0035] In some embodiments, Het

[0036] [ka] is.

[0037] In some embodiments, Het

[0038] [ka] is.

[0039] In some embodiments, Het

[0040] [ka] is.

[0041] In some embodiments, L 2 is absent. In some embodiments, L 2 is -NR 2 - (e.g., -NH-). In some embodiments, L 2 is —O—. In some embodiments, L 2 In some embodiments, L 2 Ha-CR 2 R 3 In some embodiments, R 2 and R 3 together with the carbon to which they are attached form a carbonyl. 2 and R 3 taken together with the carbon to which they are attached form an optionally substituted C-C cycloalkyl (e.g., cyclopropyl). In some embodiments, R 2 and R 3 and are both hydrogen. In some embodiments, R 2 is hydrogen and R 3 is an optionally substituted C1-C6 alkylene (e.g., methylene).

[0042] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, L 1 is -NR 2 - (e.g., -NH- or -N(Et)-). In some embodiments, L 1 is —O—. In some embodiments, L 1 In some embodiments, L 1 is an optionally substituted C1-C6 alkylene (e.g., methylene or hydroxy-methylene). In some embodiments, L 1 is an optionally substituted C1-C6 heteroalkylene (e.g., -NH-CH2-, -O-CH2-, -O-CH2-CH2-, -CH2-O-CH2-, -CH2-O-,

[0043] [ka] In some embodiments, L 1 is an optionally substituted C2-C9 heterocycle (e.g.,

[0044] [ka] )

[0045] In some embodiments, R 1 is cyano, optionally substituted C-C alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, pentafluoro-ethyl, 2-chloro-ethyl, 1-chloro-3-hydroxy-isopropyl, 2-methoxy-ethyl, or hexafluoro-isopropyl). 1 is an optionally substituted C6-C 10Aryl (e.g., phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3-isopropyl-phenyl, 4-isopropyl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-difluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 2-chloro-5-fluoro-phenyl, 2-fluoro-4-chloro-phenyl, 3-fluoro-4-chloro-phenyl, 2-bromo-4-methoxy-phenyl, 2-trifluoromethyl-5-fluoro-phenyl, 2-trifluoromethyl-5-chloro-phenyl,

[0046] [ka] In some embodiments, R 1 is an optionally substituted C6-C 10 arylC1-C6 alkyl (e.g., naphthylmethyl). In some embodiments, R 1 is an optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl, cyclohexyl, 6-methoxy-cyclohexyl, 1-cyano-cyclopropyl, bicycle[1.1.1]pentane, 1-methyl-cyclopropyl, 1-ethyl-cyclopropyl, 1-fluoro-cyclopropyl, 1-methoxy-cyclopropyl, 1-hydroxy-cyclopropyl, 2,2-dimethyl-cyclopropyl, 2,2-difluoro-cyclopropyl, cyclobutyl,

[0047] [ka] In some embodiments, R 1 is optionally substituted C-C cycloalkylC-C alkyl(cyclopropylmethyl). In some embodiments, R 1is an optionally substituted C2-C9 heteroaryl (e.g.,

[0048] [ka] )

[0049] In some embodiments, R 1 is an optionally substituted C2-C9 heterocycle (e.g.

[0050] [ka] In some embodiments, R 1 is an optionally substituted C2-C9 heterocycle C1-C6 alkyl (e.g.,

[0051] [ka] )

[0052] In some embodiments, R 5 is an optionally substituted C6-C 10 aryl (e.g., phenyl, 3,4-dimethoxy-phenyl, 3-methoxy-4-ethoxy-phenyl, 3,5-dimethoxy-phenyl, 3-methoxy-4-cyclopropoxy-phenyl, 3-methoxy-4-trifluoromethoxy-phenyl, 3-isopropoxy-4-methoxy-phenyl,

[0053] [ka] In some embodiments, R 5 is an optionally substituted C2-C9 heteroaryl (e.g.,

[0054] [ka] JPEG2025041715000030.jpg233166JPEG2025041715000031.jpg238166JPEG2025041715000032.jpg163166). In some embodiments, R 5 is an optionally substituted indazole. In some embodiments, R 5 is an optionally substituted C2-C9 heterocycle (e.g.,

[0055] [ka] In some embodiments, R 5 is an optionally substituted C2-C9 heteroarylC1-C6 alkyl (e.g.,

[0056] [ka] )

[0057] In some embodiments, R 5 is a bicyclic heterocycle, such as indazole. In some embodiments, R 5 has the following structure:

[0058] [ka] is an indazole having the formula In the formula, R 5a is hydrogen or optionally substituted C1-C6 alkyl (e.g., methyl), and R 5b is an optionally substituted C1-C6 alkyl (e.g., methyl or iso-propyl), an optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or an optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl).

[0059] In some embodiments, B has the following structure:

[0060] [ka] It has.

[0061] In some embodiments, R 1 is an optionally substituted C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, or tert-butyl), an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl.

[0062] In some embodiments, m is 0, n is 1, and L 1 is -O- and L 2 is —C(O)—. In some embodiments, m is 0, n is 0, and L 2 is —C(O)—. In some embodiments, m is 0, n is 1, and L 1 teeth

[0063] [ka] and L 2 is —C(O)—. In some embodiments, m is 1, n is 1, and L 1 teeth

[0064] [ka] and L 2 is -C(O)-.

[0065] In some embodiments, R 5 has the following structure:

[0066] [ka] is an indazole having the formula In the formula, R 5ais hydrogen or optionally substituted C1-C6 alkyl (e.g., methyl), and R 5b is an optionally substituted C1-C6 alkyl (e.g., methyl or iso-propyl), an optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or an optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl), and B has the structure:

[0067] [ka] R 1 is an optionally substituted C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, or tert-butyl), an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; m is 0, n is 1, and L 1 is -O- and L 2 is -C(O)-, m is 0, n is 0, and L 2 is -C(O)-, m is 0, n is 1, and L 1 teeth

[0068] [ka] and L 2 is —C(O)—, or m is 1, n is 1, and L 1 teeth

[0069] [ka] and L 2 is -C(O)-.

[0070] In some embodiments, m is 0, n is 1, and L 1 is -O- and L 2 is -C(O)- and R 1 is an optionally substituted C1-C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl).

[0071] In some embodiments, m is 0, n is 0, and L 2 is -C(O)- and R 1 is an optionally substituted C6-C 10 It is aryl.

[0072] In some embodiments, m is 0, n is 1, and L 1 teeth

[0073] [ka] and L 2 is -C(O)- and R 1 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl.

[0074] In some embodiments, m is 1, n is 1, and L 1 teeth

[0075] [ka] and L 2 is -C(O)- and R 1 is an optionally substituted C6-C 10 It is aryl.

[0076] In some embodiments, the compound has the structure of formula Ig:

[0077] [ka] wherein Het is an optionally substituted oxadiazole; o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; X 2 But N or CR 6 and R 1optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C-C 10 arylC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heterocycle, or optionally substituted C2-C9 heterocycleC1-C6 alkyl; Each R 4 are independently halogen, hydroxyl, optionally substituted C-C alkyl, optionally substituted C-C heteroalkyl, or two R 4 together with the carbon to which they are attached form a carbonyl or an optionally substituted C3-C7 cycloalkyl; R 5 optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 Aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocycle, optionally substituted C6-C 10 arylC1-C6 alkyl, optionally substituted C2-C9 heterocycleC1-C6 alkyl, or optionally substituted C2-C9 heteroarylC1-C6 alkyl; Each R 6 are independently hydrogen, halogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted C1-C6 alkyl.

[0078] In some embodiments, Het

[0079] [ka] is.

[0080] In some embodiments, Het

[0081] [ka] is.

[0082] In some embodiments, X 2 is N or CH. In some embodiments, X 2 is N. In some embodiments, X 2 is CH.

[0083] In some embodiments, R 1 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or an optionally substituted C6-C 10 It is aryl.

[0084] In some embodiments, R 5 is an optionally substituted C6-C 10 aryl or optionally substituted C-C heteroaryl (e.g., bicyclic heteroaryl such as indazole). 5 has the following structure:

[0085] [ka] In the formula, R 5a is hydrogen or optionally substituted C1-C6 alkyl (e.g., methyl), and R 5b is an optionally substituted C1-C6 alkyl (e.g., methyl or iso-propyl), an optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or an optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl). In some embodiments, R 5a is hydrogen.

[0086] In some embodiments, Het

[0087] [ka] , o is 0, and X 2 is N or CH, and R 1 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl (e.g., C1-C6 alkoxy or C1-C6 alkylamino), or an optionally substituted C6-C 10 aryl, and R 5 has the following structure:

[0088] [ka] In the formula, R 5b is an optionally substituted C1-C6 alkyl (e.g., methyl or iso-propyl), an optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or an optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl).

[0089] In some embodiments, the compound has the structure of Formula I:

[0090] [ka] wherein Het is an optionally substituted C2-C9 heteroaryl; m is 0 or 1, n is 0, 1, or 2; o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; X 1 and X 2 are each independently N or CR 6 and L 1 is an optionally substituted C1-C6 alkylene, an optionally substituted C1-C6 alkenylene, an optionally substituted C1-C6 heteroalkylene, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C2-C9 heteroaryl, or an optionally substituted C2-C9 heterocycle; R 1optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heterocycle; R 2 and R 3 are each independently hydrogen, optionally substituted C1-C6 alkyl, or together with the carbon to which they are attached form a carbonyl; Each R 4 are independently halogen, hydroxyl, optionally substituted C-C alkyl, optionally substituted C-C heteroalkyl, or two R 4 together with the carbon to which they are attached to form a carbonyl, R 5 optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl; Each R 6 are independently hydrogen or optionally substituted C1-C6 alkyl.

[0091] In some embodiments of any of the foregoing compounds, R 2 and R 3 together with the carbon to which they are attached to form a carbonyl. In some embodiments of any of the foregoing compounds, R 2 and R 3 are both hydrogen.

[0092] In some embodiments of any of the foregoing compounds, Het is

[0093] [ka] and In the formula, X 3 is O or S.

[0094] In some embodiments, the compound has the structure of Formula II or IIa:

[0095] [ka] It has.

[0096] In some embodiments of any of the foregoing compounds, X 3 is O. In some embodiments of any of the foregoing compounds, X 3 is S.

[0097] In some embodiments of any of the foregoing compounds, X 1 is N and X 2 is CR 6 In some embodiments of any of the foregoing compounds, X 1 is N and X 2 is N. In some embodiments of any of the foregoing compounds, X 1 is CR 6 and X 2 is N. In some embodiments of any of the foregoing compounds, R 6 is hydrogen.

[0098] In some embodiments of any of the foregoing compounds, R 5 is an optionally substituted C6-C 10 For example, in some embodiments, R 5 is a C6-C6 alkyl group substituted with one, two, three, or four substituents independently selected from C1-C6 alkyl (e.g., methyl), halogen (e.g., fluoro, chloro, or bromo), C1-C6 alkoxy (e.g., methoxy or ethoxy), and nitrile; 10 aryl, or the two substituents together form a 5- or 6-membered heterocycle (e.g., 2,2-difluoro-1,3-benzodioxole). In some embodiments of any of the foregoing compounds, R 5is phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxy-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 3,4-difluoro-phenyl, 3,4-dichloro-phenyl, 3-methoxy-4-ethoxy-phenyl, 3-chloro-4-ethoxy-phenyl, 3-fluoro-4-ethoxy-phenyl, 3-bromo-4-ethoxy-phenyl, 3-cyano-4-ethoxy-phenyl, or 2,2-difluoro-1,3-benzodioxole.

[0099] In some embodiments, the compound has the structure of Formula III or IIIa:

[0100] [ka] wherein p is 1, 2, 3, 4, or 5; Each R 7 are independently selected from halogen, nitrile, OR 8 or optionally substituted C1-C6 alkyl; Each R 8 are independently hydrogen or optionally substituted C1-C6 alkyl.

[0101] In some embodiments, the compound has the structure of Formula IV or IVa:

[0102] [ka] It has.

[0103] In some embodiments, each R 7 is OR 8 In some embodiments, each R 8 is an optionally substituted C1-C6 alkyl (e.g., methyl or ethyl).

[0104] In some embodiments of any of the foregoing compounds, R 5 is an optionally substituted C-C heteroaryl (e.g., bicyclic heteroaryl). In some embodiments of any of the foregoing compounds, R 5 teeth,

[0105] [ka] is.

[0106] In some embodiments of any of the foregoing compounds, R 5 teeth,

[0107] [ka] is.

[0108] In some embodiments of any of the foregoing compounds, R 1 is an optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl. In some embodiments, R 1 is an optionally substituted C6-C 10 For example, phenyl or C-C substituted with 1, 2, 3, 4, or 5 substituents independently selected from C-C alkyl (e.g., methyl or isopropyl), C-C alkoxy (e.g., methoxy), or halogen (e.g., chloro). 10 In some embodiments of any of the foregoing compounds, R 1 is 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxy-phenyl, phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-methyl-phenyl, 4-iso-propyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, or 4-chloro-phenyl. In some embodiments of any of the foregoing compounds, R 1is a bicyclic C6-C 10 In some embodiments of any of the foregoing compounds, R 1 is C-C cycloalkyl (e.g., cyclohexyl). In some embodiments of any of the foregoing compounds, R 1 is an optionally substituted C2-C9 heteroaryl or an optionally substituted C2-C9 heterocycle. For example, in some embodiments, R 1 teeth,

[0109] [ka] is.

[0110] In some embodiments of any of the foregoing compounds, the compound has the structure of Formula V or Va:

[0111] [ka] wherein q is 1, 2, 3, 4, or 5; R 9 is halogen or optionally substituted C1-C6 alkyl.

[0112] In some embodiments of any of the foregoing compounds, the compound has the structure of Formula VI or VIa:

[0113] [ka] It has.

[0114] In some embodiments of any of the aforementioned compounds, n is 1. In some embodiments of any of the aforementioned compounds, n is 0.

[0115] In some embodiments of any of the foregoing compounds, L 1is optionally substituted C1-C6 alkyl. For example, L 1 has the following structure:

[0116] [ka] It has.

[0117] In some embodiments of any of the foregoing compounds, L 1 is an optionally substituted C1-C6 alkenylene (e.g., ethenylene).

[0118] In some embodiments of any of the foregoing compounds, L 1 is an optionally substituted C2-C9 heterocyclene or an optionally substituted C2-C9 heteroarylene. For example,

[0119] [ka]

[0120] In some embodiments, L 1 teeth

[0121] [ka] is.

[0122] In some embodiments of any of the foregoing compounds, L 1 is an optionally substituted C1-C6 heteroalkylene. For example, in some embodiments, L 1 teeth,

[0123] [ka] is.

[0124] In some embodiments of any of the foregoing compounds, L 1 is -NH-(CR10 R 11 ) r wherein r is 1, 2, 3, 4, 5, or 6, and each R 10 and R 11 are independently hydrogen or optionally substituted C1-C6 alkyl. For example, in some embodiments, L 1 -NH-CH2-, -NH-CR 10 R 11 - and R 10 and R 11 Each of the groups is methyl or -NH-CHR 11 - and R 11 is methyl.

[0125] In some embodiments of any of the aforementioned compounds, m is 1. In some embodiments of any of the aforementioned compounds, m is 0.

[0126] In another aspect, the disclosure provides a compound having the structure of any one of compounds 1-966 in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of compounds 1-264, 266-271, 274-276, 278-299, 302-318, 320-329, 331-340, 344-354, 358, 362-364, 367, 369, 371-378, 385, 388-392, 396, 397, 399- In some embodiments, the compound is any one of compounds 1-347, 349, 350, or 354-746 in Table 1. In some embodiments, the compound is any one of compounds 1-387, 389, 393-405, 407-430, 432-439, 441-449, 452, 454-457, 459-472, 475, 477-480, 482-487, or 489-746 in Table 1. In some embodiments, the compound is any one of compounds 1-483 or 491-746 in Table 1. In some embodiments, the compound is any one of compounds 747-966. In some embodiments, the compound is any one of compounds 27, 40, 96, 128, 140, 168, 184, 204, 226, 244, 265, 268, 269, 284, 286 291, 294, 302, 305, 306, 308, 317, 319, 343, 344, 345, 346, 349, 355-357, or 359-364. In some embodiments, the compound is any one of compounds 244, 265, 269, 319, 345, 349, 355-357, 361, or 364.In some embodiments, the compound is any one of compounds 750, 767, 775-778, 780, 784, 785, 789-792, 795, 799, 812, 813, 817, 828, 838, 839, 842-844, 846, 848, 850, 851, 853, 854, 861, 862, 865, 874-881, 884-888, 890-898, 902, 903, 907, 910, 916, 928, 932, 934, 953, 957, 960, 964, or 965.

[0127] [Table 1] JPEG2025041715000066.jpg251169JPEG2025041715000067.jpg236169JPEG2025041715000068.jpg244160JPEG2025041715000069.jpg251170JPEG2025041715000070.jpg236168JPEG2025041715000071.jpg244160JPEG2025041715000072.jpg239168JPEG2025041715000073.jpg235169JPEG2025041715000074.jpg247169JPEG2025041715000075.jpg255168JPEG2025041715000076.jpg244161JPEG2025041715000077.jpg248169JPEG2025041715000078.jpg252169JPEG2025041715000079.jpg246169JPEG2025041715000080.jpg246168JPEG2025041715000081.jpg248168JPEG2025041715000082.jpg252169JPEG2025041715000083.jpg245168JPEG2025041715000084.jpg236167JPEG2025041715000085.jpg236169JPEG2025041715000086.jpg236169JPEG2025041715000087.jpg248169JPEG2025041715000088.jpg240168JPEG2025041715000089.jpg245168JPEG2025041715000090.jpg255168JPEG2025041715000091.jpg246168JPEG2025041715000092.jpg236168JPEG2025041715000093.jpg240168JPEG2025041715000094.jpg240168JPEG2025041715000095.jpg244168JPEG2025041715000096.jpg241167JPEG2025041715000097.jpg255168JPEG2025041715000098.jpg255167JPEG2025041715000099.jpg240167JPEG2025041715000100.jpg235168JPEG2025 041715000101.jpg245168JPEG2025041715000102.jpg240168JPEG2025041715000103.jpg2 40167JPEG2025041715000104.jpg250167JPEG2025041715000105.jpg251168JPEG20250417 15000106.jpg246168JPEG2025041715000107.jpg250169JPEG2025041715000108.jpg39167.

[0128] [Table 2] JPEG2025041715000110.jpg244167JPEG2025041715000111.jpg255167JPEG2025041715000112.jpg234167 JPEG2025041715000113.jpg255166JPEG2025041715000114.jpg240166JPEG2025041715000115.jpg255168 JPEG2025041715000116.jpg242168JPEG2025041715000117.jpg254166JPEG2025041715000118.jpg229167 JPEG2025041715000119.jpg240167JPEG2025041715000120.jpg250166JPEG2025041715000121.jpg163166

[0129] In another aspect, the disclosure provides a pharmaceutical composition comprising any of the foregoing compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0130] In another aspect, the present disclosure provides a method of treating a neurological disorder in a subject in need thereof, comprising administering an effective amount of any of the foregoing compounds, or a pharmaceutically acceptable salt thereof, or any of the foregoing pharmaceutical compositions.

[0131] In another aspect, the disclosure provides a method of inhibiting protein-associated toxicity in a cell (e.g., a mammalian nervous system cell) (e.g., toxicity associated with protein misfolding and / or aggregation, e.g., protein aggregation associated with the misfolding of a protein such as alpha-synuclein or ApoE4), comprising administering or contacting a cell with an effective amount of any of the foregoing compounds, or a pharmaceutically acceptable salt thereof. In some embodiments, the toxicity is alpha-synuclein-associated toxicity. In some embodiments, the toxicity is ApoE4-associated toxicity.

[0132] Non-limiting exemplary neurological disorders include, but are not limited to, Alexander disease, Alpers disease, AD, amyotrophic lateral sclerosis, ataxia-telangiectasia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington's disease, Kennedy disease, Krabbe disease, dementia with Lewy bodies, Machado-Joseph disease, multiple sclerosis, PD, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum disease, Sandhoff disease, Schilder's disease, Steele-Richardson-Olszewski disease, tabes dorsalis, frontotemporal dementia, Down syndrome, and Guillain-Barré syndrome.

[0133] In another aspect, the disclosure provides a method of treating a stearoyl-CoA desaturase (SCD)-associated disorder in a subject in need thereof, comprising administering or contacting a cell with an effective amount of any of the foregoing compounds, or a pharmaceutically acceptable salt thereof.

[0134] Non-limiting exemplary SCD-related disorders include, but are not limited to, metabolic disorders (e.g., diabetes (e.g., type 1 diabetes and type 2 diabetes), hyperglycemia, metabolic syndrome, obesity, lipid disorders, fatty liver, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and hypertension), cancer, cardiovascular disease, cerebrovascular disease, kidney disease, liver disease, skin disorders (e.g., acne (e.g., acne vulgaris)), central nervous system (CNS) disorders, dementia, multiple sclerosis, schizophrenia, mild cognitive impairment, Alzheimer's disease, cerebral amyloid angiopathy, and Down's syndrome-related dementia.

[0135] chemical terms It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0136] As used herein, the term "acryl" refers to a hydrogen or alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbons.

[0137] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). Alkylene is a divalent alkyl group.

[0138] As used herein, the term "alkenyl," alone or in combination with other groups, refers to a straight- or branched-chain hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0139] The term "alkynyl," as used herein, alone or in combination with other groups, refers to a straight- or branched-chain hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0140] As used herein, the term "amino" refers to -N(R N1 )2, wherein each R N1 are independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and these enumerated R N1 Each of the groups may be optionally substituted, or two R N1 combine to form an alkylene or heteroalkylene, and each R N2 is independently H, alkyl, or aryl. The amino group of the present invention can be unsubstituted amino (i.e., —NH) or substituted amino (i.e., —N(R N1 )2).

[0141] As used herein, the term "aryl" refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0142] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are those having 7 to 30 carbons (e.g., 7 to 16, or 7 to 20 carbons, e.g., C 1-6 Alkyl C 6-10 Aryl, C 1-10Alkyl C 6-10 Aryl, or C 1-20 Alkyl C 6-10 aryl), for example, benzyl and phenethyl. In some embodiments, akyl and aryl can each be further substituted with 1, 2, 3, or 4 substituents, as defined herein for the individual groups.

[0143] As used herein, the term "azido" refers to an -N3 group.

[0144] As used herein, the term "cyano" refers to a -CN group.

[0145] As used herein, the term "carbocyclyl" refers to a non-aromatic C 3-12 The carbocyclyl structure includes a cycloalkyl group and an unsaturated carbocyclyl radical.

[0146] As used herein, the term "cycloalkyl" refers to a saturated, non-aromatic, monovalent mono- or polycarbocyclic radical of 3 to 10, preferably 3 to 6, carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0147] As used herein, the term "halogen" refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0148] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl groups. An example of a heteroalkyl group is "alkoxy," which, as used herein, refers to alkyl-O- (e.g., methoxy and ethoxy). Heteroalkylene is a divalent heteroalkyl group.

[0149] As used herein, the term "heteroalkenyl" refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, a heteroalkenyl group can be further substituted with 1, 2, 3, or 4 substituents as described herein for an alkenyl group. An example of a heteroalkenyl group is "alkenoxy," which, as used herein, refers to alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group.

[0150] As used herein, the term "heteroalkynyl" refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1, 2, 3, or 4 substituents as described herein for alkynyl groups. An example of a heteroalkynyl group is "alkynoxy," which, as used herein, refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0151] As used herein, the term "heteroaryl" refers to an aromatic mono- or polycarbocyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be substituted with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0152] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups include those having 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, e.g., C 1-6 Alkyl C 2-9 Heteroaryl, C 1-10 Alkyl C 2-9 Heteroaryl, or C 1-20 Alkyl C 2-9 In some embodiments, the alkyl and heteroaryl can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for the individual groups.

[0153] As used herein, the term "heterocyclyl" refers to a mono- or polycyclic radical of 3 to 12 atoms having at least one ring that contains 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S, and which ring is not aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

[0154] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups include those having 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, e.g., C 1-6 Alkyl C 2-9 Heterocyclyl, C 1-10 Alkyl C 2-9 Heterocyclyl, or C 1-20 Alkyl C 2-9 In some embodiments, the alkyl and heterocyclyl can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for the individual groups.

[0155] As used herein, the term "hydroxyl" refers to an --OH group.

[0156] As used herein, the term "N-protecting group" refers to a group intended to protect an amino group from undesired reactions during synthetic procedures. Commonly used N-protecting groups are described in Greene, "Protective Groups in Organic Synthesis," 3 rdEdition (John Wiley & Sons, New York, 1999). N-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, and 4-nitrobenzoyl, as well as protected or unprotected D, L, or D, L groups such as alanine, leucine, and phenylalanine. -Chiral auxiliaries such as amino acids; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; and equivalents with benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl carbamate-forming groups such as phenyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl; and silyl groups such as trimethylsilyl.Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0157] As used herein, the term "nitro" refers to the group --NO.sub.2.

[0158] As used herein, the term "thiol" refers to a -SH group.

[0159] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups can be substituted or unsubstituted. If substituted, typically 1 to 4 substituents will be present unless otherwise specified. Substituents include, for example, aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH or mono- or dialkylamino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups can also be substituted with alkyl (unsubstituted and substituted, such as arylalkyl (e.g., substituted and unsubstituted benzyl)).

[0160] The compounds of the present invention may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of racemates, asymmetric synthesis, or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, certain disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly pairs of stereoisomers whose mirror images are non-superimposable because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" refers to a pair of molecules that are mirror images of each other and are non-superimposable. Diastereomers are most commonly stereoisomers that contain two or more asymmetrically substituted carbon atoms and represent the arrangement of substituents around one or more chiral carbon atoms, and therefore are not related to mirror images. Enantiomers of a compound can be prepared by separating the enantiomer from a racemate using one or more known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating enantiomers of the compounds described herein from racemic mixtures can be readily determined by one skilled in the art. A "racemate" or "racemic mixture" refers to a compound containing two enantiomers, and such mixtures do not exhibit optical activity: i.e., they do not rotate the plane of polarized light. A "geometric isomer" refers to isomers that differ in the orientation of substituent atoms with respect to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in the E configuration (substituents are on opposite sides of the carbon-carbon double bond) or the Z configuration (substituents are oriented on the same side). "R", "S", "S" * "," "R *"," "E," "Z," "cis," and "trans" indicate configurations relative to a core molecule. Certain disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindrance of rotation around a single bond, where the steric strain barrier to rotation creates a sufficiently high rotational barrier to isolate conformers. The compounds of the invention may be prepared as individual isomers by isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming a salt of the free base of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each isomer of the isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving isomeric mixtures of either the starting materials or the final products using various known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. The percentage optical purity is the ratio of the weight of the enantiomer to the weight of its optical isomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereomers.When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% mole fraction pure relative to the other stereoisomer. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% mole fraction pure. The mole fraction purity percentage is the ratio of moles of enantiomer to moles of that enantiomer plus moles of its enantiomer. Similarly, a mole fraction purity percentage is the ratio of moles of a diastereomer to moles of its isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has at least one chiral center, the name or structure should be understood to encompass either an enantiomer of the compound free of the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has two or more chiral centers, the name or structure should be understood to encompass a diastereomer free of the other, several diastereomers free of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers enriched in one diastereomer relative to the other diastereomer(s), or mixtures of diastereomers enriched in one or more diastereomers relative to the other diastereomers. The present invention encompasses all these forms.

[0161] definition In practicing the methods of this invention, an "effective amount" of any one compound of this invention, or any combination of compounds of this invention, or pharmaceutically acceptable salts thereof, is administered, alone or in combination, via any of the customary and acceptable methods known in the art.

[0162] As used herein, the term " pharmaceutical composition " refers to the composition containing the compound described herein, which is formulated with pharmaceutically acceptable excipients and manufactured or sold as part of the treatment regimen for the treatment of mammalian disease by the approval of government regulatory agencies.The pharmaceutical composition can be formulated for example, for oral administration (for example, tablet, capsule, caplet, gel cap or syrup) in unit dosage form; for topical administration (for example, cream, gel, lotion or ointment); for intravenous administration (for example, as a sterile solution in a solvent system suitable for intravenous use, without particulate emboli); or any other pharmaceutically acceptable formulation.

[0163] As used herein, "pharmaceutically acceptable excipient" refers to any ingredient, other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving an active compound), that is substantially non-toxic and non-irritating in a patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression acids, disintegrants, dyes (pigments), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0164] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound of Formula (I). For example, pharmaceutically acceptable salts of any of the compounds described herein include those suitable for use in contact with human and animal tissues without undue toxicity, irritation, or allergic reaction, within the scope of sound medical judgment, and at a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.

[0165] The compounds of the present invention may have ionic groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or salts may be prepared from inorganic or organic bases when the compounds of the present invention are in acidic form. Often, compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases, as well as methods for preparing suitable salts, are known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0166] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-hydroxyethanesulfonate. Salts include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0167] As used herein, the term "stearoyl-CoA desaturase (SCD)-associated disorder" refers to an undesirable physiological condition, disorder, or disease that is at least partially associated with and / or mediated by an SCD protein. In some cases, an SCD-associated disorder is associated with excessive SCD levels and / or activity. SCD introduces a double bond at the C9-C10 position of saturated fatty acids, such as palmitoyl-CoA and stearoyl-CoA, which are converted to palmitoyl-CoA and oleoyl-CoA, respectively. One SCD gene, SCD1, has been characterized in humans, with two isoforms, SCD1 and SCD5. An SCD-associated disorder may be at least partially associated with and / or mediated by SCD1 and / or SCD5. Exemplary SCD-related disorders include, but are not limited to, metabolic disorders (e.g., diabetes (e.g., type I diabetes and type II diabetes), hyperglycemia, metabolic syndrome, obesity, lipid disorders, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hypertension), cancer, cardiovascular disease, cerebrovascular disease, kidney disease, liver disease, skin disorders (e.g., acne (e.g., acne vulgaris)), central nervous system (CNS) disorders, dementia, multiple sclerosis, schizophrenia, mild cognitive impairment, Alzheimer's disease, cerebral amyloid angiopathy, and Down's syndrome-related dementia. Additional SCD-related disorders are described herein or known in the art.

[0168] As used herein, the term "subject" refers to any living organism to which a composition according to the present invention can be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal seeking or in need of treatment, in need of treatment, undergoing treatment, about to undergo treatment, or being treated by a trained professional for a particular disease or condition.

