Muscarinic acetylcholine m1 receptor antagonists

Abstract

To provide compounds which are useful as antagonists of the muscarinic acetylcholine receptor M1 (mAChR M1), and methods for preparing the compounds.SOLUTION: The present invention provides a compound having the structure of formula (IA) or (IB), or a pharmaceutically acceptable salt or solvate thereof.SELECTED DRAWING: None

Description

Background Art

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Application No. 62 / 911,807, filed on October 7, 2019, which is hereby incorporated by reference in its entirety and for all purposes.

[0002] The human muscarinic acetylcholine receptor M1 (mAChR M1) is a 479 - amino - acid protein encoded by the CHRM1 gene. mAChR M1 is one of five members of the muscarinic acetylcholine receptor (M1 - M5) family, and the receptor is widely expressed throughout the body, where it plays various roles in cognitive, sensory, motor, and autonomic functions. M1 mAChR is found in both the central nervous system and the peripheral nervous system, particularly in the cerebral cortex and sympathetic ganglia. Based on the potential role of mAChR M1 in seizure activity and motor control, highly selective mAChR M1 antagonists may have potential utility not only in the treatment of certain movement disorders, including Parkinson's disease, dystonia, and fragile X syndrome, but also in the treatment of some epileptic disorders.

Summary of the Invention

[0003] The present disclosure provides, for example, compounds and compositions that are antagonists of the muscarinic acetylcholine M1 receptor (mAChR M1), and their use as drugs, methods for their preparation, and pharmaceutical compositions comprising at least one of the disclosed compounds as an active ingredient. The present disclosure also provides for the modulation of muscarinic acetylcholine M1 receptor activity in a patient ​​​​​​​The disclosed compounds as medicaments for inhibition and / or in the manufacture of medicaments are provided for use.

[0004] In one aspect, a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IA-1) or (IB-1),

Chemical formula

Chemical formula

Chemical formula

[0005] In one aspect, a compound of formula (IA) or (IB), [Chemical formula] wherein, X is a bond, -C(R 9 )(R 10 )-, -N(R 11 )-, -O-, -S(O) n -, -CH2N(R 11 )-, or -CH2O-, Y is -CH2-, -CH2CH2-, -CH=CH-, or -CH2OCH2- and R 1 is [Chemical formula] wherein ring A is a 5- or 6-membered heteroaryl ring, or optionally, halo gen, cyano, -N(R 14 )(R 15 ), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cyclo haloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, hetero cycloalkyl, aryl, heteroaryl, S(O) n (R 16 ), or -SF5 a 5- or 6-membered heterocycloalkyl ring replaced thereby, wherein the heteroaryl or hete rocycloalkyl ring contains 1, 2, or 3 heteroatoms selected from the group consisting of O, N, or S, R 2 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alko xy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C3 -6 cycloalkoxy, C 3-6 halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl, heterocycloalkyl, aryl, or heteroaryl, and R 3 is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 3- 6-halocycloalkyl, C 3-6 halocycloalkoxy, C 1-6 alkylhydroxyl , heterocycloalkyl, aryl, or heteroaryl, or R 2 and R 3 are linked to form, optionally, a cycloalkyl or heterocycloalkyl ring substituted with halogen, C 1-6 alkyl, or C 3-6 cycloalk yl, R 4 and R 5 are independently hydrogen, deuterium, halogen, and C 1-3 alkyl selected from​ is selected, or R 3 and R 4 are linked to optionally form, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl or heterocycloalkyl substituted with cycloalkyl to form a ring, or R 4 and R 5 are linked to optionally form, halogen, C 1-6 alkyl , or C 3-6 cycloalkyl or heterocycloalkyl substituted with cycloalkyl to form a ring, R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, and C 1-3 alkyl is selected, or R 3 and R 7 are linked to optionally form, halogen, C 1-6 alkyl, or C 3-6 cycloalkyl or heterocycloalkyl substituted with cycloalkyl to form a ring, or R 4 and R 6 are linked to optionally form, halogen, C 1-6 alkyl , or C 3-6 cycloalkyl or heterocycloalkyl substituted with cycloalkyl to form a ring, or R 5 and R 7 are linked to form a bond, R 8 is,

Chemical formula

[0006] In one embodiment, a compound of formula (IIA) or (IIB),

Chemical formula

Chemical formula

Chemical formula

[0007] X is a bond, -C(R

Chemical formula

Chemical formula

[0008] In some embodiments of the compounds of formula (IA), (IB), (IIA), (IIB), or (III), or their pharmaceutically acceptable salts or solvates, X is a bond, -C(R )(R ), -N(R 9 )(R 10 ), or -O-. In some embodiments, X is a bond, -N(R 11 ), or -O-. In some embodiments, X is a bond, -N(R 11 ), or -O-.

[0009] In some embodiments of the compounds of formula (IA), (IB), (IIA), (IIB), or (III), or their pharmaceutically acceptable salts or solvates, R is 1

Chemical formula

Chemical formula

[0010] In some embodiments of the compounds of formula (IA), (IB), (IIA), (IIB), or (III), or their pharmaceutically acceptable salts or solvates, R is 8

Chemical formula

Chemical formula

[0011] Any combination of the groups described above or below for the various variable parts is contemplated in this specification. Throughout this specification, those groups and substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0012] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (IA), (IB), (IIA), (IIB), or (III), a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0013] Another aspect is a method of doing so in a subject in need of treating a neurodegenerative disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0014] Another aspect is a method of doing so in a subject in need of treating a neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments are methods of doing so in a subject in need of treating a neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is a peripheral neuropathy. Some An embodiment is a method of doing so in a subject in need of treating a neuropathy, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy. Another aspect is a method of doing so in a subject in need of treating a demyelinating disease,

[0015] comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the central nervous system. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is multiple sclerosis. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is polyneuropathy. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof,

