Inhibitors of TDP-43 and tau aggregation

Abstract

This specification describes compounds, compositions, and methods for regulating inclusion body formation and stress granule formation in cells in connection with the development of neurodegenerative diseases, musculoskeletal diseases, cancer, ophthalmic diseases, and viral infections. In another embodiment, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one of the compounds of the embodiments described above. Another embodiment is a method for treating a subject having a neurodegenerative disease or disorder, comprising administering a pharmaceutically effective amount of one of the pharmaceutical compositions or compounds of the embodiments described above to a subject in need thereof.

Description

[Technical Field]

[0001] Related applications This application claims the benefits and priority of U.S. Provisional Patent Application No. 63 / 489,407, filed on 9 March 2023, which is incorporated herein by reference. [Background technology]

[0002] One characteristic of many neurodegenerative diseases is the accumulation of protein inclusions in the brain and central nervous system. These inclusions are insoluble aggregates of proteins and other cellular components that cause cell damage and dysfunction. Proteins such as tau, α-synuclein, huntingtin, and β-amyloid have all been found to form inclusions in the brain and are associated with the development of numerous neurodegenerative diseases, including Alzheimer's disease and Huntington's disease. Recently, the TDP-43 protein has been identified as one of the major components of protein inclusions that characterize the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia with ubiquitin inclusions (FTLD-U). Since studies have shown that mutations in TDP-43 occur in familial ALS, it appears that biological abnormalities in TDP-43 are sufficient to cause neurodegenerative diseases. In addition, TDP-43 has been found to play a role in the stress granule mechanism. Biological analysis of key proteins that accumulate in other neurodegenerative diseases has significantly advanced our understanding of the pathophysiology of TDP-43 inclusions and led to the development of new drug discovery platforms. Tau aggregation is also thought to be important in the pathological processes of diseases, particularly neurodegenerative diseases.

[0003] Currently, aggregates that accumulate in neurodegenerative diseases such as ALS, FTLD-U, Parkinson's disease, and Huntington's disease are thought to accumulate slowly and be very difficult, or perhaps impossible, to deaggregate. Therefore, there is an unmet need for compositions and methods that can rapidly deaggregate these accumulating proteins, more specifically TDP-43 and tau, or completely inhibit aggregate formation. [Overview of the project]

[0004] In one embodiment, the present disclosure relates to a compound of formula (I): [ka] The formula provides stereoisomers and / or pharmaceutically acceptable salts thereof (wherein: E is a C3-C7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocykryl, or heterocyclyl, and E may be optionally substituted; E' is either absent, or E' is a C3-C7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocykryl, or heterocyclyl, and E' may be optionally substituted; R 3x and R 4 (Each of these is either H or an optional substituent that is independently selected.)

[0005] In some embodiments, E' is absent.

[0006] In another embodiment, the present disclosure relates to a compound of formula (II): [ka] The formula provides stereoisomers and / or pharmaceutically acceptable salts thereof (wherein: Z 1 is N or CR 11 and; Z 2is N or CR 12 ; Z 3 is N or CR 13 ; Z 4 is N or CR 14 ; L 1 is absent or L 1 is C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -S-, or -NR'- where C1-C6 alkylene and C1-C6 heteroalkylene are optionally substituted; A is H, halo, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclic, or heterocyclic and A may be optionally substituted; or A and R 11 together with the atom to which they are attached form an optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclic, or heterocyclic ring; R 11 , R 12 , R 13 , and R 14 are each independently H or an optionally selected substituent; each R' is H or C1-C6 alkyl; R 3x and R 4 are each independently H or an independently selected optionally selected substituent,[[ID=​​​​​​​​​​​​​​​​​​​​ Z 1 is N or CR 11 and; Z 2 is N or CR 12 and; Z 3 is N or CR 13 and; Z 4 is N or CR 14 and; L 1 It does not exist, or L 1 The substituents are C1-C6 alkylenes, C1-C6 heteroalkylenes, -O-, -S-, or -NR'-, where the C1-C6 alkylenes and C1-C6 heteroalkylenes are optionally substituted with 1 to 4 substituents independently selected from =O (oxo), OH, and halogens; A is H, Haro, C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-6 member heteroaryl, C6-C 10 A is a carbocyclyl, or a 5-10 membered heterocyclic ring, where A is one R 1 Substituted by a group, 1 to 4 independently selected R groups 2 Substituted by choice by the base; or A and R 11 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic ring, where the heteroaryl and heterocyclyl rings have 1-3 ring heteroatoms selected from N, O, and S, where each ring has 1 R 1 The base is arbitrarily replaced by 1 to 4 independently selected Rs. 2 It is replaced by choice by the base; R 11 , R 12 , R 13 , and R 14 Each of these independently corresponds to H or R 3 and; R 1 This includes H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C9 heteroalkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -NH2, or -L 2 -G, where C1-C6 alkyl groups may be optionally substituted with OH groups, and where C1-C6 heteroalkyl groups may be optionally substituted with C2-C6 heteroalkynyl groups; L 2 It does not exist, or L 2 The substituents are C1-C6 alkylenes, C1-C6 heteroalkylenes, -O-, -S-, or -NR'-, where the alkylenes and heteroalkylenes are optionally substituted with 1 to 4 substituents independently selected from =O (oxo), OH, and halogens; G is a C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyryl, or 5-10 membered heterocyclyl, where the heterocycloalkyl, heteroaryl, and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, where G has 1-4 R A Substituents may be optionally substituted; Each R A These are independently selected from the group consisting of C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, =O (oxo), OH, -NMe2, -NHMe, -NH2, CN, and halo; Each R 2 These are independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, =O (oxo), OH, -NMe2, -NHMe, -NH2, and halo; Each R 3These are independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, cyano, and halo; R 4 This is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, and halo; Each R' is either H or a C1-C6 alkyl group; R 3X This is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halo; Here, Z 1 , Z 2 , Z 3 , and Z 4 (Two or fewer of these are N)

[0008] In some embodiments, R 3x It is either H or a C1-C6 alkyl group.

[0009] In some embodiments, R 3x is either H or -Me.

[0010] In some embodiments, R 4 The elements are H, halo, C1-C6 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C1-C6 heteroalkyl.

[0011] In some embodiments, R 4 H, -Cl, -Br, -OCF3, -Me, -OMe, -Et, -nPr, -iPr, [ka] The expression is -CH2OCH3, -CH=CH2, or -CH2CH=CH2.

[0012] In some embodiments, Z 1 is CR 11 and Z 2 is CR 12 and Z 3 is CR 13 and Z 4 is CR 14 and Z

[0013] In some embodiments, Z 1 is N, Z 2 is CR 12 and Z 3 is CR 13 and Z 4 is CR 14 and Z

[0014] In some embodiments, Z 1 is CR 11 and Z 2 is N, Z 3 is CR 13 and Z 4 is CR 14 and Z

[0015] In some embodiments, Z 1 is N, Z 2 is CR 12 and Z 3 is N, Z 4 is CR 14 and Z 1

[0016] In some embodiments, Z 1 is N, Z 2 is N, Z 3 is CR 13 and Z 4 is CR 14 and Z

[0017] In some embodiments, Z 1 is CR 11 and Z 2 is N, Z 3 is CR 13 and Z 4 is N

[0018] In some embodiments, R 11 , R 12 , R 13 , and R 14 Each of these independently corresponds to H or R 3 And here, each R 3 The group is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, and halo.

[0019] In some embodiments, R 11 , R 12 , R 13 , and R 14 Each of these independently corresponds to H or R 3 And here, each R 3 These are independently selected from the group consisting of -Me, -Et, -nPr, -iPr, -CF3, -OMe, -OCF3, -OH, -F, and -Cl.

[0020] In some embodiments, L 1 It does not exist.

[0021] In some embodiments, L 1 These are C1-C6 alkylenes, C1-C6 heteroalkylenes, or -O-.

[0022] In some embodiments, L 1 These are -CH2-, -OCH2-, -NHCH2-, -N(CH3)CH2-, or -O-.

[0023] In some embodiments, A is a halo, C1-C 10 Alkyl and C1-C 10 Selected from the group consisting of heteroalkyl groups, where C1~C 10 Alkyl and C1-C 10 Heteroalkyl groups are optionally substituted with =O (oxo).

[0024] In some embodiments, A is -F, -Cl, -Me, -Et, -nPr, -iPr, [ka] -NHCH3, -N(CH3)2, [ka] It is selected from the group consisting of the following.

[0025] In some embodiments, A is a C3-C7 cycloalkyl, a 3-7 member heterocycloalkyl, or a C6-C 10 Aryl, 5-6 member heteroaryl, C6-C 10 Selected from the group consisting of carbocyclyls and 5-10 membered heterocyclic rings, A is one R 1 Substituted by a group, 1 to 4 independently selected R groups 2 It is replaced by arbitrary selection by the base.

[0026] In some embodiments, A is a C3-C7 cycloalkyl, a 3-7 member heterocycloalkyl, or a C6-C 10 Selected from the group consisting of aryls and 5-6 member heteroaryls, A is one R 1 Substituted by a group, 1 to 4 independently selected R groups 2 It is replaced by arbitrary selection by the base.

[0027] In some embodiments, A is [ka] It is selected from the group consisting of the following.

[0028] Several methods of operation, each R 2 The group is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, =O (oxo), -OH, -NMe2, -NHMe, -NH2, and halo.

[0029] Several methods of operation, each R 2These are independently selected from the group consisting of -Me, -Et, -nPr, -iPr, -CF3, -OMe, -OCF3, =O (oxo), -OH, -NMe2, -NHMe, -NH2, F, Cl, and Br.

[0030] In some embodiments, R 1 is H or -L 2 -G

[0031] In some embodiments, R 1 is, -L 2 -G

[0032] In some embodiments, L 2 It does not exist.

[0033] In some embodiments, L 2 The group is selected from the group consisting of C1-C6 alkylenes, C1-C6 heteroalkylenes, and -O-.

[0034] In some embodiments, L 2 It is -CH2-.

[0035] In some embodiments, G is a C3-C7 cycloalkyl or a 3-7 membered heterocycloalkyl, where the 3-7 membered heterocycloalkyl has 1-3 ring heteroatoms selected from N, O, and S, and G has 1-4 R A It may be optionally substituted by substituents.

[0036] In some embodiments, G is a 3- to 7-membered heterocycloalkyl group, where G is a group of 1 to 4 R groups. A It may be optionally substituted by substituents.

[0037] In some embodiments, G is [ka] It is selected from the group consisting of the following.

[0038] In some embodiments, R A These are C1-C6 alkyl groups.

[0039] In some embodiments, G is [ka] It is selected from the group consisting of the following.

[0040] In some embodiments, A is [ka] It is selected from the group consisting of the following.

[0041] In some embodiments, A is [ka] It is selected from the group consisting of the following.

[0042] In some embodiments, A and R 11 These, together with the atoms to which they are bonded, form C3-C7 cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic rings, where heteroaryls and heterocyclyls have 1-3 ring heteroatoms selected from N, O, and S, and each ring has 1 R 1 The base is arbitrarily replaced by 1 to 4 independently selected Rs. 2 It is replaced by arbitrary selection by the base.

[0043] In some embodiments, [ka] teeth, [ka] It is selected from the group consisting of the following.

[0044] In some embodiments, [ka] teeth, [ka] It is selected from the group consisting of the following.

[0045] In some embodiments, the compound is of formula (IIa): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0046] In some embodiments, the compound is of formula (IIb): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0047] In some embodiments, the compound is of formula (IIc): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0048] In some embodiments, the compound is of formula (IId): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0049] In another aspect, the present disclosure relates to a compound of formula (III): [ka] The formula provides stereoisomers and / or pharmaceutically acceptable salts thereof (wherein: X 1 , NR 1O, S, SO2, CH2, or CHR 1 and; X 2 is N or CH; R 1 These include H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C9 heteroalkyl, C1-C6 haloalkyl, -NH2, and -L 2 Selected from the group consisting of -G, where C1-C6 alkyl groups may be optionally substituted with one or more OH groups, and where C1-C6 heteroalkyl groups may be optionally substituted with C2-C6 heteroalkynyl groups; L 2 It does not exist, or L 2 These are C1-C6 alkylenes, C1-C6 heteroalkylenes, -O-, -S-, and -NR'-, where the C1-C6 alkylenes and C1-C6 heteroalkylenes are optionally substituted with 1 to 4 substituents independently selected from the group consisting of =O (oxo), OH, and halogens; G is selected from the group consisting of C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, aryl, 5-6 member heteroaryl, 6-10 member carbocyryl, and 5-10 member heterocyclyl, where the 3-7 member heterocycloalkyl, 5-6 member heteroaryl, and 5-10 member heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and G has 1-4 R A Substituents may be optionally substituted; Each R A These are independently selected from the group consisting of C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, CN, and halo; Each R 2 These are independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, and halo; Each R 3These are independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, cyano, and halo; R 3X This is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halo; R 4 This is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C9 heteroalkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, and halo; Each R' is either H or a C1-C6 alkyl group; m is either 0 or 1; n is either 0 or 1; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4).

[0050] In another aspect, the present disclosure relates to a compound of formula (III): [ka] The formula provides stereoisomers and / or pharmaceutically acceptable salts thereof (wherein: X 1 , NR 1 O, S, SO2, CH2, and CHR 1 Selected from the group consisting of; X 2 is N or CH; R 1 This is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -NH2, and -G; G is selected from the group consisting of C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyryl, and 5-10 membered heterocyclyl, where heterocycloalkyl, heteroaryl, and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, and G has 1-4 R A Substituents may be optionally substituted; Each R A These are independently selected from the group consisting of C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, CN, and halo; Each R 2 These are independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and halo; Each R 3 These are independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halo; R 3X This is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halo; R 4 This is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halo; m is either 0 or 1; n is either 0 or 1; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4).

[0051] In some embodiments, the compound is of formula (IIIa): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0052] In some embodiments, X 1 is NR1 X 2 It is CH.

[0053] In some embodiments, X 1 is CH2 or CHR 1 X 2 It is N.

[0054] In some embodiments, X 1 is NR 1 X 2 It is N.

[0055] In some embodiments, R 1 The group is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, OH, and halo.

[0056] In some embodiments, R 1 -Me, -Et, -nPr, -iPr, -OMe, -OCF3, -OH, -Cl, -F [ka] It is selected from the group consisting of the following.

[0057] In some embodiments, R 3x is either H or -Me.

[0058] In some embodiments, R 3x H is H.

[0059] In some embodiments, R 4 It is -Me.

[0060] In some embodiments, m is 1 and n is 1.

[0061] In some embodiments, m is 0 and n is 1.

[0062] In some embodiments, p is 0.

[0063] In some embodiments, q is 0.

[0064] In some embodiments, the compound is of formula (IIIb): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0065] In some embodiments, the compound is of formula (IIIc): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0066] In some embodiments, the compound is of formula (IIId): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0067] In some embodiments, the compound is of formula (IIIe): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0068] In another aspect, the present disclosure relates to a compound of formula (IV): [ka] The formula provides stereoisomers and / or pharmaceutically acceptable salts thereof (wherein: Z 1 is N or CR 11 and; Z 2 is N or CR 12 and; Z 3 is N or CR 13 and; Z 4 is N or CH; R 11 This is selected from the group consisting of H, -OH, halo, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkoxy; R 12 This is selected from the group consisting of H, -OH, halo, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkoxy; R 13 is H or halo; R 14 R is selected from the group consisting of H, halo, C1-C6 alkylene, C1-C6 heteroalkylene, 5-7 membered aryl, 5-7 membered heteroaryl, and 3-7 membered heterocycloalkyl, where R 14 is one or more R 14a It may also be replaced by optional selection; R 14a These include C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 5-7 membered aryl, 3-7 membered heterocycloalkyl, and -C(O)OR 14b A group consisting of is selected, where C1-C6 alkyl or 3-7 member heterocycloalkyl is one or more R 14b It may also be replaced by optional selection; R 14b The group is selected from the group consisting of -OH, oxo, C1-C6 alkyl, C1-C8 heteroalkyl, C2-C6 alkynyl, and 3-7 membered heterocycloalkyl, where the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6 alkyl groups; Here, Z 2 CR 12 If R 12 and R 14 These may, together with the atoms to which they are bonded, form a cycloalkyl, heterocycloalkyl, or aryl group, where the cycloalkyl or heterocycloalkyl group may be optionally substituted with one or more C1-C6 alkyl or C1-C6 heteroalkyl groups; R 3xis H or C1-C6 alkyl; R 4 (Selected from the group consisting of H, halo, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C1-C6 haloalkoxy).

[0069] In some embodiments, Z 1 CR 11 And Z 2 CR 12 And Z 3 CR 13 And Z 4 It is CH.

[0070] In some embodiments, Z 1 If Z is N, 2 CR 12 And Z 3 CR 13 And Z 4 It is CH.

[0071] In some embodiments, Z 2 If Z is N, 1 CR 11 And Z 3 CR 13 And Z 4 It is CH.

[0072] In some embodiments, Z 2 and Z 3 If Z is N, 1 CR 11 And Z 4 It is CH.

[0073] In some embodiments, Z 2 and Z 4 If Z is N, 1 CR 11 And Z 3 CR 13 That is the case.

[0074] In some embodiments, R 11 and R 12The group is selected from the group consisting of halo, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkoxy.

[0075] In some embodiments, R 11 and R 12 The group is selected from -Me, -Et, -Cl, -F, -OMe, and -OCF3.

[0076] In some embodiments, R 11 or R 12 It is -OH.

[0077] In some embodiments, R 13 It is a halo.

[0078] In some embodiments, R 13 It is -Cl.

[0079] In some embodiments, R 14 The group is selected from H, halo, C1-C3 alkylene, C1-C6 heteroalkylene, phenyl, 5-membered heteroaryl, and 4-6 membered heterocycloalkyl, where C1-C3 alkylene, C1-C6 heteroalkylene, phenyl, 5-membered heteroaryl, and 4-6 membered heterocycloalkyl contain one or more R 14a It may be replaced by optional selection.

[0080] In some embodiments, R 14 ethyl, -O-, -CH2-, -nPr, -iPr, -Cl, NHCH3, -N(CH3)2, [ka] A group consisting of R is selected, where R 14 If it contains a replaceable atom, then that atom is one or more R 14a It may be replaced by optional selection.

[0081] In some embodiments, R 14-Et, -nPr-, -iPr-, -Cl, NHCH3, -N(CH3)2, [ka] A group consisting of R is selected, where R 14 If it contains a replaceable atom, then that atom is one or more R 14a It may be replaced by optional selection.

[0082] In some embodiments, R 14 teeth, [ka] It is selected from the group consisting of the following.

[0083] In some embodiments, R 14a The group is selected from the group consisting of C1-C3 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 6-membered aryl, and 4-6 membered heterocycloalkyl, where C1-C6 heteroalkyl, C3-C7 cycloalkyl, and 5-7 membered aryl are R 14b It may be replaced by optional selection.

[0084] In some embodiments, R 14a -Me, -Et, -CH2-, nPr, [ka] A group consisting of R is selected, where R 14a If it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection.

[0085] In some embodiments, R 14a -Me, -Et, nPr, [ka] A group consisting of R is selected, where R 14aIf it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection.

[0086] In some embodiments, R 14a is -C(O)OR 14b , [ka] It is selected from the group consisting of the following.

[0087] In some embodiments, R 14b The group is selected from the group consisting of oxo, -OH, -Me, C3-C7 heteroalkyl, C2-C3 alkynyl, and 6-membered heterocycloalkyl, where the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6 alkyl groups.

[0088] In some embodiments, R 14b , oxo, -OH, -Me, [ka] A group consisting of the following is selected, where, [ka] This may be optionally substituted with an oxo or C1-C6 alkyl group.

[0089] In some embodiments, R 14b , oxo, -OH, -Me, [ka] A group consisting of the following is selected, where, [ka] This may be replaced by optional selection with -Me.

[0090] In some embodiments, Z 2 CR12 If R 12 and R 14 These may, together with the atoms to which they are bonded, form an aryl, cycloalkyl, or heterocycloalkyl group, where the cycloalkyl or heterocycloalkyl group may be optionally substituted with one or more C1-C6 alkyl or C1-C6 heteroalkyl groups.

[0091] In some embodiments, Z 2 CR 12 If so, the combined R 12 and R 14 teeth, [ka] It is selected from the group consisting of the following.

[0092] In some embodiments, R 3x These are C1-C6 alkyl groups.

[0093] In some embodiments, R 3x It is -Me.

[0094] In some embodiments, R 4 The group is selected from the group consisting of halo, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C1-C6 haloalkoxy.

[0095] In some embodiments, R 4 -Cl, -Br, -OCF3, -Me, -Et, -OMe, [ka] It is selected from the group consisting of the following.

[0096] Another embodiment is a compound selected from any of the compounds listed in Table 1, or from pharmaceutically acceptable salts thereof.

[0097] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of the embodiments described above.

[0098] Another embodiment is a method for treating a subject having a neurodegenerative disease or disorder, comprising administering to the subject in need a pharmaceutically effective amount of any one of the aforementioned embodiments of the pharmaceutical composition or compound.

[0099] In some embodiments, neurodegenerative diseases include Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Huntington's chorea, prion diseases (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, kuru disease, or scrapie), Lewy body dementia, and Diffuse Lewy body disease (DLBD), polyglutamine (polyQ) repeat disease, trinucleotide repeat disease, neurodegenerative diseases, presenile dementia, senile dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, Lewy body dementia, Down syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA type I (e.g., Werdnig-Hoffmann disease), SMA type II, SMAType III (e.g., Kugelberg-Welander disease), or congenital SMA with joint contractures), progressive spinal and bulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative diseases / motor neuron degenerative diseases, upper motor neuron disorders, lower motor neuron disorders, age-related diseases and dementia, Haller-Holden-Spats syndrome, cerebral infarction, traumatic brain injury, chronic traumatic brain injury, transient ischemic attack, Ritico-Bodig disease (amyotrophic lateral sclerosis - Parkinson's dementia), Guam-Parkinson's dementia, hippocampal sclerosis, corticobasal ganglia The group consists of degenerative diseases, Alexander disease, Alpers disease, Krabbe disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder disease, Batten disease, Cockayne syndrome, Kahns-Sayer syndrome, Gerstmann-Strössler-Scheinker syndrome and other transmissible spongiform encephalopathy, hereditary spastic paraplegia, Leigh syndrome, demyelinating diseases, neuronal ceroid lipofuscinosis, epilepsy, tremor, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injury (e.g., stroke, head injury), and autism, or any combination thereof.

[0100] In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).

[0101] In some embodiments, the neurodegenerative disease is Alzheimer's disease. [Brief explanation of the drawing]

[0102] [Figure 1]This study demonstrates that compound 183 prevents the nuclear clearance of TDP-43 after proteasome inhibition. Exemplary micrographs of iP11NA human motor neurons are shown immunostained for TDP-43 (green) and β-III tubulin (red), counterstained with Hoechst (blue), unstressed, treated with MG-132 (1 μM), or treated with a combination of compound 183 (500 nM) and MG-132 (1 μM). Magnified images from the three conditions highlight the changes from nuclear TDP-43 in unstressed neurons to diffuse intracellular staining under proteasome stress, and to the maintenance of nuclear TDP-43 in the presence of compound 183. [Figure 2-1] This shows that compound 183 maintains nuclear TDP-43 in a dose-dependent manner. (a) Exemplary micrographs of iP11NA human motor neurons treated with MG-132 (1 μM) and compound 183 (indicated concentrations), immunostained for TDP-43 (green), β-III tubulin (pink), and human nuclear antigen (red), and counterstained with Hoechst (blue). (b) Differences in TDP-43 immunostaining intensity (nucleus (ROI)-cytoplasmic (ROI)) for unstressed (gray) or human motor neurons treated with MG-132 (red, 1 μM) and compound 183 (indicated concentrations). Data are presented as points representing replicated wells, along with mean and standard deviation. Statistical analysis was performed using one-way ANOVA and Dunnett's multiple comparison test. [Figure 2-2] Same as above. [Figure 3] Compound 183 reduces aggregated TDP-43, a pathological feature of ALS, and restores nuclear localization of TDP-43. Immunoblot analysis of TDP-43 in the indicated fractions is performed from unstressed neurons, neurons treated with MG-132 (1 μM), or neurons treated with a combination of compound 183 (500 nM) and MG-132 (1 μM). Data are presented as bars with standard deviation. Statistical analysis was performed using one-way ANOVA and Dunnett's multiple comparison test. [Figure 4-1]This study demonstrates that proteasome inhibition induces splicing changes associated with TDP-43 loss of function. The expression of TDP-43 sentinel transcripts (STMN2, ELAVL3, and PFKP) in human motor neurons treated with puromycin (10 mg / mL) or MG-132 (1 μM) was compared to that of unstressed samples using qRT-PCR analysis. Data are presented as points representing replicate wells, along with the mean and standard deviation. [Figure 4-2] Same as above. [Figure 5-1] This study demonstrates that compound 183 restores the TDP-43 splicing function lost in ALS. The results were obtained by qRT-PCR analysis comparing the expression of TDP-43 sentinel transcripts (STMN2, ELAVL3, and PFKP) in human motor neurons treated with MG-132 (1 μM) and compound 183 (500 nM) with that of an MG-132 (1 μM) control. [Figure 5-2] Same as above. [Figure 6-1] Compound 183 demonstrates dose-dependent restoration of TDP-43 splicing function. The expression of TDP-43 sentinel transcripts (STMN2, ELAVL3, and PFKP) in human motor neurons treated with MG-132 (1 μM) and compound 183 (indicated concentrations) was compared to an MG-132 (1 μM) control using qRT-PCR analysis. Data are presented as points representing replicate wells, along with mean and standard deviation. Statistical analysis was performed using one-way ANOVA and Dunnett's multiple comparison test. [Figure 6-2] Same as above. [Modes for carrying out the invention]

[0103] Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease or Charcot's disease, is a fatal neurodegenerative disease occurring in approximately 1 in 100,000 people. Currently, there is no cure for ALS, and the average survival time for patients from the onset of the disease is roughly 4 years. ALS presents with motor paralysis of the distal limbs, which rapidly progresses to the proximal limbs. Studies over the past decade have shown that TDP-43 is the major protein that accumulates in affected motor neurons in sporadic ALS. The cause of sporadic ALS is unknown, but the identification of the major pathological species that accumulate in the spinal cord of ALS patients is a valuable advance in ALS research. To date, TDP-43 is the only protein that is genetically and pathologically associated with sporadic ALS, which represents the dominant form of the disease. Multiple studies have identified TDP-43 mutations associated with sporadic and familial ALS. Inhibitors of TDP-43-related cell death and inclusion bodies represent a novel therapeutic approach for ALS and may also elucidate the biochemical pathways involved in TDP-43 inclusion body formation. Therefore, TDP-43 is one of the most promising targets for drug therapy in ALS.

[0104] TDP-43 is a nuclear RNA-binding protein that translocates to the cytoplasm when cellular stress occurs, where it forms cytoplasmic inclusions. These inclusions then co-localize with reversible protein-mRNA aggregates called "stress granules" (SGs). Under many stress-inducing conditions (e.g., arsenite treatment, nutrient deficiency), TDP-43 can co-localize with SGs. The reversible nature of SG-based aggregation provides a biological pathway that can be applied to reverse the pathology and toxicity associated with TDP-43 inclusion formation. Studies have shown that drugs that inhibit SG formation also inhibit TDP-43 inclusion formation. The relationship between TDP-43 and stress granules is important because using the physiological pathways that normally regulate this reversible SG process could lead to novel methods for dispersing TDP-43 inclusions. By investigating specific elements of the SG pathway that regulate TDP-43 inclusion formation, selective approaches for therapeutic interventions that can delay or halt disease progression can be identified. The biology of stress granules also regulates autophagy and apoptosis, both of which are associated with neurodegeneration. Therefore, compounds that inhibit TDP-43 aggregation may play a role in inhibiting neurodegeneration.

[0105] Tau is a protein known to be present in numerous pathological conditions, particularly neurodegenerative disorders including Alzheimer's disease. Therefore, compounds that inhibit tau aggregation can play a role in inhibiting neurodegeneration.

[0106] compound Therefore, in one embodiment, the present disclosure relates to a compound of formula (I): [ka] The formula provides stereoisomers and / or pharmaceutically acceptable salts thereof (wherein: E is a C3-C7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocykryl, or heterocyclyl, and E may be optionally substituted; E' is either absent, or E' is a C3-C7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocykryl, or heterocyclyl, and E' may be optionally substituted; R 3x and R 4 (Each of these is either H or an optional substituent that is independently selected.)

[0107] In some embodiments, E' is absent. In some embodiments, E' is a C3-C7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocykryl, or heterocyclyl, and E' may be optionally substituted.

[0108] In some embodiments, the compound is of formula (Ia): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0109] In some embodiments, the compound is of formula (II): [ka] or its stereoisomer and / or pharmaceutically acceptable salt (in the formula: Z 1 is N or CR 11 and; Z 2 is N or CR 12 and; Z 3 is N or CR 13 and; Z 4 is N or CR 14 and; L 1 It does not exist, or L 1These are C1-C6 alkylenes, C1-C6 heteroalkylenes, -O-, -S-, or -NR'-, where the C1-C6 alkylenes and C1-C6 heteroalkylenes are substituted by arbitrary selection; A is H, halo, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocykrill, or heterocyclyl, and A may be optionally substituted; or A and R 11 These, together with the atoms to which they are bonded, form optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclic, or heterocyclic rings; R 11 , R 12 , R 13 , and R 14 Each of these is independently H or an optional substituent; Each R' is either H or a C1-C6 alkyl group; R 3x and R 4 Each of them is independently H, or an independently selected substituent by any choice. Here, Z 1 , Z 2 , Z 3 , and Z 4 (Two or fewer of these are N)

[0110] In some embodiments, the compound is of formula (II): [ka] or its stereoisomer and / or pharmaceutically acceptable salt (in the formula: Z 1 is N or CR 11 and; Z 2 is N or CR 12 and; Z 3 is N or CR 13 and; Z 4is N or CR 14 and; L 1 It does not exist, or L 1 The substituents are C1-C6 alkylenes, C1-C6 heteroalkylenes, -O-, -S-, or -NR'-, where the C1-C6 alkylenes and C1-C6 heteroalkylenes are optionally substituted with 1 to 4 substituents independently selected from =O (oxo), OH, and halogens; A is H, Haro, C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-6 member heteroaryl, C6-C 10 A is a carbocyclyl, or a 5-10 membered heterocyclic ring, where A is one R 1 Substituted by a group, 1 to 4 independently selected R groups 2 Substituted by choice by the base; or A and R 11 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic ring, where the heteroaryl and heterocyclyl rings have 1-3 ring heteroatoms selected from N, O, and S, where each ring has 1 R 1 The base is arbitrarily replaced by 1 to 4 independently selected Rs. 2 It is replaced by choice by the base; R 11 , R 12 , R 13 , and R 14 Each of these independently corresponds to H or R 3 and; R 1 This includes H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -NH2, or -L 2 -G is; L 2 It does not exist, or L 2The substituents are C1-C6 alkylenes, C1-C6 heteroalkylenes, -O-, -S-, or -NR'-, where the alkylenes and heteroalkylenes are optionally substituted with 1 to 4 substituents independently selected from =O (oxo), OH, and halogens; G is a C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, aryl, 5-6 member heteroaryl, 6-10 member carbocykryl, or 5-10 member heterocyclyl, where the 3-7 member heterocycloalkyl, 5-6 member heteroaryl, and 5-10 member heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, where G has 1-4 R A Substituents may be optionally substituted; Each R A These are independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, =O (oxo), OH, -NMe2, -NHMe, -NH2, CN, and halo; Each R 2 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, =O (oxo), OH, -NMe2, -NHMe, -NH2, or halo; Each R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, cyano, or halo; R 4 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cyano, or halo; Each R' is either H or a C1-C6 alkyl group; R 3x is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halo; Here, Z1 , Z 2 , Z 3 , and Z 4 (Two or fewer of these are N)

[0111] In some embodiments, R 3x is H or C1-C6 alkyl. In some embodiments, R 3x is H or -Me. In some embodiments, R 3x H is H. In some embodiments, R 3x It is -Me.

