TRPML modulator

Abstract

This invention provides compounds that regulate autophagy, pharmaceutically acceptable compositions thereof, and methods for using them. [Solution] For example, compounds such as N1-(2-(6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide, N1-(2-(4-(4-chloro-2-fluorophenyl)cyclohexyl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide, N1-(2-(diphenylphosphoryl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide, and 3-[({2-[4-(methoxymethyl)-4-methylpiperidine-1-yl]phenyl}sulfamoyl)methyl]-N,N-dimethylbenzene-1-sulfonamide are shown.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 119,888 filed on 1 December 2020; U.S. Provisional Application No. 62 / 950,818 filed on 19 December 2019; and U.S. Provisional Application No. 62 / 950,768 filed on 19 December 2019, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Transient receptor potential mucolipin-1 (also known as TRPML1 or ML1) modulates specific aspects of lysosomal transport, including autophagy, of lysosomal Ca 2+ It is a channel. Wang, et al., PNAS, E1373-E1381 (March See 2, 2015). In particular, TRPML1 is an inwardly rectifying current channel that transports cations from the lysosome lumen to the cytosol. See Di Paolda, et al., Cell Calcium 69:112-121 (2018). Ca from lysosomes by TRPML1 2+ The release of regulates the activity of transcription factor EB. See Medina, et al., Nat. Cell. Biol., 17(3):288-299 (2015). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Wang,et al.,PNAS,E1373-E1381(March 2,2015) [Non-Patent Document 2] Di Paolda,et al.,Cell Calcium 69:112-121(2018) [Non-Patent Document 3] Medina,et al.,Nat.Cell.Biol.,17(3):288-299(2015) [Overview of the Initiative] [Means for solving the problem]

[0004] In recent years, upregulation of autophagy has been found to be beneficial in patients with numerous diseases or disorders. For example, it has been reported that inducing autophagy promotes the removal of hepatotoxic α-1-antitrypsin (ATZ) in the liver. Pastore, et al. See al., EMBO Mol. Med. 5(3):397-412 (Mar. 2013). Furthermore, in recent years, autophagy has been found to be useful in the treatment of neurodegenerative disorders, cancer, and heart disease. See Pierzynowska, et al., Metab. Brain Dis., 33(4);989-1008 (2018) (discussing neurodegenerative disorders); Nelson & Shacka, Curr. Pathobiol. Rep., 1(4):239-245 (2013) (discussing cancer); Sciaretta, et al., Annual Review of Physiology, 80:1-26 (2018) (discussing heart disease); Maiuri & Kroemer, Cell Death & Differentiation, 26:680-689 (2019) (discussing the therapeutic applications of autophagy in general). This disclosure provides, in particular, techniques for modulating (e.g., upmodulating) autophagy. For example, in some embodiments, this disclosure demonstrates the effectiveness of specific methods for modulating TRPML1 in enhancing autophagy (e.g., TRPML1 agonism). Thus, in particular, this disclosure demonstrates that autophagy can be enhanced by targeting TRPML1 as described herein.

[0005] This disclosure also provides specific technologies for use in pharmaceuticals, in particular specific technologies for treating specific diseases, disorders, or conditions, and / or specific technologies for identifying, characterizing, and / or manufacturing specific agents and / or compositions containing or delivering them that are useful for treating such diseases, disorders, or conditions.

[0006] In some embodiments, the disclosure demonstrates that modulating (e.g., stimulating) TRPLM1 and / or otherwise enhancing autophagy is useful in treating certain diseases, disorders, or conditions.

[0007] Therefore, it is desirable to identify methods and mechanisms for promoting autophagy. Considering the role of TRPML1 in autophagy, TRPML1 modulators useful for promoting autophagy and / or treating specific diseases, disorders, or conditions are described herein.

[0008] In particular, this application provides a technique useful for adjusting TRPML1.

[0009] In some embodiments, this application relates to formula I: ZL 1 -Cy-AL 2 -V I A compound having the structure described in or a pharmaceutically acceptable salt thereof, wherein the formula is A is C 6~12 A is a 5-6 member heteroaryl containing 1-4 heteroatoms selected from aryl, N, O, and S, where A is 0, 1, 2, 3, or 4 R a It has been replaced with, Cy is a 4-12 member monocyclic or polycyclic heterocycline containing none or 1-4 heteroatoms selected from N, O, P, and S, or a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, P, and S, C 1~6 aliphatic, C 3~12 Cycloalkyl, or -C0~6 A divalent moiety selected from alkylenyl-C(O)-NH-, where Cy is optionally substituted with one or more R 1 and L 1 is absent, -NR 3 -, -O-, -S-, -C(O)-NR<0000 extraordinally difficult to define precisely the scope of the invention. 3 -, -NR 3 -C(O)-, -C(O)-C(O)-, or C 1~6 alkylenyl, C 2~6 alkynylenyl, -NR 3 -C 1~6 alkylenyl, -O-C 1~6 alkylenyl, -C(O)-C 0~6 alkylenyl, -C 0~6 alkylenyl-C(O)-, and -C​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​V is C 1~6 aliphatic, C 6~12 4-12 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from aryl, N, O, and S; 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S; 5-12 member monocyclic or bicyclic aryls; and C 3~12 Selected from monocyclic or polycyclic cycloalkyl, where V is (R 6 ) m It has been replaced with, Z is C 1~6 Aliphatic, 2-10 member heteroaliphatic, P(O)(R 3 )2, -C(O)C 1~6 Aliphatic, C(O)N(R 3 )2, C 6~12 Ariel, C 3~12 A monocyclic or polycyclic cycloalkyl, a 4-16 member monocyclic or polycyclic heterocyclyl containing 1-4 heteroatoms selected from N, O, and S, or a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S, where Z is (R 2 ) q It has been replaced with, Each R a These are independently halo, oxo, CN, and optionally substituted C. 1~6 Aliphatic or OC 1~6 It is aliphatic, Each R 1 Halo, N(R 3 )2, OH, CN, C(O)NHR 3 , and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 Independently selected from any optionally substituted groups selected from alkyl groups, Each R 2 These are halo, oxo, CN, OH, C(O)OR 2a , C 6~12 Aryl, and C 1~6 Aliphatic, C(O)C 1~6 Aliphatic and OC 1~6 Independently selected from any substituted groups chosen from aliphatic groups, R2a is an optionally substituted group selected from hydrogen, or a 4- to 12-member monocyclic or bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, C 1~6 aliphatic, C 3~12 cycloalkyl, each R 3 is independently selected from H and optionally substituted C 1~6 aliphatic, each R 5 is C 1~6 alkyl, -N(R 3 )2, -O-C 1~6 alkyl, C(O)-C 1~6 alkyl, P(O)(C 1~6 alkyl)2, C 3~12 cycloalkyl, and independently selected from 5- to 12-member heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, R 5 is optionally substituted with one or more substituents selected from halo, OH, and 2- to 12-member heteroaliphatic, each R 6 is halo, oxo, SF5, S(O)-R 5 , S(O)2-R 5 , S(O)(NH)-R 5 , S(O)2(NH)-R 5 , -CN, -C(O)-R 5 , -C​​​​​​​​​​​​​​​​​​​​​​​​​​ m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, or 4. The present invention provides the compound or a pharmaceutically acceptable salt thereof, wherein s is 0 or 1.

[0010] In some embodiments, the present disclosure relates to formula I': [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is A' is R a A 5-10 member monocyclic or bicyclic heterocyclil containing 1-4 heteroatoms selected from phenyl, N, O, P, and S, which are optionally substituted, or a 5-10 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S, Cy is non-existent, or C 1~6 A 4-14 member monocyclic or polycyclic heterocyclil containing 1-4 heteroatoms selected from aliphatic, N, O, P, and S; a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S; C 6~12 Aryl, or C 3~12 The divalent moiety is selected from cycloalkyl groups, where Cy is one or more R groups. 1 It is arbitrarily replaced with, L 1 is non-existent, -S-, -C(O)-NR 3 -, -NR 3 -C(O)-, or C 1~6 Alkirenyl, C 2~6 alkenylenyl, C 2~6 Alkynylenyl, -NR 3 -C 0~6 Alkirenyl, -OC 0~6 Alkyrenyl, -C(O)-C 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-C(O)-,-C(O)OC 0~6 Alkyrenyl, -C 1~6Alkyrenyl-OC(O)-,-C 3~6 Cycloalkyl and -NR 3 -C(O)-C 0~6 The divalent moiety is an arbitrarily substituted moiety selected from alkylenyl-O-, L 2 is, -(NR 3 ) s -S(O)-(NR 3 )-,-(NR 3 ) s -S(O)2-NR 3 -,-(NR 3 ) s -P(O)(R 3 )-,-C(O)-(NR 3 ) s -, -NR 3 -C(O)-, or -(NR 3 ) s -S(O)-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)2-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)-NR 3 -C 0~6 Alkyrenyl, -(NR 3 ) s -S(O)2-NR 3 -C 0~6 Alkyrenyl, -(NR 3 ) s -S(O)2-C 3~6 Cycloalkyl, -NR 3 -C 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-S(O)-(NR 3 ) s -, -C 1~6 Alkyrenyl-S(O)2-(NR 3 ) s - An optionally substituted divalent moiety selected from 2-6 member heteroaliphatic groups, and 4-12 member monocyclic or bicyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, V is C 1~6 aliphatic, C 6~12 Ariel, C3~12 Selected from cycloaliphatic, 4-12 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where V is (R 6 ) m It has been replaced with, Z is P(O)(R 3 )2, C(O)N(R 3 )2, C 1~6 aliphatic, C 6~12 Ariel, C 3~12 Selected from cycloaliphatic, 2-10 atom heteroaliphatic, 4-16 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where Z is (R 2 ) q It has been replaced with, Each R a These are independently H, halo, -CN, oxo, or C 1~6 aliphatic, C 3~6 Cycloliphatic and OC 1~6 An arbitrarily substituted group selected from aliphatic groups, Each R 1 is halo, oxo, -N(R 3 )2, -OH, -CN, -C(O)N(R 3 )2, and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 Independently selected from any substituted groups chosen from aliphatic groups, Each R 2 These are halo, oxo, -CN, -OH, OR 2a , -C(O)-R 2a , -C(O)OR 2a , and C 1~6 aliphatic, C 6~12 Independently selected from aryl and optionally substituted groups selected from 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, Each R 2a These are, independently, H, or C 1~6 aliphatic, C 3~12 A cycloaliphatic group, and an optionally substituted group selected from 4- to 12-membered monocyclic or bicyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, Each R 3 This is H and optionally substituted C 1~6 Selected independently from aliphatic species, Each R 5 is -N(R 3 )2, or C 1~6 Aliphatic, P(O)(C 1~6 aliphatic)2, C 3~12 A cycloaliphatic group, and an optionally substituted group selected from 5- to 12-membered monocyclic or polycyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, Each R 6 This is Halo, Oxo, -SF5, -S(O)-R 5 S(O)2-R 5 -S(O)(NH)-R 5 -S(O)2-(NH)-R 5 , -S(O)-N(R 5 )2, -S(O)2-N(R 5 )2, -CN, -C(O)-NH(R 5 ), -C(O)-N(R 5 )2, -P(O)(R 5 )2, -OR 5 , or C 1~6 aliphatic, SC 1~6 Aliphatic, 2-12 member heteroaliphatic, -C 0~6 Alkyrenyl-C(O)-R 5 , -C 0~6 Alkyrenyl-C(O)OR 5 , C 6~12 Ariel, C 3~12 Independently selected from cycloaliphatic groups and optionally substituted groups selected from 4-7 membered monocyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, 4, 5, or 6. Each s is independently 0 or 1, providing the compound or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the present disclosure relates to formula II': [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is X 1’ , X 2’ , X 3’ , and X 4’ These are N, C, and CR, respectively. a Selected independently from X 1’ , X 2’ , X 3’ , and X 4’ Cy-L 1 -Z or L 2 -When bound to V, it is C and Cy-L 1 -Z or L 2 -If not bound to V, use N or CR a And, Y 1’ and Y 2’ These are CR a is or Y 1’ and Y 2’ Together, they form an optionally substituted condensed heterocyclyl ring containing one or two heteroatoms selected from N, O, and S, or an optionally substituted condensed heteroaryl group containing one or two heteroatoms selected from N, O, and S. Cy is non-existent, C 1~6 A 4-12 member monocyclic or polycyclic heterocyclil containing 1-4 heteroatoms selected from aliphatic, N, O, P, and S; a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S; C 6~12 Aryl, or C 3~12 It is a cycloalkyl group, where Cy has one or more R groups. 1 It is arbitrarily replaced with, L1 is non-existent, -S-, -C(O)-NR 3 -, -NR 3 -C(O)-, or C 1~6 Alkirenyl, C 2~6 Alkynylenyl, -NR 3 -C 0~6 Alkirenyl, -OC 0~6 Alkyrenyl, -C(O)-C 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-C(O)-,-C(O)OC 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-OC(O)- and -NR 3 -C(O)-C 0~6 An optionally substituted group selected from alkylenyl-O-, L 2 is, -(NR 3 ) s -S(O)-(NR 3 )-,-(NR 3 ) s -S(O)2-NR 3 -,-(NR 3 ) s -P(O)(R 3 )-,-C(O)-(NR 3 ) s -, -NR 3 -C(O)-, or -(NR 3 ) s -S(O)-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)2-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)-NR 3 -C 0~6 Alkyrenyl, -(NR 3 ) s -S(O)2-NR 3 -C 0~6 Alkirenyl, -NR 3 -C 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-S(O)-(NR 3 ) s -, -C1~6 Alkyrenyl-S(O)2-(NR 3 ) s - and an optionally substituted divalent moiety selected from a 4- to 12-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S, V is C 1~6 aliphatic, C 6~12 Ariel, C 3~12 Selected from cycloaliphatic, 4-12 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where V is (R 6 ) m It has been replaced with, Z is P(O)(R 3 )2, C(O)N(R 3 )2, C 1~6 aliphatic, C 6~12 Ariel, C 3~12 Selected from cycloaliphatic, 2-10 atom heteroaliphatic, 4-16 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where Z is (R 2 ) q It has been replaced with, Each R a These are independently H, halo, -CN, or C 1~6 aliphatic, C 3~6 Cycloliphatic and OC 1~6 An arbitrarily substituted group selected from aliphatic groups, Each R 1 is, halo, -N(R 3 )2, -OH, -CN, -C(O)N(R 3 )2, and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 Independently selected from any substituted groups chosen from aliphatic groups, Each R 2 These are halo, oxo, -CN, -OH, OR2a , -C(O)-R 2a , -C(O)OR 2a , and C 1~6 aliphatic, C 6~12 Independently selected from aryl and optionally substituted groups selected from 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, Each R 2a These are, independently, H, or C 1~6 aliphatic, C 3~12 A cycloaliphatic group, and an optionally substituted group selected from 4- to 12-membered monocyclic or bicyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, Each R 3 This is H and optionally substituted C 1~6 Selected independently from aliphatic species, Each R 5 is -N(R 3 )2, or C 1~6 Aliphatic, P(O)(C 1~6 aliphatic)2, C 3~12 A cycloaliphatic group, and an optionally substituted group selected from 5- to 12-membered monocyclic or polycyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, Each R 6 This is Halo, Oxo, -SF5, -S(O)-R 5 S(O)2-R 5 -S(O)(NH)-R 5 -S(O)2-(NH)-R 5 , -S(O)-N(R 5 )2, -S(O)2-N(R 5 )2, -CN, -C(O)-NH(R 5 ), -C(O)-N(R 5 )2, -P(O)(R 5 )2, -OR 5 , or C 1~6 aliphatic, SC 1~6 Aliphatic, 2-12 member heteroaliphatic, -C 0~6 Alkyrenyl-C(O)-R 5 , -C 0~6 Alkyrenyl-C(O)OR5 , C 6~12 Ariel, C 3~12 Independently selected from cycloaliphatic groups and optionally substituted groups selected from 4-7 membered monocyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, 4, 5, or 6. Each s is independently 0 or 1, providing the compound or a pharmaceutically acceptable salt thereof.

[0012] definition Agonist: As understood by those skilled in the art, the term “agonist” generally refers to a drug whose presence or level is associated with an increased level or activity of a target compared to that observed in the absence of the drug (or at different levels of the drug). In some embodiments, the agonist is one whose presence or level correlates with a target level or activity that is equivalent to or higher than a particular reference level or activity (e.g., observed under appropriate reference conditions, e.g., a known agonist, e.g., in the presence of a positive control). In some embodiments, the agonist may be a direct agonist in that it directly affects the target (e.g., by direct interaction). In some embodiments, the agonist may be an indirect agonist in that it indirectly affects the target by acting on, for example, a modifier of the target or some other component or entity, e.g., by interacting with it.

[0013] Aliphatic: The term “aliphatic” refers to a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as “cycloaliphatic”), having a single or more bonding site to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 12 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 6 aliphatic carbon atoms (e.g., C 1~6 ) contains. In some embodiments, the aliphatic group has 1 to 5 aliphatic carbon atoms (e.g., C 1~5 ) contains. In other embodiments, the aliphatic group has 1 to 4 aliphatic carbon atoms (for example, C 1~4 ) contains. In yet another embodiment, the aliphatic group contains 1 to 3 aliphatic carbon atoms (for example, C 1~3 ) contains, and in further other embodiments, the aliphatic group comprises 1 to 2 aliphatic carbon atoms (e.g., C 1~2 ) contains. In some embodiments, the "cycloaliphatic" is a monocyclic C that is fully saturated or contains one or more unsaturated units. 3~8 Hydrocarbons or bicyclic carbon 7~10 This refers to hydrocarbons that are not aromatic and have one or more bonding sites to the remainder of the molecule. Preferred aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkylenyl, alkenyl, alkenylenyl, alkynyl, or alkynylenyl groups and their hybrids. Preferred aliphatic groups are C 1~6 It is alkyl. In some embodiments, the aliphatic is polyvalent (i.e., has multiple bonding sites to the rest of the molecule). In some embodiments, the aliphatic is divalent (i.e., has two bonding sites to the rest of the molecule). Exemplary divalent aliphatic groups may be referred to as "alkylenyl".

[0014] Alkyl: A term used alone or as part of a larger group, "alkyl" refers to (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~4 , C 1~3 , or C 1~2 This refers to an optionally substituted linear, branched, or cyclic saturated hydrocarbon group having ) ). Exemplary alkyl groups include methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, sec-butyl, isobutyl, tert-butyl), pentyl, hexyl, heptyl, -CH2-C(CH3)3, -CH2-C(CH3)2-CH2-CH3, -C(CH3)2-CH2-CH3, and -CH(CH3)-C(CH3)3. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Exemplary polycyclic cycloalkyl rings include adamantyl, [ka] These are some examples.

[0015] Alkylene: The terms "alkylene" and "alkylenyl" are used interchangeably and refer to a divalent alkyl group. In some embodiments, "alkylene" is a divalent linear or branched alkyl group. In some embodiments, "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, where n is a positive integer, for example, 1-6, 1-4, 1-3, 1-2, or 2-3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are optionally replaced by substituents. Preferred substituents are those listed below for substituted aliphatic groups, and also those described herein. It will be understood that two substituents of an alkylene group may be combined to form a ring system. In certain embodiments, two substituents may be combined to form a 3- to 7-membered ring. The substituents may be located on the same or different atoms. The term "haloalkylenyl" refers to a linear or branched alkylenyl group substituted with one or more halogen atoms (e.g., 1, 2, 3, or 4 halos, e.g., fluoro, iodo, bromo, or chloro).

[0016] Alkenyl: Used alone or as part of a larger term, the term "alkenyl" has at least one double bond and (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2~12 , C2 ~10 , C 2~8 , C 2~6 , C 2~4 , or C 2~3 The term "cycloalkenyl" refers to an optionally substituted linear, branched, or cyclic hydrocarbon group having a carbon-carbon double bond. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system having at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0017] Alkenylene: The terms "alkenylene" and "alkenylenyl" are used interchangeably and refer to a divalent alkenyl group. In some embodiments, "alkenylene" is a linear or branched divalent alkenyl group.

[0018] Alkynyl: Used alone or as part of a larger term, the term "alkynyl" has at least one triple bond and (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2~12 , C 2~10 , C 2~8 , C 2~6 , C 2~4 , or C 2~3 This refers to an optionally substituted linear or branched hydrocarbon group having ) ). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0019] Alkynylene: The terms "alkynylene" and "alkynylenyl" are used interchangeably and refer to a divalent alkynyl group. In some embodiments, "alkynylene" is a linear or branched divalent alkynyl group.

[0020] Analogy: As used herein, the term “analog” means a substance that shares one or more specific structural features, elements, components, or parts with a reference substance. Typically, an “analog” exhibits significant structural similarity to a reference substance, for example, sharing a core or common structure, but also differing in distinct specific respects. In some embodiments, an analog is a substance that can be produced from a reference substance, for example, by a chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be produced by performing a synthetic process that is substantially similar to (for example, sharing several steps) that produces the reference substance. In some embodiments, an analog is produced or can be produced by performing a synthetic process different from that used to produce the reference substance.

[0021] Antagonist: As understood by those skilled in the art, the term “antagonist” generally refers to a drug whose presence or level is associated with a reduced level or activity of a target compared to that observed in the absence of the drug (or at different levels of the drug). In some embodiments, the antagonist is one whose presence or level correlates with a target level or activity that is equivalent to or lower than a particular reference level or activity (e.g., observed under appropriate reference conditions, e.g., a known antagonist, e.g., in the presence of a positive control). In some embodiments, the antagonist may be a direct antagonist in that it directly affects the target (e.g., by direct interaction). In some embodiments, the antagonist may be an indirect antagonist in that it indirectly affects the target by acting on, for example, a modifier of the target or some other component or entity, e.g., by interacting with it.

[0022] Aryl: The term "aryl" refers to a ring with a total of 5 to 14 members (for example, C 5~14 This refers to monocyclic and bicyclic systems having ) where at least one ring in the system is aromatic, and each ring in the system has 3 to 7 ring members. In some embodiments, the "aryl" group has a total of 6 to 12 ring members (e.g., C 6~12 ) contains. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that may have one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracyl, etc. Unless otherwise specified, the "aryl" group is a hydrocarbon. In some embodiments, the "aryl" ring system is an aromatic ring (e.g., phenyl) condensed with a non-aromatic ring (e.g., cycloalkyl). Examples of condensed aryl rings include: [ka] These are some examples.

[0023] Related: As the term is used herein, two events or entities are “related” to each other if the presence, level, and / or form of one correlate with that of the other. For example, a particular entity (e.g., polypeptide, gene signature, metabolite, microorganism, etc.) is considered related to a particular disease, disorder, or condition if its presence, level, and / or form correlate with the incidence and / or susceptibility to that disease, disorder, or condition (e.g., in a relevant population). In some embodiments, two or more entities are physically “associated” with each other if they interact directly or indirectly so that they are physically close to each other and / or remain close to each other. In some embodiments, two or more entities that are physically associated with each other are covalently bonded to each other. In some embodiments, two or more entities that are physically associated with each other are not covalently bonded to each other but are non-covalently associated, for example, by hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

[0024] Biological specimen: As used herein, the term “biological specimen” usually refers to a specimen obtained from or derived from a biological source of interest described herein (e.g., tissue or organism or cell culture). In some embodiments, the source of interest includes organisms such as animals or humans. In some embodiments, the biological specimen is or contains biological tissue or biological fluid. In some embodiments, the biological specimen is or may contain bone marrow; blood; blood cells; ascites; tissue or microneedle biopsy specimens; body fluids containing cells; free suspended nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; lavage fluids or washing fluids such as tubal lavage fluid or bronchoalveolar lavage fluid; aspirates; scrapes; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells derived therefrom. In some embodiments, the biological sample is or includes cells obtained from an individual. In some embodiments, the cells obtained are or include cells derived from the individual from which the sample is obtained. In some embodiments, the sample is a “primary sample” obtained directly from a source of interest by any suitable means. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine-needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood, lymph, feces, etc.). In some embodiments, as will be apparent from the context, the term “sample” refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components of the primary sample and / or by adding one or more agents). For example, filtration using a semipermeable membrane. Such “processed sample” may include, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as mRNA amplification or reverse transcription, isolation and / or purification of specific components.

[0025] Biomarker: The term “biomarker” is used herein to mean an entity (or form thereof) whose presence or level correlates with a particular biological event or condition of interest, and as a result is considered to be a “marker” of that event or condition, in accordance with its usage in the art. To give only a few examples, in some embodiments a biomarker may or may include a marker of a particular pathological condition or a marker of the likelihood that a particular disease, disorder, or condition may develop, occur, or recur. In some embodiments a biomarker may or may include a marker of a particular disease or treatment outcome or the likelihood thereof. Accordingly, in some embodiments a biomarker predicts the relevant biological event or condition of interest, in some embodiments a biomarker predicts the prognosis of the relevant biological event or condition of interest, and in some embodiments a biomarker diagnoses the relevant biological event or condition of interest.

[0026] Carrier: As used herein, the term “carrier” refers to a diluent, auxiliary, excipient, or vehicle administered with a composition. In some exemplary embodiments, carriers may include sterile liquids, such as water, and oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, or sesame oil. In some embodiments, the carrier is or comprises one or more solid components.

[0027] Combination Therapy: As used herein, the term “combination therapy” refers to a situation in which a subject is simultaneously exposed to two or more treatment plans (e.g., two or more therapeutic agents or treatments). In some embodiments, two or more therapeutic plans may be administered simultaneously. In some embodiments, such therapeutic plans may be administered sequentially (e.g., all “doses” of the first therapeutic plan are administered before any dose of the second therapeutic plan). In some embodiments, such agents are administered in overlapping dosing plans. In some embodiments, “administration” of combination therapy may include the administration of one or more agents or treatments in combination with a subject receiving other agents or treatments. For clarity, combination therapy does not require that individual agents be administered together (or even simultaneously) in a single composition; however, in some embodiments, two or more agents or their active parts may be administered together as a combination of compositions, or even as a combination of compounds (e.g., as part of a single chemical complex or covalent bond).

[0028] Comparable: As used herein, the term “comparable” means two or more sets of drugs, entities, situations, conditions, etc., which do not necessarily have to be identical to each other, but are similar enough to allow comparison between them, such that a person skilled in the art would understand that a reasonable conclusion can be drawn based on observed differences or similarities. In some embodiments, a comparable set of conditions, situations, individuals, or groups features several substantially identical features and one or a few varying features. A person skilled in the art will understand the degree of identity required for two or more such sets of drugs, entities, situations, conditions, etc., to be considered comparable in any given context. For example, a person skilled in the art will understand that sets of situations, individuals, or groups are comparable if they feature a sufficient number and variety of substantially identical features to ensure a reasonable conclusion that differences in results or phenomena obtained under or using different sets of situations, individuals, or groups are caused by or indicate the existence of various differences in those features.

[0029] Composition: Those skilled in the art will understand that the term “composition” may be used to refer to a distinct physical entity comprising one or more specified components. Generally, unless otherwise specified, a composition may be in any form, such as a gas, gel, liquid, or solid.

[0030] Dosage Form or Unit Dosage Form: Those skilled in the art will understand that the term “dosage form” may be used to refer to a physically separated unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each unit contains a predetermined amount of the active agent. In some embodiments, such an amount is a unit dose (or its total proportion) suitable for administration according to a dosing plan (i.e., using a therapeutic dosing plan) determined to correlate with a desired or beneficial outcome when administered to a population in question. Those skilled in the art will understand that the total amount of a therapeutic composition or therapeutic agent to be administered to a particular subject may be determined by one or more attending physicians and may require administration in multiple dosage forms.

[0031] Dosage Plan or Treatment Plan: Those skilled in the art will understand that the terms “dosage plan” and “treatment plan” may be used to refer to a set of (typically two or more) unit doses administered individually to a subject, typically at intervals of a certain time. In some embodiments, a given therapeutic agent may have a recommended dosage plan that requires one or more doses. In some embodiments, the dosage plan comprises multiple doses, each of which is temporally separated from the other doses. In some embodiments, the individual doses are spaced at equal intervals from one another. In some embodiments, the dosage plan comprises multiple doses, with the individual doses separated by at least two different time periods. In some embodiments, all doses in the dosage plan are the same unit dose. In some embodiments, the different doses in the dosage plan are different amounts. In some embodiments, the dosage plan comprises an initial dose of a first dose, followed by one or more additional doses of a second dose different from the first dose. In some embodiments, the dosage plan comprises an initial dose of a first dose, followed by one or more additional doses of a second dose identical to the first dose. In some embodiments, the administration plan correlates with a desired or beneficial outcome when administered to the entire relevant population (i.e., a therapeutic administration plan).

[0032] Manipulated: Generally, the term “manipulated” refers to the aspect of being manipulated by human hands. For example, in some embodiments, a small molecule may be considered manipulated if its structure and / or production is designed and / or realized by human hands. Similarly, in some embodiments, a polynucleotide may be considered “manipulated” if two or more sequences, which are not linked to each other in order in nature, are manipulated by human hands so that they are directly linked to each other in the manipulated polynucleotide. For example, in some embodiments of the present invention, the manipulated polynucleotide includes a control sequence that is found to be operably bound to a first coding sequence but not to a second coding sequence in nature, and is linked by human hands so that the control sequence is operably bound to the second coding sequence. Similarly, a cell or organism is considered “engineered” if its genetic information is altered (for example, if novel genetic material that was not previously present is introduced, e.g., by transformation, crossing, somatic hybridization, transfusion, transduction, or other mechanism, or if previously present genetic material is altered or removed, e.g., by substitution or deletion mutation, or by a crossing procedure). As is customary and as understood by those skilled in the art, the expression products of an engineered polynucleotide, and / or the offspring of an engineered polynucleotide or cell, are usually still referred to as “engineered,” even if the actual manipulation was performed on a prior entity.

[0033] Excipients: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, white powder, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, and ethanol.

[0034] Heteroaliphatic: As used herein, the term “heteroaliphatic” or “heteroaliphatic group” means an optionally substituted hydrocarbon moiety, but non-aromatic, having 1 to 5 heteroatoms in addition to carbon atoms, and being linear (i.e., unbranched), branched, or cyclic (“heterocyclic”), and being fully saturated or containing one or more unsaturated units. The term “heteroatom” means nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. The term “nitrogen” includes substituted nitrogen. Unless otherwise specified, heteroaliphatic groups contain 1 to 10 carbon atoms, where 1 to 3 carbon atoms are optionally and independently replaced by heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1 to 4 carbon atoms, where 1 to 2 carbon atoms are optionally and independently replaced by heteroatoms selected from oxygen, nitrogen, and sulfur. In further embodiments, the heteroaliphatic group contains 1 to 3 carbon atoms, where 1 carbon atom is optionally and independently replaced by a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, exemplary heteroaliphatic groups of 1 to 10 atoms include the following: -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, -CH2-O-CH2-O-CH2-CH2-O-CH3, -CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-O-CH2-CH2-O-CH3, -CH2-O-CH2-CH2-O-CH2-CH2-O-CH3, -CH2-OC(CH3)3, -C(CH3)2-O-CH3, -C(CH 3)2-CH2-O-CH3, -CH2-CH2-O-CH2-CH3, -CH2-CH2-CH2-O-CH3, -NHC(CH3)3, -N(CH2CH3)2, -SC(CH3)3, etc.

[0035] Heteroaryl: The terms "heteroaryl" and "heteroar-", used alone or as part of a larger term, e.g., "heteroaralkyl" or "heteroaralkoxy," refer to monocyclic or bicyclic rings having 5 to 12 ring atoms (e.g., 5-6 membered monocyclic heteroaryls or 9-12 membered bicyclic heteroaryls), sharing 6, 10, or 14 π electrons in a cyclic configuration, and having 1 to 5 heteroatoms in addition to the carbon atom. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Examples of heteroaryl groups, though not limited to them, include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, indolidinyl, benzimidazolyl, prinyl, naphthilidinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrolopyridyl, pyrazolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl. As used herein, the terms “heteroaryl” and “heteroar-” include groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocyclyl rings, and whose radical or bond site lies on the aromatic heterocycle (i.e., bicyclic heteroaryl rings having 1 to 3 heteroatoms).Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranil, dibenzofuranil, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazine-3(4H)-one, benzoisoxazolyl, . [ka] These include: Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heterocyclic aromatic," any of which include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently and optionally substituted.