[0169] As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable; reduction in the extent of the condition, disorder, or disease; stabilization (i.e., not worsening) of the condition, disorder, or disease state; delay in onset or slowing of the progression of the condition, disorder, or disease; amelioration or remission (whether partial or total) of the condition, disorder, or disease state, whether detectable or undetectable; recovery of at least one measurable physical parameter, although not necessarily perceptible by the patient; or enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment. [Brief explanation of the drawings]

[0170] [Figure 1A]Figures 1A and 1B are graphs showing that growth inhibition by 1,2,4-oxadiazoles occurs via the same mechanism as toxicity rescue in the apolipoprotein E4 (ApoE4) yeast model of Alzheimer's disease. (Figure 1A) Compound 7, a representative 1,2,4-oxadiazole, was profiled under non-induced conditions with ApoE4 (top) and control (bottom) at a 12-point dose (x-axis). The y-axis represents raw OD. Compound 7 exhibited a bell-shaped dose-response curve (DRC) in the ApoE4 model. Rescue was reduced at concentrations slightly above the maximal effect (Emax). Under control conditions (bottom panel), growth was reduced at this same concentration. (Figure 1B) The relationship between Emax (rescue in ApoE4) and growth inhibition (under control conditions) correlated for the 34 1,2,4-oxadiazoles tested. The maximum rescue dose (EC100) for ApoE4 is shown on the y-axis, and the minimum inhibitory dose under control conditions (IC100) is shown on the x-axis. This correlation indicates that growth inhibition is caused by the same precise activity that rescues the toxicity of ApoE4. [Figure 1B] Same as above. [Figure 2]Figures 2A and 2B are graphs showing that exogenous oleic acid reverses growth inhibition by 1,2,4-oxadiazoles targeting Ole1 / SCD, a model rescue. Growth was measured by reading OD600 in a microplate reader and normalizing to the solvent control DMSO sample. (Figure 2A) Growth inhibition (24 h) of strain GM yap1 flr1 by 1,2,4-oxadiazoles targeting Ole1 / SCD was rescued by exogenous 0.5 mM oleic acid / palmitoleic acid, which did not affect growth inhibition by other compounds (black dots indicate other scaffolds tested). Maximum growth inhibition across doses ranging from 33 nM to 33 μM is plotted. (Figure 2B) Rescue (40 h) of a yeast alpha-synuclein ("aSyn") model by 1,2,4-oxadiazole was reversed by exogenous 0.5 mM oleate / palmitoleate and did not affect rescue by other scaffolds. Maximum model rescue across doses ranging from 33 nM to 33 μM is plotted. [Figure 3]Figures 3A and 3B are graphs showing that point mutations in yeast OLE1 confer resistance to growth inhibition and alpha-synuclein model rescue by 1,2,4-oxadiazole. Growth was measured by reading OD600 in a microplate reader. (Figure 3A) Yeast cells lacking the chromosomal copy of OLE1 and expressing OLE1 (wild-type), ole1P123T, or the ole1E188Q mutant from a pRS316-based plasmid were grown in complete synthetic medium (CSM)-glucose medium with the indicated doses of 1,2,4-oxadiazole compound 95 for 24 hours. Growth was normalized to samples treated with the solvent control dimethyl sulfoxide (DMSO) and set as "1." (Figure 3B) Yeast cells lacking the chromosomal copy of OLE1 and expressing OLE1 (wild-type), ole1P123T, or the ole1E188Q mutant from a pRS316-based plasmid were grown for 40 hours in CSM-galactose medium (which induces alpha-synuclein expression) with the indicated dose of 1,2,4-oxadiazole compound 95. Growth was normalized to samples treated with the solvent control DMSO, and rescue was set as "1." [Figure 4] Figure 1 shows that the ole1Δ deletion mutant is resistant to the growth system effects of 1,2,4-oxadiazole but not other compounds. 24-h growth (presented as raw OD) of the ole1Δ deletion strain in yeast extract-peptone-dextrose (YPD) medium was shown, with drugs added at the indicated concentrations. [Figure 5] Figure 1 shows that reducing OLE1 expression by deleting MGA2 rescues growth of the ApoE4 yeast model. Yeast cells expressing ApoE4 had the MGA2 gene deleted, and their growth was assessed over time (compared to their isogenic MGA2 wild-type counterparts). Growth was assessed by OD600. Where indicated, 0.08 or 0.32 mM oleic acid and palmitoleic acid (respectively) were added to growth medium in 0.01% Tween (final). [Figure 6]Figure 2 is a series of graphs showing that commercially available Scd inhibitors target human SCD1 / SCD5 in yeast. Yeast OLE1, or yeast that survives only on human SCD1 or SCD5, was treated with four commercially available Scd inhibitors at the indicated concentrations. Data are expressed as a percentage of the DMSO-treated condition. All four compounds potently reduced the growth of both SCD1- and SCD5-expressing yeast, but not the Ole1-expressing strain. Similar to the results shown in Figures 2A and 2B, this growth inhibition was rescued by oleate / palmitoleate competition. [Figure 7] This is a series of graphs showing that 1,2,4-oxadiazoles target human SCD1 and SCD5. Three "SCD" strains expressing yeast OLE1 or human SCD1 or SCD5 were treated with five representative 1,2,4-oxadiazoles and a cycloheximide toxicity control at the concentrations indicated on the logarithmic x-axis. The y-axis is expressed as a percentage of the DMSO-treated condition. All 1,2,4-oxadiazole compounds potently inhibited yeast expressing OLE1 and showed variable growth inhibition of SCD1 or SCD5 yeast strains. These data confirm that 1,2,4-oxadiazoles target human proteins and that SCD inhibition is associated with rescue of neurodegenerative disease models. Nearly half of all 250 1,2,4-oxadiazoles tested inhibited SCD1 or SCD5 in a manner that was rescued by oleate / palmitoleate treatment. Cycloheximide, a translation inhibitor (top left panel), inhibited growth of all three strains with the same potency, indicating that the differences in growth inhibition were due to targeting a human protein. [Figure 8A]Figures 8A-8D are graphs showing that treatment of yeast cells with 1,2,4-oxadiazole compound 95 inhibits lipid desaturation. Exponentially growing wild-type yeast cells were treated with the indicated doses of 1,2,4-oxadiazole compound 95 prior to cell lysis, lipid extraction, and analysis by broad-spectrum LC-MS / MS profiling. The relative abundance (as a fraction of the total cellular lipid signal) of the most abundant saturated lipid, phosphatidylcholine 26:0, after 1.5 and 8 hours of drug treatment is shown in Figures 8A and 8B, respectively. The relative abundance of the most abundant lipids with two or more degrees of desaturation, phosphatidylcholine 16:1 and 18:1, after 1.5 and 8 hours of drug treatment is shown in Figures 8C and 8D, respectively. The data show that after 8 hours of treatment with Compound 95, there was a more than 300-fold increase in the abundance of the saturated lipid phosphatidylcholine 26:0 and a more than 12-fold decrease in the abundance of the unsaturated lipids phosphatidylcholine 16:1 and 18:1, indicating that Compound 95 blocks cellular fatty acid desaturase activity (Ole1 is the only fatty acid desaturase in yeast). [Figure 8B] Same as above. [Figure 8C] Same as above. [Figure 8D] Same as above. [Figure 9] We demonstrate that OLE1 mutations confer resistance to growth inhibition by 1,2,4-oxadiazole, as identified by genomic sequencing of resistant mutants. Cells were plated on medium containing 10 μM 1,2,4-oxadiazole compound 155, and resistant colonies were isolated. Genomic DNA was prepared from the mutants and the parental drug-susceptible control strain. Genomic DNA sequences were aligned to a Saccharomyces cerevisiae reference strain to identify unique mutations in 1,2,4-oxadiazole-resistant mutants. The location of the mutations, the amino acid changes they encode, and the fold-increase in resistance (increase in the minimum inhibitory concentration) to compound 155 were observed. DETAILED DESCRIPTION OF THE INVENTION

[0171] The present invention relates to compounds useful for treating neurological disorders by inhibiting alpha-synuclein toxicity in cells, such as nervous system cells. Exemplary compounds described herein include compounds having a structure according to Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof.

[0172] [ka]

[0173] In some embodiments, the compound has the structure of any one of compounds 1-746 in Table 1.

[0174] Other embodiments, as well as exemplary methods for the synthesis or production of these compounds, are described herein.

[0175] Pharmaceutical use The compounds described herein are useful in the methods of the invention and, without being bound by theory, are believed to exert their desired effects via their ability to inhibit toxicity caused by protein aggregation, e.g., alpha-synuclein aggregation, in cells.

[0176] Another aspect of the present invention relates to a method for treating and / or preventing a neurological disorder, such as a neurodegenerative disease, in a subject in need thereof. The pathology of neurodegenerative diseases can be characterized by the presence of inclusion bodies in the brain tissue of affected patients.

[0177] In certain embodiments, neurological disorders that may be treated and / or prevented by the methods of the present invention include, but are not limited to, Alexander disease, Alpers disease, AD, amyotrophic lateral sclerosis, ataxia-telangiectasia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington's disease, Kennedy disease, Krabbe disease, dementia with Lewy bodies, Machado-Joseph disease, multiple sclerosis, PD, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum disease, Sandhoff disease, Schilder's disease, Steele-Richardson-Olszewski disease, tabes dorsalis, and Guillain-Barré syndrome.

[0178] The compounds described herein are useful as inhibitors of stearoyl-CoA desaturase (SCD), including SCD1 and / or SCD5. SCD inhibitors are known in the art to be useful in methods for treating and / or preventing SCD-related disorders. SCD-related disorders are described, for example, in U.S. Pat. No. 8,148,378 and International Patent Application Publications WO2011 / 047481, WO2010 / 112520, WO2010 / 045374, WO2010 / 028761, WO2009150196, and WO2009 / 106991. Accordingly, another aspect of the present invention relates to methods for treating and / or preventing SCD-related disorders in a subject in need thereof.

[0179] SCD-related disorders include metabolic abnormalities (e.g., insulin resistance, diabetes mellitus (e.g., type 1 diabetes, type 2 diabetes, non-insulin-dependent diabetes mellitus, gestational diabetes, and diabetic complications (e.g., diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, vascular complications of diabetes, and diabetic arteriosclerosis)), hyperglycemia, metabolic syndrome, hyperinsulinemia, impaired glucose tolerance, impaired glucose tolerance, weight disorders (e.g., obesity (e.g., abdominal obesity), overweight, cachexia, body mass index, and anorexia), lipid disorders (e.g., abnormal lipid levels (e.g., elevated lipid levels, e.g., in plasma), dyslipidemia (e.g., diabetic dyslipidemia), mixed dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, , hyperbetalipoproteinemia, atherosclerosis, hypercholesterolemia (e.g., familial hypercholesterolemia), low HDL, high LDL, diseases associated with lipid accumulation in the liver, familial histiocytic reticulopathy, lipoprotein lipase deficiency, polyunsaturated fatty acid (PUFA) disorders, fatty acid unsaturation index (e.g., fatty acids in the 18:1 / 18:0 ratio or other fatty acids), and dyslipidemia disorders, disorders of abnormal plasma proteins, disorders of pancreatic beta cell regeneration, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), hypertension, and microalbuminemia, leptin-related disorders, hyperleptinemia, appetite disorders, essential fatty acid deficiency, and the effects of weight gain associated with drug therapy.

[0180] Additional SCD-related disorders include cancer, including solid tumors or hematological malignancies (e.g., esophageal cancer, pancreatic cancer, endometrial cancer, kidney cancer, liver cancer, thyroid cancer, gallbladder cancer, prostate cancer, leukemia (e.g., lymphoma and myeloma), ENT-related cancers, brain cancer, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, uterine cancer, breast cancer, skin cancer, and prostate cancer), neoplasia, malignancy, metastasis, tumors (benign or malignant), carcinogenesis, and liver cancer.

[0181] Additional SCD-related disorders include cardiovascular disease (e.g., heart disease, atherosclerosis, hypertension, lipidemia, dyslipidemia, hypertension, microalbuminemia, hyperuricemia, hypercholesterolemia, dyslipidemia, hypertriglyceridemia, arteriosclerosis, coronary artery disease, myocardial infarction, vascular complications of diabetes, and diabetic arteriosclerosis), inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, hepatitis (e.g., idiopathic hepatitis), meibomianitis, cystic fibrosis, premenstrual syndrome, osteoporosis, thrombosis, cardiovascular risk, weight loss, angina pectoris, hypertension, ischemia, cardiac ischemia, reperfusion injury, angioplasty restenosis, infertility, liver disease (e.g., fatty liver, cirrhosis, nonalcoholic steatohepatitis, Hepatic fibrosis, and hepatitis C-associated steatosis), kidney disease (e.g., tubulointerstitial fibrosis, renal lipid accumulation, glomerular sclerosis, and proteinuria), osteoarthritis (e.g., osteoarthritis of the knee), gastroesophageal disease, sleep apnea, hyperparathyroidism secondary to renal osteodystrophy, peripheral vascular disease, cerebrovascular disease (e.g., stroke, ischemic stroke, and transient ischemic attack (TIA), and ischemic retinopathy), hyperandrogenemia, neuroleptic malignant syndrome, extrapyramidal symptoms, hyperuricemia, hypercoagulability, syndrome X, cataracts, polycystic ovary syndrome, breathing abnormalities, sleep-disordered breathing, lower back pain, gout, cholelithiasis, myopathy, lipid myopathy (e.g., carnitine palmitoyltransferase deficiency (CPT) CPT I or CPT II), autoimmune diseases (e.g., lupus, host-versus-graft reaction, and organ transplant rejection), asthma, inflammatory bowel disease, nephropathy, retinopathy, erythrocytic hepatic protoporphyria, iron overload, and hereditary hemochromatosis.

[0182] Still further SCD-related disorders include central nervous system (CNS) disorders, dementia, schizophrenia, mild cognitive impairment, Alzheimer's disease, cerebral amyloid angiopathy, Down syndrome-related dementia, other neurodegenerative diseases, psychiatric disorders, eye diseases, immune disorders, multiple sclerosis, neurological disorders, and depression.

[0183] Further SCD-related disorders include skin disorders (e.g., acne (e.g., acne vulgaris), psoriasis, hirsutism, rosacea, seborrheic skin, oily skin (syn seborrhea), seborrheic dermatitis, seborrhea, eczema, keloid scars, skin aging, diseases related to production or secretion from mucous membranes, wrinkles, lack of sufficient skin firmness, lack of sufficient skin hydration, insufficient sebum secretion, oily hair, shiny skin, greasy skin, greasy hair, and other skin conditions caused by lipid imbalance).

[0184] SCD-related disorders can also include diseases or conditions that are or are related to viral diseases or infections.

[0185] In some embodiments, the SCD-related disorder is acne (e.g., acne vulgaris). In some embodiments, the SCD-related disorder is diabetes (e.g., type II diabetes, including diabetes with poor glycemic control). In some embodiments, the SCD-related disorder is non-alcoholic fatty liver disease (NAFLD). In some embodiments, the SCD-related disorder is non-alcoholic steatohepatitis (NASH). In some embodiments, the SCD-related disorder is cancer. In some embodiments, the SCD-related disorder is obesity. In some embodiments, the SCD-related disorder is metabolic syndrome (e.g., dyslipidemia, obesity, insulin resistance, hypertension, microalbuminemia, hyperuricemia, and hypercoagulability), syndrome X, diabetes, insulin resistance, impaired glucose tolerance, non-insulin-dependent diabetes mellitus, type II diabetes, type I diabetes, diabetic complications, weight disorders (e.g., obesity, overweight, cachexia, and anorexia), weight loss, body mass index, leptin-related disorders, or skin disorders (e.g., eczema, acne, psoriasis, and keloid scars). In some embodiments, the SCD-related disorder is diabetes, metabolic syndrome, insulin resistance, obesity, cardiovascular disorders, CNS disorders, schizophrenia, or Alzheimer's disease.

[0186] Combination preparations and their uses The compounds of the present invention can be combined with one or more therapeutic agents. In particular, the therapeutic agents can be those that treat or prophylactically treat any of the neurological disorders described herein.

[0187] Combination therapy The compounds of the present invention can be used alone or in combination with other drugs that treat neurological disorders or symptoms associated therewith, or in combination with other types of treatment to treat, prevent, and / or reduce the risk of any neurological disorder. In combination treatment, the dosage of one or more of the therapeutic compounds may be reduced from the standard dosage when administered alone. For example, the dosage can be determined experimentally from the combination and substitution of drugs, or estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, the dosage of the compounds when combined should provide a therapeutic effect.

[0188] Pharmaceutical Compositions The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Thus, in another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.

[0189] The compounds of the present invention may be used in the form of free base, salt, solvate, and prodrug. All forms are within the scope of the present invention. According to the method of the present invention, the described compounds or their salts, solvates, or prodrugs may be administered to patients in various forms depending on the selected administration route, as will be understood by those skilled in the art. The compounds of the present invention may be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, via patch, pump, or transdermal administration, and the pharmaceutical composition will be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0190] The compounds of the present invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier, or may be enclosed in hard or soft gelatin capsules, or may be compressed into tablets, or may be incorporated directly with the food of the diet. For oral therapeutic administration, the compounds of the present invention may be combined with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0191] The compounds of the present invention may also be administered parenterally. Solutions of the compounds of the present invention can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences (2003, 20 th ed.), and The United States Pharmacopeia: The National Formulary, published in 1999 (USP 24 NF19).

[0192] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy administration via syringe is possible.

[0193] Compositions for nasal administration may be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually presented in a sterile form in single or multiple doses in a sealed container, which may be in the form of a cartridge or refill for use with a spray device. Alternatively, the sealed container may be a unit-dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser with a metered valve intended for disposal after use. When the dosage form includes an aerosol dispenser, it will contain a propellant, which may be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. Aerosol dosage forms may also be in the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, in which the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0194] The compounds of the invention may be administered to animals, for example humans, alone or in combination with pharmaceutically acceptable carriers as described herein, the proportions being determined by the solubility and chemical nature of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0195] Dosage The dosage of the compounds of the present invention and / or compositions containing the compounds of the present invention can vary depending on many factors, including the pharmacodynamic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and severity of the symptoms, the frequency of treatment and, if present, the type of concurrent treatment, and the clearance rate of the compound in the treated animal. Those skilled in the art will be able to determine appropriate dosages based on the above factors. The compounds of the present invention may be initially administered at a suitable dosage, which may be adjusted, if necessary, depending on the clinical response. Generally, satisfactory results can be obtained when the compounds of the present invention are administered to humans at a daily dose (measured as solids) of, for example, 0.05 mg to 3000 mg. Dose ranges include, for example, 10 to 1000 mg (e.g., 50 to 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered. Preferred dose ranges include, for example, 0.05-15 mg / kg or 0.5-15 mg / kg.

[0196] Alternatively, the amount of dosage can be calculated using the patient's body weight. For example, the dose of a compound or pharmaceutical composition thereof administered to a patient can be in the range of 0.1 to 50 mg / kg (e.g., 0.25 to 25 mg / kg). In exemplary non-limiting embodiments, the dose can be in the range of 0.5 to 5.0 mg / kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg / kg), or 5.0 to 20 mg / kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg). [Example]

[0197] The compounds of the present invention can be synthesized according to one or more of the general schemes 1-10 shown below, where the variables referred to in the general schemes below are as defined in Formulas I, II, III, and IV.

[0198] General Scheme 1

[0199] [ka] An appropriately substituted carboxylic acid I can be coupled with an appropriately substituted piperidine II to give the ester III, which can be hydrolyzed under various conditions to give the carboxylic acid intermediate IV, which can be condensed with a substituted N-hydroxyimidamide V to give the desired 1,2,4-oxadiazole compound VI.

[0200] General Scheme 2

[0201] [ka] An appropriately substituted carboxylic acid VII can be coupled with an appropriately protected (where PG is an N-protecting group) and substituted piperidine carboxylic acid VIII to give intermediate IX, which can be deprotected using a variety of conditions to give the free amine intermediate X. This compound can be coupled with a heterocycle halide such as XI using a metal catalyzed reaction or under thermal conditions to give the desired 1,2,4-oxadiazole (X 3 =O) or 1,2,4-thiadiazole (X 3 =S) Compound XII can be obtained.

[0202] General Scheme 3

[0203] [ka] An appropriately substituted carboxylic acid I can be coupled with an appropriately substituted piperidine XIII to give the desired heterocyclic compound XIV.

[0204] General Scheme 4

[0205] [ka] An appropriately substituted acyl halide XV (where X is a halogen atom, for example, chlorine) can be coupled with an appropriately substituted piperidine XIII to give the desired heterocyclic compound XIV.

[0206] General Scheme 5

[0207] [ka] An appropriately substituted alkyl intermediate XVI (where X is a good leaving group, e.g., a halogen atom or a triflate) can undergo nucleophilic substitution with an appropriately substituted piperidine XIII to afford the desired heterocyclic compound XIV.

[0208] General Scheme 6

[0209] [ka] An appropriately substituted carboxylic acid IV can be coupled with an appropriately substituted ketone XVII (where X is a leaving group, such as bromine) to give the intermediate compound XVII, which can be condensed with ammonium acetate to give the oxazole IXX.

[0210] General Scheme 7

[0211] [ka] A suitably protected and substituted thiomide XX can be coupled with a suitably substituted ketone XVII (where X is a leaving group, most commonly bromine) to give a protected (where PG is an amine-protecting group such as tert-butoxycarbonyl) thiazole compound XXI. This compound can be deprotected under appropriate conditions to give the intermediate piperidine XXII. This can be coupled with a suitably substituted carboxylic acid IV to give the thiazole XXIII.

[0212] General Scheme 8

[0213] [ka] A suitably protected and substituted ester III can be treated with hydrazine to give the hydrazide compound XXIV, which can be coupled with a suitably substituted acetimidate XXV to give the 1,3,4-oxadiazole XXVI.

[0214] General Scheme 9

[0215] [ka] An appropriately substituted carboxylic acid IV can be coupled with an appropriately substituted piperidine compound XXVII to give compound XXVIII. This compound can be converted to the corresponding hydroxyimidamide compound XXIX, which can be treated with an appropriately substituted acid halide (most commonly an acid chloride, where X = Cl) XXX to give the 1,2,4-oxadiazole XXXI.

[0216] General Scheme 10

[0217] [ka] The appropriately substituted oxadiazolone XXXII can be converted to the appropriately substituted compound XXXIII. This compound can be coupled with an appropriately protected piperazine compound XXXIV (wherein PG is an N-protecting group, such as a tert-butyloxycarbonylbutyl group) to give compound XXXV. This compound can be deprotected under appropriate conditions to give piperazine compound XXXVI. This can be coupled with carboxylic acid IV to give 1,2,4-oxadiazole XXXVII.

[0218] Experimental procedure The compounds of the present invention can be synthesized according to the following procedures.

[0219] In the following examples, when purification by preparative HPLC was performed, a Gilson 281 semi-preparative HPLC system was used with various stationary and mobile phases as described in the experimental section, e.g., (Column: Waters Xbridge 150 × 2.5 mm 5 μm; Mobile phase: [water (10 mM NHOAc)-acetonitrile]; B%: 36%-66%, 12 min) indicates that the following purification conditions were used: Mobile phase: A: 10 mM NHOAc in H0; B: acetonitrile Column: Waters Xbridge 150 x 2.5 mm dimensions, 5 μm particle size Flow rate: 25mL / min Monitor wavelength: 220 and 254 nm gradient:

[0220] [Table 3]

[0221] Example 1. Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one

[0222] [ka] Step 1: Preparation of 1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid

[0223] [ka] A mixture of 2-methylenesuccinic acid (2.0 g, 1.27 mL, 15.37 mmol) and 3,4-dimethylaniline (1.86 g, 15.37 mmol) in water (20 mL) was stirred at 120° C. (reflux) for 16 hours. The mixture was cooled to 25° C. and filtered. The filter cake was washed with cold water (5 mL) to give 1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid (3.0 g, 12.9 mmol, 84%) as a yellow solid. This material was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 7.40-7.35(m,2H),7.13-7.11(d,1H),4.01-3.93(m,2H),3.34-3.30(m,1H),2.75-2.67(m,2H),2.22(s,3H)2.19(s,3H);LCMS(ESI)m / z:[MH] - =232.1.

[0224] Step 2: Preparation of methyl 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylate

[0225] [ka] To a stirred solution of 1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid (1.0 g, 4.29 mmol) and methyl piperidine-4-carboxylate (737 mg, 5.15 mmol) in N,N-dimethylformamide (10 mL) was added 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.63 g, 4.29 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (1.11 g, 8.58 mmol, 1.50 mL). After stirring at 15° C. for 16 hours, water (20 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL×4). The organic layer was washed with water (10 mL), saturated aqueous sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by chromatography on silica gel eluted with 1 / 1 to 0 / 1 petroleum ether / ethyl acetate to give methyl 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylate (1.90 g, 5.30 mmol, quantitative) as a red oil. LCMS (ESI) m / z: [M+H]+ = 359.3.

[0226] Step 3: Preparation of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid

[0227] [ka] To a stirred solution of methyl 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylate (400 mg, 1.12 mmol) in tetrahydrofuran (4 mL) was added aqueous sodium hydroxide (2 M, 1.68 mL). The mixture was stirred at 40° C. for 2 hours, and then the mixture was acidified to pH 1 using concentrated hydrochloric acid. The mixture was extracted with dichloromethane (20 mL×3), and then the organic layer was washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (300 mg, 871 μmol, 78%) as a white solid, which was used directly without further purification.

[0228] Step 4: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one

[0229] [ka] To a stirred solution of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (253 mg, 734 μmol) in N,N-dimethylformamide (1 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (279 mg, 734 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (285 mg, 2.20 mmol, 384 μL). The mixture was stirred at 25° C. for 5 minutes, and then N-hydroxybenzimidamide (100 mg, 734 μmol) was added. The mixture was warmed to 25° C. and stirred for 16 hours. The mixture was then diluted with water (5 mL) and extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with water (5 mL × 2) and saturated aqueous sodium chloride solution (5 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was dissolved in N,N-dimethylformamide (2 mL) and then heated at 120 °C for 3 h. Without any additional workup, the mixture was purified by preparative HPLC (Waters Xbridge 150 × 25 5 μm column; 36 to 66% acetonitrile in 10 mM ammonium acetate solution in water, 12 min gradient) to give 1-(3,4-dimethylphenyl)-4-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one (73 mg, 164 μmol, 22%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.10-8.09(m,2H),7.55-7.49(m,3H),7.39(s,1H),7.30(s,1H),7.15-7.13(d,1H),4.54- 4.53(m,1H),4.31-4.27(m,1H),3.98-3.90(m.,2H),3.60-3.56(m,1H),3.42-3.36(m,2H). 3.15-2.95(m,2H),2.86-2.79(m,1 H),2.29-2.26(m,8H),2.03-1.97(m,2H);LCMS(ESI)m / z:[M+H] + =445.3.

[0230] Example 2: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one

[0231] [ka] Step 1: Preparation of N-hydroxy-4-methylbenzimidamide

[0232] [ka] To a stirred solution of 4-methylbenzonitrile (1.0 g, 8.54 mmol, 1.02 mL) in ethanol (10 mL) and water (1 mL) was added hydroxylamine hydrochloride (1.19 g, 17.1 mmol) and triethylamine (1.73 g, 17.1 mmol, 2.37 mL). The mixture was heated at 75° C. for 16 hours, and then the reaction mixture was concentrated under reduced pressure to give a residue that was diluted with water (5 mL) and then extracted with dichloromethane (8 mL×10). The combined organic layers were washed with saturated aqueous sodium chloride solution (8 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-hydroxy-4-methylbenzimidamide (900 mg, 5.99 mmol, 70%) as a pale green solid. 1 H NMR (400MHz, methanol-d4)d=7.49(d,J=8.2 Hz,2H),7.18(d,J=7.9 Hz,2H),2.33(s,3H).

[0233] Step 2: Preparation of methyl 1-(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one

[0234] [ka] To a stirred solution of methyl 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylate (229 mg, 666 μmol) in N,N-dimethylformamide (1 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (253 mg, 666 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (258 mg, 2.00 mmol, 349 μL). The mixture was stirred at 25° C. for 5 minutes, and then N-hydroxy-4-methylbenzimidamide (100 mg, 666 μmol) was added. After 16 hours, the reaction mixture was extracted with ethyl acetate (5 mL×3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 40%-70%, 12 min) to give 1-(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one (38 mg, 81 μmol, 12%, purity 98.4%) as a white solid. 1 H NMR(400MHz,chloroform-d)d=7.89(d,J=7.1 Hz,2H),7.29(s,1H),7.22(t,J=7.9 Hz,3H),7.05(d,J=8.2 Hz,1H),4.50-4.38(m,1H),4.20(t,J=8.4 Hz,1H),3.95-3.79(m,2H),3.49(td,J=8.5,16.9 Hz,1H),3.36-3.20(m,2H),3.12-2.97(m,1H),2.89(td,J=8.7,17.1 Hz,1H),2.79-2.69(m,1H),2.35(s,3H),2.18(d,J=13.0 Hz,7H),2.00-1.82(m,2H);LCMS(ESI)m / z:[M+H] + =459.3.

[0235] Example 3 Preparation of 1-(3,4-dimethylphenyl)-4-[4-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]pyrrolidin-2-one

[0236] [ka] Step 1: Preparation of N-hydroxy-3-methylbenzimidamide.

[0237] [ka] To a stirred solution of 3-methylbenzonitrile (1.0 g, 8.54 mmol, 1.02 mL) in ethanol (10 mL) and water (1 mL) was added hydroxylamine hydrochloride (1.19 g, 17.1 mmol) and triethylamine (1.73 g, 17.1 mmol, 2.37 mL). The mixture was heated at 75° C. for 16 hours and then concentrated under reduced pressure to give a residue that was then diluted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution (5 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to give N-hydroxy-3-methyl-benzamidine (1.05 g, solid) as a crude solid, which was used directly in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ = 7.42-7.31 (m, 2H), 7.24-7.12 (m, 2H), 4.93-4.71 (s, 1H), 3.67-3.58 (m, 1H), 2.97 (q, J = 7.3 Hz, 1H), 2.30 (s, 3H), 1.32-1.23 (m, 1H), 1.18-1.11 (m, 1H).

[0238] Step 2: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one

[0239] [ka] To a stirred solution of 1-[1-(3,4-dimethylphenyl)-5-oxo-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (229 mg, 666 μmol) in N,N-dimethylformamide (1 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (253 mg, 666 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (258 mg, 2.00 mmol, 349 μL). The mixture was stirred at 25° C. for 5 minutes, and then N-hydroxy-3-methyl-benzamidine (100 mg, 666 μmol) was added. After 16 hours, the reaction mixture was diluted with water (1 mL) and extracted with ethyl acetate (5 mL×3). The organic layers were combined, washed with saturated aqueous sodium chloride (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue that was purified by preparative HPLC (Waters Xbridge 150 × 25 5 μm column, 41% to 71% acetonitrile in 10 mM ammonium acetate solution in water, 12 min gradient) to give 1-(3,4-dimethylphenyl)-4-[4-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]pyrrolidin-2-one (118 mg, 266 μmol, 38%) as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ=7.93-7.83(m,1H),7.40-7.30(m,3H),7.16-7.07(m,1H),4.58-4.45(m,1H),4.29-4.25(m 1H),4.00-3.90(m,2H),3.59-3.55(m,1H),3.43-3.24(m,2H),3.19-3.01(m,1H),3.01-2.89(m, 1H),2.87-2.74(m,1H),2.43(s,3H),2.27-2.22(m,8H),2.07-1.90(m,2H);LCMS(ESI)m / z:[M+H] + =459.3.