[0112] In some embodiments, R 4 The group is H, C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 heteroalkyl.

[0113] In some embodiments, R 4 H, -Me, -Et, -nPr, -iPr, [ka] The expression is -CH2OCH3, -CH=CH2, or -CH2CH=CH2.

[0114] In some embodiments, Z 1 CR 11 And Z 2 CR 12 And Z 3 CR 13 And Z 4 CR 14 In some embodiments, Z 1 is N, Z 2 CR 12 Yes, Z 3 CR 13 And Z 4 CR 14 In some embodiments, Z 1 CR 11 And Z 2 is N, Z 3 CR 13 And Z 4 CR 14In some embodiments, Z 1 is N, Z 2 CR 12 And Z 3 is N, Z 4 CR 14 In some embodiments, Z 1 is N, Z 2 is N, Z 3 CR 13 And Z 4 CR 14 In some embodiments, Z 1 CR 11 And Z 2 is N, Z 3 CR 13 And Z 4 It is N.

[0115] In some embodiments, R 11 , R 12 , R 13 , and R 14 Each of these independently corresponds to H or R 3 And here, each R 3 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or halo.

[0116] In some embodiments, R 11 , R 12 , R 13 , and R 14 Each of these independently corresponds to H or R 3 And here, each R 3 These are independently -Me, -Et, -nPr, -iPr, -CF3, -OMe, -OCF3, -OH, -F, or -Cl.

[0117] In some embodiments, R 11 H is H. In some embodiments, R 12 H is H. In some embodiments, R 13 H is H. In some embodiments, R 14 H is H. In some embodiments, R 11 , R12 , R 13 , R 14 Each of these is H.

[0118] In some embodiments, L 1 It does not exist.

[0119] In some embodiments, L 1 These are C1-C6 alkylenes, C1-C6 heteroalkylenes, or -O-.

[0120] In some embodiments, L 1 is -CH2-, -OCH2-, -NHCH2-, -N(CH3)CH2-, or -O-. In some embodiments, L 1 is -CH2-. In some embodiments, L 1 is -OCH2-. In some embodiments, L 1 is -NHCH2-. In some embodiments, L 1 is -N(CH3)CH2-. In some embodiments, L 1 It is -O-.

[0121] In some embodiments, A is a halo, C1-C 10 Alkyl, or C1-C 10 It is a heteroalkyl group, where C1~C 10 Alkyl and C1-C 10 Heteroalkyl groups are optionally substituted with =O (oxo).

[0122] In some embodiments, A is -F, -Cl, -Me, -Et, -nPr, -iPr, [ka] -NHCH3, -N(CH3)2, [ka] That is the case.

[0123] In some embodiments, A is a C3-C7 cycloalkyl, a 3-7 member heterocycloalkyl, or a C6-C 10 Aryl, 5-6 member heteroaryl, C6-C 10 A is a carbocyclyl, or a 5-10 membered heterocyclic ring, where A is one R 1 Substituted by a group, 1 to 4 independently selected R groups 2 It is replaced by arbitrary selection by the base.

[0124] In some embodiments, A is a C3-C7 cycloalkyl, a 3-7 member heterocycloalkyl, or a C6-C 10 It is an aryl or 5-6 member heteroaryl, where A is one R 1 Substituted by a group, 1 to 4 independently selected R groups 2 It is replaced by arbitrary selection by the base.

[0125] In some embodiments, A is [ka] That is the case.

[0126] In some embodiments, A is [ka] That is the case.

[0127] In some embodiments, A is [ka] That is the case.

[0128] In some embodiments, A is [ka] That is the case.

[0129] In some embodiments, A is [ka] That is the case.

[0130] In some embodiments, A is [ka] That is the case.

[0131] In some embodiments, A is [ka] That is the case.

[0132] In some embodiments, A is [ka] That is the case.

[0133] In some embodiments, A is [ka] That is the case.

[0134] In some embodiments, A is [ka] That is the case.

[0135] In some embodiments, A is [ka] That is the case.

[0136] In some embodiments, A is [ka] That is the case.

[0137] In some embodiments, A is [ka] That is the case.

[0138] In some embodiments, A is [ka] That is the case.

[0139] In some embodiments, A is [ka] That is the case.

[0140] In some embodiments, A is [ka] That is the case.

[0141] In some embodiments, A is [ka] That is the case.

[0142] In some embodiments, A is [ka] That is the case.

[0143] In some embodiments, A is [ka] That is the case.

[0144] In some embodiments, A is [ka] That is the case.

[0145] In some embodiments, A is [ka] That is the case.

[0146] Several methods of operation, each R 2 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, =O (oxo), -OH, -NMe2, -NHMe, -NH2, or halo.

[0147] Several methods of operation, each R 2 These are independently -Me, -Et, -nPr, -iPr, -CF3, -OMe, -OCF3, =O (oxo), -OH, -NMe2, -NHMe, -NH2, F, Cl, or Br.

[0148] In some embodiments, R 1 is H or -L 2 -G. In some embodiments, R 1 H is H. In some embodiments, R 1 is, -L 2 -G

[0149] In some embodiments, L 2 It does not exist. In some embodiments, L 2 is a C1-C6 alkylene, a C1-C6 heteroalkylene, or -O-. In some embodiments, L 2 It is -CH2-.

[0150] In some embodiments, G is a C3-C7 cycloalkyl or a 3-7 membered heterocycloalkyl, where the 3-7 membered heterocycloalkyl has 1-3 ring heteroatoms selected from N, O, and S, and G has 1-4 R A It may be optionally substituted by substituents.

[0151] In some embodiments, G is a 3- to 7-membered heterocycloalkyl group, where G is a group of 1 to 4 R groups. A It may be optionally substituted by substituents.

[0152] In some embodiments, G is [ka] That is the case.

[0153] Several methods of operation, each R A These are independently selected from C1-C6 alkyl groups.

[0154] In some embodiments, G is [ka] That is the case.

[0155] In some embodiments, A is [ka] That is the case.

[0156] In some embodiments, A is [ka] That is the case.

[0157] In some embodiments, A and R 11 These, together with the atoms to which they are bonded, form C3-C7 cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic rings, where heteroaryls and heterocyclyls have 1-3 ring heteroatoms selected from N, O, and S, and each ring has 1 R 1 The base is arbitrarily replaced by 1 to 4 independently selected Rs. 2 It is replaced by arbitrary selection by the base.

[0158] In some embodiments, [ka] teeth, [ka] That is the case.

[0159] In some embodiments, [ka] teeth, [ka] That is the case.

[0160] In some embodiments, [ka] teeth, [ka] That is the case.

[0161] In some embodiments, [ka] teeth, [ka] That is the case.

[0162] In some embodiments, [ka] teeth, [ka] That is the case.

[0163] In some embodiments, [ka] teeth, [ka] That is the case.

[0164] In some embodiments, [ka] teeth, [ka] That is the case.

[0165] In some embodiments, [ka] teeth, [ka] That is the case.

[0166] In some embodiments, [ka] teeth, [ka] That is the case.

[0167] In some embodiments, [ka] teeth, [ka] That is the case.

[0168] In some embodiments, [ka] teeth, [ka] That is the case.

[0169] In some embodiments, [ka] teeth, [ka] That is the case.

[0170] In some embodiments, [ka] teeth, [ka] That is the case.

[0171] In some embodiments, [ka] teeth, [ka] That is the case.

[0172] In some embodiments, [ka] teeth, [ka] That is the case.

[0173] In some embodiments, [ka] teeth, [ka] That is the case.

[0174] In some embodiments, [ka] teeth, [ka] That is the case.

[0175] In some embodiments, the compound is of formula (IIa): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0176] In some embodiments, the compound is of formula (IIb): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0177] In some embodiments, the compound is of formula (IIc): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0178] In some embodiments, the compound is of formula (IId): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0179] In some embodiments, the compound is of formula (III): [ka] or its stereoisomer and / or pharmaceutically acceptable salt (in the formula: X 1 , NR 1 O, S, SO2, CH2, or CHR1 and; X 2 is N or CH; R 1 This includes H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -NH2, or -L 2 -G is; L 2 It does not exist, or L 2 The substituents are C1-C6 alkylenes, C1-C6 heteroalkylenes, -O-, -S-, or -NR'-, where the alkylenes and heteroalkylenes are optionally substituted with 1 to 4 substituents independently selected from =O (oxo), OH, and halogens; G is a C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyryl, or 5-10 membered heterocyclyl, where the heterocycloalkyl, heteroaryl, and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, where G has 1-4 R A Substituents may be optionally substituted; Each R A These are independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, CN, or halo; Each R 2 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, or halo; Each R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, cyano, or halo; R 3x is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halo; R 4 These are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cyano, or halo; Each R' is either H or a C1-C6 alkyl group; m is either 0 or 1; n is either 0 or 1; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4).

[0180] In some embodiments, the compound is of formula (III): [ka] or its stereoisomer and / or pharmaceutically acceptable salt (in the formula: X 1 , NR 1 O, S, SO2, CH2, or CHR 1 and; X 2 is N or CH; R 1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -NH2, or -G; G is a C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocyryl, or 5-10 membered heterocyclyl, where the heterocycloalkyl, heteroaryl, and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, where G has 1-4 R A Substituents may be optionally substituted; Each R A These are independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, CN, or halo; Each R 2These are independently C1-C6 alkyl, C1-C6 haloalkyl, or halo; Each R 3 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halo; R 3x is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halo; R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halo; m is either 0 or 1; n is either 0 or 1; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4).

[0181] In some embodiments, X 1 , NR 1 In some embodiments, X 1 CH2 or CHR 1 That is the case.

[0182] In some embodiments, X 2 is CH. In some embodiments, X 2 It is N.

[0183] In some embodiments, X 1 is NR 1 X 2 It is CH.

[0184] In some embodiments, X 1 is CH2 or CHR 1 X 2 It is N.

[0185] In some embodiments, X 1 is NR 1 X 2 It is N.

[0186] In some embodiments, R 1 These are C1-C6 alkyl groups.

[0187] In some embodiments, R 1 -Me, -Et, -nPr, -iPr, [ka] That is the case.

[0188] In some embodiments, R 3x is H or C1-C6 alkyl. In some embodiments, R 3x is H or -Me. In some embodiments, R 3x H is H. In some embodiments, R 3x It is -Me.

[0189] In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 -Me, -Et, -nPr, -iPr, [ka] In some embodiments, R 4 is -Me. In some embodiments, R 4 R is a halo, a C1-C6 haloalkoxy, or a C1-C6 alkoxy. In some embodiments, R 4 -Cl, -Br, -OCF3, -OMe, [ka] That is the case.

[0190] In some embodiments, m is 0. In some embodiments, m is 1.

[0191] In some embodiments, n is 0. In some embodiments, n is 1.

[0192] In some embodiments, m is 1 and n is 1. In some embodiments, m is 0 and n is 1.

[0193] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0194] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0195] In some embodiments, the compound is of formula (IIIa): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0196] In some embodiments, the compound is of formula (IIIb): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0197] In some embodiments, the compound is of formula (IIIc): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0198] In some embodiments, the compound is of formula (IIId): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0199] In some embodiments, the compound is of formula (IIIe): [ka] or its stereoisomers and / or pharmaceutically acceptable salts.

[0200] In some embodiments, the present disclosure relates to a compound of formula (IV): [ka] The formula provides stereoisomers and / or pharmaceutically acceptable salts thereof (wherein: Z 1 is N or CR 11 and; Z 2 is N or CR 12 and; Z 3 is N or CR 13 and; Z 4 is N or CH; R 11 This is selected from the group consisting of H, -OH, halo, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkoxy; R 12 This is selected from the group consisting of H, -OH, halo, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkoxy; R 13 is H or halo; R 14 R is selected from the group consisting of H, halo, C1-C6 alkylene, C1-C6 heteroalkylene, 5-7 membered aryl, 5-7 membered heteroaryl, and 3-7 membered heterocycloalkyl, where R 14 is one or more R 14a It may also be replaced by optional selection; R 14a These include C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 5-7 membered aryl, 3-7 membered heterocycloalkyl, and -C(O)OR14b A group consisting of is selected, where C1-C6 alkyl or 3-7 member heterocycloalkyl is one or more R 14b It may also be replaced by optional selection; R 14b The group is selected from the group consisting of -OH, oxo, C1-C6 alkyl, C1-C8 heteroalkyl, C2-C6 alkynyl, and 3-7 membered heterocycloalkyl, where the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6 alkyl or C1-C6 heteroalkyl groups; Here, Z 2 CR 12 If R 12 and R 14 These may, together with the atoms to which they are bonded, form a cycloalkyl, heterocycloalkyl, or aryl group, where the cycloalkyl or heterocycloalkyl group may be optionally substituted with one or more C1-C6 alkyl or C1-C6 heteroalkyl groups; R 3x is H or C1-C6 alkyl; R 4 (Selected from the group consisting of H, halo, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C1-C6 haloalkoxy).

[0201] In some embodiments, Z 1 CR 11 And Z 2 CR 12 And Z 3 CR 13 And Z 4 It is CH.

[0202] In some embodiments, Z 1 If Z is N, 2 CR 12 And Z 3 CR 13 And Z 4 It is CH.

[0203] In some embodiments, Z2 If Z is N, 1 CR 11 And Z 3 CR 13 And Z 4 It is CH.

[0204] In some embodiments, Z 2 and Z 3 If Z is N, 1 CR 11 And Z 4 It is CH.

[0205] In some embodiments, Z 2 and Z 4 If Z is N, 1 CR 11 And Z 3 CR 13 That is the case.

[0206] In some embodiments, R 11 The group is selected from the group consisting of halo, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkoxy.

[0207] In some embodiments, R 12 The group is selected from the group consisting of halo, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkoxy.

[0208] In some embodiments, R 11 The group is selected from -Me, -Et, -Cl, -F, -OMe, and -OCF3.

[0209] In some embodiments, R 12 The group is selected from -Me, -Et, -Cl, -F, -OMe, and -OCF3.

[0210] In some embodiments, R 11 It is -OH.

[0211] In some embodiments, R 12It is -OH.

[0212] In some embodiments, R 13 It is a halo.

[0213] In some embodiments, R 13 It is -Cl.

[0214] In some embodiments, R 14 The group is selected from H, halo, C1-C3 alkylene, C1-C6 heteroalkylene, 6-membered aryl, 5-membered heteroaryl, and 4-6 membered heterocycloalkyl, where C1-C3 alkylene, C1-C6 heteroalkylene, 6-membered aryl, 5-membered heteroaryl, and 4-6 membered heterocycloalkyl contain one or more R 14a It may be replaced by optional selection.

[0215] In some embodiments, R 14 -Et, -O-, -CH2-, -nPr, -iPr, -Cl, NHCH3, -N(CH3)2, [ka] A group consisting of R is selected, where R 14 If it contains a replaceable atom, then that atom is one or more R 14a It may be replaced by optional selection. In some embodiments, R 14 R is selected from the group consisting of -Et, -O-, -CH2-, -nPr, -iPr, and -Cl, where R 14 If it contains a replaceable atom, then that atom is one or more R 14a It may be replaced by optional selection. In some embodiments, R 14 NHCH3, -N(CH3)2, [ka] A group consisting of R is selected, where R 14 If it contains a replaceable atom, then that atom is one or more R 14aIt may be replaced by optional selection. In some embodiments, R 14 teeth, [ka] A group consisting of R is selected, where R 14 If it contains a replaceable atom, then that atom is one or more R 14a It may be replaced by optional selection.

[0216] In some embodiments, R 14 -Et, -nPr-, -iPr-, -Cl, NHCH3, -N(CH3)2, [ka] A group consisting of R is selected, where R 14 If it contains a replaceable atom, then that atom is one or more R 14a It may be replaced by optional selection. In some embodiments, R 14 R is selected from the group consisting of -Et, -nPr, -iPr, and -Cl, where R 14 If it contains a replaceable atom, then that atom is one or more R 14a It may be replaced by optional selection. In some embodiments, R 14 NHCH3, -N(CH3)2, [ka] A group consisting of R is selected, where R 14 If it contains a replaceable atom, then that atom is one or more R 14a It may be replaced by optional selection. In some embodiments, R 14 teeth, [ka] A group consisting of R is selected, where R 14 If it contains a replaceable atom, then that atom is one or more R 14a It may be replaced by optional selection.

[0217] In some embodiments, R 14 teeth, [ka] Selected from the group consisting of. In some embodiments, R 14 teeth, [ka] Selected from the group consisting of. In some embodiments, R 14 teeth, [ka] It is selected from the group consisting of the following.

[0218] In some embodiments, R 14a The group is selected from the group consisting of C1-C3 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 6-membered aryl, and 4-6 membered heterocycloalkyl, where C1-C6 heteroalkyl, C3-C7 cycloalkyl, and 5-7 membered aryl are R 14b It may be replaced by optional selection.

[0219] In some embodiments, R 14a -Me, -Et, -CH2-, nPr, [ka] A group consisting of R is selected, where R 14a If it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection. In some embodiments, R 14a R is selected from the group consisting of -Me, -Et, -CH2-, and nPr, where R 14a If it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection. In some embodiments, R 14a teeth, [ka] A group consisting of R is selected, where R 14a If it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection. In some embodiments, R 14a teeth, [ka] A group consisting of R is selected, where R 14a If it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection.

[0220] In some embodiments, R 14a -Me, -Et, nPr, [ka] A group consisting of R is selected, where R 14a If it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection. In some embodiments, R 14a is selected from the group consisting of -Me, -Et, and nPr, where R 14a If it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection. In some embodiments, R 14a teeth, [ka] A group consisting of R is selected, where R 14a If it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection. In some embodiments, R 14a teeth, [ka] A group consisting of R is selected, where R 14aIf it contains a replaceable atom, then that atom is one or more R 14b It may be replaced by optional selection.

[0221] In some embodiments, R 14a is -C(O)OR 14b , [ka] It is selected from the group consisting of the following.

[0222] In some embodiments, R 14b R is selected from the group consisting of oxo, -OH, -Me, C3-C7 heteroalkyl, C2-C3 alkynyl, and 6-membered heterocycloalkyl, where the 3-7 membered heterocycloalkyl may be optionally substituted with one or more C1-C6 alkyl groups. In some embodiments, R 14b The group is selected from the group consisting of oxo, -OH, and -Me.

[0223] In some embodiments, R 14b , oxo, -OH, -Me, [ka] A group consisting of the following is selected, where, [ka] R may be optionally substituted with an oxo or C1-C6 alkyl group. In some embodiments, R 14b These are oxo, -OH, -Me, and [ka] Selected from the group consisting of. In some embodiments, R 14b This may be optionally substituted with an oxo or C1-C6 alkyl group.

[0224] In some embodiments, R 14b , oxo, -OH, -Me, [ka] A group consisting of the following is selected, where, [ka] This may be optionally replaced with -Me. In some embodiments, R 14b This may be replaced by optional selection with -Me.

[0225] In some embodiments, Z 2 CR 12 If R 12 and R 14 These may, together with the atoms to which they are bonded, form an aryl, cycloalkyl, or heterocycloalkyl group, where the cycloalkyl or heterocycloalkyl group may be optionally substituted with one or more C1-C6 alkyl or C1-C6 heteroalkyl groups.

[0226] In some embodiments, Z 2 CR 12 If so, the combined R 12 and R 14 teeth, [ka] Selected from the group consisting of. In some embodiments, the combined R 12 and R 14 teeth, [ka] In some embodiments, Z 2 CR 12 If so, the combined R 12 and R 14 teeth, [ka] Selected from the group consisting of. In some embodiments, Z 2 CR 12If so, the combined R 12 and R 14 teeth, [ka] It is selected from the group consisting of the following.

[0227] In some embodiments, R 3x is a C1-C6 alkyl group. In some embodiments, R 3x These are C1-C3 alkyl groups.

[0228] In some embodiments, R 3x is -Me. In some embodiments, R 3x is -Et. In some embodiments, R 3x is nPr. In some embodiments, R 3x It is iPr.

[0229] In some embodiments, R 4 The group is selected from the group consisting of halo, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, and C1-C6 haloalkoxy.

[0230] In some embodiments, R 4 -Cl, -Br, -OCF3, -Me, -Et, -OMe, [ka] Selected from the group consisting of. In some embodiments, R 4 R4 is selected from the group consisting of -Cl, -Br, -OCF3, -Me, -Et, and -OMe. In some embodiments, R4 is [ka] It is selected from the group consisting of the following.

[0231] In some embodiments, the compound is selected from the compounds disclosed in the specification or drawings.

[0232] In some embodiments, pharmaceutical compositions are provided comprising a pharmaceutically acceptable carrier and a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0233] In some embodiments, the compound of formula (I), (II), (III), or (IV) is selected from the compounds disclosed in the specification or drawings.

[0234] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one of the compounds disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0235] In some embodiments, the compounds of formula (I), (II), (III), or (IV) or their subformulas are selected from the compounds in Table 1.

[0236] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 [Table 1-60] [Table 1-61] [Table 1-62] [Table 1-63] [Table 1-64] [Table 1-65] [Table 1-66]

[0237] Treatment method and method of use In the following methods, the use of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts) may also refer to the use of a pharmaceutical composition containing the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts). In some embodiments, the disclosure provides a method for treating subjects in need of treatment for neurodegenerative diseases or disorders, musculoskeletal diseases or disorders, cancer, ophthalmic diseases or disorders (e.g., retinal diseases or disorders), or viral infections, the method generally involves administering an effective amount of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts) to subjects in need.

[0238] In some embodiments, the subjects suffer from neurodegenerative diseases or disorders. In some embodiments, the subjects suffer from musculoskeletal diseases or disorders. In some embodiments, the subjects suffer from cancer. In some embodiments, the subjects suffer from ophthalmic diseases or disorders (e.g., retinal diseases or disorders). In some embodiments, the subjects suffer from viral infections.

[0239] In some embodiments, the present disclosure provides a method for treating a neurodegenerative disease or disorder, the method comprising administering to a subject in need an effective amount of one of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or a subformula thereof, or compounds of Table 1, or pharmaceutically acceptable salts thereof).

[0240] In some embodiments, the present disclosure provides a method for treating a musculoskeletal disorder or disability, the method comprising administering to a subject in need an effective amount of one of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or a subformula thereof, or compounds of Table 1, or pharmaceutically acceptable salts thereof).

[0241] In some embodiments, the present disclosure provides a method for treating cancer, the method comprising administering to a subject in need of it an effective amount of one of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or a subformula thereof, or compounds of Table 1, or pharmaceutically acceptable salts thereof).

[0242] In some embodiments, the present disclosure provides a method for treating an ophthalmic disease or disorder (e.g., a retinal disease or disorder) the method comprises administering an effective amount of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or subformulas thereof, or compounds of Table 1, or pharmaceutically acceptable salts thereof) to a subject in need thereof.

[0243] In some embodiments, the present disclosure provides a method for treating a viral infection, the method comprising administering to a subject in need an effective amount of one of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or a subformula thereof, or compounds of Table 1, or pharmaceutically acceptable salts thereof).

[0244] In some embodiments, the method further includes the step of diagnosing the subject with a musculoskeletal neurodegenerative disease or disorder, a musculoskeletal disease or disorder, cancer, an ophthalmic disease or disorder (e.g., a retinal disease or disorder), or a viral infection before administering any of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or compounds of Table 1, or pharmaceutically acceptable salts thereof).

[0245] In some embodiments, the method further includes the step of diagnosing a subject with a neurodegenerative disease or disorder before administering any of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof).

[0246] In some embodiments, the method further includes the step of diagnosing a subject with a neurodegenerative disease or disorder before administering any of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof).

[0247] In some embodiments, the method further includes the step of diagnosing a subject with a musculoskeletal disorder or disability before administering any of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof).

[0248] In some embodiments, the method further includes the step of diagnosing a subject with cancer before administering any of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof).

[0249] In some embodiments, the method further includes the step of diagnosing the subject with an ophthalmic disease or disorder (e.g., a retinal disease or disorder) before administering any of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof).

[0250] In some embodiments, the method further includes the step of diagnosing a subject with a viral infection before administering any of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof).

[0251] In another embodiment, the Disclosure provides a method for diagnosing neurodegenerative diseases, musculoskeletal diseases, cancers, ophthalmic diseases (e.g., retinal diseases), or viral infections in a subject, the method generally comprising administering a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound in Table 1, or a pharmaceutically acceptable salt thereof) to the subject.

[0252] In some embodiments, the present disclosure provides a method for diagnosing neurodegenerative diseases in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to the subject.

[0253] In some embodiments, the present disclosure provides a method for diagnosing musculoskeletal disorders in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0254] In some embodiments, the present disclosure provides a method for diagnosing cancer in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0255] In some embodiments, the present disclosure provides a method for diagnosing an ophthalmic disease (e.g., a retinal disease) in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0256] In some embodiments, the present disclosure provides a method for diagnosing a viral infection in a subject, the method comprising administering a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0257] In some embodiments, the subject is a mammal. In some embodiments, the subject is a nematode. In some embodiments, the subject is a human.

[0258] Stress granules and TDP-43 The term "containing stress granules" means that the number of stress granules within the target cells changes compared to a control or healthy subject, or compared to before the onset of the disease or disorder. Examples of diseases and disorders that contain stress granules include, but are not limited to, neurodegenerative diseases, musculoskeletal diseases, cancer, ophthalmic diseases (e.g., retinal diseases), and viral infections.

[0259] TDP-43 and other RNA-binding proteins function to process mRNA in both the nucleus and cytoplasm, which is accomplished, for example, by splicing mRNA, cleaving mRNA introns, cleaving untranslated regions of mRNA, or modifying protein translation in synapses, axons, dendrites, or cell bodies. Therefore, targeting other proteins that function similarly to TDP-43, or that function by processing mRNA, may also be beneficial for preventing and treating disease-induced neurodegeneration. For example, the fragile X intellectual disability 1 (FMRP) protein is essential for normal cognitive development. Signaling pathways that affect the function of TDP-43 may also affect this protein, and thus potentially improve cognitive function. This may be particularly important at synapses where neurons communicate. While not bound by theory, signaling pathways targeted by compounds of formula (I), (II), or (III) may also modify these processes that play a role in neurodegenerative or mental health diseases (e.g., schizophrenia).

[0260] The cellular stress response follows a U-shaped curve. Over-induction of this pathway, as observed in many neurodegenerative diseases, can be harmful to cells. However, reduced stimulation of this pathway can also be harmful, for example, in cases of acute stress such as stroke. Therefore, inhibition of stress granule formation may be appropriate for some diseases, while stimulation of stress granule formation may be beneficial for others.

[0261] In some embodiments, the TDP-43 protein in stress granules may be wild-type or mutant TDP-43. In some embodiments, mutant TDP-43 may include, for example, the addition, deletion, or substitution of amino acids relative to the wild-type TDP-43 sequence. In some embodiments, mutant TDP-43 may include amino acid substitutions relative to the wild-type sequence (e.g., G294A, A135T, Q331K, or Q343R substitutions). In some embodiments, the TDP-43 protein in stress granules may include post-translational modifications (e.g., phosphorylation of amino acid side chains (e.g., T103, S104, S409, or S410)).

[0262] In some embodiments, the pathology of neurodegenerative diseases or disorders, musculoskeletal diseases or disorders, cancer, ophthalmic diseases or disorders, or viral infections includes stress granules. In some embodiments, the pathology of neurodegenerative diseases, musculoskeletal diseases or disorders, cancer, ophthalmic diseases or disorders, or viral infections includes TDP-43 inclusion bodies.

[0263] In some embodiments, the formation of stress granules is inhibited by administering the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to the target. In some embodiments, administration of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to a subject inhibits stress granule formation by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete inhibition) compared to a control (e.g., baseline stress granule formation in the subject; stress granule formation in the subject before administration of the compounds disclosed herein; stress granule formation in a subject not receiving the compounds disclosed herein; or stress granule formation in a subject receiving a placebo).

[0264] In some embodiments, stress granules are deaggregated by administering a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of the compounds in Table 1, or a pharmaceutically acceptable salt thereof) to a subject requiring it. In some embodiments, by administering the compounds disclosed herein (e.g., compounds of formula (I), (II), or (III) or their subformulas, or the compounds in Table 1) to a subject, stress granules are dissipated or deaggregated by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete dissipation) compared to a control (e.g., baseline of stress granule deaggregation in the subject; deaggregation of stress granules in the subject before administration of the compounds disclosed herein; deaggregation of stress granules in a subject not treated with the compounds disclosed herein; or deaggregation of stress granules in a subject receiving a placebo).

[0265] In some embodiments, stress granule levels are reduced by administering the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to a subject in need. In some embodiments, stress granule levels are reduced by administering the compounds disclosed herein (e.g., compounds of formula (I), (II), or (III) or their subformulas, or the compounds in Table 1) to a subject by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% compared to a control (e.g., baseline stress granule levels in the subject; stress granule levels in the subject before administration of the compounds disclosed herein; stress granule levels in the subject not receiving the compounds disclosed herein; or stress granule levels in the subject receiving a placebo).