[0036] Heteroatoms: As used herein, the term “heteroatom” means nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen.

[0037] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocycle” are interchangeable and refer to stable 3- to 8-membered monocyclic heterocycle parts, stable 7- to 12-membered bicyclic heterocycle parts, or stable 10- to 16-membered polycyclic heterocycle parts, which are either saturated or partially unsaturated and have one or more, e.g., 1- to 4, of the above-defined heteroatoms in addition to the carbon atom. When used in relation to the ring atoms of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). + It is possible that the heterocyclic ring can be bonded to its pendant group with any heteroatom or carbon atom, which results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiamorpholinyl, and [ka] Examples include heterocyclyl groups, monocyclic, bicyclic, tricyclic, or polycyclic groups, preferably monocyclic, bicyclic, or tricyclic, more preferably monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, where the alkyl and heterocyclyl portions are independently and arbitrarily substituted. Examples of bicyclic heterocyclic groups include groups in which the heterocycle is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, [ka] Examples include: A bicyclic heterocycle can also be a spirocycle system (for example, a 7-11 member spirocyclic fused heterocycle having one or more heteroatoms as defined above (e.g., 1, 2, 3, or 4 heteroatoms) in addition to a carbon atom). A bicyclic heterocycle can also be a bridging ring system (for example, a 7-11 member bridging heterocycle having 1, 2, or 3 bridging atoms). Exemplary bridging ring systems include: [ka] Examples of polycyclic heterocyclic systems that are spirocyclic include: [ka] These are some examples.

[0038] Oral: As used herein, the terms “oral administration” and “administered orally” have their meanings as understood in the art and refer to the administration of a compound or composition by mouth.

[0039] Parenteral: As used herein, the terms “parenteral administration” and “administered parenterally” have their meanings as understood in the art and refer to, but are not limited to, methods of administration other than enteral and topical administration, which are usually by injection, 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.

[0040] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety containing at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moies, but not to include aromatic (e.g., aryl or heteroaryl) moies as defined herein.

[0041] Patient or Subject: As used herein, the terms “patient” or “subject” refer to any organism to which the provided composition is administered, or may be administered, for example, for experimental, diagnostic, preventive, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient or subject suffers from or is susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject has been administered, or is currently administered, a specific treatment for diagnosing and / or treating a disease, disorder, or condition.

[0042] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent exists in a unit dose suitable for administration in a treatment or dosing regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, pharmaceutical compositions may be specifically formulated for administration in solid or liquid form, which include those suitable for: oral administration, e.g., liquid drugs (aqueous solutions or non-aqueous solutions or suspensions), tablets, e.g., those targeting oral absorption, sublingual absorption, and systemic absorption, pills, powders, granules, and pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solutions or suspensions or sustained-release formulations; topical application, e.g., creams, ointments, or sustained-release patches, or sprays applied to the skin, lungs, or mouth; vaginal or rectal use, e.g., pessaries, creams, or foams; sublingual use; ocular use; transdermal use; or transnasal, transpulmonary, and other mucosal applications.

[0043] Pharmacologically acceptable: As used herein, the term "pharmaceutically acceptable" means a compound, substance, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic response, or other problems or complications, and that is commensurate with a reasonable benefit-to-risk ratio.

[0044] Pharmacopoeia-acceptable carrier: As used herein, the term “pharmacopoeia-acceptable carrier” means a pharmacopoeia-acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulant, that is involved in moving or transporting the compound of the 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 is not harmful to the patient. Some examples of substances that can function as pharmaceutically acceptable carriers include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol; pH buffers; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic, compatible substances used in pharmaceutical formulations.

[0045] pharmaceutically acceptable salts: As used herein, the term “pharmaceutically acceptable salt” means a salt of such compound that is suitable for use in the context of a pharmaceutical, i.e., a salt that is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic response, etc., within the bounds of sound medical judgment, and that is commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of an amino group formed by inorganic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or by organic acids, e.g., acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods known in the art, such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydro Examples include xyethanesulfonate, lactobionate, lactate, laurylate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Typical alkali metal salts or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, and magnesium salt.In some embodiments, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0046] Polycyclic: As used herein, the term “polycyclic” refers to a saturated or unsaturated cyclic system having 7 to 20 atoms and two or more rings (e.g., heterocyclyl, heteroaryl, cycloalkyl, or aryl rings), in which one or more carbon atoms are shared by two adjacent rings. For example, in some embodiments, a polycyclic cyclic system refers to a saturated or unsaturated cyclic system having 14 to 20 atoms and three or more rings (e.g., heterocyclyl, heteroaryl, cycloalkyl, or aryl rings), in which one or more carbon atoms are shared by two adjacent rings. The rings in a polycyclic cyclic system may be fused (i.e., bicyclic or tricyclic), spirocyclic, or a combination thereof. An example of a polycyclic system is adamantyl, [ka] These are some examples.

[0047] To prevent or prevent: As used herein, the term “to prevent” or “prevent” when used in relation to the onset of a disease, disorder, and / or condition means to reduce the risk of developing such disease, disorder, and / or condition, and / or to delay the onset of one or more characteristics or symptoms of such disease, disorder, or condition. Prevention may be considered complete if the onset of the disease, disorder, or condition is delayed for a given period of time.

[0048] Reference: As used herein, this refers to a standard substance or control on which a comparison is being made. For example, in some embodiments, a drug, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control drug, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or measured substantially simultaneously with the test or measurement of interest. In some embodiments, the reference or control is optionally a historical reference or control recorded in a tangible medium of expression. As will be understood by those skilled in the art, the reference or control is usually measured or characterized under conditions or circumstances equivalent to those being evaluated. Those skilled in the art will understand the reliance on specific available references or controls, and / or the existence of sufficient similarity to justify comparison with them.

[0049] Sample: As used herein, the term “sample” typically refers to an aliquot of a substance obtained from or derived from a source of interest. In some embodiments, the source of interest is a biological or environmental source. In some embodiments, the source of interest may be or include cells, tissues, or organisms, such as microorganisms, plants, or animals (e.g., humans). In some embodiments, the source of interest may be or include living tissues or biological fluids. In some embodiments, the source of interest may be or include preparations produced in a production process. In some embodiments, the sample is a “primary sample” obtained directly from the source of interest by any suitable means. In some embodiments, as will be apparent from the context, the term “sample” refers to a preparation obtained by processing a primary sample (e.g., by removing one or more components of the primary sample and / or by adding one or more agents).

[0050] Specific: As used herein in reference to active drugs, the term “specific” will be understood by those skilled in the art to mean distinguishing the entity or state to which the drug is a candidate target. For example, in some embodiments, a drug is said to bind “specifically” to a target if it preferentially binds to that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction depends on the presence of specific structural features of the target entity (e.g., epitopes, clefts, binding sites). It should be understood that specificity does not need to be absolute. In some embodiments, specificity may be evaluated in comparison to the specificity of the binding agent to one or more other candidate target entities (e.g., competing factors). In some embodiments, specificity is evaluated in comparison to the specificity of a specific reference binding agent. In some embodiments, specificity is evaluated in comparison to the specificity of a nonspecific reference binding agent. In some embodiments, a drug or entity does not detectably bind to a competing alternative target under conditions in which it binds to its target entity. In some embodiments, the binding agent binds to its target entity with a higher on-rate, lower off-rate, increased affinity, decreased dissociability, and / or increased stability compared to competing alternative targets(s).

[0051] Substituted or optionally substituted: As described herein, the compounds of the present invention may contain an "optionally substituted" moiety. Generally, whether followed by the term "optionally," the term "substituted" means that one or more hydrogens of a given moiety are replaced with a preferred substituent. "Substituted" applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., [ka] at least [ka] It refers to, [ka] at least [ka] (This refers to) the group. Unless otherwise specified, an "optionally substituted" group may have suitable substituents at each of its substituted positions, and if two or more positions in any given structure can be substituted with two or more substituents selected from the specified group, the substituents may be identical or different at all positions. The substituent combinations envisioned by the present invention preferably result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, means a compound that remains substantially unchanged when subjected to conditions that enable its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes provided herein. A group described as "substituted" preferably has 1 to 4 substituents, more preferably 1 or 2 substituents. A group described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0052] A suitable monovalent substituent on the replaceable carbon atom of the "optionally substituted" group is, independently, a halogen;-(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 R°, -O(CH2) 0~4C (O)OR°;-(CH2) 0~4 CH(OR°)2;-(CH2) 0~4 SR°;R° may be substituted -(CH2) 0~4 It may be substituted with Ph;R°-(CH2) 0~4 O(CH2) 0~1 It may be substituted with Ph;R° - CH=CHPh;R° - (CH2) 0~4 O(CH2) 0~1 -Pyridyl;-NO2;-CN;-N3;-(CH2) 0~4 N(R°)2;-(CH2) 0~4N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0~4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0~4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0~4 C(O)R°;-C(S)R°;-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 C(O)SR°;-(CH2) 0~4 C(O)OSiR°3;-(CH2) 0~4 OC(O)R°;-OC(O)(CH2) 0~4 SR°;-(CH2) 0~4 SC(O)R°;-(CH2) 0~4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0~4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0~4 SSR°;-(CH2) 0~4 S(O)2R°;-(CH2) 0~4 S(O)2OR°;-(CH2) 0~4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0~4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1~4 (Linear or branched alkylene) ON(R°)2; or -(C 1~4 The linear or branched alkylene is C(O)ON(R°)2, where each R° may be substituted as defined below, independently of hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, -CH2- (a 5-6 member heteroaryl ring), or a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R°, together with the atom(s) between them, form a 3-12 member saturated monocyclic or bicyclic ring, a partially unsaturated monocyclic or bicyclic ring, or a monocyclic or bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0053] Suitable monovalent substituents on R° (or rings formed with atoms between them by the occurrence of two independent appearances of R°) are, independently, halogens, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2, -O(HaroR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● ,-(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● ,-(CH2) 0~2 SR ● ,-(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● ,-(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● ,-(C 1~4 (Linear or branched alkylene) C(O)OR ● , or -SSR ● And in the formula, each R ●It is either unsubstituted, or if "halo" precedes it, it is substituted with only one or more halogens, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 The ring is independently selected from a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0054] Suitable divalent substituents on the saturated carbon atoms of the "arbitrarily substituted" groups include: =O ("oxo"), =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2~3 O-, or -S(C (R * 2)) 2~3 S- is listed, and each R that appears independently in the formula * C may be substituted with hydrogen as defined below. 1~6 Selected from an aliphatic, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A preferred divalent substituent bonded to a substituted carbon adjacent to the "optionally substituted" group is -O(CR * 2) 2~3O - are listed, and each R that appears independently in the formula * C may be substituted with hydrogen as defined below. 1~6 The rings are selected from aliphatic or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0055] R * Suitable substituents on the aliphatic group include halogens and -R ● ,-(HaroR ●), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, and in the formula, each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur.

[0056] A suitable substituent on the substituted nitrogen of the "arbitrarily substituted" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † These are listed, and in the formula, each R † C may be substituted independently with hydrogen as defined below. 1~6 An aliphatic, unsubstituted -OPh, or unsubstituted 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definition, R † The two independent occurrences of , along with the atom(s) interposed between them, form an unsubstituted 3- to 12-membered saturated monocyclic or bicyclic ring, a partially unsaturated monocyclic or bicyclic ring, or a monocyclic or bicyclic aryl ring, having 0- to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0057] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0058] Low molecular weight: As used herein, the term “low molecular weight” means organic and / or inorganic compounds with a low molecular weight. Generally, “low molecular weight” refers to molecules with a size of less than about 5 kilodaltons (kD). In some embodiments, low molecular weight is less than about 4 kD, less than 3 kD, less than about 2 kD, or less than about 1 kD. In some embodiments, low molecular weight is less than about 800 daltons (D), less than about 600 D, less than about 500 D, less than about 400 D, less than about 300 D, less than about 200 D, or less than about 100 D. In some embodiments, low molecular weight is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, low molecular weight is not a polymer.

[0059] In some embodiments, the low molecular weight does not contain a polymer portion. In some embodiments, the low molecular weight is not a protein or polypeptide and / or does not contain a protein or polypeptide (e.g., not an oligopeptide or peptide). In some embodiments, the low molecular weight is not a polynucleotide and / or does not contain a polynucleotide (e.g., not an oligonucleotide). In some embodiments, the low molecular weight is not a polysaccharide and / or does not contain a polysaccharide. For example, in some embodiments, the low molecular weight is not a glycoprotein, proteoglycan, glycolipid, etc. In some embodiments, the low molecular weight is not a lipid.

[0060] In some embodiments, the small molecule is a regulator (e.g., an inhibitor or activator). In some embodiments, the small molecule is biologically active. In some embodiments, the small molecule is detectable (e.g., containing at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent.

[0061] Those skilled in the art who read this disclosure will understand that certain low molecular weight compounds described herein may be provided and / or available in any of the following forms, for example: crystalline form (e.g., polymorphs, solvates, etc.), salt form, protected form, prodrug form, ester form, isomer form (e.g., optical isomers and / or structural isomers), isotopic form, etc.

[0062] Those skilled in the art will understand that certain low molecular weight compounds have a structure that allows them to exist in one or more stereoisomeric forms. In some embodiments, such low molecular weight compounds may be available in accordance with this disclosure in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers. In some embodiments, such low molecular weight compounds may be available in accordance with this disclosure in the form of a racemic mixture.

[0063] Those skilled in the art will understand that certain small molecules have a structure that allows them to exist in one or more tautomerized forms. In some embodiments, such small molecules may be utilized in accordance with this disclosure in the form of individual tautomers or in a form that interconverts between tautomerized forms.

[0064] Those skilled in the art will know that certain low molecular weight compounds can undergo isotopic substitution (for example, with respect to H). 2 H or 3 Regarding H;12C 11 C, 13 C, or 14 Regarding C;14N 13 N or 15 Regarding N;16O 17 O or 18 Regarding O;XXC 36 About Cl;XXF 18 It will be understood that they have a structure that enables F;XXXI (e.g., 131I). In some embodiments, such low molecules may be utilized in accordance with this disclosure in one or more isotopically modified forms or in mixtures thereof.

[0065] In some embodiments, reference to a particular low molecular weight compound may relate to a particular form of that compound. In some embodiments, a particular low molecular weight compound may be provided and / or available in salt form (e.g., an acid-added salt or a base-added salt form, depending on the compound). In some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0066] In some embodiments, if a low molecular weight compound is naturally occurring or found in nature, the compound may be provided and / or utilized in accordance with this disclosure in a form different from the form in which it is naturally occurring or found in nature. Those skilled in the art will understand that in some embodiments, a preparation of a particular low molecular weight compound containing an absolute or relative amount of the compound or a particular form of the compound that is different from the absolute or relative amount (for example, relative to another component of the preparation that contains another form of the compound) of the compound or a particular form of the compound that is present in a reference preparation of interest (e.g., a primary sample from a source of interest such as a biological or environmental source), the preparation will be different from the compound if it were present in the reference preparation or source. Accordingly, in some embodiments, for example, a preparation of a low molecular weight compound of a single stereoisomer may be considered a different form of compound from a racemic mixture of the compound; a particular salt of a low molecular weight compound may be considered a different form from another salt of the compound; a preparation containing only one form of the compound containing one conformational isomer of a double bond ((Z) or (E)) may be considered a different form of compound from one containing the other conformational isomer of the double bond ((E) or (Z)); and a preparation in which one or more atoms are different isotopes compared to those present in the reference preparation may be considered a different form.

[0067] When used in this specification, in a low molecular structure, [ka] Those skilled in the art will understand that the bond represented by this expression refers to a bond that is a single bond (e.g., a saturated bond) in some embodiments and a double bond (e.g., an unsaturated bond) in some embodiments. For example, the following structure: [ka] teeth, [ka] It is intended to encompass both.

[0068] Furthermore, those skilled in the art will understand that, when used herein, the symbols in low molecular structures are... [ka] However, you will understand that it refers to the bond point between two atoms.

[0069] Therapeutic Agent: As used herein, the term “therapeutic agent” generally refers to any agent that, when administered to an organism, induces a desired pharmacological effect. In some embodiments, an agent is considered a therapeutic agent if it exhibits a statistically significant effect in a suitable population. In some embodiments, a suitable population may be a population of model organisms. In some embodiments, a suitable population may be defined by various criteria, such as a particular age group, sex, genetic background, or pre-existing clinical symptoms. In some embodiments, a therapeutic agent is a substance that can be used to reduce, improve, alleviate, inhibit, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, a “therapeutic agent” is an agent that has required or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent that requires a prescription for administration to humans.

[0070] To treat: As used herein, the terms “to treat,” “treatment,” or “to cure” refer to any method used to partially or completely reduce, improve, alleviate, inhibit, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be applied to subjects that do not show signs of a disease, disorder, and / or condition. In some embodiments, treatment may be applied to subjects that show only the initial signs of a disease, disorder, and / or condition, for example, to reduce the risk of developing a pathology associated with the disease, disorder, and / or condition. [Modes for carrying out the invention]

[0071] TRPML1 and autophagy Autophagy is a cellular mechanism that breaks down substances and organelles within the cytoplasm. Several types of autophagy exist: (1) macroautophagy (commonly referred to as autophagy); (2) microautophagy; and (3) chaperone-mediated autophagy. See Eskelinen & Saftig, Biochimica et Biophysica Acta - Mol. Cell Res., 1793(4):664-673 (2009). In macroautophagy, autophagosomes engulf cytoplasmic waste products and fuse with lysosomes, which are the sites to which substances are transported for degradation. Lysosomes are intracellular organelles containing more than 50 soluble acid hydrolases useful for digesting cellular components. The fusion of lysosomes with autophagosomes is partially mediated by Ca2+ ion channels in the lysosomal membrane. 2+ It is activated by the release of ions containing [the specified element]. See Cao, et al., J. Bio. Chem., 292(20) 8424-8435 (2017).

[0072] Transient receptor potential mucolipin-1 (also known as TRPML1 or ML1) regulates autophagy in lysosomal Ca 2+ It is a channel. See Wang, et al., PNAS, E1373-E1381 (March 2, 2015). In particular, TRPML1 is an inward rectifying current channel that transports cations from the lysosome lumen to the cytosol. See Di Paolda, et al., Cell Calcium 69:112-121 (2018). Ca from lysosomes by TRPML1 2+ The release of regulated EB activity through local calcineurin activation, which ultimately induces autophagy and lysosome biosynthesis. See Medina, et al., Nat. Cell. Biol., 17(3):288-299 (2015).

[0073] In recent years, upregulation of autophagy has been found to be beneficial in patients with numerous diseases or disorders. For example, it has been reported that inducing autophagy promotes the removal of hepatotoxic α-1-antitrypsin (ATZ) in the liver. Pastore, et al. See al., EMBO Mol. Med. 5(3):397-412 (Mar. 2013). Furthermore, in recent years, autophagy has been found to be useful in the treatment of neurodegenerative disorders, cancer, and cardiovascular diseases. See Pierzynowska, et al., Metab. Brain Dis., 33(4);989-1008 (2018) (discussing neurodegenerative disorders); Nelson & Shacka, Curr. Pathobiol. Rep., 1(4):239-245 (2013) (discussing cancer); Sciaretta, et al., Annual Review of Physiology, 80:1-26 (2018) (discussing cardiovascular diseases); Maiuri & Kroemer, Cell Death & Differentiation, 26:680-689 (2019) (discussing the therapeutic applications of autophagy in general). Therefore, it is desirable to identify methods and mechanisms that promote autophagy. Considering the role of TRPML1 in autophagy, TRPML1 modulators useful for promoting autophagy and / or treating specific diseases, disorders, or conditions are described herein.

[0074] This disclosure provides insight that TRMPL1 may be a particularly desirable target that could enable the modulation (e.g., enhancement) of autophagy, in particular, in specific contexts.

[0075] TRPML1 modulator structure In some embodiments, the present disclosure relates to the following formula I: ZL 1 -Cy-AL 2 -V I A low molecular weight compound having the chemical structure shown in the formula or a pharmaceutically acceptable salt thereof, wherein the formula is: A is C 6~12 A is a 5-6 member heteroaryl containing 1-4 heteroatoms selected from aryl, N, O, and S, where A is 0, 1, 2, 3, or 4 R a It has been replaced with, Cy is a 4-12 member monocyclic or polycyclic heterocycline containing none or 1-4 heteroatoms selected from N, O, P, and S, or a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, P, and S, C 1~6 aliphatic, C 3~12 Cycloalkyl, or -C 0~6 The divalent moiety is selected from alkylenyl-C(O)-NH-, and Cy is one or more R 1 It is arbitrarily replaced with L 1 is non-existent, -NR 3 -, -O-, -S-, -C(O)-NR 3 -, -NR 3 -C(O)-, -C(O)-C(O)-, or C 1~6 Alkirenyl, C 2~6 Alkynylenyl, -NR 3 -C 1~6 Alkirenyl, -OC 1~6 Alkirenyl, -C(O)-C 0~6 Alkyrenyl, -C 0~6 Alkyrenyl-C(O)-, and -C 0~6 An optionally substituted group selected from alkylenyl-OC(O)-, L 2 is, -(NR 3 ) s -S(O)-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)2-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)(NR 3 )-, -S(O)2-NR 3 -, -NR 3 -C 1~6 Alkirenyl, -NR3 -C 1~6 Haloalkylenyl, -(NR 3 ) s -P(O)(R 3 )-, -C 1~6 Alkyrenyl-S(O)-, -C 1~6 Alkyrenyl-S(O)2-,-C(O)-(NR 3 ) s -,-(NR 3 ) s An optionally substituted 4- to 12-membered monocyclic or bicyclic heterocycline containing -C(O)- or 1 to 4 heteroatoms selected from N, O, and S, V is C 1~6 aliphatic, C 6~12 4-12 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from aryl, N, O, and S; 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S; 5-12 member monocyclic or bicyclic aryls; and C 3~12 Selected from monocyclic or polycyclic cycloalkyl, where V is (R 6 ) m It has been replaced with, Z is C 1~6 Aliphatic, 2-10 member heteroaliphatic, P(O)(R 3 )2, -C(O)C 1~6 Aliphatic, -C(O)N(R 3 )2, C 6~12 Ariel, C 3~12 A monocyclic or polycyclic cycloalkyl, a 4-16 member monocyclic or polycyclic heterocyclil containing 1-4 heteroatoms selected from N, O, and S, or a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S, where Z is (R 2 ) q It has been replaced with, Each R a These are independently hydrogen, halo, oxo, CN, or optionally substituted C 1~6 Aliphatic or OC 1~6 It is aliphatic, Each R 1 Halo, N(R3 )2, OH, CN, C(O)NHR 3 , and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 Independently selected from any optionally substituted groups selected from alkyl groups, Each R 2 These are halo, oxo, CN, OH, C(O)OH, C(O)OR 2a , C 6~12 Aryl, and C 1~6 Aliphatic, C(O)C 1~6 Aliphatic and OC 1~6 Independently selected from any substituted groups chosen from aliphatic groups, R 2a C is a 4- to 12-membered monocyclic or bicyclic heterocycline containing hydrogen or 1 to 4 heteroatoms selected from N, O, and S. 1~6 aliphatic, C 3~12 An optionally substituted group selected from cycloalkyl groups, Each R 3 This is H and optionally substituted C 1~6 Selected independently from aliphatic species, Each R 5 C 1~6 Alkyl, -N(R 3 )2, -OC 1~6 Alkyl, C(O)-C 1~6 Alkyl, P(O)(C 1~6 Alkyl)2, C 3~12 A cycloalkyl group is independently selected from 5-12 membered heterocyclines containing 1-4 heteroatoms selected from N, O, and S, and R 5 It is optionally substituted with one or more substituents selected from halo, OH, and 2-12 membered heteroaliphatic groups. Each R 6 This includes Halo, Oxo, SF5, and S(O)-R. 5 S(O)2-R 5 S(O)(NH)-R 5 S(O)2(NH)-R 5 -CN, -C(O)-R 5 , -C 0~6 Alkyrenyl-C(O)OR 5-C(O)-NH(R 5 ), -C(O)-N(R 5 )2, -P(O)(R 5 )2, -OR 5 , or OC 1~6 Alkyl, SC 1~6 Alkyl, C 1~6 Alkyl, C 6~12 Aryl, 2-12 member heteroaliphatic, C 3~12 Cycloalkyl, -OC 0~6 Alkirenyl-C 3~12 The group is an optionally substituted group selected from cycloalkyl groups and 4-7 membered monocyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S. m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, or 4. Provides and / or utilizes a TRMPL1 modulator, which is the low molecular weight compound or a pharmaceutically acceptable salt thereof, where s is 0 or 1.

[0076] In some embodiments, the present disclosure relates to formula I': [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is A' is R a A 5-10 member monocyclic or bicyclic heterocyclil containing 1-4 heteroatoms selected from phenyl, N, O, P, and S, which are optionally substituted, or a 5-10 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S, Cy is nonexistent, or C 1~6 A 4-14 member monocyclic or polycyclic heterocyclil containing 1-4 heteroatoms selected from aliphatic, N, O, P, and S; a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S; C 6~12 Aryl, and C 3~12 The divalent moiety is selected from cycloalkyl groups, where Cy is one or more R groups. 1It is arbitrarily replaced with, L 1 is non-existent, -S-, -C(O)-NR 3 -, -NR 3 -C(O)-, or C 1~6 Alkirenyl, C 2~6 alkenylenyl, C 2~6 Alkynylenyl, -NR 3 -C 0~6 Alkirenyl, -OC 0~6 Alkyrenyl, -C(O)-C 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-C(O)-,-C(O)OC 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-OC(O)-,-C 3~6 Cycloalkyl and -NR 3 -C(O)-C 0~6 The divalent moiety is an arbitrarily substituted moiety selected from alkylenyl-O-, L 2 is, -(NR 3 ) s -S(O)-(NR 3 )-,-(NR 3 ) s -S(O)2-NR 3 -,-(NR 3 ) s -P(O)(R 3 )-,-C(O)-(NR 3 ) s -, -NR 3 -C(O)-, or -(NR 3 ) s -S(O)-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)2-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)-NR 3 -C 0~6 Alkyrenyl, -(NR 3 ) s -S(O)2-NR 3 -C 0~6 Alkyrenyl, -(NR 3 )s -S(O)2-C 3~6 Cycloalkyl, -NR 3 -C 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-S(O)-(NR 3 ) s -, -C 1~6 Alkyrenyl-S(O)2-(NR 3 ) s - An optionally substituted divalent moiety selected from 2-6 member heteroaliphatic groups, and 4-12 member monocyclic or bicyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, V is C 1~6 aliphatic, C 6~12 Ariel, C 3~12 Selected from cycloaliphatic, 4-12 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where V is (R 6 ) m It has been replaced with, Z is P(O)(R 3 )2, C(O)N(R 3 )2, C 1~6 aliphatic, C 6~12 Ariel, C 3~12 Selected from cycloaliphatic, 2-10 atom heteroaliphatic, 4-16 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where Z is (R 2 ) q It has been replaced with, Each R a These are independently H, halo, -CN, oxo, or C 1~6 aliphatic, C 3~6 Cycloliphatic and OC 1~6 An arbitrarily substituted group selected from aliphatic groups, Each R 1 is halo, oxo, -N(R 3)2, -OH, -CN, -C(O)N(R 3 )2, and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 Independently selected from any substituted groups chosen from aliphatic groups, Each R 2 These are halo, oxo, -CN, -OH, OR 2a , -C(O)-R 2a , -C(O)OR 2a , and C 1~6 aliphatic, C 6~12 Independently selected from aryl and optionally substituted groups selected from 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, Each R 2a These are, independently, H, or C 1~6 aliphatic, C 3~12 A cycloaliphatic group, and an optionally substituted group selected from 4- to 12-membered monocyclic or bicyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, Each R 3 This is H and optionally substituted C 1~6 Selected independently from aliphatic species, Each R 5 is -N(R 3 )2, or C 1~6 Aliphatic, P(O)(C 1~6 aliphatic)2, C 3~12 A cycloaliphatic group, and an optionally substituted group selected from 5- to 12-membered monocyclic or polycyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, Each R 6 This is Halo, Oxo, -SF5, -S(O)-R 5 S(O)2-R 5 -S(O)(NH)-R 5 -S(O)2-(NH)-R 5 , -S(O)-N(R 5 )2, -S(O)2-N(R 5 )2, -CN, -C(O)-NH(R 5 ), -C(O)-N(R5 )2, -P(O)(R 5 )2, -OR 5 , or C 1~6 aliphatic, SC 1~6 Aliphatic, 2-12 member heteroaliphatic, -C 0~6 Alkyrenyl-C(O)-R 5 , -C 0~6 Alkyrenyl-C(O)OR 5 , C 6~12 Ariel, C 3~12 Independently selected from cycloaliphatic groups and optionally substituted groups selected from 4-7 membered monocyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, 4, 5, or 6. Each s is independently 0 or 1, providing the compound or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the present disclosure relates to the following formula II: [ka] A low molecular weight compound having the chemical structure shown in the formula or a pharmaceutically acceptable salt thereof, wherein the formula is: X 1’ , X 2’ , X 3’ , and X 4’ These are N, C, and CR, respectively. a Selected independently from X 1’ , X 2’ , X 3’ , or X 4’ Cy-L 1 -Z or L 2 -When bound to V, it is C and Cy-L 1 -Z or L 2 -If not bound to V, use N or CR a And, A1 is an optionally substituted condensed heterocyclyl ring containing none, one or two heteroatoms selected from N, O, and S, or an optionally substituted condensed heteroaryl group containing one or two heteroatoms selected from N, O, and S. Cy is a 4-12 member monocyclic or polycyclic heterocycline containing 1-4 heteroatoms selected from non-existent, N, O, and S; a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S; C 1~6 Aliphatic, or C 3~12 It is a cycloalkyl group, where Cy has one or more R groups. 1 It is arbitrarily replaced with L 1 is non-existent, -NR 3 -, -O-, -S-, C 1~6 Alkirenyl, C 2~6 Alkynylenyl, -NR 3 -C 1~6 Alkirenyl, -OC 1~6 Alkyrenyl, -C(O)C 0~6 Alkyrenyl, -C(O)NR 3 -, or -C(O)-C(O)-, L 2 is, -(NR 3 ) s -S(O)-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)2-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)(NR 3 )-,-S(O)2-NR 3 -, -NR 3 -C 1~6 Haloalkylenyl, -(NR 3 ) s -P(O)(R 3 )-, -C 1~6 Alkyrenyl-S(O)-, -C 1~6 Alkyrenyl-S(O)2-,-C(O)-(NR 3 ) s -,-(NR 3 ) sAn optionally substituted 4- to 12-membered monocyclic or bicyclic heterocycline containing -C(O)- or 1 to 4 heteroatoms selected from N, O, and S, V is C 1~6 aliphatic, C 6~12 4-12 member monocyclic or bicyclic heterocyclyls containing 1-4 heteroatoms selected from aryl, N, O, and S; 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S; 5-12 member monocyclic or bicyclic aryls; and C 3~12 Selected from cycloalkyl, V is (R 6 ) m It has been replaced with, Z is C 1~6 Aliphatic, 2-10 member heteroaliphatic, P(O)(R 3 )2, -C(O)C 1~6 Aliphatic, C(O)N(R 3 )2, C 6~12 Ariel, C 3~12 A 4- to 16-membered monocyclic or polycyclic heterocyclil containing 1 to 4 heteroatoms selected from cycloalkyl, N, O, and S, or a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, where Z is (R 2 ) q It has been replaced with, Each R a This is independently a hydrogen, halo, oxo, or optionally substituted C 1~6 It is aliphatic, Each R 1 N(R) 3 )2, OH, CN, C(O)NHR 3 , and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 Independently selected from any optionally substituted groups selected from alkyl groups, Each R 2 These are halo, -CN, C(O)OH, and C 1~6 Alkyl, C(O)C 1~6 Aliphatic and OC 1~6Independently selected from any substituted groups chosen from aliphatic groups, Each R 3 This is H and optionally substituted C 1~6 Selected independently from aliphatic species, Each R 5 C 1~6 Alkyl, -N(R 3 )2, -OC 1~6 Alkyl, C(O)-C 1~6 Alkyl, P(O)(C 1~6 Alkyl)2, C 3~12 A cycloalkyl group is independently selected from 5-12 membered heterocyclines containing 1-4 heteroatoms selected from N, O, and S, and R 5 It is optionally substituted with one or more substituents selected from halo and OH. Each R 6 Hello, S(O)-R 5 S(O)2-R 5 S(O)(NH)-R 5 -CN, -C(O)-R 5 , -C(O)OR 5 -C(O)-NH(R 5 ), -C(O)-N(R 5 )2, -P(O)(R 5 )2, or OC 1~6 Alkyl, C 1~6 Alkyl, C 6~12 An arbitrarily substituted group selected from aryl groups, m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, or 4. Each s independently provides and / or utilizes a TRMPL1 modulator which is the small molecule compound or a pharmaceutically acceptable salt thereof, and is either 0 or 1.