[0240] Example 4. 6-(5-(1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0241] [ka] Step 1: Preparation of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile

[0242] [ka] To a stirred solution of 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (3.0 g, 13.2 mmol) in N,N-dimethylformamide (35 mL) was added zinc cyanide (1.24 g, 10.5 mmol, 668 μL) and tetrakis(triphenylphosphine)palladium(0) (760 mg, 658 μmol) under nitrogen. The mixture was then stirred at 80° C. for 16 hours, cooled to room temperature, and extracted with ethyl acetate (60 mL×4). The combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL) and dried over anhydrous sodium sulfate. The combined organic layers were concentrated to dryness to give the crude product. The crude product was further purified by trituration with ethyl acetate and used in the next step without further purification. 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile (3.40 g) was obtained as a white solid. LCMS(ESI)m / z:[M+H] + =175.0.

[0243] Step 2: Preparation of 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile

[0244] [ka] To a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile (3.30 g, 19.0 mmol) in N,N-dimethylformamide (35 mL) was added sodium hydride (758 mg, 19 mmol, 60% dispersion in mineral oil) and iodoethane (3.84 g, 25 mmol, 1.97 mL) at 0° C. The mixture was warmed to 20° C. After 3 h, the mixture was cooled to 0° C., quenched by the addition of water (50 mL), and extracted with ethyl acetate (60 mL×4). The combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by chromatography (silica, petroleum ether:ethyl acetate=50:1 to 5:1) to give 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile (1.30 g, 6.43 mmol, 34%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 7.25(dd,J=1.8,8.3 Hz,1H),7.17(d,J=1.8 Hz,1H),6.98(d,J=8.3 Hz,1H),4.62(s,2H),3.93(q,J=7.2 Hz,2H),1.23(t,J=7.2 Hz,3H);LCMS(ESI)m / z=203.1[M+H] + .

[0245] Step 3: Preparation of 4-ethyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboximidamide

[0246] [ka] To a stirred solution of 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile (1.20 g, 5.93 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (825 mg, 11.9 mmol), triethylamine (1.20 g, 11.9 mmol, 1.64 mL), and water (2 mL), and the mixture was then heated at 75° C. After 5 h, the mixture was cooled to 20° C. and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3), and then the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-ethyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboximidamide (1.20 g, 5.10 mmol, 86%) as a white solid, which was used directly without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 9.61(s,1H),7.44(d,J=1.6 Hz,1H),7.35(dd,J=1.8,8.4 Hz,1H),7.00(d,J=8.4 Hz, 1H), 5.87 (s, 2H), 4.66 (s, 2H), 3.96 (q, J=7.0 Hz, 2H), 1.18 (t, J=7.0 Hz, 3H).

[0247] Step 4: Preparation of (E)-1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N-((4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(hydroxyimino)methyl)piperidine-4-carboxamide

[0248] [ka] To a stirred solution of 4-ethyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboximidamide (150 mg, 638 μmol) in N,N-dimethylformamide (5 mL) was added 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (220 mg, 638 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (242 mg, 638 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (247 mg, 1.91 mmol, 334 μL). After 16 h at 20 °C, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 4), and the combined organic phases were then washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (E)-1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N-((4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(hydroxyimino)methyl)piperidine-4-carboxamide (450 mg) as a yellow oil. This material was used directly without further purification. LCMS (ESI) m / z = 562.3 [M+H] + .

[0249] Step 5: Preparation of 6-(5-(1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0250] [ka] (E)-1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N-((4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)(hydroxyimino)methyl)piperidine-4-carboxamide (450 mg, 801 μmol) was heated in N,N-dimethylformamide (3 mL) at 120° C. for 3 hours. The mixture was cooled and directly purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40%-65%, 12 min) to give 6-(5-(1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (142 mg, 255 μmol, 32%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 7.70-7.60(m,2H),7.29(s,1H),7.22-7.19(m,1H),7.03(dd,J=8.3,16.9 Hz,2H),4.60(s,2H),4.56-4.40(m,1H),4.21(d,J=7.3 Hz,1H),4.00(d,J=6.5 Hz,2H),3.96-3.78(m,2H),3.49(quintet,J=8.3 Hz,1H),3.37-3.19(m,2H),3.09-2.82(m,2H),2.81-2.69(m,1H),2.18(d,J=12.8 Hz,8H),1.98-1.82(m,2H),1.26(t,J=6.8 Hz,3H);LCMS(ESI)[M+H] + =544.2.

[0251] Example 5: Morpholino(1-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methanone.

[0252] [ka] Step 1: Preparation of tert-butyl 4-(morpholine-4-carbonyl)piperidine-1-carboxylate

[0253] [ka] To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1.31 mmol) in N,N-dimethylformamide (10 mL) was added morpholine (136 mg, 1.57 mmol, 138 μL), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1.31 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (338 mg, 2.62 mmol, 457 μL). The mixture was stirred at 20° C. for 16 hours, then quenched with water (10 mL) and extracted with ethyl acetate (20 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 4-(morpholine-4-carbonyl)piperidine-1-carboxylate (700 mg) as a yellow oil, which was used directly without further purification. 1 H NMR(400 MHz,CDCl3)δ 3.72-3.51(m,5H),3.45(br.s.,1H),3.18-3.05(m,1H),2.93-2.86(m,3H),2.81(s,3H),2.75-2.71(m,2H),2.59-2.48(m,1H),1.39(s,9H).

[0254] Step 2: Preparation of morpholino(piperidin-4-yl)methanone

[0255] [ka] To a stirred solution of tert-butyl 4-(morpholine-4-carbonyl)piperidine-1-carboxylate (700 mg, 2.35 mmol) in methanol (5 mL) was added 4N hydrochloric acid in methanol (15 mL). The mixture was stirred at 20° C. for 16 hours and then concentrated under reduced pressure to give morpholino(4-piperidyl)methanone (300 mg) as a colorless oil, which was used directly without further purification. LCMS (ESI) [M+H] + =199.1.

[0256] Step 3: Preparation of 3-phenyl-1,2,4-oxadiazol-5(4H)-one

[0257] [ka] To a stirred solution of N-hydroxybenzamidine (2.0 g, 14.69 mmol) in dioxane (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.46 g, 16 mmol, 2.44 mL) and 1,1'-carbonyldiimidazole (3.57 g, 22 mmol). The mixture was stirred at 110°C for 16 h, then cooled and quenched with water (10 mL). The mixture was extracted with dichloromethane (50 mL × 4), and then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by chromatography (silica, petroleum ether:ethyl acetate = 1:1) to give 3-phenyl-1,2,4-oxadiazol-5(4H)-one (1.30 g, 8.02 mmol, 55%) as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ 7.83-7.75 (m, 2H), 7.66-7.52 (m, 3H); LCMS (ESI) m / z = 163.2 [M+H] + .

[0258] Step 4: Preparation of 5-chloro-3-phenyl-1,2,4-oxadiazole

[0259] [ka] To a stirred solution of 3-phenyl-1,2,4-oxadiazol-5(4H)-one (500 mg, 3.08 mmol) equipped with a calcium chloride tube was added N,N-dimethylformamide (1 mL). Phosphoryl chloride (10 mL) was added dropwise, and the resulting mixture was heated at 110° C. for 16 hours. The reaction mixture was cooled to 20° C. and poured into ice water (100 mL), and the resulting mixture was stirred for 30 minutes. The mixture was extracted with dichloromethane (20 mL × 5). The combined organic phase was then washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by chromatography (silica, petroleum ether:ethyl acetate = 50:1) to give 5-chloro-3-phenyl-1,2,4-oxadiazole (180 mg, 997 μmol, 32%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.10-7.98 (m, 2H), 7.57-7.46 (m, 3H).

[0260] Step 5: Preparation of morpholino(1-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methanone

[0261] [ka] To a stirred solution of morpholino(piperidin-4-yl)methanone (180 mg, 908 μmol) in N-methyl-2-pyrrolidone (5 mL) was added 5-chloro-3-phenyl-1,2,4-oxadiazole (163 mg, 908 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (234 mg, 1.82 mmol, 317 μL). The mixture was stirred at 120° C. for 16 h, then cooled and directly purified by preparative HPLC (column: Waters Xbridge 150×25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 20%-50%, 12 min) to give morpholino(1-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methanone (130 mg, 380 μmol, 42%) as a yellow solid. 1 H NMR(400 MHz, methanol-d4)δ 8.00-7.94(m,2H),7.55-7.45(m,3H),4.26(d,J=13.3 Hz,2H),3.74-3.59(m,8H),3.32-3.26(m,2H),3.08-2.98(m,1H),1.92-1.75 ppm(m,4H);LCMS(ESI)[M+H] + =343.2.

[0262] Example 6: (1-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1-yl)methanone

[0263] [ka] Step 1: Preparation of tert-butyl 4-(piperidine-1-carbonyl)piperidine-1-carboxylate.

[0264] [ka] To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1.31 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1.31 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (338 mg, 2.62 mmol, 457 μL) in N,N-dimethylformamide (1 mL) was added piperidine (133 mg, 1.57 mmol, 155 μL) at 0° C. The mixture was stirred at 25° C. for 2 hours. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford tert-butyl 4-(piperidine-1-carbonyl)piperidine-1-carboxylate (600 mg) as a yellow oil, which was used directly without further purification. 1 H NMR(400MHz,CDCl3)δ 3.73(dd,J=6.4,9.9 Hz,1H),3.55(br.s.,2H),3.44(br.s.,2H),3.29-3.15(m,2H),2.68-2.57(m,1H),1.96-1 .83(m,1H),1.77-1.62(m,8H),1.56(br.s.,4H),1.46(s,9H);LCMS(ESI)m / z=297.3[M+H] + .

[0265] Step 2: Preparation of piperidin-1-yl(piperidin-4-yl)methanone.

[0266] [ka] To a mixture of tert-butyl 4-(piperidine-1-carbonyl)piperidine-1-carboxylate (500 mg, 1.69 mmol) in methanol (5 mL) was added 4 M methanolic hydrochloric acid (10 mL) at 0 ° C. The mixture was stirred at 25 ° C. for 2 hours. The mixture was concentrated in vacuo to give piperidin-1-yl(piperidin-4-yl)methanone (300 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) [M+H] + =197.3.

[0267] Step 3: Preparation of 3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5(4H)-one.

[0268] [ka] A mixture of N-hydroxy-3,4-dimethoxybenzimidamide (1.0 g, 5.10 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (853 mg, 5.61 mmol, 845 μL), and 1,1′-carbonyldiimidazole (1.24 g, 7.65 mmol) in dioxane (10 mL) was prepared at 15° C. The mixture was warmed to 110° C. for 12 hours. The mixture was cooled to 15° C. and then poured into water (5 mL). The aqueous phase was extracted with dichloromethane (10 mL x 5), and then the combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (800 mg) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.60-7.52(m,2H),6.88(d,J=8.8 Hz,1H),3.91(d,J=6.1 Hz,6H);LCMS(ESI)m / z=223.2[M+H] + .

[0269] Step 4: Preparation of 5-chloro-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole.

[0270] [ka] 3-(3,4-Dimethoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (500 mg, 2.25 mmol) was added to a mixture of phosphoryl chloride (13.2 g, 86.1 mmol, 8 mL) and N,N-dimethylformamide (1 mL). The mixture was equipped with a calcium chloride tube and heated at 100° C. for 16 hours, at which point the mixture was cooled and concentrated under vacuum at 45° C. The residue was poured into ice water (w / w=10 / 1) (11 mL) and stirred for 10 minutes. The mixture was extracted with dichloromethane (10 mL×5), and the combined organic phase was then washed with saturated aqueous sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography (silica, petroleum ether:ethyl acetate=5:1 to 1:1 gradient) to give 5-chloro-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole (200 mg, 0.83 mmol, 37%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.67(dd,J=2.0,8.4 Hz,1H),7.53(d,J=2.0 Hz,1H),6.97(d,J=8.4 Hz,1H),3.96(d,J=2.4 Hz,6H);LCMS(ESI)m / z=241.1[M+H] + .

[0271] Step 5: Preparation of (1-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1-yl)methanone.

[0272] [ka] To a stirred solution of 5-chloro-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole (200 mg, 831 μmol) and triethylamine (252 mg, 2.49 mmol, 345 μL) in dichloromethane (2 mL) was added piperidin-1-yl(piperidin-4-yl)methanone (163 mg, 831 μmol) at 0° C. The mixture was warmed to 15° C. and stirred for 2 h, then concentrated in vacuo to give the crude product. The residue was purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 20% to 55%, 12 min) to give (1-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1-yl)methanone (36 mg, 89.7 μmol, 11%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.61(d,J=8.4 Hz,1H),7.51(s,1H),6.92(d,J=8.4 Hz,1H),4.28(d,J=13.2 Hz,2H),3.95(d,J=8.8 Hz,6H),3.65-3.41(m,4H),3.30-3.15(m,2H),2.85-2.69(m,1H),2.01-1.89(m,2H),1.88-1.79(m,2H),1.68(d,J=4.9 Hz,2H),1.61(br.s.,1H);LCMS(ESI)m / z=[M+H] + :401.2.

[0273] Example 7: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0274] [ka] Step 1: Preparation of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid.

[0275] [ka] To a stirred solution of methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate (5.0 g, 16.4 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide (2 M, 16.4 mL). The mixture was stirred at 20° C. for 2 hours and then acidified to pH 1 by adding concentrated hydrochloric acid. The mixture was extracted with dichloromethane (80 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (3.25 g, 11.2 mmol, 68%) as a yellow solid. 1 H NMR(400 MHz, methanol-d4)δ 7.87(d,J=7.5 Hz,2H),7.59-7.42(m,3H),4.39-4.20(m,3H),3.92(d,J=14.1 Hz,1H),3.24(t,J=11.5 Hz, 1H), 2.98-2.88 (m, 1H), 2.62 (s, 1H), 2.08-1.89 (m, 2H), 1.81-1.53 ​​(m, 2H).

[0276] Step 2: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0277] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (2.0 g, 6.89 mmol) in N,N-dimethylformamide (30 mL) was added N-hydroxy-3,4-dimethoxybenzimidamide (1.62 g, 8.27 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (2.67 g, 20.67 mmol, 3.61 mL), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (2.62 g, 6.89 mmol). The mixture was stirred at 20° C. for 2 hours and then warmed to 120° C. for 2 hours. The reaction mixture was quenched by the addition of water (40 mL), and the mixture was then extracted with ethyl acetate (80 mL×3). The combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by chromatography (silica, petroleum ether:ethyl acetate = 20:1 to 1:2) to give a yellow solid. The yellow solid was washed with ethyl acetate (30 mL), then the mixture was filtered, and the filter cake was dried under vacuum to give N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (1.29 g, 2.86 mmol, 42%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 7.92-7.84(m,2H),7.80(s,1H),7.58-7.44(m,3H),7.41-7.35(m,1H),7.28-7.26(m,2H),6.92(d,J=8.9 Hz,1H),4.58-4.47(m,1H),4.32(d,J=3.9 Hz,2H),3.99-3.88(m,7H),3.37-3.06(m,3H),2.28-2.13(m,2H),2.07-1.89(m,2H);LCMS(ESI)[M+H] + =451.3.

[0278] Example 8: (4-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)(4-isopropylphenyl)methanone.

[0279] [ka] Step 1: Preparation of methyl 1-(4-isopropylbenzoyl)piperidine-4-carboxylate.

[0280] [ka] To a stirred solution of 4-isopropylbenzoic acid (250 mg, 1.52 mmol) in N,N-dimethylformamide (10 mL) was added methyl piperidine-4-carboxylate (261 mg, 1.82 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (576 mg, 1.52 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (392 mg, 3.04 mmol, 530 μL). The mixture was stirred at 20° C. for 16 hours. The reaction mixture was quenched with water (10 mL), and then the mixture was extracted with ethyl acetate (20 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product methyl 1-(4-isopropylbenzoyl)piperidine-4-carboxylate (900 mg) as a yellow oil. LCMS (ESI) m / z: 290.3 [M+H] + .

[0281] Step 2: Preparation of 1-(4-isopropylbenzoyl)piperidine-4-carboxylic acid.

[0282] [ka] To a stirred solution of methyl 1-(4-isopropylbenzoyl)piperidine-4-carboxylate (900 mg, 3.11 mmol) in tetrahydrofuran (10 mL) was added aqueous sodium hydroxide (2 M, 3.11 mL). The mixture was stirred at 20° C. for 16 hours. The mixture was acidified to pH 1 by dropwise addition of concentrated hydrochloric acid. The mixture was extracted with dichloromethane (20 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product 1-(4-isopropylbenzoyl)piperidine-4-carboxylic acid (400 mg) as a yellow solid. LCMS (ESI) [M+H] + =276.2.

[0283] Step 3: Preparation of 3-fluoro-N-hydroxybenzimidamide.

[0284] [ka] To a stirred solution of 3-fluorobenzonitrile (1.0 g, 8.26 mmol, 884 μL) in ethanol (10 mL) was added hydroxylamine hydrochloride (1.15 g, 16.5 mmol), triethylamine (2.09 g, 20.7 mmol, 2.86 mL), and water (1 mL). The mixture was then heated at 75° C. for 16 hours. After cooling to 20° C., water (10 mL) was added to the solution. The mixture was extracted with ethyl acetate (20 mL×5). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-fluoro-N-hydroxybenzimidamide (2.0 g) as a green solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: 155.1 [M+H] + .

[0285] Step 4: Preparation of (E)-N-((3-fluorophenyl)(hydroxyimino)methyl)-1-(4-isopropylbenzoyl)piperidine-4-carboxamide.

[0286] [ka] To a stirred solution of 1-(4-isopropylbenzoyl)piperidine-4-carboxylic acid (400 mg, 1.45 mmol) in N,N-dimethylformamide (10 mL) was added 3-fluoro-N-hydroxybenzimidamide (223 mg, 1.45 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (550 mg, 1.45 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (563 mg, 4.36 mmol, 761 μL). The mixture was stirred at 20° C. for 16 hours. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (20 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (E)-N-((3-fluorophenyl)(hydroxyimino)methyl)-1-(4-isopropylbenzoyl)piperidine-4-carboxamide (350 mg) as a yellow oil. LCMS (ESI) m / z: 412.3 [M+H] + .

[0287] Step 5: Preparation of (4-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)(4-isopropylphenyl)methanone.

[0288] [ka] (E)-N-((3-fluorophenyl)(hydroxyimino)methyl)-1-(4-isopropylbenzoyl)piperidine-4-carboxamide (350 mg, 851 μmol) was added to N,N-dimethylformamide (3 mL), and the mixture was stirred at 120° C. for 16 hours. The reaction mixture was cooled and purified by direct injection and preparative HPLC (Column: Waters Xbridge 150 × 2.5 mm 5 μm; Mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 50% to 80%, 12 min) to give (4-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)(4-isopropylphenyl)methanone (82 mg, 210 μmol, 25%) as a yellow oil. 1 H NMR(400 MHz, methanol-d4)δ 7.92(d,J=7.8 Hz,1H),7.79(d,J=9.7 Hz,1H),7.57(d,J=5.6 Hz,1H),7.42-7.28(m,5H),4.69-4.50(m,1H),3.89(br.s.,1H),3.53-3 .42(m,1H),3.39-3.34(m,1H),3.32-3.28(m,1H),2.99(td,J=6.9,13.8 Hz,1H),2.43-2.09(m,2H),2.07-1.83(m,2H),1.30(s,3H),1.29(s,3H);LCMS(ESI)m / z[M+H] + =394.2.

[0289] Example 9: N-(2-oxo-2-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide.

[0290] [ka] Step 1: Preparation of methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate.

[0291] [ka] To a stirred solution of 2-benzamidoacetic acid (3.0 g, 16.7 mmol) in N,N-dimethylformamide (30 mL) was added methyl piperidine-4-carboxylate (2.88 g, 20.09 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (6.35 g, 16.7 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (6.49 g, 50.2 mmol, 8.77 mL). The mixture was stirred at 20° C. for 3 hours and then quenched by the addition of water (40 mL). The mixture was extracted with ethyl acetate (80 mL×4). The combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by chromatography (silica, petroleum ether:ethyl acetate = 5:1 to 1:1) to give methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate (7.0 g, 23.0 mmol, quantitative) as a yellow oil. LCMS (ESI) m / z = 305.1 [M+H] + .

[0292] Step 2: Preparation of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid.

[0293] [ka] To a stirred solution of methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate (7.0 g, 23.0 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide (2 M, 23 mL). The mixture was then stirred at 20° C. for 16 hours. The mixture was then acidified to pH 1 using concentrated hydrochloric acid and then extracted with dichloromethane (80 mL×4). The organic phases were combined, washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (4.20 g, 14.47 mmol, 63%) as a yellow solid, which was used directly in the next step without further purification.1 H NMR(400 MHz, methanol-d4)δ 7.93-7.85(m,2H),7.59-7.54(m,1H),7.52-7.46(m,2H),4.42-4.33(m,1H),4.29(s,2H),4.01-3.87( m,1H),3.30-3.20(m,1H),2.97-2.88(m,1H),2.63-2.52(m,1H),2.06-1.92(m,2H),1.80-1.55(m,2H).

[0294] Step 3: Preparation of N-(2-oxo-2-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide.

[0295] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (200 mg, 689 μmol) in N,N-dimethylformamide (4 mL) was added N-hydroxybenzamidine (112 mg, 826 μmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (261 mg, 689 μmol), and N,N-diisopropylethylamine (267 mg, 2.07 mmol, 360.96 μL). The reaction mixture was then stirred at 20° C. for 2 hours, quenched by the addition of water (5 mL), and extracted with ethyl acetate (20 mL×4). The organic extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude residue. To the residue was added N,N-dimethylformamide (4 mL), and the resulting mixture was stirred at 120° C. for 2 hours, concentrated in vacuo, and purified by preparative HPLC (column: Luna C8 100×30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-(2-oxo-2-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide (74 mg, 189 μmol, 27%) as a white solid. 1H NMR(400 MHz,CDCl3)δ 8.13-8.08(m,2H),7.88(d,J=7.2 Hz,2H),7.55-7.46(m,6H),7.36(br.s.,1H),4.51(d,J=13.7 Hz,1H),4.33(d,J=3.8 Hz,2H),3.94(d,J=13.3 Hz,1H),3.42-3.32(m,2H),3.20(t,J=10.5 Hz,1H),2.28(br.s.,2H),2.11-1.96(m,2H);LCMS(ESI)m / z:[M+H] + =391.1.

[0296] Example 10: N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0297] [ka] Step 1: Preparation of N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0298] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) and N-hydroxy-4-methoxybenzimidamide (82 mg, 496 μmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylamine (106 mg, 827 μmol, 144 μL) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μmol) at 15° C., and the mixture was stirred for 15 hours. The mixture was heated to 110° C. and stirred for 5 hours. After cooling, the mixture was directly purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30% to 65%, 12 min) to give N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (87 mg, 205 μmol, 50%) as a yellow solid. 1 H NMR(400 MHz, methanol-d4)δ 7.98(d,J=8.8 Hz,2H),7.88(d,J=7.5 Hz,2H),7.60-7.51(m,1H),7.51-7.38(m,2H),7.04(d,J=8.4 Hz,2H),4.46(d,J=13.2 Hz,1H),4.38-4.21(m,2H),4.04(d,J=13.7 Hz,1H),3.86(s,3H),3.47-3.34(m,2H),3.07(t,J=11.9 Hz,1H),2.31-2.15(m,2H),2.05-1.80(m,2H);LCMS(ESI)m / z[M+H] += 421.1.

[0299] Example 11

[0300] [ka] Step 1: Preparation of N-hydroxy-3-methoxybenzimidamide.

[0301] [ka] To a stirred solution of 3-methoxybenzonitrile (2.0 g, 15.0 mmol, 1.83 mL) in ethanol (20 mL) was added hydroxylamine hydrochloride (2.09 g, 30.0 mmol), triethylamine (3.04 g, 30.0 mmol, 4.16 mL), and water (2 mL). The mixture was then heated at 75° C. for 5 hours. After cooling to 20° C., water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL×4). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The combined organic phases were concentrated in vacuo to give N-hydroxy-3-methoxybenzimidamide (2.60 g) as a white solid, which was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.37-7.24 (m, 3H), 7.10-6.88 (m, 1H), 5.84 (br.s., 2H), 3.82 (s, 3H).

[0302] Step 2: Preparation of N-(2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0303] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) in N,N-dimethylformamide (3 mL) was added N-hydroxy-3-methoxybenzimidamide (82 mg, 496 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1.24 mmol, 216 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was cooled and directly purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 35%-60%, 12 min) to give N-(2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (83 mg, 198 μmol, 48%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 7.91-7.85(m,2H),7.72-7.68(m,1H),7.62(dd,J=1.5,2.5 Hz,1H),7.57-7.52(m,1H),7.51-7.45(m,2H),7.42(t,J=8.0 Hz,1H),7.38-7.32(m,1H),7.08(ddd,J=0.9,2.6,8.3 Hz,1H),4.52(d,J=13.6 Hz,1H),4.33(d,J=4.0 Hz,2H),3.95(br.s.,1H),3.91(s,3H),3.42-3.32(m,2H),3.25-3.13(m,1H),2.33-2.22(m,2H),2.11-1.94(m,2H);LCMS(ESI)m / z:[M+H] + =421.2.

[0304] Example 12: N-(2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide

[0305] [ka] Step 1: Preparation of N-hydroxy-2-methoxybenzimidamide.

[0306] [ka] To a stirred solution of 2-methoxybenzonitrile (2.0 g, 15.0 mmol, 1.83 mL) in ethanol (20 mL) was added hydroxylamine hydrochloride (2.09 g, 30.0 mmol), triethylamine (3.04 g, 30.0 mmol, 4.16 mL), and water (2 mL), and the mixture was then heated to 70° C. for 15 hours. The mixture was cooled, quenched with water (20 mL), extracted with dichloromethane (30 mL×3), and the combined organic phases were washed with water (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give N-hydroxy-2-methoxybenzimidamide (2.80 g) as a pale green solid, which was used directly in the next step. 1 H NMR (400 MHz, methanol-d₄) δ 7.47-7.30 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 3.86 (s, 3H).

[0307] Step 2: Preparation of N-(2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0308] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) and N-hydroxy-2-methoxybenzimidamide (68 mg, 413 μmol) in N,N-dimethylformamide (2 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (106 mg, 826 μmol, 144 μL) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μmol), and the mixture was stirred at 15° C. for 15 hours. The mixture was then heated to 110° C. and stirred for 5 hours. After cooling, the mixture was directly purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 25% to 60%, 12 min) to give N-(2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (90 mg, 212 μmol, 51%) as a yellow solid. 1 H NMR(400 MHz, methanol-d4)δ 7.96(d,J=7.5 Hz,1H),7.88(d,J=7.9 Hz,2H),7.61-7.41(m,4H),7.18(d,J=8.8 Hz,1H),7.09(t,J=7.5 Hz,1H),4.47(d,J=13.2 Hz,1H),4.37-4.23(m,2H),4.12-4.00(m,1H),3.93(s,3H),3.50-3.35(m,2H),3.08(t,J=11.5 Hz,1H),2.33-2.15(m,2H),2.12-1.79(m,2H);LCMS(ESI)m / z:[M+H] += 421.1.

[0309] Example 13: N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]-4-methyl-benzamide.

[0310] [ka] Step 1: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-4-methylbenzamide.

[0311] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (150 mg, 518 μmol) in N,N-dimethylformamide (2 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1.56 mmol, 271 μL), and 2-[(4-methylbenzoyl)amino]acetic acid (105 mg, 544 μmol). The mixture was stirred at 20° C. for 5 hours. The crude product was purified by preparative HPLC (column: Luna C8 100 × 30 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30% to 60%, 12 min) to give N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-4-methylbenzamide. 1 H NMR (400MHz, methanol-d4) δ=7.77(d,J=7.5 Hz,2H),7.66(d,J=8.2 Hz,1H),7.59(s,1H),7.29(d,J=7.7 Hz,2H),7.08(d,J=8.4 Hz,1H),4.47(d,J=12.8 Hz,1H),4.29(m,J=6.0 Hz,2H),4.05(d,J=14.1 Hz,1H),3.89(s,6H),3.50-3.34(m,3H),3.06(t,J=12.0 Hz,1H),2.40(s,3H),2.32-2.13(t,2H),2.07-1.79(m,3H);LCMS(ESI)m / z:[M+H] + =465.3.

[0312] Example 14: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3-methylbenzamide.

[0313] [ka] Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3-methylbenzamide.

[0314] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (200 mg, 691 μmol) in N,N-dimethylformamide (2 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (268 mg, 2.07 mmol, 362 μL), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (262 mg, 691 μmol), and 2-[(3-methylbenzoyl)amino]acetic acid (133 mg, 691 μmol). The mixture was stirred at 20° C. for 16 hours. The crude product was purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]-3-methyl-benzamide (157 mg, 338 μmol, 49%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=8.48(t,J=5.5 Hz,1H),7.72-7.63(m,2H),7.58(dd,J=2.0,8.4 Hz,1H),7.46(d,J=1.8 Hz,1H),7.34(d,J=4.9 Hz,2H),7.11(d,J=8.4 Hz,1H),4.32(br d,J=13.0 Hz,1H),4.15(dd,J=2.3,5.4 Hz,2H),3.96(d,J=13.7 Hz,1H),3.87-3.77(m,6H),3.51-3.39(m,1H),3.24(s,1H),2.90(t,J=11.6 Hz,1H),2.35(s,3H),2.20-2.04(m,2H),1.89-1.75(m,1H),1.72-1.54(m,1H);LCMS(ESI)m / z:[M+H] + =465.3.

[0315] Example 15: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide

[0316] [ka] Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide.

[0317] [ka] To a stirred solution of 1-[2-[(3,4-dimethylbenzoyl)amino]acetyl]piperidine-4-carboxylic acid (200 mg, 628 μmol) and N-hydroxy-3,4-dimethoxy-benzamidine (184 mg, 942 μmol) in N,N-dimethylformamide (1.50 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (238 mg, 628 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (243 mg, 1.88 mmol, 329 μL). The mixture was stirred at 20° C. for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. N,N-Dimethylformamide (2 mL) was added, and the mixture was then heated to 120°C and stirred for an additional 4 hours. The mixture was cooled to 25°C, and then water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30% to 65%, 12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]-3,4-dimethyl-benzamide (209 mg, 436 μmol, 69%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=8.40(s,1H),7.66(s,1H),7.59(br d,J=7.9 Hz,2H),7.46(s,1H),7.21(br d,J=7.7 Hz,1H),7.11(br d,J=8.4 Hz,1H),4.32(br d,J=12.6 Hz,1H),4.14(br s,2H),3.96(br d,J=13.5 Hz,1H),3.89-3.72(m,6H),3.43(br t,J=10.8 Hz,1H),3.28-3.17(m,1H),2.90(br t,J=11.5 Hz,1H),2.26(s,6H),2.20-2.10(m,2H),1.80(br d,J=10.4 Hz,1H),1.64(br d,J=10.1 Hz,1H). (ESI)m / z:[M+H] + =479.3.

[0318] Example 16: N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide

[0319] [ka] Step 1: Preparation of tert-butyl 2-(3,4-dimethylbenzamido)acetate.