[0266] In some embodiments, stress granules include tar DNA-binding protein-43 (TDP-43), T cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA-binding protein-like 1 (TIAR, TIAL1), GTPase-activating protein-binding protein 1 (G3BP-1), GTPase-activating protein-binding protein 2 (G3BP-2), tristetraproline (TTP, ZFP36), fused-in-sarcoma (FUS), or fragile X intellectual disability protein (FMRP, FMR1).

[0267] In some embodiments, stress granules include tar DNA-binding protein-43 (TDP-43), T cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA-binding protein-like 1 (TIAR, TIAL1), GTPase-activating protein-binding protein 1 (G3BP-1), GTPase-activating protein-binding protein 2 (G3BP-2), fusion protein in sarcoma (FUS), or fragile X intellectual disability protein (FMRP, FMR1).

[0268] In some embodiments, stress granules include tar DNA-binding protein-43 (TDP-43), T cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA-binding protein-like 1 (TIAR, TIAL1), GTPase-activating protein-binding protein 1 (G3BP-1), GTPase-activating protein-binding protein 2 (G3BP-2), or fusion protein (FUS) in sarcomas.

[0269] In some embodiments, the stress granules contain tar DNA-binding protein-43 (TDP-43).

[0270] In some embodiments, the stress granules contain intracellular antigen 1 (TIA-1) of T cells.

[0271] In some embodiments, the stress granules include TIA-1 cytotoxic granule-associated RNA-binding protein-like 1 (TIAR, TIAL1).

[0272] In some embodiments, the stress granules contain GTPase-activated protein-binding protein 1 (G3BP-1).

[0273] In some embodiments, the stress granules contain GTPase-activated protein-binding protein 2 (G3BP-2).

[0274] In some embodiments, the stress granules include tristetraproline (TTP, ZFP36).

[0275] In some embodiments, stress granules include fusion proteins (FUS) in sarcomas.

[0276] In some embodiments, the stress granules include fragile X-mental retardation protein (FMRP, FMR1).

[0277] In other embodiments, the Disclosure provides a method for modulating the formation of TDP-43 inclusions in a subject, the method generally comprising administering a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to a subject requiring it. In some embodiments, the formation of TDP-43 inclusions is inhibited. In some embodiments, the TDP-43 inclusions are deaggregated. In some embodiments, the formation of TDP-43 inclusions is stimulated.

[0278] In some embodiments, the formation of TDP-43 inclusion bodies is inhibited by administering the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to the target. In some embodiments, administration of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to a subject inhibits the formation of TDP-43 inclusions by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete inhibition) compared to a control (e.g., baseline TDP-43 inclusion formation in the subject; TDP-43 inclusion formation in the subject before administration of the compounds disclosed herein; TDP-43 inclusion formation in the subject not receiving the compounds disclosed herein; or TDP-43 inclusion formation in the subject receiving placebo).

[0279] In some embodiments, TDP-43 inclusion bodies are deaggregated by administering a compound disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to a target. In some embodiments, administering the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to a subject results in the TDP-43 inclusions being dissipated or deaggregated by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete dissipation) compared to a control (e.g., baseline of TDP-43 inclusion deaggregation in the subject; deaggregation of TDP-43 inclusions in the subject before administration of the compounds disclosed herein; deaggregation of TDP-43 inclusions in the subject not receiving the compounds disclosed herein; or deaggregation of TDP-43 inclusions in the subject receiving a placebo).

[0280] In some embodiments, post-translational modifications of the TDP-43 protein in stress granules are regulated by administering compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or compounds of Table 1, or pharmaceutically acceptable salts thereof).

[0281] In another embodiment, the Disclosure provides a method for regulating the formation of tau aggregates in a subject, the method generally comprising administering a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of Table 1, or a pharmaceutically acceptable salt thereof) to a subject requiring it. In some embodiments, the formation of tau aggregates is inhibited. In some embodiments, the tau aggregates are deaggregated.

[0282] In some embodiments, the formation of tau aggregates is inhibited by administering the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to a target. In some embodiments, administration of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to a subject inhibits tau aggregate formation by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete inhibition) compared to a control (e.g., baseline tau aggregate formation in the subject; tau aggregate formation in the subject before administration of the compounds disclosed herein; tau aggregate formation in a subject not receiving the compounds disclosed herein; or tau aggregate formation in a subject receiving a placebo).

[0283] In some embodiments, tau aggregates are deaggregated by administering a compound disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to a target. In some embodiments, administration of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) to a subject results in the tau aggregates being dispersed or deaggregated by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or 100% (i.e., complete dissipation) compared to a control (e.g., baseline of tau aggregate deaggregation in the subject; deaggregation of tau aggregates in the subject before administration of the compounds disclosed herein; deaggregation of tau aggregates in a subject not receiving the compounds disclosed herein; or deaggregation of tau aggregates in a subject receiving a placebo).

[0284] Neurodegenerative diseases While not bound by theory, the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts) can be used to slow the progression of neurodegenerative diseases in which the pathology involves stress granules. Such diseases include ALS and frontotemporal dementia, in which TDP-43 or tau is the dominant protein that accumulates and forms the pathogenesis. This group also includes Alzheimer's disease and FTLD-U, in which TDP-43 and other stress granule proteins co-localize with tau pathogenesis. Modulators of TDP-43 inclusions, such as the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts), can act to block enzymes that signal the formation of stress granules (e.g., three enzymes that phosphorylate eIF2a: PERK, GCN2, and HRI), so the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts) can also reverse stress granule formation to one that would not contain TDP-43. Accordingly, the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts) can be used to treat neurodegenerative diseases and disorders in which the pathophysiology involves stress granules, such as Huntington's disease and Creutzfeldt-Jakob disease. The compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts) can also be used to treat neurodegenerative diseases and disorders associated with TDP-43 multisystem proteinosis.

[0285] As used herein, the term “neurodegenerative disease” refers to a neurological disorder characterized by the loss or degeneration of neurons. The term “neurodegenerative disease” includes diseases caused by the death (apoptosis) of neurons resulting from the involvement of genetic factors or abnormal protein accumulation. In addition, neurodegenerative diseases include neurodegenerative motor disorders and neurodegenerative conditions associated with memory loss or dementia. Neurodegenerative diseases also include tauopathies and alpha-synucleinopathy. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with dementia (ALSD), Huntington's disease (HD), Huntington's chorea, prion diseases (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, kuru disease, or spongiform encephalopathy). Lewy body dementia, diffuse Lewy body disease (DLBD), polyglutamine (polyQ) repeat disease, trinucleotide repeat disease, neurodegenerative diseases, presenile dementia, senile dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, Lewy body dementia, Down syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA type I (e.g., Werdnig-Hoffmann disease), SMA type II, SMAType III (e.g., Kugelberg-Verander disease) and congenital SMA with joint contractures), progressive spinal and bulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative diseases / motor neuron degenerative diseases, upper motor neuron disorders, lower motor neuron disorders, age-related diseases and dementia, Haller-Holden-Spats syndrome, Ritico-Bodig disease (amyotrophic lateral sclerosis - Parkinsonian dementia), Guam-Parkinsonian cognition Examples include alpha-synuclein disorders, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Alpers disease, Krabbe disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Schilder disease, Batten disease, Cockayne syndrome, Kahns-Sayre syndrome, Gerstmann-Strössler-Scheinker syndrome, hereditary spastic paraplegia, Leigh syndrome, demyelinating disorders, epilepsy, tremor, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injury (e.g., stroke, head injury), and autism. As used herein, the term "alpha-synucleinopathy" refers to a neurodegenerative disorder or disease involving alpha-synuclein or abnormal aggregation of alpha-synuclein in nerve cells in the brain. Alpha-synucleinopathy is not limited to this category, but includes Parkinson's disease, Parkinson's disease with dementia, Lewy body dementia, Pick's disease, Down syndrome, multiple system atrophy, amyotrophic lateral sclerosis (ALS), and Haller-Bolden-Spats syndrome.

[0286] As used herein, the term “tauopathy” refers to neurodegenerative diseases associated with the pathological aggregation of tau proteins in the brain. Tauopathies include, but are not limited to, Alzheimer’s disease, Pick’s disease, corticobasal degeneration, argyrophilic granulopathy (AGD), progressive supranuclear palsy, frontotemporal dementia, frontotemporal dementia, or Pick complex.

[0287] In some embodiments, neurodegenerative diseases include Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Huntington's chorea, prion diseases (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, kuru disease, and scrapie), Lewy body dementia, and biliary malformations. Lewy body dementia (DLBD), polyglutamine (polyQ) repeat disease, trinucleotide repeat disease, neurodegenerative diseases, presenile dementia, senile dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, Lewy body dementia, Down syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA type I (e.g., Werdnig-Hoffmann disease), SMA type II, SMAType III (e.g., Kugelberg-Welander disease) and congenital SMA with joint contractures), progressive spinal and bulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative diseases / motor neuron degenerative diseases, upper motor neuron disorders, lower motor neuron disorders, age-related diseases and dementia, Haller-Holden-Spats syndrome, cerebral infarction, traumatic brain injury, chronic traumatic brain injury, transient ischemic attack, Ritico-Bodig disease (amyotrophic lateral sclerosis - Parkinson's dementia), Guam-Parkinson's dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Alpers disease, Krabben disease The following are selected from the group consisting of diseases, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder disease, Batten disease, Cockayne syndrome, Kahns-Sayer syndrome, Gerstmann-Strössler-Scheinker syndrome and other transmissible spongiform encephalopathy, hereditary spastic paraplegia, Leigh syndrome, demyelinating disorders, neuronal ceroid lipofuscinosis, epilepsy, tremor, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injury (e.g., stroke, head injury), autism, other diseases or disorders associated with abnormal expression or aggregation of TDP-43 or tau and changes in proteostasis, and any combination thereof.

[0288] In some embodiments, neurodegenerative diseases include Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Huntington's chorea, Creutzfeldt-Jakob disease, senile dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, primary progressive aphasia, and cerebral cortex disease. The following conditions are selected from the group consisting of basal ganglia dementia, Parkinson's disease, Parkinson's disease with dementia, Lewy body dementia, Down syndrome, multiple system atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, spinal degenerative diseases / motor neuron degenerative diseases, Haller-Bolden-Spats syndrome, cerebral infarction, traumatic brain injury, chronic traumatic brain injury, transient ischemic attack, Ritico-Bodig disease (amyotrophic lateral sclerosis - Parkinson's dementia), hippocampal sclerosis, corticobasal degeneration, Alexander disease, Cockayne syndrome, and any combination thereof.

[0289] In some embodiments, the neurodegenerative disease is frontotemporal dementia (FTD). In some embodiments, the neurodegenerative disease is Alzheimer's disease or amyotrophic lateral sclerosis (ALS).

[0290] Musculoskeletal disorders Musculoskeletal disorders and conditions as defined herein are conditions affecting muscles, ligaments, tendons, and joints, as well as the skeletal structures that support them. While not theoretically bound, it has been shown that the abnormal expression of certain proteins, such as the full-length isoform of DUX4, inhibits protein turnover in skeletal muscle cells and increases the expression and aggregation of cytotoxic proteins, including insoluble TDP-43 (Homma, S. et al. Ann Clin Transl Neurol (2015) 2:151-166). Therefore, compounds of formula (I), (II), or (III) can be used to prevent or treat musculoskeletal disorders, such as those resulting in the accumulation of TDP-43 and other stress granule proteins, for example, in the nucleus, cytoplasm, or cell body of muscle cells or motor neurons. Exemplary musculoskeletal disorders include muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Friedreich's ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy (MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, muscle loss, spasticity, multifocal motor neuropathy, inflammatory muscle disease, paralysis, and other diseases or disorders associated with abnormal TDP-43 expression and changes in proteostasis. In addition, compounds of formula (I), (II), or (III) can be used to prevent or treat symptoms caused by or associated with the above-mentioned musculoskeletal disorders, such as kyphosis, hypotonia, foot drop, motor dysfunction, muscle weakness, muscle atrophy, neuronal loss, muscle spasms, altered or abnormal gait, abnormal muscle tone, increased astrocytes (e.g., increased astrocytes in the spinal cord), liver disease, inflammation, headache, and pain (e.g., back pain, neck pain, leg pain, inflammatory pain). In some embodiments, musculoskeletal disorders or symptoms of musculoskeletal disorders may overlap with neurodegenerative disorders or symptoms of neurodegenerative disorders.

[0291] In some embodiments, musculoskeletal disorders are selected from the group consisting of muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Friedreich's ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy (MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, muscle loss, multifocal motor neuropathy, inflammatory muscle disease, paralysis, and other diseases or disorders associated with abnormal expression or aggregation of TDP-43 or tau and changes in proteostasis.

[0292] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or subformulas thereof, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) can be used to prevent or treat symptoms caused by or associated with the above-mentioned musculoskeletal disorders, such as kyphosis, hypotonia, foot drop, motor dysfunction, muscle weakness, muscle atrophy, neuronal loss, muscle spasms, altered or abnormal gait, abnormal muscle tone, astrocyte increase (e.g., astrocyte increase in the spinal cord), liver disease, respiratory disease or respiratory failure, inflammation, headache, and pain (e.g., back pain, neck pain, leg pain, or inflammatory pain).

[0293] cancer Cancer cells proliferate rapidly in hypoxic environments by activating various components of the cellular stress response. Researchers have shown that drugs targeting various components of the stress response could be anti-cancer agents. For example, rapamycin blocks mTOR, upregulates autophagy, and inhibits certain types of tumors. Proteasome inhibitors, such as Velcade (Millennium Pharma), are used to treat some cancers. HSP90 inhibitors, such as 17-allylaminogeldanamycin (17AAG), are currently undergoing clinical trials for cancer. While not theoretically bound, recent advances in understanding the role of TDP-43 in RNA processing and transcription factor signaling suggest that compounds of formulas (I), (II), or (III) may also be used in cancer treatment. In addition, TDP-43 modulators can be combined with one or more cancer treatments, such as chemotherapy and radiotherapy.

[0294] In this context, "cancer" refers to the presence of cells that possess characteristics typical of oncogenic cells, such as uncontrolled proliferation, immortality, metastatic ability, rapid growth and proliferation rates, and certain characteristic morphological features. While cancer cells often take the form of tumors, such cells may exist independently within an animal or they may be non-tumor-forming cancer cells, such as leukemia cells. In some situations, cancer cells are tumors, and such cells may exist locally within an animal or they may circulate in the bloodstream as independent cells, such as leukemia cells. Examples of cancers, though not limited to these, include breast cancer, melanoma, adrenal cancer, biliary tract cancer, bladder cancer, cancer of the brain or central nervous system, bronchial cancer, blastoma, carcinoma, chondrosarcoma, cancer of the mouth or pharynx, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, hepatocellular carcinoma, hepatocellular carcinoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmic cancer, osteosarcoma, ovarian cancer, pancreatic cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small intestine or appendiceal cancer, small cell lung cancer, squamous cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, urinary bladder cancer, uterine or endometrial cancer, and vulvar cancer.

[0295] Other exemplary cancers include, but are not limited to, ACTH-producing tumors, acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, adrenal cortical carcinoma, and bladder cancer. Examples of cancers include brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, ophthalmic cancer, Hodgkin lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small cell or non-small cell), malignant ascites, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin lymphoma, osteosarcoma, ovarian cancer, ovarian (germ cell) cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, gestational trophoblastic tumor, uterine cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0296] Exemplary lymphomas include Hodgkin lymphoma and non-Hodgkin lymphoma. Further examples of non-Hodgkin lymphomas include, but are not limited to, B-cell lymphomas (e.g., diffuse large B-cell lymphoma, mediastinal primary B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, hairy cell leukemia, and These include primary central nervous system (CNS) lymphomas, and T-cell lymphomas (e.g., progenitor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphomas (e.g., smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphoma-type adult T-cell lymphoma), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy-associated T-cell lymphoma (EATL) (e.g., type I EATL and type II EATL), and anaplastic large cell lymphoma (ALCL)).

[0297] In some embodiments, cancer is selected from the group consisting of breast cancer, melanoma, adrenal cancer, biliary tract cancer, bladder cancer, cancer of the brain or central nervous system, bronchial cancer, blastoma, carcinoma, chondrosarcoma, cancer of the mouth or pharynx, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, hepatocellular carcinoma, hepatocellular carcinoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, eye cancer, osteosarcoma, ovarian cancer, pancreatic cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small intestine or appendiceal cancer, small cell lung cancer, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, urinary bladder cancer, uterine or endometrial cancer, vulvar cancer, and any combination thereof.

[0298] In some embodiments, cancer is selected from the group consisting of blastoma, carcinoma, glioblastoma, hepatocellular carcinoma, lymphoma, leukemia, and any combination thereof.

[0299] In some embodiments, the cancer is selected from Hodgkin lymphoma or non-Hodgkin lymphoma. In some embodiments, the cancer is non-Hodgkin lymphoma, which is B-cell lymphoma (e.g., diffuse large B-cell lymphoma, mediastinal primary B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, hairy cell leukemia, and primary The diagnosis is selected from the group consisting of central nervous system (CNS) lymphomas and T-cell lymphomas (e.g., progenitor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma (e.g., smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphoma-type adult T-cell lymphoma), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy-associated T-cell lymphoma (EATL) (e.g., type I EATL and type II EATL), and anaplastic large cell lymphoma (ALCL)).

[0300] ophthalmological diseases Ophthalmic diseases and disorders as defined herein (e.g., retinal diseases and disorders) affect the retina and other parts of the eye, potentially causing visual impairment and blindness. Some ophthalmic diseases (e.g., retinal diseases) are characterized by the accumulation of protein inclusions and stress granules within or between cells of the eye, e.g., retinal cells and surrounding tissues. In addition, ophthalmic diseases (e.g., retinal diseases) can also be symptoms or prodromal states of neurodegenerative diseases such as ALS and FTD. Therefore, the use of compounds that can inhibit the formation of protein inclusions and stress granules, including compounds of formula (I), (II), (III), or (IV), can play an important role in the prevention or treatment of ophthalmic diseases (e.g., retinal diseases).

[0301] Examples of ophthalmic diseases (e.g., retinal diseases) include, but are not limited to, macular degeneration (e.g., age-related macular degeneration), diabetic retinopathy, histoplasmosis, macular hole, macular fold formation, crystallin retinopathy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity, Usher syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroidal agenesis, Leber congenital amaurosis, retinal schizophrenia (e.g., juvenile retinal schizophrenia), Stargardt disease, and oculopalsy.

[0302] In some embodiments, the ophthalmic disease or disorder (e.g., retinal disease or disorder) is selected from macular degeneration (e.g., age-related macular degeneration), diabetic retinopathy, histoplasmosis, macular hole, macular fold formation, crystallin retinopathy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity, Usher syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroidal agenesis, Leber congenital amaurosis, retinal schizophrenia (e.g., juvenile retinal schizophrenia), Stargardt disease, ophthalmoplegia, and the like.

[0303] In some embodiments, the ophthalmic disease or disorder (e.g., retinal disease or disorder) is selected from macular degeneration (e.g., age-related macular degeneration), diabetic retinopathy, histoplasmosis, macular hole, macular fold formation, crystallin retinopathy, retinoblastoma, retinopathy of prematurity, Usher syndrome, Refsum disease, retinitis pigmentosa, onchocerciasis, choroidal agenesis, Leber congenital amaurosis, retinal schizophrenia (e.g., juvenile retinal schizophrenia), Stargardt disease, and the like.

[0304] Viral infection Stress granules are often formed during viral diseases because viral infections often involve the hijacking of cellular regeneration mechanisms to produce viral proteins. In this case, inhibitors of stress granules may be useful in interfering with viral function. Other viruses appear to inhibit SG formation, thereby preventing cells from recruiting a stress response. In such cases, stress granule inducers may interfere with viral activity and help fight viral infections (e.g., salvulinal, eIF2a phosphatase inhibitors, and stress granule inducers). Two viruses whose SG biology has been investigated include West Nile virus and respiratory syncytial virus (RSV). Therefore, the use of compounds that can inhibit the formation of protein inclusions and stress granules, including compounds of formulas (I), (II), (III), or (IV), may be useful in the prevention or treatment of viral infections.

[0305] Examples of viruses that may be affected include, but are not limited to, West Nile virus, respiratory syncytial virus (RSV), Epstein-Barr virus (EBV), hepatitis A, B, C, and D viruses, herpesviruses, influenza viruses, varicella, avian influenza viruses, smallpox, poliovirus, HIV, and Ebola virus.

[0306] In some embodiments, the viral infection is caused by a virus selected from the group consisting of West Nile virus, respiratory syncytial virus (RSV), herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis A virus, hepatitis B virus, hepatitis C virus, influenza virus, varicella, avian influenza virus, smallpox, poliovirus, HIV-1, HIV-2, Ebola virus, and any combination thereof.

[0307] In some embodiments, the viral infection is caused by a virus selected from the group consisting of herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis A virus, hepatitis B virus, hepatitis C virus, HIV-1, HIV-2, Ebola virus, and any combination thereof.

[0308] In some embodiments, the viral infection is HIV-1 or HIV-2.

[0309] definition Unless otherwise specified or implied by the context, the following terms and phrases have the meanings set forth below. Unless otherwise specified or made clear by the context, the following terms and phrases do not exclude the meanings that the term or phrase acquires in the art to which it pertains. The definitions are provided to help describe specific embodiments and are not intended to limit the claimed compounds and methods, for the scope of this disclosure is limited only by the claims. Furthermore, unless specifically required by the context, singular terms shall include plural forms and plural terms shall include singular forms.

[0310] As used herein, the terms “compound” and “agent” are used interchangeably to refer to inhibitors / antagonists / agonists of the compounds disclosed herein. In some embodiments, the compound is an organic or inorganic low molecular weight having a molecular weight of, for example, less than 7500 amu, preferably less than 5000 amu, and more preferably less than 2000, 1500, 1000, 750, 600, or 500 amu. In some embodiments, a certain class of organic or inorganic low molecular weights is, for example, a non-peptidyl containing two, one, or zero peptide or saccharide bonds.

[0311] Unless otherwise specified, all numerical values ​​used herein to express quantities of components or reaction conditions should be understood to be modified in all cases by the term “approximately.” When used with percentages, “approximately” may mean ±1%, ±2%, ±5%, or ±10%.

[0312] The singular terms "a," "an," and "the" refer to one or more unless otherwise specified in the context. Similarly, the word "or" is intended to include "and" unless otherwise specified in the context.

[0313] Methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this disclosure, but preferred methods and materials are described below.

[0314] As used herein, the term “administration” refers to the placement of a composition into a target by a method or route that results in the localization of at least a portion of the composition at the site of interest, such that the desired effect is produced. Compounds or compositions described herein may be administered by any suitable route known in the art, including, but not limited to, oral or parenteral routes, such as intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, subarachnoid, and topical administration (including oral and sublingual administration).

[0315] The terms “reduce,” “reduced,” “decrease,” “decrease,” or “inhibit” are all used herein to mean a statistically significant reduction. In some embodiments, the terms “reduced,” “decrease,” or “inhibit” mean a reduction of at least 0.1% compared to a reference level, for example, a reduction of at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% compared to a reference level, or a reduction up to 100% (e.g., a level that does not exist compared to a reference sample), or any reduction between 1% and 100%, for example, between 10% and 100%.

[0316] The terms “increased,” “enhance,” “enhance,” or “activate” are all used herein in general to mean an increase of a statistically significant amount. In some embodiments, the terms “increased,” “enhance,” or “activate” mean an increase of at least 0.1% compared to a reference level, for example, a decrease of at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% compared to a reference level, or an increase up to 100% (e.g., a level that does not exist compared to a reference sample), or any increase between 1 and 100%, for example, between 10 and 100%.

[0317] The terms “to treat,” “to treat,” and “treatment” as used herein mean a method of alleviating, improving, inhibiting, reversing, or delaying or halting the progression, exacerbation, or worsening of a disease or disorder or its symptoms or related conditions. In some embodiments, at least one symptom or related condition of a disease or disorder is alleviated by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%.

[0318] As used herein, the “therapeutic dose” or “effective dose” of a compound or combination means the amount of the compound or combination that, when administered to a subject once or multiple times, is more effective than expected in the absence of such treatment in treating a disease or disorder (e.g., a disorder described herein) in a subject, or in curing, alleviating, reducing, or improving a subject having a disease or disorder (e.g., a disorder described herein). Determining the therapeutic dose or effective dose is well within the capabilities of those skilled in the art. Generally, the therapeutic dose or effective dose may vary depending on the subject’s medical history, age, condition, sex, and the severity and type of the subject’s medical condition, as well as the administration of other pharmaceutically active agents.

[0319] As used herein, “subject” means human or animal. Typically, animals are vertebrates such as primates, rodents, domestic animals, or game animals. Examples of primates include chimpanzees, crab-eating macaques, spider monkeys, and macaques, e.g., rhesus macaques. Examples of rodents include mice, rats, marmots, ferrets, rabbits, and hamsters. Examples of domestic and game animals include cattle, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cats, canid species, e.g., dogs, foxes, wolves, bird species, e.g., chickens, emus, ostriches, and fish, e.g., trout, catfish, and salmon. Patients or subjects include any subset of those described above, e.g., one or more groups or species, e.g., all of the above except humans, primates, or rodents. In some embodiments, subjects are mammals, e.g., primates, e.g., humans. The terms "patient" and "subject" are used interchangeably in this specification.

[0320] As used herein, the terms “stress granule modulator” and “stress granule modulator” refer to compounds and compositions of formula (I), (II), or (III) that regulate the formation or deaggregation of stress granules.

[0321] As used herein, the term "TDP-43 inclusion body" refers to a protein aggregate containing the TDP-43 protein. The TDP-43 protein in the inclusion body may be the wild-type or mutant form of TDP-43.

[0322] As used herein, the terms "TDP-43 inclusion body modulator" and "TDP-43 inclusion body modulator" refer to compounds and compositions of formula (I), (II), or (III) that regulate the formation or deaggregation of cytoplasmic TDP-43 inclusion bodies.

[0323] As used herein, the terms "tau aggregate modulator" and "tau aggregate modulator" refer to compounds and compositions of formula (I), (II), or (III) that regulate the formation or deaggregation of tau aggregates.

[0324] Selected chemical definitions Throughout this specification, substituents of the compounds disclosed herein are listed in groups or ranges. The compounds disclosed herein are intended to include, specifically, any individual subcombinations of the constituent elements of such groups and ranges. For example, "C 1~6 The term "alkyl" is intended to specifically disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl elements individually.

[0325] In compounds disclosed herein in which a variable region appears two or more times, each variable region may be a different region selected from the Markush group that defines the variable region. For example, if a structure is described as having two R groups present simultaneously on the same compound, the two R groups may represent different regions selected from the Markush group defined for R.

[0326] Furthermore, it will be understood that certain features of the compounds disclosed herein, described in the context of a different embodiment for clarity, can also be provided in combination in a single embodiment. Conversely, various features of the compounds disclosed herein, described in the context of a single embodiment for brevity, can also be provided separately or in any suitable sub-combination.

[0327] Where a compound or a group of compounds disclosed herein are shown in terms of both a chemical name and a formula, in the event of any inconsistency, the formula shall prevail.

[0328] symbol [ka] Whether used as a bond or shown perpendicular to a bond, the indicated portion indicates a point where it is bonded to the rest of the structure (e.g., a molecule or a solid support).

[0329] The following terms are intended to have the meanings set forth below and are useful in understanding the wording and intended scope of this disclosure.

[0330] In general, the term “substituted” means that one or more hydrogens of a given moiety are replaced by a suitable substituent, whether preceded by the term “optionally.” Unless otherwise specified, a group “optionally substituted” may have suitable substituents at each of its substituted positions, and if two or more positions in any given structure can be replaced by two or more substituents selected from a given group, those substituents may be the same or different at each position. The substituent combinations envisioned under this disclosure preferably result in the formation of a stable or chemically viable compound.

[0331] As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions that enable the generation, detection, recovery, purification, or use of the compound for one or more purposes disclosed herein.

[0332] Suitable substituents for optionally substituted alkyl, alkenyl, alkylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkylene, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, cycloalkyl, heterocycloalkyl, carbocykyl, heterocyclyl, aryl, and heteroaryl groups include halogen, =O, -CN, and -OR. cc , -NR dd R ee , -S(O) kk R cc , -NR cc S(O)2R cc -S(O)2NR ddR ee 、-C(=O)OR cc 、-OC(=O)OR cc 、-OC(=O)R cc 、-OC(=S)OR cc 、-C(=S)OR cc 、-O(C=S)R cc 、-C(=O)NR dd R ee 、-NR cc C(=O)R cc 、-C(=S)NR dd R ee 、-NR cc C(=S)R cc 、-NR cc (C=O)OR cc 、-O(C=O)NR dd R ee 、-NR cc (C=S)OR cc 、-O(C=S)NR dd R ee 、-NR cc (C=O)NR dd R ee 、-NR cc (C=S)NR dd R ee 、-C(=S)R cc 、-C(=O)R cc, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C2~C9 heteroalkynyl, C1~C6 haloalkyl, C1~C6 haloalkoxy, C1~C6 heteroalkyl, carbocyryl, (C1~C6-alkylene)-carbocyryl, (C1~C6-heteroalkylene)-carbocyryl, heterocyclyl, (C1~C6-alkylene)-heterocyclyl, (C1~C6-heteroalkylene)-heterocyclyl, aryl, (C1~C6-alkylene)-aryl, (C1~C6-heteroalkyl Examples include (C1-C6-alkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, where each of the alkyl, alkenyl, alkylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkylene, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, cycloalkyl, heterocycloalkyl, carbocykrill, heterocyclyl, aryl, and heteroaryl are halogens, OR cc -NO2, -CN, -NR cc C(=O)W, -NR dd R ee , -S(O) k R cc , -C(=O)OR cc -C(=O)NR dd R ee -C(=O)R cc , is optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, carbocykryl, heterocyclyl, aryl, or heteroaryl, where R ccis hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 heteroalkyl, carbocyryl, (C1-C6-alkylene)-carbocyryl, (C1-C6-heteroalkylene)-carbocyryl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, each of which may be optionally substituted with one or more of halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl; R dd and R ee Each of these is independently selected from hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; k is 0, 1, or 2. The compounds disclosed herein are not intended to be limited in any form to the exemplary list of substituents described above.