[0016] In some embodiments of the methods described herein, the method further comprises administering one or more immunomodulatory agents. In some embodiments, the one or more immunomodulatory agents are, for example, IFN-β1 molecules; corticosteroids; polymers of glutamic acid, lysine, alanine, tyrosine, or glatiramer; antibodies or fragments thereof against alpha-4 integrin, or natalizumab; anthraquinone molecules or mitoxantrone; S1P1 functional modifiers or fingolimod; NRF2 functional modifiers or dimethyl fumarate; antibodies against the alpha subunit of the IL-2 receptor (CD25) of T cells, or daclizumab; antibodies against CD52, or alemtuzumab; antibodies against CD20, or ocrelizumab; and inhibitors of dihydroorotate dehydrogenase, or teriflunomide, etc., selected from. In some embodiments, the one or more immunomodulatory agents are IFN-β1 molecules; corticosteroids; polymers of glutamic acid, lysine, alanine, tyrosine, or glatiramer; antibodies or fragments thereof against alpha-4 integrin, or natalizumab; anthraquinone molecules or mitoxantrone; S1P1 functional modifiers or fingolimod; NRF2 functional modifiers or dimethyl fumarate; antibodies against the alpha subunit of the IL-2 receptor (CD25) of T cells, or daclizumab; antibodies against CD52, or alemtuzumab; antibodies against CD20, or ocrelizumab; and inhibitors of dihydroorotate dehydrogenase, or teriflunomide, etc., selected from. such as; corticosteroids such as; polymers of glutamic acid, lysine, alanine, tyrosine, or glatiramer such as; antibodies or fragments thereof against alpha-4 integrin, or natalizumab such as; anthraquinone molecules or mitoxantrone such as; S1P1 functional modifiers or fingolimod such as; NRF2 functional modifiers or dimethyl fumarate such as; antibodies against the alpha subunit of the IL-2 receptor (CD25) of T cells, or daclizumab such as; antibodies against CD52, or alemtuzumab such as; antibodies against CD20, or ocrelizumab such as; and inhibitors of dihydroorotate dehydrogenase, or teriflunomide such as or glatiramer; antibodies or fragments thereof against alpha-4 integrin, or natalizumab; anthraquinone molecules or mitoxantrone; S1P1 functional modifiers or fingolimod; NRF2 functional modifiers or dimethyl fumarate; antibodies against the alpha subunit of the IL-2 receptor (CD25) of T cells, or daclizumab; antibodies against CD52, or alemtuzumab; antibodies against CD20, or ocrelizumab; and inhibitors of dihydroorotate dehydrogenase, or teriflunomide or natalizumab; anthraquinone molecules or mitoxantrone; S1P1 functional modifiers or fingolimod; NRF2 functional modifiers or dimethyl fumarate; antibodies against the alpha subunit of the IL-2 receptor (CD25) of T cells, or daclizumab; antibodies against CD52, or alemtuzumab; antibodies against CD20, or ocrelizumab; and inhibitors of dihydroorotate dehydrogenase, or teriflunomide functional modifiers or fingolimod; NRF2 functional modifiers or dimethyl fumarate; antibodies against the alpha subunit of the IL-2 receptor (CD25) of T cells, or daclizumab; antibodies against CD52, or alemtuzumab; antibodies against CD20, or ocrelizumab; and inhibitors of dihydroorotate dehydrogenase, or teriflunomide or dimethyl fumarate; antibodies against the alpha subunit of the IL-2 receptor (CD25) of T cells, or daclizumab; antibodies against CD52, or alemtuzumab; antibodies against CD20, or ocrelizumab; and inhibitors of dihydroorotate dehydrogenase, or teriflunomide or daclizumab; antibodies against CD52, or alemtuzumab; antibodies against CD20, or ocrelizumab; and inhibitors of dihydroorotate dehydrogenase, or teriflunomide or alemtuzumab; antibodies against CD20, or ocrelizumab; and inhibitors of dihydroorotate dehydrogenase, or teriflunomide or teriflunomide, etc., selected from.

[0017] Another aspect is a method of modulating muscarinic acetylcholine receptor M1 activity in a subject, comprising administering to the subject a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, acts as a selective M1 antagonist. A method of modulating muscarinic acetylcholine receptor M1 activity in a subject, comprising administering to the subject a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof. A method of modulating muscarinic acetylcholine receptor M1 activity in a subject, comprising administering to the subject a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, acts as a selective M1 antagonist. or (III), or a pharmaceutically acceptable salt or solvate thereof, acts as a selective M1 antagonist. acts as a selective M1 antagonist.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The present disclosure is at least partially directed to inhibiting muscarinic acetylcholine M1 receptors. It is directed to compounds that can be thus formed.

[0019] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, and a reference to "a cell" includes a reference to one or more cells (or a plurality of cells) and their equivalents. When ranges are used herein with respect to physical properties such as molecular weight or chemical properties such as chemical formula, all combinations and subcombinations of the range, as well as specific embodiments therein are intended to be included. The term "about" when referring to a numerical value or numerical range means that the recited numerical value or numerical range is a approximate value within experimental variability (or within statistical experimental error), and thus, the numerical value or numerical range may vary by 1% to 15% of the recited numerical value or numerical range. In embodiments, about means within the standard deviation of the measurements generally accepted in the art. In embodiments, about means a range extending from + / - 10% of a particular value. In embodiments, about includes the particular value. The term "comprising" (and related terms such as "comprise" or "comprises" or "has" or "including") is not intended to exclude other particular embodiments, e.g., embodiments of any substance

[0020] I. Definitions When used in the specification and the appended claims, unless otherwise defined, the following terms have the meanings set forth below.

[0021] As used herein, C1-C x means C1-C2, C1-C3...C1-C x and includes. C1-C x refers to the number of carbon atoms constituting the moiety it designates (excluding any substituent groups). Similarly, C1- x means C1-2, C1-3...C1- x and includes. C1-C x refers to the number of carbon atoms constituting the moiety it designates (excluding any substituent).