[0320] [ka] To a stirred solution of 3,4-dimethylbenzoic acid (2.0 g, 13.3 mmol) and tert-butyl 2-aminoacetate (1.92 g, 14.7 mmol) in N,N-dimethylformamide (20 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (3.44 g, 26.6 mmol, 4.65 mL) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (5.06 g, 13.3 mmol). After stirring at 15° C. for 3 hours, the mixture was treated with water (30 mL) and extracted with ethyl acetate (30 mL×3), and the combined organic phases were washed with water (20 mL), 1N hydrochloric acid (30 mL), saturated aqueous sodium bicarbonate solution (30 mL), saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl 2-(3,4-dimethylbenzamido)acetate (4.0 g) as a light brown oil, which was used directly in the next step without further purification. 1 H NMR(400 MHz, CDCl3)δ 7.52(d,J=1.6 Hz,1H),7.46(dd,J=1.9,7.9 Hz,1H),7.11(d,J=7.8 Hz,1H),4.08-4.04(m,2H),2.23(s,6H),1.44(s,9H).

[0321] Step 2: Preparation of 2-(3,4-dimethylbenzamido)acetic acid

[0322] [ka] A solution of tert-butyl 2-(3,4-dimethylbenzamido)acetate (4.0 g, 15.2 mmol) in TFA (20 mL) and dichloromethane (20 mL) was stirred at 15° C. for 20 hours. The mixture was concentrated, and the residue was treated with water (10 mL) and extracted with dichloromethane / methanol (20 / 1, 20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(3,4-dimethylbenzamido)acetic acid (3.20 g) as a yellow oil, which was used directly in the next step without further purification.

[0323] Step 3: Preparation of methyl 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate.

[0324] [ka] To a stirred solution of 2-(3,4-dimethylbenzamido)acetic acid (3.20 g, 15.4 mmol) and methyl piperidine-4-carboxylate (2.65 g, 18.5 mmol) in N,N-dimethylformamide (20 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (3.99 g, 30.9 mmol, 5.39 mL) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (5.86 g, 15.4 mmol) at 0° C. The mixture was then slowly warmed to 15° C. and stirred for 15 hours. The mixture was treated with water (30 mL) at 0° C. and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (20 mL), 1N hydrochloric acid (30 mL), saturated aqueous sodium bicarbonate (30 mL), saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Purification by chromatography (silica, 10:1 to 1:2 petroleum ether / ethyl acetate) afforded methyl 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate (3.50 g, 10.5 mmol, 68%) as a white solid. 1H NMR(400 MHz,CDCl3)δ 7.62(s,1H),7.57(d,J=7.9 Hz,1H),7.28(m,1H),7.19(d,J=7.5 Hz,1H),4.39(d,J=13.2 Hz,1H),4.24(d,J=3.5 Hz,2H),3.78(d,J=13.7 Hz,1H),3.71(s,3H),3.17(t,J=11.0 Hz, 1H), 3.02-2.91 (m, 1H), 2.67-2.54 (m, 1H), 2.30 (s, 6H), 1.98 (m, 2H), 1.80-1.64 (m, 2H).

[0325] Step 4: Preparation of 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid.

[0326] [ka] To a stirred solution of methyl 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate (3.50 g, 10.5 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added aqueous sodium hydroxide (2 M, 7.90 mL) and the mixture was stirred for 5 hours at 15° C. The mixture was concentrated to remove tetrahydrofuran and methanol, and the residue was then acidified with 1 N hydrochloric acid to pH=2-3 at 0° C. The mixture was then extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm 10 μm; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 10% to 40%, 20 min) to give 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (1.80 g, 5.65 mmol, 54%) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ8.39(s,1H),7.67(s,1H),7.61(d,J=7.7 Hz,1H),7.24(d,J=7.7 Hz,1H),4.21(d,J=12.7 Hz,1H),4.12(d,J=4.9 Hz,2H),3.85(d,J=13.8 Hz,1H),3.14(t,J=11.7 Hz,1H),2.79(t,J=11.5 Hz,1H),2.28(s,6H),1.86(m,2H),1.63-1.32(m,2H).

[0327] Step 5: Preparation of N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide.

[0328] [ka] To a stirred solution of 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (150 mg, 471 μmol) and N-hydroxy-4-methoxybenzimidamide (93 mg, 565 μmol) in N,N-dimethylformamide (2 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (121 mg, 942 μmol, 164 μL) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (178 mg, 471 μmol) at 15° C. After 15 h, the mixture was heated to 110° C. and stirred for 5 h. The mixture was cooled and directly purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40% to 70%, 12 min) to give N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide (110 mg, 244 μmol, 52%) as a pale yellow solid. 1H NMR (400 MHz, methanol-d4) δ7.98(d,J=9.3 Hz,2H),7.66(s,1H),7.60(d,J=7.5 Hz,1H),7.23(d,J=7.9 Hz,1H),7.05(d,J=9.3 Hz,2H),4.46(d,J=13.2 Hz,1H),4.34-4.23(m,2H),4.04(d,J=13.7 Hz,1H),3.86(s,3H),3.47-3.36(m,2H),3.07(t,J=11.0 Hz,1H),2.42-2.26(s,6H),2.21(d,J=17.6 Hz,2H),2.04-1.82(m,2H);LCMS(ESI)m / z:[M+H] + =449.2.

[0329] Example 17: N-(2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide.

[0330] [ka] Step 1: Preparation of N-(2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide.

[0331] [ka] To a stirred solution of 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (150 mg, 471 μmol) in N,N-dimethylformamide (3 mL) was added N-hydroxy-3-methoxybenzimidamide (93 mg, 565 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (178 mg, 471 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (182 mg, 1.41 mmol, 246 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was cooled and then directly purified by preparative HPLC (column: Luna C8 100×30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40%-70%, 12 min) to give N-(2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide (119 mg, 263 μmol, 56%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.63-7.47(m,4H),7.32(t,J=7.9 Hz,1H),7.23-7.20(m,1H),7.15-7.10(m,1H),6.98(dd,J=1.8,8.3 Hz,1H),4.48-4.37(m,1H),4.22(d,J=3.9 Hz,2H),3.88-3.82(m,1H),3.81(s,3H),3.31-3.22(m,2H),3.13-3.04(m,1 H),2.24(s,6H),2.22-2.12(m,2H),2.00-1.87(m,2H);LCMS(ESI)m / z:[M+H] + =449.3.

[0332] Example 18: 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one

[0333] [ka] Step 1: Preparation of 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one.

[0334] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (150 mg, 518 μmol) in N,N-dimethylformamide (1.5 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1.56 mmol, 271 μL), and 5-oxo-1-phenyl-pyrrolidine-3-carboxylic acid (111 mg, 544 μmol). The mixture was stirred at 20° C. for 16 hours. The mixture was filtered, and the filtrate was directly purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30% to 60%, 12 min) to give 4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one (86 mg, 181 μmol, 35%) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.69-7.56(m,4H),7.38(br t,J=7.2 Hz,2H),7.22-7.16(m,1H),7.08(br d,J=8.4 Hz,1H),4.56-4.42(m,1H),4.19-4.04(m,3H),3.89(s,6H),3.86-3.81(m,1H),3.50-3.37(m,2H), 3.14-3.00(m,1H),2.94-2.78(m,2H),2.31-2.16(m,2H),2.01-1.81(m,2H);LCMS(ESI)m / z:[M+H] + =477.3.

[0335] Example 19: 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-(3,4-dimethylphenyl)pyrrolidin-2-one. Step 1: Preparation of 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-(3,4-dimethylphenyl)pyrrolidin-2-one.

[0336] [ka] To a stirred solution of 1-[1-(3,4-dimethylphenyl)-5-oxo-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (200 mg, 581 μmol) in N,N-dimethylformamide (1.5 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (220 mg, 581 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (225 mg, 1.74 mmol, 304 μL), and N-hydroxy-3,4-dimethoxy-benzamidine (125 mg, 639 μmol). The mixture was stirred at 20° C. for 12 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in N,N-dimethylformamide (2 mL) and then heated at 120°C for 5 hours. The mixture was cooled to 25°C, then diluted with water (5 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 35% to 65%, 12 min) to give 4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-(3,4-dimethylphenyl)pyrrolidin-2-one (7 mg, 15 μmol, 3%) as a pink solid. 1H NMR (400MHz, methanol-d4)δ=7.66(br d,J=8.2 Hz,1H),7.58(s,1H),7.36(s,1H),7.27(br d,J=8.2 Hz,1H),7.16-7.04(m,2H),4.49(br d,J=8.4 Hz,1H),4.18-3.98(m,3H),3.93-3.77(m,7H),3.48-3.36(m,2H),3.12-2.97(m,1 H),2.92-2.78(m,2H),2.32-2.14(m,8H),2.01-1.79(m,2H);LCMS(ESI)m / z:[M+H] + =505.4.

[0337] Example 20: 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one.

[0338] [ka] Step 1: Preparation of N-hydroxy-4-methoxybenzimidamide.

[0339] [ka] To a stirred solution of 4-methoxybenzonitrile (2.0 g, 15.02 mmol) in ethanol (20 mL) were added hydroxylamine hydrochloride (2.09 g, 30.0 mmol), triethylamine (3.04 g, 30.0 mmol, 4.16 mL), and water (2 mL), and the mixture was then heated to 70° C. for 15 hours. The mixture was treated with water (20 mL) and extracted with dichloromethane (30 mL×3). The combined organic phases were washed with water (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude N-hydroxy-4-methoxybenzimidamide (2.50 g) as a white solid, which was used directly in the next step. 1H NMR (400 MHz, methanol-d₄) δ 7.61-7.48 (m, 2H), 6.98-6.85 (m, 2H), 3.81 (s, 3H).

[0340] Step 2: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one.

[0341] [ka] To a stirred solution of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (250 mg, 726 μmol) and N-hydroxy-4-methoxybenzimidamide (120 mg, 726 μmol) in N,N-dimethylformamide (3 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (187 mg, 1.45 mmol, 253 μL) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (275 mg, 726 μmol), and after 15 h at 15° C., the mixture was heated to 110° C. and stirred for 5 h. The reaction mixture was cooled and directly purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 36%-66%, 12 min) to give 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one (101 mg, 213 μmol, 29%) as a pale yellow solid. 1H NMR(400 MHz, methanol-d4)δ 7.98(d,J=7.5 Hz,2H),7.36(s,1H),7.27(d,J=7.9 Hz,1H),7.13(d,J=8.4 Hz,1H),7.04(d,J=8.4 Hz,2H),4.47(m.,1H),4.19-3.96(m,3H),3.86(s,3H),3.84-3.78(m,1H),3.42(m,2H),3.16 -2.98(m,1H),2.93-2.74(m,2H),2.37-2.10(m,8H),2.02-1.78(m,2H);LCMS(ESI)m / z:[M+H] + =475.3.

[0342] Example 21: 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one.

[0343] [ka] Step 1: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one.

[0344] [ka] To a stirred solution of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (200 mg, 581 μmol) in N,N-dimethylformamide (3 mL) was added N-hydroxy-3-methoxybenzimidamide (96 mg, 581 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (220 mg, 581 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (225 mg, 1.74 mmol, 304 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was directly purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40%-60%, 12 min) to give 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one (80 mg, 168 μmol, 29%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.72-7.67(m,1H),7.62(s,1H),7.45-7.37(m,2H),7.30(d,J=2.3 Hz,1H),7.15(d,J=8.3 Hz,1H),7.11-7.06(m,1H),4.61-4.47(m,1H),4.30(dd,J=7.3,9.5 Hz,1H),3.91(s,5H),3.64-3.54(m,1H),3.46-3.30(m,2H),3.21-3.05(m,1H),3.03-2.92(m,1H),2.89-2.79(m,1H),2.28(d,J=13.1 Hz,8H),2.10-1.90(m,2H);LCMS(ESI)m / z:[M+H] + =475.3.

[0345] Example 22: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-N-methylbenzamide.

[0346] [ka] Step 1: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-N-methylbenzamide.

[0347] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (150 mg, 518 μmol) in N,N-dimethylformamide (2 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1.56 mmol, 271 μL) and 2-[benzoyl(methyl)amino]acetic acid (105 mg, 544 μmol). The mixture was stirred at 20°C for 5 hours, then cooled and directly purified by preparative HPLC (column: Luna C8 100x30 5µm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]-N-methyl-benzamide (133 mg, 282µmol, 54%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=7.59(dd,J=1.8,8.4 Hz,1H),7.49-7.32(m,5H),7.27(br d,J=6.8 Hz,1H),7.16-7.08(m,1H),4.44-4.24(m,2H),4.21-4.03(m,1H),4.02-3.88(m,1H),3.88-3.74(m,6H),3.56(br d,J=13.7 Hz,1H),3.48-3.33(m,1H),3.11-2.77(m,5H),2.20-1.99(m,2H),1.86(br t,J=12.6 Hz,1H),1.74-1.48(m,2H),1.43-1.26(m,1H);LCMS(ESI)m / z:[M+H] + =465.3.

[0348] Example 23: N-(2-(4-(3-(3,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0349] [ka] Step 1: Preparation of 3,4-dichloro-N-hydroxybenzimidamide.

[0350] [ka] To a stirred solution of 3,4-dichlorobenzonitrile (1.0 g, 5.81 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (807 mg, 11.6 mmol), triethylamine (1.18 g, 11.6 mmol, 1.61 mL), and water (2 mL). The mixture was heated at 75° C. for 5 hours and then cooled to 20° C. Water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL×4). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give 3,4-dichloro-N-hydroxybenzimidamide (1.20 g) as a white solid, which was used directly without further purification.1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.69-7.58 (m, 2H), 5.95 (s, 2H).

[0351] Step 2: Preparation of N-(2-(4-(3-(3,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0352] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (200 mg, 688.92 μmol) in N,N-dimethylformamide (4 mL) was added 3,4-dichloro-N-hydroxybenzimidamide (169 mg, 826 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (261 mg, 688.92 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (267 mg, 2.07 mmol, 360 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was then cooled and directly purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40%-70%, 12 min) to give N-(2-(4-(3-(3,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (92 mg, 201 μmol, 29%) as a white solid. 1H NMR(400 MHz,CDCl3)δ 8.14-8.09(m,1H),7.85(dd,J=2.0,8.2 Hz,1H),7.78(d,J=7.1 Hz,2H),7.39(s,4H),7.25(br.s.,1H),4.43(d,J=13.7 Hz,1H),4.24(d,J=3.5 Hz,2H),3.84(d,J=14.1 Hz,1H),3.33-3.22(m,2H),3.14-3.03(m,1H),2.23-2.13(m,2H),1.99-1.86(m,2H);LCMS(ESI)m / z:[M+H] + =459.1.

[0353] Example 24: N-(2-(4-(3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0354] [ka] Step 1: Preparation of 3,4-difluoro-N-hydroxybenzimidamide.

[0355] [ka] To a stirred solution of 3,4-difluorobenzonitrile (1.0 g, 7.19 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (999 mg, 14.4 mmol), triethylamine (1.46 g, 14.4 mmol, 1.99 mL), and water (2 mL). The mixture was heated at 75° C. for 2 hours. After cooling to 20° C., water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (30 mL×4). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3,4-difluoro-N-hydroxybenzimidamide (1.24 g) as a white solid, which was used directly without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.68 (ddd, J=2.0, 8.0, 12.2 Hz, 1H), 7.55 (br.s., 1H), 7.50-7.39 (m, 1H), 5.92 (br.s., 2H).

[0356] Step 2: Preparation of N-(2-(4-(3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0357] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) in N,N-dimethylformamide (4 mL) was added 3,4-difluoro-N-hydroxybenzimidamide (85 mg, 496 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1.24 mmol, 216 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was cooled and then directly purified by preparative HPLC (column: Luna C8 100×30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 35%-60%, 12 min) to give N-(2-(4-(3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (50 mg, 118 μmol, 28%) as a white solid. 1H NMR(400 MHz,CDCl3)δ 7.78(d,J=7.1 Hz,4H),7.44(d,J=7.1 Hz,1H),7.42-7.35(m,2H),7.23(d,J=8.4 Hz,2H),4.43(d,J=13.7 Hz,1H),4.23(d,J=4.0 Hz,2H),3.84(d,J=13.7 Hz,1H),3.32-3.21(m,2H),3.13-3.03(m,1H),2.23-2.12(m,2H),1.99-1.84(m,2H);LCMS(ESI)m / z:[M+H] + =427.2.

[0358] Example 25: 2-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0359] [ka] Step 1: Preparation of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)carbamate.

[0360] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (2.0 g, 6.91 mmol) in N,N-dimethylformamide (20 mL) was added 2-(tert-butoxycarbonylamino)acetic acid (1.21 g, 6.91 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.62 g, 6.91 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (2.68 g, 20.7 mmol, 3.62 mL). The mixture was stirred at 15° C. for 2 hours. The reaction mixture was cooled to room temperature with the addition of water (20 mL). The mixture was quenched by addition of HCl, and then the mixture was extracted with ethyl acetate (60 mL × 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue. Purification by chromatography (silica, petroleum ether:ethyl acetate = 5:1 to 1:1) gave tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)carbamate (2.60 g, 5.82 mmol, 84%) as a brown solid, which was used directly without further purification. LCMS (ESI) m / z: [M+H] + =447.2.

[0361] Step 2: Preparation of 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone.

[0362] [ka] To a stirred solution of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)carbamate (2.50 g, 5.60 mmol) in methanol (10 mL) was added hydrogen chloride in methanol (4 M, 30 mL). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated to give the crude product. A portion of the crude product (0.1 g) was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 20% to 50%, 12 min) to obtain 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (32 mg) for analysis. The remaining crude 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (1.90 g, 5.49 mmol, 98%) obtained as a brown solid was used directly. 1 H NMR(400 MHz,CDCl3)δ 7.73-7.67(m,1H),7.58(d,J=1.5 Hz,1H),6.98(d,J=8.4 Hz,1H),4.54(d,J=12.2 Hz,1H),3.98(d,J=7.2 Hz,6H),3.84(d,J=12.0 Hz,1H),3.54(s,2H),3.34-3.21(m,2H),3.08(d,J=12.3 Hz,1H),2.21(d,J=13.1 Hz,2H),1.98(d,J=9.4 Hz,2H);LCMS(ESI)m / z:[M+H] + =347.1.

[0363] Step 3: Preparation of 2-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0364] [ka] To a stirred solution of 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (185 mg, 537 μmol) in N,N-dimethylformamide (3 mL) was added 2-chlorobenzoic acid (70 mg, 447 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (231 mg, 1.79 mmol, 312 μL). The mixture was stirred at 20° C. for 2 h and then directly purified by preparative HPLC (column: Waters Xbridge 150×2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 26%-56%, 12 min) to give 2-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (124 mg, 256 μmol, 57%) as a pink solid. 1 H NMR(400 MHz,CDCl3)δ 7.72(ddd,J=1.9,6.3,7.9 Hz,2H),7.59(d,J=1.9 Hz,1H),7.49-7.33(m,4H),6.98(d,J=8.4 Hz,1H),4.52(d,J=13.6 Hz,1H),4.36(d,J=4.0 Hz,2H),3.99(d,J=7.8 Hz,6H),3.92(d,J=13.8 Hz,1H),3.41-3.30(m,2H),3.16(t,J=10.9 Hz,1H),2.33-2.21(m,2H),2.11-1.94(m,2H);LCMS(ESI)m / z:[M+H] + =485.2.

[0365] Example 26: 3-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0366] [ka] Step 1: Preparation of 3-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0367] [ka] To a stirred solution of 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (185 mg, 537 μmol) in N,N-dimethylformamide (3 mL) was added 3-chlorobenzoic acid (70 mg, 447 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (231 mg, 1.79 mmol, 312 μL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was directly purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 26%-56%, 12 min) to give 3-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (126 mg, 261 μmol, 58%) as a white solid. 1H NMR(400MHz,CDCl3)δ 7.89-7.86(m,1H),7.72(d,J=2.0 Hz,2H),7.59(d,J=1.9 Hz,1H),7.54-7.50(m,1H),7.45-7.39(m,1H),7.34(br.s.,1H),6.98(d,J=8.5 Hz,1H),4.53(d,J=14.3 Hz,1H),4.31(d,J=3.9 Hz,2H),3.98(d,J=7.4 Hz,6H),3.96-3.87(m,1H),3.41-3.30(m,2H),3.18(t,J=10.9 Hz,1H),2.33-2.22(m,2H),2.10-1.94(m,2H);LCMS(ESI)m / z:[M+H] + =485.3.

[0368] Example 27: 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0369] [ka] Step 1: Preparation of 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0370] [ka] To a stirred solution of 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (185 mg, 536.5 μmol) in N,N-dimethylformamide (3 mL) was added 4-chlorobenzoic acid (70 mg, 447 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (231 mg, 1.79 mmol, 312 μL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was directly purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (144 mg, 294 μmol, 66%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.82(d,J=8.5 Hz,2H),7.71(dd,J=1.9,8.3 Hz,1H),7.59(d,J=1.8 Hz,1H),7.45(d,J=8.5 Hz,2H),7.33(br.s.,1H),6.98(d,J=8.4 Hz,1H),4.52(d,J=14.2 Hz,1H),4.31(d,J=3.9 Hz,2H),3.98(d,J=7.3 Hz,6H),3.92(d,J=13.7 Hz,1H),3.41-3.30(m,2H),3.17(t,J=10.7 Hz,1H),2.34-2.21(m,2H),2.10-1.94(m,2H);LCMS(ESI)m / z:[M+H] + =485.2.

[0371] Example 28: N-(1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-1-oxopropan-2-yl)benzamide.

[0372] [ka] Step 1: Preparation of N-(1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-1-oxopropan-2-yl)benzamide.

[0373] [ka] A stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (150 mg, 518 μmol) in N,N-dimethylformamide (2 mL) gave (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1.56 mmol, 271 μL), and 2-benzamidopropanoic acid (105 mg, 544 μmol). The mixture was stirred at 20° C. for 7 h, and then the crude product was directly purified by preparative HPLC (column: Luna C8 100×30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile; B%: 35%-60%, 12 min] to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2-oxo-ethyl]benzamide (52 mg, 112 μmol, 22%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=8.63(br dd,J=7.3,16.1 Hz,1H),7.88(br d,J=7.3 Hz,2H),7.66-7.34(m,5H),7.11(br d,J=7.9 Hz,1H),4.97(br d,J=6.0 Hz,1H),4.45-4.22(m,1H),4.08-3.94(m,1H),3.82(s,6H),3.42(br t,J=10.7 Hz,1H),3.29-3.21(m,1H),3.00-2.80(m,1H),2.09(br d,J=11.9 Hz,2H),1.87-1.56(m,1H),1.29(s,3H);LCMS(ESI)m / z:[M+H] + =465.3.

[0374] Example 29: N-(1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-methyl-1-oxopropan-2-yl)benzamide.

[0375] [ka] Step 1: Preparation of N-(1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-methyl-1-oxopropan-2-yl)benzamide.

[0376] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (150 mg, 518 μmol) in N,N-dimethylformamide (2 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1.56 mmol, 271 μL), and 2-benzamido-2-methyl-propanoic acid (112 mg, 544 μmol). The mixture was stirred at 20° C. for 5 hours. The crude product was directly purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 27%–57%, 12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-1,1-dimethyl-2-oxo-ethyl]benzamide (47 mg, 99 μmol, 19%) as a pale yellow solid. 1 H NMR (400MHz, methanol-d4)δ=7.88-7.81(m,2H),7.62(dd,J=2.0,8.4 Hz,1H),7.57-7.51(m,2H),7.49-7.42(m,2H),7.06(d,J=8.4 Hz,1H),4.61-4.45(m,2H),3.88(d,J=5.1 Hz,6H),3.13(s,3H),2.08(br s,2H),1.90-1.74(m,2H),1.60(s,6H);LCMS(ESI)m / z:[M+H] + =477.1.

[0377] Example 30: 2-(benzylamino)-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone.

[0378] [ka] Step 1: Preparation of 2-(benzylamino)-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone.

[0379] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (150 mg, 518 μmol) in N,N-dimethylformamide (1.50 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1.56 mmol, 271 μL), and 2-(benzylamino)acetic acid (89 mg, 544 μmol). The mixture was stirred at 20°C for 16 hours, filtered, and the crude filtrate was directly purified by preparative HPLC (column: Luna C8 100x30 5µm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give 2-(benzylamino)-1-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]ethanone (48 mg, 110µmol, 21%) as a yellow solid. 1 H NMR (400MHz, methanol-d4) δ=7.65(dd,J=1.8,8.2 Hz,1H),7.57(d,J=1.8 Hz,1H),7.40-7.30(m,4H),7.28-7.22(m,1H),7.06(d,J=8.4 Hz,1H),4.45(br d,J=13.7 Hz,1H),3.94-3.83(m,7H),3.78(s,2H),3.57-3.44(m,2H),3.40-3.33(m,1H),3.27-3.20(m,1H),3.01(t,J=11.2 Hz,1H),2.17(dd,J=2.8,13.3 Hz,2H),1.93-1.73(m,2H);LCMS(ESI)m / z:[M+H] + =437.3.

[0380] Example 31: 2-(benzyloxy)-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone.

[0381] [ka] Step 1: Preparation of 2-(benzyloxy)-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone.

[0382] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (150 mg, 518 μmol) in N,N-dimethylformamide (2 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1.56 mmol, 271 μL), and 2-benzyloxyacetic acid (90 mg, 544 μmol, 77 μL). The mixture was stirred at 20° C. for 5 hours. The crude product was directly purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 32% to 62%, 12 min) to give 2-benzyloxy-1-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]ethanone (68 mg, 157 μmol, 30%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=7.60(dd,J=1.9,8.3 Hz,1H),7.48(d,J=1.9 Hz,1H),7.40-7.35(m,4H),7.34-7.26(m,1H),7.14(d,J=8.4 Hz,1H),4.54(s,2H),4.33(br d,J=13.2 Hz,1H),4.25(br d,J=7.8 Hz,2H),3.93-3.78(m,7H),3.43(tt,J=3.9,11.0 Hz,1H),3.22(br t,J=11.7 Hz,1H),2.90(br t,J=11.7 Hz,1H),2.17-2.04(m,2H),1.88-1.59(m,2H);LCMS(ESI)m / z:[M+H] + =438.3.

[0383] Example 32: N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]ethyl]benzamide

[0384] [ka] Step 1: Preparation of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)carbamate.

[0385] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (750 mg, 2.59 mmol) in N,N-dimethylformamide (1 mL) was added cesium carbonate (844 mg, 2.59 mmol) and tert-butyl N-(2-bromoethyl)carbamate (871 mg, 3.89 mmol). The mixture was stirred at 50° C. for 16 hours. The reaction mixture was cooled and then extracted with ethyl acetate (5 mL × 2). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]ethyl]carbamate (1.30 g), which was used directly without further purification. LCMS(ESI)m / z=433.3[M+H] + .

[0386] Step 2: Preparation of 2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanamine.

[0387] [ka] A solution of tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]ethyl]carbamate (1.0 g, 2.31 mmol) in hydrochloric acid / ethyl acetate (4 M, 25 mL) was stirred at 25° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to give 2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]ethanamine (750 mg), which was used directly without further purification. LCMS (ESI) m / z=333.1 [M+H] + .

[0388] Step 3: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide

[0389] [ka] To a mixture of 2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]ethanamine (200 mg, 602 μmol) and benzoyl chloride (109 mg, 782 μmol, 90 μL) in dichloromethane (1 mL) was added triethylamine (182 mg, 1.81 mmol, 250 μL) at 0° C. The mixture was stirred at 20°C for 5 hours and then directly purified by preparative HPLC (column: Luna C8 100x30 5µm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-50%, 12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]ethyl]benzamide (25 mg, 56µmol, 9%) as a white solid. 1 H NMR (400MHz, methanol-d4)δ=7.86-7.79(m,2H),7.66(dd,J=1.8,8.4 Hz,1H),7.58(d,J=1.8 Hz,1H),7.55-7.43(m,3H),7.07(d,J=8.6 Hz,1H),3.89(s,6H),3.58(t,J=6.8 Hz,2H),3.16-3.09(m,2H),2.67(t,J=6.8 Hz,2H),2.37-2.29(m,2H),2.18(br d,J=11.2 Hz,2H),2.07-1.91(m,3H);LCMS(ESI)m / z:[M+H] + =437.3.

[0390] Example 33: (E)-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-4-phenylbut-2-ene-1,4-dione

[0391] [ka] Step 1: Preparation of (E)-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-4-phenylbut-2-ene-1,4-dione

[0392] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (250 mg, 864 μmol) in N,N-dimethylformamide (4 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (327 mg, 864 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (335 mg, 2.59 mmol, 452 μL), and (£)-4-oxo-4-phenyl-but-2-enoic acid (152 mg, 864 μmol). The mixture was stirred at 20° C. for 5 h, and then the crude mixture was directly purified by preparative HPLC (column: Luna C8 100×30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40%-70%, 12 min) to give (E)-1-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-4-phenyl-but-2-ene-1,4-dione (118 mg, 251 μmol, 29%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=8.03(br d,J=7.3 Hz,2H),7.75(d,J=15.4 Hz,1H),7.71-7.65(m,1H),7.61-7.53(m,3H),7.51-7.43(m,2H),7.11(d,J=8.4 Hz,1H),4.41(br d,J=13.2 Hz,1H),4.11-3.99(m,1H),3.88-3.77(m,6H),3.54-3.34(m,2H),3.02(br t,J=11.2 Hz,1H),2.15(br d,J=13.0 Hz,2H),1.88-1.67(m,2H);LCMS(ESI)m / z:[M+H] + =448.2.

[0393] Example 34: 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-((2,2,2-trifluoro-1-phenylethyl)amino)ethanone.

[0394] [ka] Step 1: Preparation of 2,2,2-trifluoro-1-phenylethyl trifluoromethanesulfonate.

[0395] [ka] To a stirred solution of 2,2,2-trifluoro-1-phenylethanol (100 mg, 568 μmol, 76 μL) in dichloromethane (2 mL) was added 2,6-dimethylpyridine (121 mg, 1.14 mmol, 132 μL) and trifluoroacetic anhydride (288 mg, 1.02 mmol, 168 μL) at 0° C. The mixture was stirred at 0° C. for 0.5 h, then diluted with dichloromethane (5 mL) and water (5 mL), and the phases were separated. The aqueous phase was extracted with dichloromethane (15 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2,2,2-trifluoro-1-phenylethyl trifluoromethanesulfonate (380 mg) as a brown oil. This material was used directly without further purification.

[0396] Step 2: Preparation of 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-((2,2,2-trifluoro-1-phenylethyl)amino)ethanone

[0397] [ka] To a stirred solution of 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (120 mg, 346 μmol) in dichloromethane (2.5 mL) were added 2,2,2-trifluoro-1-phenylethyl trifluoromethanesulfonate (213 mg, 692.88 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (179 mg, 1.39 mmol, 242 μL). The mixture was stirred at 40° C. for 16 hours. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40% to 70%, 12 min) to give 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-((2,2,2-trifluoro-1-phenylethyl)amino)ethanone (52 mg, 101 μmol, 29%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.63-7.56(m,1H),7.51-7.37(m,6H),7.14(d,J=8.4 Hz,1H),4.53-4.43(m,1H),4.30(br.s.,1H),3.84(s,6H),3.71(d,J=10.2 Hz,1H),3.44-3.36(m,2H),3.18-3.07(m,1H),2.99(d,J=5.5 Hz,1H),2.87(br.s.,1H),2.08(d,J=12.5 Hz,2H),1.75-1.56(m,2H);LCMS(ESI)m / z:[M+H] + =505.3.