[0078] In some embodiments, the present disclosure relates to formula II': [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is X 1’ , X2’ , X 3’ , and X 4’ These are N, C, and CR, respectively. a Selected independently from X 1’ , X 2’ , X 3’ , and X 4’ Cy-L 1 -Z or L 2 -When bound to V, it is C and Cy-L 1 -Z or L 2 -If not bound to V, use N or CR a And, Y 1’ and Y 2’ These are C, N, and CR, respectively. a Selected from or Y 1’ Or Y 2’ If one of them does not exist, Y 1’ Or Y 2’ The other is C, N, and CR a Selected from, Cy is nonexistent, or C 1~6 4- to 12-membered monocyclic or polycyclic heterocyclils containing 1 to 4 heteroatoms selected from aliphatic, N, O, P, and S; 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S; and C 3~12 The divalent moiety is selected from cycloalkyl groups, where Cy is one or more R groups. 1 It is arbitrarily replaced with, L 1 is non-existent, -S-, -C(O)-NR 3 -, -NR 3 -C(O)-, or C 1~6 Alkirenyl, C 2~6 Alkynylenyl, -NR 3 -C 0~6 Alkirenyl, -OC 0~6 Alkyrenyl, -C(O)-C 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-C(O)-,-C(O)OC 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-OC(O)-,-C3~6 Cycloalkyl, and -NR 3 -C(O)-C 0~6 An optionally substituted divalent group selected from alkyleneyl -O-, L 2 is -(NR 3 ) s -S(O)-(NR 3 )-, -(NR 3 ) s -S(O)2-NR 3 -,-(NR 3 ) s -P(O)(R 3 )-,-C(O)-(NR 3 ) s -,-NR 3 -C(O)-, or -(NR 3 ) s -S(O)-C 0~6 alkyleneyl -,-(NR 3 ) s -S(O)2-C 0~6 alkyleneyl -,-(NR 3 ) s -S(O)-NR 3 -C 0~6 alkyleneyl,-(NR 3 ) s -S(O)2-NR 3 -C 0~6 alkyleneyl,-(NR 3 ) s -S(O)2-C 3~6 cycloalkyl,-NR 3 -C<​​​​​​​​​​​​​​​​​​​​Selected from cycloaliphatic, 4-12 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where V is (R 6 ) m It has been replaced with, Z is P(O)(R 3 )2, C(O)N(R 3 )2, C 1~6 aliphatic, C 6~12 Ariel, C 3~12 Selected from cycloaliphatic, 2-10 atom heteroaliphatic, 4-16 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where Z is (R 2 ) q It has been replaced with, Each R a These are independently H, halo, -CN, oxo, or C 1~6 Aliphatic and OC 1~6 Either an arbitrarily substituted group selected from aliphatic groups, or two R groups. a When present on adjacent atoms, they together form an optionally substituted condensed heterocyclyl ring containing one or two heteroatoms selected from N, O, and S, or an optionally substituted condensed heteroaryl group containing one or two heteroatoms selected from N, O, and S, and each R 1 is, halo, -N(R 3 )2, -OH, -CN, -C(O)N(R 3 )2, and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 Independently selected from any substituted groups chosen from aliphatic groups, Each R 2 These are halo, oxo, -CN, -OH, OR 2a , -C(O)-R 2a , -C(O)OR 2a , and C 1~6 aliphatic, C6~12 Independently selected from aryl and optionally substituted groups selected from 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, Each R 2a These are, independently, H, or C 1~6 aliphatic, C 3~12 A cycloaliphatic group, and an optionally substituted group selected from 4- to 12-membered monocyclic or bicyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, Each R 3 This is H and optionally substituted C 1~6 Selected independently from aliphatic species, Each R 5 is -N(R 3 )2, or C 1~6 Aliphatic, P(O)(C 1~6 aliphatic)2, C 3~12 A cycloaliphatic group, and an optionally substituted group selected from 5- to 12-membered monocyclic or polycyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, Each R 6 This is Halo, Oxo, -SF5, -S(O)-R 5 S(O)2-R 5 -S(O)(NH)-R 5 -S(O)2-(NH)-R 5 , -S(O)-N(R 5 )2, -S(O)2-N(R 5 )2, -CN, -C(O)-NH(R 5 ), -C(O)-N(R 5 )2, -P(O)(R 5 )2, -OR 5 , or C 1~6 aliphatic, SC 1~6 Aliphatic, 2-12 member heteroaliphatic, -C 0~6 Alkyrenyl-C(O)-R 5 , -C 0~6 Alkyrenyl-C(O)OR 5 , C 6~12 Ariel, C 3~12Independently selected from cycloaliphatic groups and optionally substituted groups selected from 4-7 membered monocyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, 4, 5, or 6. Each s is independently 0 or 1, providing the compound or a pharmaceutically acceptable salt thereof.

[0079] Compounds of formulas I, I', II, and / or II' are described in relation to exemplary embodiments of this specification.

[0080] As generally defined above for compounds of formula I', A' is R a A 5-10 member monocyclic or bicyclic heterocyclil containing 1-4 heteroatoms selected from phenyl, N, O, P, and S, which are optionally substituted, or a 5-10 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S.

[0081] In some embodiments, A' is phenyl.

[0082] In some embodiments, A' is a nine-membered bicyclic heteroaryl compound containing one to four heteroatoms selected from N, O, and S. In some embodiments, A' is indazolyl.

[0083] In some embodiments, A' is a 5-6 member monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S. In some embodiments, A' is pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, or isoxazolyl.

[0084] In some embodiments, A’ is a 9- or 10-membered bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A’ is isoindolinyl, tetrahydroquinoxalinyl, tetrahydropyrazolopyridinyltetrahydroquinoxalinyl, or dihydrobenzimidazolonyl.

[0085] In some embodiments, A’ is selected from Table A’ below. Table A’

Chemical Structure

[0086] In some embodiments, A’ is

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0087] As generally defined above for the compounds of Formula II and / or II’, X 1’ , X 2’ , X 3’ , and X 4’ are each independently selected from N, C, and CR a , where X 1’ , X 2’ , X 3’ , or X 4’ is Cy-L 1-Z or L 2 -When bonded to V, the bond valency is C or N, as long as the bond valency allows. That is, X 1’ , X 2’ , X 3’ , and X 4’ One of the following is Cy-L 1 -Z or L 2 -When coupled to V, the variable part X 1’ , X 2’ , X 3’ , or X 4’ The value is C-Cy-L 1 -Z or CL 2 -V and X 1’ , X 2’ , X 3’ , and X 4’ The values ​​of the remaining variable parts are N and CR. a Selected independently from Cy-L 1 -Z and L 2 -V will be understood to appear only once in compounds of formula II or II'.

[0088] In some embodiments, X 1’ , X 2’ , X 3’ , and X 4’ Each of these is C or CR a And here, X 1’ , X 2’ , X 3’ , or X 4’ Cy-L 1 -Z or L 2 -When coupled to V, it is C, and the remaining variable part is CR a In some embodiments, X 1’ C-Cy-L 1 -Z and X 2’ CL 2 -V and X 3’ and X 4’ These are CR a In some embodiments, X 2’ C-Cy-L 1 -Z and X 3’ CL 2 -V and X 1’ and X4’ These are CR a In some embodiments, X 3’ C-Cy-L 1 -Z and X 4’ CL 2 -V and X 1’ and X 2’ These are CR a In some embodiments, X 4’ C-Cy-L 1 -Z and X 1’ CL 2 -V and X 2’ and X 3’ These are CR a That is the case.

[0089] With respect to equation II', as generally defined above, Y 1’ and Y 2’ These are C, N, and CR, respectively. a Selected from or Y 1’ Or Y 2’ If one of them does not exist, Y 1’ Or Y 2’ The other is C, N, and CR a Selected from. In some embodiments, Y 1’ and Y2’ Each of these is CR a In some embodiments, Y 1’ and Y 2’ Each of them is CR a If so, then the two R a They can come together to form a ring, and equation II' is as follows: [ka] It can be represented by the formula, where A1' is an optionally substituted condensed heterocyclyl ring containing one or two heteroatoms selected from N, O, and S, or an optionally substituted condensed heteroaryl group containing one or two heteroatoms selected from N, O, and S.

[0090] As generally defined above with respect to formula II, A1 is absent, or an optionally substituted condensed heterocyclyl ring containing one or two heteroatoms selected from N, O, and S, or an optionally substituted condensed heteroaryl group containing one or two heteroatoms selected from N, O, and S. In some embodiments, A1 is absent, and the compound of formula II is as follows: [ka] Represented by Z, L 1 Cy, X1', X 1’ , X 2’ , X 3’ , X 4’ L and V are as defined in the Classes and Subclasses herein.

[0091] In some embodiments, A1 is absent, and each X 1’ , X 2’ , X 3’ , and X 4’ is C or CR a And here, X 1’ , X 2’ , X 3’ , or X 4’ Cy-L 1 -Z or L 2 -When bonded to V, it is C, and the compound of formula II is as follows: [ka] It is expressed by the formula, where Z, L 1 Cy, R a L and V are as defined in the Classes and Subclasses herein.

[0092] In some embodiments of formula II', Y 1’ and Y 2’ Each of these is CR a X 1’ , X 2’ , X 3’ , and X 4’Each of these is C or CR a And here, X 1’ , X 2’ , X 3’ , or X 4’ Cy-L 1 -Z or L 2 -When bonded to V, it is C, and the compound of formula II' is as follows: [ka] It is expressed by the formula, where Z, L 1 Cy, R a L and V are as defined in the Classes and Subclasses herein.

[0093] In some embodiments of formula II', Y 1’ and Y 2’ Each of these is CR a X 1’ , X 2’ , X 3’ , and X 4’ Each of these is C or CR a And here, X 1’ , X 2’ , X 3’ , or X 4’ Cy-L 1 -Z or L 2 -When bonded to V, it is C, and the compound of formula II' is as follows: [ka] It is expressed by the formula, where Z, L 1 Cy, R a L and V are as defined in the Classes and Subclasses herein.

[0094] For compounds of formulas I, I', II, II', or any other formulas provided herein, each R is defined as generally above. a These are independently H, halo, -CN, oxo, or C 1~6 Aliphatic and OC 1~6脂Either an arbitrarily substituted group selected from the fat group, or two R groups. a When present on adjacent atoms, they form an optionally substituted condensed heterocyclyl ring or an optionally substituted condensed heteroaryl group containing one or two heteroatoms selected from N, O, and S.

[0095] In some embodiments, R a It is hydrogen.

[0096] In some embodiments, R a is an arbitrarily substituted C 1~6 It is aliphatic. In some embodiments, R a is an arbitrarily substituted C 1~6 It is alkyl. In some embodiments, R a is an arbitrarily substituted C 1~3 It is alkyl. In some embodiments, R a It is methyl.

[0097] In some embodiments, R a is an arbitrarily replaced OC 1~6 It is alkyl. In some embodiments, R a is an arbitrarily replaced OC 1~3 It is alkyl. In some embodiments, R a This is OCH3.

[0098] In some embodiments, R a is a halo. In some embodiments, R a is bromo, chloro, fluoro, or iodine. In some embodiments, R a is bromo. In some embodiments, R a is chloro. In some embodiments, R a is fluoro. In some embodiments, R a It is iodine.

[0099] In some embodiments, R a is CN.

[0100] In some embodiments, two R a When present on adjacent atoms, they form an optionally substituted condensed heterocyclyl ring or an optionally substituted condensed heteroaryl group containing one or two heteroatoms selected from N, O, and S.

[0101] In some embodiments, the compounds of formula I, I', II, or II' are as follows: [ka] It is expressed by the formula, where Cy, L 1 , L 2 Z and V are described in this specification as classes and subclasses.

[0102] As generally defined above for compounds of formulas I, I', II, II', or any other formulas provided herein, Cy is absent or a 4-12 member monocyclic or bicyclic heterocyclyl containing 1-4 heteroatoms selected from N, O, P, and S, a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, P, and S, C 1~6 Aliphatic, or C 3~12 A divalent moiety selected from cycloalkyl groups, where Cy is one or more R groups. 1 It is arbitrarily replaced.

[0103] In some embodiments, Cy is absent, C 1~6 A 4-12 member monocyclic or polycyclic heterocycline containing 1-4 heteroatoms selected from aliphatic, N, O, P, and S; a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S; or C 3~12 It is a cycloaliphatic compound, where Cy is one or more R 1It is optionally substituted with . In any of formulas I, I', II, II', or any other formula provided herein, Cy will be understood to be the divalent part. That is, any reference to a particular Cy group is intended to refer to the divalent form of the group referred to.

[0104] In some embodiments, Cy is one or more R 1 It is arbitrarily substituted, i.e., 0, 1, 2, 3, or 4 R 1 It is substituted with. In some embodiments, Cy is unsubstituted (i.e., 0 R 1 (It is replaced by...). In some embodiments, Cy is 1, 2, 3, or 4 R 1 It is replaced by one R. In some embodiments, Cy is replaced by one R 1 It is replaced by two R 1 It is replaced by three R 1 It is replaced by . In some embodiments, Cy is replaced by 4 R 1 It has been replaced with.

[0105] In some embodiments, Cy is absent.

[0106] In some embodiments, Cy is a 4-12 member monocyclic or polycyclic heterocycline containing 1-4 heteroatoms selected from N, O, and S. In some embodiments, Cy is a 4-7 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 4-7 member monocyclic heterocycline containing 1 heteroatom selected from N, O, P, and S. In some embodiments, Cy is a 4-4 member monocyclic heterocycline containing 1 heteroatom selected from N, O, P, and S. In some embodiments, Cy is a 4 member monocyclic heterocycline containing 1 heteroatom selected from N, O, P, and S. In some embodiments, Cy is a 5 member monocyclic heterocycline containing 1-2 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 6 member monocyclic heterocycline containing 1-3 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a seven-membered monocyclic heterocyclyl containing one to three heteroatoms selected from N, O, P, and S. In some embodiments, Cy is azetidinyl, pyrrolidinyl, piperdinyl, piperazinyl, or azepanyl.

[0107] In some embodiments, Cy is one or more R 1 This is azetidinil that has been arbitrarily substituted.

[0108] In some embodiments, Cy is one or more R 1 It is a piperdinyl optionally substituted with . In some embodiments, Cy is an unsubstituted piperdinyl. In some embodiments, Cy is one or more R 1 This is piperdinyl substituted with [the specified compound].

[0109] In some embodiments, Cy is one or more R 1 It is a piperazinyl optionally substituted with . In some embodiments, Cy is an unsubstituted piperazinyl. In some embodiments, Cy is one or more R 1 It is a perazinyl substituted with [the specified compound].

[0110] In some embodiments, Cy is one or more R1 It is an azepanyl optionally substituted with . In some embodiments, Cy is an unsubstituted azepanyl. In some embodiments, Cy is one or more R 1 This is azepanil substituted with [the specified compound].

[0111] In some embodiments, Cy is one or more R 1 Replaced arbitrarily [ka] In some embodiments, Cy is an unsubstituted [ka] In some embodiments, Cy is one or more R 1 Replaced with [ka] That is the case.

[0112] In some embodiments, Cy is a 7- to 12-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 10- to 12-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 10-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is an 11-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 12-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is, [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] That is the case.

[0113] In some embodiments, Cy is a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 5- or 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is a 5-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is a 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S.

[0114] In some embodiments, Cy is a 7- to 12-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 9- to 12-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 9-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is an 11-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is a 12-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, P, and S.

[0115] In some embodiments, Cy is C 1~6 It is aliphatic. In some embodiments, Cy is C 1~6 It is an alkylenyl. In some embodiments, Cy is C 1~6 It is alkylenyl.

[0116] In some embodiments, Cy is C 3~12 It is cycloaliphatic. In some embodiments, Cy is C 3~12 It is a cycloalkyl group. In some embodiments, Cy is C 3~6 It is a cycloalkyl compound. In some embodiments, Cy is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Cy is cyclobutyl. In some embodiments, Cy is cyclopentyl. In some embodiments, Cy is cyclohexyl.

[0117] In some embodiments, Cy is absent, or a 4-12 member monocyclic or bicyclic heterocycline containing 1-4 heteroatoms selected from N, O, P, and S, or a 5-12 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, P, and S, or C 1~6 Aliphatic, or C 3~12 A divalent moiety selected from cycloalkyl groups, where Cy is one or more R groups. 1 It is optionally substituted, and Cy is not piperazinyl. In some embodiments, Cy is a 4- to 12-membered monocyclic or bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, P, and S, where Cy is not piperazinyl.

[0118] As generally defined above, each R 1 N(R) 3 )2, OH, CN, C(O)NHR 3 , and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 It is independently selected from any optionally substituted groups selected from alkyl groups.

[0119] For compounds of formulas I, I', II, II', or any other formulas provided herein, each R is defined as generally above. 1 is, halo, -N(R 3 )2, -OH, -CN, -C(O)N(R 3 )2, and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 It is independently selected from any optionally substituted groups selected from aliphatic groups.

[0120] In some embodiments, R 1 is a halo. In some embodiments, R 1 is bromo, chloro, fluoro, or iodine. In some embodiments, R 1 is bromo. In some embodiments, R 1 is chloro. In some embodiments, R 1 is fluoro. In some embodiments, R 1 It is iodine.

[0121] In some embodiments, R 1 is -N(R 3 )2. In some embodiments, R 1 is NH2. In some embodiments, R 1 is N(H)(C 1~6 It is aliphatic. In some embodiments, R 1 is N(H)(CH3). In some embodiments, R 1 It is N(CH3)2.

[0122] In some embodiments, R 1 is -OH. In some embodiments, R 1 It is -CN.

[0123] In some embodiments, R 1 is -C(O)N(R 3 )2. In some embodiments, R 1 is -C(O)NHR 3In some embodiments, R 1 It is C(O)NH2.

[0124] In some embodiments, R 1 is an arbitrarily substituted C 1~6 It is aliphatic. In some embodiments, R 1 is an arbitrarily substituted C 1~6 It is alkyl. In some embodiments, R 1 is an arbitrarily substituted C 1~4 It is alkyl. In some embodiments, R 1 R is optionally substituted with methyl, ethyl, propyl, or butyl. In some embodiments, R 1 It is methyl.

[0125] In some embodiments, R 1 N(R) 3 )-C(O)-C 1~6 It is aliphatic. In some embodiments, R 1 N(R) 3 )-C(O)-C 1~6 It is alkyl.

[0126] In some embodiments, R is optionally substituted. 1 The substituents on the optionally substituted carbon atoms of the group are selected from the following: halo, OH, NH2, and oxo.

[0127] In some embodiments, Cy is selected from Table Cy. Table Cy -CH2-, -CH2-C(O)-NH-, [ka]

[0128] For compounds of formulas I, I', II, II', or any other formulas provided herein, L is defined as generally above. 1 is non-existent, -NR 3 -, -O-, -S-, C 1~6 Alkirenyl, C 2~6Alkynylenyl, -NR 3 -C 1~6 Alkirenyl, -OC 1~6 Alkyrenyl, -C(O)C 0~6 Alkyrenyl, -C(O)NR 3 -, or -C(O)-C(O)-. In any of formulas I, I', II, II', or any other formula provided herein, L1 It will be understood that this is the divalent part. That is, a specific L 1 References to a base are intended to refer to the divalent form of the base being referred to.

[0129] In some embodiments, L 1 is non-existent, -S-, -C(O)-NR 3 -, -NR 3 -C(O)-, -C(O)-C(O)-, or C 1~6 Alkirenyl, C 2~6 Alkynylenyl, -NR 3 -C 0~6 Alkirenyl, -OC 0~6 Alkyrenyl, -C(O)-C 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-C(O)-,-C(O)OC 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-OC(O)-,-C 3~6 Cycloalkyl and -NR 3 -C(O)-C 0~6 It is an arbitrarily substituted group selected from alkylenyl-O-.

[0130] In some embodiments, L 1 It is non-existent.

[0131] In some embodiments, L 1 -NR 3 - is. In some embodiments, L 1 is -N(C 1~6 (Aliphatic) - In some embodiments, L 1 In some embodiments, L1 It is -NH-.

[0132] In some embodiments, L 1 is -O-. In some embodiments, L 1 It is -S-.

[0133] In some embodiments, L 1 is -C(O)-NR 3 - is. In some embodiments, L 1 It is -C(O)-NH-. In some embodiments, L 1 is -C(O)-N(C 1~6 (Aliphatic) - In some embodiments, L 1 It is -C(O)-N(CH3)-.

[0134] In some embodiments, L 1 -NR 3 It is -C(O)-. In some embodiments, L 1 is -N(C 1~6 It is aliphatic)-C(O)-. In some embodiments, L 1 is -N(CH3)-C(O)-. In some embodiments, L 1 It is -NHC(O)-.

[0135] In some embodiments, L 1 It is -C(O)-C(O)-.

[0136] In some embodiments, L 1 is an arbitrarily substituted C 1~6 It is an alkylenyl. In some embodiments, L 1 is an arbitrarily substituted C 1~4 It is an alkylenyl. In some embodiments, L 1 C 1~6 It is an alkylenyl. In some embodiments, L 1 is, -(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 C substituted with R° 1~6It is an alkylenyl. In some embodiments, L 1 C is a C substituted with one or more R°. 1~6 It is an alkylenyl, where R° is a halo (e.g., fluoro, bromo, chloro, iodine). In some embodiments, L 1 is -CH2-. In some embodiments, L 1 is -(CH2)2-. In some embodiments, L 1 is -(CH2)3-. In some embodiments, L 1 is -CH(CF3)-. In some embodiments, L 1 is -CH(CH3)-. In some embodiments, L 1 is -CH2-CH(CH3)-. In some embodiments, L 1 It is -C(CH3)2-.

[0137] In some embodiments, L 1 is an arbitrarily substituted C 2~6 It is alkynylenyl. In some embodiments, L 1 teeth, [ka] That is the case.

[0138] In some embodiments, L 1 This is an arbitrarily replaced -NR 3 -C 1~6 It is an alkylenyl. In some embodiments, L 1 is, -(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 -NR3-C substituted with R° 1~6 It is an alkylenyl. In some embodiments, L 1 -NR substituted with one or more R° 3 -C 1~6 It is an alkylenyl, where R° is a halo (e.g., fluoro, bromo, chloro, iodine). In some embodiments, L 1This is an arbitrarily substituted -OC 1~6 It is an alkylenyl. In some embodiments, L 1 is, -(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 -OC substituted with R° 1~6 It is an alkylenyl. In some embodiments, L 1 -OC substituted with one or more R° 1~6 It is an alkylenyl, where R° is a halo (e.g., fluoro, bromo, chloro, iodine). In some embodiments, L 1 This is an arbitrarily substituted -OC 1~3 It is an alkylenyl. In some embodiments, L 1 It is -O-CH2-.

[0139] In some embodiments, L 1 This is the arbitrarily substituted -C(O)C 0~6 It is an alkylenyl. In some embodiments, L 1 is -C(O)-. In some embodiments, L 1 is -C(O)-CH2-. In some embodiments, L 1 is -C(O)-C(CH3)2-. In some embodiments, L 1 This is an arbitrarily substituted -C 0~6 It is alkylenyl-C(O)-. In some embodiments, L 1 This is an arbitrarily substituted -C 1~3 It is alkylenyl-C(O)-. In some embodiments, L 1 is -CH2-C(O)-. In some embodiments, L 1 is -CH(CH3)-C(O)-. In some embodiments, L 1 It is -C(CH3)2-C(O)-. In some embodiments, L 1 This is an arbitrarily substituted -C 0~6 It is alkylenyl-OC(O)-. In some embodiments, L 1 This is an arbitrarily substituted -C 1~3 It is alkylenyl-OC(O)-. In some embodiments, L1 is -OC(O)-. In some embodiments, L 1 is -CH2-OC(O)-. In some embodiments, L 1 It is -C(CH3)2-C(O)O-.

[0140] In some embodiments, L 1 is -C(O)-NR 3 - is. In some embodiments, L 1 It is -C(O)-NH-. In some embodiments, L 1 is -C(O)-N(C 1~6 (Aliphatic) - In some embodiments, L 1 It is -C(O)-N(CH3)-.

[0141] In some embodiments, L 1 It is -C(O)-C(O)-.

[0142] In some embodiments, L 1 C 3~6 It is a cycloalkyl group. In some embodiments, L 1 teeth, [ka] That is the case.

[0143] As generally defined above for formulas I, I', II, II', or any other formulas provided herein, Z is C 1~6 Aliphatic, 2- to 10-member heteroaliphatic, P(O)(R 3 )2, -C(O)C 1~6 Aliphatic, C(O)N(R 3 )2, C 6~12 Ariel, C 3~12 A 4- to 16-membered monocyclic or polycyclic heterocyclil containing 1 to 4 heteroatoms selected from cycloalkyl, N, O, and S, or a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, where Z is (R 2 )q It has been replaced with.

[0144] In some embodiments, Z is P(O)(R 3 )2, C(O)N(R 3 )2, C 1~6 aliphatic, C 6~12 Ariel, C 3~12 Selected from cycloaliphatic, 2-10 atom heteroaliphatic, 4-16 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where Z is (R 2 ) q It has been replaced with.

[0145] In some embodiments, Z is (R 2 ) q It is replaced by . As generally defined above, q is 0, 1, 2, 3, 4, 5, or 6. That is, in some embodiments, Z is 0, 1, 2, 3, 4, 5, or 6 R 2 It is substituted with. In some embodiments, Z is not substituted (i.e., 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. In some embodiments, q is 5. In some embodiments, q is 6.

[0146] In some embodiments, Z is P(O)(R 3 )2. In some embodiments, Z is P(O)(C 1~6 It is aliphatic (Aliphatic) 2. In some embodiments, Z is P(O)(CH3)2.

[0147] In some embodiments, Z is -C(O)N(R 3 )2. In some embodiments, Z is -C(O)N(C 1~6 It is aliphatic (2). In some embodiments, Z is -C(O)NH(C 1~6It is an aliphatic molecule. In some embodiments, Z is -C(O)NHC(CH3)3. In some embodiments, Z is -C(O)N(CH3)(C(CH3)3). In some embodiments, Z is -C(O)N(CH3)2.

[0148] In some embodiments, Z is C 1~6 It is aliphatic. In some embodiments, Z is C 1~6 It is alkyl. In some embodiments, Z is C 1~3 It is alkyl. In some embodiments, Z is methyl, ethyl, propyl (e.g., isopropyl, n-propyl), or butyl (e.g., n-butyl, isobutyl, tert-butyl). In some embodiments, Z is methyl. In some embodiments, Z is ethyl. In some embodiments, Z is isopropyl. In some embodiments, Z is tert-butyl. In some embodiments, Z is -CH2-C(CH3)2-CH2-CH3. In some embodiments, Z is -C(CH3)2-CH2-CH3. In some embodiments, Z is 1, 2, or 3 R 2 It is a methyl substituted with . In some embodiments, Z is a methyl substituted with 1, 2, or 3 halos. In some embodiments, Z is a methyl substituted with 1, 2, or 3 fluoros. In some embodiments, Z is a methyl substituted with 1, 2, 3, or 4 R 2 It is ethyl substituted with . In some embodiments, Z is ethyl substituted with 1, 2, 3, or 4 halos. In some embodiments, Z is ethyl substituted with 1, 2, 3, or 4 fluoros. In some embodiments, Z is ethyl substituted with 1, 2, 3, or 4 R 2 It is isopropyl substituted with [the specified compound].

[0149] In some embodiments, Z is C 6~12 It is an aryl compound. In some embodiments, Z is phenyl. In some embodiments, Z is 0, 1, 2, 3, 4, 5, or 6 R compounds. 2It is a phenyl substituted with R. In some embodiments, Z is an unsubstituted phenyl (i.e., Z is 0 R). 2 (phenyl substituted with ). In some embodiments, Z is 1, 2, 3, 4, or 5 R 2 It is a phenyl substituted with R. In some embodiments, Z is one or two R 2 It is a phenyl substituted with . In some embodiments, Z is one R 2 It is a phenyl substituted with R. In some embodiments, Z is R 2 A phenyl substituted with R 2 Hello, -C(O)-R 2a , -C(O)OR 2a , as well as selected from 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S.

[0150] In some embodiments, Z is a 2- to 10-membered heteroaliphatic. In some embodiments, Z is a 2- to 5-membered heteroaliphatic. In some embodiments, Z is 1, 2, or 3 R 2 It is a 2- to 5-membered heteroaliphatic molecule substituted with . In some embodiments, Z is -O-CH3, -O-CH2-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, -OC(CH3)3, -NHC(CH3)3, -N(CH2CH3)2. In some embodiments, Z is -O-CH3. In some embodiments, Z is -CH2-O-CH3-. In some embodiments, Z is -O-CH2-CH2-O-CH2-CH2-O-CH3. In some embodiments, Z is -O-CH2-CH2-O-CH3-. In some embodiments, Z is -OC(CH3)3. In some embodiments, Z is -O-CH2-CH3. In some embodiments, Z is -NHC(CH3)3. In some embodiments, Z is -N(CH2CH3)2.

[0151] In some embodiments, Z is C 3~12It is a cycloalkyl (e.g., monocyclic or polycyclic cycloalkyl). In some embodiments, Z is C 3~6 It is a monocyclic cycloalkyl group. In some embodiments, Z is cyclopropyl. In some embodiments, Z is cyclobutyl. In some embodiments, Z is cyclopentyl. In some embodiments, Z is cyclohexyl. In some embodiments, Z is 1, 2, 3, or 4 R 2 It is a cyclopropyl substituted with . In some embodiments, Z is 1, 2, 3, 4, 5, or 6 R 2 It is cyclobutyl substituted with. In some embodiments, Z is 1, 2, 3, 4, 5, or 6 R 2 It is cyclopentyl substituted with. In some embodiments, Z is 1, 2, 3, 4, 5, or 6 R 2 It is a cyclohexyl substituted with [a specific compound].

[0152] In some embodiments, Z is C 5~12 It is a polycyclic cycloalkyl compound. In some embodiments, Z is C 10~12 It is a polycyclic cycloalkyl compound. In some embodiments, Z is adamantyl.