[0022] "Amino" refers to the -NH2 radical.

[0023] "Cyano" refers to the -CN radical.

[0024] "Hydroxyl" refers to the -OH radical.

[0025] "Nitro" refers to the -NO2 radical.

[0026] "Oxa" refers to the -O- radical.

[0027] "Oxo" refers to the =O radical.

[0028] "Thioxo" refers to the =S group

[0029] "Imino" refers to the =N-H radical.

[0030] "Oximo" refers to the =N-OH radical.

[0031] "Alkyl" or "alkylene" consists of only carbon and hydrogen atoms and contains no unsaturation First, a straight-chain or branched hydrocarbon chain radical having 1 to 15 carbon atoms (e.g., C1-C 15 alkyl or C1-C 15 alki l) is indicated. In certain embodiments, the alki l contains 1 to 13 carbon atoms (e.g., C1-C 13 alkyl or C1-C 13 alkyl). In certain embodiments, the alkyl contains 1 to 8 carbon atoms (e.g., C 1-C8 alkyl or C1-C8 alkyl). In other embodiments, the alkyl contains 1 to 6 carbon atoms (e.g., C1-C6 alkyl or C1-C6 alkyl). In other em bodiments, the alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl or C1-C5 alkyl). In other embodiments, the alkyl contains 1 to 4 carbon atoms ( e.g., C1-C4 alkyl or C1-C4 alkyl). In other embodiments, the alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl or C1-C3 alkyl ). In other embodiments, the alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 a lkyl or C1-C2 alkyl). In other embodiments, the alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15 alkyl or C5-C 15 alkyl). In other embodiments the alkyl contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl or C5- C8 alkyl). In other embodiments, the alkyl contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl or C2-C5 alkyl). In other embodiments, the alkyl contains 3 to Containing 5 carbon atoms (e.g., C3-C5 alkyl or C3-C5 alkylene). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-meth ylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec -butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert -butyl), and 1-pentyl (n-pentyl). The alkyl is bonded to the remainder of the molecule by a single bond. Unless otherwise specified herein, the alkyl group is optionally substituted with halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR , -SR a , -OC(O)R a , -N(R a )2, -C( a )O)R , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O) t R f ( where t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R f (t is 1 or 2) and -S(O) t N(R a )2 (t is 1 or 2 ), wherein each R a is independently hydrogen, alkyl, haloalkyl, cycloalkyl is alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R is independently substituted with one or more of the substituents of alkyl, haloalkyl, cycloalkyl, f aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl. Thus, the alkyl group can be substituted or unsubstituted. In embodiments, the alkyl group is substituted with at least one substituent, and when the alkyl group is substituted with a plurality of substituents, each substituent can optionally be different. In embodiments, the alkyl group is substituted with at least one size-limiting substituent, and when the alkyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. In embodiments, the alkyl group is substituted with at least one lower substituent, and when the alkyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different.

[0032] "Alkoxy" refers to a group bonded through an oxygen atom of the formula -O-alkyl, where alkyl is the alkyl chain as defined above.

[0033] "Alkenyl" consists of only carbon and hydrogen atoms, contains at least one carbon-carbon double bond, and refers to a branched hydrocarbon chain radical group having 2 to 12 carbon atoms. In certain embodiments, alkenyl contains 2 to 8 carbon atoms. In other embodiments, alkenyl contains 2 to 4 carbon atoms. Alkenyl is bonded to the remainder of the molecule by a single bond, such as, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Otherwise, unless otherwise specified in this specification, the alkenyl group is optionally halogen, cyano , nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)-R f , -N(R a )2, -C(O)R a , -C(O)OR a , -C( O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O) t R f (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R f (t is 1 or 2) and -S(O) t N(R a )2(t is 1 or 2), wherein each R a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocy chloroalkyl, heteroaryl, or heteroarylalkyl, and each R f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocyclo alkyl, heteroaryl, or heteroarylalkyl substituted with one or more of the following substituents: Therefore, the alkenyl group can be substituted or unsubstituted. In an embodiment , the alkenyl group is substituted with at least one substituent, and when the alkenyl group has a plurality of substituents When substituted with a group, each substituent can optionally be different. In an embodiment, the alkenyl group is at least substituted with one size-limiting substituent, and when the alkenyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. In an embodiment, the alkenyl group is substituted with at least one lower substituent, and when the alkenyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different.

[0034] "Alkynyl" refers to a branched hydrocarbon chain radical group consisting of only carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms. In certain embodiments, alkynyl contains 2 to 8 carbon atoms. In other embodiments, alkynyl has 2 to 4 carbon atoms. Alkynyl is bonded to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specified herein, the alkynyl group can optionally be halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR , - a , - SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C (O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N( R a )C(O)R f , -N(R a )S(O) t R f (t is 1 or 2), -S(O )t OR a (t is 1 or 2), -S(O) t R f (t is 1 or 2) and -S(O) t N(R a )2 (t is 1 or 2), wherein each R a is, independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, hetero cycloalkyl, heteroaryl, or heteroarylalkyl, and each R f is, inde pendently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocyclo alkyl, heteroaryl, or heteroarylalkyl and is substituted with one or more of the following substituents. Thus, the alkynyl group can be substituted or unsubstituted. In embodiments the alkynyl group is substituted with at least one substituent, and when the alkynyl group is substituted with a plurality of substituents, each substituent can optionally be different. In embodiments, the alkynyl group is substituted with at least one size-limiting substituent, and when the alkynyl group is substituted with a plurality of size-limiting substituents each size-limiting substituent can optionally be different. In embodiments, the alkynyl group is substituted with at least one lower substituent, and when the alkynyl group is substituted with a plurality of lower substituents each lower substituent can optionally be different.