[0398] Example 35: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-thiadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide

[0399] [ka] Step 1: Preparation of tert-butyl 4-(3-bromo-1,2,4-thiadiazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[0400] [ka] A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (500 mg, 2.51 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (931 mg, 3.01 mmol), and cesium fluoride (762 mg, 5.02 mmol, 185 μL) in dioxane (3.5 mL) was degassed and purged with nitrogen three times, followed by the addition of 4-di-tert-butylphosphanyl-N,N-dimethylaniline; dichloropalladium (88 mg, 125.50 μmol, 88 μL, 0.05 equiv.). The mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The mixture was cooled to 25° C. and concentrated under vacuum at 40° C. The residue was poured into water (15 mL), and the aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by chromatography (silica, petroleum ether / ethyl acetate (20 / 1 to 2 / 1)) to give tert-butyl 4-(3-bromo-1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (260 mg, 750.92 μmol, 30%) as a yellow oil. LCMS (ESI) m / z: 368.3 [M+Na] + .

[0401] Step 2: Preparation of tert-butyl 4-(3-(3,4-dimethoxyphenyl)-1,2,4-thiadiazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[0402] [ka] A mixture of tert-butyl 4-(3-bromo-1,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (260 mg, 751 μmol), (3,4-dimethoxyphenyl)boronic acid (163 mg, 901 μmol), and sodium carbonate (103 mg, 976 μmol) in water (400 μL) and dimethoxyethane (1.2 mL) was degassed and purged with nitrogen three times, and then tetrakis(triphenylphosphine)palladium(0) (17 mg, 15 μmol) was added. The mixture was stirred at 100° C. under a nitrogen atmosphere for 6 hours. The mixture was cooled to 25° C. and concentrated under vacuum at 40° C. The residue was poured into water (5 mL), and the aqueous phase was extracted with dichloromethane (10 mL×3). The combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude residue was purified by preparative TLC (silica, petroleum ether / ethyl acetate=3:1) to give tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (122 mg, 303 μmol, 40%) as a yellow oil. LCMS (ESI) m / z: 404.1 [M+H] + .

[0403] Step 3: Preparation of tert-butyl 4-(3-(3,4-dimethoxyphenyl)-1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate

[0404] [ka] To a stirred solution of tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 248 μmol) in methanol (10 mL) was added palladium(0) on carbon (10%, 150 mg) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi) at 20° C. for 48 hours. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1,2,4-thiadiazol-5-yl]piperidine-1-carboxylate (79 mg), which was used in the next step without further purification. LCMS (ESI) m / z: 406.2 [M+H] + .

[0405] Step 4: Preparation of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1,2,4-thiadiazole

[0406] [ka] A solution of tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1,2,4-thiadiazol-5-yl]piperidine-1-carboxylate (79 mg, 195 μmol) in hydrochloric acid / ethyl acetate (4 M, 15 mL) was stirred for 3 hours at 20° C. The reaction mixture was concentrated in vacuo to give 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-thiadiazole (65 mg), which was used in the next step without further purification.

[0407] Step 5: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-thiadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide

[0408] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-thiadiazole (65 mg, 214 μmol) and 2-benzamidoacetic acid (46 mg, 257 μmol) in N,N-dimethylformamide (1 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (81 mg, 214 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (69 mg, 536 μmol, 93 μL). After 2 h, the reaction mixture was directly purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 26%-56%, 12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-thiadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]benzamide (10 mg, 22 μmol, 10%) as a yellow solid. 1 H NMR (400MHz, methanol-d4) δ=7.92-7.82(m,4H),7.59-7.52(m,1H),7.51-7.44(m,2H),7.06(d,J=8.4 Hz,1H),4.61(d,J=12.9 Hz,1H),4.41-4.24(m,2H),4.11(br d,J=14.9 Hz,1H),3.98-3.84(m,6H),3.63-3.52(m,1H),3.39(br t,J=11.7 Hz,1H),2.99(br t,J=11.6 Hz,1H),2.35-2.20(m,2H),2.03-1.74(m,2H);LCMS(ESI)m / z:[M+H] + =467.2.

[0409] Example 36: N-(2-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)-2-oxoethyl)benzamide

[0410] [ka] Step 1: Preparation of (Z)-tert-butyl 4-(N'-hydroxycarbamimidoyl)piperidine-1-carboxylate

[0411] [ka] A mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (2.0 g, 9.51 mmol), hydroxylamine hydrochloride (1.32 g, 19.0 mmol), and triethylamine (1.92 g, 19.0 mmol, 2.64 mL) in ethanol (20 mL) and water (2 mL) was heated at 75° C. for 16 hours. The reaction mixture was cooled, diluted with water (10 mL), and extracted with ethyl acetate (15 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-[(Z)-N′-hydroxycarbamimidoyl]piperidine-1-carboxylate (1.90 g), which was used directly without further purification. 1 H NMR (400MHz, methanol-d4) δ=4.15(br d,J=13.3 Hz,2H),2.78(br s,2H),2.27(tt,J=3.6,12.1 Hz,1H),1.84-1.70(m,2H),1.62(dq,J=4.3,12.6 Hz,2H),1.53-1.39(m,9H).

[0412] Step 2: Preparation of tert-butyl 4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate

[0413] [ka] To a stirred solution of tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1-carboxylate (750 mg, 3.08 mmol) in N,N-dimethylformamide (5 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (1.17 g, 3.08 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (1.19 g, 9.24 mmol, 1.61 mL), and 3,4-dimethoxybenzoic acid (561 mg, 3.08 mmol). The mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Tetrahydrofuran (500 μL) and tetrabutylammonium fluoride / tetrahydrofuran (1 M, 4.62 mL) were added to the residue, and the resulting mixture was heated at 50 °C for 16 hours. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate = 5:1) to give tert-butyl 4-[5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate (970 mg, 2.49 mmol, 81%) as a white solid. LCMS (ESI) m / z: 412.3 [M+Na] + =334.2.

[0414] Step 3: Preparation of 5-(3,4-dimethoxyphenyl)-3-(piperidin-4-yl)-1,2,4-oxadiazole

[0415] [ka] A solution of tert-butyl 4-[5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate (750 mg, 1.93 mmol) in hydrochloric acid / ethyl acetate (4 M, 30 mL) was stirred for 0.5 h at 20° C. The reaction mixture was concentrated under reduced pressure to give 5-(3,4-dimethoxyphenyl)-3-(4-piperidyl)-1,2,4-oxadiazole (683 mg), which was used directly without further purification.

[0416] Step 4: Preparation of N-(2-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)-2-oxoethyl)benzamide

[0417] [ka] To a stirred solution of 5-(3,4-dimethoxyphenyl)-3-(4-piperidyl)-1,2,4-oxadiazole (180 mg, 622 μmol) in N,N-dimethylformamide (2 mL) was added 2-benzamidoacetic acid (111 mg, 622 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (235 mg, 622 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (241 mg, 1.87 mmol, 325 μL). The mixture was stirred at 20° C. for 16 hours. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-[2-[4-[5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl]-1-piperidyl]-2-oxo-ethyl]benzamide (169 mg, 376 μmol, 60%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=8.55(br t,J=5.4 Hz,1H),7.87(br d,J=7.5 Hz,2H),7.70(br d,J=8.4 Hz,1H),7.57-7.41(m,4H),7.17(br d,J=8.4 Hz,1H),4.34(br d,J=12.3 Hz,1H),4.16(br d,J=4.2 Hz,2H),3.97(br d,J=13.0 Hz,1H),3.90-3.74(m,6H),3.27-3.09(m,2H),2.88(br t,J=11.6 Hz,1H),2.03(br t,J=11.8 Hz,2H),1.75(br d,J=10.4 Hz,1H),1.59(br d,J=9.9 Hz,1H);LCMS(ESI)m / z:[M+H] + =451.2.

[0418] Example 37: N-(2-(4-(4-(3,4-dimethoxyphenyl)oxazol-2-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0419] [ka] Step 1: Preparation of 2-bromo-1-(3,4-dimethoxyphenyl)ethanone.

[0420] [ka] To a stirred solution of 1-(3,4-dimethoxyphenyl)ethanone (1.0 g, 5.55 mmol) in dichloromethane (6 mL) and methanol (3 mL) was added benzyltrimethylammonium tribromide (2.16 g, 5.55 mmol). After 16 h, the mixture was diluted with dichloromethane (80 mL) and water (40 mL), the organic layer was separated, and the aqueous phase was extracted with dichloromethane (80 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (1.20 g, 4.63 mmol, 83%) as a brown solid. 1H NMR(400 MHz, CDCl3)δ 7.63(s,1H),7.57(d,J=2.1 Hz,1H),6.94(d,J=8.4 Hz,1H),4.43(s,2H),3.98(d,J=8.4 Hz,6H).

[0421] Step 2: Preparation of 2-(3,4-dimethoxyphenyl)-2-oxoethyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate.

[0422] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (200 mg, 689 μmol) in acetonitrile (6 mL) under nitrogen was added 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (214 mg, 826 μmol) and triethylamine (209 mg, 2.07 mmol, 286 μL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated in vacuo to give 2-(3,4-dimethoxyphenyl)-2-oxoethyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate (233 mg, 497 μmol, 72%) as a yellow solid, which was used directly without further purification. LCMS (ESI) m / z: [M+H] + =469.3.

[0423] Step 3: Preparation of N-(2-(4-(4-(3,4-dimethoxyphenyl)oxazol-2-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0424] [ka] To a stirred solution of 2-(3,4-dimethoxyphenyl)-2-oxoethyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate (180 mg, 384 μmol) in acetic acid (8 mL) under nitrogen was added ammonium acetate (148 mg, 1.92 mmol), and the mixture was then heated at 100° C. for 16 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-55%, 12 min) to give N-(2-(4-(4-(3,4-dimethoxyphenyl)oxazol-2-yl)piperidin-1-yl)-2-oxoethyl)benzamide (55 mg, 120 μmol, 31%) as a pink solid. 1 H NMR(400 MHz,CDCl3)δ 7.92-7.84(m,2H),7.80(s,1H),7.58-7.44(m,3H),7.41-7.35(m,1H),7.28-7.26(m,2H),6.92(d,J=8.9 Hz,1H),4.58-4.47(m,1H),4.32(d,J=3.9 Hz,2H),3.99-3.88(m,7H),3.37-3.06(m,3H),2.28-2.13(m,2H),2.07-1.89(m,2H);LCMS(ESI)m / z:[M+H] + =450.3.

[0425] Example 38: N-(2-(4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0426] [ka] Step 1: Preparation of tert-butyl 4-carbamothioylpiperidine-1-carboxylate.

[0427] [ka] To a stirred solution of tert-butyl 4-carbamoylpiperidine-1-carboxylate (1.0 g, 4.38 mmol) in dimethoxyethane (16 mL) and dichloromethane (8 mL) was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (885 mg, 2.19 mmol). The mixture was stirred at 20° C. for 16 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous potassium carbonate (10 mL×2). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to give tert-butyl 4-carbamothioylpiperidine-1-carboxylate (1.0 g) as a yellow solid, which was used directly without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 9.45(br.s.,1H),9.17(br.s.,1H),4.14-3.98(m,2H),3.91-3.79(m,1H),2.80-2.66(m,2H),1.74-1.55(m,4H),1.46(s,9H).

[0428] Step 2: Preparation of tert-butyl 4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate.

[0429] [ka] To a stirred solution of tert-butyl 4-carbamothioylpiperidine-1-carboxylate (200 mg, 818.5 μmol) in N,N-dimethylformamide (5 mL) were added 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (212 mg, 818.50 μmol) and potassium carbonate (124 mg, 900 μmol). The mixture was stirred at 110° C. for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (40 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate (300 mg, 742 μmol, 91%) as a yellow solid, which was used directly without further purification. LCMS(ESI)m / z:[M+H] + =405.3.

[0430] Step 3: Preparation of 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)thiazole.

[0431] [ka] To a stirred solution of tert-butyl 4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate (300 mg, 742 μmol) in methanol (3 mL) was added hydrogen chloride in methanol (4 M, 10 mL). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)thiazole (260 mg) as a yellow solid. LCMS (ESI) m / z: [M+H] + =305.1.

[0432] Step 4: Preparation of N-(2-(4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0433] [ka] To a stirred solution of 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)thiazole (203 mg, 670 μmol) in N,N-dimethylformamide (4 mL) was added 2-benzamidoacetic acid (100 mg, 558 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (211 mg, 558 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (288 mg, 2.23 mmol, 389 μL). The mixture was stirred at 20° C. for 16 hours. The reaction mixture was directly purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-(2-(4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidin-1-yl)-2-oxoethyl)benzamide (111 mg, 239 μmol, 43%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 7.91-7.85(m,2H),7.57-7.42(m,5H),7.39(br.s.,1H),6.94(d,J=8.2 Hz,1H),4.70(d,J=13.6 Hz,1H),4.40-4.26(m,2H),3.97(d,J=19.7 Hz,7H),3.43-3.26(m,2H),3.05-2.95(m,1H),2.37-2.23(m,2H),1.98-1.83(m,2H);LCMS(ESI)m / z:[M+H] + =466.3.

[0434] Example 39: N-(2-(4-(5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0435] [ka] Step 1: Ethyl 3,4-dimethoxybenzimidamide.

[0436] [ka] To a stirred solution of 3,4-dimethoxybenzonitrile (2.0 g, 12.3 mmol) in dry ethanol (50 mL) was added acetyl chloride (7.70 g, 98.1 mmol, 7.0 mL) dropwise at 0° C. After the addition was complete, the mixture was warmed to 15° C. and stirred for 30 hours. The reaction was concentrated in vacuo, and then saturated hydrochloric acid in ethanol (50 mL) was added. After 5 hours, the mixture was concentrated in vacuo to give crude ethyl 3,4-dimethoxybenzenecarboximidate (2.50 g) as a pale yellow solid, which was used directly in the next step.

[0437] Step 2: Methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate.

[0438] [ka] To a stirred solution of 2-benzamidoacetic acid (3.0 g, 16.7 mmol) and methyl piperidine-4-carboxylate (3.60 g, 25.1 mmol) in dry N,N-dimethylformamide (50 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (4.33 g, 33.5 mmol, 5.9 mL) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (7.0 g, 18.4 mmol) at 0° C. The mixture was then warmed to 15° C. and stirred for 15 hours. The mixture was poured into ice water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with 1N hydrochloric acid (30 mL × 2), saturated aqueous sodium chloride solution (30 mL), and saturated aqueous sodium chloride solution (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give crude methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate (5.30 g) as a brown oil, which was used directly in the next step. 1H NMR(400 MHz, methanol-d4)δ 7.87(d,J=7.1 Hz,2H),7.58-7.51(m,1H),7.49-7.40(m,2H),4.39-4.29(m,1H),4.28-4.17(m,2H),3.96-3.84(m,1H),3. 68(s,3H),3.28-3.17(m,1H),2.96-2.86(m,1H),2.69-2.62(m,1H),2.00-1.88(m,2H),1.78-1.51(m,2H).

[0439] Step 3: N-(2-(4-(hydrazinecarbonyl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0440] [ka] A solution of methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate (500 mg, 1.64 mmol) and hydrazine hydrate (328 mg, 6.56 mmol, 318 μL) in methanol (3 mL) was heated to 80° C. for 15 h. The mixture was concentrated in vacuo to give a crude residue, which was washed with tert-butyl methyl ether (10 mL) to give N-[2-[4-(hydrazinecarbonyl)-1-piperidyl]-2-oxo-ethyl]benzamide (500 mg) as a pale yellow solid, which was used directly without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 9.03(s,1H),8.54(t,J=5.6 Hz,1H),7.94-7.82(m,2H),7.60-7.43(m,3H),4.41-4.29(m,1H),4.13(d,J=5.6 Hz,2H),3.93(d,J=12.9 Hz,1H),3.05(t,J=11.9 Hz,1H),2.68-2.57(m,1H),2.34(tdd,J=3.9,7.5,11.2 Hz,1H),1.73-1.34(m,4H).

[0441] Step 4: N-(2-(4-(5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0442] [ka] A solution of N-[2-[4-(hydrazinecarbonyl)-1-piperidyl]-2-oxo-ethyl]benzamide (200 mg, 657 μmol) and ethyl 3,4-dimethoxybenzenecarboximidate (151 mg, 723 μmol) in ethanol (4 mL) was heated to 80° C. for 15 h. The mixture was concentrated to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 20% to 35%, 12 min) to give N-[2-[4-[5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-1-piperidyl]-2-oxo-ethyl]benzamide (23 mg, 48 μmol, 7%) as a white solid. 1 H NMR(400 MHz, methanol-d4)δ 7.92-7.82(m,2H),7.62(dd,J=1.8,8.4 Hz,1H),7.59-7.52(m,2H),7.51-7.44(m,2H),7.12(d,J=8.4 Hz,1H),4.49(d,J=13.2 Hz,1H),4.38-4.24(m,2H),4.06(d,J=13.7 Hz,1H),3.97-3.80(m,6H),3.48-3.34(m,2H),3.06(t,J=11.2 Hz,1H),2.33-2.15(m,2H),2.06-1.94(m,1H),1.92-1.75(m,1H);LCMS(ESI)m / z:[M+H] + =451.2.

[0443] Example 40: N-(2-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0444] [ka] Step 1: Preparation of 1,3-dimethyl-1H-indazole-6-carbonitrile.

[0445] [ka] To a stirred solution of 6-bromo-1,3-dimethyl-1H-indazole (400 mg, 1.78 mmol) in N,N-dimethylformamide (5 mL) under nitrogen, zinc cyanide (209 mg, 1.78 mmol, 112 μL) and tetrakis(triphenylphosphine)palladium(0) (205 mg, 178 μmol, 0.10 equiv.) were added. The mixture was heated at 100° C. for 16 hours, then cooled to 20° C., water (10 mL) was added, and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL) and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under vacuum to give the crude product. Petroleum ether (40 mL) was added to the crude product, then the mixture was filtered and the filter cake was dried under vacuum to give 1,3-dimethyl-1H-indazole-6-carbonitrile (250 mg, 1.46 mmol, 82%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.78-7.71 (m, 2H), 7.34 (dd, J=1.3, 8.3 Hz, 1H), 4.07 (s, 3H), 2.61 (s, 3H).

[0446] Step 2: Preparation of (Z)-N'-hydroxy-1,3-dimethyl-1H-indazole-6-carboximidamide.

[0447] [ka] To a stirred solution of 1,3-dimethyl-1H-indazole-6-carbonitrile (100 mg, 584 μmol) in ethanol (2 mL) was added hydroxylamine hydrochloride (81 mg, 1.17 mmol), triethylamine (118 mg, 1.17 mmol, 161 μL), and water (200 μL). The mixture was heated at 75° C. for 2 hours. After cooling to 20° C., water (5 mL) was added to the solution. The mixture was extracted with dichloromethane (30 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum to give (Z)-N′-hydroxy-1,3-dimethyl-1H-indazole-6-carboximidamide (140 mg) as a white solid. LCMS (ESI) m / z: [M+H] + =205.1.

[0448] Step 3: Preparation of N-(2-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0449] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) in N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxy-1,3-dimethyl-1H-indazole-6-carboximidamide (101 mg, 496 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1.24 mmol, 216 μL). The mixture was stirred at 20°C for 2 hours and then heated at 120°C for 2 hours. The reaction mixture was cooled and then directly purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-65%, 12 min) to give N-(2-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (46 mg, 101 μmol, 25%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 8.02(s,1H),7.81-7.73(m,3H),7.66(dd,J=0.6,8.4 Hz,1H),7.48-7.42(m,1H),7.42-7.35(m,2H),7.26(br.s.,1H),4.46(d,J=14.1 Hz,1H),4.24(d,J=3.9 Hz,2H),4.01(s,3H),3.86(d,J=13.7 Hz,1H),3.29(ddd,J=3.6,10.5,14.2 Hz,2H),3.13-3.04(m,1H),2.53(s,3H),2.26-2.15(m,2H),2.04-1.89(m,2H);LCMS(ESI)m / z:[M+H] + =459.3.

[0450] Example 41: N-(2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0451] [ka] Step 1: Preparation of 4-fluoro-N-hydroxybenzimidamide.

[0452] [ka] To a stirred solution of 4-fluorobenzonitrile (1.0 g, 8.26 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (1.15 g, 16.5 mmol), triethylamine (1.67 g, 16.52 mmol, 2.29 mL), and water (1 mL). The mixture was heated at 75° C. for 2 hours. After cooling to 20° C., water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give 4-fluoro-N-hydroxybenzimidamide (1.0 g, 6.49 mmol, 79%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.85-7.64 (m, 2H), 7.21 (t, J = 8.9 Hz, 2H), 5.84 (br.s., 2H).

[0453] Step 2: Preparation of N-(2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0454] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) in N,N-dimethylformamide (3 mL) was added 4-fluoro-N-hydroxybenzimidamide (76 mg, 496 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1.24 mmol, 216 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was cooled and then directly purified by preparative HPLC (column: Luna C18 150 × 2.5 mm 5 μm; mobile phase: [water (0.225% FA)-acetonitrile]; B%: 35% to 65%, 12 min) to give N-(2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (56 mg, 135 μmol, 33%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 8.13-8.07(m,2H),7.90-7.86(m,2H),7.58-7.52(m,1H),7.51-7.45(m,2 H),7.35(br.s.,1H),7.23-7.16(m,2H),4.56-4.47(m,1H),4.33(d,J=3.9 Hz,2H),3.93(d,J=13.9 Hz,1H),3.41-3.31(m,2H),3.23-3.13(m,1H),2.33-2.21(m,2H),2.02(ddq,J=4.1,10.5,14.2 Hz,2H);LCMS(ESI)m / z:[M+H] + =409.2.

[0455] Example 42: N-(2-(4-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0456] [ka] Step 1: Preparation of N-(2-(4-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0457] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) in N,N-dimethylformamide (4 mL) was added 3-fluoro-N-hydroxybenzimidamide (76 mg, 496 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1.24 mmol, 216 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was cooled and then directly purified by preparative HPLC (column: Luna C8 100*30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 35%-60%, 12 min) to give N-(2-(4-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (59 mg, 145 μmol, 35%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.85-7.76(m,3H),7.71(d,J=9.3 Hz,1H),7.49-7.35(m,4H),7.26(br.s.,1H),7.15(s,1H),4.43(d,J=13.7 Hz,1H),4.24(d,J=3.5 Hz,2H),3.84(d,J=14.1 Hz,1H),3.33-3.22(m,2H),3.14-3.04(m,1H),2.26-2.13(m,2H),2.00-1.85 ppm(m,2H);LCMS(ESI)m / z:[M+H] + =409.2.

[0458] Example 43: N-(2-(4-(3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0459] [ka] Step 1: Preparation of 2-fluoro-N-hydroxybenzimidamide.

[0460] [ka] To a stirred solution of 2-fluorobenzonitrile (1.0 g, 8.26 mmol, 877 μL) in ethanol (10 mL) was added hydroxylamine hydrochloride (1.15 g, 16.5 mmol), triethylamine (1.67 g, 16.5 mmol, 2.29 mL), and water (1 mL). The mixture was heated at 75° C. for 2 hours. After cooling to 20° C., water (20 mL) was added. The mixture was extracted with dichloromethane (40 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give 2-fluoro-N-hydroxybenzimidamide (1.20 g, 7.79 mmol, 94%) as a white solid. LCMS (ESI) m / z: [M+H] + =155.1.

[0461] Step 2: Preparation of N-(2-(4-(3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0462] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (150 mg, 516.7 μmol) in N,N-dimethylformamide (4 mL) was added 2-fluoro-N-hydroxybenzimidamide (95 mg, 620 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (195 mg, 516.7 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (200 mg, 1.55 mmol, 270 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was cooled and then directly purified by preparative HPLC (column: Luna C8 100*30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-(2-(4-(3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (85 mg, 208.6 μmol, 40%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 7.98(s,1H),7.81-7.75(m,2H),7.48-7.34(m,4H),7.28-7.20(m,2H),7.16(d,J=8.5 Hz,1H),4.42(d,J=14.1 Hz,1H),4.23(d,J=3.9 Hz,2H),3.84(d,J=13.9 Hz,1H),3.29(dt,J=4.1,10.4 Hz,2H),3.14-3.04(m,1H),2.25-2.13(m,2H),2.02-1.86(m,2H);LCMS(ESI)m / z:[M+H] + =409.2.

[0463] Example 44: 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-phenylethanone.

[0464] [ka] Step 1: Preparation of 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-phenylethanone.

[0465] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (150 mg, 518 μmol) in N,N-dimethylformamide (1.50 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1.56 mmol, 271 μL), and 2-phenylacetic acid (74 mg, 544 μmol, 68 μL). The mixture was stirred at 20° C. for 16 hours. The crude product was directly purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 35% to 65%, 12 min) to give 1-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-phenyl-ethanone (24 mg, 59 μmol, 11%) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.63(dd,J=2.0,8.4 Hz,1H),7.55(d,J=1.8 Hz,1H),7.39-7.20(m,5H),7.05(d,J=8.4 Hz,1H),4.49(br d,J=13.5 Hz,1H),4.04(br d,J=13.2 Hz,1H),3.88(s,6H),3.82(s,2H),3.34(br d,J=2.6 Hz,1H),3.29-3.23(m,1H),3.05-2.95(m,1H),2.19-2.11(m,1H),2.06-1.98(m,1H),1.83-1.71(m,1H),1.67-1.54(m,1H);LCMS(ESI)m / z:[M+H] + =408.3.

[0466] Example 45: 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(6-methylpyrazin-2-yl)ethanone.

[0467] [ka] Step 1: Preparation of diethyl 2-(6-methylpyrazin-2-yl)malonate.

[0468] [ka] To a stirred solution of 2-chloro-6-methylpyrazine (1.0 g, 7.78 mmol) in N,N-dimethylformamide (20 mL) was added diethyl malonate (3.12 g, 19.5 mmol, 2.94 mL) and potassium carbonate (2.69 g, 19.5 mmol), and the mixture was stirred at 110 °C for 16 h. The reaction mixture was cooled to 20 °C, quenched with water (20 mL), and then extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (silica, petroleum ether:ethyl acetate = 50:1 to 10:1) afforded diethyl 2-(6-methylpyrazin-2-yl)malonate (180 mg, 713.5 μmol, 9%) as a green oil. 1 H NMR(400 MHz,CDCl3)δ 8.58(s,1H),8.44(s,1H),4.91(s,1H),4.20-4.15(q,J=7.2 Hz,4H),2.58(s,3H),1.25-1.22(t,J=7.2 Hz,6H);LCMS(ESI)m / z:253.1[M+H] + .

[0469] Step 2: Preparation of 2-(6-methylpyrazin-2-yl)acetic acid.

[0470] [ka] To a stirred solution of diethyl 2-(6-methylpyrazin-2-yl)malonate (180 mg, 713.5 μmol) in ethanol (10 mL) was added sodium hydroxide (2 M, 1.96 mL) and the mixture was warmed to 60° C. for 2 hours. The reaction was cooled to 20° C. and acidified with 1 M hydrochloric acid (5 mL). The mixture was concentrated in vacuo to give 2-(6-methylpyrazin-2-yl)acetic acid (1.42 g) as a pale yellow solid, which was used directly without further purification.

[0471] Step 3: Preparation of 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(6-methylpyrazin-2-yl)ethanone.

[0472] [ka] To a stirred solution of 2-(6-methylpyrazin-2-yl)acetic acid (1.05 g, 415 μmol, 6% purity) in N,N-dimethylformamide (4 mL) was added 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (120 mg, 415 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (157 mg, 415 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (214 mg, 1.66 mmol, 289 μL). The mixture was stirred at 20° C. for 4 hours. The reaction mixture was directly purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 25% to 50%, 12 min) to give 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(6-methylpyrazin-2-yl)ethanone (26 mg, 62 μmol, 15%) as a yellow solid. 1H NMR(400 MHz, methanol-d4)δ 8.41(s,2H),7.68(dd,J=1.9,8.3 Hz,1H),7.61(d,J=1.8 Hz,1H),7.10(d,J=8.4 Hz,1H),4.51(d,J=13.4 Hz,1H),4.22(d,J=13.9 Hz,1H),4.12-3.93(m,2H),3.92(s,6H),3.52-3.38(m,2H),3.12-3.02(m,1 H),2.57(s,3H),2.28-2.17(m,2H),2.04-1.80(m,2H);LCMS(ESI)m / z:[M+H] + =424.2.

[0473] Example 46: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)acetamide.

[0474] [ka] Step 1: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)acetamide.

[0475] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (250 mg, 864 μmol) in N,N-dimethylformamide (1.5 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (327 mg, 864 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (335 mg, 2.59 mmol, 452 μL), and 2-acetamidoacetic acid (106 mg, 907 μmol). The mixture was stirred at 20° C. for 16 hours. The crude product was purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 20% to 50%, 12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]acetamide (36 mg, 94 μmol, 11%) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.69(dd,J=1.9,8.3 Hz,1H),7.61(d,J=1.9 Hz,1H),7.10(d,J=8.4 Hz,1H),4.47(br d,J=14.2 Hz,1H),4.21-4.06(m,2H),3.98(br d,J=13.1 Hz,1H),3.92(s,6H),3.47-3.38(m,2H),3.13-3.00(m,1H),2.31-2.16(m,2H),2.05(s,3H),2.00-1.79(m,2H);LCMS(ESI)m / z:[M+H] + =389.2.

[0476] Example 47: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)isobutyramide.

[0477] [ka] Step 1: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)isobutyramide.

[0478] [ka] To a stirred solution of 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (150 mg, 433 μmol) in dichloromethane (3 mL) was added isobutyryl chloride (55 mg, 520 μmol, 54 μL) and triethylamine (131 mg, 1.30 mmol, 180 μL) at 0° C. The mixture was warmed and stirred at 20° C. for 1 h. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by HPLC preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 23%-53%, 12 min) to give N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)isobutyramide (85 mg, 204 μmol, 47%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.74-7.68(m,1H),7.58(d,J=1.9 Hz,1H),6.98(d,J=8.4 Hz,1H),6.63(br.s.,1H),4.49(d,J=13.3 Hz,1H),4.12(d,J=4.0 Hz,2H),3.98(d,J=7.3 Hz,6H),3.87(d,J=14.1 Hz,1H),3.36-3.26(m,2H),3.13(t,J=10.9 Hz,1H),2.50(td,J=6.9,13.8 Hz,1H),2.23(br.s.,2H),2.06-1.92(m,2H),1.22(d,J=6.9 Hz,6H);LCMS(ESI)m / z:[M+H] + =417.3.

[0479] Example 48: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)cyclohexanecarboxamide.

[0480] [ka] Step 1: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)cyclohexanecarboxamide.