[0333] As used herein, the term “optional substituent” means any substituent suitable for alkyl, alkenyl, alkylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkylene, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, cycloalkyl, heterocycloalkyl, carbocykyl, heterocyclyl, aryl, and heteroaryl groups, including halogens, =O, -CN, -OR cc , -NR dd R ee , -S(O) kk R cc , -NR cc S(O)2R cc -S(O)2NR dd R ee , -C(=O)OR cc , -OC(=O)OR cc -OC(=O)R cc , -OC(=S)OR cc, -C(=S)OR cc -O(C=S)R cc -C(=O)NR dd R ee , -NR cc C(=O)R cc -C(=S)NR dd R ee , -NR cc C(=S)R cc , -NR cc (C=O)OR cc -O(C=O)NR dd R ee , -NR cc (C=S)OR cc -O(C=S)NR dd R ee , -NR cc (C=O)NR dd R ee , -NR cc (C=S)NR dd R ee -C(=S)R cc -C(=O)R cc , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C9 heteroalkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1- C6 Examples include heteroalkyl, carbocyryl, (C1~C6-alkylene)-carbocyryl, (C1~C6-heteroalkylene)-carbocyryl, heterocyclyl, (C1~C6-alkylene)-heterocyclyl, (C1~C6-heteroalkylene)-heterocyclyl, aryl, (C1~C6-alkylene)-aryl, (C1~C6-heteroalkylene)-aryl, heteroaryl, (C1~C6-alkylene)-heteroaryl, or (C1~C6-heteroalkylene)-heteroaryl, where each of the above alkyl, alkenyl, alkylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkylene, heteroalkynyl, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, heterocycloalkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl are halogen, -OR cc -NO2, -CN, -NR cc C(=O)Rdd , -NR dd R ee , -S(O) k R cc , -C(=O)OR cc -C(=O)NR dd R ee -C(=O)R cc , is optionally substituted with one or more of the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, carbocykryl, heterocyclyl, aryl, or heteroaryl, where R cc is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 heteroalkyl, carbocyryl, (C1-C6-alkylene)-carbocyryl, (C1-C6-heteroalkylene)-carbocyryl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, each of which may be optionally substituted with one or more of halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl; R dd and R ee Each of these is independently selected from hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; k is 0, 1, or 2. The compounds disclosed herein are not intended to be limited in any form to the exemplary list of substituents described above.

[0334] As used herein, "alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C24"). 24 This refers to an alkyl radical. In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C12"). 12Alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7) and n-octyl (C8). Each example of alkyl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkyl"). In some embodiments, the alkyl group is unsubstituted C 1~10 It is an alkyl group (e.g., -CH3). In some embodiments, the alkyl group is a substituted C 1~6 It is alkyl. As used herein, the term "alkylene" refers to an alkyl group having one additional open valence, i.e., a divalent group. Exemplary alkylene groups include, but are not limited to, -CH2CH2- and -CH2-C(CH3)-CH2-.

[0335] As used herein, the term "alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C24"). 24 This refers to an alkenyl group. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C2-C10"). 10 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be located internally (as in 2-butenyl) or at the terminal (as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). Examples of C2-C6 alkenyl groups include the above C 2~4 Examples include alkenyl groups, and pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Each example of an alkenyl group may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In some embodiments, the alkenyl group is unsubstituted C 2~10 It is an alkenyl. In some embodiments, the alkenyl group is a substituted C 2~6 It is Alkenil.

[0336] As used herein, the term "alkynyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2-C24"). 24 This refers to an "alkenyl" group. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C2-C10"). 10 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C2-C5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-C4 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C2-C3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be located internally (as in 2-butynyl) or at the terminal (as in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). Each example of an alkynyl group may be independently substituted by choice, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In some embodiments, the alkynyl group is unsubstituted C 2~10 It is an alkynyl group. In some embodiments, the alkynyl group is a substituted C 2~6 It is alkinyl.

[0337] As used herein, the term “heteroalkyl” means a stable acyclic linear or branched chain or combination thereof comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The O, N, P, S, and Si of the heteroatom(s) can be positioned at any position in the heteroalkyl group. Examples of heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -NHCH2-, -C(O)-NH-, -C(O)N(CH3)-, -C(O)N(CH2CH3)-, -C(O)N(CH2CF3)-, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. For example, up to two or three heteroatoms may be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The term "heteroalkyl" is used, followed by a specific heteroalkyl group, e.g., -CH2O, -NR. C R D When such descriptions are given, the term heteroalkyl and -CH2O or -NR may be used. C R D It will be understood that these are not overlapping or mutually exclusive. Rather, specific heteroalkyl groups are listed for further clarification. Thus, the term "heteroalkyl" refers to specific heteroalkyl groups, e.g., -CH2O, -NR C R D This specification should not be interpreted as excluding such items.

[0338] As used herein, the term "heteroalkylene" refers to a heteroalkyl group having one additional open valence, i.e., a divalent group. Exemplary heteroalkylene groups include, but are not limited to, -CH2-CH2-O-CH2-, -CH2-O-, and -CH2-CH2-NH-CH2-.

[0339] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring system) having 6 to 14 ring carbon atoms and 0 heteroatoms provided to the aromatic ring system (“C6~ 14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). Aryl groups are, for example, C6~C 10 It may be written as a member aryl, where the term "member" refers to the non-hydrogen ring atom within that part. Each example of an aryl group may be independently optionally substituted, i.e., unsubstituted (e.g., "unsubstituted aryl") or substituted with one or more substituents (e.g., "substituted aryl"). In some embodiments, the aryl group is unsubstituted C6-C 14 It is aryl. In some embodiments, the aryl group is substituted C6-C 14 It is an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracyl.

[0340] As used herein, “heteroaryl” means a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring system) radical having a ring carbon atom provided to the aromatic ring system and one or more (e.g., 1 to 4) ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, as long as the valence allows. A heteroaryl bicyclic system may contain one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems in which the heteroaryl ring as defined above is fused with one or more aryl groups, and the bond site is located in the aryl or heteroaryl ring, in which case the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl), the bonding site can be on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 5- to 10-membered heteroaryls, where the term “member” refers to the non-hydrogen ring atom in that part. In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having a ring carbon atom provided to the aromatic ring system and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having a ring carbon atom provided to the aromatic ring system and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom provided to the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").In some embodiments, the 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each example of the heteroaryl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl. Examples of heteroaryl groups, but not limited to, include imidazolyl, pyridinyl, and quinolinyl.

[0341] As used herein, "cycloalkyl" means a saturated or partially unsaturated but non-aromatic ring system having 3 to 14 ring carbon atoms ("C3-C3"). 14 A cycloalkyl group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system having zero heteroatoms ("carbocyaryl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10Cycloalkyl groups are sometimes described as, for example, C4-C7 member cycloalkyl groups, where the term "member" refers to the non-hydrogen ring atom within that group. Examples of C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Examples of C3-C8 cycloalkyl groups include, but are not limited to, the C3-C6 cycloalkyl groups mentioned above, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), and bicyclo[3.1.1]heptanyl (C7). 10 The cycloalkyl groups are not limited to the above-mentioned C3-C8 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9). 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 Examples include the above. As the above examples show, cycloalkyl groups may be monocyclic ("monocyclic cycloalkyl"), or they may contain fused rings, crosslinked rings, or spiro rings, for example, bicyclic ("bicyclic cycloalkyl"), and they may be saturated or partially unsaturated. Each example of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In some embodiments, the cycloalkyl group is unsubstituted C3-C 10 It is a cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted C3-C3 group.10 They are cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclohexanyl, cyclohexenyl, cyclooctinyl, and bicyclo[4.4.0]decanyl.

[0342] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) cyclic radical having 3 to 14 ring atoms containing carbon and 1 to 6 ring heteroatoms, which are saturated or partially unsaturated but not aromatic, where each heteroatom is independently selected from nitrogen, oxygen, sulfur (e.g., -S-, -S(O)-, and -S(O)2-), boron, phosphorus, and silicon ("3-14 membered heterocycloalkyl"). In heterocycloalkyl groups containing one or more nitrogen atoms, the bond sites may be carbon or nitrogen atoms, as long as their valence allows. Heterocycloalkyl groups may be monocyclic ("monocyclic heterocycloalkyl") or polycyclic ("polycyclic heterocycloalkyl"), for example, bicyclic ("bicyclic heterocycloalkyl"). Heterocycloalkyl groups may be fused ring systems, bridging ring systems, or spiro-ring systems. Bicyclic heterocycloalkyls may contain one or more heteroatoms in one or both rings. Heterocycloalkyls may be described, for example, as 3- to 7-membered heterocycloalkyls, where the term “member” refers to the non-hydrogen ring atom in the part, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each example of a heterocycloalkyl may be independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl"). In some embodiments, the heterocycloalkyl is an unsubstituted 3- to 14-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a substituted 3- to 14-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 10-membered heterocycloalkyl having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocycloalkyl"). In some embodiments, the heterocycloalkyl group is a 5-8 membered heterocycloalkyl group having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocycloalkyl group").In some embodiments, the heterocycloalkyl group is a 5-6 member heterocycloalkyl group having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 member heterocycloalkyl group"). In some embodiments, the 5-6 member heterocycloalkyl group has 1-3 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heterocycloalkyl group has 1-2 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heterocycloalkyl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl groups, but not limited to, include piperidinyl, piperazinyl, 3,4-dihydro-2H-pyranyl, and octahydroindolyl.

[0343] As used herein, “carbocyclyl” refers to a polycyclic, partially unsaturated cyclic radical having 6 to 20 carbon atoms and at least one fused aryl ring. The term “member” refers to a non-hydrogen ring atom within that part. Each example of a carbocyclyl group may be independently and optionally substituted, i.e., unsubstituted (“unsubstituted carbocyclyl”) or substituted with one or more substituents (“substituted carbocyclyl”). In some embodiments, the carbocyclyl group is an unsubstituted 6 to 20-membered carbocyclyl. In some embodiments, the carbocyclyl group is a substituted 6 to 20-membered carbocyclyl. Examples of carbocyclyl groups, but not limited to, include indenyl and tetrahydronaphthyl.

[0344] As used herein, “heterocyclyl” refers to a polycyclic, partially unsaturated cyclic radical having 5 to 20 atoms, including carbon and 1 to 6 heteroatoms (a “5-20 membered heterocyclyl”), where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and where the polycyclic, partially unsaturated cyclic system has at least one aromatic ring (e.g., aryl or heteroaryl). In some embodiments, the heterocyclyl group has 5 to 14 ring atoms (a “5-14 membered heterocyclyl”). The term “member” refers to a non-hydrogen ring atom within that part. Each example of a heterocyclyl group may independently be optionally substituted, i.e., unsubstituted (a “unsubstituted heterocyclyl”) or substituted with one or more substituents (a “substituted heterocyclyl”). In some embodiments, the heterocyclyl group is an unsubstituted 5-20 membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 5- to 20-membered heterocyclyl. Examples of heterocyclyl groups include, but are not limited to, 1,2,3,4-tetrahydroquinolyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, 1,4,6,7-tetrahydropyrano[4,3-b]pyrrole, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, and 5,6,7,8-tetrahydroquinolinyl.

[0345] As used herein, "cyano" refers to the -CN radical.

[0346] As used herein, "halo" or "halogen" means, unless otherwise specified, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom, either independently or as part of another substituent.

[0347] As used herein, "haloalkyl" can encompass an alkyl structure substituted with one or more halo groups or combinations thereof. For example, the term "fluoroalkyl" encompasses a haloalkyl group (e.g., -C1~C6 alkyl-CF3, -C1~C6 alkyl-CH2F) where the halo is fluorine. Non-limiting examples of haloalkyls include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, difluoromethyl, and fluoroisopropyl.

[0348] As used herein, "hydroxy" refers to the -OH group of a radical.

[0349] As used herein, "nitro" refers to -NO2.

[0350] As used herein, "oxo" (=O) refers to a carbonyl group in which both bonds from oxygen are bonded to the same atom. For example, an oxo-substituted carbon atom forms a carbonyl group C=O.

[0351] Two or more substituents may be optionally linked to form an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, a carbocyclyl group, or a heterocarbocyclyl group. Such so-called ring-forming substituents are typically, though not always, bonded to a cyclic base structure. In one embodiment, the ring-forming substituent is bonded to an adjacent member of the base structure. For example, two ring-forming substituents bonded to adjacent members of a cyclic base structure form a condensed cyclic structure. In another embodiment, the ring-forming substituent is bonded to a single member of the base structure. For example, two ring-forming substituents bonded to a single member of a cyclic base structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituent is bonded to a non-adjacent member of the base structure.

[0352] The compounds described herein may contain one or more chiral centers and thus may exist in various isomeric forms, such as enantiomers or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC); or preferred isomers can be prepared by asymmetric synthesis. This disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0353] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer-rich). In other words, an "S" type compound is substantially free of "R" type compounds and is therefore enantiomer-rich of "R" type compounds. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight of such enantiomer. In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0354] In the compositions provided herein, enantiomers may be present together with other active or inactive components. For example, a pharmaceutical composition containing an enantiomers of a pure R compound may, for example, comprise about 90% excipients and about 10% of the enantiomers of a pure R compound. In some embodiments, the enantiomers of a pure R compound in such a composition may comprise, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomers of a pure S compound may, for example, comprise about 90% excipients and about 10% of the enantiomers of a pure S compound. In some embodiments, the enantiomers of a pure S compound in such a composition may comprise, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In some embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0355] The compounds disclosed herein may also include one or more isotopic substitutions. Isotopes include atoms with the same atomic number but different mass numbers. For example, H is, 1 H, 2 H (D or deuterium), and 3 It may be any isotopic form including H (T or tritium), and C is 12 C, 13 C, and 14 It may be any isotopic form including C, and O is, 16 O and 18 This includes any isotopic form, including O. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to contain hydrogen in its isotopic composition at its natural abundance. Furthermore, unless otherwise specified, when a position is specifically designated as "D" or "deuterium," that position is understood to contain deuterium at an abundance at least 3000 times higher than its natural abundance of 0.015% (i.e., the terms "D" or "deuterium" indicate an incorporation of at least approximately 45% deuterium).

[0356] One or more constituent atoms of the compounds disclosed herein may be replaced or substituted with isotopes of atoms of non-natural abundance. In some embodiments, the compounds contain one or more deuterium atoms. For example, one or more hydrogen atoms in the compounds disclosed herein may be replaced or substituted with deuterium. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain one, two, three, four, five, six, seven, eight, or nine deuterium atoms. Methods for synthesizing the inclusion of isotopes in organic compounds are known in the art.

[0357] Many of the terms listed above may be used repeatedly in the definitions of formulas or bases, and in each case, independently of each other, have one of the meanings listed above.

[0358] It should be understood that "substitution" or "substituted with" implies that such a substitution follows the allowable valencies of the substituted atom and substituent, and that the substitution implicitly results in a stable compound, such as one that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc.

[0359] The intended equivalents of the above compounds include compounds that otherwise correspond to them and possess the same general properties (e.g., the ability to inhibit the formation of TDP-43 inclusions), and which have undergone one or more simple substituent modifications that do not adversely affect the efficacy of the compounds. Generally, the compounds of this disclosure can be prepared using readily available starting materials, reagents, and conventional synthetic procedures by methods or variations thereof, as exemplified in the general reaction schemes below. Modifications of these reactions, which are known in themselves but not mentioned herein, may also be utilized.

[0360] For the purposes of this disclosure, chemical elements are identified according to the periodic table of elements (CAS system) on the inside cover of Handbook of Chemistry and Physics, 67th Ed., 1986-87. As used herein, the term “hydrocarbon” is intended to encompass all permissible compounds having at least one hydrogen atom and one carbon atom. In broad embodiments, permissible hydrocarbons include organic compounds that may be substituted or unsubstituted, acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic.

[0361] Pharmaceutical composition and route of administration Pharmaceutical compositions containing the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or pharmaceutically acceptable salts thereof) can be used to treat or improve the disorders described herein, such as neurodegenerative diseases, cancer, ophthalmic diseases (e.g., retinal diseases), or viral infections.

[0362] The amount and concentration of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts) in a pharmaceutical composition, as well as the amount of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as the subject's medically relevant characteristics (e.g., age, weight, sex, other medical conditions), the solubility of the compound in the pharmaceutical composition, the potency and activity of the compound, and the mode of administration of the pharmaceutical composition.

[0363] The compounds disclosed herein (for example, compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts) can be administered alone, but it is preferable to administer the compounds as a pharmaceutical composition, in which case the compounds are combined with one or more pharmaceutically acceptable diluents, excipients, or carriers.

[0364] The compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts) may be formulated for administration in any convenient manner for use in human or animal pharmaceuticals. In some embodiments, the compounds contained in the pharmaceutical preparations may be active in themselves or may be prodrugs that can be converted to active compounds, for example, in a physiological environment. Regardless of the chosen route of administration, the compounds or pharmaceutical compositions of the disclosed herein may be formulated into pharmaceutically acceptable dosage forms as described below, or by other conventional methods known to those skilled in the art.

[0365] Accordingly, another aspect of this disclosure provides a pharmaceutical composition comprising an effective amount of one or more of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or compounds of Table 1, or pharmaceutically acceptable salts thereof), formulated with one or more pharmaceutically acceptable carriers, additives, or diluents. The pharmaceutical compositions disclosed herein can be formulated, in particular, for administration in solid or liquid form. The pharmaceutical compositions disclosed herein can be administered to a target by various routes of administration, including, but not limited to, oral administration; parenteral administration; topical administration; vaginal or rectal, sublingual; intraocular; transdermal; transmucosal; transnasal; or intrathecal administration. In addition, the compounds disclosed herein can be implanted or injected into a patient using a drug delivery system.

[0366] As used herein, the term “therapeutic dose” means an amount of a compound, substance, or composition containing a compound disclosed herein (e.g., a compound of formula (I), (II), (III), or (IV) or a subformula thereof, or a compound of the compounds in Table 1, or a pharmaceutically acceptable salt thereof) that is effective in producing several desired therapeutic effects (e.g., by inhibiting TDP-43 inclusion bodies in at least a subpopulation of cells in animals, thereby blocking the biological consequences of their function in the treated cells, with a reasonable benefit / risk ratio applicable to any medical treatment).

[0367] When used herein, the terms “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” mean an administration in which a compound, drug, or other substance enters the patient’s system and is subjected to metabolism and other similar processes, rather than an administration that directly enters the central nervous system, such as subcutaneous administration.

[0368] The term "pharmaceutically acceptable" is used herein to mean a compound, substance, composition, or dosage form that is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic response, or other problems or complications, within the bounds of sound medical judgment, and that is commensurate with a reasonable benefit-to-risk ratio.

[0369] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in moving or transporting the antagonist of a subject from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and must not be harmful to the patient. Some examples of materials that can function as a pharmaceutically acceptable carrier include, but are not limited to, sugars, starches, cellulose, tragacanth powder, malt, gelatin, talc, excipients, oils, glycols, polyols, esters, agar, buffers, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, cyclodextrin, and other non-toxic, compatible substances used in pharmaceutical formulations.

[0370] The term "pharmaceutically acceptable salt" encompasses salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound of the disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either in its raw state or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. When a compound of the disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either in its raw state or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as alginic acid, and salts of organic acids such as glucuronic acid or galacturonic acid. Certain compounds disclosed herein contain both basic and acidic functional groups that enable the compound to be converted into either a base addition salt or an acid addition salt. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for this disclosure.

[0371] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings, fragrances, preservatives, and antioxidants may also be present in the composition.

[0372] The formulations of this disclosure include those suitable for oral, nasal, topical (including oral and sublingual) administration, rectal, vaginal, or parenteral administration. The formulations can be conveniently provided as unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. Generally, the amount of active ingredient that can be combined with a carrier material to produce a single dosage form is the amount of compound that produces a therapeutic effect.

[0373] Methods for preparing these formulations or compositions include the step of combining the compounds of the Disclosure with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by uniformly and tightly combining the compounds of the Disclosure with a liquid carrier, or a micronized solid carrier, or both, and then, if necessary, shaping the product.

[0374] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges, powders, granules, or liquids or suspensions. In the solid dosage forms of the present disclosure for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, which include, but are not limited to, fillers or bulking agents; binders; humectants; disintegrants; dissolution retarders; absorption enhancers; wetting agents; absorbents; lubricants; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also include buffers. Similar types of solid compositions can also be used as fillers for soft gelatin capsules and hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0375] Exemplary modes of administration include, but are not limited to, injection, infusion, intravenous infusion, inhalation, or oral ingestion. "Injection" includes, but is not limited to, intravenous, intramuscular, intraarterial, subarachnoid, intraventricular, intracapsular, intraorbital, intracardiac, intratracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, intracerebrospinal, and intrasternal injections and infusions. In some embodiments, the composition is administered by intravenous infusion or injection.

[0376] As used herein, the terms "parenteral administration" and "administered parenterally" mean, but are not limited to, conventional injection methods of administration other than enteral and local administration, including, but are not limited to, intravenous, intramuscular, intra-arterial, subarachnoid, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0377] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols, and suitable mixtures thereof, vegetable oils, and organic esters for injection, such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using a coating material such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using a surfactant.

[0378] These compositions may also contain auxiliary agents, such as preservatives, humectants, emulsifiers, and dispersants. Microbial activity can be reliably prevented by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It is also desirable to include, for example, sugars and sodium chloride in the compositions of the present invention. In addition, prolonged absorption of injectable dosage forms can be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

[0379] Injectable depot formulations are prepared by forming a microencapsulation matrix in which the target compound is contained within a biodegradable polymer such as polylactic acid-polyglycolide. The drug release rate can be controlled depending on the ratio of the drug to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0380] Dosage The actual dosage levels of the active ingredients in the pharmaceutical compositions disclosed herein can be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a particular patient, composition, and mode of administration, without causing toxicity to the patient.

[0381] The selected dosage level depends on a variety of factors, including the activity of the specific compound of this disclosure or its ester, salt, or amide used; the route of administration, time of administration, elimination rate, and duration of treatment of the specific compound used; other drugs, compounds, or materials used in combination with the specific compound used; the age, sex, weight, condition, overall health, and medical history of the patient being treated; and similar factors well known in the medical field.

[0382] Toxicity and therapeutic efficacy are measured, for example, in LD50. 50 (A lethal dose for 50% of the population) and ED 50 The therapeutic dose (LD50) can be determined by standard medical procedures in cell cultures or experimental animals. The dose-to-toxicity ratio is the therapeutic index. 50 / ED 50 It can be expressed as a ratio. Compositions exhibiting a high therapeutic index are preferred.

[0383] Data obtained from cell culture assays and animal studies can be used to devise a range of dosages for human use. The dosage of such compounds is preferably one with little to no toxicity. 50 This is within the range of blood concentrations including [the substance]. The dosage may vary within this range depending on the dosage form used and the route of administration utilized.

[0384] The effective therapeutic dose can first be estimated by cell culture assay. The dose is determined in the cell culture. 50 The drug may be formulated in animal models to achieve a circulating plasma concentration range that includes the concentration of the therapeutic agent that achieves maximum half-reduction of symptoms. Plasma levels may be measured, for example, by high-performance liquid chromatography. The effect of a particular dose may be monitored by a suitable bioassay.

[0385] The dosage may be determined by a physician and may be adjusted as needed to match the observed therapeutic effect. Generally, the composition is administered so as to provide an effective dose of the compounds disclosed herein (e.g., compounds of formula (I), (II), (III), or (IV) or their subformulas, or the compounds in Table 1, or their pharmaceutically acceptable salts).

[0386] Regarding the duration and frequency of treatment, it is typical for an experienced clinician to monitor the patient to determine when the treatment provides therapeutic benefit and whether to increase or decrease the dosage, increase or decrease the frequency of administration, discontinue or restart treatment, or make other changes to the treatment regimen. The administration schedule may vary depending on several clinical factors, such as the patient's sensitivity to the drug.

[0387] This disclosure intends to provide formulations of the subject compound in any of the pharmaceutical compositions and preparations described above. Furthermore, this disclosure intends to provide administration via any of the aforementioned routes of administration. Those skilled in the art can select an appropriate formulation and route of administration based on the condition being treated, as well as the overall health, age, and size of the patient being treated. [Examples]

[0388] Examples are provided below to facilitate a more complete understanding of the compounds and methods disclosed herein. The following examples illustrate exemplary forms of preparing the compounds and practicing the methods disclosed herein. However, since alternative methods can be used to obtain similar results, the scope of this disclosure is not limited to the specific embodiments disclosed in these examples, and these examples are for illustrative purposes only.

[0389] General notes: All oxygen or moisture-sensitive reactions were carried out under an N2 atmosphere in glassware purged with N2, after being heated and dried under vacuum (0.5 mmHg) before use. All reagents and solvents were purchased from commercial suppliers and used as received, or synthesized according to the references in the footnotes. NMR spectra were obtained using a Bruker 400 (400 MHz). 1 H, 75MHz 13 C) or Varian (400MHz) 1 H, 75MHz 13C) Recorded using a spectrometer. Proton and carbon chemical shifts are reported in ppm(δ) relative to the NMR solvent. Data are reported as follows: chemical shift, multiplicity (br=broad, s=singleline, t=tripleline, q=quadrupline, m=multiline; coupling constants (multiple possible) (unit: Hz)). Unless otherwise specified, NMR data were collected at 25°C. Flash chromatography was performed using 100-200 mesh silica gel. Liquid chromatography / mass spectrometry (LCMS) was performed using Agilent 1200HPLC and 6110MS. Analytical thin-layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was achieved by UV light and potassium permanganate (KMnO4) aqueous solution staining, followed by heating.

[0390] [Table 2-1] [Table 2-2] [Table 2-3]

[0391] Example 1: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-methylpiperidine-4-yl)-2-(trifluoromethoxyphenyl)thiophen-2-yl)methanone (compound 103) [ka] Step 1: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)phenyl)piperidine A mixture of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (1.00 g, 2.10 mmol) in HCl (10 mL, 2 M in ethyl phosphate) was stirred at 25°C for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness to obtain the desired product (0.95 g, 95.2% yield) as a yellow solid.

[0392] Step 2: 1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)phenyl)piperidine To a mixture of compound 2 (950 mg, 2.56 mmol) in DCM (90 mL), NaBH(OAc)3 (4.88 g, 23.03 mmol), HCHO (831 mg, 10.24 mmol, 37 wt% in H2O), and Na2SO4 (182 mg, 1.28 mmol) were added, and the mixture was stirred at 25°C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the desired product (850 mg, yield 77.6%) as a yellow solid.

[0393] Step 3 tert-butyl(S)-(1-(3-methyl-5-(4-(1-methylpiperidine-4-yl)-2-(trifluoromethoxy)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate Compound 3 (400 mg, 1.04 mmol) was mixed with 1,4-dioxane (8 mL) and H2O (1 mL). Compound 4 (364 mg, 0.93 mmol), K3PO4 (661 mg, 3.11 mmol), and Pd(dppf)Cl2*DCM (127 mg, 0.16 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. LC-MS confirmed the completion of the reaction. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the desired product (160 mg, yield 25.8%) as a yellow oil.

[0394] Step 4 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-methylpiperidine-4-yl)-2-(trifluoromethoxy)phenyl)thiophen-2-yl)methanone A mixture of compound 5 (160 mg, 0.28 mmol) in HCl (3 mL, 2 M in Â) was stirred at 25°C for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired product (compound 103; 27.6 mg, yield 20.9%) as a white solid. MS(ESI):C 23 H 28 F3N3O2S Mass calculation value: 468.20, measured value in m / z: 468.2 [M+H] + . 1 H NMR (400 MHz, MeOD) 7.75 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.4, 1.6 Hz, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 4.03 - 3.93 (m, 2H), 3.86 - 3.73 (m, 2H), 3.72 - 3.60 (m, 3H), 3.22 - 3.10 (m, 2H), 3.03 - 2.95 (m, 1H), 2.92 (s, 3H), 2.49 - 2.39 (m, 1H), 2.36 (s, 3H), 2.19 - 2.08 (m, 3H), 2.04 - 1.92 (m, 2H).

[0395] Example 2: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(5-(1-methylpiperidine-4-yl)pyridine-2-yl)thiophen-2-yl)methanone (compound 104) [ka] Step 1: Synthesis of tert-butyl(S)-(1-(5-(5-chloropyridine-2-yl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (390 mg, 1 mmol) in DMF (10 mL), (5-chloropyridine-2-yl)boronic acid (157.6 mg, 1 mmol), Cs2CO3 (979.2 mg, 3 mmol), Pd(dppf)Cl2DCM (163.5 mg, 0.2 mmol), and CuCl (99 mg, 1 mmol) were added. The mixture was stirred under N2 at 100°C for 16 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography PE:EA=1:1 to obtain tert-butyl(S)-(1-(5-(5-chloropyridine-2-yl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (85 mg, yield 19.11%) as a yellow solid. LCMS(ESI) C 20 H 25 ClN3O3S+ [M + H]+ m / z Calculated value 422.13, measured value 422.

[0396] Step 2: Synthesis of tert-butyl(S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-yl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-(5-chloropyridine-2-yl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (430 mg, 1.02 mmol) in dioxane / H2O=8:1 (18 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (227.4 mg, 1.02 mmol), K3PO4 (649 mg, 3.06 mmol), and Pd(dppf)Cl2DCM (166.3 mg, 0.2 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH:EA=2:1) ​​to obtain tert-butyl(S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-yl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (200 mg, yield 32.5%) as a brown solid. LCMS(ESI) C26H34N4O3S+ [M + H]+ m / z Calculated value 482.24, measured value 483.

[0397] Step 3: Synthesis of tert-butyl(S)-(1-(3-methyl-5-(5-(1-methylpiperidine-4-yl)pyridine-2-yl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate A solution of tert-butyl(S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-yl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (448 mg, 0.88 mmol) and PtO2 (19.9 mg, 0.088 mmol) in EA (20 mL) was stirred under H2 at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The resulting mixture was filtered and concentrated under reduced pressure to obtain tert-butyl(S)-(1-(3-methyl-5-(5-(1-methylpiperidine-4-yl)pyridine-2-yl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (380 mg, yield 80.3%) as a yellow oil. LCMS(ESI) C28H40N3O4S+ [M + H]+ m / z Calculated value 514.28, measured value 514.