[0153] In some embodiments, Z is a 4- to 16-membered monocyclic or polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is a 4- to 6-membered monocyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is a 4-membered monocyclic heterocycline containing 1 heteroatom selected from N, O, and S. In some embodiments, Z is a 5-membered monocyclic heterocycline containing 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Z is a 6-membered monocyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is a 0, 1, 2, 3, 4, 5, or 6 R 2 It is a 4- to 6-membered monocyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S, which are substituted with .

[0154] In some embodiments, Z is a 10- to 12-membered bicyclic heterocycline. In some embodiments, Z is a 10- to 12-membered condensed bicyclic heterocycline. In some embodiments, Z is a 10- to 12-membered bridged bicyclic heterocycline. In some embodiments, Z has 0, 1, 2, 3, 4, 5, or 6 R 2 It is a 10- to 12-membered bridged bicyclic heterocycline that has been substituted with [a specific compound].

[0155] In some embodiments, Z is a 10- to 16-membered polycyclic heterocycline. In some embodiments, Z is a 10-membered polycyclic heterocycline. In some embodiments, Z is an 11-membered polycyclic heterocycline. In some embodiments, Z is a 12-membered polycyclic heterocycline. In some embodiments, Z is a 13-membered polycyclic heterocycline. In some embodiments, Z is a 14-membered polycyclic heterocycline. In some embodiments, Z is a 15-membered polycyclic heterocycline. In some embodiments, Z is a 16-membered polycyclic heterocycline. In some embodiments, the polycyclic Z portion consists of a spirocyclic portion and a condensed tricyclic portion.

[0156] In some embodiments, Z is a 9- to 12-membered spirocyclic heterocycline. In some embodiments, Z is a 9-membered spirocyclic heterocycline. In some embodiments, Z is a 10-membered spirocyclic heterocycline. In some embodiments, Z is an 11-membered spirocyclic heterocycline. In some embodiments, Z is a 12-membered spirocyclic heterocycline. In some embodiments, Z is a 0, 1, 2, 3, 4, 5, or 6 R 2 These are 9- to 12-membered spirocyclic heterocyclines that have been substituted with [a specific compound].

[0157] In some embodiments, Z is a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is a 5-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is a 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S.

[0158] In some embodiments, Z is an 8- to 12-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is an 8-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is a 9-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is a 10-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is an 11-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is a 12-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S.

[0159] For compounds of formulas I, I', II, II', or any other formulas provided herein, each R is defined as generally above. 2 These are halo, CN, C(O)OH, and C 1~6 Aliphatic, C(O)C 1~6 Aliphatic and OC 1~6 It is independently selected from any optionally substituted groups selected from aliphatic groups.

[0160] Several methods of operation, each R 2 These are halo, oxo, -CN, -OH, OR 2a , -C(O)-R 2a , -C(O)OR 2a , and C 1~6aliphatic, C 6~12 The group is independently selected from aryl groups and any substituted groups selected from 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S.

[0161] In some embodiments, R 2 is a halo. In some embodiments, R 2 The compound is selected from fluoro, chloro, bromo, and iodine.

[0162] In some embodiments, R 2 It is oxo.

[0163] In some embodiments, R 2 It is -CN.

[0164] In some embodiments, R 2 It is -OH.

[0165] In some embodiments, R 2 C(O)-R 2a In some embodiments, R 2 This is an arbitrarily substituted C(O)-C 1~6 It is aliphatic. In some embodiments, R 2 is halogen;-(CH2) 0~4 R°;-(CH2) 0~4 C(O)-C substituted with OR° 1~6 It is aliphatic. In some embodiments, R 2 C(O)-C substituted with halogen 1~6 It is a 3-6 member saturated, partially unsaturated, or aryl ring having aliphatic or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0166] In some embodiments, R 2 C(O)OR 2a In some embodiments, R 2 is C(O)OH. In some embodiments, R 2This is the arbitrarily substituted C(O)OC 1~6 It is aliphatic. In some embodiments, R 2 is halogen;-(CH2) 0~4 R°;-(CH2) 0~4 It is a C(O)O-C1~6 aliphatic molecule substituted with OR°. In some embodiments, R 2 C(O)OC substituted with halogen 1~6 It is a 3-6 member saturated, partially unsaturated, or aryl ring having aliphatic or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0167] In some embodiments, R 2 is an arbitrarily substituted C 6~12 It is an arrow. In some embodiments, R 2 R is an optionally substituted phenyl. In some embodiments, R 2 is halogen;-(CH2) 0~4 R°;-(CH2) 0~4 This is phenyl substituted with OR°.

[0168] In some embodiments, R 2 is an arbitrarily substituted C 1~6 It is aliphatic. In some embodiments, R 2 is an arbitrarily substituted C 1~6 It is alkyl. In some embodiments, R 2 is an arbitrarily substituted C 1~4 It is alkyl. In some embodiments, R 2 is an arbitrarily substituted C 1~2 It is alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 R is propyl (e.g., n-propyl, isopropyl). In some embodiments, R 2 is butyl (e.g., n-butyl, isobutyl, tert-butyl, sec-butyl). In some embodiments, R 2 is halogen;-(CH2) 0~4R°;-(CH2) 0~4 C replaced by OR° 1~6 It is aliphatic. In some embodiments, R 2 C is a halogen-substituted C 1~6 It is a 3-6 member saturated, partially unsaturated, or aryl ring having aliphatic or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0169] In some embodiments, R 2 This is an arbitrarily substituted OR 2a In some embodiments, R 2 is an arbitrarily replaced OC 1~6 It is aliphatic. In some embodiments, R 2 is an arbitrarily replaced OC 1~6 It is alkyl. In some embodiments, R 2 is an arbitrarily replaced OC 1~4 It is alkyl. In some embodiments, R 2 is an arbitrarily replaced OC 1~2 It is alkyl. In some embodiments, R 2 R is O-methyl. In some embodiments, R 2 is O-ethyl. In some embodiments, R 2 This is O-propyl (e.g., On-propyl, O-isopropyl).

[0170] In some embodiments, R 2 R is a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 2 R is a 5-6 member monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S. In some embodiments, R 2 R is a five-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 2 It is a six-membered bicyclic heteroaryl compound containing 1 to 4 heteroatoms selected from N, O, and S.

[0171] In some embodiments, R is optionally substituted. 2 The substituents on any optionally substituted carbon atoms of the group are halos (e.g., bromo, chloro, fluoro, iodo) as defined herein and above.

[0172] As generally defined above for compounds of formulas I, I', II, II', or any other formulas provided herein, in some embodiments, each R 2a These are, independently, H, or C 1~6 aliphatic, C 3~12 The group is an optionally substituted group selected from cycloaliphatic groups and 4-12 membered monocyclic or bicyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S. In some embodiments, R 2a H is H. In some embodiments, R 2a is an arbitrarily substituted C 1~6 It is aliphatic. In some embodiments, R 2a C 3~12 It is cycloaliphatic. In some embodiments, R 2a A monocyclic or bicyclic heterocycline with 4 to 12 members containing 1 to 4 heteroatoms selected from N, O, and S.

[0173] For compounds of formulas I, I', II, II', or any other formulas provided herein, each R is defined as generally above. 3 This is H and optionally substituted C 1~6 Selected independently of aliphatic elements. In some embodiments, R 3 H is H. In some embodiments, R 3 is an arbitrarily substituted C 1~6 It is aliphatic. In some embodiments, R 3 is an arbitrarily substituted C 1~6 It is alkyl. In some embodiments, R 3 is an arbitrarily substituted C 1~4 It is alkyl. In some embodiments, R 3 is an arbitrarily substituted C 1~2It is alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 It is tert-butyl.

[0174] In some embodiments, R is optionally substituted. 3 The substituents on the carbon atoms of the group are halos (e.g., bromo, chloro, fluoro, iodo).

[0175] In some embodiments, Z is selected from Table Z. Table Z Halo (e.g., bromo, chloro, fluoro, iodine), -CH3, -CH2-CH3, -CH2-O-CH3, -CH(CH3)-CH2-O-CH3, -CH2-O-CH2-CH3, -CH2-CH2-CH2-O-CH3, -CH2-CH2-O-CH2-CH 3、 -CH2-O-CH2-CH2-O-CH 3、 -CH2-OH, -CH(OH)-CH3, -CH2-CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-OC(CH3)3, -CH2-O-CF2-CH2F, -C(CH3)F2, -CF2-CHF2, -CF2-CH3, -CF2-CH2-O-CH3, -CH2-O-CHF2, -C H2-O-CH2-CHF2, -CH2-O-CF3, -O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, -O-CH2-CH2-O-CH 3, -OC(CH3)3, -O-CH2-CH3, -O-CHF2, -O-CF3, -O-CH2-CHF2, -NH-C(CH3)3, -N(CH2CH3)2, [ka] [ka] [ka] [ka] [ka]

[0176] For compounds of formulas I, I', II, II', or any other formulas provided herein, L is defined as generally above. 2 is non-existent, -(NR 3 ) s -S(O)-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)2-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)(NR 3 )-,-S(O)2-NR 3 -, -NR 3 -C 1~6 Haloalkylenyl, -(NR 3 ) s -P(O)(R 3 )-, -C 1~6 Alkyrenyl-S(O)-, -C 1~6 Alkyrenyl-S(O)2-,-C(O)-(NR 3 ) s -,-(NR 3 ) s An optionally substituted 4- to 12-membered monocyclic or bicyclic heterocycline containing -C(O)-, or 1 to 4 heteroatoms selected from N, O, and S. In any of formulas I, II, II', or any other formula provided herein, L 2 It will be understood that this is the divalent part. That is, a specific L 2 References to a base are intended to refer to the divalent form of the base being referred to.

[0177] In some embodiments, L 2 is, -(NR 3 ) s -S(O)-(NR 3)-,-(NR 3 ) s -S(O)2-NR 3 -,-(NR 3 ) s -P(O)(R 3 )-,-C(O)-(NR 3 ) s -, -NR 3 -C(O)-, or -(NR 3 ) s -S(O)-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)2-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)-NR 3 -C 0~6 Alkyrenyl, -(NR 3 ) s -S(O)2-NR 3 -C 0~6 Alkyrenyl, -(NR 3 ) s -S(O)2-C 3~6 Cycloalkyl, -NR 3 -C 0~6 Alkyrenyl, -C 1~6 Alkyrenyl-S(O)-(NR 3 ) s -, -C 1~6 Alkyrenyl-S(O)2-(NR 3 ) s - An optionally substituted divalent moiety selected from 2- to 6-membered heteroaliphatic groups, and 4- to 12-membered monocyclic or bicyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S.

[0178] In some embodiments, L 2 It is non-existent.

[0179] In some embodiments, L 2 is, -(NR 3 ) s -S(O)-(NR 3 )-. In some embodiments, L 2 is S(O)-(NR 3)-. In some embodiments, L 2 It is S(O)-(NH)-. In some embodiments, L 2 is S(O)-N(C 1~6 (Aliphatic) - In some embodiments, L 2 It is S(O)-N(CH3)-. In some embodiments, L 2 is, -(NR 3 )-S(O)-(NR 3 )-is.

[0180] In some embodiments, L 2 is, -(NR 3 ) s -S(O)2-NR 3 - is. In some embodiments, L 2 is S(O)2-(NR 3 )-. In some embodiments, L 2 It is S(O)2-(NH)-. In some embodiments, L 2 is S(O)2-N(C 1~6 (Aliphatic) - In some embodiments, L 2 It is S(O)2-N(CH3)-. In some embodiments, L 2 is, -(NR 3 )-S(O)2-(NR 3 )-is.

[0181] In some embodiments, L 2 is, -(NR 3 ) s -P(O)(R 3 )-. In some embodiments, L 2 is -P(O)(R 3 )-. In some embodiments, L 2 is, -(NR 3 )-P(O)(R 3 )-. In some embodiments, L 2 It is -P(O)(CH3)-. In some embodiments, L 2 It is -NH-P(O)(CH3)-.

[0182] In some embodiments, L 2 is -C(O)-(NR 3 ) s - is. In some embodiments, L 2 It is -C(O)-NH-. In some embodiments, L 2 is -C(O)-. In some embodiments, L 2 is -N(R 3 )-C(O)-.

[0183] In some embodiments, L 2 -NR 3 It is -C(O)-. In some embodiments, L 2 It is -NH-C(O)-.

[0184] In some embodiments, L 2 is an arbitrarily substituted -(NR 3 ) s -S(O)-C 0~6 It is an alkylenyl. In some embodiments, L 2 This is an arbitrarily substituted S(O)-C 0~6 It is an alkylenyl. In some embodiments, L 2 is an arbitrarily substituted -(NR 3 ) s -S(O)-C 1~6 Alkyrenyl. In some embodiments, L 2 This is an arbitrarily substituted -S(O)-C 1~6 It is an alkylenyl. In some embodiments, L 2 is, -(NR 3 ) s -S(O)-. In some embodiments, L 2 is -S(O)-. In some embodiments, L 2 -NR 3 -S(O)-. In some embodiments, L 2 It is -NHS(O)-. In some embodiments, L 2 It is -N(CH3)-S(O)-.

[0185] In some embodiments, L 2 is, -(NR3 ) s -S(O)2-C 0~6 It is an alkylenyl. In some embodiments, L 2 This is an arbitrarily substituted S(O)2-C 0~6 It is an alkylenyl. In some embodiments, L 2 is an arbitrarily substituted -(NR 3 ) s -S(O)2-C 1~6 It is an alkylenyl. In some embodiments, L 2 This is an arbitrarily substituted -S(O)2-C 1~6 It is an alkylenyl. In some embodiments, L 2 is, -(NR 3 ) s It is -S(O)2-. In some embodiments, L 2 is -S(O)2-. In some embodiments, L 2 -NR 3 It is -S(O)2-. In some embodiments, L 2 is -NH-S(O)2-. In some embodiments, L 2 It is -N(CH3)-S(O)2-. In some embodiments, L 2 It is -NH-S(O)2-CH2-. In some embodiments, L 2 It is -NH-S(O)2-(CH2)3. In some embodiments, L 2 It is -NH-S(O)2. In some embodiments, L 2 It is -N(CH3)-S(O)2-.

[0186] In some embodiments, L 2 is an arbitrarily substituted -(NR 3 ) s -S(O)-NR 3 -C 1~6 Alkyrenyl. In some embodiments, L 2 This is an arbitrarily substituted S(O)-NR 3 -C 1~6 It is an alkylenyl. In some embodiments, L 2 This is an arbitrarily replaced -NR 3 -S(O)-NR3 -C 1~6 It is alkylenyl.

[0187] In some embodiments, L 2 is an arbitrarily substituted -(NR 3 ) s -S(O)2-NR 3 -C 1~6 It is an alkylenyl. In some embodiments, L 2 This is an arbitrarily substituted S(O)2-NR 3 -C 1~6 It is an alkylenyl. In some embodiments, L 2 This is an arbitrarily replaced -NR 3 -S(O)2-NR 3 -C 1~6 It is alkylenyl.

[0188] In some embodiments, L 2 This is an arbitrarily replaced -NR 3 -C 0~6 It is an alkylenyl. In some embodiments, L 2 -NR 3 - is. In some embodiments, L 2 This is an arbitrarily replaced -NR 3 -C 1~6 It is an alkylenyl. In some embodiments, L 2 is halogen;-(CH2) 0~4 R°; and / or -(CH2) 0~4 OR° replaced by -NR3-C 1~6 It is an alkylenyl. In some embodiments, L 2 This is an arbitrarily replaced -NR 3 -C 1~3 It is an alkylenyl. In some embodiments, L 2 This is an arbitrarily replaced -NR 3 -C2 alkylenyl. In some embodiments, L 2 This is an arbitrarily replaced -NR 3 -C1 alkylenyl. In some embodiments, L 2 -NR 3 -CH2-. In some embodiments, L2 is -NH-CH2-. In some embodiments, L 2 is -N(CH3)-CH2-. In some embodiments, L 2 -NR 3 It is -CH(CH3)-. In some embodiments, L 2 It is -NH-CH(CH3)-. In some embodiments, L 2 is -N(CH3)-CH(CH3)-. In some embodiments, L 2 It is -NH-CH(CF3)-.

[0189] In some embodiments, L 2 -NR 3 -C 1~6 It is a haloalkylenyl.

[0190] In some embodiments, L 2 This is an arbitrarily substituted -C 1~6 Alkyrenyl-S(O)-(NR 3 ) s - is. In some embodiments, L 2 This is an arbitrarily substituted -C 1~6 It is alkylenyl-S(O)-. In some embodiments, L 2 This is an arbitrarily substituted -C 1~6 Alkyrenyl-S(O)-(NR 3 )-. In some embodiments, L 2 It is -CH2-S(O)-.

[0191] In some embodiments, L 2 This is an arbitrarily substituted -C 1~6 It is alkylenyl-S(O)2. In some embodiments, L 2 This is an arbitrarily substituted -C 1~3 It is alkylenyl-S(O)2-. In some embodiments, L 2 is an optionally substituted -C1alkylenyl-S(O)2-. In some embodiments, L 2 It is -CH2-S(O)2. In some embodiments, L 2is -CH(CH3)-S(O)2-. In some embodiments, L 2 It is -C(CH3)2-S(O)2-. In some embodiments, L 2 teeth, [ka] That is the case.

[0192] In some embodiments, L 2 teeth, [ka] That is the case.

[0193] In some embodiments, L 2 is -C(O)-(NR 3 ) s - is. In some embodiments, L 2 It is -C(O)-NH-. In some embodiments, L 2 It is -C(O)-N(CH3)-.

[0194] In some embodiments, L 2 is, -(NR 3 ) s It is -C(O)-. In some embodiments, L 2 is, -(NR 3 )-C(O)-. In some embodiments, L 2 It is -NH-C(O)-. In some embodiments, L 2 is -N(C 1~6 It is aliphatic)-C(O). In some embodiments, L 2 is -N(CH3)-C(O)-. In some embodiments, L 2 It is -C(O)-.

[0195] In some embodiments, L 2 L is an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2 L is an optionally substituted 4- to 6-membered monocyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 L is an optionally substituted four-membered monocyclic heterocycline containing one heteroatom selected from N, O, and S. In some embodiments, L 2 L is an optionally substituted five-membered monocyclic heterocycline containing one to four heteroatoms selected from N, O, and S. In some embodiments, L 2 It is an optionally substituted 6-membered monocyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S.

[0196] In some embodiments, L 2 L is an optionally substituted 8- to 12-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 L is an optionally substituted 8-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 L is an optionally substituted 9-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 L is an optionally substituted 10-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 L is an optionally substituted 11-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 It is an optionally substituted 12-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S.

[0197] In some embodiments, L 2 L is a 2- to 6-membered heteroaliphatic. In some embodiments, L 2 It is -CH(CH3)-S-.

[0198] In some embodiments, L is optionally substituted. 2 The substituents on the optionally substituted carbon atoms of the group are halogens;-(CH2) 0~4 R°;-(CH2) 0~4 OR°. In some embodiments, L is optionally substituted. 2 A substituent on any substituted carbon atom of the group is a halo or C 1~6 It is an aliphatic.

[0199] As generally defined above for compounds of formulas I, I', II, II', or any other formulas provided herein, V is C 1~6 aliphatic, C 6~12 4- to 12-membered monocyclic or bicyclic heterocyclyls containing 1 to 4 heteroatoms selected from aryl, N, O, and S; 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S; 5- to 12-membered monocyclic or bicyclic aryls; and C 3~12 Selected from cycloalkyl, where V is (R 6 ) m It has been replaced with.

[0200] In some embodiments, V is C 1~6 aliphatic, C 6~12 Ariel, C 3~12 Selected from cycloaliphatic, 4-12 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where V is (R 6 ) m It has been replaced with.

[0201] For each of equations I, II, and II', as generally defined above, V is (R 6 ) m It is replaced by . As generally defined above, m is 0, 1, 2, 3, or 4. That is, in some embodiments, V is 0, 1, 2, 3, or 4 R6 It is substituted with. In some embodiments, V is not substituted (i.e., m is 0). In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0202] In some embodiments, V is C 1~6 It is aliphatic. In some embodiments, V is C 1~6 It is alkyl. In some embodiments, V is selected from methyl, ethyl, propyl, butyl, propyl, and hexyl.

[0203] In some embodiments, V is C 6~12 It is an aryl compound (e.g., monocyclic or bicyclic). In some embodiments, V is phenyl. In some embodiments, V is naphthalenyl.

[0204] In some embodiments, V is C 3~12 It is cycloaliphatic (e.g., monocyclic or polycyclic). In some embodiments, V is C 3~12 It is a cycloalkyl (e.g., monocyclic or polycyclic). In some embodiments, V is C 3~6 It is a monocyclic cycloalkyl. In some embodiments, V is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, V is cyclopropyl. In some embodiments, V is cyclobutyl. In some embodiments, V is cyclopentyl. In some embodiments, V is cyclohexyl. In some embodiments, V is C 5~12 It is a polycyclic cycloalkyl compound. In some embodiments, V is adamantyl.

[0205] In some embodiments, V is a 4- to 12-membered monocyclic or polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 4- to 6-membered monocyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 4-membered heterocycline containing 1 heteroatom selected from N, O, and S. In some embodiments, V is a 5-membered heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 6-membered heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is morpholinyl. In some embodiments, V is piperadinyl. In some embodiments, V is piperidinyl.

[0206] In some embodiments, V is a 7- to 12-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 7-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is an 8-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 9-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 10-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is an 11-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 12-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S.

[0207] In some embodiments, V is a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 5-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is thiophenyl. In some embodiments, V is pyrazolyl. In some embodiments, V is a 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is pyridyl.

[0208] In some embodiments, V is a 7- to 12-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 7-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is an 8-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 9-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is an 11-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is a 12-membered bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is indolyl.

[0209] For compounds of formulas I, I', II, II', or any other formulas provided herein, each R is defined as generally above. 6 Hello, S(O)-R 5 S(O)2-R 5 S(O)(NH)-R 5 -CN, -C(O)-R 5, -C(O)OR 5 -C(O)-NH(R 5 ), -C(O)-N(R 5 )2, -P(O)(R 5 )2, or OC 1~6 Alkyl, C 1~6 Alkyl and C 6~12 It is independently selected from any substituted group selected from the aryl group.

[0210] Several methods of operation, each R 6 This is Halo, Oxo, -SF5, -S(O)-R 5 S(O)2-R 5 -S(O)(NH)-R 5 -S(O)2-(NH)-R 5 , -S(O)-N(R 5 )2, -S(O)2-N(R 5 )2, -CN, -C(O)-NH(R 5 ), -C(O)-N(R 5 )2, -P(O)(R 5 )2, -OR 5 , or C 1~6 aliphatic, SC 1~6 Aliphatic, 2- to 12-member heteroaliphatic, -C 0~6 Alkyrenyl-C(O)-R 5 , -C 0~6 Alkyrenyl-C(O)OR 5 , C 6~12 Ariel, C 3~12 The groups are independently selected from cycloaliphatic groups and optionally substituted groups selected from 4- to 7-membered monocyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S.

[0211] In some embodiments, R 6 Hello, S(O)-R 5 S(O)2-R 5 , or optionally replaced C 1~6 It is an aliphatic.

[0212] In some embodiments, R 6 is a halo. In some embodiments, R 6is chloro, fluoro, bromo, or iodine. In some embodiments, R 6 is fluoro. In some embodiments, R 6 is chloro. In some embodiments, R 6 is bromo. In some embodiments, R 6 It is iodine.

[0213] In some embodiments, R 6 It is oxo.

[0214] In some embodiments, R 6 It is SF5.

[0215] In some embodiments, R 6 is -S(O)-R 5 In some embodiments, R 6 This is an arbitrarily substituted -S(O)-C 1~6 It is aliphatic. In some embodiments, R 6 It is -S(O)-CH3.

[0216] In some embodiments, R 6 is -S(O)2-R 5 In some embodiments, R 6 This is an arbitrarily substituted -S(O)2-C 1~6 It is aliphatic. In some embodiments, R 6 It is -S(O)2-CH3. In some embodiments, R 6 It is -S(O)2-CH2CH3. In some embodiments, R 6 is -S(O)2-CHF2. In some embodiments, R 6 It is -S(O)2-CF3.

[0217] In some embodiments, R 6 is -S(O)-N(R 5 )2. In some embodiments, R 6 This is the arbitrarily substituted -S(O)-N(C 1~6 It is aliphatic (2). In some embodiments, R6 is -S(O)N(CH3)2. In some embodiments, R 6 is -S(O)-NH(C 1~6 It is aliphatic. In some embodiments, R 6 It is -S(O)-NH-CH3.

[0218] In some embodiments, R 6 is -S(O)2-N(R 5 )2. In some embodiments, R 6 This is the arbitrarily substituted -S(O)2-N(C 1~6 It is aliphatic (2). In some embodiments, R 6 is -S(O)2-N(CH3)2. In some embodiments, R 6 is -S(O)2-NH(C 1~6 It is aliphatic. In some embodiments, R 6 It is -S(O)2-NH-CH3.

[0219] In some embodiments, R 6 It is -CN.

[0220] In some embodiments, R 6 This is an arbitrarily substituted -C 0~6 Alkyrenyl-C(O)-R 5 In some embodiments, R 6 This is an arbitrarily substituted -C 1~6 Alkyrenyl-C(O)-R 5 In some embodiments, R 6 is -C(O)-R 5 In some embodiments, R 6 It is -C(O)-CH3. In some embodiments, R 6 It is -C(O)-CH(CH3)2. In some embodiments, R 6 R6 is -C(O)-CF3. In some embodiments, R6 is -C(O)-pyrrolidinyl.

[0221] In some embodiments, R 6 This is an arbitrarily substituted -C0~6 Alkyrenyl-C(O)OR 5 In some embodiments, R 6 This is the arbitrarily substituted -C(O)OC 1~6 It is aliphatic. In some embodiments, R 6 It is -C(O)O-CH3. In some embodiments, R 6 It is -C(O)O-CH2CH3. In some embodiments, R 6 The molecule is -C(CH3)2-C(O)O-CH3.

[0222] In some embodiments, R 6 is -C(O)-NH(R 5 ) In some embodiments, R 6 It is -C(O)-NH(CH3). In some embodiments, R 6 It is -C(O)-NH-cyclopropyl.

[0223] In some embodiments, R 6 is -C(O)-N(R 5 )2. In some embodiments, R 6 It is -C(O)N(CH3)2.

[0224] In some embodiments, R 6 is -P(O)(R 5 )2. In some embodiments, R 6 It is -P(O)(CH3)2.

[0225] In some embodiments, R 6 is -OR 5 In some embodiments, R 6 is -O-cyclopentyl. In some embodiments, R 6 is an arbitrarily replaced OC 1~6 It is aliphatic. In some embodiments, R 6 is an arbitrarily replaced OC 1~6 It is alkyl. In some embodiments, R 6 is -O-CH3. In some embodiments, R 6It is O-CH2CH3. In some embodiments, R 6 It is O-CH2-CH2-CH3. In some embodiments, R 6 It is O-CF3. In some embodiments, R 6 It is O-CH(CH3)2. In some embodiments, R 6 is -O-CH2-CF3. In some embodiments, R 6 It is -O-CHF2.

[0226] In some embodiments, R 6 is an arbitrarily substituted C 1~6 It is aliphatic. In some embodiments, R 6 is an arbitrarily substituted C 1~6 It is alkyl. In some embodiments, R 6 is an arbitrarily substituted C 1~4 It is alkyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 R is propyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is butyl. In some embodiments, R 6 is tert-butyl. In some embodiments, R 6 is pentyl. In some embodiments, R 6 is neopentyl. In some embodiments, R 6 is -CH2F. In some embodiments, R 6 is -CHF2. In some embodiments, R 6 is CF3. In some embodiments, R 6 is -CH2-CF3. In some embodiments, R 6 is -CF2-CH3. In some embodiments, R 6 is -CF2-CF3. In some embodiments, R 6 It is -C(CH3)2-CF3. In some embodiments, R 6It is -C(CH3)2-CN.

[0227] In some embodiments, R 6 This is an arbitrarily replaced SC 1~6 It is aliphatic. In some embodiments, R 6 This is S-CH3.

[0228] In some embodiments, R 6 R is an optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R 6 It is -C(CH3)2-OCH3. In some embodiments, R 6 is -O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH3. In some embodiments, R 6 is -O-CH2-CH2-O-CH2-CH2-O-CH3. In some embodiments, R 6 It is -CF2-CF2-O-CH3.

[0229] In some embodiments, R 6 is an arbitrarily substituted C 6~12 It is an arrow. In some embodiments, R 6 It is phenyl.

[0230] In some embodiments, R 6 is an arbitrarily substituted C 3~12 It is cycloaliphatic. In some embodiments, R 6 is an arbitrarily substituted C 3~12 It is cycloalkyl. In some embodiments, R 6 R is cyclopropyl. In some embodiments, R 6 is cyclobutyl. In some embodiments, R 6 is cyclopentyl. In some embodiments, R 6 It is cyclohexyl.

[0231] In some embodiments, R 6R is a 4- to 7-membered monocyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 6 It is dioxolanil.

[0232] In some embodiments, R is optionally substituted. 6 The substituents on the optionally substituted carbon atoms are halo (e.g., bromo, chloro, fluoro, iodo), -(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 R°, -O-(CH2) 0~4 C(O)OR°, OH, CN, or oxo, where R° is C 1~6 It is an aliphatic.

[0233] For each of equations I, II, and II', as generally defined above, each R 5 C 1~6 Alkyl, -N(R 3 )2, -OC 1~6 Alkyl, C(O)-C 1~6 Alkyl, P(O)(C 1~6 Alkyl)2, C 3~12 A cycloalkyl group is independently selected from 5- to 12-membered heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, where R 5 It is optionally substituted with one or more substituents selected from a halo, an OH group, and a 2- to 12-membered heteroaliphatic group.

[0234] Several methods of operation, each R 5 is -N(R 3 )2, or C 1~6 Aliphatic, P(O)(C 1~6 aliphatic)2, C 3~12 The group is an optionally substituted group selected from cycloaliphatic groups and 5- to 12-membered heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S.

[0235] In some embodiments, R 5 is -N(R 3)2. In some embodiments, R 5 This is the arbitrarily substituted -N(C 1~6 It is aliphatic (2). In some embodiments, R 5 This is the arbitrarily substituted -NH(C 1~6 It is aliphatic. In some embodiments, R 5 is -NH2. In some embodiments, R 5 is -NH(CH3). In some embodiments, R 5 This is -N(CH3)2.

[0236] In some embodiments, R 5 is an arbitrarily substituted C 1~6 It is aliphatic. In some embodiments, R 5 is an arbitrarily substituted C 1~6 It is alkyl. In some embodiments, R 5 C 1~6 It is alkyl, and here, R 5 It is optionally substituted with one or more substituents selected from a halo, an OH group, and a 2- to 12-membered heteroaliphatic group.

[0237] In some embodiments, R 5 This is the arbitrarily substituted P(O)(C 1~6 It is aliphatic 2.

[0238] In some embodiments, R 5 is an arbitrarily substituted C 3~12 It is cycloaliphatic. In some embodiments, R 5 is cyclopentyl. In some embodiments, R 5 C 3~12 It is cycloaliphatic, and here, R 5 It is optionally substituted with one or more substituents selected from a halo, an OH group, and a 2- to 12-membered heteroaliphatic group.

[0239] In some embodiments, R 5 R is a 5- to 12-membered heterocycline (e.g., monocyclic or polycyclic) containing 1 to 4 heteroatoms selected from N, O, and S, where R5 It is optionally substituted with one or more substituents selected from halo and OH.

[0240] In some embodiments, V is selected from Table V. Table V -CH2CH2CH3, [ka] [ka] [ka] [ka] [ka] [ka]

[0241] In some embodiments, this application relates to formula IIa-1: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein Z, L 1 Cy, L 2 , V, and R a This provides the compounds or pharmaceutically acceptable salts thereof, as defined in the classes and subclasses provided herein.

[0242] In some embodiments, this application relates to formula IIa-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein Z, L 2 , V, and R a This provides the compounds or pharmaceutically acceptable salts thereof, as defined in the classes and subclasses provided herein.