[0481] [ka] To a stirred solution of 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (150 mg, 433 μmol) in dichloromethane (3 mL) was added cyclohexanecarbonyl chloride (76 mg, 520 μmol, 69 μL) and triethylamine (131 mg, 1.30 mmol, 180 μL) at 0° C. The mixture was warmed and stirred at 20° C. for 1 h. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 23% to 53%, 12 min) to give N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)cyclohexanecarboxamide (78 mg, 171 μmol, 39%) as a white solid. 1H NMR(400MHz,CDCl3)δ 7.73-7.68(m,1H),7.60-7.57(m,1H),6.98(d,J=8.4 Hz,1H),6.64-6.59(m,1H),4.53-4.45(m,1H),4.11(d,J=4.0 Hz,2H),3.98(d,J=7.2 Hz,6H),3.86(d,J=13.3 Hz,1H),3.36-3.26(m,2H),3.12(t,J=10.7 Hz,1H),2.28-2.18(m,3H),2.05-1.89(m,4H),1.82(d,J=12.3 Hz,2H),1.71(d,J=10.9 Hz,1H),1.54-1.42(m,2H),1.37-1.22(m,3H);LCMS(ESI)m / z:[M+H] + =457.3.

[0482] Example 49: 1-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-(2-phenylethyl)piperidine-4-carboxamide.

[0483] [ka] Step 1: Preparation of tert-butyl 4-(phenethylcarbamoyl)piperidine-1-carboxylate.

[0484] [ka] To a stirred solution of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (1.0 g, 4.36 mmol) in dichloromethane (15 mL) was added 2-phenylethanamine (528 mg, 4.36 mmol, 544 μL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (835 mg, 4.36 mmol), and triethylamine (44 mg, 436 μmol, 60 μL). The mixture was stirred at 20 °C for 5 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by chromatography (silica, 10 / 1 to 1 / 1 petroleum ether / ethyl acetate) to give tert-butyl 4-(2-phenylethylcarbamoyl)piperidine-1-carboxylate (800 mg, 2.41 mmol, 55%) as a white solid. LCMS (ESI) m / z: 355.2 [M+Na] + .

[0485] Step 2: Preparation of N-phenethylpiperidine-4-carboxamide.

[0486] [ka] A solution of tert-butyl 4-(2-phenylethylcarbamoyl)piperidine-1-carboxylate (800 mg, 2.41 mmol) in 4 N hydrochloric acid / ethyl acetate (10 mL) was stirred for 0.5 h at 20° C. The reaction mixture was concentrated in vacuo to give N-(2-phenylethyl)piperidine-4-carboxamide (720 mg) as the hydrochloride salt and as a white solid.

[0487] Step 3: Preparation of 5-chloro-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole.

[0488] [ka] 3-(3,4-Dimethoxyphenyl)-4H-1,2,4-oxadiazol-5-one (900 mg, 4.05 mmol) was added to a mixture of N,N-dimethylformamide (2 mL) and phosphoryl chloride (24.8 g, 161.4 mmol, 15 mL). The mixture was equipped with a calcium chloride tube and heated at 100° C. for 16 hours. The mixture was cooled to 0° C. and concentrated under reduced pressure. The residue was poured into ice water (20 mL) and stirred for 10 minutes, and then the aqueous phase was extracted with dichloromethane (10 mL×5). The combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=5 / 1, 1 / 1) to give 5-chloro-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole (104 mg, 432 μmol, 11%) as a white solid.

[0489] Step 4: Preparation of 1-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine-4-carboxamide.

[0490] [ka] To a stirred solution of 5-chloro-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole (95 mg, 395 μmol) in N-methyl-2-pyrrolidone (2 mL) was added N-(2-phenylethyl)piperidine-4-carboxamide (110 mg, 474 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (102 mg, 790 μmol, 137 μL) at 20° C. The mixture was then heated to 120° C. and stirred for 5 hours. The crude product was purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 25% to 65%, 12 min) to give the compound 1-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-(2-phenylethyl)piperidine-4-carboxamide (117 mg, 266 μmol, 67%) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.57(dd,J=2.0,8.4 Hz,1H),7.51(d,J=1.9 Hz,1H),7.33-7.27(m,2H),7.25-7.18(m,3H),7.06(d,J=8.4 Hz,1H),4.22(br d,J=13.3 Hz,2H),3.90(s,6H),3.44(t,J=7.3 Hz,2H),3.27-3.17(m,2H),2.82(t,J=7.2 Hz,2H),2.51-2.40(m,1H),1.92-1.67(m,4H);LCMS(ESI)m / z:[M+H] + =437.3.

[0491] Example 50: 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one.

[0492] [ka] Step 1: Preparation of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carbonitrile.

[0493] [ka] To a stirred solution of 1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid (1.0 g, 4.29 mmol) in N,N-dimethylformamide (10 mL) was added piperidine-4-carbonitrile (567 mg, 5.15 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (1.63 g, 4.29 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (1.66 g, 12.87 mmol, 2.25 mL). The mixture was stirred at 20° C. for 16 hours. The reaction mixture was quenched with water (10 mL), and then the mixture was extracted with ethyl acetate (20 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a yellow oil (1.6 g). A portion of the crude product (0.3 g) was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 20% to 50%, 12 min) to give 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carbonitrile (144 mg) for analysis. The remainder of the crude product was used directly without purification. 1 H NMR(400 MHz, methanol-d4)δ 7.37(d,J=2.5 Hz,1H),7.31-7.25(m,1H),7.15(d,J=8.2 Hz,1H),4.08(d,J=7.0 Hz,5H),3.59-3.37(m,2H),3.16-3.03(m,1H),2.91-2.79(m,2H),2.28(d,J=10.2 Hz,6H),2.10-1.72(m,4H);LCMS(ESI)m / z:[M+H] + =326.2.

[0494] Step 2: Preparation of (Z)-1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'-hydroxypiperidine-4-carboximidamide.

[0495] [ka] To a stirred solution of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carbonitrile (1.30 g, 4.00 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (555 mg, 8.00 mmol), triethylamine (809 mg, 8.00 mmol, 1.11 mL), and water (1 mL). The mixture was heated at 75° C. for 2 hours. After cooling to 20° C., water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown solid (1.4 g). A portion of the crude product (0.3 g) was purified by preparative HPLC (column: Luna C18 150 × 2.5 mm 5 μm; mobile phase: [water (0.225% TFA)-acetonitrile]; B%: 15% to 40%, 12 min) to give (Z)-1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'-hydroxypiperidine-4-carboximidamide. The remainder was used directly in the next step. 1 H NMR(400 MHz,DMSO-d6)δ 8.86-8.77(m,1H),8.15(s,1H),7.45-7.33(m,2H),7.12(dd,J=8.2,2.4 Hz,1H),5.36(br.s.,2H),4.47-4.32(m,1H),4.06-3.86(m,3H),3.75-3.60(m ,1H),3.07(br.s.,1H),2.80-2.57(m,3H),2.36-2.24(m,1H),2.21(d,J=11.8 Hz,6H),1.83-1.67(m,2H),1.56 ppm(br.s.,2H);LCMS(ESI)m / z:[M+H] + =359.3.

[0496] Step 3: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one.

[0497] [ka] To a stirred solution of (Z)-1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'-hydroxypiperidine-4-carboximidamide (300 mg, 837 μmol) in tetrahydrofuran (8 mL) were added 4-methylbenzoyl chloride (155 mg, 1.00 mmol, 132 μL) and triethylamine (254 mg, 2.51 mmol, 348 μL) at 0°C, and the mixture was then warmed to 20°C. After 3 hours, ethyl acetate and water were added to the reaction mixture, and the organic phase was separated. The organic phase was washed with water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. To the residue were added tetrahydrofuran (8 mL) and tetrabutylammonium fluoride in tetrahydrofuran (1 M, 2.51 mL) solution, and the mixture was then warmed to 50°C for 16 hours. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (column: Luna C18 100*30 5 μm; mobile phase: [water (0.225% TFA)-acetonitrile]; B%: 45% to 75%, 12 min) to give the racemic form of 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one (106 mg, 0.23 mmol, 28%) as a white solid. 1H NMR(400 MHz,CDCl3)δ 8.06-7.99(m,2H),7.41-7.33(m,3H),7.31(d,J=2.0 Hz,1H),7.15(d,J=8.0 Hz,1H),4.60(t,J=13.2 Hz,1H),4.30(dd,J=7.4,9.5 Hz,1H),4.04-3.88(m,2H),3.60(quintet,J=8.5 Hz,1H),3.42-3.31(m,1H),3.25-3.14(m,1H),3.11-2.94(m,2H),2.88-2.78(m ,1H),2.47(s,3H),2.32-2.12(m,8H),2.03-1.86(m,2H);LCMS(ESI)m / z:[M+H] + =459.3.

[0498] Example 51: 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one.

[0499] [ka] Step 1: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one

[0500] [ka] To a stirred solution of (Z)-1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'-hydroxypiperidine-4-carboximidamide (280 mg, 781 μmol) in tetrahydrofuran (8 mL) were added 3-methylbenzoyl chloride (144 mg, 937 μmol, 123 μL) and triethylamine (237 mg, 2.34 mmol, 324 μL) at 0°C, and the mixture was stirred at 20°C for 3 hours. Ethyl acetate and water were added to the reaction mixture, and the organic phase was separated. The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. To the residue were added tetrahydrofuran (8 mL) and tetrabutylammonium fluoride in tetrahydrofuran solution (1 M, 2.34 mL). The mixture was warmed to 50°C and stirred for 16 hours. The reaction mixture was cooled and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Luna C8 100 × 30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40% to 75%, 12 min) to give the racemic 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one (156 mg, 0.34 mmol, 44%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 7.99-7.91(m,2H),7.43(d,J=1.0 Hz,3H),7.32-7.29(m,1H),7.15(d,J=8.3 Hz,1H),4.60(t,J=14.1 Hz,1H),4.30(dd,J=7.3,9.6 Hz,1H),4.04-3.88(m,2H),3.65-3.54(m,1H),3.37(d,J=7.0 Hz,1H),3.21(d,J=3.5 Hz,1H),3.11-2.94(m,2H),2.88-2.78(m,1H),2.48(s,3H),2.32-2.13(m,8H),1.93(d,J=12.2 Hz,2H);LCMS(ESI)m / z:[M+H] + =459.3.

[0501] Example 52: (4-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)(4-isopropylphenyl)methanone.

[0502] [ka] Step 1: Preparation of 1-(4-isopropylbenzoyl)piperidine-4-carbonitrile.

[0503] [ka] To a stirred solution of 4-isopropylbenzoic acid (1.0 g, 6.09 mmol) in N,N-dimethylformamide (10 mL) was added piperidine-4-carbonitrile (805 mg, 7.31 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (2.31 g, 6.09 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (2.36 g, 18.27 mmol, 3.19 mL). The mixture was stirred at 20° C. for 16 hours. The reaction mixture was quenched with water (10 mL), and then the mixture was extracted with ethyl acetate (40 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and HCl. 、 Filtration and concentration gave a yellow oil (1.8 g). A portion of the crude product (0.2 g) was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 25% to 55%, 12 min) to give 1-(4-isopropylbenzoyl)piperidine-4-carbonitrile (115 mg) as a sample for analysis. The remainder was used directly. 1 H NMR(400 MHz, methanol-d4)δ 7.37(s,4H),4.16-3.40(m,4H),3.15-3.07(m,1H),3.02-2.93(m,1H),2.10-1.76(m,4H),1.31-1.26(m,6H);LCMS(ESI)m / z:[M+H]+ =257.2.

[0504] Step 2: Preparation of N-hydroxy-1-(4-isopropylbenzoyl)piperidine-4-carboximidamide.

[0505] [ka] To a stirred solution of 1-(4-isopropylbenzoyl)piperidine-4-carbonitrile (1.60 g, 6.24 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (867 mg, 12.5 mmol), triethylamine (1.26 g, 12.48 mmol, 1.73 mL), and water (1.50 mL). The mixture was heated at 75° C. for 2 hours. After cooling to 20° C., water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give N-hydroxy-1-(4-isopropylbenzoyl)piperidine-4-carboximidamide (1.60 g, 5.53 mmol, 89%) as a white solid, which was used directly without further purification. 1 H NMR (400 MHz, methanol-d₄) δ 7.40-7.33 (m, 4H), 4.78-4.58 (m, 1H), 3.94-3.73 (m, 1H), 3.22 (d, J = 7.3 Hz, 2H), 3.02-2.95 (m, 1H), 2.50-2.35 (m, 1H), 1.96-1.67 (m, 4H), 1.31-1.27 (m, 6H).

[0506] Step 3: Preparation of (4-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)(4-isopropylphenyl)methanone.

[0507] [ka] To a stirred solution of N-hydroxy-1-(4-isopropylbenzoyl)piperidine-4-carboximidamide (200 mg, 691 μmol) in tetrahydrofuran (5 mL) was added 3-fluorobenzoyl chloride (131 mg, 829 μmol, 99 μL) and triethylamine (209 mg, 2.07 mmol, 287 μL) at 0° C. The mixture was warmed and then stirred at 20° C. for 16 hours. Ethyl acetate and water were added to the reaction mixture, and the organic phase was separated. The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. To the resulting residue was added tetrahydrofuran (5 mL) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 2.07 mL), and the mixture was then warmed at 50° C. for 16 hours. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 50% to 80%, 12 min) to give (4-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)(4-isopropylphenyl)methanone (76 mg, 193.5 μmol, 28%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 7.85(d,J=7.7 Hz,1H),7.78-7.72(m,1H),7.45(dt,J=5.6,8.0 Hz,1H),7.32-7.27(m,2H),7.26-7.20(m,2H),7.18(s,1H),4.76-3.64(m,2H),3.20-2.97(m,3H),2.86(td,J=6.9,13.8 Hz,1H),2.18-1.74(m,4H),1.19(d,J=6.9 Hz,6H);LCMS(ESI)m / z:[M+H] + =394.2.

[0508] Example 53: (4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1-yl)methanone.

[0509] [ka] Step 1: Preparation of 4-ethoxy-3-methoxybenzonitrile.

[0510] [ka] To a stirred solution of 4-hydroxy-3-methoxybenzonitrile (5.0 g, 33.5 mmol) in N,N-dimethylformamide (50 mL) was added iodoethane (6.27 g, 40.2 mmol, 3.22 mL) and potassium carbonate (9.27 g, 67.0 mmol) at 0 °C, and the reaction was then warmed and stirred at 40 °C for 16 h. The reaction mixture was quenched by the addition of water (50 mL), and the mixture was then extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-ethoxy-3-methoxybenzonitrile (5.80 g, 32.7 mmol, 98%) as a white solid. 1 H NMR(400 MHz, CDCl3)δ 7.20-7.16(m,1H),7.00(d,J=1.9 Hz,1H),6.81(d,J=8.4 Hz,1H),4.07(q,J=6.9 Hz,2H),3.82(s,3H),1.45-1.39(m,3H).

[0511] Step 2: Preparation of (Z)-4-ethoxy-N'-hydroxy-3-methoxybenzimidamide.

[0512] [ka] To a stirred solution of 4-ethoxy-3-methoxybenzonitrile (5.80 g, 32.7 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (4.55 g, 65.5 mmol), triethylamine (6.62 g, 65.46 mmol, 9.07 mL), and water (5 mL). The mixture was heated at 75° C. for 2 hours. After cooling to 20° C., the solvent was evaporated under vacuum, and water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (60 mL × 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum to give (Z)-4-ethoxy-N'-hydroxy-3-methoxybenzimidamide (5.96 g, 28.4 mmol, 87%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.44(br.s.,1H),7.28-7.14(m,2H),6.90(d,J=8.4 Hz,1H),5.73(s,2H),4.00(q,J=6.9 Hz,2H),3.75(s,3H),1.31(t,J=7.1 Hz,3H).

[0513] Step 3: Preparation of tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate.

[0514] [ka] To a stirred solution of (Z)-4-ethoxy-N'-hydroxy-3-methoxybenzimidamide (1.0 g, 4.76 mmol) in N,N-dimethylformamide (15 mL) was added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.09 g, 4.76 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (1.81 g, 4.76 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (1.85 g, 14.28 mmol, 2.49 mL). The mixture was stirred at 20°C for 16 hours and then heated at 120°C for 2 hours. The reaction mixture was cooled and then quenched by the addition of water (40 mL), and the mixture was then extracted with ethyl acetate (80 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (2.56 g) as a yellow oil. LCMS (ESI) m / z: [M+H] + =404.3.

[0515] Step 4: Preparation of 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole.

[0516] [ka] To a stirred solution of tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (1.0 g, 2.48 mmol) in methanol (5 mL) was added 4 M methanolic hydrochloric acid (20 mL). The mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give crude 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (900 mg) as a yellow solid, which was used directly without further purification. LCMS (ESI) m / z: [M+H]+ =304.1

[0517] Step 5: Preparation of (4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1-yl)methanone

[0518] [ka] To a stirred solution of 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (200 mg, 659 μmol) in dichloromethane (3 mL) was added piperidine-1-carbonyl chloride (116 mg, 791 μmol, 98 μL) and triethylamine (200 mg, 1.98 mmol, 274 μL) at 0° C. The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40% to 70%, 12 min) to give (4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1-yl)methanone (65 mg, 158 μmol, 24%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 7.71-7.66(m,1H),7.59(d,J=1.9 Hz,1H),6.96(d,J=8.4 Hz,1H),4.19(q,J=6.9 Hz,2H),3.98(s,3H),3.75(d,J=13.6 Hz,2H),3.29-3.13(m,5H),3.04-2.94(m,2H),2.17(dd,J=3.1,13.3 Hz,2H),2.05-1.93(m,2H),1.60(d,J=8.4 Hz,6H),1.53(t,J=7.0 Hz,3H);LCMS(ESI)m / z:[M+H] + =415.3.

[0519] Example 54: (4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1-yl)methanone.

[0520] [ka] Step 1: Preparation of (4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1-yl)methanone.

[0521] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (100 mg, 346 μmol) in dichloromethane (3 mL) was added piperidine-1-carbonyl chloride (61 mg, 415 μmol, 51 μL) and triethylamine (104 mg, 1.04 mmol, 143 μL) at 0° C. The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 35% to 65%, 12 min) to give (4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1-yl)methanone (81 mg, 202 μmol, 58%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.74-7.68(m,1H),7.59(d,J=1.9 Hz,1H),6.98(d,J=8.4 Hz,1H),3.98(d,J=8.4 Hz,6H),3.76(d,J=13.4 Hz,2H),3.29-3.14(m,5H),3.04-2.95(m,2H),2.17(dd,J=13.3,3.4 Hz,2H),2.05-1.94(m,2H),1.60 ppm(d,J=8.5 Hz,6H);LCMS(ESI)m / z:[M+H] +=401.3.

[0522] Example 55: 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(isoquinolin-1-ylamino)ethanone.

[0523] [ka] Step 1: Preparation of 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(isoquinolin-1-ylamino)ethanone.

[0524] [ka] To a stirred solution of 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (150 mg, 433 μmol) in toluene (2 mL) under nitrogen was added 1-chloroisoquinoline (70 mg, 433 μmol), cesium carbonate (423 mg, 1.30 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (26 mg, 43 μmol, 0.10 equiv.), and palladium(II) acetate (9 mg, 43 μmol, 0.10 equiv.). The mixture was stirred at 100° C. for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (column: Luna C8 100*30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40%-70%, 12 min) to give 1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(isoquinolin-1-ylamino)ethanone (57 mg, 119 μmol, 27%) as a white solid. 1H NMR(400MHz,CDCl3)δ 8.04-7.96(m,2H),7.75-7.50(m,5H),7.03-6.95(m,2H),6.66(br.s.,1H),4.60(d,J=13.7 Hz,1H),4.45(br.s.,2H),4.08(d,J=12.5 Hz,1H),3.98(d,J=7.9 Hz,6H),3.46-3.30(m,2H),3.24-3.13(m,1H),2.28(br.s.,2H),2.13-1.97(m,2H);LCMS(ESI)m / z:[M+H] + =474.3.

[0525] Example 56: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)-2-oxoethyl)benzamide.

[0526] [ka] Step 1: Preparation of 5-chloro-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole.

[0527] [ka] To a mixture of N,N-dimethylformamide (1 mL) and phosphoryl chloride (8.25 g, 53.8 mmol, 5 mL) was added 3-(3,4-dimethoxyphenyl)-4H-1,2,4-oxadiazol-5-one (300 mg, 1.35 mmol) under a calcium chloride tube at 25°C. The mixture was heated to 100°C and stirred for 16 hours. The mixture was cooled to 25°C and carefully concentrated in vacuo. The residue was poured into ice water (20 mL) and stirred for 10 minutes. The aqueous phase was extracted with dichloromethane (10 mL x 5). The combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give 5-chloro-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole (99 mg, 414 μmol, 31%) as a white solid. LCMS (ESI) m / z: 241.1 [M+H] + .

[0528] Step 2: Preparation of tert-butyl 4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazine-1-carboxylate.

[0529] [ka] To a stirred solution of 5-chloro-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole (90 mg, 374 μmol) and tert-butyl piperazine-1-carboxylate (83 mg, 448.80 μmol) in N-methyl-2-pyrrolidone (1.50 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (96 mg, 748 μmol, 130 μL). The mixture was stirred at 120° C. for 2 hours. The mixture was cooled to 25° C. and concentrated under vacuum at 40° C. The residue was poured into water (10 mL), and the aqueous phase was then extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperazine-1-carboxylate (900 mg), which was used directly without further purification.

[0530] Step 3: Preparation of 3-(3,4-dimethoxyphenyl)-5-(piperazin-1-yl)-1,2,4-oxadiazole.

[0531] [ka] A solution of tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperazine-1-carboxylate (146 mg, 374 μmol) in hydrochloric acid / ethyl acetate (4 M, 10 mL) was stirred for 2 hours at 20° C. The reaction mixture was concentrated in vacuo to give 3-(3,4-dimethoxyphenyl)-5-piperazin-1-yl-1,2,4-oxadiazole hydrochloride (900 mg), which was used directly without further purification.

[0532] Step 4: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl)-2-oxoethyl)benzamide.

[0533] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-piperazin-1-yl-1,2,4-oxadiazole hydrochloride (667 mg, 306 μmol) and 2-benzamidoacetic acid (137 mg, 765 μmol) in N,N-dimethylformamide (2 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (174 mg, 459 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (118 mg, 918.51 μmol, 160 μL) at 20° C. The mixture was stirred at 20° C. for 5 hours. The reaction mixture was directly purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 25% to 60%, 12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperazin-1-yl]-2-oxo-ethyl]benzamide (55 mg, 121 μmol, 39%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=8.59(br t,J=5.6 Hz,1H),7.93-7.83(m,2H),7.60-7.44(m,4H),7.39(d,J=1.9 Hz,1H),7.08(d,J=8.5 Hz,1H),4.20(d,J=5.6 Hz,2H),3.81(d,J=1.1 Hz,6H),3.73-3.58(m,8H);LCMS(ESI)m / z:[M+H] + =452.2.

[0534] Example 57: (1-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1-yl)methanone.

[0535] [ka] Step 1: Preparation of tert-butyl 4-(piperidine-1-carbonyl)piperidine-1-carboxylate.

[0536] [ka] To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 4.36 mmol) in N,N-dimethylformamide (15 mL) was added piperidine (445 mg, 5.23 mmol, 518 μL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.99 g, 5.23 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (1.69 g, 13.1 mmol, 2.29 mL). The mixture was stirred at 20° C. for 3 hours. The reaction mixture was quenched by the addition of water (20 mL), and then the mixture was extracted with ethyl acetate (40 mL x 4). The combined organic phases were then washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 4-(piperidine-1-carbonyl)piperidine-1-carboxylate (1.90 g) as a yellow oil, which was used directly without further purification. LCMS (ESI) m / z: [M+H] + =297.2

[0537] Step 2: Preparation of piperidin-1-yl(piperidin-4-yl)methanone.

[0538] [ka] To a stirred solution of tert-butyl 4-(piperidine-1-carbonyl)piperidine-1-carboxylate (500 mg, 1.69 mmol) in methanol (5 mL) was added 4N hydrogen chloride in methanol (15 mL). The mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give piperidin-1-yl(piperidin-4-yl)methanone (400 mg) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 3.51-3.36 (m, 4H), 3.28-3.18 (m, 2H), 2.90 (s, 4H), 1.82-1.68 (m, 4H), 1.64-1.37 (m, 6H).

[0539] Step 3: Preparation of 3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one.

[0540] [ka] To a stirred solution of 4-ethoxy-N-hydroxy-3-methoxybenzimidamide (800 mg, 3.81 mmol) in dioxane (8 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (638 mg, 4.19 mmol, 631 μL) and 1,1′-carbonyldiimidazole (926 mg, 5.72 mmol). The mixture was stirred at 110° C. for 16 hours. The reaction mixture was quenched by the addition of water (10 mL), and then the mixture was extracted with dichloromethane (50 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography (silica, dichloromethane:methanol=50:1) gave 3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (1.20 g, quant.) as a yellow oil. LCMS (ESI) m / z: [M+H] + =237.1.

[0541] Step 4: Preparation of 5-chloro-3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazole.

[0542] [ka] A stirred mixture of 3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (500 mg, 2.12 mmol) and N,N-dimethylformamide (1 mL) was equipped with a calcium chloride tube and phosphoryl chloride (10 mL) was added dropwise. The mixture was heated at 110° C. for 16 hours. The reaction mixture was cooled to 20° C., then poured into ice water (100 mL) and stirred for 30 minutes. The mixture was extracted with dichloromethane (20 mL×5), and the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-chloro-3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazole (360 mg, 1.41 mmol, 67%) as a brown solid. LCMS (ESI) m / z: [M+H] + =255.1

[0543] Step 5: Preparation of (1-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1-yl)methanone.

[0544] [ka] To a stirred solution of piperidin-1-yl(piperidin-4-yl)methanone (100 mg, 509 μmol) in N-methyl-2-pyrrolidone (4 mL) was added 5-chloro-3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazole (194 mg, 764 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (131 mg, 1.02 mmol, 177 μL). The mixture was stirred at 120° C. for 16 hours. The reaction mixture was directly purified by preparative HPLC (column: Luna C8 100*30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 35%-65%, 12 min) to give (1-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1-yl)methanone (61 mg, 147.6 μmol, 29%) as a yellow solid.1 H NMR(400 MHz,CDCl3)δ 7.53-7.47(m,1H),7.42(d,J=1.9 Hz,1H),6.84(d,J=8.5 Hz,1H),4.24-4.16(m,2H),4.08(q,J=6.9 Hz,2H),3.87(s,3H),3.50(br.s.,2H),3.40(br.s.,2H),3.19-3.09(m,2H),2.69(tt,J=3.8,10.7 Hz,1H),1.94-1.71(m,4H),1.63-1.48(m,6H),1.42(t,J=7.0 Hz,3H);LCMS(ESI)m / z:[M+H] + =415.3.

[0545] Example 58: N-(2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide.

[0546] [ka] Step 1: N-(2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide.

[0547] [ka] To a stirred solution of 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (150 mg, 471 μmol) and N-hydroxy-2-methoxybenzimidamide (78 mg, 471 μmol) in N,N-dimethylformamide (2 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (121 mg, 942 μmol, 164 μL) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (178 mg, 471 μmol) at 15° C. The mixture was stirred for 15 hours, then the mixture was heated to 110° C. and stirred for 5 hours. The mixture was cooled and then purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 37%-67%, 12 min) to give N-(2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4-dimethylbenzamide (110 mg, 244 μmol, 52%) as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ7.96(dd,J=1.5,7.7 Hz,1H),7.66(s,1H),7.60(d,J=7.9 Hz,1H),7.56-7.49(m,1H),7.23(d,J=7.5 Hz,1H),7.18(d,J=8.4 Hz,1H),7.09(t,J=7.5 Hz,1H),4.47(d,J=12.8 Hz,1H),4.35-4.23(m,2H),4.04(d,J=13.7 Hz,1H),3.92(s,3H),3.49-3.35(m,2H),3.07(t,J=11.0 Hz,1H),2.32(s,6H),2.27-2.10(m,2H),2.06-1.83(m,2H);LCMS(ESI)m / z:[M+H] + =449.3.

[0548] Example 59: N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2-oxo-ethyl]benzamide, optical isomer 1 and Example 60: N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2-oxo-ethyl]benzamide, optical isomer 2

[0549] [ka] Step 1: Preparation of N-[(R)-2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2-oxo-ethyl]benzamide and N-[(S)-2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2-oxo-ethyl]benzamide.

[0550] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (150 mg, 518 μmol) and 2-benzamidopropanoic acid (105 mg, 544 μmol) in N,N-dimethylformamide (2 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1.56 mmol, 271 μL). The mixture was stirred at 20° C. for 5 hours. The crude product was purified by preparative HPLC (column: Luna C18 150×25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 35%-65%, 12 min) to give rac-N-(1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-1-oxopropan-2-yl)benzamide, and the product was then purified by SFC separation (column: AD (250×30 mm, 5 μm); mobile phase: [Neu-IPA]; B%: 42%-42%, min) to give N-[2- [4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2-oxo-ethyl]benzamide, enantiomer 1 (63 mg, 134.93 μmol, 26%) was obtained as a white solid, and N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2-oxo-ethyl]benzamide, enantiomer 2 (56 mg, 120 μmol, 23%) was obtained as a white solid.

[0551] N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2-oxo-ethyl]benzamide, enantiomer 1: 1H NMR(400MHz,DMSO-d6)δ=8.63(br dd,J=7.3,16.1 Hz,1H),7.88(br d,J=7.5 Hz,2H),7.62-7.41(m,5H),7.11(br d,J=8.2 Hz,1H),4.97(br d,J=6.4 Hz,1H),4.43-4.24(m,1H),4.10-3.95(m,1H),3.82(s,6H),3.42(br t,J=10.8 Hz,1H),3.30-3.21(m,1H),2.99-2.83(m,1H),2.09(br d,J=11.9 Hz,2H),1.83-1.60(m,2H),1.30(br s,3H);LCMS(ESI)m / z:[M+H] + =465.3. Mirror image excess rate = 100%.

[0552] N-[2-[4-[3-(3,4-ジメトキシフェニル)-1,2,4-オキサジアゾール-5 -イル]-1-ピペリジル]-1-メチル-2-オキソ-エチル]ベンズアミド, optical anomaly 2: 1 H NMR(400MHz,DMSO-d6)δ=8.65(br dd,J=7.6,16.1 Hz,1H),7.98-7.86(m,2H),7.70-7.41(m,5H),7.13(br d,J=8.2 Hz,1H),5.00(br d,J=5.5 Hz,1H),4.49-4.24(m,1H),4.12-3.96(m,1H),3.85(s,6H),3.45(br t,J=10.7 Hz,1H),3.27(br s,1H),3.05-2.83(m,1H),2.12(br d,J=12.5 Hz,2H),1.89-1.61(m,2H),1.32(br s,3H);LCMS(ESI)m / z:[M+H] + =465.3. Mirror image excess rate = 99.6

[0553] Example 61: (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-1-yl)phenyl)methylium, enantiomer 1 and Example 62: (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-1-yl)phenyl)methylium, enantiomer 2

[0554] [ka] Step 1: Preparation of (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-1-yl)phenyl)methylium, enantiomer 1 and (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-1-yl)phenyl)methylium, enantiomer 2.