[0398] Step 4: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(5-(1-methylpiperidine-4-yl)pyridine-2-yl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(3-methyl-5-(5-(1-methylpiperidine-4-yl)pyridine-2-yl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (220 mg, 0.45 mmol) in 4 mL of ethyl acetate, HCl (3 mL, 2 M in ethyl acetate) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(5-(1-methylpiperidine-4-yl)pyridine-2-yl)thiophen-2-yl)methanone (compound 104; 34.7 mg, yield 19.7%) as a yellow solid. LCMS(ESI) C22H30N3O2S+ [M + H]+ m / z Calculated value 400.21, measured value 400. 1H NMR (400 MHz, MeOD) δ 8.89 (d, J = 2.1 Hz, 2H), 8.24 (dd, J = 8.3, 2.2 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 4.04 - 3.95 (m, 2H), 3.84 (dt, J = 11.7, 7.5 Hz, 1H), 3.75 (ddd, J = 17.7, 10.6, 5.8 Hz, 2H), 3.66 (s, 2H), 3.22 (dd, J = 8.1, 3.1 Hz, 1H), 3.20 - 3.13 (m, 1H), 2.96 (d, J = 15.5 Hz, 3H), 2.45 (td, J = 14.0, 7.5 Hz, 1H), 2.37 (s, 3H), 2.17 (ddt, J = 22.6, 14.6, 8.5 Hz, 5H).

[0399] Example 3: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(6-(1-methylpiperidine-4-yl)pyridine-3-yl)thiophen-2-yl)methanone (compound 108) [ka] Step 1: tert-butyl(S)-(1-(5-(6-chloropyridine-3-yl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of (6-chloropyridine-3-yl)boranediol (230 mg, 1.4616 mmol) in EtOH / DME = 1:1 (8 mL), tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (569 mg, 1.4616 mmol), Na2CO3 (464.8 mg, 4.3848 mmol), and Pd(PPh3)4 (337.8 mg, 0.2923 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (520 mg, yield 75.89%) as a yellow solid. LCMS(ESI) C11H14ClNO4S+ [M + H]+ m / z Calculated value 422, measured value 422.

[0400] Step 2 tert-butyl(S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'-tetrahydro-(2,4'-bipyridine)-5-yl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-(6-chloropyridine-3-yl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (520 mg, 1.2324 mmol) in dioxane / H2O=8:1 (18 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (412.5 mg, 1.8486 mmol), K3PO4 (915.6 mg, 4.3134 mmol), and Pd(dppf)Cl2DCM (201.1 mg, 0.2464 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (210 mg, 31.78% yield) as a yellow solid. LCMS(ESI) C26H35N4O3S+ [M + H]+ m / z Calculated value 483, measured value 483.

[0401] Step 3 tert-butyl(S)-(1-(3-methyl-5-(6-(1-methylpiperidine-4-yl)pyridine-3-yl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(3-methyl-5-(1'-methyl-1',2',3',6'-tetrahydro-(2,4'-bipyridine)-5-yl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (210 mg, 0.4351 mmol) in toluene (5 mL), PtO2 (19.7 mg) was added. The mixture was stirred under H2 at room temperature for 16 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure to obtain the desired product (200 mg, yield 85.36%) as a yellow solid. LCMS(ESI) C26H37N4O3S+ [M + H]+ m / z Calculated value 485, measured value 485.

[0402] Step 4 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(6-(1-methylpiperidine-4-yl)pyridine-3-yl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(3-methyl-5-(6-(1-methylpiperidine-4-yl)pyridine-3-yl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (100 mg, 0.2063 mmol) in HCl (2 mL), HCl (5 mL, 2 M in HCl) was added. The mixture was stirred at room temperature for 16 hours. After the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the desired product (compound 108 mg, yield 17.01%) as a yellow solid. LC-MS (ESI) C21H29N4OS+ [M + H]+ m / z Calculated value 385, measured value 385. 1H NMR (400 MHz, MeOD) δ 8.82 (d, J = 2.0 Hz, 1H), 8.06 - 8.05 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 4.05 - 3.98 (m, 2H), 3.88 - 3.77 (m, 2H), 3.74 - 3.63 (m, 3H), 3.25 - 3.05 (m, 3H), 2.96 (d, J = 8.0 Hz, 3H), 2.47 (d, J = 7.6 Hz, 1H), 2.39 (s, 3H), 2.16 - 2.10 (m, 5H).

[0403] Example 4: Synthesis of (S)-(3-allyl-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-yl)(3-aminopyrrolidine-1-yl)methanone (compound 109) [ka] Step 1 tert-butyl(S)-(1-(3-allyl-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(3-bromo-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (650 mg, 1.1273 mmol) in dioxane / H2O=8:1 (18 mL), 4,4,5,5-tetramethyl-2-(propa-2-en-1-yl)-1,3,2-dioxaborolane (189.4 mg, 1.1273 mmol), K3PO4 (717.8 mg, 3.3819 mmol), and Pd(dppf)Cl2DCM (91.9 mg, 0.1127 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (390 mg, 57.90% yield) as a yellow solid. LCMS(ESI) C31H44N3O3S+ [M + H]+ m / z Calculated value 538, measured value 538.

[0404] Step 2: (S)-(3-allyl-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-yl)(3-aminopyrrolidine-1-yl)methanone To a solution of tert-butyl(S)-(1-(3-allyl-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (150 mg, 0.2789 mmol) in toluene (2 mL), 2 M HCl (5 mL) in toluene was added. The mixture was stirred at room temperature for 16 hours. After the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the desired product (compound 109; 30 mg, yield 22.12%) as a yellow solid. LC-MS (ESI) C26H36N3OS + [M + H]+ m / z Calculated value 438, measured value 438. 1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 6.02 (m, 1H), 5.21 - 5.07 (m, 2H), 4.06 - 3.94 (m, 2H), 3.88 - 3.65 (m, 3H), 3.58 (m, 3H), 3.52 (d, J = 6.4 Hz, 2H), 3.23 (m, 2H), 3.03 - 2.91 (m, 1H), 2.45 (m, 1H), 2.23 - 1.97 (m, 5H), 1.43 (d, J = 6.8 Hz, 6H).

[0405] Example 5: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-isopropylpiperidine-4-yl)phenyl)-3-propylthiophen-2-yl)methanone (compound 110) [ka] Step 1 tert-butyl(S)-(1-(5-(4-(1-isopropylpiperidine-4-yl)phenyl)-3-propylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(3-allyl-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (150 mg, 0.2789 mmol) in  (5 mL), PtO2 (12.7 mg) was added. The mixture was stirred under H2 at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. After removing the solvent, the residue was purified by flash chromatography to obtain the desired product as a yellow solid. MS(ESI): C31H45N3O3S Mass calculation 539, m / z measurement 540 [M+H]+.

[0406] Step 2 (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-isopropylpiperidine-4-yl)phenyl)-3-propylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(4-(1-isopropylpiperidine-4-yl)phenyl)-3-propylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (150 mg, 0.2779 mmol) in siRNA (2 mL), HCl (5 mL, 2 M in siRNA) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired product (compound 110; 30 mg, yield 22.09%) as a yellow solid. MS(ESI): C26H38N3OS, calculated mass 440, measured m / z 440[M+H]+. 1 H NMR (400 MHz, MeOD) δ 7.68 - 7.60 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 4.05 - 3.95 (m, 2H), 3.89 - 3.65 (m, 3H), 3.58 (m, 3H), 3.23 (m, 2H), 3.02 - 2.92 (m, 1H), 2.75 - 2.67 (m, 2H), 2.46 (m, 1H), 2.24 - 1.97 (m, 5H), 1.72 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H), 0.99 (t, J = 7.2 Hz, 3H).

[0407] Example 6: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(3-methoxy-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 111) [ka] Step 1: 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6-tetrahydropyridine To a 4 mL solution of tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (580 mg, 1.4 mmol) in ethyl acetate, HCl (5 mL, 2 M in EA) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The resulting mixture was concentrated under reduced pressure to obtain 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (509 mg, yield 110%) as a yellow oil. LC-MS (ESI) C18H27BNO3+ [M + H]+ m / z Calculated value 316.21, measured value 316.

[0408] Step 2: 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine To a solution of 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (1100 mg, 3.5 mmol) in DCM (20 mL), HCHO (314.4 mg, 10.5 mmol, 37 wt% in H2O) and NaBH(OAc)3 (440 mg, 10.5 mmol) were added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The residue was concentrated under reduced pressure to obtain 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine (900 mg, yield 74.4%) as a yellow solid. LCMS(ESI) C19H29BNO3+ [M + H]+ m / z Calculated value 330.23, measured value 330.

[0409] Step 3 (S)-(1-(5-(3-Methoxy-4-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (800 mg, 2.05 mmol) in dioxane / H2O=8:1 (18 mL), 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine (676.6 mg, 2.05 mmol), K3PO4 (1308.6 mg, 6.16 mmol), and Pd(dppf)Cl2DCM (335.4 mg, 0.41 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using MeOH:EA=1:10 as the eluent to obtain tert-butyl(S)-(1-(5-(3-methoxy-4-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (448 mg, yield 40.5%) as a yellow solid. LCMS(ESI) C28H37N3O4S+ [M + H]+ m / z Calculated value 511.25, measured value 512.

[0410] Step 4 tert-butyl(S)-(1-(5-(3-methoxy-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate A solution of tert-butyl(S)-(1-(5-(3-methoxy-4-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (448 mg, 0.88 mmol) and PtO2 (19.9 mg, 0.088 mmol) in ELISA (20 mL) was stirred under H2 at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The resulting mixture was filtered and concentrated under reduced pressure to obtain tert-butyl(S)-(1-(5-(3-methoxy-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (380 mg, yield 80.3%) as a yellow oil. LCMS(ESI) C28H39N3O4S+ [M + H]+ m / z Calculated value 513.27, measured value 514.

[0411] Step 5 (S)-(3-aminopyrrolidine-1-yl)(5-methoxy-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(3-methoxy-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (380 mg, 0.74 mmol) in 4 mL of HCl (5 mL, 2 M in HCl). The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The resulting mixture was concentrated under reduced pressure to obtain (S)-(3-aminopyrrolidine-1-yl)(5-(3-methoxy-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 111; 350 mg) as a yellow solid. LC-MS(ESI) C23H32N3O2S+ [M + H] + m / z calculated value: 414.22, measured value: 414. 1H NMR (400 MHz, MeOD) δ 7.30 (s, 1H), 7.24 (s, 2H), 7.22 (s, 1H), 4.01 (t, J = 7.2 Hz, 2H), 3.94 (d, J = 7.1 Hz, 3H), 3.87 (dt, J = 9.2, 6.2 Hz, 1H), 3.83 - 3.69 (m, 2H), 3.63 (d, J = 12.3 Hz, 2H), 3.25 - 3.12 (m, 2H), 2.93 (s, 3H), 2.52 - 2.42 (m, 1H), 2.38 (s, 3H), 2.23 - 1.92 (m, 6H).

[0412] Example 7: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-methylpiperidine-4-yl)-3-(trifluoromethoxyphenyl)thiophen-2-yl)methanone (compound 112) [ka] Step 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl)piperidine A solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (470 mg, 1.00 mmol) in HCl (5 mL, 2 M in ethyl phosphate) was stirred at 25°C for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness to obtain the desired product (445 mg, 96.4% yield) as a yellow solid.

[0413] Step 2: 1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl)piperidine To a mixture of compound 2 (445 mg, 1.20 mmol) in DCM (45 mL), NaBH(OAc)3 (2.29 g, 10.79 mmol), HCHO (389 mg, 4.80 mmol), and Na2SO4 (85 mg, 0.60 mmol) were added, and the mixture was stirred at 25°C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. It was then diluted with ethyl acetate and filtered. The filtrate was concentrated to dryness to obtain the desired product (450 mg, yield 87.7%) as a yellow oil.

[0414] Step 3 tert-butyl(S)-(1-(3-methyl-5-(4-(1-methylpiperidine-4-yl)-3-(trifluoromethoxy)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate Compound 3 (450 mg, 1.17 mmol) was mixed with 1,4-dioxane (10 mL) and H2O (1.2 mL). Compound 4 (409 mg, 1.05 mmol), K3PO4 (620 mg, 2.92 mmol), and Pd(dppf)Cl2*DCM (143 mg, 0.18 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (MeOH / DCM = 8%) to obtain the desired product (280 mg, yield 38.0%) as a black solid.

[0415] Step 4 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-methylpiperidine-4-yl)-3-(trifluoromethoxy)phenyl)thiophen-2-yl)methanone A solution of compound 5 (280 mg, 0.49 mmol) in HCl (3 mL, 2 M in Â) was stirred at 25°C for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired product (compound 112; 22.4 mg, yield 9.6%) as a white solid. MS(ESI):C 23 H 29F3N3O2S Mass calculation value: 468.20, measured value in m / z: 468.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.65 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 3.82 - 3.72 (m, 2H), 3.68 - 3.54 (m, 2H), 3.32 (s, 1H), 3.10 - 3.00 (m, 3H), 2.35 (s, 3H), 2.33 (s, 3H), 2.26 - 2.15 (m, 3H), 1.92 - 1.82 (m, 3H), 1.81 - 1.72 (m, 2H).

[0416] Example 8: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-isopropylpiperidine-4-yl)phenyl)-3-vinylthiophen-2-yl)methanone (compound 117) [ka] Step 1 tert-butyl(S)-(1-(3-bromo-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(3,5-dibromothiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (1 g, 0.0022 mol) in dioxane / H2O=8:1 (18 mL), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.72 g, 0.0022 mmol), K3PO4 (1.4 g, 0.0066 mol), and Pd(dppf)Cl2DCM (0.18 g, 0.0002 mol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (0.8 g, yield 54.55%) as a yellow solid. MS(ESI):C28H39BrN3O3S Mass calculation value 576, m / z measured value 576[M+H]+.

[0417] Step 2 tert-butyl(S)-(1-(5-(4-(1-isopropylpiperidine-4-yl)phenyl)-3-vinylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(3-bromo-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (800 mg, 1.3875 mmol) in 10 mL of toluene and 1 mL of H2O, potassium vinyltrifluoroborate (205.98 mg, 1.5262 mmol), t-BuOK (504.54 mg, 4.1625 mmol), and Pd(dppf)Cl2DCM (113.22 mg, 0.1387 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (500 mg, yield 61.69%) as a yellow oil. MS(ESI):C30H42N3O3S Mass calculation value 524, m / z measured value 524 [M+H]+.

[0418] Step 3 (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-isopropylpiperidine-4-yl)phenyl)-3-vinylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(4-(1-isopropylpiperidine-4-yl)phenyl)-3-vinylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (140 mg, 0.2673 mmol) in HCl (2 mL, 2 M in HCl) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired product (compound 117; 20 mg, yield 15.90%) as a white solid. MS(ESI): C25H34N3OS Mass calculation value 424, m / z measurement value 424 [M+H]+. 1H NMR (400 MHz, MeOD) δ 7.72 - 7.64 (m, 3H), 7.37 (d, J = 8.4 Hz, 2H), 6.84 (m, 1H), 5.88 (m, 1H), 5.44 (m, 1H), 3.99 (d, J = 10.8 Hz, 2H), 3.86 - 3.64 (m, 3H), 3.59 (m, 3H), 3.23 (m, 2H), 2.98 (m, 1H), 2.46 (m, 1H), 2.24 - 1.97 (m, 5H), 1.43 (d, J = 6.8 Hz, 6H).

[0419] Example 9: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-ethyl-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 118) [ka] Step 1 tert-butyl(S)-(1-(3-ethyl-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-(4-(1-isopropylpiperidine-4-yl)phenyl)-3-vinylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (350 mg, 0.6683 mmol) in  (5 mL), PtO2 (30.35 mg) was added. The mixture was stirred under H2 at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The residue was purified by flash chromatography to obtain the desired product (300 mg, yield 76.85%) as a yellow solid. MS(ESI):C30H44N3O3S Mass calculation value 526, m / z measured value 526 [M+H]+.

[0420] Step 2: (S)-(3-aminopyrrolidine-1-yl)(3-ethyl-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(3-ethyl-5-(4-(1-isopropylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (300 mg, 0.5706 mmol) in ethyl acetate (2 mL), 2 M HCl (5 mL) in ethyl acetate was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired mass was found. The residue was purified by preparative HPLC to obtain the desired product (compound 118; 30 mg, yield 11.11%) as a yellow solid. MS(ESI): C25H36N3OS Mass calculation value 426, m / z measurement value 426 [M+H] + . 1H NMR (400 MHz, MeOD) δ 7.68 - 7.63 (m, 2H), 7.37 (s, 1H), 7.35 (d, J = 3.6 Hz, 2H), 4.04 - 3.91 (m, 2H), 3.88 - 3.72 (m, 2H), 3.69 - 3.54 (m, 4H), 3.23 (m, 2H), 2.97 (m, 1H), 2.76 (q, J = 7.6 Hz, 2H), 2.44 (m, 1H), 2.22 - 2.02 (m, 5H), 1.43 (d, J = 6.8 Hz, 6H), 1.29 (t, J = 7.6 Hz, 3H).

[0421] Example 10: Synthesis of ((S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-2-yl)methyl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 119) [ka] Step 1 (4-(4-bromophenyl)piperidine-1-yl)(tetrahydro-2H-pyran-2-yl)methanone To a mixture of 4-(4-bromophenyl)piperidine (600 mg, 2.50 mmol) in DMF (10 mL), oxane-2-carboxylic acid (390 mg, 3.00 mmol), DIEA (1.29 g, 9.99 mmol), and HATU (1.14 g, 3.00 mmol) were added, and the mixture was stirred at 50°C for 12 hours. LC-MS confirmed the completion of the reaction. The reaction mixture was diluted with H2O (30 mL) and extracted with  (15 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (EA / PE = 20%) to obtain the desired product (920 mg, yield 94.1%) as a yellow oil.

[0422] Step 2 (4-(4-bromophenyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)piperidine To a mixture of compound 3 (920 mg, 2.6117 mmol) in THF (9 mL), BH3 (144.48 mg, 10.446 mmol) was added, and the mixture was stirred at 75°C for 4 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. After cooling the reaction mixture in an ice bath, methanol (5 mL) was carefully added. HCl (6 M, 8 mL) was rapidly added dropwise, and the mixture was heated under reflux for 30 minutes. The volatile substances were then concentrated under vacuum, and the resulting mixture was cooled in an ice bath and 50% NaOH aqueous solution (10 mL) was added (pH > 10). The mixture was then diluted with water and extracted with diethyl ether (50 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 20%~30%) to obtain compound 4 (830 mg, yield 86.4%) as a colorless oil.

[0423] Step 3: 1-((tetrahydro-2H-pyran-2-yl)methyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a mixture of compound 4 (830 mg, 2.45 mmol) in 1,4-dioxane (15 mL), B2Pin2 (748 mg, 2.94 mmol), KOAc (722 mg, 7.36 mmol), and Pd(dppf)Cl2DCM (301 mg, 0.37 mmol) were added, and the mixture was stirred under N2 at 100°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 5 (1.00 g, yield 84.6%) as a black oil.

[0424] Step 4 ((3S)-1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-2-yl)methyl)piperidine-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate Compound 5 (500 mg, 1.30 mmol) was mixed with 1,4-dioxane (14 mL) and H2O (2 mL). Compound 6 (404 mg, 1.04 mmol), K3PO4 (826 mg, 3.89 mmol), and Pd(dppf)Cl2*DCM (159 mg, 0.19 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. LC-MS confirmed the completion of the reaction. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (MeOH / DCM = 5%) to obtain compound 7 (280 mg, yield 34.2%) as a yellow solid.

[0425] Step 5 ((S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-2-yl)methyl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone A mixture of compound 7 (140 mg, 0.25 mmol) in HCl / Â (2 mL) was stirred at 25°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain compound 119 (109.3 mg, yield 94.8%) as a white solid. LC-MS (ESI):C 27 H 37 N3O2S Mass calculation value: 467.26, m / z measured value: 468.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.4 Hz, 2H), 7.41 - 7.29 (m, 2H), 7.24 (s, 1H), 4.06 - 3.95 (m, 3H), 3.83 (s, 3H), 3.75 - 3.63 (m, 3H), 3.57 - 3.48 (m, 1H), 3.26 - 3.03 (m, 4H), 2.98 - 2.85 (m, 1H), 2.49 - 2.39 (m, 1H), 2.35 (s, 3H), 2.18 - 2.05 (m, 4H), 2.03 - 1.88 (m, 2H), 1.68 - 1.55 (m, 4H), 1.36 - 1.26 (m, 1H).

[0426] Example 11: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(2-chloro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 120) [ka] Step 1: 4-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6-tetrahydropyridine A mixture of tert-butyl 4-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (600 g, 1.43 mmol) in HCl / Â (6 mL) was stirred at 25°C for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness to obtain the desired product (560 mg, yield 86.0%) as a yellow solid.

[0427] Step 2: 4-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine To a mixture of compound 2 (560 mg, 1.75 mmol) in DCM (50 mL), NaBH(OAc)3 (3.34 g, 15.77 mmol), HCHO (569 mg, 7.01 mmol, 37 wt% in H2O), and Na2SO4 (124 mg, 0.88 mmol) were added, and the mixture was stirred at 25°C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (EA / MeOH = 5 / 1) to obtain the desired product (480 mg, yield 73.9%) as a yellow solid.

[0428] Step 3 tert-butyl(S)-(1-(5-(2-chloro-4-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate Compound 3 (480 mg, 1.44 mmol) was mixed with 1,4-dioxane (16 mL) and H2O (2 mL). Compound 4 (504 mg, 1.29 mmol), K3PO4 (916 mg, 4.32 mmol), and Pd(dppf)Cl2*DCM (176 mg, 0.22 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. LC-MS confirmed the completion of the reaction. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (MeOH / DCM = 5%~6%) to obtain the desired product (410 mg, yield 49.79%) as a yellow solid.

[0429] Step 4 tert-butyl(S)-(1-(5-(2-chloro-4-(1-methylpiperidine--4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a mixture of compound 5 (410 mg, 0.79 mmol) in  (4 mL), PtO2 (41 mg, 0.18 mmol) was added, and the mixture was stirred at 25°C for 32 hours under an H2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain the desired composition (390 mg, yield 85.3%) as a yellow solid.

[0430] Step 5 (S)-(3-aminopyrrolidine-1-yl)(5-(2-chloro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone A mixture of compound 6 (240 mg, 0.46 mmol) in HCl / Â (3 mL) was stirred at 25°C for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired product (compound 120; 12.6 mg, yield 6.2%) as a white solid. MS(ESI):C 22H 29 ClN3OS Mass calculation value: 418.17, measured value in m / z: 418.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.58 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 4.03 - 3.96 (m, 2H), 3.89 - 3.75 (m, 2H), 3.74 - 3.59 (m, 3H), 3.16 (t, J = 12 Hz, 2H), 2.94 (s, 4H), 2.50 - 2.40 (m, 1H), 2.37 (s, 3H), 2.19 - 2.10 (m, 3H), 2.07 - 1.92 (m, 2H).

[0431] The following compounds were prepared in the same manner as compound 120: [Table 6]

[0432] Example 12: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(2-(1-methylpiperidine-4-yl)pyrimidine-5-yl)thiophen-2-yl)methanone (compound 124) [ka] Step 1: 2-(1-methylpiperidine-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine To a mixture of 2-(piperidine-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (100 mg, 0.35 mmol) in DCM (10 mL), NaBH(OAc)3 (660 mg, 3.11 mmol), HCHO (112 mg, 1.38 mmol), and Na2SO4 (25 mg, 0.17 mmol) were added, and the mixture was stirred at 25°C for 12 hours. After the reaction, the mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0%~30%) to obtain the desired product (200 mg, yield 85.8%) as a white solid.

[0433] Step 2 tert-butyl(S)-(1-(3-methyl-5-(2-(1-methylpiperidine-4-yl)pyrimidine-5-yl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate Compound 2 (200 mg, 0.66 mmol) was mixed with 1,4-dioxane (8 mL) and H2O (1 mL). Compound 3 (231 mg, 0.59 mmol), K3PO4 (420 mg, 1.98 mmol), and Pd(dppf)Cl2*DCM (81 mg, 0.10 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography using MeOH / DCM = 0%~30% as the eluent to obtain Compound 4 (100 mg, yield 28.1%) as a black solid.

[0434] Step 3 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(2-(1-methylpiperidine-4-yl)pyrimidine-5-yl)thiophen-2-yl)methanone A mixture of compound 4 (100 mg, 0.2059 mmol) in HCl / Â (2 mL) was stirred at 25°C for 3 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated to dryness, and the crude product was purified by preparative HPLC to obtain the desired product, compound 124 (7 mg, yield 8.7%), as a white solid. MS(ESI):C 20 H 27N5OS Mass calculation value: 385.19, m / z measured value: 386.1 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 9.01 (s, 2H), 8.52 (s, 2H), 7.45 (s, 1H), 3.95 - 3.77 (m, 3H), 3.75 - 3.67 (m, 1H), 3.57 - 3.41 (m, 3H), 3.22 - 3.13 (m, 1H), 3.05 - 2.92 (m, 2H), 2.81 - 2.75 (m, 3H), 2.37 (s, 3H), 2.35 - 2.24 (m, 3H), 2.22 - 2.11 (m, 2H), 2.05 - 1.97 (m, 1H).

[0435] The following compounds are prepared in the same manner as described in this example: [Table 7]

[0436] Example 13: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(2-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 128) [ka] Step 1: 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a solution of tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (600 mg, 1.4767 mmol) in siRNA (2 mL), HCl (5 mL, 2 M in EtOAC) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure to obtain the desired product (500 mg, 94.30% yield) as a colorless oil.

[0437] Step 2: 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methylpiperidine A mixture of 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (500 mg, 1.6383 mmol) in DCM (50 mL) is mixed with NaBH(OAc)3 (3124.9 mg, 14.744 mmol), aqueous formaldehyde solution (531.3 mg, 6.5532 mmol), and Na2SO4. 4( (69.8 mg, 0.4914 mmol) was added, and the mixture was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. After the reaction, the solvent was removed under reduced pressure, water was added, and the mixture was extracted three times with RINKAN. The RINKAN phases were combined, washed with brine, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to obtain the desired product (730 mg, 97.71% yield) as a colorless oil.

[0438] Step 3 tert-butyl(S)-(1-(5-(2-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methylpiperidine (250 mg, 0.7832 mmol) in dioxane / H2O=8:1 (9 mL), tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (304.9 mg, 0.7832 mmol), K3PO4 (498.7 mg, 2.3496 mmol), and Pd(dppf)Cl2DCM (127.9 mg, 0.1566 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (150 mg, yield 34.36%) as a yellow solid.

[0439] Step 4 (S)-(3-aminopyrrolidine-1-yl)(5-(2-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(2-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (150 mg, 0.2990 mmol) in siRNA (2 mL), HCl (3 mL, 2 M in siRNA) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired product (compound 128; 30 mg, yield 22.47%) as a yellow solid. MS(ESI): C22H29FN3OS Mass calculation value 402, m / z measurement value 402 [M+H]+. 1H NMR (400 MHz, MeOD) δ 7.53 (t, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.02 (m, 2H), 3.66 (m, 2H), 3.51 (m, 2H), 3.23 (s, 1H), 2.91 (d, J = 11.6 Hz, 2H), 2.49 (m, 1H), 2.23 (d, J = 2.4 Hz, 6H), 2.07 (m, 3H), 1.80 - 1.62 (m, 5H).

[0440] Example 14: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(2-fluoro-4-(piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 129) [ka] Step 1: tert-butyl 4-(4-bromo-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.50 g, 4.80 mmol) in 1,4-dioxane (16 mL) and H2O (4 mL), 1-bromo-2-fluoro-4-iodobenzene (2.17 g, 7.20 mmol), K3PO4 (1.66 g, 12.00 mL), and Pd(dppf)Cl2DCM (0.59 g, 0.70 mmol) were added, and the mixture was stirred under N2 at 80°C for 16 hours. TLC (PE / EA = 5:1) indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (EA / PE = 8%) to obtain the desired product (1.30 g, yield 68.7%) as a pale yellow oil.

[0441] Step 2: tert-butyl 4-(4-bromo-3-fluorophenyl)piperidine-1-carboxylate To a mixture of compound 3 (1.30 g, 3.60 mmol) in siRNA (30 mL), PtO2 (0.13 mg, 0.50 mmol) was added, and the mixture was stirred at 25°C for 48 hours under an H2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain the desired composition (1.30 g, yield 69.4%) as a yellow oil.

[0442] Step 3: tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate To a mixture of compound 4 (1.30 g, 3.60 mmol) in 1,4-dioxane (20 mL), B2Pin2 (1.10 g, 4.30 mmol), KOAc (1.06 g, 10.80 mmol), and Pd(dppf)Cl2 (0.40 g, 0.50 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (EA / PE = 8%) to obtain the desired product (1.10 g, yield 66.6%) as a colorless oil.

[0443] Step 4 tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)-3-fluorophenyl)piperidine-1-carboxylate Compound 5 (200 mg, 0.49 mmol) and Compound 6 (192 mg, 0.49 mmol) were mixed in 1,4-dioxane (8 mL) and H2O (1 mL). K3PO4 (313 mg, 1.98 mmol) and Pd(dppf)Cl2 (60 mg, 0.07 mmol) were added, and the mixture was stirred at 95°C for 16 hours under an N2 atmosphere. LC-MS confirmed the completion of the reaction. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (EA / PE = 30%) to obtain the desired product (150 mg, yield 46.5%) as a pale yellow oil. LC-MS (ESI):C31 H 43 FN3O5S Mass calculation value: 588.29, measured value in m / z: 588.5 [M+H] + .

[0444] Step 5 (S)-(3-aminopyrrolidine-1-yl)(5-(2-fluoro-4-(piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a mixture of compound 7 (150 mg, 0.25 mmol) in  (2 mL), HCl (5 mL, 2 M in Â) was added. The mixture was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired product (compound 129; 10.8 mg, yield 25.5%) as a white solid. LC-MS (ESI):C 21 H 26 FN3OS Mass calculation value: 387.18, m / z measured value: 388.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.49 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.24 - 7.12 (m, 2H), 4.01 - 3.92 (m, 2H), 3.86 - 3.72 (m, 2H), 3.68 - 3.61 (m, 1H), 3.55 - 3.48 (m, 2H), 3.20 - 3.09 (m, 2H), 3.02 - 2.93 (m, 1H), 2.46 - 2.34 (m, 4H), 2.15 - 2.03 (m, 3H), 1.98 - 1.85 (m, 2H).

[0445] Example 15: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(2-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 134) [ka] Step 1: tert-butyl 4-(4-bromo-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of 1-bromo-4-iodo-2-methylbenzene (1000 mg, 3.4 mmol) in dioxane / H2O=8:1 (18 mL), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1044.8 mg, 3.4 mmol), K2CO3 (1396.4 mg, 10.1 mmol), and Pd(dppf)Cl2DCM (549.6 mg, 0.67 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5:1) to obtain tert-butyl 4-(4-bromo-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (580 mg, yield 46.3%) as a yellow oily substance. LCMS (ESI) C17H23BrNO2+ [M + H]+ m / z Calculated value 352.09, measured value 352.