[0035] The term "heteroalkyl", alone or in combination with another term, unless otherwise specified means a stable straight or branched chain, or combinations thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and nitrogen and sulfur atoms can be optionally oxidized and nitrogen heteroatoms can be optionally quaternized. Optionally, it can be quaternized and is unsaturated - free. Heteroatom(s) (e.g., O, N, S, Si, or P) may be located at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule . Heteroalkyl is an acyclic chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2- CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2 , -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -Si(CH3)3, , -O-CH3, -O-CH2-CH3, and -CN. For example, up to two or three heteroatoms such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3 may be consecutive. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N , S, Si, or P). The heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain up to eight optionally different heteroatoms (e.g., , O, N, S, Si, or P). The heteroalkyl group may be substituted or unsubstituted. In embodiments, the heteroalkyl group is substituted with at least one substituent, and when the heteroalkyl group is substituted with multiple substituents, each substituent may be optionally different. ​ In an embodiment, the heteroalkyl group is substituted with at least one size-limiting substituent, and when the heteroalkyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. In an embodiment, the heteroalkyl group is substituted with at least one lower substituent, and when the heteroalkyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different. When the heteroalkyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. In an embodiment, the heteroalkyl group is substituted with at least one lower substituent, and when the heteroalkyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different. When the heteroalkyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different.

[0036] "Heteroalkenyl" refers to a stable straight-chain or branched-chain, or a combination thereof, containing at least one carbon-carbon double bond and at least one heteroatom (e.g., O, N, P, Si, and S), and the nitrogen atom and sulfur atom can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized. The heteroalkenyl group can be substituted or unsubstituted. In an embodiment, the heteroalkenyl group is substituted with at least one substituent, and when the heteroalkenyl group is substituted with a plurality of substituents, each substituent can optionally be different. In an embodiment, the heteroalkenyl group is substituted with at least one size-limiting substituent, and when the heteroalkenyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. In an embodiment, the heteroalkenyl group is substituted with at least one lower substituent, and when the heteroalkenyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different. When the heteroalkenyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. In an embodiment, the heteroalkenyl group is substituted with at least one lower substituent, and when the heteroalkenyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different. When the heteroalkenyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different. In an embodiment, the heteroalkenyl group is substituted with at least one size-limiting substituent, and when the heteroalkenyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. When the heteroalkenyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. In an embodiment, the heteroalkenyl group is substituted with at least one lower substituent, and when the heteroalkenyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different. When the heteroalkenyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different.

[0037] "Heteroalkynyl" refers to a stable straight-chain or branched-chain, or a combination thereof, containing at least one carbon-carbon triple bond and at least one heteroatom (e.g., O, N, P, Si, and S), and the nitrogen atom and sulfur atom can optionally be oxidized. In an embodiment, the heteroalkynyl group is substituted with at least one size-limiting substituent, and when the heteroalkynyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. In an embodiment, the heteroalkynyl group is substituted with at least one lower substituent, and when the heteroalkynyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different. When the heteroalkynyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. ​​​The nitrogen heteroatom can optionally be quaternized. The heteroalkynyl group can be substituted or unsubstituted. In embodiments, the heteroalkynyl group is substituted with at least one substituent. When the heteroalkynyl group is substituted with a plurality of substituents, each substituent can optionally be different. In embodiments, the heteroalkynyl group is substituted with at least one size-limiting substituent. When the heteroalkynyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different. In embodiments, the heteroalkynyl group is substituted with at least one lower substituent. When the heteroalkynyl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different.

[0038] The term "heteroalkylene", by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from heteroalkyl, including but not limited to -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH -CH2-. For heteroalkylene groups, the heteroatoms can also occupy either or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, in the case of alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups as used herein include groups bonded to the remainder of the molecule through heteroatoms such as -C(O )R', -C(O)NR', -NR'R'', -OR', -SR', and / or -S O2R'. "Hetero" )R', -C(O)NR', -NR'R'', -OR', -SR', and / or -S O2R', etc. "Hetero" After "alkyl" is listed, if specific heteroalkyl groups, such as -NR’R’’, etc., are listed, it will be understood that the terms heteroalkyl and -NR’R’’ are neither redundant nor mutually exclusive. Rather, specific heteroalkyl groups are listed for clarification. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, such as -NR’R’’, etc.

[0039] The term "heteroalkenylene" means a divalent radical derived from heteroalkenyl, either by itself or as part of another substituent, unless otherwise specified.

[0040] The term "heteroalkynylene" means a divalent radical derived from heteroalkynyl, either by itself or as part of another substituent, unless otherwise specified.

[0041] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from 6 to 18 carbon atoms, and at least one of the rings of the ring system is completely unsaturated, i.e., it contains a cyclic delocalized (4n + 2)π electron system according to Hückel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically Ru, halogen, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroary lalkyl, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、 -R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O) N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、 -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), and -R b -S(O) t N(R a )2(t is 1 or 2), and each R a is, independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, ari -yl (optionally substituted with one or more halogen groups), aralkyl, heterocycloalkyl , heteroaryl, or heteroarylalkyl, and each R b is independently a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c is a straight-chain or branched alkylene or alkenylene chain selected from one or more substituents that substitute an aryl group. Thus, the aryl group can be substituted or unsubstituted. In embodiments, the aryl group is substituted with at least one substituent , and when the aryl group is substituted with a plurality of substituents, each substituent can optionally be different . In embodiments, the aryl group is substituted with at least one size-limiting substituent , and when the aryl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent can optionally be different . In embodiments, the aryl group is substituted with at least one lower substituent , and when the aryl group is substituted with a plurality of lower substituents, each lower substituent can optionally be different.

[0042] "Aryloxy" refers to a radical bonded through an oxygen atom of the formula -O-aryl , where aryl is as defined above.

[0043] "Aralkyl" refers to a radical of the formula -R c aryl, where R c is an alkylene chain as defined above, for example, methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for the aryl group.

[0044] ​"Arylalkyloxy" refers to a radical bonded through the oxygen atom of the formula -O-arylalkyl, where arylalkyl is as defined above. and arylalkyl is as defined above.