[0243] In some embodiments, this application relates to formula IIa-3: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein Z, Cy, R a , and R 6 This provides the compounds or pharmaceutically acceptable salts thereof, as defined in the classes and subclasses provided herein.

[0244] In some embodiments, this application relates to formula IIa-4: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein Z, L 1 Cy, R a , and R 6 This provides the compounds or pharmaceutically acceptable salts thereof, as defined in the classes and subclasses provided herein.

[0245] In some embodiments, this application relates to formula IIb-1: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein Z, R 6 , and m provide the compounds or pharmaceutically acceptable salts thereof as defined in the classes and subclasses provided herein.

[0246] In some embodiments, this application relates to formula IIc: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein R 2 , R 6 q and q provide the compound or a pharmaceutically acceptable salt thereof, as defined in the classes and subclasses provided herein.

[0247] In some embodiments, this application relates to formula IId: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein R a Z, L 1 , R 6 , and m provide the compounds or pharmaceutically acceptable salts thereof as defined in the classes and subclasses provided herein.

[0248] In some embodiments, this application relates to formula IId-1: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein R a Z, L 1 Cy, R 6 , and m provide the compounds or pharmaceutically acceptable salts thereof as defined in the classes and subclasses provided herein.

[0249] In some embodiments, this application relates to formula IId-2: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein R a Z, L 1 Cy, R 6, and m provide the compounds or pharmaceutically acceptable salts thereof as defined in the classes and subclasses provided herein.

[0250] In some embodiments, this application relates to formula IId-3: [ka]

[0251] A compound of or a pharmaceutically acceptable salt thereof, wherein R a Z, L 1 Cy, R 6 , and m provide the compound or pharmaceutically acceptable salts thereof as defined in the classes and subclasses provided herein. It should be understood that the embodiments described above can be combined with each other as if each combination were specifically and individually enumerated.

[0252] In some embodiments, this application relates to formula IIe: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein Z, L 1 , L 2 , V, and R a This provides the compounds or pharmaceutically acceptable salts thereof, as defined in the classes and subclasses provided herein.

[0253] In some embodiments, the compounds of the present disclosure are selected from Table A. [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 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 Table 1-78 Table 1-79 Table 1-80 Table 1-81 Table 1-82 Table 1-83 Table 1-84 Table 1-85 Table 1-86 Table 1-87 Table 1-88 Table 1-89

Table 1-90

Table 1-100

Table 1-110

Table 1-120

Table 1-123

[0254] In some embodiments, the compounds of the present disclosure are selected from Table B. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 Table 2-44 Table 2-45 Table 2-46 Table 2-47 Table 2-48 Table 2-49 Table 2-50 Table 2-51 Table 2-52 Table 2-53 Table 2-54 Table 2-55 Table 2-56 Table 2-57 Table 2-58 Table 2-59 Table 2-60 Table 2-61 Table 2-62 Table 2-63 Table 2-64 Table 2-65 Table 2-66 Table 2-67 Table 2-68 Table 2-69 Table 2-70 Table 2-71 Table 2-72 Table 2-73 Table 2-74 Table 2-75 Table 2-76 Table 2-77 Table 2-78 Table 2-79 Table 2-80 Table 2-81 Table 2-82 Table 2-83 Table 2-84 Table 2-85 Table 2-86 Table 2-87 Table 2-88 Table 2-89 Table 2-90 Table 2-91 Table 2-92 Table 2-93 Table 2-94 Table 2-95 [Table 2-96] [Table 2-97] [Table 2-98] [Table 2-99] [Table 2-100] [Table 2-101] [Table 2-102]

[0255] Features In particular, in some embodiments, the Disclosure describes one or more features of specific TRPML1 modulators provided by the Disclosure and / or useful for implementing the Disclosure.

[0256] In some embodiments, the Disclosure provides techniques for evaluating one or more meaningful features, and / or techniques for identifying, selecting, prioritizing, and / or characterizing one or more useful TRPML1 modulators.

[0257] In some embodiments, the Disclosure provides certain biological and / or chemical assays that facilitate and / or enable the evaluation of one or more features of TRPML1 expression and / or activity, and / or the evaluation of the effects of TRPML1 modulators(or other modulators) on such expression and / or activity. Alternatively or additionally, the Disclosure provides techniques for identifying and / or characterizing one or more aspects of biological pathways(or other) in which TRPML1 is involved (e.g., autophagy pathways(or other)), thereby enabling the identification and / or characterization of additional useful targets within such pathways(or other) and / or modulators(or other modulators) that affect such pathways(or other) (whether or not they target TRPML1 itself).

[0258] composition In some embodiments, the present disclosure provides and / or utilizes compositions comprising and / or delivering the compounds described herein (for example, together with one or more other components).

[0259] In some embodiments, the present disclosure includes, and / or, the compounds reported herein (e.g., compounds of formulas I-IIc), or their intermediates, degradation products, or active metabolites. For example, the present invention provides a system or environment, for instance, which may contain TRPML1 activity, and provides a composition for delivering such activity when it is brought into contact with the system or environment, or otherwise administered to the system or environment. In some embodiments, administration of such a composition to the system or environment achieves the regulation of autophagy and lysosome biosynthesis as described herein.

[0260] In some embodiments, as described herein, the provided composition may be a pharmaceutical composition in that it comprises an active agent (e.g., compounds of formulas I to IIc or their active metabolites) and one or more pharmaceutically acceptable excipients (e.g., one or more pharmaceutically acceptable auxiliaries, carriers, excipients, and / or vehicles). In some such embodiments, the provided pharmaceutical composition comprises the compounds described herein (e.g., compounds of formulas I to IIc) or their active metabolites and / or is delivered to a relevant system or environment described herein (e.g., to an object to which it needs to be delivered).

[0261] In some embodiments, the provided composition (e.g., a pharmaceutical composition) comprises a compound (e.g., one described herein) in the form of a salt, for example, a pharmaceutically acceptable salt.

[0262] In some embodiments, the provided composition (e.g., a pharmaceutical composition) may be formulated for administration to a subject (e.g., a human) by a specific route (e.g., orally, parenterally, by inhalation or intranasal spray, topically (e.g., as a powder, ointment, or intravenous infusion), rectally, orally, vaginally, into the cisterna magna, or via an implanted reservoir, etc.).

[0263] In some embodiments, the provided composition (e.g., a pharmaceutical composition) contains or delivers an amount of the compound described herein (or its active metabolite) that, when administered according to a treatment plan, is effective in measurably regulating TRPML1 activity in a subject or biological sample and / or in inducing autophagy and / or lysosome biosynthesis.

[0264] In certain embodiments, the compounds or compositions provided are formulated for administration to patients in need of such compositions. In some embodiments, the compounds or compositions described herein may be administered in doses and / or routes of administration that are effective in treating or reducing the severity of the diseases or disorders described herein.

[0265] In some embodiments, the compositions described herein (e.g., pharmaceutical compositions) can be formulated into unit dosage forms (for example, this may result in ease of administration and / or uniformity of dosage).

[0266] Those skilled in the art will understand that the effective dose may vary from subject to subject depending on various factors, including, for example, the disorder or severity of the disorder being treated; the activity of the specific compound used; the specific composition used and its route of administration; the patient's species, age, weight, sex, and diet; the subject's overall condition; the time of administration; the elimination rate of the specific compound used; the duration of treatment; and drugs used in combination with or simultaneously with the specific compound used.

[0267] In some embodiments, an appropriate dosage level may be in the range of approximately 0.01 mg / kg body weight of the subject to approximately 50 mg / kg body weight of the subject per day, administered at least once daily, in order to obtain the desired therapeutic effect.

[0268] Applications and Uses This application provides various applications and uses of the compounds and / or compositions described herein, for example, taking into account their activities and / or characteristics as described herein. In some embodiments, such uses may include therapeutic and / or diagnostic uses. Alternatively, in some embodiments, such uses may include research, manufacturing, and / or other technical uses.

[0269] In particular, in some embodiments, the present disclosure provides techniques for modulating TRPML1 activity. In some embodiments, the present application relates to a method for modulating TRPML1 activity in a subject, comprising administering a compound provided or a composition described herein to the subject.

[0270] Diseases, disorders, and conditions This disclosure demonstrates that the compounds and / or compositions described herein may be useful in medicine (for example, in the treatment of one or more diseases, disorders, or conditions).

[0271] In particular, this disclosure provides the insight that targeting (e.g., stimulating) TRPML1, as described herein, may be a particularly effective strategy for regulating (e.g., enhancing) autophagy and / or lysosomal biosynthesis.

[0272] In some embodiments, the diseases, disorders, or conditions that can be treated as described herein may be, or include, diseases, disorders, or conditions associated with TRPML1 deficiency. Furthermore, in some embodiments, this disclosure confirms that TRPML1 deficiency is associated with certain diseases, disorders, or conditions, some or all of which can be treated in accordance with this disclosure.

[0273] In some embodiments, the treatment provided herein involves administering a TRMPL1 modulator described herein in an amount effective in regulating TRMPL1 activity in lysosomes and / or increasing autophagy.

[0274] In some embodiments, the diseases, disorders, or conditions suitable for the treatments described herein are or include liver disease, neurodegenerative disorders, cancer, or heart disease.

[0275] In some embodiments, diseases, disorders, or conditions suitable for the treatments described herein are or include lysosomal storage disorders, such as Niemann-Pick disease type C (NPC), Gaucher disease, and Pompe disease.

[0276] In some embodiments, diseases, disorders, or conditions suitable for the treatments described herein are common age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0277] In some embodiments, the disease, disorder, or condition suitable for the treatment described herein is mucolipidosis type IV (ML4), a neurodegenerative lysosomal storage disorder caused by mutations in TRPML1.

[0278] In some embodiments, the diseases, disorders, or conditions for which the treatments described herein are suitable are related to reactive oxygen species or oxidative stress.

[0279] In some embodiments, the disease, disorder, or condition is a muscle disease, liver disease, metabolic disease, atherosclerotic disease, inflammatory bowel disease, neurodegenerative disease, neoplastic disease, or infectious disease.

[0280] In some embodiments, the disease, disorder, or condition is a muscle disease. In some embodiments, the muscle disease is a muscular dystrophy. In some embodiments, the muscular dystrophy is Duchenne muscular dystrophy.

[0281] In some embodiments, the disease, disorder, or condition is a liver disease. In some embodiments, the disease, disorder, or condition is a metabolic disease. In some embodiments, the disease, disorder, or condition is an arteriosclerotic disease. In some embodiments, the disease, disorder, or condition is an inflammatory bowel disease. In some embodiments, the disease, disorder, or condition is an arteriosclerotic disease. In some embodiments, the disease, disorder, or condition is a neurodegenerative disease. In some embodiments, the disease, disorder, or condition is a neoplastic disease. In some embodiments, the disease, disorder, or condition is an infectious disease.

[0282] In some embodiments, the infectious disease is an infection with Heliobacter pylori or Mycobacterium tuberculosis. In some embodiments, the infectious disease is an infection with Heliobacter pylori. In some embodiments, the infectious disease is an infection with Mycobacterium tuberculosis. In some embodiments, the infectious disease is tuberculosis.

[0283] In some embodiments, this application relates, for example, to the use of the compounds and / or compositions described herein for the manufacture of agents for modulating TRPML1 activity.

[0284] In some embodiments, this application relates to the use of compounds and / or compositions described herein for the manufacture of agents for treating diseases, disorders, or conditions by modulating TRPML1 activity, for example. In some embodiments, the disease, disorder, or condition is liver disease, neurodegenerative disorder, cancer, or heart disease.

[0285] Exemplary Embodiments The following numbered embodiments are illustrative of certain aspects of the present disclosure, but are not limiting. 1.Formula II: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is X 1’ , X 2’ , X 3’ , and X 4’ These are N, C, and CR, respectively. a’ Selected independently from X 1’ , X 2’ , X 3’ , and X 4’ Cy-L 1 -Z or L 2-When bonded to V, it is C, and A1 is absent, an optionally substituted condensed heterocyclyl ring containing one or two heteroatoms selected from N, O, and S, or an optionally substituted condensed heteroaryl group containing one or two heteroatoms selected from N, O, and S. Cy is a 4- to 12-membered monocyclic or bicyclic heterocycline containing no heteroatoms, 1 to 4 heteroatoms selected from N, O, P, and S, or a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. 1~6 Aliphatic, or C 3~12 It is a cycloalkyl group, where Cy has one or more R groups. 1 It is arbitrarily replaced with, L 1 is non-existent, -NR 3 -, -O-, -S-, C 1~6 Alkirenyl, C 2~6 Alki Alkynylenyl, -NR 3 -C 1~6 Alkirenyl, -OC 1~6 Alkyrenyl, -C(O)C 0~6 Alkyrenyl, -C(O)NR 3 -, -C(O)-C(O)-, L 2 is, -(NR 3 ) s -S(O)-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)2-C 0~6 Alkyrenyl-,-(NR 3 ) s -S(O)(NR 3 )-,-S(O)2-NR 3 -, -NR 3 -C 1~6 Haloalkylenyl, -(NR 3 ) s -P(O)(R 3 )-, -C 1~6 Alkyrenyl-S(O)-, -C 1~6 Alkyrenyl-S(O)2-,-C(O)-(NR 3) s -,-(NR 3 ) s An optionally substituted 4- to 12-membered monocyclic or bicyclic heterocycline containing -C(O)- or 1 to 4 heteroatoms selected from N, O, and S, V is C 1~6 aliphatic, C 6~12 4-12 member monocyclic or bicyclic heterocyclyls containing 1-4 heteroatoms selected from aryl, N, O, and S; 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S; 5-12 member monocyclic or bicyclic aryls; and C 3~12 Selected from cycloalkyl, V is (R 6 ) m It has been replaced with, Z is C 1~6 Aliphatic, heteroaliphatic with 2-10 atoms, P(O)(R 3 )2, -C(O)C 1~6 Aliphatic, C(O)N(R 3 )2, C 6~12 Ariel, C 3~12 A 4- to 16-membered monocyclic or polycyclic heterocyclil containing 1 to 4 heteroatoms selected from cycloalkyl, N, O, and S, or a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, where Z is (R 2 ) q It has been replaced with, Each R a This is independently a halo, oxo, or optionally substituted C 1~6 It is aliphatic, Each R 1 N(R) 3 )2, OH, CN, C(O)NHR 3 , and C 1~6 Aliphatic and N(R) 3 )-C(O)-C 1~6 Independently selected from any optionally substituted groups selected from alkyl groups, Each R 2 These are halo, -CN, C(O)OH, and C 1~6 Alkyl, C(O)C 1~6Aliphatic and OC 1~6 Independently selected from any substituted groups chosen from aliphatic groups, Each R 3 This is H and optionally substituted C 1~6 Selected independently from aliphatic species, Each R 5 C 1~6 Alkyl, -N(C 1~6 Alkyl)2,-OC 1~6 Alkyl, C(O)-C 1~6 Alkyl, P(O)(C 1~6 Alkyl)2, C 3~12 A cycloalkyl group is independently selected from 5- to 12-membered heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, and R 5 It is optionally substituted with one or more substituents selected from halo and OH. Each R 6 Hello, S(O)-R 5 S(O)2-R 5 S(O)(NH)-R 5 -CN, -C(O)-R 5 , -C(O)OR 5 -C(O)-NH(R 5 ), -C(O)-N(R 5 )2, -P(O)(R 5 )2, or OC 1~6 Alkyl, C 1~6 Alkyl, C 6~12 An arbitrarily substituted group selected from aryl groups, m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, or 4. s is 0 or 1, wherein the compound or a pharmaceutically acceptable salt thereof. 2. The compound according to Embodiment 1, wherein Cy is absent or is a 4- to 12-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. 3. The compound according to any one of the prior embodiments, wherein Cy is absent. 4. The compound according to any one of the prior embodiments, wherein Cy is a 4- to 12-membered monocyclic or bicyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S. 5. The compound according to any one of the prior embodiments, wherein Cy is a 4- to 6-membered monocyclic heterocycline containing 1 to 3 heteroatoms selected from N, O, and S. 6. The compound according to any one of the prior embodiments, wherein Cy is piperdinyl or piperazinyl. 7. A compound according to any one of the prior embodiments, wherein Cy is selected from Table Cy. 8.L 1 However, it does not exist, -NR 3 -, or C 1~6 A compound according to any one of the prior embodiments, which is an alkylenyl compound. 9.L 1 A compound according to any one of the prior embodiments, wherein the compound is absent. 10L 1 ga-NR 3 - The compound described in any one of the prior embodiments. 11.L 2 However, non-existent, -(NR 3 ) s -S(O)-C 0~6 Alkyrenyl, or -(NR 3 ) s -S(O)2-C 0~6 A compound according to any one of the prior embodiments, which is an alkylenyl compound. 12. L2 However, non-existent, -(NR 3 ) s -S(O)-, or -(NR 3 ) s A compound according to any one of the prior embodiments, wherein the compound is -S(O)2-. 13.L 2 is not present or -(NR 3 ) s A compound according to any one of the prior embodiments, wherein the compound is -S(O)2-. 14.L 2 However, -NR 3A compound according to any one of the prior embodiments, wherein the compound is -S(O)2-. 15.L 2 However, the compound is -NH-S(O)2 as described in any one of the prior embodiments. 16.Z is C 6~12 A 4- to 12-membered monocyclic or polycyclic heterocycline containing an aryl, a heteroaliphatic with 2 to 10 atoms, or 1 to 4 heteroatoms selected from N, O, and S, or a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, wherein Z is (R 2 ) q A compound according to any one of the prior embodiments, which is substituted with 17.Z is C 6~12 The compound according to any one of the prior embodiments, which is a 4- to 12-membered monocyclic or polycyclic heterocyclil containing aryl or 1 to 4 heteroatoms selected from N, O, and S. 18.Z is C 6~12 A compound according to any one of the prior embodiments, wherein Z is aryl. 19. Z is 1, 2, 3, or 4 R 2 C replaced by 6~12 A compound according to any one of the prior embodiments, wherein the compound is an aryl compound. 20.R 2 A compound according to any one of the prior embodiments, wherein the compound is a halo. 21. A compound according to any one of the prior embodiments, wherein Z is selected from Table Z. 22. V is C 6~12 The compound according to any one of the prior embodiments, which is a 4- to 12-membered monocyclic or bicyclic heterocycline containing aryl or 1 to 4 heteroatoms selected from N, O, and S. 23. V is C 6~12 A compound according to any one of the prior embodiments, wherein 24.V is aryl, with 1, 2, 3, or 4 R 6 C replaced by 6~12 A compound according to any one of the prior embodiments, wherein the compound is an aryl compound. 25.R 6 But, Hello, S(O)-R 5S(O)2-R 5 S(O)(NH)-R 5 , or optionally replaced OC 1~6 A compound according to any one of the prior embodiments, wherein the compound is alkyl. 26.R 6 However, S(O)-R 5 S(O)2-R 5 , or optionally replaced C 1~6 A compound according to any one of the prior embodiments, wherein the compound is alkyl. 27.R 6 A compound according to any one of the prior embodiments, wherein the compound is a halo. 28.R 6 A compound according to any one of the prior embodiments, wherein is fluoro or chloro. 29.R 6 However, S(O)2-R 5 The compound described in any one of the prior embodiments. 30.R 6 However, -S(O)2-C 1~6 A compound according to any one of the prior embodiments, wherein the compound is alkyl. 31.R 6 However, the compound is -S(O)2-CH3 as described in any one of the prior embodiments. 32.R 6 However, -S(O)2-N(C 1~6 A compound according to any one of the prior embodiments, wherein the compound is alkyl)2. 33.R 6 However, the compound is -S(O)2-N(CH3)2 as described in any one of the prior embodiments. 34. A compound according to any one of the prior embodiments, wherein V is selected from Table V. 36. The above compound is of formula IIa-1: [ka] The compound according to any one of the prior embodiments, which is the compound or a pharmaceutically acceptable salt thereof. 37. The above compound is of formula IIa-2: [ka] The compound according to any one of the prior embodiments, which is the compound or a pharmaceutically acceptable salt thereof. 38. The above compound is of formula IIb-1: [ka] The compound according to any one of the prior embodiments, which is the compound or a pharmaceutically acceptable salt thereof. 39. The above compound is of formula IIc: [ka] The compound according to any one of the prior embodiments, which is the compound or a pharmaceutically acceptable salt thereof. 40. A compound selected from Table A. 41. A compound selected from Table B. 42. A pharmaceutical composition comprising a compound described in any one of the prior embodiments and a pharmaceutically acceptable carrier, auxiliary agent, or vehicle. 43. A method for preparing TRPML1, comprising administering a compound described in any one of the prior embodiments. 44. A method for treating a disease, disorder, or condition, comprising administering a compound described in any one of the prior embodiments. 45. The method according to Embodiment 44, wherein the disease, disorder, or condition is a lysosome storage disorder. 46. ​​The method according to embodiment 45, wherein the lysosome storage disorder is selected from Niemann-Pick disease type C, Gaucher disease, and Pompe disease. 47. The method according to Embodiment 45, wherein the disease, disorder, or condition is a common neurodegenerative disease due to aging. 48. The method according to Embodiment 47, wherein the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, and Huntington's disease. 49. The method according to Embodiment 45, wherein the disease, disorder, or condition is mucolipidosis type IV (ML4), a neurodegenerative lysosomal storage disorder caused by a mutation in TRPML1. [Examples]

[0286] The teachings of the present invention include descriptions provided in embodiments which are not intended to limit the scope of any claim. Unless otherwise stated in the past tense, what is included in the embodiments is not intended to imply that experiments have actually been performed. The following non-limiting examples are provided to further illustrate the teachings of the present invention. Those skilled in the art will understand that, in light of this application, numerous modifications may be made in the particular embodiments provided herein and still obtain similar or comparable results without departing from the gist and scope of the teachings of the present invention. [Table 3-1] [Table 3-2]

[0287] Example of synthesis As shown in the examples below, in certain representative embodiments, the compounds are prepared by the following general procedure. While the general method illustrates the synthesis of specific compounds of the present invention, it will be understood that the following general method and other methods known to those skilled in the art may be applied to all compounds described herein and to each of their subclasses and chemical species.

[0288] A. Specific synthetic intermediates Scheme 1: Synthesis procedure for 1-(2,3-dimethoxyphenyl)ethane-1-one [ka] Step 1: Synthesis of 1-(2,3-dimethoxyphenyl)ethane-1-ol: To a stirred solution of 2,3-dimethoxybenzaldehyde (1 g, 6.01 mmol, 1 equivalent) in THF (20 mL), a 3 M solution of methylmagnesium bromide in diethyl ether (3 ml, 9.03 mmol, 1.5 equivalents) was added dropwise at 0°C. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 1-(2,3-dimethoxyphenyl)ethane-1-ol (0.7 g, 64%). LCMS: 183.09 [M+H] + .

[0289] Step 2: Synthesis of 1-(2,3-dimethoxyphenyl)ethane-1-one: To a mixture of 1-(2,3-dimethoxyphenyl)ethane-1-ol (0.8 g, 4.39 mmol, 1 equivalent) in acetone (20 ml), 2 M Jones' reagent (6.6 ml, 13.18 mmol, 3 equivalents) in aqueous H2SO4 was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with isopropanol and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 1-(2,3-dimethoxyphenyl)ethane-1-one (0.6 g, 76%). LCMS: 181.08 [M+1] + .

[0290] Synthesis procedure for 1-methyl-1H-indole-4-carbaldehyde [ka] Step 1: Synthesis of 1-methyl-1H-indole-4-carbaldehyde: To a stirred solution of 1H-indole-4-carbaldehyde (1 g, 6.8 mmol, 1 equivalent) in DMF (10 mL), NaH (0.130 g, 7.4 mmol, 1.1 equivalents) was added under a nitrogen atmosphere at 0°C, followed by the addition of methyl iodide (1.06 g, 7.5 mmol, 1.1 equivalents). The reaction mixture was stirred at 0°C for 1 hour. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the title compound, 1-methyl-1H-indole-4-carbaldehyde (0.90 g, 82.56%). LCMS: 160.07 [M+H] + .

[0291] Scheme 2 [ka] Step 1: General synthesis procedure for 1-Boc-4-aryl-3,6-dihydropyridine derivatives: Method A (Ar=a / c / f): In a Pyrex® tube, each aryl halide (1.1 equivalents) in a mixture of 1,4-dioxane:H2O (4:1, 10 volumes), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (1 equivalent), and a 2M Na2CO3 solution (3 equivalents) were added, and the reaction mixture was purged with argon for 15 minutes. Then, tetrakis(triphenylphosphine)palladium (0) (0.1 equivalents) was added to the reactant under an argon atmosphere, and the reaction mixture was purged with argon for 15 minutes. Next, a screw cap was attached to the tube, and the reactant was stirred at 90°C for 3 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water, and ethyl acetate was extracted. The combined organic layers were washed with water and brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude products were purified by silica gel column chromatography to obtain the respective 1-Boc-4-aryl-3,6-dihydropyridine derivatives.

[0292] Method B (Ar=b / e / g): In a Pyrex® tube, each aryl halide (1.1 equivalents), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (1 equivalent), and potassium carbonate (2 equivalents) were added in a mixture of DMF:H2O (5:1, 10 volumes). The reaction mixture was purged with argon for 10 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 equivalent) was added to the reaction mixture under an argon atmosphere, and the reaction mixture was purged with argon for 5 minutes. Next, a screw cap was attached to the tube, and the reaction mixture was stirred at 80°C for 16 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water, and ethyl acetate was extracted. The combined organic layers were washed with water and brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude products were purified by silica gel column chromatography to obtain the respective 1-Boc-4-aryl-3,6-dihydropyridine derivatives.

[0293] Method C (Ar=d): 1,4-dioxane:H2 in a Pyrex® tube. Each aryl halide (1.1 equivalents), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (1 equivalent), and cesium carbonate (2 equivalents) were added to a mixture of O(4:1, 10 vol). The reaction mixture was purged with argon for 10 minutes. Then, dichlorobis(triphenylphosphine)palladium(II) (0.1 equivalent) was added to the reactant under an argon atmosphere, and the reaction mixture was purged with argon for 15 minutes. Next, a screw cap was attached to the tube, and the reactant was stirred at 80°C for 12 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water, and ethyl acetate was extracted. The combined organic layers were washed with water and brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude products were purified by silica gel column chromatography to obtain each of the 1-Boc-4-aryl-3,6-dihydropyridine derivatives.

[0294] Step 2: General synthesis procedure for 1-Boc-4-arylpiperidine derivatives:

[0295] Method A (Ar=a / b): The solution of each 1-Boc-4-aryl-3,6-dihydropyridine (1 equivalent) in ethyl acetate was purged with nitrogen for 10 minutes. Platinum(IV) oxide (10% w / w) was added to the reactants at room temperature under a nitrogen atmosphere. The reaction mixture was purged with hydrogen for 2-3 minutes and stirred at room temperature for 3 hours under a hydrogen atmosphere (pressure of 100 Psi). The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure to obtain each 1-Boc-4-arylpiperidine derivative. The crude products were used in the next step without further purification.

[0296] Method B (Ar=c / d / e / f / g): A solution of each 1-Boc-4-aryl-3,6-dihydropyridine (1 equivalent) in methanol was purged with nitrogen for 10 minutes. 10-20% palladium-carbon (10% w / w) was added to the reactants at room temperature under a nitrogen atmosphere. The reaction mixture was purged with hydrogen for 2-3 minutes and stirred at room temperature for 12 hours under a hydrogen atmosphere with balloon pressure. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite pad, and the Celite pad was washed with methanol. The filtrate was concentrated to dryness under reduced pressure to obtain each 1-Boc-4-arylpiperidine derivative. The crude products were used in the next step without further purification.

[0297] Step 3: General procedure for the synthesis of 4-arylpiperidine derivatives:

[0298] Method A (Ar=a / c / e / f / g): To a stirred solution of each 1-Boc-4-arylpiperidine (1 equivalent) in 5 volumes of DCM, 5 volumes of 50% trifluoroacetic acid solution in DCM were added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 to 16 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain each 4-arylpiperidine derivative. The crude products were used in the next step without further purification.

[0299] Method B (Ar=b / d): To a stirred solution of each 1-Boc-4-arylpiperidine (1 equivalent) in 10 volumes of 1,4-dioxane, 5 volumes of a 4M HCl solution in 1,4-dioxane were added at 5-10°C. The reaction mixture was warmed to room temperature and stirred for 4-16 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in saturated NaHCO3 aqueous solution and extracted by DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain each 4-arylpiperidine derivative. The crude products were used in the next step without further purification. [Table 4-1] [Table 4-2]

[0300] Synthesis of 3-(piperidine-4-yl)isoxazole [ka] Step 1: Synthesis of (E)-4-((hydroxyimino)methyl)piperidine-1-carboxylate tert-butyl: 4-Formylpiperidine-1-carboxylate tert-butyl (1g, 4.6 mmol, To a stirred solution in 10 mL of water (1 equivalent) and methanol (10 mL), hydroxylamine hydrochloride (390 mg, 5.6 mmol, 1.2 equivalents) was added, followed by Na₂CO₃ (248 mg, 2.3 mmol, 0.5 equivalents). The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to obtain the title compound, (E)-4-((hydroxyimino)methyl)piperidine-1-carboxylate tert-butyl (the reaction was repeated on a 1 g scale) (1.9 g, crude product, combined yield from 2 x 1 g batches). This compound was used in the next step without further purification. LCMS: 229.15 [M+H] + .

[0301] Step 2: Synthesis of (Z)-4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate tert-butyl: To a stirred solution of (E)-4-((hydroxyimino)methyl)piperidine-1-carboxylate tert-butyl (1 g, 4.4 mmol, 1 equivalent) in DMF (3 mL), N-chlorosuccinimide (0.59 g, 4.4 mmol, 1 equivalent) was added. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water, the resulting solid was filtered off, and dried under reduced pressure to obtain the title compound, (Z)-4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate tert-butyl (1 g, crude product). This compound was used in the next step without further purification. LCMS: 263.11 [M+H] + .

[0302] Step 3: Synthesis of 4-(5-(trimethylsilyl)isoxazole-3-yl)piperidine-1-carboxylate tert-butyl: (Z)-4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate tert-butyl (1.7 g, 6.4 mmol, 1 equivalent) was stirred in ethyl acetate (100 mL) to which ethynyltrimethylsilane (3.14 g, 32 mmol, 5 equivalents) was added, followed by triethylamine (1.24 g, 9.6 mmol, 1.5 equivalents) at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 4-(5-(trimethylsilyl)isoxazole-3-yl)piperidine-1-carboxylate tert-butyl (2 g, 96%). LCMS: 325.19 [M+H] + .

[0303] Step 4: Synthesis of 4-(isoxazole-3-yl)piperidine-1-carboxylate tert-butyl: To a stirred solution of 4-(5-(trimethylsilyl)isoxazole-3-yl)piperidine-1-carboxylate tert-butyl (1.4 g, 4.3 mmol, 1 equivalent) in a mixture of water (1 mL) and methanol (10 mL), potassium hydrogen fluoride (33 mg, 0.43 mmol, 0.1 equivalent) was added. The reaction mixture was stirred at room temperature for 6 days. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous Na2SO4, and concentrated under reduced pressure to obtain the title compound, 4-(isoxazole-3-yl)piperidine-1-carboxylate tert-butyl (1 g, crude product). This compound was used in the next step without further purification. LCMS: 253.15 [M+H] + .

[0304] Step 5: Synthesis of 3-(piperidine-4-yl)isoxazole: To a stirred solution of 4-(isoxazole-3-yl)piperidine-1-carboxylate tert-butyl (1 g, 4 mmol, 1 equivalent) in DCM (20 mL), trifluoroacetic acid (10 mL) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound, 3-(piperidine-4-yl)isoxazole (1 g, crude product). This compound was used in the next step without further purification. LCMS: 153.09 [M+H] + .