[0446] Step 2: tert-butyl 4-(4-bromo-3-methylphenyl)piperidine-1-carboxylate 4-(4-bromo-3-methylphenyl)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (580 mg, 1.53 mmol) was dissolved in 10 mL of siRNA, to which PtO2 (34.8 mg, 0.15 mmol) was added. The mixture was stirred under H2 at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The resulting mixture was filtered and concentrated under reduced pressure to obtain tert-butyl 4-(4-bromo-3-methylphenyl)piperidine-1-carboxylate (513 mg, yield 83.6%) as a yellow oil. LC-MS (ESI) C13H19BrN+ [M + H]+ m / z Calculated value 268.07, measured value 268.

[0447] Step 3: 4-(4-bromo-3-methylphenyl)piperidine To a 5 mL HCl solution of tert-butyl 4-(4-bromo-3-methylphenyl)piperidine-1-carboxylate (513 mg, 1.44 mmol), HCl (5 mL, 2 M in HCl) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The resulting mixture was filtered and concentrated under reduced pressure to obtain 4-(4-bromo-3-methylphenyl)piperidine (533 mg, yield 72.62%) as a yellow oil. LC-MS (ESI) C12H17BrN+ [M + H]+ m / z Calculated value 254.06, measured value 254.

[0448] Step 4: 4-(4-bromo-3-methylphenyl)-1-methylpiperidine To a solution of 4-(4-bromo-3-methylphenyl)piperidine (533 mg, 2.1 mmol) in DCM (5 mL), HCHO (125.8 mg, 4.2 mmol, 37 wt% in H2O) and NaBH(OAc)3 (1333.4 mg, 6.3 mmol) were added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain 4-(4-bromo-3-methylphenyl)-1-methylpiperidine (200 mg, yield 33.8%) as a yellow oil. LC-MS (ESI) C13H19BrN+ [M + H]+ m / z Calculated value 268.07, measured value 268.

[0449] Step 5: 1-Methyl-4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a solution of 4-(4-bromo-3-methylphenyl)-1-methylpiperidine (200 mg, 0.75 mmol) in dioxane (10 mL), B2Pin2 (189.4 mg, 0.75 mmol), KOAc (220 mg, 2.2 mmol), and Pd(dppf)Cl2DCM (121.7 mg, 0.15 mmol) were added. The mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Â5 / petroleum ether = 5:1) to obtain 1-methyl-4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (250 mg, yield 101%) as a yellow solid. LCMS(ESI) C19H31BNO2+ [M + H]+ m / z Calculated value 316.25, measured value 316.

[0450] Step 6 tert-butyl(S)-(1-(3-methyl-5-(2-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (280 mg, 0.72 mmol) in dioxane / H2O=8:1 (18 mL), 1-methyl-4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (226.7 mg, 0.72 mmol), K3PO4 (458 mg, 2.16 mmol), and Pd(dppf)Cl2DCM (117.4 mg, 0.14 mmol) were added. The mixture was stirred at 95°C for 16 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl phosphate = 1:5) to obtain tert-butyl(S)-(1-(3-methyl-5-(2-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (200 mg, yield 53%) as a yellow oily substance. LCMS(ESI) C28H40N3O3S+ [M + H]+ m / z Calculated value 498.28, measured value 498.

[0451] Step 7 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(2-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(3-methyl-5-(2-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (200 mg, 0.39 mmol) in 4 mL of ethyl acetate, HCl (3 mL, 2 M in ethyl acetate) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(2-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 134; 7.1 mg, yield 4.4%) as a yellow solid. LCMS(ESI) C24H34N3OS+ [M + H]+ m / z Calculated value 412.24, measured value 412. 1 H NMR (400 MHz, MeOD) δ 7.25 (d, J = 7.9 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.84 (s, 1H), 3.88 (t, J = 7.2 Hz, 2H), 3.81 - 3.70 (m, 1H), 3.69 - 3.57 (m, 2H), 3.52 (d, J = 12.1 Hz, 2H), 3.05 (t, J = 11.8 Hz, 2H), 2.87 - 2.73 (m, 4H), 2.40 - 2.29 (m, 4H), 2.26 (s, 3H), 2.04 (dd, J = 17.5, 13.1 Hz, 3H), 1.89 (dd, J = 24.7, 12.0 Hz, 2H).

[0452] Example 16: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(3-chloro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 135) [ka] Step 1: 4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine A solution of tert-butyl 4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (292 mg, 0.69 mmol) in HCl (3 mL, 2 M in ethyl phosphate) was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness to obtain the desired product (300 mg, 94.5% yield) as a colorless oil.

[0453] Step 2: 4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methylpiperidine To a mixture of compound 2 (300 mg, 0.93 mmol) in DCM (30 mL), STAB (1.78 g, 8.39 mmol), HCHO (303 mg, 3.73 mmol), and Na2SO4 (40 mg, 0.28 mmol) were added, and the mixture was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. It was then diluted with ethyl acetate and filtered. The filtrate was concentrated to dryness to obtain the desired product (360 mg, 97.7% yield) as a yellow oil.

[0454] Step 3 tert-butyl(S)-(1-(5-(3-chloro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate Compound 3 (285 mg, 0.85 mmol) and Compound 4 (300 mg, 0.77 mmol) were mixed in 1,4-dioxane (8 mL) and H2O (1 mL). K3PO4 (540 mg, 2.54 mmol) and Pd(dppf)Cl2 (104 mg, 0.13 mmol) were added, and the mixture was stirred at 95°C for 16 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (MeOH / DCM = 20%) to obtain the desired product (227 mg, yield 43.90%) as a black solid.

[0455] Step 4 (S)-(3-aminopyrrolidine-1-yl)(5-(3-chloro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone A solution of compound 5 (227 mg, 0.44 mmol) in HCl (3 mL, 2 M in Â) was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired product (compound 135; 58.5 mg, yield 30.7%) as an off-white solid. MS(ESI):C 22 H 29 ClN3OS Mass calculation value: 418.17, measured value in m / z: 418.1 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.65 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 3.82 - 3.72 (m, 2H), 3.68 - 3.54 (m, 2H), 3.32 (s, 1H), 3.10 - 3.00 (m, 3H), 2.35 (s, 3H), 2.33 (s, 3H), 2.26 - 2.15 (m, 3H), 1.92 - 1.82 (m, 3H), 1.81 - 1.72 (m, 2H).

[0456] Example 17: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(3-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 136) [ka] Step 1: Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.2 mmol) and 4-bromo-2-fluoro-1-iodobenzene (1.44 g, 4.8 mmol) in dioxane / H2O = 4:1 (10 mL), K2PO3 (1.33 g, 9.6 mmol) and Pd(dppf)Cl2DCM (0.26 g, 0.36 mmol) were added, and the mixture was stirred under N2 at 80°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.84 g, yield 71.88%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.26 - 7.21 (m, 2H), 7.13 - 7.09 (m, 1H), 5.94 - 5.92 (m, 1H), 4.06 (9, J = 5.8, 2H), 3.61 (t, J = 5.8 Hz, 2H), 2.49 - 2.44 (m, 2H), 1.49 (s, 9H).

[0457] Step 2: Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate To a 5 mL solution of tert-butyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (840 mg, 2.3514 mmol) in RINKAN, PtO2 (84.4 mg, 0.3715 mmol) was added, and the mixture was stirred under an H2 atmosphere at 25°C for 48 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate (500 mg, yield 58.6%) as a colorless oil. LCMS (ESI): C15H21BrFNO2 + [M - Me + H] m / z Calculated value 345.0, measured value 344.9.

[0458] Step 3: Synthesis of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate (500 mg, 1.3918 mmol) and B2Pin2 (424.1 mg, 1.6701 mmol) in dioxane (10 mL), Pd(dppf)Cl2DCM (227.3 mg, 0.2783 mmol) and KOAc (409.8 mg, 4.1754 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (438 mg, yield 75.9%) as a white solid. LCMS(ESI):C21H31BFNO4 [M - Me] m / z Calculated value 391.23, measured value 391.3.

[0459] Step 4: Synthesis of 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a solution of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (438 mg, 1.078 mmol) in 2 mL of HCl, HCl (4 mL, 2 M in HCl) was added, and the mixture was stirred at 25°C for 12 hours. After the reaction, the solvent was removed under reduced pressure to obtain 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (400 mg, yield 97.26%) as a yellowish solid. LCMS (ESI) C17H26BFNO2 + [M + H] m / z Calculated value 306.20, measured value 306.3.

[0460] Step 5: Synthesis of 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methylpiperidine To a solution of 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (400 mg, 1.3106 mmol) in DCM, HCHO (157.43 mg, 5.2424 mmol) and NaBH(OAc)3 (833.3 mg, 3.9318 mmol) were added, and the mixture was stirred at 25°C for 2 hours. After the reaction, the mixture was filtered, and the solvent was removed under reduced pressure to obtain 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methylpiperidine (400 mg, yield 90.83%) as a yellowish oil. LCMS(ESI) C18H28BFNO2+ [M + H] m / z: Calculated value 320.21, measured value 320.1.

[0461] Step 6: Synthesis of tert-butyl(S)-(1-(5-(3-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (150 mg, 0.3853 mmol) and 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methylpiperidine (160 mg, 0.5008 mmol) in EtOH / DME (1:1), Na2CO3 (122.5 mg, 1.1559 mmol) and Pd(PPh3)4 (44.5 mg, 0.0385 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl(S)-(1-(5-(3-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (60 mg, yield 30.42%) as a white solid. LCMS(ESI) C27H37FN3O3S+ [M + H] m / z Calculated value 502.25, measured value 502.3.

[0462] Step 7: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(3-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(3-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (60 mg, 0.1196 mmol) in 2 mL of HCl (4 mL, 2 M in HCl), the mixture was stirred at 25°C for 4 hours. After the reaction, the mixture was filtered, and the filter cake was washed several times with HCl to obtain (S)-(3-aminopyrrolidine-1-yl)(5-(3-fluoro-4-(1-methylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 136; 13.7 mg, yield 27.34%) as a white solid. LCMS(ESI) C22H29FN3OS+ [M + H] m / z: Calculated value 402.20, measured value 402.2. 1H NMR (400 MHz, MeOD) δ 7.47 (d, J = 8.0 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.30 (s, 1H), 4.01 - 3.97 (m, 2H), 3.88 - 3.70 (m, 3H), 3.64 (d, J = 12.1 Hz, 2H), 3.25 - 3.20 (m, 3H), 2.93 (s, 3H), 2.48 - 2.43 (m, 1H), 2.36 (s, 3H), 2.18 - 2.10 (m, 5H).

[0463] Example 18: Synthesis of ((S)-3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-3-yl)methyl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 139) [ka] Step 1 tert-butyl((3S)-1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-3-yl)methyl)piperidine-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(3-methyl-5-(4-(piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (340 mg, 0.724 mmol) in DCM (6 mL), oxan-3-carbaldehyde (247.9 mg, 2.172 mmol), NaBH(OAc)3 (230.17 mg, 1.086 mmol), and HOAc (87 mg, 1.448 mmol) were added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The resulting mixture was diluted with H2O (20 mL) and extracted three times with siRNA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (300 mg, 65.68% yield) as a yellow oily substance.

[0464] Step 2 ((S)-3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-3-yl)methyl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl((3S)-1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-3-yl)methyl)piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (300 mg, 0.5284 mmol) in DCM (5 mL), TFA (903.72 mg, 7.926 mmol) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The residue was purified by preparative HPLC to obtain the desired product (compound 139; 30 mg, yield 10.92%) as a yellow solid. MS(ESI): C27H38N3O2S Mass calculation value 468, m / z measurement value 468 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 4.01 - 3.91 (m, 3H), 3.86 - 3.66 (m, 6H), 3.54 - 3.47 (m, 1H), 3.19 - 3.03 (m, 4H), 2.94 (t, J = 11.6 Hz, 1H), 2.44 (m, 1H), 2.35 (s, 3H), 2.24 - 1.92 (m, 8H), 1.68 (m, 2H), 1.51 - 1.41 (m, 1H).

[0465] Example 19: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(3-fluoro-4-(piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 140) [ka] Step 1: Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate To a 5 mL solution of NiCl2·DME (0.07 g, 0.3 mmol) and dtbppy (0.1 g, 0.3 mmol) in DMA, 4-bromo-2-fluoro-1-iodobenzene (0.5 g, 1.7 mmol), 1-(tert-butyl)4-(1,3-dioxoisoindorin-2-yl)piperidine-1,4-dicarboxylate (0.96 g, 2.5 mmol), and Zn powder (0.22 g, 3.4 mmol) were added, and the mixture was stirred under N2 at 40°C for 16 hours. After the reaction, H2O was added, and the mixture was extracted three times with ELISA. The RINKAN phase was combined, washed with brine, dried over Na2SO4, filtered, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate (183 mg, yield 29.41%) as a colorless oil.

[0466] Step 2: Synthesis of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate (183 mg, 0.5094 mmol) and B2Pin2 (155.3 mg, 0.6112 mmol) in dioxane (6 mL), Pd(dppf)Cl2DCM (41.6 mg, 0.0509 mmol) and KOAc (150 mg, 1.5282 mmol) were added, and the mixture was stirred under N2 at 100°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (150 mg, yield 71.02%) as a white solid.

[0467] Step 3: Synthesis of tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)-2-fluorophenyl)piperidine-1-carboxylate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (140 mg, 0.3596 mmol) and tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (146.1 mg, 0.3596 mmol) in dioxane / H2O (9 mL, v:v=8:1), K3PO4 (229 mg, 1.0788 mmol) and Pd(dppf)Cl2DCM (58.7 mg, 0.0719 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)-2-fluorophenyl)piperidine-1-carboxylate (90 mg, yield 41.46%) as a white solid. LCMS(ESI):C31H43FN3O5S + [M + H] m / z Calculated value 588.29, measured value 588.3.

[0468] Step 4: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(3-fluoro-4-(piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)-2-fluorophenyl)piperidine-1-carboxylate (85 mg, 0.1444 mmol) in 2 mL of HCl (4 mL, 2 M in HCl) was added, and the mixture was stirred at 25°C for 12 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain (S)-(3-aminopyrrolidine-1-yl)(5-(3-fluoro-4-(piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 140; 13.7 mg, yield 24.24%) as a yellow solid. LCMS(ESI) C21H27FN3OS+ [M + H] m / z: Calculated value 388.19, measured value 388.1. 1 H NMR (400 MHz, MeOD) δ 7.47 - 7.45 (m, 1H), 7.42 - 7.35 (m, 2H), 7.29 (s, 1H), 3.99 - 3.94 (m, 2H), 3.87 - 3.80 (m, 1H), 3.78 - 3.71 (m, 1H), 3.69 - 3.63 (m, 1H), 3.52 (d, J = 12.8 Hz, 2H), 3.27 - 3.14 (m, 3H), 2.46 - 2.37 (m, 1H), 2.35 (s, 3H), 2.15 - 1.97 (m, 5H).

[0469] Example 20: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-(3-methoxypropyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 141) [ka] Step 1: Synthesis of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate TEA was added to a 100 mL solution of 4-(4-bromophenyl)piperidine (8 g, 33.3 mmol) and Boc2O (8.72 g, 39.9 mmol) in DCM, and the mixture was stirred at 25°C for 12 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (10.09 g, yield 87.99%) as a yellowish oil. 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 4.24 (d, J = 13.2 Hz, 1H), 2.79 (t, J = 12.2 Hz, 2H), 2.64 - 2.57 (m, 1H), 1.81 - 1.78 (m, 2H), 1.63 - 1.53 (m, 3H), 1.48 (s, 9H).

[0470] Step 2: Synthesis of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate To a 100 mL solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (10 g, 29.3 mmol), B2Pin2 (8.93 g, 35.1 mmol), and KOAc (8.63 g, 87.9 mmol) in dioxane, Pd(dppf)Cl2DCM (2.39 g, 2.9 mmol) was added, and the mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (10 g, yield 87.03%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 4.24 (d, J = 13.4 Hz, 1H), 2.79 (t, J = 12.6, 2H), 2.68 - 2.62 (m, 1H), 1.81 (d, J = 12.6 Hz, 1H), 1.68 - 1.58 (m, 1H), 1.48 (s, 9H), 1.33 (s, 12H).

[0471] Step 3: Synthesis of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a 20 mL solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (10 g, 25.8 mmol) in HCl, HCl (60 mL, 2 M in HCl) was added, and the mixture was stirred at 25°C for 16 hours. After the reaction, the solvent was removed under reduced pressure to obtain 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine hydrochloride (8 g, yield 94.96%) as a yellow solid. LCMS (ESI): C17H27BNO2+ [M + H] m / z Calculated value 288.21, measured value 288.2.

[0472] Step 4: Synthesis of tert-butyl(S)-(1-(3-methyl-5-(4-(piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (9.62 g, 24.7 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine hydrochloride (8 g, 24.7 mmol), and K3PO4 (15.73 g, 74.1 mmol) in dioxane / H2O (90 mL, v:v=8:1), Pd(dppf)Cl2DCM (2.02 g, 2.47 mmol) was added, and the mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl(S)-(1-(3-methyl-5-(4-(piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (14 g crude product, 92.48% yield) as a brown solid. LCMS(ESI) C26H36N3O3S + [M + H] m / z Calculated value 470.25, measured value 470.3.

[0473] Step 5: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-(3-methoxypropyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a 5 mL solution of tert-butyl(S)-(1-(3-methyl-5-(4-(piperidine-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (300 mg, 0.6388 mmol) and 1-bromo-3-methoxypropane (195.5 mg, 1.2776 mmol) in MeCN, K2CO3 was added, and the mixture was stirred at 70°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl(S)-(1-(5-(4-(1-(3-methoxypropyl)piperidine-4-yl)phenyl)-3-methylthiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (160 mg, yield 43.93%) as a yellow solid. LCMS(ESI) C30H44N3O4S + [M + H] m / z: Calculated value 542.31, measured value 542.3.

[0474] Step 6: Synthesis of tert-butyl(S)-(1-(5-(4-(1-(3-methoxypropyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-(4-(1-(3-methoxypropyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (160 mg, 0.2953 mmol) in 2 mL of HCl (4 mL, 2 M in HCl), the mixture was stirred at 25°C for 12 hours. After the reaction, the mixture was filtered, and the filter cake was washed several times with HCl to obtain (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-(3-methoxypropyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 141; 15.2 mg, yield 10.8%) as a yellow solid. LCMS(ESI) C25H36N3O2S+ [M + H] m / z: Calculated value 442.25, measured value 442.2. 1 H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.25 (s, 1H), 4.01 - 3.98 (m, 2H), 3.87 - 3.68 (m, 5H), 3.54 - 3.52 (m, 2H), 3.37 (s, 3H), 3.28 - 3.24 (m, 2H), 3.17 - 3.11 (m, 2H), 2.98 - 2.92 (m, 1H), 2.50 - 2.41 (m, 1H), 2.36 (s, 3H), 2.16 - 2.00 (m, 7H).

[0475] The following compounds are prepared in the same manner as described in this example: [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0476] Example 21: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 142) [ka] Step 1 tert-butyl(S)-(1-(5-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(3-methyl-5-(4-(piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (300 mg, 0.6388 mmol) in MeCN (6 mL), 1-bromo-2-methoxyethane (177.57 mg, 1.2776 mmol) and K2CO3 (264.87 mg, 1.9164 mmol) were added. The mixture was stirred at 70°C for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (DCM / MeOH=95 / 5) to obtain tert-butyl(S)-(1-(5-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (110 mg, yield 29.37%) as a yellow solid.

[0477] Step 2 (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(4-(1-(2-methoxyethyl)piperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (110 mg, 0.2084 mmol) in siRNA (4 mL), HCl (3 mL, 2 M in siRNA) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired product (compound 142; 20 mg, yield 20.20%) as a yellow solid. MS(ESI): C24H34N3O2S Mass calculation 428, m / z measurement 428 [M+H]+. 1H NMR (400 MHz, MeOD) δ 7.46 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.09 (s, 1H), 3.67 (m, 2H), 3.57 - 3.44 (m, 4H), 3.25 (t, J = 3.6 Hz, 4H), 3.03 (d, J = 11.2 Hz, 2H), 2.55 (t, J = 5.6 Hz, 2H), 2.47 (m, 1H), 2.22 (s, 3H), 2.13 (m, 3H), 1.78 - 1.67 (m, 5H).

[0478] Example 22: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(3-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 144) [ka] Step 1: tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate To a 15 mL solution of NiCl2-DME (0.15 g, 0.00068 mol) and dtbbpy (0.18 g, 0.00068 mol) in DMA, 4-bromo-1-iodo-2-methylbenzene (1 g, 0.0034 mol), 1-(tert-butyl)4-(1,3-dioxoisoindorin-2-yl)piperidine-1,4-dicarboxylate (1.91 g, 0.0051 mol), and Zn powder (0.44 g, 0.0068 mmol) were added, and the mixture was stirred under N2 at 40°C for 16 hours. After the reaction, H2O was added, and the mixture was extracted three times with ELISA. The EA phases were combined, washed with brine, dried over Na2SO4, filtered, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate (0.4 g, yield 29.41%) as a yellow oil.

[0479] Step 2: 4-(4-bromo-2-methylphenyl)piperidine To a solution of tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate (400 mg, 1.1258 mmol) in siRNA (2 mL), HCl (5 mL, 2 M in siRNA) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The mixture was filtered and concentrated under reduced pressure to obtain the desired product (280 mg, yield 88.07%) as a yellow solid.

[0480] Step 3: 4-(4-bromo-2-methylphenyl)-1-methylpiperidine To a solution of 4-(4-bromo-2-methylphenyl)piperidine (280 mg, 1.1016 mmol) in DCM (15 mL), 37% HCHO (268.2 mg), Na2SO4 (93.9 mg, 0.6609 mmol), and NaBH(OAc)3 (1400.8 mg, 6.6095 mmol) were added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. 15 mL of NaHCO3 was added, and the mixture was extracted with RINKAN (3 x 20 mL). The RINKAN phase was combined, washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. The residue was purified by silica gel column chromatography to obtain the desired product (210 mg, yield 63.97%) as a yellow oil.

[0481] Step 4: 1-Methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a solution of 4-(4-bromo-2-methylphenyl)-1-methylpiperidine (210 mg, 0.7830 mmol) in 1,4-dioxane (8 mL), B2Pin2 (218.7 mg, 0.8613 mmol), Pd(dppf)Cl2DCM (127.8 mg, 0.1566 mmol), and KOAc (230.5 mg, 2.349 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (170 mg, yield 61.98%) as a yellow solid.

[0482] Step 5 tert-butyl(S)-(1-(3-methyl-5-(3-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of 1-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (170 mg, 0.5392 mmol) in dioxane / H2O = 8:1 (9 mL), tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (209.9 mg, 0.5392 mmol), K3PO4 (343.4 mg, 1.6176 mmol), and Pd(dppf)Cl2DCM (88.0 mg, 0.1078 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (190 mg, 63.72% yield) as a yellow solid.

[0483] Step 6 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(3-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(3-methyl-5-(3-methyl-4-(1-methylpiperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (190 mg, 0.3818 mmol) in HCl (3 mL), HCl (5 mL, 2 M in HCl) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired product (compound 144; 20 mg, yield 11.86%) as a yellow solid. MS(ESI): C23H32N3OS Mass calculation 398, m / z measurement 398 [M+H] + . 1H NMR (400 MHz, MeOD) δ 7.45 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.6 Hz, 1H), 7.20 (s, 1H), 3.83 - 3.75 (m, 2H), 3.65 (m, 2H), 3.37 (d, J = 5.2 Hz, 1H), 3.06 (d, J = 11.6 Hz, 2H), 2.88 - 2.77 (m, 1H), 2.39 (d, J = 6.0 Hz, 6H), 2.34 (s, 3H), 2.29 - 2.18 (m, 3H), 1.83 (m, 5H).

[0484] Example 23: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 147) [ka] Step 1 tert-butyl(S)-(1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(3-methyl-5-(4-(piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (260 mg, 0.5536 mmol) in DCM (6 mL), oxan-4-carbaldehyde (442.32 mg, 3.8752 mmol), sodium triacetoxyborohydride (175.99 mg, 0.8304 mmol), and HOAc (66.49 mg, 1.1072 mmol) were added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (180 mg, yield 51.54%) as a yellow solid.

[0485] Step 2 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(3-methyl-5-(4-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (180 mg, 0.3170 mmol) in DCM (5 mL), TFA (542.17 mg, 4.755 mmol) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired product (compound 147; 30 mg, yield 18.20%) as a yellow solid. MS(ESI): C27H37N3O2S Mass calculation value 467, m / z measurement value 468 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 7.64 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 (s, 1H), 4.06 - 3.92 (m, 4H), 3.89 - 3.75 (m, 2H), 3.73 - 3.58 (m, 3H), 3.49 (t, J = 11.6 Hz, 2H), 3.02 (d, J = 5.6 Hz, 4H), 2.93 (t, J = 11.6 Hz, 1H), 2.49 - 2.34 (m, 4H), 2.22 - 1.99 (m, 6H), 1.76 (d, J = 12.8 Hz, 2H), 1.47 - 1.36 (m, 2H).

[0486] Example 24: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-cyclohexylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 148) [ka] Step 1 tert-butyl(S)-(1-(3-methyl-5-(4-(piperazine-1-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (200 mg, 0.6940 mmol) in dioxane / H2O=8:1 (9 mL), tert-butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidine-3-yl)carbamate (270.18 mg, 0.6940 mmol), K3PO4 (441.95 mg, 2.082 mmol), and Pd(dppf)Cl2DCM (113.26 mg, 0.1388 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (130 mg, yield 35.82%) as a yellow solid.

[0487] Step 2 tert-butyl(S)-(1-(5-(4-(4-cyclohexylpiperazine-1-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(3-methyl-5-(4-(piperazine-1-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (130 mg, 0.2762 mmol) in EtOH (5 mL), cyclohexanone (189.75 mg, 1.9334 mmol), NaBH3CN (26.03 mg, 0.4143 mmol), and HOAc (33.17 mg, 0.5524 mmol) were added. The mixture was stirred at 65°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (90 mg, yield 53.04%) as a yellow solid.

[0488] Step 3 (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-cyclohexylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(4-(4-cyclohexylpiperazine-1-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (90 mg, 0.1628 mmol) in HCl (3 mL), HCl (4 mL, 2 M in HCl) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The mixture was filtered and concentrated under reduced pressure to obtain the desired product (compound 148; 40 mg, yield 48.83%) as a yellow solid. MS(ESI): C26H37N4OS Mass calculation 453, m / z measurement 453 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 7.48 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.88 (dd, J = 15.6, 10.8 Hz, 4H), 3.82 - 3.64 (m, 2H), 3.59 (dd, J = 15.6, 10.4 Hz, 3H), 3.26 (s, 1H), 3.16 (s, 1H), 3.09 (t, J = 12.4 Hz, 2H), 2.35 (td, J = 13.6, 7.2 Hz, 1H), 2.25 (s, 3H), 2.12 (d, J = 11.2 Hz, 2H), 2.04 (dd, J = 11.6, 6.4 Hz, 1H), 1.89 (t, J = 12.8 Hz, 2H), 1.64 (d, J = 12.8 Hz, 1H), 1.57 - 1.06 (m, 6H).

[0489] Example 25: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(3-methyl-4-(piperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 149) [ka] Step 1: Synthesis of 1-(tert-butyl)4-(1,3-dioxoisoindorin-2-yl)piperidine-1,4-dicarboxylate To a 60 mL solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10 g, 43.4 mmol), 2-hydroxyisoindole-1,3-dione (7.08 g, 43.4 mmol), and DMAP (0.27 g, 2.1 mmol) in DCM, DCC in 40 mL of DCM was added, and the mixture was stirred at 25°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain 1-(tert-butyl)4-(1,3-dioxoisoindorin-2-yl)piperidine-1,4-dicarboxylate (10.7 g, yield = 64.98%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.90 - 7.87 (m, 2H), 7.82 - 7.79 (m, 2H), 4.04 (d, J = 12.0 Hz, 2H), 3.05 - 2.98 (m, 2H), 2.95 - 2.88 (m, 1H), 2.19 - 2.05 (m, 2H), 1.89 - 1.81 (m, 2H), 1.47 (s, 9H).

[0490] Step 2: Synthesis of tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate To a 10 mL solution of NiCl2·DME (0.15 g, 0.6 mmol) and dtbppy (0.2 g, 0.7 mmol) in DMA, 4-bromo-1-iodo-2-methylbenzene (1 g, 3.4 mmol), 1-(tert-butyl)4-(1,3-dioxoisoindorin-2-yl)piperidine-1,4-dicarboxylate (1.91 g, 5.1 mmol), and Zn powder (0.44 g, 6.8 mmol) were added, and the mixture was stirred under N2 at 40°C for 16 hours. After the reaction, H2O was added, and the mixture was extracted three times with ELISA. The siRNA phase was combined, washed with brine, dried over Na2SO4, filtered, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate (0.73 g, yield = 58.82%) as a colorless oil. The calculated m / z value by LCMS(ESI) C16H22BrNO2+ [M-Me+H] was 339.08, and the measured value was 339.0.

[0491] Step 3: Synthesis of tert-butyl 4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate To a 100 mL solution of tert-butyl 4-(4-bromo-2-methylphenyl)piperidine-1-carboxylate (730 mg, 2.0547 mmol), B2Pin2 (626.2 mg, 2.4656 mmol), and KOAc (605 mg, 6.1641 mmol) in dioxane, Pd(dppf)Cl2DCM (335.6 g, 0.4109 mmol) was added, and the mixture was stirred under N2 at 100°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (446 mg, yield 53%) as a white solid. LCMS(ESI):C19H29BNO4+ [M - t Bu + 2H] m / z: Calculated value 346.22, measured value 346.1.

[0492] Step 4: Synthesis of tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)-2-methylphenyl)piperidine-1-carboxylate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (120 mg, 0.3082 mmol), tert-butyl4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (148.8 mg, 0.3698 mmol), and K3PO4 (196.3 mg, 0.9245 mmol) in dioxane / H2O (9 mL, v:v=8:1), Pd(dppf)Cl2DCM (50.3 mg, 0.0616 mmol) was added, and the mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)-2-methylphenyl)piperidine-1-carboxylate (82 mg, yield 45.04%) as a yellow solid. LCMS(ESI) C32H46N3O5S+ [M + H] m / z Calculated value 584.32, measured value 584.3.