[0045] "Arylalkenyl" refers to a radical of the formula -R d -aryl, where R d is an alkenylene chain as defined above. The aryl moiety of the arylalkenyl group is optionally substituted as described above for aryl groups. The alkenylene chain moiety of the arylalkenyl group is optionally substituted as defined above for alkenylene groups. The aryl moiety of the arylalkenyl group is optionally substituted as described above for aryl groups. The alkenylene chain moiety of the arylalkenyl group is optionally substituted as defined above for alkenylene groups. The aryl moiety of the arylalkenyl group is optionally substituted as described above for aryl groups. The alkenylene chain moiety of the arylalkenyl group is optionally substituted as defined above for alkenylene groups. The aryl moiety of the arylalkenyl group is optionally substituted as described above for aryl groups. The alkenylene chain moiety of the arylalkenyl group is optionally substituted as defined above for alkenylene groups.

[0046] "Arylalkynyl" refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above. The aryl moiety of the arylalkynyl group is optionally substituted as described above for aryl groups. The alkynylene chain moiety of the arylalkynyl group is optionally substituted as defined above for alkynylene groups. The aryl moiety of the arylalkynyl group is optionally substituted as described above for aryl groups. The alkynylene chain moiety of the arylalkynyl group is optionally substituted as defined above for alkynylene groups. The aryl moiety of the arylalkynyl group is optionally substituted as described above for aryl groups. The alkynylene chain moiety of the arylalkynyl group is optionally substituted as defined above for alkynylene groups. The aryl moiety of the arylalkynyl group is optionally substituted as described above for aryl groups. The alkynylene chain moiety of the arylalkynyl group is optionally substituted as defined above for alkynylene groups.

[0047] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including fused, bridged, or spiro ring systems having 3 to 15 carbon atoms. In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkyl contains 5 to 7 carbon atoms. Cycloalkyl is bonded to the remainder of the molecule by a single bond. Cycloalkyl is saturated (i.e., contains only single C-C bonds) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyl include, for example, In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkyl contains 5 to 7 carbon atoms. Cycloalkyl is bonded to the remainder of the molecule by a single bond. Cycloalkyl is saturated (i.e., contains only single C-C bonds) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyl include, for example, In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkyl contains 5 to 7 carbon atoms. Cycloalkyl is bonded to the remainder of the molecule by a single bond. Cycloalkyl is saturated (i.e., contains only single C-C bonds) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyl include, for example, In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkyl contains 5 to 7 carbon atoms. Cycloalkyl is bonded to the remainder of the molecule by a single bond. Cycloalkyl is saturated (i.e., contains only single C-C bonds) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyl include, for example, Cycloalkyl is bonded to the remainder of the molecule by a single bond. Cycloalkyl is saturated (i.e., contains only single C-C bonds) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyl include, for example, Cycloalkyl is bonded to the remainder of the molecule by a single bond. Cycloalkyl is saturated (i.e., contains only single C-C bonds) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyl include, for example, Cycloalkyl is bonded to the remainder of the molecule by a single bond. Cycloalkyl is saturated (i.e., contains only single C-C bonds) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyl include, for example, then cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , and cyclooctyl are included. In certain embodiments, the cycloalkyl has 3 to 8 carbon atoms (e.g., C3-C8 cycloalkyl or C3-C8 cycloalkyl ). In other embodiments, the cycloalkyl has 3 to 7 carbon atoms (e.g., C3- C7 cycloalkyl or C3-C7 cycloalkyl). In other embodiments, the cycloalkyl has 3 to 6 carbon atoms (e.g., C3-C6 cycloalkyl or C3-C 6 cycloalkyl). In other embodiments, the cycloalkyl has 3 to 5 carbon atoms (e.g., C3-C5 cycloalkyl or C3-C5 cycloalkyl). In other embodiments the cycloalkyl has 3 to 4 carbon atoms (e.g., C3-C4 cycloalkyl or C3-C4 cycloalkyl). A partially unsaturated cycloalkyl is also referred to as a "cycloalk enyl". Examples of monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cyclo alkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo [2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]hep tanil, spiro[4.4]nonanyl, and the like. Unless otherwise specified herein the term "cycloalkyl" optionally includes alkyl, alkenyl, alkynyl, halo gen, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralk ynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2 - R b -N(R a )2 - R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2 - R b -O-R c -C(O)N(R a )2 - R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), and -R b -S(O) t N(R a )2(t is 1 or 2), and each R a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl( optionally substituted with one or more halogen groups), aralkyl, heterocycloalkyl, hete roaryl, or heteroarylalkyl, and each R bis, independently, a direct bond or is a straight-chain or branched-chain alkylene or alkenylene chain, and R c is a straight-chain or is a branched-chain alkylene or alkenylene chain, and is selected from one or more substituents groups and means including a cycloalkyl group substituted by the group. Therefore, the cycloalkyl group may be substituted or unsubstituted. In an embodiment, the cycloalkyl group is substituted with at least one substituent, and when the cycloalkyl group is substituted with a plurality of substituents, each substituent group may optionally be different. In an embodiment, the cycloalkyl group is substituted with at least one size limiting substituent, and when the cycloalkyl group is substituted with a plurality of size limiting substituents, each size limiting substituent may optionally be different. In an embodiment, the cycloalkyl group is substituted with at least one lower substituent, and when the cycloalkyl group is substituted with a plurality of lower substituents, each lower substituent may optionally be different.

[0048] "Cycloalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-cycloalkyl, and cycloalkyl is as defined above. is as defined above.

[0049] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent. is as defined above.

[0050] "Haloalkyl" refers to an alkyl radical as defined above substituted by one or more halogen radicals as defined above. is as defined above.

[0051] "Haloalkoxy" refers to an alkoxy radical as defined above substituted by one or more halogen radicals as defined above. is as defined above.