[0305] Synthesis of 3-formyl-2-methoxybenzonitrile [ka] Step 1: Synthesis of 3-formyl-2-hydroxybenzonitrile: Hexamethylenetetramine (1.8 g, 12.59 mmol, 1.5 equivalents) was added to a stirred solution of 2-hydroxybenzonitrile (1 g, 8.39 mmol, 1 equivalent) in acetic acid (10 mL). The reaction mixture was stirred at 120 °C for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compounds, 3-formyl-2-hydroxybenzonitrile (105 mg, 8.5%) and 5-formyl-2-hydroxybenzonitrile (330 mg, 27%). LC-MS: No ionization.

[0306] Step 2: Synthesis of 3-formyl-2-methoxybenzonitrile: To a stirred solution of 3-formyl-2-hydroxybenzonitrile (100 mg, 0.68 mmol, 1 equivalent) in DMF (2 mL), potassium carbonate (188 mg, 1.36 mmol, 2 equivalents) was added, followed by iodomethane (145 mg, 1.02 mmol, 1.5 equivalents). The reaction mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to obtain the title compound, 3-formyl-2-methoxybenzonitrile (100 mg, crude product). This compound was used in the next step without further purification. LCMS: No ionization.

[0307] Synthesis of (pyridine-2-ylmethoxy)benzaldehyde derivatives [ka] General synthesis procedure for (pyridine-2-ylmethoxy)benzaldehyde derivatives: To a stirred solution of each hydroxybenzaldehyde (1 equivalent) in DMF (10 volumes), potassium carbonate (3 equivalents) was added, followed by 2-(chloromethyl)pyridine hydrochloride (1.1 equivalents). The reaction mixture was stirred at 80 °C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain each (pyridine-2-ylmethoxy)benzaldehyde derivative. [Table 5] Synthesis of [1,1'-biphenyl]-4-carbaldehyde [ka]

[0308] In a Pyrex® tube, solutions of 4-bromobenzaldehyde (1.86 g, 10.06 mmol, 1.2 equivalents), phenylboric acid (1 g, 8.38 mmol, 1 equivalent), and K3PO4 (4.44 g, 20.9 mmol, 2.5 equivalents) in 3 mL of water and 6 mL of 1,4-dioxane were added. The tube was sealed with a septum, and the reaction mixture was purged with argon using an argon balloon for 15 minutes. Next, PdCl2 (dppf) (183 mg, 0.25 mmol, 0.03 equivalents) was added to the reaction mixture under an argon atmosphere, and argon purging was continued for 5 minutes. The tube was then sealed with a screw cap, and the reaction mixture was heated at 100°C for 12 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, the reaction mixture was filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain the title compound, [1,1'-biphenyl]-4-carbaldehyde (500 mg, crude product). This compound was used without further purification. LCMS: No ionization.

[0309] Synthesis of 3,4-dimethoxypicoline aldehyde. [ka] To a stirred solution of 3,4-dimethoxypyridine (250 mg, 1.79 mmol, 1 equivalent) in THF (5 mL), a solution of 1.6 M n-BuLi in hexane (1.2 mL, 1.97 mmol, 1.1 equivalent) was added dropwise at -78°C under an argon atmosphere. The reaction mixture was stirred at the same temperature for 30 minutes. Then, DMF (0.31 mL, 3.95 mmol, 2.2 equivalents) was added to the reaction mixture at -78°C under an argon atmosphere. The reaction mixture was stirred at the same temperature under an argon atmosphere for 30 minutes. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound in question, 3,4-dimethoxypicolinealdehyde (62 mg, 20.6%). LCMS: 168.10 [M+H] + .

[0310] Synthesis of 4,5-dimethoxynicotinaldehyde [ka] Step 1: Synthesis of 4-chloro-3-methoxypyridine: To a stirred solution of 4-chloropyridine-3-ol (1 g, 7.71 mmol, 1 equivalent) in toluene (10 mL), a solution of 1 M cyanomethylenetributylphosphorane (CMBP) in toluene (23.1 mL, 23.1 mmol, 3 equivalents) was added, followed by methanol (0.93 mL, 23.1 mmol, 3 equivalents) at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 4-chloro-3-methoxypyridine (280 mg, 25.45%). LCMS: 144.00 [M+H] + .

[0311] Step 2: Synthesis of 4-chloro-5-methoxynicotinaldehyde: A stirred solution of 4-chloro-3-methoxypyridine (180 mg, 1.25 mmol, 1 equivalent) in THF (5 mL) was cooled to -78°C, and a solution of 2 M LDA in THF (1.25 mL, 2.51 mmol, 2 equivalents) was added to it. The reaction mixture was stirred at the same temperature for 30 minutes. Next, N,N-dimethylformamide (0.19 mL, 2.51 mmol, 2 equivalents) was added to the reaction mixture at -78°C. The reaction mixture was gradually warmed to room temperature and stirred for 2.5 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to 0°C, quenched with saturated NH4Cl aqueous solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain the title compound, 4-chloro-5-methoxynicotinaldehyde (210 mg, crude product). This compound was used in the next step without further purification. LC-MS: 172.00 [M+H] + .

[0312] Step 3: Synthesis of 4,5-dimethoxynicotinaldehyde: To a stirred solution of 4-chloro-5-methoxynicotinaldehyde (200 mg, 1.16 mmol, 1 equivalent) in methanol (5 mL), sodium methoxide (126 mg, 2.33 mmol, 2 equivalents) was added, and the reaction mixture was stirred at 60°C for 5 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 4,5-dimethoxynicotinaldehyde (83 mg, 43%). LCMS: 168.10 [M+H] + .

[0313] Synthesis of 2,3-dimethoxyisonicotinaldehyde [ka] To a stirred solution of 2,3-dimethoxypyridine (1 g, 7.18 mmol, 1 equivalent) in THF, a solution of 2.5 M n-BuLi in hexane (6.33 mL, 15.7 mmol, 2.2 equivalents) was added dropwise under an argon atmosphere at -78°C. The reaction mixture was warmed to 0°C and stirred for 1 hour. Then, DMF (2.4 mL, 31.4 mmol, 4.38 equivalents) was added dropwise to the reaction mixture under an argon atmosphere at -78°C. The reaction mixture was warmed to 0°C and stirred under an argon atmosphere for 30 minutes. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound indicated in the title, 2,3-dimethoxyisonicotinaldehyde (250 mg, 20.83%). LCMS: 168.00 [M+H] + .

[0314] Synthesis of 4-(4-chlorophenyl)piperidine [ka] Step 1: Synthesis of 4-(4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl A solution of 1-bromo-4-chlorobenzene (2 g, 10.44 mmol, 1 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (3.87 g, 12.53 mmol, 1.2 equivalents), and potassium carbonate (2.8 g, 20.6 mmol, 2.5 equivalents) in a mixture of water (4 mL) and DMF (20 mL) was placed in a Pyrex® tube. The tube was sealed with a septum, and the reaction mixture was purged with argon using an argon balloon for 15 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (752 mg, 1.04 mmol, 0.1 equivalent) was added to the reaction mixture under an argon atmosphere, and argon purging was continued for 5 minutes. Next, the tube was sealed with a screw cap, and the reaction mixture was heated at 80°C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, the reaction mixture was filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 4-(4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (1.5 g, 49%). LCMS: 294.10 [M+H] + .

[0315] Step 2: Synthesis of tert-butyl 4-(4-chlorophenyl)piperidine-1-carboxylate 4-(4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (1 g, 3.4 mmol, 1 equivalent) was stirred in ethyl acetate (20 mL). The reaction mixture was purged with nitrogen for 5 minutes, and platinum(IV) oxide (150 mg, 15% w / w) was added under a nitrogen atmosphere. The reaction mixture was then purged with hydrogen for 2 minutes, and stirred under a hydrogen atmosphere using a hydrogen balloon at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure to obtain the title compound, 4-(4-chlorophenyl)piperidine-1-carboxylate tert-butyl (900 mg, crude product). This compound was used in the next step without further purification. LCMS: 296.10 [M+H] + .

[0316] Step 3: Synthesis of 4-(4-chlorophenyl)piperidine To a stirred solution of 4-(4-chlorophenyl)piperidine-1-carboxylate tert-butyl (990 mg, 3.35 mmol, 1 equivalent) in DCM (5 mL), trifluoroacetic acid (5 mL) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3 aqueous solution and extracted by DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 4-(4-chlorophenyl)piperidine (600 g, 91.6%). LCMS: 196.10 [M+H] + .

[0317] Synthesis of 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate tert-butyl [ka] Step 1: Synthesis procedure for pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-methyl To a stirred solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (5 g, 23.23 mmol, 1 equivalent) in acetone (20 mL), cesium carbonate (15.14 g, 46.46 mmol, 2 equivalents) was added, followed by iodomethane (4.9 g, 34.85 mmol, 1.5 equivalents). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain the title compound, pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-methyl (3 g, crude product). This compound was used in the next step without further purification. LCMS: 230.15 [M+H] + .

[0318] Step 2: Synthesis procedure for tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate: To a stirred solution of pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-methyl (3 g, 13.33 mmol, 1 equivalent) in methanol (10 mL), sodium borohydride (1.5 g, 39.99 mmol, 3 equivalents) was gradually added at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 3-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl (1 g, 50%). LCMS: 202.15 [M+H] + .

[0319] Step 3: Synthesis procedure for 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate tert-butyl: 3-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl (500 mg, 2.53 mmol, 1 equivalent), triethylamine (0.71 mL, 5.07 mmol, 2 equivalents), and DMAP (31 mg, 0.025 mmol, 0.01 equivalents) were stirred in DCM (5 mL) to which methanesulfonyl chloride (0.24 mL, 3.04 mmol, 1.2 equivalents) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain the title compound, 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate tert-butyl (600 mg, crude product). This compound was used in the next step without further purification.

[0320] B. Synthesis example Example 1: Preparation of the compound The compounds of the present invention can be prepared by a number of methods known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized, as will be understood by those skilled in the art, by using the methods described below in conjunction with known synthetic methods or variations thereof in the field of organic synthesis chemistry. Preferred methods, though not limited to those described below, include the methods described below. The compounds of the present invention can be synthesized by following the steps outlined in general schemes 1, 2, 3, and 4, which include assembly intermediates III, IV, V, VI, VII, and VIII in different orders. Starting materials are commercially available or prepared by known procedures in reported literature, or as illustrated. General Scheme 1 [ka] In the formula, Cy, L 1 , R a , R 6 , and Z are as defined herein. General Scheme 2 [ka] In the formula, Cy, L 1 , R a , R 6 , and Z are as defined herein. General Scheme 3 [ka] In the formula, Cy, L 1 , R a , R 6 , and Z are as defined herein. General Scheme 4 [ka] In the formula, Cy, L 1 , R a , R 6 , and Z are as defined herein.

[0321] A general outline of the method for preparing target molecules IIa and IIc using intermediates III, IV, V, VI, VII, and VIII is shown in general schemes 1-4. Intermediate Va or Vc can be obtained by substitution of intermediate amine (III) with aryl halide (IV) under standard nucleophilic substitution conditions using a base in solvent DMSO or DMF, e.g., N,N-diisopropylethylamine, and / or potassium carbonate or cesium carbonate. Intermediate (Vb) can also be obtained by Buchwald NC coupling or Suzuki CC coupling of aryl halide (IV) with 2° amine or boronic acid (III) at high temperature in the presence of a palladium catalyst. After multiple steps of chemical transformation from intermediates V-VII, the formation of the final compounds of formulas I, I', II, and / or II' provided herein is obtained. The mixture of enantiomers, diastereomers, and cis / trans isomers obtained by the process can be separated into their single components by chiral salt chromatography, normal phase chromatography, reverse phase chromatography, or chiral column chromatography, depending on the nature of the separation.

[0322] In the above explanation and formula, various bases Cy, L 1 , R a , R 6 It should be understood that, and Z, as well as other variables, are as defined above unless otherwise specified. Furthermore, for synthetic purposes, the compounds of general schemes 1-4 are merely representative examples using radicals selected to illustrate general synthetic methods of the compounds of formulas I, I', II, and / or II' provided herein.

[0323] Example A1: N1-(2-(6'-fluoro-1'-methylspiro[cyclohexa Synthesis of n-1,3'-indoline]-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-305) [ka] Step 1: Synthesis procedure for 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid 6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-3-en-4-yl (A1.3) To a stirred solution of 6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-4-one (A1.1) (720 mg 3 mmol, 1 equivalent) in anhydrous THF (10 mL), DBU (1.17 mL, 7.7 mmol, 2.5 equivalents) was added at 0°C, and the reaction mixture was stirred at the same temperature for 10 minutes. Then, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (A1.2) (1.39 g, 4.6 mmol, 1.5 equivalents) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound in the title, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid 6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-3-en-4-yl(A1.3) (800 mg, 50.3%). LCMS: 516.10 [M+H] + .

[0324] Step 2: Synthesis procedure for 2-(6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-3-en-4-yl)nitrobenzene (A1.5) A solution of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid 6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-3-en-4-yl (A1.3) (800 mg, 1.5 mmol, 1 equivalent), (2-nitrophenyl)boronic acid (A1.4) (280 mg, 1.7 mmol, 1.1 equivalents), and cesium carbonate (1 g, 3.1 mmol, 2 equivalents) in a mixture of water (4 mL) and 1,4-dioxane (16 mL) was placed in a Pyrex® tube. The tube was sealed with a septum and the reaction mixture was purged with argon for 10 minutes. Then, bis(triphenylphosphine)palladium(II) dichloride (54 mg, 0.07 mmol, 0.05 equivalents) was added to the reaction mixture under an argon atmosphere. Next, screw caps were attached to the tubes, and the reaction mixture was heated at 100°C for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 2-(6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-3-en-4-yl)nitrobenzene (A1.5) (450 mg, 86.5%). LCMS: 339.15 [M+H] + .

[0325] Step 3: Synthesis procedure for 2-(6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-4-yl)aniline (A1.6) An autoclave containing a solution of 2-(6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-3-en-4-yl)nitrobenzene (A1.5) (450 mg, 1.3 mmol, 1 equivalent) in methanol (10 mL) was purged with nitrogen for 5 minutes. 10% palladium-carbon (135 mg, 30% w / w) was added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was purged with hydrogen and stirred at room temperature for 2 hours under a hydrogen atmosphere (pressure of 60 psi). The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound in question, 2-(6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-4-yl)aniline (A1.6) (200 mg, 47.8). LCMS: 313.20 [M+H] + .

[0326] Step 4: Synthesis procedure for N1-(2-(6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-305) To a stirred solution of 2-(6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-4-yl)aniline (A1.6) (200 mg, 0.6 mmol, 1 equivalent) in acetonitrile (4 mL), pyridine (0.1 mL, 1.2 mmol, 2 equivalents) was added at 0°C, and the reaction mixture was stirred at the same temperature for 10 minutes. Then, compound A1.7 (200 mg, 0.7 mmol, 1.1 equivalents) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound N1-(2-(6'-fluoro-1'-methylspiro[cyclohexane-1,3'-indoline]-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-305), as indicated in the title. Yield: 60 mg, 17.14%; Appearance: Off-white solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.42 - 7.14 (m, 2H), 7.27 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 6.8 Hz, 1H), 7.04 (d, J= 8.0 Hz, 1H), 6.38 - 6.31 (m, 2H), 3.04 (s, 2H), 2.74 - 2.65 (m, 1H), 2.68 (s, 3H), 2.62 (s, 6H), 1.73 - 1.55 (m, 4H), 1.44 - 1.33 (m, 2H), 1.12 (d, J = 12.0 Hz, 2H); HPLC purity: 99.52%; C 28 H 32 LCMS calculated value for FN3O4S2: 557.18; Measured value: 558.40 [M+H] + .

[0327] Example A2: Synthesis of 4-((4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-2-methyl-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-39) [ka] Step 1: Synthesis procedure for 8-(4-chloro-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (A2.3) To a stirred mixture of 1,4-dioxane (250 mL) containing 1,4-dioxane (23 g, 248 mmol, 2 equivalents) (0.1 equivalent), 1,4-dioxane (250 mL) was added. The reaction mixture was purged with argon for 20 minutes, followed by the addition of tris(dibenzylideneacetone)dipalladium (0) (3.4 g, 3.7 mmol, 0.03 equivalents) and BINAP (4.62 g, 7.4 mmol, 0.06 equivalents). The reaction mixture was stirred at 80°C for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through a Celite pad, washed with ethyl acetate, and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 8-(4-chloro-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (A2.3) (20 g, 60%). LCMS: 272.08 [M+H] + .

[0328] Step 2: Synthesis procedure for 1-(4-chloro-2-fluorophenyl)piperidine-4-one (A2.4) 8-(4-chloro-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (A2.3) (20 g) was stirred in THF (70 mL) and 10% H2SO4 (300 mL) was added at 0°C. The resulting reaction mixture was stirred at 90°C for 12 hours. The reaction was monitored by TLC. After stirring was complete, the reaction mixture was quenched with saturated aqueous solutions extracted with sodium bicarbonate and ethyl acetate. The combined organic layers were washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1-(4-chloro-2-fluorophenyl)piperidine-4-one (A2.4) (15 g, 89%). LCMS: 228.05 [M+H] + .

[0329] Step 3: Synthesis procedure for 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid 1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl (A2.6) A mixture of 1-(4-chloro-2-fluorophenyl)piperidine-4-one (A2.4) (5 g, 22.05 mmol, 1 equivalent) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (A2.5) (4.5 mL, 26.46 mmol, 1.2 equivalents) was stirred in 50 mL of THF. DBU (3.9 mL, 26.46 mmol, 1.2 equivalents) was added, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid 1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl (A2.6) (9g, 80%). LCMS: 509.99 [M+H] + .

[0330] Step 4: Synthesis procedure for 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A2.8): A mixture of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid 1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl (A2.6) (9 g, 17.68 mmol, 1 equivalent) and bispinacolate diborone (A2.7) (4.47 g, 17.68 mmol, 1 equivalent) in 1,4-dioxane (70 mL) was purged with argon for 10 minutes. Subsequently, dppf (0.29 g, 0.053 mmol, 3 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.39 g, 0.53 mmol, 0.03 equivalents) were added, and the mixture was stirred at 100°C for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A2.8). Yield: 4.5 g, 76%; Appearance: pale yellow solid; 1 H NMR (400 MHz, CdCl3) δ 7.09 - 6.93 (m, 2H), 6.88 (t, J = 9.1 Hz, 1H), 6.59 (dq, J = 4.5, 2.2 Hz, 1H), 3.68 (q, J = 2.9 Hz, 2H), 3.18 (q, J = 6.4, 6.0 Hz, 2H), 2.40 (m, J = 6.8, 3.5, 2.9 Hz, 2H), 1.28 (d, J = 5.1 Hz, 12H);C 17 H 22 LCMS calculated value for BClFNO2: 337.14; measured value: 338.14 [M+H] + .

[0331] Step 5: General synthesis procedure for 4-((4-bromo-2-methyl-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.11) To a stirred solution of 4-bromo-2-methyl-1H-imidazole (A2.9) (0.5 g, 3.11 mmol, 1 equivalent) in acetonitrile (20 mL), pyridine (0.5 g, 6.21 mmol, 2 equivalents) was added at 0°C, followed by the addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A2.10) (0.97 g, 3.42 mmol, 1.1 equivalents) at 0°C. The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the precipitated solid was filtered and washed with acetonitrile. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography followed by preparative HPLC to obtain 4-((4-bromo-2-methyl-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.11) (1g, 79.3%). LCMS: 407.96 [M+H] + .

[0332] Step 6: General synthesis procedure for 4-((4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-2-methyl-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.12) 4-((4-bromo-2-methyl-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.11) (0.25 g, 0.61 mmol, 1 equivalent) and 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A2.8) (0.27 g, 0.80 mmol, 1.3 equivalents) were stirred in 1,4-dioxane and water (10:2 mL), to which Cs2CO3 (0.4 g, 1.23 mmol, 2 equivalents) and PdCl2(PPh3)2 (0.043 g, 0.061 mmol, 0.1 equivalent) were added at room temperature. The reaction mixture was stirred at 65°C for 7 hours, and the progress of the reaction was monitored by TLC. After stirring was complete, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with water, dried on Na2SO4, and concentrated. The crude residue was purified by silica gel column chromatography to obtain the compound 4-((4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-2-methyl-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.12) (0.24 g, 71.1%). LCMS: 539.09 [M+H] + .

[0333] Step 7: General synthesis procedure for 4-((4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-2-methyl-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.13) 4-((4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-2-methyl-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.12) (0.23 g, 0.43 mmol, 1 equivalent) was stirred in ethyl acetate (25 mL), to which PtO2 (0.12 g) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours under hydrogen gas pressure (75 psi). The progress of the reaction was monitored by TLC. After stirring was complete, the reaction mixture was filtered through a Celite pad, the Celite pad was washed with ethyl acetate, and the filtrate was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 4-((4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-2-methyl-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-39). Yield: 10 mg, 4.33%; Appearance: Off-white solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.50 (s, 1H), 7.31 (dd, J = 12.4, 2.5 Hz, 1H), 7.17 (dd, J = 8.7, 2.5 Hz, 1H), 7.06 (t, J = 9.1 Hz, 1H), 3.39 - 3.33 (m, 2H), 2.78 - 2.68 (m, 8H), 2.61 (m, 1H), 2.47 (m, 3H), 2.00 - 1.92 (m, 2H), 1.68 (tt, J = 12.0, 6.1 Hz, 2H);HPLC purity: >99%;C 23 H 26 LCMS calculated value for ClFN4O4S2: 540.11; measured value: 541.30 [M+H] + .

[0334] The following examples were prepared using standard chemical operations and techniques similar to those used in the preparation of the previously described examples. [Table 6-1] [Table 6-2]

[0335] Example A3: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-33) and N1-(5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-29) [ka] Step 1: Synthesis of 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (A3.2): To a stirred solution of 5-chloro-1,3-dimethyl-1H-pyrazole (A3.1) (3.85 g, 29.6 mmol, 1 equivalent) in H2SO4 (15 mL), KNO3 (3.59 g, 35.5 mmol, 1.2 equivalents) was added in several portions at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was poured into ice water. The resulting solid was separated, dissolved in DCM, and washed with water. The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product, 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (A3.2) (3.8 g, 73%). LCMS: 176.01 [M+H] + .

[0336] Step 2: Synthesis of 4-(1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A3.4): 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (A3.2) (2 g, 11 mmol, 1 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A3.3) (3.88 g, 12.5 mmol, 1.1 equivalent) were stirred in 1,4-dioxane (50 mL). 2 M Na2CO3 (3.29 g, 34.2 mmol, 3 equivalents) was added to the mixture, and the reaction mixture was purged with argon for 15 minutes. Subsequently, tetrakis(triphenylphosphine)palladium (0) (1.32 g, 1.14 mmol, 0.1 equivalent) was added, and the mixture was stirred at 100°C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through Celite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 4-(1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A3.4) (3.5 g, 94%). LCMS: 323.16 [M+H] + .

[0337] Step 3: Synthesis of 4-(1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)-1,2,3,6-tetrahydropyridine, TFA salt (A3.5): To a stirred solution of 4-(1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A3.4) (3.5 g, 10.8 mmol, 1 equivalent) in DCM (40 mL), TFA (20 mL) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 12 hours, and the progress of the reaction was monitored by TLC. After stirring was complete, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with diethyl ether, and the resulting precipitate was filtered and concentrated to obtain the target compound, 4-(1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)-1,2,3,6-tetrahydropyridine, TFA salt (A3.5) (2 g, 82%).

[0338] Step 4: Synthesis of 1-(4-chloro-2-fluorophenyl)-4-(1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)-1,2,3,6-tetrahydropyridine (A3.7): To a stirred mixture of 4-(1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)-1,2,3,6-tetrahydropyridine, TFA salt (A3.5) (2g, 5.9 mmol, 1 equivalent), 1-bromo-4-chloro-2-fluorobenzene (A3.6) (1.37g, 6.5 mmol, 1.1 equivalents) in 1,4-dioxane (100mL) was added, followed by Cs2CO3 (3.88g, 11.9 mmol, 2 equivalents). The reaction mixture was purged with argon, and then Davephos (0.47g / m³ 11.9 mmol, 0.2 equivalents) and Pd2(dba)3 (0.54g, 0.59 mmol, 0.1 equivalents) were added. The reaction mixture was stirred at 90°C for 1 hour. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 1-(4-chloro-2-fluorophenyl)-4-(1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)-1,2,3,6-tetrahydropyridine (A3.7) (1.5 g, 63.5%). LCMS: m / z 351.09 [M+H] + .

[0339] Step 5: Synthesis of 5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-4-amine (A3.8): To a stirred solution of 1-(4-chloro-2-fluorophenyl)-4-(1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)-1,2,3,6-tetrahydropyridine (A3.7) (0.6 g, 1.7 mmol, 1 equivalent) in a mixture of ethanol (20 mL) and water (6 mL), ammonium chloride (0.45 g, 8.5 mmol, 5 equivalents) was added, followed by the addition of Fe powder (0.47 g, 8.57 mmol, 5 equivalents) at room temperature. The resulting reaction mixture was refluxed at 90°C for 3 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through Celite, and the filtrate was evaporated to dryness. The crude product was diluted with water, extracted with ethyl acetate, washed with water and brine, dried on anhydrous sodium sulfate, and removed by distillation under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-4-amine (A3.8) (500 mg, 90%). 321.12: [M+H] + .

[0340] Step 6: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide, (A-29): 5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-4-amine (A3.8) (100 mg, 0.31 mmol, 1 equivalent) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A3.9) (0.11 gm 0.37 mmol, 1.2 equivalents) were stirred in acetonitrile (3 mL), to which pyridine (0.075 mL, 0.93 mmol, 3 equivalents) was added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After stirring was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the compound N1-(5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide, (A-29). Yield: 35 mg, 19%; Appearance: Off-white solid; 1 H NMR (400 MHz, DMSO-d6) δ 9.49 (bs, 1H), 7.93 - 7.83 (m, 4H), 7.31 (dd, J = 12.6, 2.5 Hz, 1H), 7.15 (ddd, J = 8.6, 2.6, 1.2 Hz, 1H), 7.02 (t, J = 9.1 Hz, 1H), 5.65 (m, 1H), 3.53 (d, J = 14.3 Hz, 5H), 2.98 (t, J = 5.5 Hz, 2H), 2.58 (s, 6H), 2.17 (d, J = 4.0 Hz, 2H), 1.71 (s, 3H);HPLC purity:98.3%;C 24 H 27 LCMS calculated value for ClFN5O4S2: 567.12; Measured value: 568.35 [M+H] + .

[0341] Step 7: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide, (A-33): To a stirred solution of N1-(5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-29) (0.20 g, 0.35 mmol, 1 equivalent) in ethyl acetate (10 mL), PtO2 (0.10 g) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 6 hours under a hydrogen gas pressure of 100 psi. The progress of the reaction was monitored by TLC. After stirring was complete, the reaction mixture was filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was removed by distillation under reduced pressure. The crude product was purified by column chromatography followed by preparative HPLC to obtain the title compound, N1-(5-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide, (A-33). Yield: 50 mg, 25%; Appearance: Off-white solid; 1 H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.96 (m, 4H), 7.38 - 7.29 (m, 1H), 7.23 - 7.15 (m, 1H), 7.06 (t, J = 9.0 Hz, 1H), 3.71 (s, 3H), 3.33 (m, 2H), 2.64 - 2.50 (m, 9H), 2.11 - 1.96 (m, 2H), 1.48 (d, J = 32.2 Hz, 5H); HPLC purity: 96.85%; C 24 H 29 LCMS calculated value for ClFN5O4S2: 569.13; Measured value: 570.1 [M+H] + .

[0342] Example A4: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-75): [ka] Step 1: Synthesis of N-(1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.2): To a stirred solution of 1,3-dimethyl-1H-pyrazole-5-amine (A4.1) (3 g, 27 mmol, 1 equivalent) in ethyl acetate (30 mL), potassium acetate (2.91 g, 29.70 mmol, 1.1 equivalent) and acetic anhydride (3.03 g, 29.7 mmol, 1.1 equivalent) were added at 0°C. The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target product, N-(1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.2) (4 g, 96.8%). LCMS: 154.09 [M+H] + .

[0343] Step 2: Synthesis of N-(4-bromo-1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.3): To a stirred solution of N-(1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.2) (4 g, 26.14 mmol, 1 equivalent) in DCM (40 mL), NBS (5.58 g, 31.37 mmol, 1.2 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After stirring was complete, the reaction mixture was diluted in DCM and washed with sodium thiosulfate solution. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound, N-(4-bromo-1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.3) (5.5 g, crude product). The crude product was used directly in the next step without purification. LCMS: 232 [M+H] + .

[0344] Step 3: Synthesis of N-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.5): To a stirred solution of N-(4-bromo-1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.3) (1.5 g, 6.46 mmol, 1 equivalent) and 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A4.4) (4.3 g, 12.93 mmol, 2 equivalents) in 1,4-dioxane:H2O (4:1, 30 mL), K2CO3 (1.78 g, 10.29 mmol, 2 equivalents) was added at room temperature. The reaction mixture was purged with argon for 10 minutes, followed by the addition of X-phos (0.061 g, 0.12 mmol, 0.02 equivalents) and Pd(OAC)2 (0.1 g, 0.45 mmol, 0.07 equivalents). The reaction mixture was stirred at 100°C for 12 hours. The progress of the reaction was monitored by TLC. After stirring, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated. The crude residue was purified by column chromatography to obtain the target compound, N-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.5) (1 g, 42.7%). LCMS: 363.13 [M+H] + .

[0345] Step 4: Synthesis of N-(4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.6): To a stirred solution of N-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.5) (1 g, 2.75 mmol, 1 equivalent) in MeOH:ethyl acetate (1:1, 20 mL), PtO2 (0.2 g) was added at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours under a hydrogen gas pressure of 50 psi. The reaction was monitored by TLC. After completion, the reaction mixture was filtered through a Celite pad, and the filtrate was removed under reduced pressure. The crude product was purified by column chromatography followed by preparative HPLC to obtain the title compound, N-(4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.6) (0.7 g, 71%). LCMS: 365.15 [M+H] + .

[0346] Step 5: Synthesis of 4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-5-amine (A4.7): The solution of N-(4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-5-yl)acetamide (A4.6) (0.71 g, 1.94 mmol, 1 equivalent) in a mixture of ethanol and sodium hydroxide solution (50% aqueous solution) (1:1, 14 mL) was stirred at 90°C for 16 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was diluted with water and extracted by DCM. The combined organic extract was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the title compound, 4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-5-amine (A4.7) (0.45 g, 72.5%). LCMS: 323.14 [M+H] + .

[0347] Step 6: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-75): To a stirred solution of 4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-5-amine (A4.7) (0.45 g, 1.39 mmol, 1 equivalent) in ACN (10 mL), pyridine (0.22 mL, 2.78 mmol, 2 equivalents) was added at 0°C. The reaction mixture was stirred at the same temperature for 10 minutes, and then 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A4.8) (0.44 g, 1.53 mmol, 1.1 equivalents) was added at 0°C. The reaction mixture was stirred at 80°C for 12 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extract was washed with water and brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the compound N1-(4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dimethyl-1H-pyrazole-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-75), as indicated in the title. Yield: 20 mg, 2.5%; Appearance: Off-white solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.02 (d, J = 1.3 Hz, 4H), 7.29 (dd, J = 12.3, 2.5 Hz, 1H), 7.19 - 7.11 (m, 1H), 6.98 (t, J = 9.1 Hz, 1H), 3.52 (s, 3H), 3.18 (d, J = 11.4 Hz, 2H), 2.66 (s, 6H), 2.22 (t, J = 12.0 Hz, 2H), 2.10 (s, 3H), 1.81 (ddd, J = 15.4, 7.8, 3.3 Hz, 1H), 1.72 - 1.64 (m, 2H), 1.08 (s, 2H);HPLC purity:98.14%;C 24 H 29LCMS calculated value for ClFN5O4S2: 569.13; Measured value: 570.20 [M+H] + .