[0555] [ka] To a stirred solution of N-hydroxy-4-methylbenzimidamide (300 mg, 2.0 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (834 mg, 2.20 mmol), and 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (688 mg, 2.00 mmol) in N,N-dimethylformamide (10 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (516 mg, 4.00 mmol, 698 μL) at 0° C. The reaction was then warmed to 25° C. After 17 hours, the reaction was warmed to 90° C. After 3 hours, the mixture was cooled, diluted with water (10 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue, which was purified by preparative HPLC (column: Phenomenex luna(2) C18 250 × 50 10 μm; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 40% to 70%, 20 min) to give the racemic 1-(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one (600 mg, 1.31 mmol, 65%). This was purified by SFC (column: AS (250 × 30 mm, 5 μm); mobile phase: [CO base-methanol]; B%: 40%-40%) to give (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-1-yl)phenyl)methylium, enantiomer 1 (193 mg, 421 μmol, 21%) as a white solid and (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-1-yl)phenyl)methylium, enantiomer 2 (199 mg, 433 μmol, 22%) as a white solid.

[0556] (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-1-yl)phenyl)methylium, enantiomer 1: 1 H NMR(400MHz,DMSO-d6)δ=7.91(br d,J=6.9 Hz,2H),7.43(br s,1H),7.38(br d,J=8.0 Hz,3H),7.12(br d,J=6.3 Hz,1H),4.35(br s,1H),4.09-3.98(m,2H),3.92(td,J=5.0,10.0 Hz,1H),3.80-3.63(m,1H),3.45(br t,J=10.8 Hz,1H),3.36(br s,1H),3.00-2.90(m,1H),2.82-2.65(m,2H),2.39(s,3H),2.27-2.10(m,8H),1.91-1.61(m,2H);LCMS(ESI)m / z:[M+H] += 459.3; enantiomeric excess = 98.6

[0557] (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-1-yl)phenyl)methylium, enantiomer 2: 1 H NMR(400MHz,DMSO-d6)δ=7.91(br d,J=6.9 Hz,2H),7.43(br s,1H),7.38(br d,J=8.0 Hz,3H),7.12(br d,J=6.4 Hz,1H),4.35(br s,1H),4.11-3.97(m,2H),3.92(td,J=5.0,9.9 Hz,1H),3.81-3.68(m,1H),3.53-3.37(m,1H),3.36(br s,1H),3.02-2.90(m,1H),2.82-2.65(m,2H),2.39(s,3H),2.25-2.09(m,8H),1.89-1.62(m,2H);LCMS(ESI)m / z:[M+H] + = 459.3; enantiomeric excess = 99%.

[0558] Example 63: 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1 and Example 64: 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2

[0559] [ka] Step 1: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1 and 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2.

[0560] [ka] To a stirred solution of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (350 mg, 1.02 mmol) and N-hydroxy-4-methoxybenzimidamide (168 mg, 1.02 mmol) in N,N-dimethylformamide (3 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (262 mg, 2.03 mmol, 354 μL) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (385 mg, 1.02 mmol), and the mixture was stirred at 15° C. for 15 hours. The mixture was then heated to 110° C. and stirred for 5 hours. The mixture was cooled and purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 37%-67%, 12 min) to give racemic 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one (0.2 g) as a white solid. This was purified by SFC separation: (Column: OJ (250 × 30 mm, 10 μm); Mobile phase: [CO base-ethanol]; B%: 45%-45%) to give ((1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1 (84 mg, 177 μmol, 17%) as a white solid and 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2 (96 mg, 198 μmol, 19%) as a yellow solid.

[0561] 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1: 1H NMR(400 MHz, methanol-d4)δ 7.98(dd,J=2.2,8.8 Hz,2H),7.36(s,1H),7.27(d,J=7.9 Hz,1H),7.13(d,J=8.4 Hz,1H),7.04(d,J=7.1 Hz,2H),4.53-4.43(m,1H),4.18-3.99(m,3H),3.95-3.73(m,4H),3.49-3.36(m,2H),3.14- 3.01(m,1H),2.93-2.77(m,2H),2.47-2.04(m,8H),2.01-1.80(m,2H);LCMS(ESI)m / z:[M+H] + = 475.3; enantiomeric excess = 100%.

[0562] 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2: 1 H NMR(400 MHz, methanol-d4)δ 7.98(dd,J=2.4,9.0 Hz,2H),7.36(s,1H),7.27(d,J=8.4 Hz,1H),7.13(d,J=8.4 Hz,1H),7.04(d,J=7.1 Hz,2H),4.48(d,J=7.5 Hz,1H),4.16-4.00(m,3H),3.92-3.74(m,4H),3.49-3.37(m,2H),3.13-3.03(m,1 H),2.91-2.80(m,2H),2.34-2.11(m,8H),1.98-1.83(m,2H);LCMS(ESI)m / z:[M+H] + = 475.3; enantiomeric excess = 100%.

[0563] Example 65: (4S)-4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one

[0564] [ka] Step 1: (4R)-4-benzyl-3-[(3S)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]oxazolidin-2-one

[0565] [ka] To a stirred solution of 5-oxo-1-phenyl-pyrrolidine-3-carboxylic acid (20.0 g, 97.5 mmol) in chloroform (100 mL) was added (4R)-4-benzyloxazolidin-2-one (20.72 g, 117 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (20.74 g, 108.2 mmol), and DMAP (6.43 g, 52.6 mmol) at 0° C. After the addition, the mixture was stirred for 15 minutes, then warmed and stirred at 20° C. for 18 hours. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate = 1 / 1 to 1:9) to give (4R)-4-benzyl-3-[(3S)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]oxazolidin-2-one (10.0 g, 27.4 mmol, 28%) and (4R)-4-benzyl-3-[(3R)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]oxazolidin-2-one (10.0 g, 27 mmol, 28%) as white solids, respectively. LCMS (ESI) m / z: 365.1 [M+H] + .

[0566] Step 2: (3S)-5-oxo-1-phenyl-pyrrolidine-3-carboxylic acid

[0567] [ka] To a stirred solution of lithium hydroxide monohydrate (2.63 g, 62.8 mmol) in water (30 mL) was added hydrogen peroxide (15.5 g, 456.6 mmol, 13.2 mL) dropwise at 0° C. The mixture was stirred for 30 minutes. To the mixture was then added tetrahydrofuran (80 mL), water (30 mL), followed by dropwise addition of a solution of 3-[(3S)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]-4-phenyl-oxazolidin-2-one (10.0 g, 28.5 mmol) in tetrahydrofuran (80 mL). The mixture was stirred at 0° C. for 1 hour, quenched at 0° C. by adding a solution of sodium sulfate in water (10 mL), and made basic (pH 11) by adding aqueous sodium carbonate. The mixture was extracted with ethyl acetate (100 mL), acidified to pH 2 with 1 M HCl, and extracted again with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (3S)-5-oxo-1-phenyl-pyrrolidine-3-carboxylic acid (4.80 g, 23.39 mmol, 82%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.57 (dd, J = 0.9, 8.6 Hz, 2H), 7.40-7.34 (m, 2H), 7.20-7.15 (m, 1H), 4.18-4.13 (m, 1H), 4.10-4.04 (m, 1H), 3.45-3.35 (m, 1H), 3.03-2.86 (m, 2H).

[0568] Step 3: Methyl 1-[(3S)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylate

[0569] [ka] A mixture of (3S)-5-oxo-1-phenyl-pyrrolidine-3-carboxylic acid (4.50 g, 21.93 mmol), methyl piperidine-4-carboxylate (3.77 g, 26.32 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (27.91 g, 43.86 mmol, 26.08 mL, 50% purity) in ethyl acetate, and triethylamine (44.38 g, 438.60 mmol, 60 mL) in dichloromethane (60 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 20° C. for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL). The organic layer was washed with saturated aqueous sodium chloride solution (50 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography (silica, petroleum ether / ethyl acetate=1:1) to give methyl 1-[(3S)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylate (4.70 g, 14.2 mmol, 65%) as a white solid. 1 H NMR(400MHz,chloroform-d)δ 7.56(d,J=7.7 Hz,2H),7.35(t,J=7.5 Hz,2H),7.16-7.11(m,1H),4.47-4.34(m,1H),4.24(dd,J=7.3,9.5 Hz,1H),3.91-3.81(m,2H),3.69(s,3H),3.52(quintet,J=8.5 Hz,1H),3.24-3.12(m,1H),2.98-2.87(m,2H),2.80-2.73(m,1H),2.64-2.52(m,1H),1.97(br dd,J=4.3,8.3 Hz,2H),1.73-1.63(m,2H).

[0570] Step 4: 1-[(3S)-5-Oxo-1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid.

[0571] [ka] To a stirred solution of methyl 1-[(3S)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylate (3.00 g, 9.08 mmol) in tetrahydrofuran (60 mL) was added a solution of lithium hydroxide monohydrate in water (0.5 M, 21.79 mL). The mixture was then stirred at 0 °C for 2 hours. The mixture was acidified to pH 4-5 with 1 M HCl and then extracted with dichloromethane (60 mL; 30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL; 20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-[(3S)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (2.70 g, 8.53 mmol, 94%) as a white solid.

[0572] Step 5: (4S)-4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one

[0573] [ka] A mixture of N'-hydroxy-3,4-dimethoxy-benzamidine (1.04 g, 5.32 mmol), 1-[(3S)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (1.40 g, 4.43 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (2.18 g, 5.76 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (1.72 g, 13.29 mmol, 2.32 mL) in N,N-dimethylformamide (8.00 mL) was stirred at 20°C for 15 hours and at 110°C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (Phenomenex Luna C18 250 × 50 mm × 10 μm column; mobile phase: water / 10 mM ammonium carbonate / acetonitrile; B%: 30% to 60%, 30 min). The desired compound (4S)-4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one (608 mg, 1.28 mmol, 29%) was isolated as a pale yellow solid. 1 H NMR(400MHz,chloroform-d)δ 7.68(br d,J=8.2 Hz,1H),7.61-7.53(m,3H),7.40-7.33(m,2H),7.18-7.12(m,1H),6.95(d,J=8.4 Hz,1H),4.61-4.46(m,1H),4.30(dd,J=7.2,9.6 Hz,1H),4.01-3.92(m,8H),3.57(quintet,J=8.4 Hz,1H),3.43-3.26(m,2H),3.14-2.91(m,2H),2.86-2.80(m,1H),2.23(br t,J=13.1 Hz,2H),2.02-1.93(m,2H);LCMS(ESI)m / z:[M+H] + =477.3.

[0574] Example 66 [(4R)-4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one]

[0575] [ka] Step 1: Preparation of (4R)-4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one.

[0576] [ka] To a stirred solution of 1-[(3R)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (115 mg, 363.52 μmol) and N′-hydroxy-3,4-dimethoxy-benzamidine (71 mg, 363.52 μmol) in N,N-dimethylformamide (500 μL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (137 mg, 363.52 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (93 mg, 727 μmol, 126 μL) at 25° C. The mixture was then stirred at 25° C. for 2 hours and at 110° C. for 2 hours. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by chromatography (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: water / ammonium carbonate (10 mM) / acetonitrile; B%: 25% to 60%, 12 min) to give (4R)-4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one (32 mg, 67.45 μmol, 19%) as a yellow solid. 1H NMR(400MHz,chloroform-d)δ=7.68(br d,J=8.2 Hz,1H),7.61-7.55(t,3H),7.37(t,J=7.8 Hz,2H),7.19-7.14(t,1H),6.95(d,J=8.4 Hz,1H),4.60-4.46(m,1H),4.31(dd,J=7.2,9.6 Hz,1H),3.98-3.94(m,7H),3.98-3.92(m,1H),3.58(quintet,J=8.5 Hz,1H),3.43-3.26(m,2H),3.16-2.91(m,2H),2.88-2.79(m,1H),2.24(br t,J=13.3 Hz,2H),2.06-1.88(m,2H);LCMS(ESI)m / z:[M+H] + =477.3.

[0577] Example 67: 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-(3,4-dimethylphenyl)pyrrolidin-2-one, enantiomer 1 and Example 68: 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-(3,4-dimethylphenyl)pyrrolidin-2-one, enantiomer 2. Step 1: Preparation of 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-(3,4-dimethylphenyl)pyrrolidin-2-one

[0578] [ka] To a stirred solution of 1-[1-(3,4-dimethylphenyl)-5-oxo-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (351 mg, 1.02 mmol) in N,N-dimethylformamide (1.50 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (386 mg, 1.02 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (395 mg, 3.06 mmol, 534 μL), and N-hydroxy-3,4-dimethoxy-benzamidine (200 mg, 1.02 mmol). The mixture was stirred at 20° C. for 12 hours. The reaction mixture was then diluted with water (5 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. N,N-Dimethylformamide (2 mL) was added to the residue, and the resulting mixture was heated at 120 °C for 5 hours. The mixture was cooled to 25 °C, diluted by adding water (5 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge 150 × 25 μm; mobile phase: water / ammonium carbonate (10 mM) / acetonitrile; B%: 33% to 63%, 12 min) to give racemic 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-(3,4-dimethylphenyl)pyrrolidin-2-one. This was separated by chiral SFC (column: AS (250 × 30 mm, 10 μm); mobile phase: [CO2 base-methanol]; B%: 40%-40%, min) to initially give 4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-(3,4-dimethylphenyl)pyrrolidin-2-one, enantiomer 1 (51 mg, 102 μmol, 10%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=7.61(br d,J=8.4 Hz,1H),7.48(s,1H),7.43(br s,1H),7.38(br d,J=7.5 Hz,1H),7.16-7.10(m,2H),4.37(br s,1H),4.08-3.99(m,2H),3.96-3.88(m,1H),3.85(s,6H),3.79-3.67(m,1H),3.45(br t,J=10.8 Hz,1H),3.32-3.28(m,1H),3.02-2.87(m,1H),2.82-2.70(m,2H),2.24-2.18(m,6H),2.18-2.10(m,2H),1.91-1.61(m,2H);LCMS(ESI)m / z:[M+H] + = 505.4, and secondly, 4-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-(3,4-dimethylphenyl)pyrrolidin-2-one, enantiomer 2 (48 mg, 95 μmol, 9%) was also obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=7.61(br d,J=8.4 Hz,1H),7.48(s,1H),7.43(br s,1H),7.41-7.35(m,1H),7.17-7.10(m,2H),4.37(br s,1H),4.09-3.99(m,2H),3.98-3.89(m,1H),3.85(s,6H),3.78-3.68(m,1H),3.50-3.39(m,1H),3.35(br s,1H),3.00-2.88(m,1H),2.81-2.70(m,2H),2.26-2.19(m,6H),2.17-2.09(m,2H),1.88-1.63(m,2H);LCMS(ESI)m / z:[M+H] + =505.4

[0579] Example 69 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1 and Example 70 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2

[0580] [ka] Step 1: Preparation of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid

[0581] [ka] To a stirred solution of methyl 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylate (470 mg, 1.31 mmol) in tetrahydrofuran (5 mL) was added sodium hydroxide (2 M, 1.31 mL). The mixture was stirred at 20° C. for 16 hours. The mixture was acidified to pH=1 using concentrated hydrochloric acid. The mixture was extracted with dichloromethane (20 mL×4). The organic layers were combined, washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (300 mg) as a brown solid. LCMS (ESI) m / z: [M+H] + =345.2.

[0582] Step 2: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1 and 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2

[0583] [ka] To a stirred solution of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (300 mg, 871 μmol) in N,N-dimethylformamide (4 mL) was added N-hydroxy-3-methoxy-benzamidine (173 mg, 1.05 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (330 mg, 871 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (337 mg, 2.61 mmol, 456 μL). The mixture was stirred at 20° C. for 2 hours and then at 120° C. for 2 hours. The reaction mixture was cooled, concentrated under reduced pressure and purified by preparative HPLC (column: Luna C8 100*30 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 45%-65%, 12 min) to give (rac)-1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, which was purified by chiral-SFC (column: AD (250 mm*30 mm, 5 mm); mobile phase: [base-isopropanol]; B%: 42%-42%, min) to give first 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one. )-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1 (75 mg, 158.7 μmol, 18%, 100% ee) was obtained as a white solid, followed by 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2 (75 mg, 160 μmol, 18%, 99.7% ee) as a yellow solid.

[0584] 1-(3,4-Dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1. 1H NMR(400 MHz, CDCl3)δ 7.63-7.57(m,1H),7.55-7.50(m,1H),7.31(d,J=12.3 Hz,2H),7.22-7.19(m,1H),7.05(d,J=8.2 Hz,1H),7.00(d,J=1.8 Hz,1H),4.53-4.37(m,1H),4.21(dd,J=7.3,9.6 Hz,1H),3.95-3.77(m,5H),3.49(td,J=8.6,16.9 Hz,1H),3.36-3.20(m,2H),3.12-2.96(m,1H),2.89(td,J=8.3,16.9 Hz,1H),2.79-2.70(m,1H),2.18(d,J=13.1 Hz,8H),1.99-1.83(m,2H);LCMS(ESI)m / z:[M+H] + =475.1.

[0585] 1-(3,4-ジメチルフェニル)-4-(4-(3-(3-メトキシフェニル))-1,2,4-オThe optical anomaly 2. 1 H NMR(400 MHz, CDCl3)δ 7.63-7.57(m,1H),7.53(s,1H),7.36-7.27(m,2H),7.21(d,J=2.0 Hz,1H),7.05(d,J=8.0 Hz,1H),7.00(d,J=2.0 Hz,1H),4.53-4.37(m,1H),4.21(dd,J=7.3,9.5 Hz,1H),3.96-3.77(m,5H),3.55-3.44(m,1H),3.37-3.19(m,2H),3.12-2.82(m,2H),2.76(d,J=9.4 Hz,1H),2.18(d,J=13.1 Hz,8H),1.92(br.s.,2H);LCMS(ESI)m / z:[M+H] + =475.1.

[0586] Example 71 (1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one), Enantiomer 1 and Example 72 (1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one), Enantiomer 2 Racemic 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one (80 mg) was purified by SFC separation (column: AD (250 × 30 mm, 5 μm); mobile phase: [CO₂ base-isopropanol]; B%: 50%-50%, min) to initially give 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one. First, 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1 (26 mg, 59 μmol, 7%) was obtained as a white solid, and second, 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2 (23 mg, 52 μmol, 6%) was obtained as a white solid.

[0587] 1-(3,4-Dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1. 1H NMR(400 MHz,CDCl3)δ 8.06-8.00(m,2H),7.41-7.33(m,3H),7.32-7.29(m,1H),7.15(d,J=8.3 Hz,1H),4.66-4.54(m,1H),4.30(dd,J=7.4,9.5 Hz,1H),4.05-3.88(m,2H),3.65-3.55(m,1H),3.43-3.30(m,1H),3.20(d,J=3.4 Hz,1H),3.12-2.94(m,2H),2.85(d,J=9.7 Hz,1H),2.47(s,3H),2.32-2.14(m,8H),1.94(br.s.,2H);LCMS(ESI)m / z:[M+H] + =459.3.

[0588] 1-(3,4-Dimethylphenyl)-4-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2. 1 H NMR(400 MHz,CDCl3)δ 7.96-7.90(m,2H),7.32-7.24(m,3H),7.22-7.19(m,1H),7.05(d,J=8.2 Hz,1H),4.58-4.43(m,1H),4.20(s,1H),3.94-3.79(m,2H),3.50(quintet,J=8.5 Hz,1H),3.28(br.s.,1H),3.10(d,J=3.9 Hz,1H),3.02-2.84(m,2H),2.78-2.68(m,1H),2.38(s,3H),2.23-2.03(m,8H),1.83(d,J=10.8 Hz, 2H); LCMS (ESI) m / z: [M+H] + =459.3

[0589] Example 73 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1 and Example 74 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2 Racemic 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one (120 mg) was purified by SFC separation (column: OJ (250 mm × 30 mm, 5 mm); mobile phase: [CO2 base-ethanol]; B%: 30%-30%, min) to initially give 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one. 2,4-Oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1 (39 mg, 86.7 μmol, 11%) was obtained as a pink solid, and secondly, 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2 (36 mg, 77.9 μmol, 10%) was obtained as a pink solid.

[0590] 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 1: 1 H NMR(400 MHz,CDCl3)δ 7.94(br.s.,2H),7.39(d,J=15.0 Hz,3H),7.29(br.s.,1H),7.12(d,J=8.4 Hz,1H),4.58(t,J=13.9 Hz,1H),4.28(t,J=8.6 Hz,1H),4.01-3.87(m,2H),3.62-3.53(m,1H),3.35(br.s.,1H),3.19(br.s.,1H),3 .08-2.93(m,2H),2.86-2.76(m,1H),2.45(s,3H),2.32-2.11(m,8H),1.90(d,J=13.7 Hz, 2H); LCMS (ESI) m / z: [M+H] + =459.3.

[0591] 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, enantiomer 2: 1 H NMR (400 MHz, methanol-d4) δ 8.00-7.90 (m, 2H), 7.53-7.45 (m, 2H), 7.41-7.37 (m, 1H), 7.32-7.27 (m, 1H), 7.19-7.13 (m, 1H), 4.53 (dd, J = 3.5, 13.2 Hz,1H),4.19-4.03(m,3H),3.90-3.80(m,1H),3.49-3.39(m,1H),3.30-3.20(m,1H),3.12-3.00(m ,1H),2.94-2.82(m,2H),2.47(s,3H),2.35-2.11(m,8H),1.99-1.77(m,2H);LCMS(ESI)m / z:[M+H] + =459.3.

[0592] Example 75: (2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone).

[0593] [ka] Step 1: Preparation of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)carbamate.

[0594] [ka] To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (2.0 g, 6.91 mmol) in N,N-dimethylformamide (20 mL) was added 2-(tert-butoxycarbonylamino)acetic acid (1.21 g, 6.91 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (2.62 g, 6.91 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (2.68 g, 20.7 mmol, 3.62 mL). The mixture was stirred at 15° C. for 2 hours. The reaction mixture was quenched by the addition of water (20 mL), and then the mixture was extracted with ethyl acetate (60 mL×4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude material, which was purified by chromatography (silica, petroleum ether:ethyl acetate = 5:1 to 1:1) to give tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)carbamate (2.60 g, 5.82 mmol, 84%) as a brown solid. LCMS (ESI) m / z: [M+H] + =447.2.

[0595] Step 2: Preparation of 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone

[0596] [ka] To a stirred solution of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)carbamate (2.50 g, 5.60 mmol) in methanol (10 mL) was added hydrogen chloride in methanol (30 mL). The mixture was stirred at 20° C. for 1 hour and then concentrated to give 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (1.90 g, 5.49 mmol, 97.95%), which was isolated as a brown solid and used in the next step without further purification. A small amount (0.1 g) of the crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 20% to 50%, 12 min) to give a pure sample for analysis: 2-amino-1-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone (32 mg). 1 H NMR(400 MHz,CDCl3)δ 7.73-7.67(m,1H),7.58(d,J=1.5 Hz,1H),6.98(d,J=8.4 Hz,1H),4.54(d,J=12.2 Hz,1H),3.98(d,J=7.2 Hz,6H),3.84(d,J=12.0 Hz,1H),3.54(s,2H),3.34-3.21(m,2H),3.08(d,J=12.3 Hz,1H),2.21(d,J=13.1 Hz,2H),1.98(d,J=9.4 Hz,2H);LCMS(ESI)m / z:[M+H] + =347.1.

[0597] Example 76: (5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethoxy)choman-4-one).

[0598] [ka] Step 1: Preparation of tert-butyl 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate

[0599] [ka] To a stirred solution of (Z)-N'-hydroxybenzimidamide (214 mg, 1.57 mmol) in N,N-dimethylformamide (5 mL) was added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1.31 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1.31 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (507 mg, 3.93 mmol, 686 μL). The mixture was stirred at 20°C for 2 hours and then heated at 120°C for 2 hours. The reaction mixture was quenched with water (10 mL), and then the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was extracted with petroleum ether (30 mL × 2). The combined organic extracts were concentrated under reduced pressure to obtain tert-butyl 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (310 mg, 941 μmol, 72%) as a yellow oil. This product was used in the next step without further purification.

[0600] Step 2: Preparation of 3-phenyl-5-(piperidin-4-yl)-1,2,4-oxadiazole.

[0601] [ka] To a stirred solution of tert-butyl 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (310 mg, 941 μmol) in ethyl acetate (2 mL) was added an anhydrous solution of hydrochloric acid in ethyl acetate (20 mL). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude 3-phenyl-5-(piperidin-4-yl)-1,2,4-oxadiazole (233 mg) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) m / z: [M+H] + =230.2.

[0602] Step 3: Preparation of 5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethoxy)choman-4-one.

[0603] [ka] To a stirred solution of 2-((5-hydroxy-2,2-dimethyl-4-oxochoman-7-yl)oxy)acetic acid (150 mg, 563 μmol) in N,N-dimethylformamide (2 mL) was added 3-phenyl-5-(piperidin-4-yl)-1,2,4-oxadiazole (142 mg, 620 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (213 mg, 563 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (291 mg, 2.25 mmol, 393 μL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 45% to 75%, 12 min) to give 5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethoxy)choman-4-one (120 mg, 250.6 μmol, 44%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 12.00(s,1H),8.12-8.07(m,2H),7.56-7.48(m,3H),6.07(d,J=2.4 Hz,1H),6.04(d,J=2.3 Hz,1H),4.74(s,2H),4.46(d,J=13.8 Hz,1H),3.98(d,J=13.1 Hz,1H),3.42-3.28(m,2H),3.13(t,J=11.1 Hz,1H),2.71(s,2H),2.23(br.s.,2H),2.07-1.92(m,2H),1.49-1.46(m,6H);LCMS(ESI)m / z:[M+H] + =478.2.

[0604] Example 77 (7-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethoxy)-5-hydroxy-2,2-dimethylchoman-4-one).

[0605] [ka] Step 1: Preparation of 7-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethoxy)-5-hydroxy-2,2-dimethylchoman-4-one.

[0606] [ka] To a stirred solution of 2-((5-hydroxy-2,2-dimethyl-4-oxochoman-7-yl)oxy)acetic acid (150 mg, 563 μmol) in N,N-dimethylformamide (2 mL) was added 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (195 mg, 676 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (213 mg, 563 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (291 mg, 2.25 mmol, 393 μL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40% to 70%, 12 min) to give 7-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethoxy)-5-hydroxy-2,2-dimethylchoman-4-one (133 mg, 245.66 μmol, 44%) as a white solid. 1H NMR(400MHz,CDCl3)δ 12.00(s,1H),7.71(dd,J=1.9,8.3 Hz,1H),7.58(d,J=1.9 Hz,1H),6.98(d,J=8.4 Hz,1H),6.06(d,J=2.4 Hz,1H),6.03(d,J=2.4 Hz,1H),4.74(s,2H),4.47(d,J=14.2 Hz,1H),4.01-3.94(m,7H),3.41-3.26(m,2H),3.11(t,J=11.0 Hz,1H),2.71(s,2H),2.22(br.s.,2H),2.06-1.93(m,2H),1.47(s,6H);LCMS(ESI)m / z:[M+H] + =538.3.

[0607] Example 78: (N-(2-oxo-2-(4-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide.

[0608] [ka] Step 1: Preparation of (Z)-N'-hydroxypicoline imidamide.

[0609] [ka] To a stirred solution of picolinonitrile (3.0 g, 28.8 mmol, 2.78 mL) in ethanol (30 mL) was added hydroxylamine hydrochloride (4.01 g, 57.6 mmol), triethylamine (5.83 g, 57.6 mmol, 8.0 mL), and water (5 mL). The mixture was heated at 75° C. for 5 hours. The mixture was then concentrated to give a residue. The solid residue was triturated with water (30 mL), filtered, and dried under reduced pressure to give (Z)-N′-hydroxypicoline imidamide (2.0 g, 14.6 mmol, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.57 (d, J = 4.5 Hz, 1H), 7.92-7.75 (m, 2H), 7.47-7.35 (m, 1H), 5.85 (br.s., 2H).

[0610] Step 2: Preparation of N-(2-oxo-2-(4-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide

[0611] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) in N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxypicoline imidamide (56 mg, 413 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1.24 mmol, 216 μL), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (156 mg, 413 μmol). The mixture was stirred at 20°C for 2 hours and then heated at 120°C for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 20% to 55%, 12 min) to afford N-(2-oxo-2-(4-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide (75 mg, 192 μmol, 47%) as a yellow solid. 1H NMR(400 MHz,CDCl3)δ 8.84(td,J=0.8,4.0 Hz,1H),8.18-8.12(m,1H),7.93-7.84(m,3H),7.58-7.43(m,4H),7.35(br.s.,1H),4.53(d,J=13.6 Hz,1H),4.32(t,J=3.5 Hz,2H),3.93(d,J=14.1 Hz,1H),3.45-3.31(m,2H),3.21-3.10(m,1H),2.37-2.24(m,2H),2.15-1.98(m,2H);LCMS(ESI)m / z:[M+H] + =392.2.

[0612] Example 79: N-(2-oxo-2-(4-(3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide

[0613] [ka] Step 1: Preparation of (Z)-N'-hydroxyquinoline-2-carboximidamide.

[0614] [ka] To a stirred solution of quinoline-2-carbonitrile (900 mg, 5.84 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (811 mg, 11.7 mmol), triethylamine (1.18 g, 11.7 mmol, 1.6 mL), and water (1 mL). The mixture was heated at 75° C. for 5 hours. The reaction mixture was cooled, filtered, and the filter cake was dried under vacuum to give (Z)-N′-hydroxyquinoline-2-carboximidamide (1.0 g, 5.34 mmol, 91%) as a pale yellow solid, which was used directly without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 10.23(s,1H),8.34(d,J=8.7 Hz,1H),8.10-7.93(m,3H),7.80(s,1H),7.67-7.59(m,1H),6.02(br.s.,2H).

[0615] Step 2: Preparation of N-(2-oxo-2-(4-(3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide

[0616] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) in N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxyquinoline-2-carboximidamide (77 mg, 413 μmol), N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1.24 mmol, 216 μL), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (156 mg, 413 μmol). The mixture was first stirred at 20°C for 2 hours and then heated at 120°C for 2 hours. The reaction mixture was cooled and directly purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-(2-oxo-2-(4-(3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide (66 mg, 150 μmol, 36%) as a yellow solid. 1H NMR(400 MHz,CDCl3)δ 8.26(dd,J=2.1,8.5 Hz,2H),8.14(d,J=8.5 Hz,1H),7.86-7.77(m,3H),7.72(dt,J=1.3,7.7 Hz,1H),7.61-7.53(m,1H),7.49-7.34(m,3H),7.27(br.s.,1H),4.50(d,J=13.8 Hz,1H),4.24(d,J=3.6 Hz,2H),3.87(d,J=13.8 Hz,1H),3.42-3.22(m,2H),3.09-2.98(m,1H),2.31-2.16(m,2H),2.10-1.91(m,2H);LCMS(ESI)m / z:[M+H] + =442.2.

[0617] Example 80: 4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(2-phenylcyclopropyl)piperidine-1-carboxamide

[0618] [ka] Step 1: (2-Isocyanatocyclopropyl)benzene.

[0619] [ka] To a stirred solution of 2-phenylcyclopropanecarboxylic acid (1.0 g, 6.17 mmol) in toluene (10 mL) under nitrogen was added diphenylphosphoryl azide (2.04 g, 7.40 mmol, 1.60 mL) and triethylamine (935 mg, 9.25 mmol, 1.28 mL). The mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled and then concentrated in vacuo to give (2-isocyanatocyclopropyl)benzene (2.0 g) as a yellow oil, which was used directly without further purification.

[0620] Step 2: Preparation of methyl 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylate.