[0052] "Halocycloalkyl" refers to a cycloalkyl radical as defined above which is substituted by one or more halogen radicals as defined above.

[0053] "Halocycloalkoxy" refers to an alkoxy radical as defined above which is substituted by one or more halogen radicals as defined above.

[0054] "Alkylhydroxyl" refers to an alkyl radical as defined above which is substituted by one or more hydroxyl radicals as defined above.

[0055] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a heterocycloalkyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including fused ring systems, spiro ring systems, or bridged ring systems. The heteroatoms in the heterocycloalkyl group are optionally oxidized. Where present, one or more nitrogen atoms are optionally quaternized. The heterocycloalkyl group is partially or fully saturated. In some embodiments, the heterocycloalkyl is attached to the remainder of the molecule via any atom(s) of the ring(s). Examples of such heterocycloalkyl groups include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2 (s) -oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazoli dinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidini lu quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrah dropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl are included, but not limited to these. In this spec ification, unless otherwise specifically stated, the term "heterocycloalkyl" optionally, a lkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, thioxo, cyano , nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, hete rocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2 , -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C (O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C (O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O)t R a ( t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S( O) t R a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2), wherein R a is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, hetero aryl, or heteroarylalkyl, and each R b is, independently, a direct bond or is a straight-chain or branched-chain alkylene or alkenylene chain, and R c is a straight-chain or branched-chain alkylene or alkenylene chain selected from those having one or more substituents as defined above, including a heterocycloalkyl radical substituted by substituents. In embodiments, the heterocycloalkyl group may be substituted or unsubstituted. In embodiments, the heterocycloalkyl group is substituted with at least one substituent, and when the heterocycloalkyl group is substituted with a plurality of substituents, each substituent may optionally be different. In embodiments, the heterocycloalkyl group is substituted with at least one size-limiting substituent, and when the heterocycloalkyl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent may optionally be different. In embodiments, the heterocycloalkyl group is substituted with at least one lower substituent, and when the heterocycloalkyl group is substituted with a plurality of lower substituents, each lower The moieties may optionally be different. In embodiments, as used herein, the term "heteroalkyl ring" is a heterocycloalkyl ring.

[0056] "Heteroaryl" refers to a radical derived from a 5- to 18-membered aromatic ring radical containing 1 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings of the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2)π electron system according to Hückel's theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl group is / are optionally oxidized. When present, one or more nitrogen atoms are optionally quaternized. Heteroaryl is attached to the remainder of the molecule via any atom of the ring(s). Unless otherwise specified herein, the term "heteroaryl" optionally includes alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cyclo alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R -OR -R -OC(O)-R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O )-N(R a )2, -R b -N(R a )2, -R b -C(O)R a -R b -C(O)O R a 、 -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a 、 -R b -N(R a )C(O)R a 、 -R b -N(R a ) S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2 )、 -R b -S(O) t R a (t is 1 or 2) and -R b -S(O) t N(R a )2(t is 1 or 2), and R a is, independently, hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R is, independently, a direct bond or a straight or branched alkylene or alkenylene chain, and the one or more substituents selected from those in which one R b is a straight or branched alkylene or alkenylene chain are substituted heterocyclic aryl radicals as defined above, which means including. Therefore, the heteroaryl group can be substituted or unsubstituted. In embodiments, the heteroaryl group is substituted with at least one substituent, and the heteroaryl c is selected from those substituted by one or more substituents which are straight or branched alkylene or alkenylene chains as defined above. Including the heteroaryl radical defined above. It means containing. Therefore, the heteroaryl group can be substituted or unsubstituted. In embodiments, the heteroaryl group is substituted with at least one substituent, and the heteroaryl When the Ru group is substituted with a plurality of substituents, each substituent may optionally be different. In an embodiment, he The heteroaryl group is substituted with at least one size-limiting substituent, and when the heteroaryl group is substituted with a plurality of size-limiting substituents, each size-limiting substituent may optionally be different. In an embodiment, the heteroaryl group is substituted with at least one lower substituent, and when the heteroaryl group is substituted with a plurality of lower substituents, each lower substituent may optionally be different.

[0057] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen, wherein the point of attachment of the heteroaryl radical to the remainder of the molecule is via a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for the heteroaryl radical. As described above for the heteroaryl radical.

[0058] "C-heteroaryl" refers to a heteroaryl radical as defined above, wherein the point of attachment of the heteroaryl radical to the remainder of the molecule is via a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for the heteroaryl radical. As described above for the heteroaryl radical.

[0059] "Heteroaryloxy" refers to a radical bonded through an oxygen atom of the formula -O-heteroaryl, where heteroaryl is as defined above.

[0060] "Heteroarylalkyl" refers to a radical of the formula -R c -heteroaryl, where R c is the alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl When it is the case, the heteroaryl is optionally bonded to the alkyl radical by a nitrogen atom. Hetero The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain The heteroaryl moiety of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0061] "Heteroarylalkoxy" refers to a radical bonded through the oxygen atom of the formula -O-R c -heteroaryl, where R is an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally bonded to the alkyl radical by a nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain The heteroaryl moiety of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group. group.

[0062] "Optional" or "optionally" means that the subsequently described event or situation may occur and may not occur, and this description means that it includes both the case where the event or situation occurs and the case where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and this description means that it includes both the substituted aryl group and the aryl group having no substituent

[0063] In an embodiment, the above terms (e.g., "alkyl", "alkenyl", "alkynyl", "heteroalkyl", "heteroalkenyl", "heteroalkyl", "cycloalkyl ", "heterocycloalkyl", "aryl", and "heteroaryl") each include both substituted and unsubstituted forms of the indicated radicals. Preferred substituents for each type of radical are provided below.