[0348] Example A5: Synthetic scheme for the synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-pyrazole-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-55) [ka] Step 1: Synthesis of 4-(3-amino-1-methyl-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A5.3): To a mixture of 4-bromo-1-methyl-1H-pyrazole-3-amine (A5.1) (1.5 g, 8.5 mmol, 1 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A5.2) (3.42 g, 11 mmol, 1.3 equivalents) in a 1,4-dioxane:H2O mixture (4:1, 20 mL), Cs2CO3 (5.55 g, 17.03 mmol, 2 equivalents) was added at room temperature. The reaction mixture was purged with argon for 10 minutes, followed by the addition of dichlorobis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2) (0.41 g, 0.59 mmol, 0.07 equivalents), and the mixture was stirred at 100°C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate, washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 4-(3-amino-1-methyl-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A5.3) (1.8 g, 75.9%). LCMS: 279.17 [M+H]+.

[0349] Step 2: Synthesis of 4-(3-amino-1-methyl-1H-pyrazole-4-yl)piperidine-1-carboxylate tert-butyl (A5.4): To a stirred solution of 4-(3-amino-1-methyl-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (A5.3) (1.8 g, 6.4 mmol, 1 equivalent) in a mixture of methanol and ethyl acetate (1:1, 36 mL), triethylsilane (16 mL, 97.12 mmol, 15 equivalents) and Pd / C (0.36 g) were added at 0°C. The reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere (balloon pressure). The reaction was monitored by TLC. After completion, the reaction mixture was filtered through a Celite pad, and the filtrate was removed under reduced pressure. The crude product was purified by column chromatography to obtain the target compound, 4-(3-amino-1-methyl-1H-pyrazole-4-yl)piperidine-1-carboxylic acid tert-butyl (A5.4) (1.3 g, 71.8%). LCMS: 281.19 [M+H]+.

[0350] Step 3: Synthesis of 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido-1-methyl-1H-pyrazole-4-yl)piperidine-1-carboxylate tert-butyl (A5.6): To a stirred solution of 4-(3-amino-1-methyl-1H-pyrazole-4-yl)piperidine-1-carboxylate tert-butyl (A5.4) (1.3 g, 4.63 mmol, 1 equivalent) in acetonitrile (25 mL), pyridine (0.73 mL, 9.27 mmol, 2 equivalents) was added at 0°C, and the reaction mixture was stirred at the same temperature for 5 minutes. Subsequently, 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A5.5) (1.44 g, 5.10 mmol, 1.1 equivalents) was added in several portions. The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and brine, dried on anhydrous sodium sulfate, and removed by distillation under reduced pressure. The crude product was purified by column chromatography to obtain the target compound, 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-1-methyl-1H-pyrazole-4-yl)piperidine-1-carboxylate tert-butyl (A5.6) (1.5 g, 61.4%). LCMS: 528.19 [M +H] +.

[0351] Step 4: Synthesis of N1,N1-dimethyl-N4-(1-methyl-4-(piperidine-4-yl)-1H-pyrazole-3-yl)benzene-1,4-disulfonamide (A5.7): To a stirred solution of 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-1-methyl-1H-pyrazole-4-yl)piperidine-1-carboxylate tert-butyl (A5.6) (1.5 g, 2.8 mmol, 1 equivalent) in DCM (7.5 mL, 5 volumes), TFA (7.5 mL, 5 volumes) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was evaporated to dryness, and the crude salt was neutralized using a saturated sodium bicarbonate solution to a pH of approximately 7, and extracted with DCM. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under reduced pressure to obtain the target compound, N1,N1-dimethyl-N4-(1-methyl-4-(piperidine-4-yl)-1H-pyrazole-3-yl)benzene-1,4-disulfonamide (A5.7) (0.5 g, crude product). The crude product was used directly in the next step without purification. LCMS: 428.13 [M+H]+.

[0352] Step 5: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-pyrazole-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-55) To a stirred solution of N1,N1-dimethyl-N4-(1-methyl-4-(piperidine-4-yl)-1H-pyrazole-3-yl)benzene-1,4-disulfonamide (A5.7) (0.12 g, 0.57 mmol, 1 equivalent) and 1-bromo-4-chloro-2-fluorobenzene (A5.8) (0.27 g, 0.63 mmol, 1.1 equivalent) in 1,4-dioxane (5 mL), NaOtBu (0.11 g, 1.14 mmol, 2 equivalents) was added at room temperature. The reaction mixture was purged with argon for 10 minutes, followed by the addition of Davephos (13.45 mg, 0.03 mmol, 0.06 equivalents) and Pd2(dba)3 (15.66 mg, 0.02 mmol, 0.03 equivalents). The reaction mixture was stirred at 90°C for 12 hours, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried on Na2SO4, and concentrated. The crude residue was purified by silica gel column chromatography to obtain the target compound, N1-(4-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-pyrazole-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-55). Yield: 0.018 mg, 5.1%; Appearance: Off-white solid; 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.06 - 7.92 (m, 4H), 7.52 (s, 1H), 7.31 (dd, J = 12.5, 2.5 Hz, 1H), 7.22 - 7.14 (m, 1H), 7.06 (t, J = 9.1 Hz, 1H), 3.62 (s, 3H), 3.30 (m, 2H), 2.65-2.57 (m, 8H), 2.38 (m, 1H), 1.73 (d, J = 10.8 Hz, 2H), 1.55 (qd, J = 12.2, 3.7 Hz, 2H); HPLC purity: over 99%; LCMS calculated value for C23H27ClFN5O4S2: 555.12; measured value: 556.1 [M+H]+. Example A6: Synthesis of N1-(2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3,3]heptan-2-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-296): [ka] Step 1: Synthesis of 6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (A6.3): A solution of 2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl hydrochloride (A6.1) (850 mg, 3.62 mmol, 1 equivalent), 1-bromo-4-chloro-2-fluorobenzene (A6.2) (833 mg, 3.98 mmol, 1.1 equivalent), and cesium carbonate (2.36 g, 7.23 mmol, 2 equivalents) in toluene (15 mL) was placed in a Pyrex® tube. The tube was sealed with a septum, and the reaction mixture was purged with argon for 15 minutes. Tris(dibenzylideneacetone)dipalladium (0) (99 mg, 0.108 mmol, 0.3 equivalents) and BINAP (157 gm² 0.253 mmol, 0.07 equivalents) were added to the reaction mixture under an argon atmosphere. Next, a screw cap was attached to the tube, and the reaction mixture was heated at 100°C for 5 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (A6.3) (1 g, 84.74%). LCMS: 327.10 [M+H] + . Step 2: Synthesis of 2-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane, TFA salt (A6.4): To a stirred solution of 6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (A6.3) (1 g, 3.07 mmol, 1 equivalent) in DCM (20 mL), trifluoroacetic acid (1.75 mL, 12.27 mmol, 4 equivalents) was added at room temperature, and the reaction mixture was stirred at the same temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated to dryness under reduced pressure. The residue was then evaporated to dryness together with DCM under reduced pressure to obtain the title compound, 2-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane (A6.4) (1.1 g, crude product), as the TFA salt. This compound was used in the next step without further purification. LCMS: 227.10 [M+H] + . Step 3: Synthesis of 2-(4-chloro-2-fluorophenyl)-6-(2-nitrophenyl)-2,6-diazaspiro[3.3]heptane (A6.6): Potassium carbonate and 1-fluoro-2-nitrobenzene (A6.5) (0.528 g, 3.75 mmol, 1.1 equivalent) were added to a stirred solution of 2-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane, TFA salt (A6.4) (1.1 g, 3.41 mmol, 1 equivalent) in DMF (20 mL). The reaction mixture was heated at 85 °C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ice water, and extracted with ethyl acetate. The combined organic layers were washed with ice-cold water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain the title compound, 2-(4-chloro-2-fluorophenyl)-6-(2-nitrophenyl)-2,6-diazaspiro[3.3]heptane (A6.6) (0.71 g, crude product). This compound was used in the next step without further purification. LCMS: 348.10 [M+H] + . Step 4: Synthesis of 2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)aniline (A6.7): To a stirred solution of 2-(4-chloro-2-fluorophenyl)-6-(2-nitrophenyl)-2,6-diazaspiro[3.3]heptane (A6.6) (600 mg, 1.73 mmol, 1 equivalent) in a mixture of water (2 mL) and ethanol (10 mL), iron powder (386 mg, 6.92 mmol, 4 equivalents) and ammonium chloride (370 mg, 6.92 mmol, 4 equivalents) were added. The reaction mixture was heated at 80°C for 5 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound in question, 2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)aniline (A6.7) (310 mg, 56.56%). LCMS: 318.10 [M+H] + . Step 5: Synthesis of N1-(2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A6.9): To a stirred solution of 2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)aniline (A6.7) (200 mg, 0.631 mmol, 1 equivalent) in acetonitrile (5 mL), pyridine (0.1 mL, 1.26 mmol, 2 equivalents) was added, followed by the addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A6.8) (196 mg, 0.694 mmol, 1.1 equivalents) at room temperature. The reaction mixture was stirred for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with 1N aqueous HCl and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography. The compound was further tritulate with diethyl ether, the solid was filtered off, and dried under reduced pressure to obtain the title compound, N1-(2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-296). Yield: 30 mg, 8.42%; Appearance: White solid; 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.95 (s, 4H), 7.24 (d, J = 12.4 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.58 (t, J = 9.2 Hz, 1H), 6.52 (t, HPLC purity: 99.53%;C 25 H 26 LCMS calculated value for ClFN4O4S2: 564.11; Measured value: 565.15 [M+H] + .

[0353] Example A7: Synthesis of N1-(4-(1-(2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-pyrazole-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-40): [ka] Step 1: Synthesis of 4-(3-amino-1-methyl-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A7.3): To a mixture of 4-bromo-1-methyl-1H-pyrazole-3-amine (A7.1) (1.5 g, 8.5 mmol, 1 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A7.2) (3.42 g, 11 mmol, 1.3 equivalents) in a 1,4-dioxane:H2O mixture (4:1, 20 mL), Cs2CO3 (5.55 g, 17.03 mmol, 2 equivalents) was added at room temperature. The reaction mixture was purged with argon for 10 minutes, followed by the addition of dichlorobis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2) (0.41 g, 0.59 mmol, 0.07 equivalents), and the mixture was stirred at 100°C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate, washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 4-(3-amino-1-methyl-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A7.3) (1.5 g, 63.5%). LCMS: 279.17 [M+H] + .

[0354] Step 2: Synthesis of 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-1-methyl-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A7.5): To a stirred solution of 4-(3-amino-1-methyl-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A7.3) (1.5 g, 5.39 mmol, 1 equivalent) in acetonitrile (20 mL), pyridine (0.9 mL, 10.79 mmol, 2 equivalents) was added at 0°C. The reaction mixture was stirred at the same temperature for 5 minutes, and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A7.4) (1.68 g, 5.93 mmol, 1.1 equivalents) was added in several portions. The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the title compound, 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-1-methyl-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A7.5) (1.85 g, 65.3%). LCMS: 526.17 [M+H] + .

[0355] Step 3: Synthesis of N1,N1-dimethyl-N4-(1-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-pyrazole-3-yl)benzene-1,4-disulfonamide (A7.6): To a stirred solution of 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-1-methyl-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A7.5) (1.85 g, 3.5 mmol, 1 equivalent) in DCM (9.25 mL, 5 volumes), TFA (9.25 mL, 5 volumes) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, and the progress of the reaction was monitored by TLC. After stirring was complete, the reaction mixture was evaporated to dryness, and a saturated sodium bicarbonate solution was added to the reaction mixture until the pH was approximately 8. The resulting solid was filtered and concentrated under reduced pressure to obtain the target N1,N1-dimethyl-N4-(1-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-pyrazole-3-yl)benzene-1,4-disulfonamide (A7.6) (0.8 g, crude product). The crude product was used directly in the next step without purification. LCMS: 426.12 [M+H] + .

[0356] Step 4: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1-methyl-1H-pyrazole-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A7.8): To a stirred solution of N1,N1-dimethyl-N4-(1-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-pyrazole-3-yl)benzene-1,4-disulfonamide (A7.6) (0.32 g, 1.5 mmol, 1 equivalent) and 1-bromo-4-chloro-2-fluorobenzene (A7.7) (0.71 g, 1.68 mmol, 1.1 equivalent) in 1,4-dioxane (20 mL), NaOtBu (0.29 g, 3 mmol, 2 equivalents) was added at room temperature. The reaction mixture was purged with argon for 15 minutes, followed by the addition of Davephos (3 mg, 0.09 mmol, 0.06 equivalents) and Pd2(dba)3 (42 mg, 0.46 mmol, 0.03 equivalents). The reaction mixture was stirred at 90°C for 12 hours. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated. The crude residue was purified by silica gel column chromatography to obtain the target compound, N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1-methyl-1H-pyrazole-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A7.8) (0.33 g, 35.8%). LCMS: 554.10 [M+H] + .

[0357] Step 5: Synthesis of N1-(4-(1-(2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-pyrazole-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A7.9): To a stirred solution of N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-1-methyl-1H-pyrazole-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A7.8) (0.3 g, 0.54 mmol, 1 equivalent) in methanol:ethyl acetate (1:1, 9 mL), triethylsilane (0.94 mL, 8.12 mmol, 15 equivalents) and Pd / C (0.06 g) were added at 0°C. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 12 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a Celite pad, and the filtrate was removed under reduced pressure. The crude product was diluted with water, extracted with ethyl acetate, washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target N1-(4-(1-(2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-pyrazole-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-40). Yield: 0.015 g, 5.3%; Appearance: Off-white solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.06 - 7.93 (m, 4H), 7.53 (s, 1H), 7.17 - 7.01 (m, 3H), 7.01 - 6.91 (m, 1H), 3.64 (s, 3H), 3.35 HPLC purity:97.08%;C 23 H 28 LCMS calculated value for FN5O4S2: 521.16; Measured value: 522.40 [M + H] + .

[0358] Example A8: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-3-methylisoxazole-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-65): [ka] Step 1: Synthesis of 4-(5-amino-3-methylisoxazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A8.3): 3-methylisoxazole-5-amine (A8.1) (1 g, 10 mmol, 1 equivalent) was stirred in acetic acid (15 mL) to which 4-oxopiperidine-1-carboxylate tert-butyl (A8.2) (3.04 g, 15 mmol, 1.5 equivalents) was added. The reaction mixture was stirred at 70 °C for 12 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was concentrated, the crude product was based with 10% NaOH solution, and extracted with ethyl acetate. The combined organic extract was dried over anhydrous sodium sulfate and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 4-(5-amino-3-methylisoxazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A8.3) (2 g, 70%). LCMS: 280.16 [M+H] + .

[0359] Step 2: Synthesis of 4-(5-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-3-methylisoxazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A8.5): To a mixture of 4-(5-amino-3-methylisoxazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A8.3) (2 g, 7.16 mmol, 1 equivalent) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A8.4) (2.44 g, 8.6 mmol, 1.2 equivalents) in anhydrous THF (15 mL), LiHMDS (11 mL, 10.7 mmol, 1.5 equivalents) was added at -78°C. The reaction mixture was stirred at the same temperature for 15 minutes, and then stirred again at room temperature for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with 1N HCl and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and removed by distillation under reduced pressure. The crude product was triturated with diethyl ether and concentrated under reduced pressure to obtain the target product, 4-(5-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-3-methylisoxazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl(A8.5) (3g, 79%). LCMS: 527.16 [M+H] + .

[0360] Step 3: Synthesis of N1,N1-dimethyl-N4-(3-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl)isoxazole-5-yl)benzene-1,4-disulfonamide, TFA salt (A8.6): To a stirred solution of 4-(5-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamide)-3-methylisoxazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (A8.5) (2 g, 3.8 mmol, 1 equivalent) in DCM (50 mL), TFA (20 mL) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated, the crude product was triturated with diethyl ether, and dried under reduced pressure to obtain the target compound, N1,N1-dimethyl-N4-(3-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl)isoxazole-5-yl)benzene-1,4-disulfonamide, TFA salt (A8.6) (2 g, crude product). The crude product was used directly in the next step without purification. LCMS: 427.10 [M+H] + .

[0361] Step 4: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-3-methylisoxazole-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A8.8): To a mixture of N1,N1-dimethyl-N4-(3-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl)isoxazole-5-yl)benzene-1,4-disulfonamide, TFA salt (A8.6) (2 g, 3.6 mmol, 1 equivalent) and 2-bromo-4-chloro-1-fluorobenzene (A8.7) (0.92 g, 4.4 mmol, 1.2 equivalents) in 1,4-dioxane (50 mL), NaOtBu (1.41 g, 14.7 mmol, 4 equivalents) was added. The reaction mixture was purged with nitrogen, and then Davephos (84 mg, 2.16 mmol, 0.06 equivalents) and Pd2(dba)3 (98 mg, 0.11 mmol, 0.03 equivalents) were added. The reaction mixture was stirred at 90 °C for 12 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite pad, and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was triturated with hexane and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the target product, N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-3-methylisoxazole-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-65). Yield: 30 mg, 2%; Appearance: Orange solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.08 - 7.92 (m, 4H), 7.33 (dt, J = 11.4, 3.2 Hz, 1H), 7.17 (dd, J = 8.8, 2.5 Hz, 1H), 7.05 (t, J = 9.1 Hz, 1H), 5.83 - 5.69 (m, 1H), 3.59 (q, J = 3.6 Hz, 2H), 3.11 (t, J = 5.5 Hz, 2H), 2.63 (s, 6H), 2.89 (m, 2H), 2.16 (s, 3H), one exchangeable proton was not observed due to water in the solvent; HPLC purity: 95.85%; C 23 H 24 LCMS calculated value for ClFN4O5S2: 554.09; Measured value: 555.0 [M+H] + .

[0362] Example A9: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3,4-thiadiazole-2-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-64): [ka] Step 1: Synthesis of 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylate ethyl (A9.3): To a stirred solution of 1-bromo-4-chloro-2-fluorobenzene (A9.1) (1 g, 4.7 mmol, 1 equivalent) and piperidine-4-carboxylate ethyl (A9.2) (1.1 g, 7.1 mmol, 1.5 equivalents) in DMF (20 mL), Cs2CO3 (3 g, 9.4 mmol, 2 equivalents) was added. The reaction mixture was purged with argon for 15 minutes, followed by the addition of Davephos (110 mg, 0.28 mmol, 0.06 equivalents) and Pd2(dba)3 (430 mg, 0.47 mmol, 0.1 equivalents). The reaction mixture was stirred at 100°C for 4 hours, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated. The crude residue was purified by silica gel column chromatography to obtain the target ethyl 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylate (A9.3) (500 mg, 38%). LCMS: 286.09 [M+H] + .

[0363] Step 2: Synthesis of 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylic acid (A9.4): To a stirred solution of ethyl 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylic acid (A9.3) (0.5 g, 2.78 mmol, 1 equivalent) in ethanol:water (5:1, 12 mL), LiOH (83 mg, 3.5 mmol, 2 equivalents) was added at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated, the residue was acidified with dilute hydrochloric acid, and extracted by DCM. The combined organic extract was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound, 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylic acid (A9.4) (400 mg, crude product). The crude product was used directly in the next step without purification. LCMS: 258.06 [M+H]+.

[0364] Step 3: Synthesis of 2-(1-(4-chloro-2-fluorophenyl)piperidine-4-carbonyl)hydrazine-1-carbothioamide (A9.6): To a stirred solution of 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylic acid (A9.4) (400 mg, 1.5 mmol, 1 equivalent) in DMF (10 mL), HATU (855 mg, 2.2 mmol, 1.5 equivalents) and NMM (454 mg, 4.5 mmol, 3 equivalents) were added at room temperature. The reaction mixture was stirred for 10 minutes, followed by the addition of hydrazinecarbothioamide (A9.5) (170 mg, 1.86 mmol, 1.2 equivalents). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water, then methanol was added, the resulting solid was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(1-(4-chloro-2-fluorophenyl)piperidine-4-carbonyl)hydrazine-1-carbothioamide (A9.6) (450 mg, 87%). LCMS: 331.07 [M+H] + .

[0365] Step 4: Synthesis of 5-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3,4-thiadiazole-2-amine (A9.7): A solution of 2-(1-(4-chloro-2-fluorophenyl)piperidine-4-carbonyl)hydrazine-1-carbothioamide (A9.6) (450 mg, 1.3 mmol, 1 equivalent) in H2SO4 (15 mL) was stirred overnight at room temperature. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with ice water, then ammonia solution and methanol were added. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the target product, 5-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3,4-thiadiazole-2-amine (A9.7) (400 mg, crude product). The crude product was used directly in the next step without purification. LCMS: 313.06 [M+H] + .

[0366] Step 5: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3,4-thiadiazole-2-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide, (A-64): To a stirred solution of 5-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3,4-thiadiazole-2-amine (A9.7) (400 mg, 1.2 mmol, 1 equivalent) in acetonitrile (20 mL), pyridine (0.21 mL, 2.4 mmol, 2 equivalents) was added at 0°C. The reaction mixture was stirred for 15 minutes, followed by the addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A9.8) (407 g, 1.4 mmol, 1.2 equivalents). The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the compound in question, N1-(5-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3,4-thiadiazole-2-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-64). Yield: 60 mg, 8%; Appearance: Off-white solid;1 H NMR (400 MHz, DMSO-d6) δ 14.27 (s, 1H), 8.08 - 8.00 (m, 2H), 7.96 - 7.88 (m, 2H), 7.32 (dd, J = 12.4, 2.5 Hz, 1H), 7.17 (ddd, J = 8.8, 2.4, 1.0 Hz, 1H), 7.07 (t, J = 9.1 Hz, 1H), 3.39 - 3.32 (m, 2H), 3.13 - 3.06 (m, 1H), 2.83 - 2.6 (m, 2H), 2.64 (s, 6H), 2.13 - 2.04 (m, 2H), 1.88 - 1.73 (m, 2H);HPLC purity:96.07%;C 21 H 23 LCMS calculated value for ClFN5O4S3: 559.06; Measured value: 559.9 [M+H] + .

[0367] Example A10: Synthesis of N1-(3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-1,2,4-triazole-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-95): [ka] Step 1: Synthesis of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (A10.2): To a stirred solution of compound (A10.1) (5 g, 22 mmol, 1 equivalent) in DMF (25 mL), K2CO3 (4.56 g, 33 mmol, 1.5 equivalents) was added at 0°C, followed by the addition of methyl iodide (1.64 g, 26.4 mmol, 1.2 equivalents) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography to obtain the target compound, 3,5-dibromo-1-methyl-1H-1,2,4-triazole (A10.2). The reaction was repeated on a 5 g scale. The total yield was 9 g, 85.87%. LCMS: 239.87 [M+H] + .

[0368] Step 2: Synthesis of 3-bromo-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.4): To a stirred solution of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (A10.2) (4 g, 16.8 mmol, 1 equivalent) in 1,4-dioxane (30 mL), DIPEA (5.8 g, 33.6 mmol, 2 equivalents) and DMA (15 mL) were added at room temperature, followed by the addition of (4-methoxyphenyl)methaneamine (A10.3) (9.2 g, 67.2 mmol, 4 equivalents). The reaction mixture was stirred at 120 °C for 12 hours. The progress of the reaction was monitored by TLC. After stirring, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with water, dried over Na₂SO₄, and concentrated. The crude product was purified by silica gel column chromatography to obtain the target compound, 3-bromo-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.4) (2.6 g, 53%). LCMS: 297.03 [M+H] + .

[0369] Step 3: Synthesis of 3-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.6): A mixture of 3-bromo-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.4) (1 g, 3.37 mmol, 1 equivalent), 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A10.5) (1.25 g, 3.71 mmol, 1.1 equivalent), and Na2CO3 (0.71 g, 6.75 mmol, 2 equivalents) in a mixture of 1,4-dioxane and water (4:1, 10 mL) was purged with argon for 15 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.27 g, 2.36 mmol, 0.07 equivalent). The reaction mixture was stirred at 90 °C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 3-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.6) (1 g, 69.4%). LCMS: 428.16 [M+H] + .

[0370] Step 4: Synthesis of 3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.7): 3-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.6) (1 g, 2.34 mmol, 1 equivalent) was stirred in methanol (20 mL), to which Pd / C (0.2 g) was added. The reaction mixture was stirred at room temperature for 12 hours under hydrogen balloon pressure. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.7) (0.5 g, 50%). LCMS: 430.17 [M+H] + .

[0371] Step 5: Synthesis of 3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.8): 3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.7) (0.5 g, 1.16 mmol, 1 equivalent) was poured into TFA (2.5 mL) at 0°C and then stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated. The crude product was washed with water and pentane to obtain the target compound, 3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.8) (0.3 g, 82.87%). LCMS: 310.12 [M+H] + .

[0372] Step 6: Synthesis of N1-(3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-1,2,4-triazole-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-95): To a stirred solution of 3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-1,2,4-triazole-5-amine (A10.8) (0.3 g, 0.97 mmol, 1 equivalent) in DMF (15 mL), NaH (0.14 g, 5.8 mmol, 6 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A10.9) (0.41 g, 1.45 mmol, 1.5 equivalents). The reaction mixture was stirred at 80°C for 12 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography followed by preparative HPLC to obtain the target compound, N1-(3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1-methyl-1H-1,2,4-triazole-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-95). Yield: 0.07 g, 13.2%; Appearance: White solid; 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 12.2, 2.4 Hz, 1H), 7.21 - 7.13 (m, 1H), 7.08 (t, J = 9.1 Hz, 1H), 3.45 (s, 3H), 3.38 (d, J = 12.2 Hz, 2H), 2.91 - 2.89 (m, 1H), 2.80 - 2.69 (m, 2H), 2.64 (s, 6H), 2.10 - 1.97 (m, 2H), 1.81 - 1.73 (m, 2H);HPLC purity: >99%;C 22 H26 LCMS calculated value for ClFN6O4S2: 556.11; Measured value: 557.10 [M+H] + .

[0373] Example A11: Synthesis of 4-((3-(1-(5-chloro-3-fluoropyridine-2-yl)piperidine-4-yl)-1H-pyrazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-96): [ka] Step 1: Synthesis of piperidine-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl (A11.2): To a stirred solution of piperidine-4-carboxylate ethyl (A11.1) (10 g, 63.61 mmol, 1 equivalent) and Boc anhydride (13.4 mL, 95.41 mmol, 1.5 equivalents) in DCM (300 mL), TEA (13.4 mL, 95.41 mmol, 1.5 equivalents) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target product, piperidine-1,4-dicarboxylate 1-(tert-butyl)4-ethyl (A11.2) (8 g, 48.89%). LCMS: 358.16 [M+H] + .

[0374] Step 2: Synthesis of 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate tert-butyl (A11.4): To a stirred solution of piperidine-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl (A11.2) (3 g, 11.66 mmol, 1 equivalent) and N,O-dimethylhydroxylamine (A11.3) (1.3 g, 13.99 mmol, 1.2 equivalents) in THF (100 mL), isopropyl magnesium chloride (11.66 mL, 23.32 mmol, 2 equivalents) was added dropwise at -20°C. The reaction mixture was stirred at -5°C for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried on anhydrous sodium sulfate, and removed by distillation under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate tert-butyl (A11.4) (2.1 g, 66.12%). LCMS: 273.17 [M+H] + .

[0375] Step 3: Synthesis of 4-acetylpiperidine-1-carboxylate tert-butyl (A11.5): Methylmagnesium chloride (10.29 mL, 30.87 mmol, 2.9 equivalents) was added to a stirred solution of 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate tert-butyl (A11.4) (2 g, 10.64 mmol, 1 equivalent) in THF (40 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with NH4Cl and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 4-acetylpiperidine-1-carboxylate tert-butyl (A11.5) (1.3 g, 89.82%). LCMS: 228.15 [M+H] + .

[0376] Step 4: Synthesis of (Z)-4-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate tert-butyl (A11.6): A solution of 4-acetylpiperidine-1-carboxylate tert-butyl (A11.5) (2 g, 8.80 mmol, 1 equivalent) in DMF-DMA (6.3 g, 53.79 mmol, 6 equivalents) was stirred at 110°C for 12 hours. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with water and 1% HCl, dried over Na2SO4, and concentrated to obtain the desired (Z)-4-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate tert-butyl (A11.6) (2 g crude product). The crude product was used directly in the next step without further purification. LCMS: 283.19 [M+H] + .

[0377] Step 5: Synthesis of 4-(1H-pyrazole-3-yl)piperidine-1-carboxylate tert-butyl (A11.7): (Z)-4-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate tert-butyl (A11.6) (2 g, 7.80 mmol, 1 equivalent) was mixed in hydrazine hydrate (30 mL) and stirred. The reaction mixture was stirred at 110 °C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target 4-(1H-pyrazole-3-yl)piperidine-1-carboxylate tert-butyl (A11.7). LCMS: 252.16 [M+H] + .

[0378] Step 6: Synthesis of 4-(1-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-1H-pyrazole-3-yl)piperidine-1-carboxylate tert-butyl (A11.9): To a stirred solution of 4-(1H-pyrazole-3-yl)piperidine-1-carboxylate tert-butyl (A11.7) (0.45 g, 1.77 mmol, 1 equivalent) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A11.8) (0.61 g, 2.15 mmol, 1.2 equivalents) in ACN (8 mL), pyridine (0.42 mL, 5.31 mmol, 3 equivalents) was added at 0°C, followed by compound 11.8 (0.21 g, 0.75 mmol, 1.1 equivalents). The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried on anhydrous sodium sulfate, and removed by distillation under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 4-(1-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-1H-pyrazole-3-yl)piperidine-1-carboxylate tert-butyl (A11.9). LCMS: 499.16 [M+H] + .

[0379] Step 7: Synthesis of N,N-dimethyl-4-((3-(piperidine-4-yl)-1H-pyrazole-1-yl)sulfonyl)benzenesulfonamide (A11.10): To a stirred solution of 4-(1-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-1H-pyrazole-3-yl)piperidine-1-carboxylate tert-butyl (A11.9) (0.3 g, 0.60 mmol, 1 equivalent) in DCM (5 mL), 50% TFA (2 mL) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After stirring was complete, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with ether and concentrated to obtain the title compound, N,N-dimethyl-4-((3-(piperidine-4-yl)-1H-pyrazole-1-yl)sulfonyl)benzenesulfonamide (A11.10) (0.26 g, crude product). The crude product was used directly in the next step without purification. LCMS: 399.11 [M+H] + .

[0380] Step 8: Synthesis of 4-((3-(1-(5-chloro-3-fluoropyridine-2-yl)piperidine-4-yl)-1H-pyrazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-96): To a stirred solution of N,N-dimethyl-4-((3-(piperidine-4-yl)-1H-pyrazole-1-yl)sulfonyl)benzenesulfonamide (A11.10) (0.07 g, 0.18 mmol, 1 equivalent) and 5-chloro-2,3-difluoropyridine (A11.11) (39 mg, 0.26 mmol, 1.5 equivalents) in DMF (3 mL), DIPEA (0.15 mL, 0.88 mmol, 5 equivalents) was added at room temperature. The reaction mixture was stirred at 100 °C for 12 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with water and 1% HCl, dried over Na₂SO₄, and concentrated. The crude product was purified by silica gel column chromatography, followed by preparative HPLC, to obtain the target compound, 4-((3-(1-(5-chloro-3-fluoropyridine-2-yl)piperidine-4-yl)-1H-pyrazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-96). Yield: 2 mg, 9%; Appearance: White solid; 1 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.9 Hz, 1H), 8.18 (d, J = 8.2 Hz, 2H), 8.13 - 7.98 (m, 3H), 7.80 (d, J = 13.0 Hz, 1H), 6.65 (d, J = 2.7 Hz, 1H), 3.92 (d, J = 13.4 Hz, 2H), 2.64 (s, 6H), 2.94 (dt, J = 32.4, 12.3 Hz, 3H), 1.93 - 1.84 (m, 2H), 1.72 - 1.60 (m, 2H);HPLC purity:98.54%;C 21 H 23 LC for ClFN5O4S2 MS calculated value: 527.09; Measured value: 528.0 [M+H] + .