[0493] Step 5: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(3-methyl-4-(piperidine-4-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)-2-methylphenyl)piperidine-1-carboxylate (82 mg, 0.1402 mmol) in 2 mL of HCl (4 mL, 2 M in HCl) was added, and the mixture was stirred at 25°C for 12 hours. After the reaction, the mixture was filtered, and the filter cake was washed several times with HCl to obtain (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(3-methyl-4-(piperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 149; 20.2 mg, yield 34.95%) as a yellow solid. LCMS(ESI) C22H30N3OS+ [M + H] m / z: Calculated value 384.21, measured value 384.1. 1 H NMR (400 MHz, MeOD) δ 7.49 - 7.46 (m, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.23 (s, 2H), 4.02 (s, 2H), 3.85 - 3.71 (m, 3H), 3.52 (d, J = 10.5 Hz, 2H), 3.20 (s, 3H), 2.50 - 2.42 (m, 4H), 2.35 (s, 3H), 2.20 - 2.12 (m, 1H), 2.01 - 1.94 (m, 4H).

[0494] Example 26: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)phenyl)thiophen-2-yl)methanone (compound 151) [ka] Step 1: 1-(tetrahydro-2H-pyran-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (700 mg, 2.4289 mmol) in EtOH (10 mL), oxan-4-one (1702.2 mg, 17.002 mmol), NaBH3CN (228.9 mg, 3.6433 mmol), and HOAc (291.7 mg, 4.8578 mmol) were added. The mixture was stirred at 65°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (DCM / MeOH = 95 / 5) to obtain 1-(tetrahydro-2H-pyran-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (500 mg, yield 49.76%) as a yellow solid.

[0495] Step 2 tert-butyl(S)-(1-(3-methyl-5-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of 1-(tetrahydro-2H-pyran-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (300 mg, 0.8058 mmol) in dioxane / H2O = 8:1 (9 mL), tert-butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidine-3-yl)carbamate (313.7 mg, 0.8058 mmol), K3PO4 (513.1 mg, 2.4173 mmol), and Pd(dppf)Cl2DCM (131.5 mg, 0.1611 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS showed that the reaction was complete and the desired MS was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (180 mg, 36.24% yield) as a yellow solid.

[0496] Step 3 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(3-methyl-5-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazine-1-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (180 mg, 0.3245 mmol) in DCM (5 mL), TFA (555 mg, 4.8675 mmol) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired product (compound 151; 50 mg, yield 32.20%) as a yellow solid. MS(ESI): C25H35N4O2S Mass calculation 455, m / z measurement 455 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.53 (d, J = 8.8 Hz, 2H), 7.10 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.03 (dd, J = 11.2, 3.6 Hz, 2H), 3.79 (dt, J = 13.6, 6.8 Hz, 2H), 3.72 - 3.55 (m, 2H), 3.45 (t, J = 11.6 Hz, 2H), 3.37 (d, J = 5.6 Hz, 1H), 3.31 - 3.24 (m, 4H), 2.88 - 2.71 (m, 4H), 2.51 (t, J = 11.6 Hz, 1H), 2.33 (s, 3H),2.18 (s, 1H), 1.92 (d, J = 11.6 Hz, 2H), 1.83 (td, J = 13.2, 6.8 Hz, 1H), 1.68 - 1.47 (m, 2H).

[0497] Example 27: Synthesis of ((S)-3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(4-(tetrahydrofuran-3-yl)piperazine-1-yl)phenyl)thiophen-2-yl)methanone (compound 152) [ka] Step 1: 1-(tetrahydrofuran-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (700 mg, 2.4289 mmol) in EtOH (10 mL), oxolan-3-one (1463.7 mg, 17.002 mmol), NaBH3CN (228.9 mg, 3.6433 mmol), and HOAc (291.7 mg, 4.8578 mmol) were added. The mixture was stirred at 65°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (DCM / MeOH = 95 / 5) to obtain 1-(tetrahydrofuran-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (500 mg, yield 51.71%) as a yellow solid.

[0498] Step 2 tert-butyl((3S)-1-(3-methyl-5-(4-(4-(tetrahydrofuran-3-yl)piperazine-1-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of 1-(tetrahydrofuran-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (250 mg, 0.6978 mmol) in dioxane / H2O=8:1 (9 mL), tert-butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidine-3-yl)carbamate (271.7 mg, 0.6978 mmol), K3PO4 (444.4 mg, 2.0934 mmol), and Pd(dppf)Cl2DCM (113.9 mg, 0.1395 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS showed that the reaction was complete and the desired MS was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (180 mg, 42.93% yield) as a yellow solid.

[0499] Step 3 ((S)-3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(4-(tetrahydrofuran-3-yl)piperazine-1-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl((3S)-1-(3-methyl-5-(4-(4-(tetrahydrofuran-3-yl)piperazine-1-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (180 mg, 0.3329 mmol) in DCM (5 mL), TFA (569.4 mg, 4.9935 mmol) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired product (compound 152; 40 mg, yield 24.54%) as a yellow solid. MS(ESI): C24H33N4O2S Mass calculation value 441, m / z measurement value 441[M+H]+. 1H NMR (400 MHz, MeOD) δ 7.53 (d, J = 8.8 Hz, 2H), 7.10 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.03 - 3.89 (m, 2H), 3.86 - 3.75 (m, 3H), 3.73 - 3.55 (m, 3H), 3.37 (d, J = 5.2 Hz, 1H), 3.28 (t, J = 5.2 Hz, 4H), 3.13 - 3.00 (m, 1H), 2.75 (dt, J = 10.4, 4.8 Hz, 2H), 2.71 - 2.59 (m, 2H), 2.33 (s, 3H), 2.16 (dd, J = 12.0, 4.4 Hz, 2H), 1.92 (dd, J = 12.4, 7.6 Hz, 1H), 1.88 - 1.77 (m, 1H).

[0500] Example 28: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-cyclopentylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 153) [ka] Step 1: Synthesis of 1-cyclopentyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (288 mg, 1 mmol) in EtOH (10 mL), cyclopentanone (84 mg, 1 mmol), NaBH3CN (94.2 mg, 1.5 mmol), and AcOH (60 mg, 1 mmol) were added. The mixture was stirred at 65°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / siRNA = 3 / 7) to obtain 1-cyclopentyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (208 mg, yield 55.5%) as a white solid. LCMS(ESI) C21H34BN2O2+ [M + H]+ m / z Calculated value 357.27, measured value 357.

[0501] Step 2: Synthesis of tert-butyl(S)-(1-(5-(4-(4-cyclopentylpiperazine-1-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (227 mg, 0.58 mmol) in dioxane / H2O=8:1 (18 mL), 1-cyclopentyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (207.8 mg, 0.58 mmol), K3PO4 (371.3 mg, 1.75 mmol), and Pd(dppf)Cl2DCM (95.2 mg, 0.12 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (100% ethyl acetate) to obtain tert-butyl(S)-(1-(5-(4-(4-cyclopentylpiperazine-1-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (150 mg, yield 45.4%) as a white solid. LCMS(ESI) C30H43N4O3S+ [M + H]+ m / z Calculated value 539.31, measured value 539.

[0502] Step 3: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-cyclopentylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(4-(4-cyclopentylpiperazine-1-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (150 mg, 0.28 mmol) in 4 mL of ethyl acetate, HCl (3 mL, 2 M in ethyl acetate) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-cyclopentylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 153; 53.3 mg, yield 39.3%) as a yellow solid. LCMS(ESI) C26H37N3OS+ [M + H] + m / z Calculated value 439.27, measured value 438.1 H NMR (400 MHz, MeOD) δ 7.60 (d, J = 5.1 Hz, 2H), 7.17 (s, 1H), 7.11 (d, J = 5.4 Hz, 2H), 4.03 (s, 2H), 3.95 (d, J = 9.0 Hz, 2H), 3.86 (s, 1H), 3.74 (s, 4H), 3.65 (s, 1H), 3.28 (s, 4H), 2.46 (s, 1H), 2.36 (s, 3H), 2.24 (s, 4H), 1.89 (s, 4H), 1.73 (s, 2H).

[0503] Example 29: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-ethylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 155) [ka] Step 1: 1-Ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine To a mixture of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (400 mg, 1.39 mmol) and acetaldehyde (306 mg, 6.94 mmol) in EtOH (15 mL), AcOH (167 mg, 2.78 mmol) and sodium cyanoborohydride (262 mg, 4.16 mmol) were added, and the mixture was stirred at 65°C for 6 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (MeOH / DCM = 4%~5%) to obtain the desired product (380 mg, yield 77.9%) as a pale yellow oil.

[0504] Step 2 tert-butyl(S)-(1-(5-(4-(4-ethylpiperazine-1-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate Compound 2 (270 mg, 0.85 mmol) and Compound 3 (332 mg, 0.85 mmol) were mixed in 1,4-dioxane (8 mL) and H2O (1 mL). K3PO4 (544 mg, 2.56 mmol) and Pd(dppf)Cl2 (139 mg, 0.17 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (Â / PE = 0%~100%) to obtain Compound 4 (300 mg, yield 63.4%) as a brown solid.

[0505] Step 3 (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-ethylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone A mixture of compound 4 (300 mg, 0.60 mmol) in HCl / Â (3 mL) was stirred at 25°C for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired product (compound 155; 117.6 mg, yield 48.1%) as a white solid. LC-MS (ESI):C 22 H 31 N4OS Mass calculation value: 399.22, m / z measured value: 399.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.50 (d, J = 8.4 Hz, 2H), 7.07 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 3.82 - 3.70 (m, 2H), 3.68 - 3.51 (m, 2H), 3.36 - 3.31 (m, 1H), 3.28 - 3.24 (m, 4H), 2.70 - 2.60 (m, 4H), 2.54 - 2.45 (m, 2H), 2.31 (s, 3H), 2.15 (s, 1H), 1.87 - 1.72 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H).

[0506] Example 30: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 156) [ka] Step 1: tert-butyl(S)-(1-(3-methyl-5-(4-(piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (600 mg, 2.0891 mmol) in dioxane / H2O=8:1 (18 mL), tert-butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidine-3-yl)carbamate (813.30 mg, 2.0891 mmol), K3PO4 (1330.36 mg, 6.2673 mmol), and Pd(dppf)Cl2DCM (340.94 mg, 0.4178 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:MeOH=2:1) ​​to obtain the desired product (700 mg, yield 67.78%) as a yellow solid.

[0507] Step 2 tert-butyl(S)-(1-(5-(4-(1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)piperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tetrahydro-4H-thiopyran-4-one 1,1-dioxide (63.11 mg, 0.4259 mmol) in DCE (8 mL), tert-butyl(S)-(1-(3-methyl-5-(4-(piperidine-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (200 mg, 0.4259 mmol), NaBH(OAc)3 (126.37 mg, 0.5962 mmol), and HOAc (25.6 mg, 0.4259 mmol) were added. The mixture was stirred at 40°C for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired product (50 mg, yield 17.55%) as a yellow solid.

[0508] Step 3 (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)piperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(4-(1-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)piperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (50 mg, 0.0831 mmol) in siRNA (4 mL), HCl (2 mL, 2 M in siRNA) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. The mixture was filtered and concentrated under reduced pressure to obtain the desired product (compound 156; 23 mg, yield 49.70%) as a solid. MS(ESI): C26H36N3O3S2 Mass calculation 502, m / z measurement 502 [M+H]+. 1H NMR (400 MHz, MeOD) δ 7.53 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 3.89 (t, J = 7.6 Hz, 2H), 3.80 - 3.64 (m, 2H), 3.65 - 3.49 (m, 4H), 3.31 - 3.21 (m, 4H), 3.15 (d, J = 12.8 Hz, 2H), 2.86 (d, J = 7.6 Hz, 1H), 2.49 (d, J = 12.4 Hz, 2H), 2.41 - 2.21 (m, 6H), 2.08 (d, J = 6.4 Hz, 5H).

[0509] Example 31: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-cyclobutylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 158) [ka] Step 1: 1-Cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (700 mg, 2.4289 mmol) in EtOH (10 mL), cyclobutanone (1191.69 mg, 17.002 mmol), NaBH3CN (228.95 mg, 3.6433 mmol), and HOAc (291.71 mg, 4.8578 mmol) were added. The mixture was stirred at 65°C for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (DCM / MeOH = 95 / 5) to obtain 1-cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (650 mg, yield 70.37%) as a yellow solid.

[0510] Step 2 tert-butyl(S)-(1-(5-(4-(4-cyclobutylpiperazine-1-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of 1-cyclobutyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (300 mg, 0.8765 mmol) in dioxane / H2O=8:1 (9 mL), tert-butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidine-3-yl)carbamate (341.23 mg, 0.8765 mmol), K3PO4 (558.16 mg, 2.6295 mmol), and Pd(dppf)Cl2DCM (143.04 mg, 0.1753 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS showed that the reaction was complete and the desired MS was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (150 mg, 29.36% yield) as a yellow solid.

[0511] Step 3 (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-cyclobutylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(4-(4-cyclobutylpiperazine-1-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (100 mg, 0.1906 mmol) in HCl (2 mL, 2 M in HCl) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The mixture was filtered and concentrated under reduced pressure to obtain the desired product (compound 158; 20 mg, yield 22.25%) as a yellow solid. MS(ESI): C24H33N4OS Mass calculation value 425, m / z measurement value 425 [M+H] + . 1H NMR (400 MHz, MeOD) δ 7.48 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 3.87 (dd, J = 23.6, 10.4 Hz, 4H), 3.73 (dt, J = 29.4, 7.6 Hz, 3H), 3.60 (dd, J = 15.2, 6.8 Hz, 1H), 3.48 (d, J = 10.8 Hz, 2H), 3.11 - 2.92 (m, 4H), 2.45 - 2.18 (m, 8H), 2.03 (d, J = 5.2 Hz, 1H), 1.81 (dt, J = (19.6, 9.2 Hz, 2H).

[0512] Example 32: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-isopropylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 159) [ka] Step 1: 1-Isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine To a mixture of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (400 mg, 1.39 mmol) in DCM (40 mL), STAB (2.06 g, 9.72 mmol), acetone (322 mg, 5.56 mmol), and Na2SO4 (118 mg, 0.83 mmol) were added, and the mixture was stirred at 25°C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness.  (20 mL x 3) was added, and the mixture was concentrated to dryness. The mixture was diluted with saturated NaHCO3 solution (50 mL) and then extracted with  (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to dryness. The crude product was purified by silica gel column chromatography (MeOH / DCM = 7%) to obtain the desired product (200 mg, yield 39.3%) as a yellow solid.

[0513] Step 2 tert-butyl(S)-(1-(5-(4-(4-isopropylpiperazine-1-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of compound 2 (200 mg, 0.61 mmol) and compound 3 (189 mg, 0.48 mmol) in 1,4-dioxane (6 mL) and H2O (1 mL), K3PO4 (386 mg, 1.82 mmol) and Pd(dppf)Cl2 (99 mg, 0.12 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (Â / PE = 92%) to obtain the desired product (124 mg, yield 36.0%) as a yellow solid.

[0514] Step 3 (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-isopropylpiperazine-1-yl)phenyl)-3-methylthiophen-2-yl)methanone A mixture of compound 4 (124 mg, 0.24 mmol) in HCl / Â (2 mL) was stirred at 25°C for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired product (compound 159; 14.5 mg, yield 14.2%) as a white solid. MS(ESI):C 23 H 32 N4OS Mass calculation value: 412.23 m / z measured value: 413.2 m / z [M+H] + . 1H NMR (400 MHz, MeOD) δ 7.52 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.83 - 3.73 (m, 2H), 3.69 - 3.51 (m, 2H), 3.38 - 3.33 (m, 1H), 3.30 - 3.24 (m, 4H), 2.79 - 2.69 (m, 5H), 2.33 (s, 3H), 2.24 - 2.12 (m, 1H), 1.91 - 1.73 (m, 1H), 1.14 (d, J = 6.4 Hz, 6H).

[0515] Example 33: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(piperazine-1-yl)phenyl)thiophene-2-yl)methanone (compound 162) [ka] Step 1: Synthesis of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate To a 60 mL solution of 1-(4-bromophenyl)piperazine (5 g, 20.7 mmol) in DCM, Boc2O (5.42 g, 24.8 mmol) and TEA (3.52 g, 34.7 mmol) were added, and the mixture was stirred at 25°C for 2 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (7.043 g, yield = 98.55%) as an off-white solid. MS(ESI):C15H22BrN2O2 Mass calculation 341.09, measured value 341.0 [M+H] +

[0516] Step 2: Synthesis of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate To a 50 mL solution of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (7 g, 20.5 mmol) and B2Pin2 (6.25 g, 24.6 mmol) in 1,4-dioxane, Pd(dppf)Cl2DCM (3.35 g, 4.1 mmol) and KOAc (6.04 g, 61.5 mmol) were added, and the mixture was stirred under N2 at 100°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-yl pivalate (8 g, yield 98.05%) as a yellow solid. MS(ESI):C21H34BN2O4 Calculated mass: 389.26, Measured mass: 389.2 [M+H] +

[0517] Step 3: Synthesis of tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)phenyl)piperazine-1-carboxylate To a 9 mL solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (200 mg, 0.5137 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (171.0 mg, 0.6164 mmol) in dioxane / H2O (v:v=8:1), Pd(dppf)Cl2DCM (83.9 mg, 0.1027 mmol) and K3PO4 (327.1 mg, 1.5411 mmol) were added, and the mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)phenyl)piperazine-1-carboxylate (150 mg, yield 50.55%) as a yellow solid. MS(ESI):C30H43N4O5S Mass calculation value 571.30, measured value 571.3 [M+H] +

[0518] Step 4: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(piperazine-1-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-4-(4-(5-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)-4-methylthiophen-2-yl)phenyl)piperazine-1-carboxylate (150 mg, 0.2624 mmol) in 2 mL of HCl, HCl (4 mL, 2 M in HCl) was added, and the mixture was stirred at 25°C for 12 hours. After the reaction, the mixture was filtered, and the filter cake was washed several times with HCl to obtain (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(piperazine-1-yl)phenyl)thiophen-2-yl)methanone (compound 162; 64.5 mg, yield 63.03%) as a yellow solid. MS(ESI):C20H27N4OS Mass calculation 371.19, measured value 371.1 [M+H] + . 1H NMR (400 MHz,MeOD) δ 7.62 (d,J=8.2 Hz,2H),7.22 - 7.19 (m,3H),4.02 - 4.00 (m,2H),3.89 - 3.83 (m,1H),3.80 - 3.72 (m,2H),3.62 - 3.59 (m,4H),3.49 - 3.46 (m,4H),2.51 - 2.45 (m,1H),2.35 (s,3H),2.19 - 2.16 (m,1H).

[0519] Example 35: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(isochroman-6-yl)-3-methylthiophen-2-yl)methanone (compound 165) [ka] Step 1: 2-(isochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 6-bromo-3,4-dihydro-1H-2-benzopyran (250 mg, 1.17 mmol) in dioxane (10 mL), B2Pin2 (298 mg, 1.17 mmol), KOAc (345.4 mg, 3.52 mmol), and Pd(dppf)Cl2DCM (191.5 mg, 0.23 mmol) were added. The mixture was stirred at 100°C for 16 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using siRNA:PE=1:8 as the eluent to obtain 2-(isochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, yield 62.25%) as a yellow oil. LCMS(ESI) C15H22BO3+ [M + H] + m / z Calculated value 261.17, measured value 261.

[0520] Step 2 tert-butyl(S)-(1-(5-(isochroman-6-yl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (300 mg, 0.77 mmol) in dioxane / H2O=8:1 (18 mL), 2-(isochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.77 mmol), K3PO4 (490.7 mg, 2.31 mmol), and Pd(dppf)Cl2DCM (125.8 mg, 0.15 mmol) were added. The mixture was stirred at 95°C for 16 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl(S)-(1-(5-(isochroman-6-yl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (200 mg, yield 55.7%) as a yellow oily substance. LCMS(ESI) C26H35N4O3S+ [M + H]+ m / z Calculated value 443.20, measured value 483.

[0521] Step 4 (S)-(3-aminopyrrolidine-1-yl)(5-(isochroman-6-yl)-3-methylthiophen-2-yl)methanone To a 4 mL solution of tert-butyl(S)-(1-(5-(isochroman-6-yl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (200 mg, 0.45 mmol) in ethyl acetate, HCl (3 mL, 2 M in ethyl acetate) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain (S)-(3-aminopyrrolidine-1-yl)(5-(isochroman-6-yl)-3-methylthiophen-2-yl)methanone (compound 165; 88.6 mg, yield 54.4%) as a yellow solid. LC-MS (ESI) C19H23N2O2S+ [M + H]+ m / z Calculated value 343.15, measured value 343. 1H NMR (400 MHz, MeOD) δ 7.46 - 7.39 (m, 2H), 7.23 (s, 1H), 7.04 (t, J = 8.4 Hz, 1H), 4.75 (s, 2H), 4.00 (d, J = 8.3 Hz, 2H), 3.99 (s, 2H), 3.88 - 3.76 (m, 2H), 3.75 - 3.62 (m, 2H), 2.87 (t, J = 5.7 Hz, 2H), 2.52 - 2.40 (m, 1H), 2.36 (s, 3H), 2.21 - 2.09 (m, 1H).

[0522] Example 36: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-(dimethylamino)tetrahydro-2H-pyran-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 166) [ka] Step 1: 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carbonitrile NaH (2.04 g, 60% in oil) was added in small amounts to a solution of 2-(4-bromophenyl)acetonitrile (4 g, 0.0204 mol) in dry DMF (40 mL), and the mixture was stirred at 0°C for 1 hour. Then, 1-bromo-2-(2-bromoethoxy)ethane (4.73 g, 0.0204 mol) was added to the above solution at 0°C, and the mixture was stirred overnight at room temperature. LC-MS indicated that the reaction was complete and the desired MS was found. After the completion of the reaction, the mixture was quenched by the addition of water and then extracted with ethyl acetate. The combined organic layer was washed with water and saturated NaCl solution, dried over anhydrous Na2SO4, and evaporated under vacuum. The residue was purified by flash chromatography (PE / EA = 90 / 10) to obtain 4-(4-bromophenyl)oxane-4-carbonitrile (4.4 g, yield 73.04%) as a yellow solid.

[0523] Step 2: 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylic acid A solution of 9M H2SO4 was added to 4-(4-bromophenyl)oxane-4-carbonitrile (4 g, 1 equivalent) and refluxed overnight at 100°C. After the reaction was complete, the mixture was diluted with water and then extracted with ethyl acetate. The combined organic layer was washed with water and saturated NaCl solution, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude product was purified by silica gel column chromatography to obtain the desired product (4 g, yield 84.00%) as a yellow solid.

[0524] Step 3: 4-(4-bromophenyl)tetrahydro-2H-pyran-4-amine 4-(4-bromophenyl)oxane-4-carboxylic acid (4 g, 1 equivalent) was added to a three-necked round-bottom flask under N2 conditions, and then toluene (56 mL) and TEA (3.43 g, 2.2 equivalents) were added via syringe. DPPA (4.66 g, 1.1 equivalents) was added via syringe, and the mixture was stirred under N2 conditions at 90°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and diluted with SiO2. The combined organic layer was washed with NaHCO3 solution and brine, dried over anhydrous Na2SO4, and evaporated under vacuum. Then 5M HCl solution (11 mL) was added, and the mixture was refluxed at 100°C for 5 hours. After the mixture cooled to room temperature, toluene was added and evaporated under vacuum. The resulting solid was dissolved in saturated NaHCO3 solution (300 mL) and SiO2 (300 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude product was purified by silica gel column chromatography to obtain the desired product (2.5 g, yield 57.14%) as a yellow solid.

[0525] Step 4: 4-(4-bromophenyl)-N,N-dimethyltetrahydro-2H-pyran-4-amine To a solution of 4-(4-bromophenyl)oxan-4-amine (1 g, 0.0039 mol) in DCM (50 mL), 37% HCHO (0.95 g, 0.0117 mol), Na₂SO₄ (0.33 g, 0.0023 mol), and sodium triacetoxyborohydride (4.96 g, 0.0234 mol) were added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. 50 mL of NaHCO₃ was added to the reaction mixture and extracted with RINKAN (3 x 50 mL). The organic layers were combined, washed with brine, dried over anhydrous Na₂SO₄, and evaporated under vacuum. The crude product was purified by silica gel column chromatography to obtain the desired product (1.1 g, yield 89.74%) as a yellow solid.

[0526] Step 5: N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-amine To a solution of 4-(4-bromophenyl)-N,N-dimethyloxane-4-amine (400 mg, 1.4075 mmol) in 1,4-dioxane (8 mL), B2Pin2 (393.16 mg, 1.5482 mmol), Pd(dppf)Cl2DCM (229.7 mg, 0.2815 mmol), and KOAc (414.4 mg, 4.2225 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (300 mg, yield 57.91%) as a yellow solid.

[0527] Step 6 tert-butyl(S)-(1-(5-(4-(4-(dimethylamino)tetrahydro-2H-pyran-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-amine (300 mg, 0.9056 mmol) in dioxane / H2O = 8:1 (9 mL), tert-butyl N-((3S)-1-((5-bromo-3-methylthiophen-2-yl)carbonyl)pyrrolidine-3-yl)carbamate (352.56 mg, 0.9056 mmol), K3PO4 (576.70 mg, 2.7168 mmol), and Pd(dppf)Cl2DCM (147.79 mg, 0.1811 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. LC-MS showed that the reaction was complete and the desired product was found. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (Â1:MeOH = 10:1) to obtain 120 mg of the desired product, yielding 23.21% as a yellow solid.

[0528] Step 7 (S)-(3-aminopyrrolidine-1-yl)(5-(4-(4-(dimethylamino)tetrahydro-2H-pyran-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(5-(4-(4-(dimethylamino)tetrahydro-2H-pyran-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (120 mg, 0.2336 mmol) in siRNA (4 mL), 2 M HCl (5 mL) in EA was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The mixture was filtered and concentrated under reduced pressure to obtain the desired product (compound 166; 60 mg, yield 58.99%) as a yellow oil. MS(ESI): C23H32N3O2S Mass calculation value 414, m / z measurement value 414 [M+H]+. 1H NMR (400 MHz, MeOD) δ 7.89 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.43 (s, 1H), 4.01 (d, J = 8.8 Hz, 4H), 3.91 - 3.68 (m, 3H), 3.25 (t, J = 11.6 Hz, 2H), 2.98 (d, J = 12.8 Hz, 2H), 2.67 (s, 6H), 2.52 - 2.42 (m, 1H), 2.38 (s, 3H), 2.19 (t, J = 10.8 Hz, 3H).

[0529] Example 34: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-(oxetan-3-yl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 164) [ka] Step 1: 4-(4-bromophenyl)-1-(oxetan-3-yl)piperidine To a solution of 4-(4-bromophenyl)piperidine (240 mg, 1 mmol) in DCM (10 mL), oxetan-3-one (72 mg, 1 mmol), NaBH(OAc)3 (317.7 mg, 1.5 mmol), and HOAc (60 mg, 1 mmol) were added. The mixture was stirred at room temperature for 3 hours. LC-MS indicated that the reaction was complete and the desired product was found. The resulting mixture was washed with H2O (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-(4-bromophenyl)-1-cyclobutylpiperidine (290 mg, yield 93.07%) as a yellow solid.

[0530] Step 2: 1-(oxetan-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-(oxetan-3-yl)piperidine (290 mg, 0.98 mmol) in dioxane (10 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (248 mg, 0.98 mmol), potassium acetate (288 mg, 3 mmol), and PdCl2 (dppf) (160 mg, 0.19 mmol) were added. The mixture was stirred at 95°C for 16 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by chromatography using ethyl eluent to obtain 1-(oxetan-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (258 mg, yield 73%) as a yellow oil.

[0531] Step 3 tert-butyl(S)-(1-(3-methyl-5-(4-(1-(oxetan-3-yl)piperidine-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (280 mg, 0.72 mmol) in dioxane / H2O=8:1 (18 mL), 1-(oxetan-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (247 mg, 0.72 mmol), K3PO4 (458 mg, 2.15 mmol), and Pd(dppf)Cl2DCM (117.4 mg, 0.14 mmol) were added. The mixture was stirred at 95°C for 16 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 8) to obtain tert-butyl(S)-(1-(3-methyl-5-(4-(1-(oxetan-3-yl)piperidine-4-yl)phenyl)thiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (190 mg, yield 47.7%) as a yellow oily substance. LCMS(ESI) C29H40N3O4S+ [M + H] + m / z Calculated value 526.28, measured value 526.

[0532] Step 4 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-(oxetan-3-yl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone To a solution of tert-butyl(S)-(1-(3-methyl-5-(4-(1-(oxetan-3-yl)piperidine-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate (190 mg, 0.36 mmol) in 4 mL of ethyl acetate, HCl (3 mL, 2 M in ethyl acetate) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired product was found. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-(oxetan-3-yl)piperidine-4-yl)phenyl)thiophene-2-yl)methanone (compound 164; 20 mg, yield 11%) as a white solid. LCMS(ESI) C24H31N3O2S+ [M + H] + m / z Calculated value 426.22, measured value 426. 1 H NMR (400 MHz, MeOD) δ 7.63 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.25 (s, 1H), 4.87 (dd, J = 11.9, 6.0 Hz, 3H), 4.43 (s, 1H), 4.02 - 3.94 (m, 2H),3.81 (tdd, J = 11.8, 8.9, 5.1 Hz, 2H), 3.69 (dd, J = 15.0, 6.7 Hz, 1H), 3.61 (d, J = 9.6 Hz, 2H), 3.11 - 2.89 (m, 3H), 2.44 (td, J = 13.9, 7.6 Hz, 1H), 2.37 (d, J = 8.5 Hz, 3H), 2.14 (td, J = 13.2, 6.1 Hz, 3H), 2.07 - 1.97 (m, 2H).

[0533] Example 37: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-(tetrahydro-2H-thiopyran-4-yl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone (compound 167) [ka] Step 1: 4-(4-bromophenyl)-1-(tetrahydro-2H-thiopyran-4-yl)piperidine To a solution of 4-(4-bromophenyl)piperidine (1.0 g, 4.2 mmol) and thian-4-one (0.73 g, 6.3 mmol) in EtOH (6 mL), NaBH3CN (0.32 g, 5 mmol), followed by HOAc (0.5 g, 8.4 mmol), was added, and the mixture was stirred at 25°C for 12 hours. After the reaction, NaOH (30 mL, 1N in H2O) was added, and the mixture was stirred for 30 minutes. The mixture was extracted three times with SiO2. The SiO2 phases were combined, washed with brine, dried over Na2SO4, filtered, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain 4-(4-bromophenyl)-1-(thian-4-yl)piperidine (crude product 1.5 g, yield 95%) as a yellowish solid.