[0064] As used herein, "substituent" means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl 2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F , -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2 , -OCHBr2, -OCHI2, -OCHF2, -CN, -OH, -NH2, -COO H, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, - NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHS O2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), un substituted alkenyl (e.g., C2-C8 alkenyl, C2-C6 alkenyl, or C2- C4 alkenyl), unsubstituted alkynyl (e.g., C2-C8 alkynyl, C2-C6 alk ynyl, or C2-C4 alkynyl), unsubstituted heteroalkyl (e.g., 2-8 membered hete roalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted hete roalkenyl (e.g., 3-8 membered heteroalkenyl, 3-6 membered heteroalkenyl, or 3 -4 membered heteroalkenyl), unsubstituted heteroalkynyl (e.g., 3-8 membered heteroalky nyl, 3-6 membered heteroalkynyl, or 3-4 membered heteroalkynyl), unsubstituted cycloal Lukyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5- C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocyclo alkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsub stituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl , or 5- to 6-membered heteroaryl), and (B) alkyl (e.g., C 1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) substituted with at least one substituent selected from the following, alkenyl (e.g., C2-C 20 , C2-C 12 , C2-C8, C2-C6, or C2-C4), alkynyl (e.g., C2-C 20 , C2-C 12 , C2-C8, C2- C6, or C2-C4), heteroalkyl (e.g., 2- to 20-membered, 2- to 12-membered, 2- to 8 -membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), heteroalkenyl (e.g., 3 - to 20-membered, 3- to 12-membered, 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, or 4- to 5-membered), heteroalk ynyl (e.g., 3- to 20-membered, 3- to 12-membered, 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, or 4- to 5-membered), cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6 , or C5-C6), heterocycloalkyl (e.g., 3- to 10-membered, 3- to 8-membered, 3- to 6 -membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), aryl (e.g., C6-C 12 , C6- C10 or phenyl), or heteroaryl (e.g., 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered): (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHC l2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2 F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl 2, -OCHBr2, -OCHI2, -OCHF2, -CN, -OH, -NH2, -CO OH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NH SO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted alkenyl (e.g., C2-C8 alkenyl, C2-C6 alkenyl, or C2 -C4 alkenyl), unsubstituted alkynyl (e.g., C2-C8 alkynyl, C2-C6 alk ynyl, or C2-C4 alkynyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered he teroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted he teroalkenyl (e.g., 3- to 8-membered heteroalkenyl, 3- to 6-membered heteroalkenyl, or 3- to 4-membered heteroalkenyl), unsubstituted heteroalkynyl (e.g., 3- to 8-membered heteroalk ynyl, 3- to 6-membered heteroalkynyl, or 3- to 4-membered heteroalkynyl), unsubstituted cyclo alkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5 -C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocyclo alkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), un substituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl yl, or 5- to 6-membered heteroaryl), and (ii) alkyl substituted with at least one substituent selected from the following (e.g., , C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C 2), alkenyl (e.g., C2-C 20 , C2-C 12 , C2-C8, C2-C6, or C2-C4), alkynyl (e.g., C2-C 20 , C2-C 12 , C2-C8, C 2-C6, or C2-C4), heteroalkyl (e.g., 2- to 20-membered, 2- to 12-membered, 2 - to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), heteroalkenyl (e.g., , 3- to 20-membered, 3- to 12-membered, 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, or 4- to 5-membered), hetero alkynyl (e.g., 3- to 20-membered, 3- to 12-membered, 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, or 4- to 5-membered), cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4- C6, or C5-C6), heterocycloalkyl (e.g., 3- to 10-membered, 3- to 8-membered, 3 - to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), aryl (e.g., C6-C 12 , C 6-C 10 , or phenyl), or heteroaryl (e.g., 5- to 12-membered, 5- to 10 membered, 5- to 9-membered, or 5- to 6-membered): (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH Cl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH 2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHC l2, -OCHBr2, -OCHI2, -OCHF2, -CN, -OH, -NH2, -C OOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2 , -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -N HSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted al kyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl) , unsubstituted alkenyl (e.g., C2-C8 alkenyl, C2-C6 alkenyl, or C 2-C4 alkenyl), unsubstituted alkynyl (e.g., C2-C8 alkynyl, C2-C6 alkynyl, or C2-C4 alkynyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted he teroalkenyl (e.g., 3-8 membered heteroalkenyl, 3-6 membered heteroalkenyl, or 3-4 membered heteroalkenyl), unsubstituted heteroalkynyl (e.g., 3-8 membered hetero alkylnyl, 3-6 membered heteroalkylnyl, or 3-4 membered heteroalkylnyl), unsubstituted cyc loalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C 5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocyclo alkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl, C 10Aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) alkyl substituted with at least one substituent selected from the following (e.g., , C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C 2), alkenyl (e.g., C2-C 20 , C2-C 12 , C2-C8, C2-C6, or C2-C4), alkynyl (e.g., C2-C 20 , C2-C 12 , C2-C8, C 2-C6, or C2-C4), heteroalkyl (e.g., 2- to 20-membered, 2- to 12-membered, 2 - to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), heteroalkenyl (e.g., , 3- to 20-membered, 3- to 12-membered, 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, or 4- to 5-membered), hetero alkynyl (e.g., 3- to 20-membered, 3- to 12-membered, 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, or 4- to 5-membered), cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4- C6, or C5-C6), heterocycloalkyl (e.g., 3- to 10-membered, 3- to 8-membered, 3 - to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), aryl (e.g., C6-C 12 , C 6-C 10 , or phenyl), or heteroaryl (e.g., 5- to 12-membered, 5- to 10 membered, 5- to 9-membered, or 5- to 6-membered): oxo, halogen, -CCl3, -CBr3, -CF 3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, - OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -CN, - OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO 3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NH C(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH , -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted alkenyl (e.g., C2-C8 alkenyl, C2-C6 alkenyl, or C2-C4 alkenyl), unsubstituted alkynyl (e.g., C2-C8 a lkynyl, C2-C6 alkynyl, or C2-C4 alkynyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered hetero alkyl), unsubstituted heteroalkenyl (e.g., 3-8 membered heteroalkenyl, 3-6 membered he teroalkenyl, or 3-4 membered heteroalkenyl), unsubstituted heteroalkynyl (e.g ., 3-8 membered heteroalkynyl, 3-6 membered heteroalkynyl, or 3-4 membered heteroal kynyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cyclo alkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., , 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered hete rocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl , or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl , 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0065] As used herein, "size-limited substituent" or "size-limited substituent group" means a group selected from all of the substituents described above for "substituent", and each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C alkyl wherein each substituted or unsubstituted alkenyl is substituted or unsubstituted C2-C alkenyl 20 and each substituted or unsubstituted alkynyl is substituted or unsubstituted C2-C alkynyl 20 wherein each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2-20 membered heteroalkyl and each substituted or unsubstituted heteroalkenyl is substituted or unsubstituted 3-20 membered heteroalkenyl 20 and each substituted or unsubstituted heteroalkynyl is substituted or unsubstituted 3-20 membered heteroalkynyl wherein each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C3 -C8 cycloalkyl and each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3-8 membered heterocycloalkyl wherein each substituted or unsubstituted aryl is substituted or unsubstituted C6-C aryl and each substituted or unsubstituted heteroaryl is substituted or unsubstituted 5-10 membered heteroaryl "Lower substituent" or "lower substituent group", as used herein, means a group selected from all of the substituents described above for "substituent", and each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C8 alkyl 10 wherein each substituted or unsubstituted alkenyl is substituted or unsubstituted C2-C