[0381] Example A12: Synthesis of 4-((3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-2-oxoimidazolidine-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-86): [ka] Step 1: Synthesis of (2-((1-(4-chloro-2-fluorophenyl)piperidine-4-yl)amino)ethyl)carbamate tert-butyl (A12.3): To a stirred solution of 1-(4-chloro-2-fluorophenyl)piperidine-4-one (A12.1) (3.5 g, 11.32 mmol, 1 equivalent) and (2-aminoethyl)carbamate tert-butyl (A12.2) (1.81 g, 11.32 mmol, 1 equivalent) in methanol (50 mL), acetic acid (3.23 mL, 56.61 mmol, 5 equivalents) was added at room temperature. The reaction mixture was stirred at room temperature for 3.5 hours, followed by the addition of sodium borohydride cyanohydride (2.13 g, 33.96 mmol, 3 equivalents). The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was diluted with a saturated solution of sodium bicarbonate and DCM. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the title compound, (2-((1-(4-chloro-2-fluorophenyl)piperidine-4-yl)amino)ethyl)carbamate tert-butyl (A12.3) (3.5 g, 83.3%). LCMS: 372.18 [M+H] + .

[0382] Step 2: Synthesis of N1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)ethane-1,2-diamine (A12.4): To a stirred solution of (2-((1-(4-chloro-2-fluorophenyl)piperidine-4-yl)amino)ethyl)carbamate tert-butyl (A12.3) (3.5 g, 9.41 mmol, 1 equivalent) in DCM (35 mL), HCl (35 mL) in 1,4-dioxane was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was concentrated, the resulting residue was washed with ether, and dried under reduced pressure to obtain the target compound, N1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)ethane-1,2-diamine (A12.4) (2.4 g, 94.11%). LCMS: 272.13 [M+H] + .

[0383] Step 3: Synthesis of 1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)imidazolidined-2-one (A12.5): To a stirred solution of N1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)ethane-1,2-diamine (A12.4) (2.4 g, 8.83 mmol, 1 equivalent) in ACN (25 mL), CDI (1.57 g, 9.71 mmol, 1.1 equivalents) was added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with a saturated solution of sodium bicarbonate and DCM. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by column chromatography to obtain the title compound, 1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)imidazolidined-2-one (A12.5) (1.3 g, 49.42%). LCMS: 298.10 [M+H] + .

[0384] Step 4: Synthesis of 4-((3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-2-oxoimidazolidine-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-86): To a stirred solution of 1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)imidazolidin-2-one (A12.5) (0.4 g, 1.34 mmol, 1 equivalent) in THF (8 mL), NaH (0.06 g, 2.68 mmol, 2 equivalents) was added at 0°C. The reaction mixture was stirred at the same temperature for 5 minutes, followed by the addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A12.6) (0.41 g, 1.47 mmol, 1.1 equivalents). The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by preparative HPLC to obtain the compound of the title, 4-((3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-2-oxoimidazolidine-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-86). Yield: 30 mg, 8%; Appearance: White solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.1 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 12.4 Hz, 1H), 7.16 - 7.14 (m, 1H), 7.06 -7.03 (m, 1H), 3.86 (t, J = 7.6 Hz, 2H), 3.62 (m, 1H), 3.50 - 3.41 (m, 2H), 2.67 (s, 9H), 1.74 (q, J = 11.7 Hz, 2H), 1.62 (t, J = 7.8 Hz, 3H);HPLC purity:98.25%;C 22 H 26 LCMS calculated value for ClFN4O5S2: 544.10; Measured value: 545.10 [M+H] + .

[0385] Example A13: Synthesis of 4-((3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-67) [ka] Step 1: Synthesis of 1-(4-chloro-2-fluorophenyl)piperidine-4-oneoxime (A13.2): To a stirred solution of 1-(4-chloro-2-fluorophenyl)piperidine-4-one (A13.1) (3.5 g, 15.42 mmol, 1 equivalent) in ethanol (35 mL) and water (35 mL), hydroxylamine hydrochloride (1.6 g, 23.12 mmol, 1.5 equivalents) was added. The reaction mixture was refluxed for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was poured into ice water, the resulting solid was filtered, and concentrated under reduced pressure to obtain the target product, 1-(4-chloro-2-fluorophenyl)piperidine-4-one oxime (A13.2) (3.6 g, crude product). LCMS: 243.06 [M+H] + .

[0386] Step 2: Synthesis of 1-(4-chloro-2-fluorophenyl)piperidine-4-amine (A13.3): 1-(4-chloro-2-fluorophenyl)piperidine-4-one oxime (A13.2) (3.5 g, 14.52 mmol, 1 equivalent) was stirred in methanol (40 mL), to which Raney nickel (1.8 g, 50%) was added at room temperature. The reaction mixture was stirred at room temperature for 12 hours under hydrogen gas balloon pressure. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through Celite and removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 1-(4-chloro-2-fluorophenyl)piperidine-4-amine (A13.3) (2.1 g, 63.44%). LCMS: 229.08 [M+H] + .

[0387] Step 3: Synthesis of 1-(4-chloro-2-fluorophenyl)-4-isocyanatopiperidin (A13.4): To a stirred solution of triphosgene (1.56 g, 5.26 mmol, 1 equivalent) in DCM (20 mL), 1-(4-chloro-2-fluorophenyl)piperidine-4-amine (A13.3) (1.2 g, 5.26 mmol, 1 equivalent) and DIPEA (3.6 mL, 21.05 mmol, 4 equivalents) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and DCM. The organic layer was washed with brine, dried on anhydrous sodium sulfate, and removed under reduced pressure to obtain the target product, 1-(4-chloro-2-fluorophenyl)-4-isocyanatopiperidine (A13.4) (1.3 g, 97.77%). LCMS: 255.06 [M+H] + .

[0388] Step 4: Synthesis of 1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-3-(2,2-dimethoxyethyl)urea (A13.6): 1-(4-chloro-2-fluorophenyl)-4-isocyanatopiperidine (A13.4) (1.3 g, 5.12 mmol, 1 equivalent) was stirred in acetonitrile (10 mL), to which 2,2-dimethoxyethane-1-amine (A13.5) (0.81 g, 7.67 mmol, 1.5 equivalents) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the resulting precipitate was filtered off and dried under reduced pressure to obtain the target product, 1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-3-(2,2-dimethoxyethyl)urea (A13.6) (1.5 g, 88.96%). LCMS: 360.14 [M+H] + .

[0389] Step 5: Synthesis of 1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dihydro-2H-imidazole-2-one (A13.7): 1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-3-(2,2-dimethoxyethyl)urea (A13.6) (1.5 g, 4.18 mmol, 1 equivalent) was stirred in methanol (15 mL) and water (15 mL), to which 1 M HCl (15 mL) was added. The reaction mixture was stirred at room temperature for 72 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate, and removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound, 1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dihydro-2H-imidazole-2-one (A13.7) (1.1 g, 89%). LCMS: 296.09 [M+H] + .

[0390] Step 6: Synthesis of 4-((3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-67): To a stirred solution of 1-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-1,3-dihydro-2H-imidazole-2-one (A13.7) (0.3 g, 1.02 mmol, 1 equivalent) in THF (6 mL), NaH (41 mg, 31.02 mmol, 1 equivalent) was added at 0°C. The reaction mixture was stirred at the same temperature for 5 minutes, followed by the addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A13.8) (0.29 g, 1.02 mmol, 1 equivalent). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was poured into ice-cold water, the resulting precipitate was filtered, and dried under reduced pressure. The crude product was purified by column chromatography followed by preparative HPLC to obtain the target product, 4-((3-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-67). Yield: 30 mg, 5.44%; Appearance: White solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.28 - 8.21 (m, 2H), 8.09 - 8.02 (m, 2H), 7.31 (dd, J = 12.8 Hz, 12.4 Hz, 1H), 7 - 7.15 (m, 1H), 7.21 - 6.98 (m, 3H), 3.90 - 3.84 (m, 1H), 3.38 - 3.35 (m, 2H), 2.75 (t, J = 12 Hz, 2H), 2.67 (s, 6H), 1.93 - 1.85 (m, 2H), 1.76 - 1.74 (m, 2H);HPLC purity:98.23%;C 22 H 24 LCMS calculated value for ClFN4O5S2: 542.09; Measured value: 543.10 [M+H] + .

[0391] Example A14: Synthesis of N1-(2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-19) and N1-(2-(1-(4-chloro-2-fluorophenyl)piperidine-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-22): [ka] Step 1: Synthesis of 1-(4-chloro-2-fluorophenyl)-4-(2-nitrophenyl)-1,2,3,6-tetrahydropyridine (A14.3): To a stirred solution of 1-chloro-2-nitrobenzene (A14.1) (0.2 g, 1.2 mmol, 1 equivalent) and 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A14.2) (0.47 g, 1.4 mmol, 1.1 equivalent) in a mixture of 1,4-dioxane and water (4:1), K3PO4 (0.81 g, 3.7 mmol, 3 equivalents) was added, the mixture was purged with argon for 30 minutes, and then tetrakis(triphenylphosphine)palladium (0) (0.15 g, 0.1 mmol, 0.1 equivalent) was added, and the mixture was stirred overnight at 100°C. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through Celite and removed under reduced pressure. The crude product was purified by column chromatography to obtain the target product, 1-(4-chloro-2-fluorophenyl)-4-(2-nitrophenyl)-1,2,3,6-tetrahydropyridine (A14.3) (0.3 g, 71%). LCMS: 333.07 [M+H] + .

[0392] Step 2: Synthesis of 2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)aniline (A14.4): To a stirred solution of 1-(4-chloro-2-fluorophenyl)-4-(2-nitrophenyl)-1,2,3,6-tetrahydropyridine (A14.3) (0.3 g, 1.5 mmol, 1 equivalent) in a mixture of ethanol (3 mL) and water (1.2 mL), iron powder (0.24 g, 7.5 mmol, 5 equivalents) and ammonium chloride (0.24 g, 7.5 mmol, 5 equivalents) were added at room temperature. The resulting reaction mixture was heated at 80°C for 3 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite pad, and the filtrate was removed by distillation. The crude reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried on anhydrous sodium sulfate, and removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound in question, 2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)aniline (A14.4) (0.2 g, 44%). LCMS: 3 03.10 [M+H] + .

[0393] Step 3: Synthesis of N1-(2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-19): To a stirred solution of 2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-yl)aniline (A14.4) (0.1 g, 0.33 mmol, 1 equivalent) in acetonitrile (1 mL), pyridine (0.08 mL, 0.99 mmol, 3 equivalents) was added at 0°C, followed by the addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A14.5) (0.11 g, 0.397 mmol, 1.2 equivalents). The reaction mixture was stirred overnight at room temperature, and the progress of the reaction was monitored by TLC. After stirring was complete, the reaction mixture was concentrated under reduced pressure...

Claims

1. Equation (I): 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is A' is R ａ A 5-10 member monocyclic or bicyclic heterocyclil containing 1-4 heteroatoms selected from phenyl, N, O, P, and S, which are optionally substituted, or a 5-10 member monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S, Cy is non-existent, or C １～６ A 4- to 14-membered monocyclic or polycyclic heterocyclil containing 1 to 4 heteroatoms selected from aliphatic, N, O, P, and S; a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; C ６～１２ Aryl, or C ３～１２ The divalent moiety is selected from cycloalkyl groups, and Cy has one or more R groups. １ It is arbitrarily replaced with, L １ is an optionally substituted divalent moiety selected from non-existence, -S-, -C(O)-NR ３ -, -NR ３ -, -C(O)-, or C １～６ alkylenyl, C ２～６ alkenylenyl, C ２～６ alkynylenyl, -NR ３ -, -C ０～６ alkylenyl, -O-C ０～６ alkylenyl, -C(O)-C ０～６ alkylenyl, -C １～６ alkylenyl-C(O)-, -C(O)O-C ０～６ alkylenyl, -C １～６ alkylenyl-O-C(O)-, -C ３～６ cycloalkyl, and -NR ３ -, -C(O)-C ０～６ alkylenyl-O-; and L ２ is, -(NR ３ ) ｓ -S(O)-(NR ３ )-,-(NR ３ ) ｓ -S(O) ２ -NR ３ -, - (NR ３ ) ｓ -P(O)(R ３ )-, -C(O)-(NR ３ ) ｓ -, -NR ３ -C(O)-, or -(NR ３ ) ｓ -S(O)-C ０～６ Alkyrenyl-,-(NR) ３ ) ｓ -S(O) ２ -C ０～６ Alkyrenyl-,-(NR) ３ ) ｓ -S(O)-NR ３ -C ０～６ Alkyrenyl, -(NR) ３ ) ｓ -S(O) ２ -NR ３ -C ０～６ Alkyrenyl, -(NR) ３ ) ｓ -S(O) ２ -C ３～６ Cycloalkyl, -NR ３ -C ０～６ Alkyrenyl, -C １～６ Alkyrenyl-S(O)-(NR) ３ ) ｓ -, -C １～６ Alkyrenyl-S(O) ２ - (NR ３ ) ｓ - An optionally substituted divalent moiety selected from 2-6 member heteroaliphatic groups, and 4- to 12 member monocyclic or bicyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, V is C １～６ aliphatic, C ６～１２ Ariel, C ３～１２ Selected from cycloaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclils containing 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, where V is (R ６ ) ｍ It has been replaced with, Z is P(O)(R ３ ) ２ , C(O)N(R ３ ) ２ , C １～６ aliphatic, C ６～１２ Ariel, C ３～１２ Selected from cycloaliphatic, 2-10 heteroaliphatic atoms, 4-16 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where Z is (R ２ ) ｑ It has been replaced with, Each R ａ These are independently H, halo, -CN, oxo, or C １～６ aliphatic, C ３～６ Cycloliphatic and O-C １～６ An arbitrarily substituted group selected from aliphatic groups, Each R １ is independently selected from optionally substituted groups selected from halo, oxo, -N(R ３ ), ２ , -OH, -CN, -C(O)N(R ３ ), ２ , and C １～６ aliphatic and N(R ３ )-C(O)-C １～６ aliphatic, Each R ２ These are halo, oxo, -CN, -OH, and O-R. ２ａ , -C(O)-R ２ａ , -C(O)O-R ２ａ , and C １～６ aliphatic, C ６～１２ Independently selected from aryl and optionally substituted groups selected from 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, Each R ２ａ is independently H, or C １～６ aliphatic, C ３～１２ cycloaliphatic, and is an optionally substituted group selected from monocyclic or bicyclic heterocyclyl of 4 to 12 members containing 1 to 4 heteroatoms selected from N, O, and S, Each R ３ This is H and optionally substituted C １～６ Selected independently from aliphatic species, Each R ５ is -N(R ３ ) ２ , or C １～６ Aliphatic, P(O)(C １～６ aliphatic) ２ , C ３～１２ The group is optionally substituted from cycloaliphatic groups and 5- to 12-membered monocyclic or polycyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S. Each R ６ is Halo, Oxo, -SF ５ , -S(O)-R ５ , S(O) ２ -R ５ , -S(O)(NH)-R ５ , -S(O) ２ -(NH)-R ５ , -S(O)-N(R ５ ) ２ , -S(O) ２ -N(R) ５ ) ２ , -CN, -C(O)-NH(R ５ ), -C(O)-N(R ５ ) ２ , -P(O)(R ５ ) ２ , -O-R ５ , or C １～６ aliphatic, S-C １～６ Aliphatic, 2-12 member heteroaliphatic, -C ０～６ Alkyrenyl-C(O)-R ５ , -C ０～６ Alkyrenyl-C(O)O-R ５ , C ６～１２ Ariel, C ３～１２ Independently selected from cycloaliphatic groups and optionally substituted groups selected from 4-7 membered monocyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, 4, 5, or 6. Each s is independently 0 or 1, the compound or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein A' is phenyl.

3. The compound according to claim 1, wherein A' is a nine-membered bicyclic heteroaryl compound comprising one to four heteroatoms selected from N, O, and S.

4. The compound according to claim 1, wherein A' is a 5-6 member monocyclic heteroaryl compound containing 1-4 heteroatoms selected from N, O, and S.

5. The compound according to claim 1, wherein A' is a nine-membered bicyclic heterocycline containing one to four heteroatoms selected from N, O, and S.

6. The compound according to claim 1, wherein A' is selected from Table A'.

7. A' is, 【Chemistry 2】 The compound according to claim 6.

8. The compound according to any one of claims 1 to 7, wherein Cy is absent or a 4- to 12-membered monocyclic or polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S.

9. The compound according to any one of claims 1 to 8, wherein Cy is absent.

10. The compound according to any one of claims 1 to 8, wherein Cy is a 4- to 7-membered monocyclic heterocycline containing 1 to 3 heteroatoms selected from N, O, and S.

11. The compound according to claim 10, wherein Cy is a 4- to 7-membered monocyclic heterocycline containing one heteroatom selected from N, O, and S.

12. The compound according to claim 11, wherein Cy is piperidinyl.

13. The compound according to claim 1, wherein Cy is selected from the Cy table.

14. L １ However, non-existence or C １～６ Alkirenyl, -NR ３ -C ０～６ Alkyrenyl, -C(O)C ０～６ Alkyrenyl, -C １～６ Alkyrenyl-C(O)- and -C １～６ The compound according to any one of claims 1 to 13, wherein the group is optionally substituted with an alkylenyl-OC(O)- group.

15. L １ The compound according to any one of claims 1 to 14, wherein the compound is absent.

16. L １ C is arbitrarily substituted. ３～６ A compound according to any one of claims 1 to 14, wherein it is a cycloalkyl compound.

17. L １ However, -NR ３ - The compound according to any one of claims 1 to 14.

18. L ２ C is arbitrarily substituted. １～６ The compound according to any one of claims 1 to 17, wherein it is an alkylenyl compound.

19. L ２ However, -C is arbitrarily substituted. １～６ Alkyrenyl-S(O) ２ - (NR ３ ) ｓ ,-(NR ３ ) ｓ -S(O)-C ０～６ Alkyrenyl, or -(NR ３ ) ｓ -S(O) ２ -C ０～６ The compound according to any one of claims 1 to 17, wherein it is an alkylenyl compound.

20. L ２ However, non-existent, -C １～６ Alkyrenyl-S(O) ２ ,-(NR ３ ) ｓ -S(O)-, or -(NR ３ ) ｓ -S(O) ２ - The compound according to any one of claims 1 to 17.

21. L ２ However, non-existent, -C １～６ Alkyrenyl-S(O) ２ , or -NR ３ -S(O) ２ - The compound according to claim 20.

22. L ２ However, -NR ３ -S(O) ２ - The compound according to claim 21.

23. L ２ But -NH-S(O) ２ - The compound according to claim 22.

24. L ２ However, -C １～６ Alkyrenyl-S(O) ２ The compound according to claim 21.

25. L ２ However, -CH(CH ３ )-S(O) ２ - The compound according to claim 24.

26. Z is C ６～１２ A 4- to 16-membered monocyclic or polycyclic heterocyclil containing an aryl, a heteroaliphatic with 2 to 10 atoms, or 1 to 4 heteroatoms selected from N, O, and S, or a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, wherein Z is (R ２ ) ｑ A compound according to any one of claims 1 to 25, which is substituted with

27. Z is C ６～１２ The compound according to any one of claims 1 to 26, which is a 4 to 16-membered monocyclic or polycyclic heterocyclil containing aryl or 1 to 4 heteroatoms selected from N, O, and S.

28. Z is C ６～１２ The compound according to claim 27, wherein it is an aryl compound.

29. The compound according to claim 27, wherein Z is a 4- to 16-membered monocyclic or polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S.

30. The compound according to claim 29, wherein Z is a 10- to 16-membered polycyclic heterocycline containing 1 to 4 heteroatoms selected from N, O, and S.

31. Z is 0, 1, 2, 3, or 4 R ２ It is replaced by each R ２ However, independently, halo or O-R ２ａ And R ２ａ C is arbitrarily substituted. １～６ The compound according to any one of claims 1 to 30, which is aliphatic.

32. Z is 0, 1, 2, 3, or 4 R ２ It is replaced with R ２ The compound according to claim 31, wherein the compound is a halo.

33. The compound according to claim 1, wherein Z is selected from Table Z.

34. V is C ６～１２ The compound according to any one of claims 1 to 33, which is a 4- to 12-membered monocyclic or polycyclic heterocycline containing aryl or 1 to 4 heteroatoms selected from N, O, and S.

35. V is C ６～１２ The compound according to any one of claims 1 to 34, wherein it is an aryl compound.

36. V is 0, 1, 2, 3, or 4 R ６ It is replaced by each R ６ However, independently, Haro, S(O)-R ５ , S(O) ２ -R ５ , S(O)(NH)-R ５ , or optionally substituted O-C １～６ The compound according to claim 35, which is aliphatic.

37. R ６ However, S(O)-R ５ , S(O) ２ -R ５ , or optionally replaced C １～６ The compound according to any one of claims 1 to 36, wherein the compound is aliphatic.

38. R ６ The compound according to any one of claims 1 to 36, wherein the compound is a halo.

39. R ６ The compound according to claim 38, wherein is fluoro or chloro.

40. R ６ However, -S(O) ２ -R ５ The compound according to claim 37.

41. R ６ However, -S(O) ２ -C １～６ The compound according to claim 40, which is aliphatic.

42. R ６ However, -S(O) ２ -CH ３ or -S(O) ２ - CHF ２ The compound according to claim 41.

43. R ６ However, -S(O) ２ -N(C) １～６ aliphatic) ２ The compound according to claim 37.

44. R ６ However, -S(O) ２ -N(CH ３ ) ２ The compound according to claim 43.

45. The compound according to claim 1, wherein V is selected from Table V.

46. The aforementioned compound is formula IIa-1: 【Transformation 3】 The compound according to claim 1, which is the same as or a pharmaceutically acceptable salt thereof.

47. The aforementioned compound is formula IIa-2: 【Chemistry 4】 The compound according to claim 1, which is the same as or a pharmaceutically acceptable salt thereof.

48. The aforementioned compound is formula IIa-3: 【Transformation 5】 The compound according to claim 1, wherein the compound is as described above.

49. The aforementioned compound is formula IIb: 【Transformation 6】 The compound according to claim 1, which is the same as or a pharmaceutically acceptable salt thereof.

50. The aforementioned compound is formula IIb-1: 【Transformation 7】 The compound according to claim 1, which is the same as or a pharmaceutically acceptable salt thereof.

51. The aforementioned compound is of formula IId: 【Transformation 8】 The compound according to claim 1, which is the same as or a pharmaceutically acceptable salt thereof.

52. The aforementioned compound is formula IId-1: 【Chemistry 9】 The compound according to claim 1, which is the same as or a pharmaceutically acceptable salt thereof.

53. The aforementioned compound is formula IId-2: 【Chemistry 10】 The compound according to claim 1, which is the same as or a pharmaceutically acceptable salt thereof.

54. The aforementioned compound is formula IId-3: 【Chemistry 11】 The compound according to claim 1, which is the same as or a pharmaceutically acceptable salt thereof.

55. Formula II': 【Chemistry 12】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is X １ ', X ２ ', X ３ ', and X ４ ' represents N, C, and CR respectively. ａ Selected independently from X １ ', X ２ ', X ３ ', and X ４ ' is Cy-L １ -Z or L ２ When bonded to -V, it is C or N, and Cy-L １ -Z or L ２ -If not coupled to V, CR ａ And, Y １ 'and Y ２ ' are C, N, and CR respectively ａ Selected from or Y １ 'or Y ２ If one of the two does not exist, Y １ 'or Y ２ The other of ' is C, N, and CR ａ Selected from, Cy is non-existent, or C １～６ A 4- to 14-membered monocyclic or polycyclic heterocyclil containing 1 to 4 heteroatoms selected from aliphatic, N, O, P, and S; a 5- to 12-membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; C ６～１２ Aryl, or C ３～１２ The divalent moiety is selected from cycloalkyl groups, and Cy has one or more R groups. １ It is arbitrarily replaced with, L １ is non-existent, S-, -C(O)-NR ３ -, -NR ３ -C(O)-, or C １～６ Alkirenyl, C ２～６ Alkynylenyl, -NR ３ -C ０～６ Alkyrenyl, -O-C ０～６ Alkyrenyl, -C(O)-C ０～６ Alkyrenyl, -C １～６ Alkyrenyl-C(O)-,-C(O)O-C ０～６ Alkyrenyl, -C １～６ Alkyrenyl-O-C(O)-, -C ３～６ Cycloalkyl and -NR ３ -C(O)-C ０～６ It is an arbitrarily substituted group selected from alkylenyl-O-, L ２ is, -(NR ３ ) ｓ -S(O)-(NR ３ )-,-(NR ３ ) ｓ -S(O) ２ -NR ３ -, - (NR ３ ) ｓ -P(O)(R ３ )-, -C(O)-(NR ３ ) ｓ -, -NR ３ -C(O)-, or -(NR ３ ) ｓ -S(O)-C ０～６ Alkyrenyl-,-(NR) ３ ) ｓ -S(O) ２ -C ０～６ Alkyrenyl-,-(NR) ３ ) ｓ -S(O)-NR ３ -C ０～６ Alkyrenyl, -(NR) ３ ) ｓ -S(O) ２ -NR ３ -C ０～６ Alkyrenyl, -(NR) ３ ) ｓ -S(O) ２ -C ３～６ Cycloalkyl, -NR ３ -C ０～６ Alkyrenyl, -C １～６ Alkyrenyl-S(O)-(NR) ３ ) ｓ -, -C １～６ Alkyrenyl-S(O) ２ - (NR ３ ) ｓ - An optionally substituted divalent moiety selected from 2-6 member heteroaliphatic groups, and 4- to 12 member monocyclic or bicyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, V is C １～６ aliphatic, C ６～１２ Ariel, C ３～１２ Selected from cycloaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclils containing 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, where V is (R ６ ) ｍ It has been replaced with, Z is P(O)(R ３ ) ２ , C(O)N(R ３ ) ２ , C １～６ aliphatic, C ６～１２ Ariel, C ３～１２ Selected from cycloaliphatic, 2-10 heteroaliphatic atoms, 4-16 member monocyclic or polycyclic heterocyclils containing 1-4 heteroatoms selected from N, O, and S, and 5-12 member monocyclic or bicyclic heteroaryls containing 1-4 heteroatoms selected from N, O, and S, where Z is (R ２ ) ｑ It has been replaced with, Each R ａ These are independently H, halo, -CN, oxo, or C １～６ aliphatic, C ３～６ Cycloaliphatic and O-C １～６ Either an arbitrarily substituted group selected from aliphatic groups, or two R groups. ａ When present on adjacent atoms, they form an optionally substituted condensed heterocyclyl ring or an optionally substituted condensed heteroaryl group containing one or two heteroatoms selected from N, O, and S. Each R １ is halo, oxo, -N(R) ３ ) ２ , -OH, -CN, -C(O)N(R ３ ) ２ , and C １～６ Aliphatic and N(R) ３ )-C(O)-C １～６ Independently selected from any substituted groups chosen from aliphatic groups, Each R ２ These are halo, oxo, -CN, -OH, and O-R. ２ａ , -C(O)-R ２ａ , -C(O)O-R ２ａ , and C １～６ aliphatic, C ６～１２ Independently selected from aryl and optionally substituted groups selected from 5- to 12-membered monocyclic or bicyclic heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S, Each R ２ａ These are, independently, H, or C １～６ aliphatic, C ３～１２ A cycloaliphatic group, and an optionally substituted group selected from 4- to 12-membered monocyclic or bicyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S, Each R ３ This is H and optionally substituted C １～６ Selected independently from aliphatic species, Each R ５ is -N(R ３ ) ２ , or C １～６ Aliphatic, P(O)(C １～６ aliphatic) ２ , C ３～１２ The group is optionally substituted from cycloaliphatic groups and 5- to 12-membered monocyclic or polycyclic heterocyclines containing 1 to 4 heteroatoms selected from N, O, and S. Each R ６ is Halo, Oxo, -SF ５ , -S(O)-R ５ , S(O) ２ -R ５ , -S(O)(NH)-R ５ , -S(O) ２ -(NH)-R ５ , -S(O)-N(R ５ ) ２ , -S(O) ２ -N(R) ５ ) ２ , -CN, -C(O)-NH(R ５ ), -C(O)-N(R ５ ) ２ , -P(O)(R ５ ) ２ , -O-R ５ , or C １～６ aliphatic, S-C １～６ Aliphatic, 2-12 member heteroaliphatic, -C ０～６ Alkyrenyl-C(O)-R ５ , -C ０～６ Alkyrenyl-C(O)O-R ５ , C ６～１２ Ariel, C ３～１２ Independently selected from cycloaliphatic groups and optionally substituted groups selected from 4-7 membered monocyclic heterocyclines containing 1-4 heteroatoms selected from N, O, and S, m is 0, 1, 2, 3, or 4. q is 0, 1, 2, 3, 4, 5, or 6. Each s is independently 0 or 1, the compound or a pharmaceutically acceptable salt thereof.

56. X １ ', X ２ ', X ３ ', and X ４ ', respectively, C and CR ａ Selected independently from X １ ', X ２ ', X ３ ', and X ４ 'but, Cy-L １ -Z or L ２ When bonded to -V, it is C, and Cy-L １ -Z or L ２ -If not coupled to V, CR ａ The compound according to claim 55.

57. Y １ 'and Y ２ ', each CR ａ The compound according to claim 55 or 56.

58. A compound selected from Table A.

59. Compounds selected from Table B.

60. A pharmaceutical composition comprising a compound according to any one of claims 1 to 59 and a pharmaceutically acceptable carrier, auxiliary agent, or vehicle.

61. A method for preparing TRPML1, comprising administering a compound or composition described in any one of claims 1 to 59 to a target.

62. A method for treating a disease, disorder, or condition, comprising administering a compound or composition thereof as described in any one of claims 1 to 59.

63. The method according to claim 62, wherein the disease, disorder, or condition is a lysosome storage disorder.

64. The method according to claim 63, wherein the lysosome storage disorder is selected from Niemann-Pick disease type C, Gaucher disease, and Pompe disease.

65. The method according to claim 62, wherein the disease, disorder, or condition is a common neurodegenerative disease due to aging.

66. The method according to claim 62, wherein the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, and Huntington's disease.

67. The method according to claim 62, wherein the disease, disorder, or condition is mucolipidosis type IV (ML4), a neurodegenerative lysosomal storage disorder caused by a mutation in TRPML1.

68. The method according to claim 62, wherein the disease, disorder, or condition is a muscle disease, liver disease, metabolic disease, arteriosclerotic disease, inflammatory bowel disease, arteriosclerotic disease, neurodegenerative disease, neoplastic disease, or infectious disease.

69. The method according to claim 68, wherein the disease, disorder, or condition is a muscle disease.

70. The method according to claim 69, wherein the muscle disease is muscular dystrophy.

71. The method according to claim 70, wherein the muscular dystrophy is Duchenne muscular dystrophy.

72. The method according to claim 68, wherein the disease, disorder, or condition is an infectious disease.

73. The method according to claim 72, wherein the infectious disease is an infection with Heliobacter pylori or Mycobacterium tuberculosis.

74. The method according to claim 73, wherein the infectious disease is an infection with Mycobacterium tuberculosis.

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