[0621] [ka] To a stirred solution of methyl piperidine-4-carboxylate (800 mg, 5.59 mmol) in toluene (10 mL) was added (2-isocyanatocyclopropyl)benzene (2.0 g, 12.58 mmol, 2.25 equiv.) and N-ethyl-N-(propan-2-yl)propan-2-amine (722 mg, 5.59 mmol, 975 μL). After 16 h, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (50 mL × 3), and then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a residue, which was purified by chromatography (silica, petroleum ether:ethyl acetate = 50:1 to 2:1) to give methyl 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylate (820 mg, 2.71 mmol, 48%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 7.22-7.19(m,1H),7.17(s,1H),7.10(d,J=7.4 Hz,3H),4.75(br.s.,1H),3.79(d,J=13.3 Hz,2H),3.63(s,3H),2.89-2.73(m,3H),2.47-2.33(m,1H),2.02-1.78(m,3H),1.61(dd,J=2.1,13.1 Hz,2H),1.16-1.11(m,1H),1.08-1.03(m,1H).

[0622] Step 3: Preparation of 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid.

[0623] [ka] To a stirred solution of methyl 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylate (770 mg, 2.55 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide (1 M, 5.10 mL). After 2 hours, the reaction was acidified with 1 M hydrochloric acid (8 mL). The mixture was extracted with dichloromethane (40 mL × 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid (660 mg, 2.29 mmol, 90%) as a yellow solid, which was used directly without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 12.22(s,1H),7.33-7.01(m,5H),6.78(d,J=2.5 Hz,1H),3.85(d,J=13.3 Hz,2H),2.81-2.66(m,3H),2.40(br.s.,1H),1.95-1.69(m,3H),1.39(d,J=12.0 Hz,2H),1.21-1.13(m,1H),1.10-1.04(m,1H).

[0624] Step 4: Preparation of 4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(2-phenylcyclopropyl)piperidine-1-carboxamide.

[0625] [ka] To a stirred solution of 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid (100 mg, 347 μmol) in N,N-dimethylformamide (2 mL) was added (Z)-4-ethoxy-N'-hydroxy-3-methoxybenzimidamide (72 mg, 347 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (131 mg, 347 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (134 mg, 1.04 mmol, 181 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was cooled and then purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40% to 75%, 12 min) to give 4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-(2-phenylcyclopropyl)piperidine-1-carboxamide (81 mg, 173 μmol, 50%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 7.70-7.66(m,1H),7.58(d,J=1.9 Hz,1H),7.31(s,1H),7.27(s,1H),7.23-7.17(m,3H),6.97(d,J=8.5 Hz,1H),4.91(s,1H),4.19(q,J=7.0 Hz,2H),3.98(s,5H),3.25-3.16(m,1H),3.13-3.03(m,2H),2.91-2.85(m,1H),2.18(dd,J=3.5,13.4 Hz,2H),2.07(ddd,J=3.3,6.2,9.5 Hz,1H),2.03-1.91(m,2H),1.53(t,J=7.0 Hz,3H),1.28-1.22(m,1H),1.17(td,J=5.0,9.7 Hz,1H);LCMS(ESI)m / z:[M+H] + =463.2.

[0626] Example 81: N-(2-phenylcyclopropyl)-4-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide.

[0627] [ka] Step 1: Preparation of N-(2-phenylcyclopropyl)-4-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide.

[0628] [ka] To a stirred solution of 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid (130 mg, 451 μmol) in N,N-dimethylformamide (1 mL) was added (Z)-N'-hydroxypicoline imidamide (74 mg, 541 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (170 mg, 451 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (174 mg, 1.35 mmol, 236 μL). The mixture was stirred at 20°C for 2 hours and then heated at 110°C for 2 hours. The reaction mixture was cooled and then purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-(2-phenylcyclopropyl)-4-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide (47 mg, 121.6 μmol, 27%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 8.76(d,J=4.0 Hz,1H),8.12-7.97(m,2H),7.65-7.55(m,1H),7.30-7.19(m,2H),7.18-7.05(m,3H),6.87(br.s.,1H),3.96(d,J=13.2 Hz,2H),2.93(t,J=11.7 Hz,2H),2.71(d,J=3.1 Hz,1H),2.06(d,J=11.5 Hz,2H),1.89(br.s.,1H),1.68(d,J=11.9 Hz,3H),1.20-1.04(m,2H);LCMS(ESI)m / z:[M+H] + =390.1.

[0629] Example 82: N-(2-phenylcyclopropyl)-4-(3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide

[0630] [ka] Step 1: Preparation of N-(2-phenylcyclopropyl)-4-(3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide.

[0631] [ka] To a stirred solution of 1-[(2-phenylcyclopropyl)carbamoyl]piperidine-4-carboxylic acid (130 mg, 451 μmol) in N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxyquinoline-2-carboximidamide (101 mg, 541 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (170 mg, 451 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (174 mg, 1.35 mmol, 236 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 2 hours. The reaction mixture was cooled and then purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40% to 70%, 12 min) to give N-(2-phenylcyclopropyl)-4-(3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide (34 mg, 77 μmol, 17%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.60(s,1H),8.22-8.07(m,3H),7.88(br.s.,1H),7.74(d,J=7.5 Hz,1H),7.30-7.20(m,2H),7.18-7.06(m,3H),6.89(br.s.,1H),3.99(d,J=13.7 Hz,2H),3.45-3.37(m,1H),2.94(t,J=11.7 Hz,2H),2.72(d,J=3.5 Hz,1H),2.10(d,J=11.0 Hz,2H),1.89(br.s.,1H),1.72(d,J=11.5 Hz,2H),1.18(td,J=4.6,9.3 Hz,1H),1.11-1.05(m,1H);LCMS(ESI)m / z:[M+H] + =440.1.

[0632] Example 83: 4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine-1-carboxamide.

[0633] [ka] Step 1: Preparation of 4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine-1-carboxamide.

[0634] [ka] To a stirred solution of (2-isocyanatoethyl)benzene (72 mg, 494 μmol, 68 μL) in toluene (2 mL) was added 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (150 mg, 494 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (63 mg, 494 μmol, 86 μL). The mixture was then stirred at 20° C. for 16 hours. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 35% to 60%, 12 min) to give 4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine-1-carboxamide (58 mg, 130 μmol, 26%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.59(dd,J=2.0,8.4 Hz,1H),7.49(d,J=1.9 Hz,1H),7.28-7.22(m,2H),7.18-7.12(m,3H),6.87(d,J=8.4 Hz,1H),4.40(br.s.,1H),4.10(q,J=7.0 Hz,2H),3.88(s,3H),3.86-3.80(m,2H),3.48-3.41(m,2H),3.14-3.05(m,1H),2.97-2.88(m,2H),2.78(t,J=6.8 Hz,2H),2.04(dd,J=3.2,13.1 Hz,2H),1.89-1.77(m,2H),1.43(t,J=7.0 Hz,3H);LCMS(ESI)m / z:[M+H]+ =451.3.

[0635] Example 84: 4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, Example 85: (R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, and Example 86: (S)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one.

[0636] [ka] Step 1: Preparation of 4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, (S)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, and (R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one

[0637] [ka] To a stirred solution of 5-oxo-1-phenyl-pyrrolidine-3-carboxylic acid (200 mg, 975 μmol) in N,N-dimethylformamide (4 mL) was added 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-piperidyl)-1,2,4-oxadiazole (295 mg, 975 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (369 mg, 975 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (377 mg, 2.92 mmol, 510 μL). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 40% to 70%, 12 min) to give racemic 4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one (151 mg, 31%). A portion of this racemic mixture (140 mg) was subjected to SFC separation (column: OJ (250 × 30 mm, 5 μm); mobile phase: [CO₂ base-isopropanol]; B%: 45% to 45%, min) to give (R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one (64 mg, 132 μmol, 14%, purity 99.7%) as a white solid, followed by (S)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one (65 mg, 133.9 μmol, 14%, purity 99.58%) also as a white solid.

[0638] 4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one: 1H NMR(400 MHz,DMSO-d6)δ 7.68(d,J=8.0 Hz,2H),7.62-7.56(m,1H),7.48(s,1H),7.39(t,J=6.7 Hz,2H),7.19-7.09(m,2H),4.38(d,J=13.8 Hz,1H),4.14-3.93(m,5H),3.85(s,3H),3.80-3.71(m,1H),3.51-3.40(m,1H),3.30(br.s.,1 H),3.00-2.89(m,1H),2.83-2.73(m,2H),2.22-2.09(m,2H),1.90-1.64(m,2H),1.37(t,J=7.0 Hz,3H);LCMS(ESI)m / z:[M+H] + =491.2.

[0639] (R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one: 1 H NMR(400 MHz,DMSO-d6)δ 7.68(d,J=7.9 Hz,2H),7.62-7.56(m,1H),7.51-7.46(m,1H),7.39(t,J=6.7 Hz,2H),7.19-7.09(m,2H),4.38(d,J=13.4 Hz,1H),4.13-3.95(m,5H),3.85(s,3H),3.80-3.71(m,1H),3.44(d,J=10.0 Hz,2H),2.94(br.s.,1H),2.81-2.74(m,2H),2.16(t,J=13.6 Hz,2H),1.91-1.64(m,2H),1.37(t,J=6.9 Hz,3H);LCMS(ESI)m / z:[M+H] + =491.1.

[0640] (S)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one. 1H NMR(400 MHz,DMSO-d6)δ 7.66(d,J=6.6 Hz,2H),7.57(d,J=8.4 Hz,1H),7.46(s,1H),7.41-7.33(m,2H),7.17-7.07(m,2H),4.37(d,J=12.8 Hz,1H),4.12-3.92(m,5H),3.83(s,3H),3.78-3.69(m,1H),3.43(t,J=10.6 Hz,1H),3.28(br.s.,1H),2.92(t,J=13.0 Hz,1H),2.81-2.70(m,2H),2.14(t,J=13.5 Hz,2H),1.88-1.78(m,1H),1.74-1.64(m,1H),1.35(t,J=7.1 Hz,3H);LCMS(ESI)m / z:C27H30N4O5[M+H] + =491.1

[0641] Alternatively, Example 85: (4R)-4-[4-[3-(4-ethoxy-3-methoxy-phenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one can be prepared in an enantioselective manner as follows:

[0642] [ka] Step 1: Preparation of (4R)-4-[4-[3-(4-ethoxy-3-methoxy-phenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one.

[0643] [ka] To a stirred solution of 1-[(3R)-5-oxo-1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (100 mg, 316 μmol) and 4-ethoxy-N′-hydroxy-3-methoxy-benzamidine (66 mg, 316 μmol) in DMF (1.50 mL) was added (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (119 mg, 316 μmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (81 mg, 632 μmol, 110 μL) at 25° C. After 12 h, the mixture was heated and stirred at 110° C. for 1 h. The mixture was cooled and then purified by preparative HPLC (Waters Xbridge 150 × 25 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 25% to 65%, 12 min) to give (4R)-4-[4-[3-(4-ethoxy-3-methoxy-phenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1-phenyl-pyrrolidin-2-one (59 mg, 122 μmol, 39%) as a pink solid. 1 H NMR(400MHz,chloroform-d)δ=7.66(br d,J=8.2 Hz,1H),7.61-7.54(m,3H),7.37(m,J=7.9 Hz,2H),7.19-7.14(m,1H),6.94(d,J=8.4 Hz,1H),4.59-4.46(m,1H),4.31(dd,J=7.3,9.7 Hz,1H),4.17(q,J=7.0 Hz,2H),3.99-3.90(m,5H),3.58(quintet,J=8.4 Hz,1H),3.43-3.26(m,2H),3.16-2.92(m,2H),2.88-2.79(m,1H),2.24(br t,J=12.9 Hz,2H),2.05-1.89(m,2H),1.50(t,J=6.9 Hz,3H);LCMS(ESI)m / z:[M+H] + =491.3.

[0644] Example 87: N-(2-(4-(3-(3-chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0645] [ka] Step 1: Preparation of 3-chloro-4-ethoxybenzonitrile.

[0646] [ka] To a stirred solution of 3-chloro-4-hydroxybenzonitrile (2.0 g, 13.0 mmol) in N,N-dimethylformamide (20 mL) was added iodoethane (2.44 g, 15.6 mmol, 1.25 mL) and potassium carbonate (3.60 g, 26.1 mmol) at 0° C. The reaction was warmed to 40° C. After 16 h, the reaction mixture was quenched by the addition of water (30 mL), and the mixture was then extracted with ethyl acetate (60 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 3-chloro-4-ethoxybenzonitrile (2.50 g) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ 7.57(d,J=1.9 Hz,1H),7.45(dd,J=2.0,8.7 Hz,1H),6.88(d,J=8.5 Hz,1H),4.10(q,J=7.0 Hz,2H),1.43(t,J=7.0 Hz,3H).

[0647] Step 2: Preparation of (Z)-3-chloro-4-ethoxy-N'-hydroxybenzimidamide.

[0648] [ka] To a stirred solution of 3-chloro-4-ethoxybenzonitrile (2.40 g, 13.2 mmol) in ethanol (30 mL) was added hydroxylamine hydrochloride (1.84 g, 26.4 mmol), triethylamine (2.67 g, 26.4 mmol, 3.66 mL), and water (3 mL). The mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered, and the filter cake was dried under vacuum to give (Z)-3-chloro-4-ethoxy-N′-hydroxybenzimidamide (700 mg, 3.62 mmol, 69%) as a brown oil. 1 H NMR(400 MHz,DMSO-d6)δ 9.59(s,1H),7.72(d,J=2.0 Hz,2H),7.14(d,J=8.8 Hz,1H),5.83(s,2H),4.14(q,J=6.9 Hz,2H),1.45-1.30(m,3H).

[0649] Step 3: Preparation of N-(2-(4-(3-(3-chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide

[0650] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) in N,N-dimethylformamide (2 mL) was added (Z)-3-chloro-4-ethoxy-N'-hydroxybenzimidamide (97 mg, 455 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1.24 mmol, 216 μL). The mixture was stirred at 20°C for 2 hours and then heated at 120°C for 2 hours. The reaction mixture was cooled and then purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 45% to 80%, 12 min) to give N-(2-(4-(3-(3-chloro-4-ethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (104 mg, 223 μmol, 54%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 8.12(d,J=2.0 Hz,1H),7.95(dd,J=2.1,8.6 Hz,1H),7.91-7.86(m,2H),7.58-7.44(m,3H),7.35(br.s.,1H),7.02(d,J=8.7 Hz,1H),4.51(d,J=13.7 Hz,1H),4.33(d,J=3.9 Hz,2H),4.21(q,J=7.0 Hz,2H),3.93(d,J=13.9 Hz,1H),3.41-3.29(m,2H),3.18(t,J=10.8 Hz,1H),2.33-2.20(m,2H),2.09-1.93(m,2H),1.53(t,J=7.0 Hz,3H);LCMS(ESI)m / z:[M+H] + =469.3.

[0651] Example 88: N-(2-(4-(3-( 1 H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide

[0652] [ka] Step 1: 1 Preparation of H-indazole-6-carbonitrile

[0653] [ka] To a stirred solution of 6-bromo-1H-indazole (1.0 g, 5.08 mmol) in N,N-dimethylformamide (12 mL) was added zinc cyanide (595 mg, 5.08 mmol, 322 μL) and tetrakis(triphenylphosphine)palladium(0) (586 mg, 508 μmol), and the mixture was degassed with nitrogen three times. The mixture was heated at 100° C. under nitrogen for 4 hours. The reaction was cooled to 20° C., water (15 mL) was added, and the reaction mixture was extracted with ethyl acetate (40 mL × 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. This was triturated with petroleum ether (30 mL) and dichloromethane (5 mL), and the mixture was filtered. The filter cake was dried under vacuum to give 1H-indazole-6-carbonitrile (880 mg) as a yellow solid, which was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 13.65 (br.s., 1H), 8.33-8.12 (m, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.88-7.80 (m, 1H).

[0654] Step 2: Preparation of (Z)-N'-hydroxy-1H-indazole-6-carboximidamide.

[0655] [ka] To a stirred solution of 1H-indazole-6-carbonitrile (800 mg, 5.59 mmol) in ethanol (1 mL) was added hydroxylamine hydrochloride (776 mg, 11.18 mmol), triethylamine (1.13 g, 11.18 mmol, 1.55 mL), and water (100 μL). The mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled, concentrated under reduced pressure, and then diluted with water (5 mL). The solid that formed was filtered, and the filter cake was dried under reduced pressure to give (Z)-N′-hydroxy-1H-indazole-6-carboximidamide (500 mg, 2.84 mmol, 51%) as a yellow solid, which was used directly without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 13.22-13.10(m,1H),9.68(br.s.,1H),8.04(s,1H),7.78(s,1H),7.70-7.66(m,1H),7.47-7.42(m,1H),5.87(br.s.,2H).

[0656] Step 3: N-(2-(4-(3-( 1 Preparation of H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

[0657] [ka] To a stirred solution of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μmol) in N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxy-1H-indazole-6-carboximidamide (94 mg, 537 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1.24 mmol, 216 μL). The mixture was stirred at 20° C. for 1 hour and then heated at 110° C. for 1 hour. The reaction mixture was directly purified by preparative HPLC (column: Luna C18 100*30 5μm; mobile phase: [water (0.225% TFA)-acetonitrile]; B%: 30%~55%, 12 min) to give N-(2-(4-(3-( 1 H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide (21 mg, 44 μmol, 11%) was obtained as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ 13.34(br s,1H),8.55(t,J=5.6 Hz,1H),8.18-8.16(m,1H),7.94-7.89(m,1H),7.88-7.83(m,2H),7.72(dd,J=1.1,8.4 Hz,1H),7.54-7.41(m,3H),4.36-4.27(m,1H),4.16(d,J=5.7 Hz,2H),3.97(br d,J=14.1 Hz,1H),3.59(br s,1H),3.47(s,1H),3.34-3.24(m,1H),2.98-2.88(m,1H),2.20-2.08(m,2H),1.89-1.77(m,1H),1.66(br d,J=11.5 Hz,1H);LCMS(ESI)m / z:[M+H] + =431.1.

[0658] Example 89: 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, Example 90: 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, enantiomer 1 and Example 91: (R)-4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, enantiomer 2.

[0659] [ka] Step 1: Preparation of 1,3-dimethyl-1H-indazole-6-carbonitrile.

[0660] [ka] To a stirred solution of 6-bromo-1,3-dimethyl-1H-indazole (480 mg, 2.13 mmol) in N,N-dimethylformamide (5 mL) under nitrogen was added zinc cyanide (250 mg, 2.13 mmol) and tetrakis(triphenylphosphine)palladium(0) (246 mg, 213 μmol), and the mixture was then heated to 100° C. After 16 h, the reaction was cooled to 20° C., water (10 mL) was added, and the reaction mixture was extracted with ethyl acetate (40 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give the crude product. The residue was triturated with petroleum ether (30 mL), then filtered and the filter cake dried under vacuum to give 1,3-dimethyl-1H-indazole-6-carbonitrile (300 mg, 1.75 mmol, 82%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.78-7.71 (m, 2H), 7.38-7.31 (m, 1H), 4.08 (s, 3H), 2.61 (s, 3H).

[0661] Step 2: Preparation of (Z)-N'-hydroxy-1,3-dimethyl-1H-indazole-6-carboximidamide.

[0662] [ka] To a stirred solution of 1,3-dimethyl-1H-indazole-6-carbonitrile (300 mg, 1.75 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (243 mg, 3.50 mmol), triethylamine (354 mg, 3.50 mmol, 485 μL), and water (500 μL). The mixture was heated at 80° C. for 5 hours, then cooled, filtered, and the filter cake was dried under vacuum to give (Z)-N′-hydroxy-1,3-dimethyl-1H-indazole-6-carboximidamide (290 mg, 1.42 mmol, 81%) as a white solid, which was used directly without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 9.71(s,1H),7.86(s,1H),7.65(d,J=8.5 Hz,1H),7.49(d,J=8.5 Hz,1H),5.90(s,2H),3.97(s,3H),2.47(s,3H).

[0663] Step 3: Preparation of methyl 1-(5-oxo-1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate.

[0664] [ka] To a stirred solution of 5-oxo-1-phenylpyrrolidine-3-carboxylic acid (500 mg, 2.44 mmol) in N,N-dimethylformamide (10 mL) was added methyl piperidine-4-carboxylate (349 mg, 2.44 mmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (925 mg, 2.44 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (946 mg, 7.32 mmol, 1.28 mL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was quenched by the addition of water (20 mL) and then extracted with ethyl acetate (40 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography (silica, petroleum ether:ethyl acetate=20:1 to 1:1) gave methyl 1-(5-oxo-1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate (940 mg) as a yellow oil.

[0665] Step 4: Preparation of 1-(5-oxo-1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid

[0666] [ka] To a stirred solution of methyl 1-(5-oxo-1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate (900 mg, 2.72 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide (2 M, 2.72 mL). After 2 hours, the reaction mixture was acidified to pH 1 with 1 M hydrochloric acid (6 mL). The mixture was extracted with ethyl acetate (40 mL × 3). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-(5-oxo-1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (600 mg, 1.90 mmol, 70%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ 12.37-12.17(m,1H),7.66(dd,J=5.8,7.2 Hz,2H),7.38(t,J=7.9 Hz,2H),7.19-7.09(m,1H),4.28-4.19(m,1H),4.04(s,1H),3.93(br.s.,2 H),3.76-3.66(m,1H),3.18(br.s.,1H),2.86-2.67(m,4H),1.87(t,J=13.2 Hz,2H),1.61-1.35(m,2H).

[0667] Step 5: Preparation of 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, enantiomer 1 and 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, enantiomer 2.

[0668] [ka] To a stirred solution of 1-(5-oxo-1-phenyl-pyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (150 mg, 474 μmol) in N,N-dimethylformamide (2 mL) was added N'-hydroxy-1,3-dimethyl-indazole-6-carboxamidine (96 mg, 474 μmol), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (179 mg, 474 μmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (183 mg, 1.42 mmol, 248 μL). The mixture was stirred at 20° C. for 2 hours and then heated at 120° C. for 1 hour. The reaction mixture was cooled and then purified by preparative HPLC (column: Waters Xbridge 150 × 2.5 mm 5 μm; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 30%-55%, 12 min) to give racemic 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one (85 mg) as a white solid. A portion (25 mg, 53 μmol, 11%, purity 99.83%) was retained for analysis. The remainder (60 mg) was purified by SFC (column: OJ (250 × 30 mm, 5 μm); mobile phase: [CO base-methanol]; B%: 45%-45%, min) to give 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, enantiomer 1 (27 mg, 56 μmol, 12%) as a brown solid, followed by 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, enantiomer 2 (26 mg, 55 μmol, 12%) as a white solid.

[0669] 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one: 1 H NMR(400 MHz,CDCl3)δ 8.13-8.07(m,1H),7.83(s,1H),7.78-7.72(m,1H),7.61(d,J=8.0 Hz,2H),7.39(t,J=7.9 Hz,2H),7.18(s,1H),4.65-4.50(m,1H),4.34(t,J=7.3 Hz,1H),4.09(d,J=3.3 Hz,3H),4.05-3.92(m,2H),3.60(quintet,J=8.4 Hz,1H),3.46-3.32(m,2H),2.98(d,J=6.7 Hz,2H),2.91-2.81(m,1H),2.61(s,3H),2.35-2.22(m,2H),2.02(d,J=6.1 Hz,2H);LCMS(ESI)m / z:[M+H] + =485.2.

[0670] 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, enantiomer 1: 1 H NMR(400 MHz,CDCl3)δ 8.12(d,J=4.1 Hz,1H),7.86(br d,J=8.5 Hz,1H),7.80-7.74(m,1H),7.63(d,J=7.9 Hz,2H),7.41(t,J=8.0 Hz,2H),7.23-7.18(m,1H),4.67-4.52(m,1H),4.36(br t,J=7.0 Hz,1H),4.11(d,J=3.4 Hz,3H),4.07-3.94(m,2H),3.62(quintet,J=8.5 Hz,1H),3.49-3.35(m,2H),3.22-2.96(m,2H),2.93-2.81(m,1H),2.63(s,3H),2.37-2.25(m,2H),2.11-1.97(m,2H);LCMS(ESI)m / z:[M+H] + =485.3.

[0671] 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, enantiomer 2: 1 H NMR(400 MHz,CDCl3)δ 8.12(d,J=3.9 Hz,1H),7.86(d,J=8.4 Hz,1H),7.80-7.74(m,1H),7.63(d,J=8.3 Hz,2H),7.41(t,J=8.0 Hz,2H),7.24-7.18(m,1H),4.66-4.53(m,1H),4.36(br t,J=7.3 Hz,1H),4.11(d,J=3.5 Hz,3H),4.07-3.94(m,2H),3.62(quintet,J=8.5 Hz,1H),3.48-3.36(m,2H),...

Claims

1. 1. A pharmaceutical composition for use in treating a neurological disorder in a subject in need thereof, comprising a compound having the structure of formula Ia: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein B has the structure of formula Ib, Ic, Id, Ie, or If, or B is absent, and formulas Ib, Ic, Id, Ie, and If have the structure: 【Chemistry 2】 The dashed lines represent optional double bonds; Het is -C(O)NH- or 【Chemistry 3】 and m is 0 or 1; n is 0, 1, or 2; o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; p and r are independently 0 or 1; X １ is CR ６ and X ２ is N, X ３ is O, L １ is -O-, optionally substituted C １ -C ６ Alkylene, optionally substituted C １ -C ６ Alkenylene, optionally substituted C １ -C ６ Heteroalkylene, optionally substituted C ３ -C ７ Cycloalkyl, optionally substituted C ２ -C ９ Heteroaryl, or optionally substituted C ２ -C ９ is a heterocyclic ring, L ２ is absent, -O-, -SO ２ - or -CR ２ R ３ - and R １ is optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, C １ -C ６ Alkyl, halo, C ２ -C ９ C optionally substituted with 1 to 4 substituents selected from the group consisting of heterocyclyl and cyano ６ -C １０ Aryl, optionally substituted C ３ -C ７ Cycloalkyl, optionally substituted C ３ -C ７ Cycloalkyl C １ -C ６ Alkyl, optionally substituted C ２ -C ９ Heteroaryl, optionally substituted C ２ -C ９ Heteroaryl C １ -C ６ Alkyl, C ２ -C ９ Heterocycle, or optionally substituted C ２ -C ９ Heterocycle C １ -C ６ is alkyl, R ２ and R ３ each independently represents hydrogen, optionally substituted C １ -C ６ alkyl, or together with the carbon to which they are attached, carbonyl or optionally substituted C ３ -C ７ Forming a cycloalkyl, Each R ４ are independently halogen, hydroxyl, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl or two R ４ together with the carbon to which they are attached form a carbonyl or an optionally substituted C ３ -C ７ Forming a cycloalkyl, R ５ C ６ -C １０ Aryl, C ３ -C １２ Carbocyclyl, halogen, hydroxyl, C １ -C ６ Alkyl, C ２ -C ９ Heterocyclyl, NH ２ , Mono-C １ -C ６ Alkylamino, di-C １ -C ６ C optionally substituted with 1 to 4 substituents selected from alkylamino, azido, cyano, nitro and thiol ２ -C ９ Heteroaryl, or optionally substituted C ２ -C ９ is a heterocyclic ring, Each R ６ are independently hydrogen, halogen, hydroxy, optionally substituted C １ -C ６ Heteroalkyl, or optionally substituted C １ -C ６ The pharmaceutical composition, wherein said aryl is alkyl.

2. B has the structure of formula Ib: 【Chemistry 4】 2. The pharmaceutical composition of claim 1, having the formula:

3. B has the following structure: 【Chemistry 5】 3. The pharmaceutical composition of claim 2, having the formula:

4. B has the structure of formula Ic: 【Chemistry 6】 2. The pharmaceutical composition of claim 1, having the formula:

5. B has the structure of formula Id: 【Chemistry 7】 2. The pharmaceutical composition of claim 1, having the formula:

6. B has the structure of formula Ie: 【Chemistry 8】 2. The pharmaceutical composition of claim 1, having the formula:

7. B has the structure of formula If: 【Chemistry 9】 2. The pharmaceutical composition of claim 1, having the formula:

8. L ２ is -O- or -CR ２ R ３ The pharmaceutical composition of claim 1, wherein

9. L １ is optionally substituted C １ -C ６ Heteroalkylene or optionally substituted C ２ -C ９ The pharmaceutical composition of claim 1 which is a heterocycle.

10. R １ is optionally substituted C ６ -C １０ Aryl, optionally substituted C ２ -C ９ Heterocycle, or optionally substituted C ２ -C ９ Heterocycle C １ -C ６ The pharmaceutical composition of claim 1 , wherein the aryl group is alkyl.

11. R ５ is optionally substituted C ６ -C １０ Aryl or optionally substituted C ２ -C ９ The pharmaceutical composition of claim 1 , wherein the compound is heteroaryl.

12. R ５ is optionally substituted C ２ -C ９ Heterocycle or optionally substituted C ２ -C ９ Heteroaryl C １ -C ６ The pharmaceutical composition of claim 1 , wherein the aryl group is alkyl.

13. 1. A pharmaceutical composition for use in treating a neurological disorder in a subject in need thereof, comprising a compound having the structure of Formula I: 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof, In the formula, Het is 【Chemistry 11】 and m is 0 or 1; n is 0, 1, or 2; o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; X １ is CR ４ and X ２ is N, X ３ is O, L １ is optionally substituted C １ -C ６ Alkylene, optionally substituted C １ -C ６ Alkenylene, optionally substituted C １ -C ６ Heteroalkylene, optionally substituted C ３ -C ７ Cycloalkyl, optionally substituted C ２ -C ９ Heteroaryl, or optionally substituted C ２ -C ９ is a heterocyclic ring, R １ is optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, C １ -C ６ Alkyl, C ２ -C ７ C optionally substituted with 1 to 4 substituents selected from the group consisting of heterocyclyl, halo and cyano ６ -C １０ Aryl, optionally substituted C ３ -C ７ Cycloalkyl, optionally substituted C ２ -C ９ Heteroaryl, or C ２ -C ９ is a heterocyclic ring, R ２ and R ３ each independently represents hydrogen, optionally substituted C １ -C ６ alkyl or, together with the carbon to which they are attached, form a carbonyl; Each R ４ are independently halogen, hydroxyl, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl or two R ４ together with the carbon to which they are attached to form a carbonyl, R ５ is optionally substituted C ６ -C １０ Aryl, or C ６ -C １０ Aryl, C ３ -C １２ Carbocyclyl, halogen, hydroxyl, C １ -C ６ Alkyl, C ２ -C ９ Heterocyclyl, NH ２ , Mono-C １ -C ６ Alkylamino, di-C １ -C ６ C optionally substituted with 1 to 4 substituents selected from alkylamino, azido, cyano, nitro and thiol ２ -C ９ is heteroaryl, Each R ６ are independently hydrogen or optionally substituted C １ -C ６ The pharmaceutical composition, wherein said aryl is alkyl.

14. A pharmaceutical composition for use in treating a neurological disorder in a subject in need thereof, comprising a compound selected from the group consisting of compounds 1 to 966 as set forth in the table below, or a pharma- ceutically acceptable salt thereof: 【Table 1】

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, for use in treating a neurological disorder in a subject in need of such treatment.

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