[0534] Step 2: 1-(tetrahydro-2H-thiopyran-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a mixture of compound 3 (300 mg, 0.88 mmol) in 1,4-dioxane (7 mL), B2Pin2 (246 mg, 0.97 mmol), KOAc (260 mg, 2.64 mmol), and Pd(dppf)Cl2DCM (719 mg, 0.88 mmol) were added, and the mixture was stirred under N2 at 100°C for 12 hours. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / siRNA = 2 / 1) to obtain the desired product (180 mg, yield 47.4%) as a black solid.

[0535] Step 3 tert-butyl(S)-(1-(3-methyl-5-(4-(1-(tetrahydro-2H-thiopyran-4-yl)piperidine-4-yl)phenyl)thiophene-2-carbonyl)pyrrolidine-3-yl)carbamate Compound 4 (179 mg, 0.46 mmol) was mixed with 1,4-dioxane (4 mL) and H2O (0.5 mL). Compound 5 (150 mg, 0.39 mmol), K3PO4 (245 mg, 1.16 mmol), and Pd(dppf)Cl2DCM (314 mg, 0.39 mmol) were added, and the mixture was stirred under N2 at 95°C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (Â / PE = 1 / 1) to obtain the desired product (150 mg, yield 61.5%) as a black solid.

[0536] Step 4 (S)-(3-aminopyrrolidine-1-yl)(3-methyl-5-(4-(1-(tetrahydro-2H-thiopyran-4-yl)piperidine-4-yl)phenyl)thiophen-2-yl)methanone A mixture of compound 6 (150 mg, 0.26 mmol) in HCl / Â (3 mL) was stirred at 25°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired product (compound 167; 21.7 mg, yield 16.9%) as a white solid. LC-MS (ESI):C 26 H 36 N3OS2 mass calculation value: 470.23, m / z measured value: 470.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.52 (s, 1.5 H), 7.61 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 4.02 - 3.89 (m, 2H), 3.88 - 3.71 (m, 2H), 3.69 - 3.61 (m, 1H), 3.51 (d, J = 12.0 Hz, 2H), 3.27 - 3.15 (m, 3H), 2.92 - 2.74 (m, 5H), 2.48 - 2.38 (m, 3H), 2.35 (s, 3H), 2.16 - 2.02 (m, 5H), 1.97 - 1.85 (m, 2H).

[0537] Example 38: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-ethylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 176) [ka] Step 1: Synthesis of 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine To a solution of 4-(4-bromophenyl)-1-ethylpiperidine (220 mg, 0.82 mmol) in dioxane (10 mL), B2Pin2 (208.3 mg, 0.82 mmol), KOAc (241.5 mg, 2.46 mmol), and Pd(dppf)Cl2DCM (133.9 mg, 0.16 mmol) were added. The mixture was stirred at 100°C for 16 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography EA:MeOH=9:1 to obtain 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (180 mg, yield 66.1%) as a yellow solid.

[0538] Step 2: Synthesis of tert-butyl(S)-(1-(5-(4-(1-ethylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate To a solution of tert-butyl(S)-(1-(5-bromo-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (220 mg, 0.56 mmol) in dioxane / H2O=8:1 (18 mL), 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (178 mg, 0.56 mmol), K3PO4 (360 mg, 1.7 mmol), and Pd(dppf)Cl2DCM (92.2 mg, 0.11 mmol) were added. The mixture was stirred under N2 at 95°C for 16 hours. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH / ethyl acetate = 1 / 9) to obtain tert-butyl(S)-(1-(5-(4-(1-ethylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (185 mg, yield 59.2%) as a yellow solid. LCMS(ESI) C28H40N3O3S+ [M + H]+ m / z Calculated value 498.28, measured value 498.

[0539] Step 3: Synthesis of (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-ethylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone To a 4 mL solution of tert-butyl(S)-(1-(5-(4-(1-ethylpiperidine-4-yl)phenyl)-3-methylthiophen-2-carbonyl)pyrrolidine-3-yl)carbamate (185 mg, 0.37 mmol) in ethyl phosphate, HCl (3 mL, 2 M in ethyl phosphate) was added. The mixture was stirred at room temperature for 16 hours. LC-MS indicated that the reaction was complete and the desired MS was found. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain (S)-(3-aminopyrrolidine-1-yl)(5-(4-(1-ethylpiperidine-4-yl)phenyl)-3-methylthiophen-2-yl)methanone (compound 176; 7.6 mg, yield 5%) as a white solid. LCMS(ESI) C23H32N3OS+ [M + H]+ m / z Calculated value 398.2, measured value 398. 1H NMR (400 MHz, MeOD) δ 7.58 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.21 (s, 1H), 3.79 (dt, J = 11.7, 7.0...

Claims

1. Compound of formula (I): 【Chemistry 241】 or its stereoisomers and / or pharmaceutically acceptable salts (wherein formula: E is C ３ ~C ７ E is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocykryl, or heterocyclyl, and E may be optionally substituted; E' does not exist, or E' is C ３ ~C ７ It is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocykryl, or heterocyclyl, where E' may be optionally substituted; R ３ｘ and R ４ Each of these is either H or an optional substituent that is independently selected.

2. The compound according to claim 1, wherein E' is absent.

3. Compound of formula (II): 【Chemistry 242】 or its stereoisomers and / or pharmaceutically acceptable salts (wherein formula: Z １ is N or CR １１ And; Z ２ is N or CR １２ ; Z ３ is N or CR １３ And; Z ４ is N or CR １４ And; L １ It does not exist, or L １ C １ ~C ６ Alkylene, C １ ~C ６ A heteroalkylene, -O-, -S-, or -NR'-, where C １ ~C ６ Alkylene and C １ ~C ６ Heteroalkylenes are substituted by optional means; A is H, Haro, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ A is a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocykryl, or heterocyclyl, where A may be optionally substituted; or A and R １１ They, together with the atoms to which they are bonded, form optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbocyclic, or heterocyclic rings; R １１ , R １２ , R １３ , and R １４ Each of these is independently H or an optional substituent; Each R' is either H or C １ ~C ６ It is alkyl; R ３ｘ and R ４ Each of them is independently H, or an independently selected substituent by choice. Here, Z １ Z ２ Z ３ , and Z ４ Two or fewer of these are N).

4. Compound of formula (II): 【Chemistry 243】 or its stereoisomers and / or pharmaceutically acceptable salts (wherein formula: Z １ is N or CR １１ And; Z ２ is N or CR １２ And; Z ３ is N or CR １３ And; Z ４ is N or CR １４ And; L １ It does not exist, or L １ C １ ~C ６ Alkylene, C １ ~C ６ A heteroalkylene, -O-, -S-, or -NR'-, where C １ ~C ６ Alkylene and C １ ~C ６ Heteroalkylenes are optionally substituted with 1 to 4 substituents independently selected from =O (oxo), OH, and halogens; A is H, Haro, C １ ~C １０ Alkyl, C １ ~C １０ Heteroalkyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, 3-7 member heterocycloalkyl, C ６ ~C １０ Aryl, 5-6 member heteroaryl, C ６ ~C １０ A is a carbocyclyl or a 5- to 10-membered heterocyclic ring, where A is one R １ Substituted by a group, 1 to 4 independently selected R ２ Substituted by choice by the base; or A and R １１ Together with the atoms to which they are bonded, C ３ ~C ７ They form cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic rings, where the heteroaryl and heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, where each of the rings has 1 R １ The base is arbitrarily replaced by 1 to 4 independently selected Rs. ２ It is substituted by choice depending on the base; R １１ , R １２ , R １３ , and R １４ Each of these independently corresponds to H or R ３ And; R １ is H, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C ２ ~C ９ heteroalkynyl, C １ ~C ６ heteroalkyl, C １ ~C ６ haloalkyl, -NH ２ or -L ２ -G, where the C １ ~C ６ alkyl may be optionally substituted with OH, and the C １ ~C ６ heteroalkyl may be optionally substituted with C ２ ~C ６ heteroalkynyl; L ２ It does not exist, or L ２ C １ ~C ６ Alkylene, C １ ~C ６ A heteroalkylene, -O-, -S-, or -NR'-, where C １ ~C ６ Alkylene and C １ ~C ６ Heteroalkylenes are independently and optionally substituted with 1 to 4 substituents selected from =O (oxo), OH, and halogens; G is C ３ ~C ７ The compounds are cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocykryl, or 5-10 membered heterocyclyl, where the 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, where G is 1-4 R Ａ Substituents may be optionally substituted; Each R Ａ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, =O (oxo), OH, -NMe ２ , -NHMe, -NH ２ Selected from the group consisting of CN and halos; Each R ２ Independently, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, =O (oxo), -OH, -NMe ２ , -NHMe, -NH ２ Selected from the group consisting of , and halo; Each R ３ Independently, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Selected from the group consisting of haloalkoxys, OH, cyano, and halo; R ４ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Selected from the group consisting of haloalkoxys, cyanos, and halos; Each R' is either H or C １ ~C ６ It is alkyl; R ３Ｘ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C １ ~C ６ Selected from the group consisting of haloalkyl, cyano, and halo; Here, Z １ Z ２ Z ３ , and Z ４ Two or fewer of these are N).

5. R ３ｘ However, H or C １ ~C ６ The compound according to claim 3 or 4, wherein it is alkyl.

6. R ３ｘ The compound according to claim 3 or 4, wherein the compound is H or -Me.

7. R ４ However, H, Haro, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C ２ ~C ６ Alkenyl, or C １ ~C ６ A compound according to any one of claims 3 to 6, which is a heteroalkyl compound.

8. R ４ が、H、-Cl、-Br、-OCF ３ 、-Me、-OMe、-Et、-nPr、-iPr、 【Chemistry 244】 -CH ２ OCH ３ ien-CH=CH ２ , or -CH ２ CH=CH ２ The compound according to any one of claims 3 to 7.

9. Z １ CR １１ Z ２ CR １２ Z ３ CR １３ Z ４ CR １４ The compound according to any one of claims 3 to 8.

10. Z １ N is Z ２ CR １２ Yes, Z ３ CR １３ Z ４ CR １４ The compound according to any one of claims 3 to 8.

11. Z １ CR １１ Z ２ N is Z ３ CR １３ Z ４ CR １４ The compound according to any one of claims 3 to 8.

12. Z １ N is Z ２ CR １２ Z ３ N is Z ４ CR １４ The compound according to any one of claims 3 to 8.

13. Z １ N is Z ２ N is Z ３ CR １３ Z ４ CR １４ The compound according to any one of claims 3 to 8.

14. Z １ CR １１ Z ２ N is Z ３ CR １３ Z ４ A compound according to any one of claims 3 to 8, wherein is N.

15. R １１ , R １２ , R １３ , and R １４ Each of these independently, H or R ３ And here, each R ３ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ A compound according to any one of claims 3 to 14, selected from the group consisting of haloalkoxy, OH, and halo.

16. R １１ , R １２ , R １３ , and R １４ Each of these independently, H or R ３ And here, each R ３ -Me, -Et, -nPr, -iPr, -CF ３ , -OMe, -OCF ３ A compound according to any one of claims 3 to 14, selected from the group consisting of -OH, -F, and -Cl.

17. L １ A compound according to any one of claims 3 to 16, wherein the compound is not present.

18. L １ However, C １ ~C ６ Alkylene, C １ ~C ６ A compound according to any one of claims 3 to 16, wherein the compound is a heteroalkylene or -O-.

19. L １ However, -CH ２ -, -OCH ２ -, -NHCH ２ -, -N(CH ３ )CH ２ The compound according to any one of claims 3 to 16, wherein it is - or -O-.

20. A is Hello, C １ ~C １０ Alkyl and C １ ~C １０ Selected from the group consisting of heteroalkyls, where C １ ~C １０ Alkyl and C １ ~C １０ The compound according to any one of claims 3 to 19, wherein the heteroalkyl group is optionally substituted with =O (oxo).

21. A is -F, -Cl, -Me, -Et, -nPr, -iPr, 【Chemistry 245】 -NHCH ３ 、-N(CH ３ ) ２ 、 【Chemistry 246】 A compound according to any one of claims 3 to 19, selected from the group consisting of the following.

22. A is C ３ ~C ７ Cycloalkyl, 3-7 member heterocycloalkyl, C ６ ~C １０ Aryl, 5-6 member heteroaryl, C ６ ~C １０ Selected from the group consisting of carbocyclyls and 5- to 10-membered heterocyclic rings, A is one R １ Substituted by a group, 1 to 4 independently selected R ２ The compound according to any one of claims 4 to 19, wherein the group is optionally substituted by a group.

23. A is C ３ ~C ７ Cycloalkyl, 3-7 member heterocycloalkyl, C ６ ~C １０ Selected from the group consisting of aryls and 5-6 member heteroaryls, A is one R １ Substituted by a group, 1 to 4 independently selected R ２ The compound according to any one of claims 4 to 19, wherein the group is optionally substituted by a group.

24. A, 【Chemistry 247】 A compound according to any one of claims 3 to 19, selected from the group consisting of the following.

25. Each R ２ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, =O (oxo), -OH, -NMe ２ , -NHMe, -NH ２ A compound according to any one of claims 4 to 24, selected from the group consisting of , and halo.

26. Each R ２ -Me, -Et, -nPr, -iPr, -CF ３ , -OMe, -OCF ３ , = O (oxo), -OH, -NMe ２ , -NHMe, -NH ２ A compound according to any one of claims 4 to 24, selected from the group consisting of F, Cl, and Br.

27. R １ However, H or -L ２ A compound according to any one of claims 4 to 24, wherein the compound is -G.

28. R １ However, -L ２ A compound according to any one of claims 4 to 24, wherein the compound is -G.

29. L ２ A compound according to any one of claims 4 to 28, wherein the compound is not present.

30. L ２ However, C １ ~C ６ Alkylene, C １ ~C ６ A compound according to any one of claims 4 to 28, selected from the group consisting of heteroalkylenes and -O-.

31. L ２ However, -CH ２ - The compound according to any one of claims 4 to 28.

32. G is C ３ ~C ７ A cycloalkyl or a 3-7 membered heterocycloalkyl, where the 3-7 membered heterocycloalkyl has 1-3 ring heteroatoms selected from N, O, and S, where G is 1-4 R Ａ The compound according to any one of claims 4 to 31, which may be optionally substituted by substituents.

33. G is a 3- to 7-membered heterocycloalkyl group, where G is a group of 1 to 4 R groups. Ａ The compound according to any one of claims 4 to 31, which may be optionally substituted by substituents.

34. G is 【Chemistry 248】 A compound according to any one of claims 4 to 31, selected from the group consisting of the following.

35. Each R Ａ Independently, C １ ~C ６ A compound according to any one of claims 4 to 34, wherein it is alkyl.

36. G is 【Chemistry 249】 A compound according to any one of claims 4 to 35, selected from the group consisting of the above.

37. A, [Chemical 250] A compound according to any one of claims 3 to 35, selected from the group consisting of the following.

38. A, 【Chemistry 251】 A compound according to any one of claims 3 to 24, selected from the group consisting of the following.

39. A and R １１ However, together with the atoms to which they are bonded, C ３ ~C ７ They form cycloalkyl, aryl, 5-6 membered heteroaryl, or 3-7 membered heterocyclic rings, where the 5-6 membered heteroaryl and 3-7 membered heterocyclil have 1-3 ring heteroatoms selected from N, O, and S, and each of the rings has 1 R １ The base is arbitrarily replaced by 1 to 4 independently selected Rs. ２ The compound according to any one of claims 4 to 19, wherein the group is optionally substituted by a group. 【Request Item 40】 【Chemistry 252】 but, 【Chemistry 253】 A compound according to any one of claims 3 to 19, selected from the group consisting of the following. 【Request Item 41】 【Chemistry 254】 but, 【Chemistry 255】 A compound according to any one of claims 3 to 19, selected from the group consisting of the following.

42. The compound in question is of formula (IIa): 【Chemistry 256】 The compound according to claim 3 or 4, or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof.

43. The compound in question is of formula (IIb): 【Chemistry 257】 The compound according to claim 3 or 4, or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof.

44. The compound in question is of formula (IIc): 【Chemistry 258】 The compound according to claim 3 or 4, or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof.

45. The compound in question is of formula (IId): 【Chemistry 259】 The compound according to claim 3 or 4, or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof.

46. Compound of formula (III): 【Chemical 260】 or its stereoisomers and / or pharmaceutically acceptable salts (wherein formula: X １ NR １ O, S, SO ２ ,CH ２ , or CHR １ And; X ２ is N or CH; R １ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ２ ~C ９ Heteroalkyl, C １ ~C ６ Haloalkyl, -NH ２ , and -L ２ - Selected from the group consisting of G, where C １ ~C ６ The alkyl group may be optionally substituted with one or more OH groups, where the C １ ~C ６ Heteroalkyl is C ２ ~C ６ It may also be optionally substituted with a heteroalkynyl; L ２ It does not exist, or L ２ C １ ~C ６ Alkylene, C １ ~C ６ Heteroalkylene, -O-, -S-, and -NR'-, where C １ ~C ６ Alkylene and C １ ~C ６ Heteroalkylenes are optionally substituted with 1 to 4 substituents independently selected from the group consisting of =O (oxo), OH, and halogens; G is C ３ ~C ７ Selected from the group consisting of cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocykryl, and 5-10 membered heterocyclyl, where the 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, where G has 1-4 R Ａ Substituents may be optionally substituted; Each R Ａ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Selected from the group consisting of haloalkoxys, OH, CN, and halo; Each R ２ Independently, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, -NH ２ Selected from the group consisting of , and halo; Each R ３ Independently, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Selected from the group consisting of haloalkoxys, OH, cyano, and halo; R ３Ｘ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C １ ~C ６ Selected from the group consisting of haloalkyl, cyano, and halo; R ４ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ２ ~C ９ Heteralalkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Selected from the group consisting of haloalkoxys, cyanos, and halos; Each R' is either H or C １ ~C ６ It is alkyl; m is either 0 or 1; n is either 0 or 1; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4).

47. Compound of formula (III): 【Chemistry 261】 or its stereoisomers and / or pharmaceutically acceptable salts (wherein formula: X １ NR １ O, S, SO ２ ,CH ２ , and CHR １ Selected from the group consisting of; X ２ is N or CH; R １ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, -NH ２ Selected from the group consisting of , and -G; G is C ３ ~C ７ Selected from the group consisting of cycloalkyl, 3-7 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl, 6-10 membered carbocykryl, and 5-10 membered heterocyclyl, where the 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 5-10 membered heterocyclyl have 1-3 ring heteroatoms selected from N, O, and S, where G has 1-4 R Ａ Substituents may be optionally substituted; Each R Ａ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Selected from the group consisting of haloalkoxys, OH, CN, and halo; Each R ２ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Selected from the group consisting of haloalkyl and halo; Each R ３ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Selected from the group consisting of haloalkyl, cyano, and halo; R ３Ｘ H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C １ ~C ６ Selected from the group consisting of haloalkyl, cyano, and halo; R ４ H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Selected from the group consisting of haloalkyl, cyano, and halo; m is either 0 or 1; n is either 0 or 1; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4).

48. The compound in question is of formula (IIIa): 【Chemistry 262】 The compound according to claim 47, or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof.

49. X １ NR １ X ２ The compound according to any one of claims 46 to 48, wherein is CH.

50. X １ CH ２ or CHR １ X ２ The compound according to any one of claims 46 to 48, wherein is N.

51. X １ NR １ X ２ The compound according to any one of claims 46 to 48, wherein is N.

52. R １ However, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ A compound according to any one of claims 46 to 51, selected from the group consisting of haloalkyl, OH, and halo.

53. Each R １ However, -Me, -Et, -nPr, -iPr, -OMe, -OCF ３ , -OH, -Cl, -F, 【Chemical 263】 A compound according to any one of claims 46 to 51, selected from the group consisting of the following.

54. R ３ｘ The compound according to any one of claims 46 to 53, wherein the compound is H or -Me.

55. R ３ｘ The compound according to any one of claims 46 to 53, wherein is H.

56. R ４ The compound according to any one of claims 46 to 55, wherein is -Me.

57. The compound according to any one of claims 46 to 56, wherein m is 1 and n is 1.

58. The compound according to any one of claims 46 to 56, wherein m is 0 and n is 1.

59. The compound according to any one of claims 46 to 58, wherein p is 0.

60. The compound according to any one of claims 46 to 59, wherein q is 0.

61. The compound in question is of formula (IIIb): 【Chemistry 264】 The compound according to any one of claims 46 to 60, or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof.

62. The compound in question is of formula (IIIc): 【Chemical 265】 The compound according to any one of claims 46 to 60, or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof.

63. The compound in question is of formula (IIId): 【Chemical 266】 The compound according to any one of claims 46 to 60, or a stereoisomer thereof and / or a pharmaceutically acceptable salt thereof.

64. The compound in question is of formula (IIIe): 【Chemistry 267】 The compound according to any one of claims 46 to 60, or a pharmaceutically acceptable salt thereof.

65. Compound of formula (IV): 【Chemical 268】 or its stereoisomers and / or pharmaceutically acceptable salts (wherein formula: Z １ is N or CR １１ And; Z ２ is N or CR １２ And; Z ３ is N or CR １３ And; Z ４ is N or CH; R １１ H, -OH, halo, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl and C １ ~C ６ Selected from the group consisting of haloalkoxys; R １２ H, -OH, halo, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl and C １ ~C ６ Selected from the group consisting of haloalkoxys; R １３ is H or halo; R １４ H, Halo, C １ ~C ６ Alkylene, C １ ~C ６ Selected from the group consisting of heteroalkylenes, 5-7 membered aryls, 5-7 membered heteroaryls, and 3-7 membered heterocycloalkyls, where R １４ is one or more R １４ａ It may also be replaced by optional selection; R １４ａ C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C ３ ~C ７ Cycloalkyl, 5-7 membered aryl, 3-7 membered heterocycloalkyl, and -C(O)OR １４ｂ Selected from the group consisting of, where C １ ~C ６ Alkyl or 3- to 7-membered heterocycloalkyl groups contain one or more R １４ｂ It may also be replaced by optional selection; R １４ｂ is -OH, oxo, C １ ~C ６ Alkyl, C １ ~C ８ Heteroalkyl, C ２ ~C ６ Selected from the group consisting of alkynyl and 3- to 7-membered heterocycloalkyl groups, where the 3- to 7-membered heterocycloalkyl group comprises one or more carbon atoms. １ ~C ６ It may be optionally substituted with an alkyl group; Here, Z ２ CR １２ If R １２ and R １４ These may, together with the atoms to which they are bonded, form a cycloalkyl, heterocycloalkyl, or aryl group, where the cycloalkyl or heterocycloalkyl group comprises one or more C １ ~C ６ Alkyl or C １ ~C ６ They may be optionally substituted with heteroalkyl groups; R ３ｘ is H or C １ ~C ６ It is alkyl; R ４ H, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl and C １ ~C ６ (Selected from the group consisting of haloalkoxys).

66. Z １ CR １１ Z ２ CR １２ Z ３ CR １３ Z ４ The compound according to claim 65, wherein is CH.

67. Z １ If Z is N, ２ CR １２ Z ３ CR １３ Z ４ The compound according to claim 65, wherein is CH.

68. Z ２ If Z is N, １ CR １１ Z ３ CR １３ Z ４ The compound according to claim 65, wherein is CH.

69. Z ２ and Z ３ If Z is N, １ CR １１ Z ４ The compound according to claim 65, wherein is CH.

70. Z ２ and Z ４ If Z is N, １ CR １１ Z ３ CR １３ The compound according to claim 65.

71. R １１ But, hello, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl and C １ ~C ６ The compound according to claim 65, selected from the group consisting of haloalkoxys.

72. R １２ But, hello, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl and C １ ~C ６ The compound according to claim 65, selected from the group consisting of haloalkoxys.

73. R １１ However, -Me, -Et, -Cl, -F, -OMe, and -OCF ３ A compound according to claim 71, selected from the group consisting of the following.

74. R １２ However, -Me, -Et, -Cl, -F, -OMe, and -OCF ３ A compound according to claim 71, selected from the group consisting of the following.

75. R １１ The compound according to claim 71, wherein the OH group is -OH.

76. R １２ The compound according to claim 71, wherein the OH group is -OH.

77. R １３ The compound according to claim 65, wherein is a halo.

78. R １３ The compound according to claim 77, wherein is -Cl.

79. R １４ However, H, Haro, C １ ~C ３ Alkylene, C １ ~C ６ Selected from the group consisting of heteroalkylenes, phenyl, 5-membered heteroaryls, and 4- to 6-membered heterocycloalkyls, where C １ ~C ３ Alkylene, C １ ~C ６ Heteroalkylene, phenyl, 5-membered heteroaryl, and 4-6 membered heterocycloalkyl groups, with one or more R １４ａ The compound according to claim 65, which may be optionally substituted.

80. R １４ が、-Et、-O-、-CH ２ -、-nPr、-iPr、-Cl、NHCH ３ 、-N(CH ３ ) ２ 、 【Chemistry 269】 A group consisting of R is selected, where R １４ If it contains a replaceable atom, then that atom is one or more R １４ａ The compound according to claim 79, which may be optionally substituted.

81. ( １４ The ３ 、!(C) ３ ) ２ 、 【Chemistry 270】 A compound according to claim 80, selected from the group consisting of the following.

82. R １４ but, 【Chemistry 271】 A compound according to claim 79, selected from the group consisting of the following.

83. R １４ａ However, C １ ~C ３ Alkyl, C １ ~C ６ Heteroalkyl, C ３ ~C ６ Selected from the group consisting of cycloalkyl, 6-membered aryl, and 4- to 6-membered heterocycloalkyl, where C １ ~C ６ Heteroalkyl, C ３ ~C ７ Cycloalkyl and 5- to 7-membered aryl compounds are R １４ｂ The compound according to claim 79, 80, or 82, which may be optionally substituted.

84. R １４ａ is -Me, -Et, -CH ２ -, -nPr, 【Chemistry 272】 A group consisting of R is selected, where R １４ａ If it contains a replaceable atom, then that atom is one or more R １４ｂ The compound according to claim 83, which may be optionally substituted.

85. R １４ａ However, -Me, -Et, nPr, 【Chemistry 273】 A group consisting of R is selected, where R １４ａ If it contains a replaceable atom, then that atom is one or more R １４ｂ The compound according to claim 84, which may be optionally substituted.

85. R １４ａ が、-C(O)OR １４ｂ 、 【Chemistry 274】 A compound according to claim 79, 82, or 83, selected from the group consisting of the above.

87. R １４ｂ However, oxo, -OH, -Me, C ３ ~C ７ Heteroalkyl, C ２ ~C ３ Selected from the group consisting of alkynyl and 6-membered heterocycloalkyl groups, where the 3- to 7-membered heterocycloalkyl group contains one or more C １ ~C ６ The compound according to claim 79, 83, or 85, which may be optionally substituted with an alkyl group.

88. R １４ｂ However, oxo, -OH, -Me, 【Chemistry 275】 Selected from the group consisting of the above, where, 【Chemistry 276】 However, oxo or C １ ~C ６ The compound according to claim 86, which may be optionally substituted with an alkyl group.

89. R １４ｂ However, oxo, -OH, -Me, 【Chemistry 277】 Selected from the group consisting of the above, where, 【Chemistry 278】 The compound according to claim 87, wherein -Me may be optionally substituted.

90. Z ２ CR １２ If R １２ and R １４ However, these may combine with the atoms to which they are bonded to form an aryl, cycloalkyl, or heterocycloalkyl group, where the cycloalkyl or heterocycloalkyl group is composed of one or more C atoms. １ ~C ６ Alkyl or C １ ~C ６ The compound according to any one of claims 79 to 88, which may be optionally substituted with a heteroalkyl group.

91. Z ２ CR １２ If so, the combined R １２ and R １４ but, 【Chemistry 279】 A compound according to claim 89, selected from the group consisting of the following.

92. R ３ｘ C １ ~C ６ The compound according to claim 65, wherein it is alkyl.

93. R ３ｘ The compound according to claim 91, wherein is -Me.

94. R ４ But, hello, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl and C １ ~C ６ The compound according to claim 65, selected from the group consisting of haloalkoxys.

95. R ４ が、----B2、--FF ３ --.------.- 【Chemistry 280】 A compound according to claim 93, selected from the group consisting of the following.

96. A compound selected from any of the compounds listed in Table 1, or its stereoisomers, and / or pharmaceutically acceptable salts.

97. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 95.

98. A method for treating a subject having a neurodegenerative disease or disorder, comprising administering to the subject in need of such treatment a pharmaceutically effective amount of the pharmaceutical composition according to claim 96 or a compound according to any one of claims 1 to 94.

99. The aforementioned neurodegenerative diseases include Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Huntington's chorea, prion diseases (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, kuru disease, or scrapie), Lewy body dementia, and diffuse prion disease. Bee body disease (DLBD), polyglutamine (polyQ) repeat disease, trinucleotide repeat disease, neurodegenerative diseases, presenile dementia, senile dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-related dementia, Parkinson's disease, Parkinson's disease with dementia, Lewy body dementia, Down syndrome, multiple system atrophy, spinal muscular atrophy (SMA, for example, SMA SMA type I (e.g., Werdnig-Hoffmann disease), SMA type II, SMA type III (e.g., Kugelberg-Welander disease), or congenital SMA with joint contractures), progressive spinal and bulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative diseases / motor neuron degenerative diseases, upper motor neuron disorders, lower motor neuron disorders, age-related diseases and dementia, Haller-Holden-Spats syndrome, cerebral infarction, traumatic brain injury, chronic traumatic brain injury, transient ischemic attack, Ritico-Bodig disease (amyotrophic lateral sclerosis - Parkinson's dementia), Guam-Parkinson's dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Aples diseaseThe method according to claim 97, comprising a selection from the group consisting of disease, Krabbe disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder disease, Batten disease, Cockayne syndrome, Kahns-Sayer syndrome, Gerstmann-Strössler-Scheinker syndrome and other transmissible spongiform encephalopathy, hereditary spastic paraplegia, Leigh syndrome, demyelinating disorders, neuronal ceroid lipofuscinosis, epilepsy, tremor, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injury (e.g., stroke, head injury), and autism, or any combination thereof.

100. The method according to claim 97, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).

101. The method according to claim 97, wherein the neurodegenerative disease is Alzheimer's disease.

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