[0066] and each substituted or unsubstituted alkynyl is substituted or unsubstituted C2-C alkynyl wherein each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2-20 membered heteroalkyl ​R is a substituted or unsubstituted C2-C8 alkenyl, and each substituted or unsubstituted alkynyl is a substituted or unsubstituted C2-C8 alkynyl, and each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, and each substituted or unsubstituted heteroalkenyl is a substituted or unsubstituted 3- to 8-membered heteroalkenyl, and each substituted or unsubstituted heteroalkynyl is a substituted or unsubstituted 3- to 8-membered heteroalkynyl, and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0067] In some embodiments, each substituent described in the compounds herein is at least substituted with one substituent. More specifically, in some embodiments, each substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heteroalkyl described in the compounds herein, substituted heteroalkenyl, substituted heteroalkynyl, substituted cycloalkyl, substituted heterocycloalkyl , substituted heteroaryl, substituted alkylene, substituted alkenylene, substituted alkynylene, substituted heteroalkylene, substituted heteroalkenylene, substituted heteroalkynylene , substituted cycloalkylene, substituted heterocycloalkyl, substituted arylene, and / or substituted heteroarylene is substituted with at least one substituent. In other embodiments , at least one or all of these groups are at least one size-limiting group ​is substituted with a substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0068] In embodiments of other compounds herein, each substituted or unsubstituted alkyl may be substituted or un substituted C1-C 20 alkyl, each substituted or unsubstituted alkenyl may be substituted or un substituted C1-C 20 alkenyl, each substituted or unsubstituted alkynyl may be substituted or un substituted C1-C 20 alkynyl, each substituted or unsubstituted heteroalkyl may be substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted heteroalkenyl may be substituted or unsubstituted 3- to 20-membered heteroalkenyl, each substituted or unsubstituted heteroalkynyl is substituted or unsubstituted 3- to 20-membered heteroalkynyl, each substituted or unsubstituted cyclo alkyl is substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted hetero cycloalkyl is substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C6-C 10 aryl, and / or each substituted or unsubstituted heteroaryl is substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is substituted or unsubstituted C1-C 20 alkylene, each substituted or unsubstituted alkenylene is substituted or unsubstituted C1-C 20 alkenylene, each substituted or unsubstituted alkynylene is substituted or unsubstituted C1-C 20 alkynylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, and each substituted or unsubstituted hetero alkenylene is a substituted or unsubstituted 3- to 20-membered heteroalkenylene, and each substituted or unsubstituted heteroalkynylene is a substituted or unsubstituted 3- to 20-membered heteroalkynylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered hetero cycloalkyl, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsub stituted 5- to 10-membered heteroarylene.

[0069] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 8 alkyl, each substituted or unsubstituted alkenyl is a substituted or unsubstituted C2-C8 al kenyl, each substituted or unsubstituted alkynyl is a substituted or unsubstituted C2-C8 alkynyl and each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl and each substituted or unsubstituted heteroalkenyl is a substituted or unsubstituted 3- to 8-membered hetero alkenyl, each substituted or unsubstituted heteroalkynyl is a substituted or unsubstituted 3- to 8-membered heteroalkynyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3 -C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 aryl, and / or each substituted or unsubstituted heteroaryl R is a substituted or unsubstituted 5- to 9-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, and each substituted or unsubstituted alkenylene is a substituted or unsubstituted C1-C8 alkenylene, and each substituted or unsubstituted alkynylene is a substituted or unsubstituted C2-C8 alkynylene, and each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 8-membered heteroalkylene, and each substituted or unsubstituted heteroalkenylene is a substituted or unsubstituted 3- to 8-membered heteroalkenylene, and each substituted or unsubstituted heteroalkynylene is a substituted or unsubstituted 3- to 8-membered heteroalkynylene, and each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and each substituted or unsubstituted arylene is a substituted or unsubstituted phenylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 6-membered heteroarylene. In some embodiments, the compound is a chemical species described in this application (e.g., in the sections, figures, or tables of the following examples).

[0070] In embodiments, the substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted Alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, substituted or unsubstituted heteroalkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., each being unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted heteroalkyl, unsubstituted heteroalkenyl, unsubstituted heteroalkynyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted alkenylene, unsubstituted alkynylene, unsubstituted heteroalkylene, unsubstituted heteroalkenylene, unsubstituted heteroalkynylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkyl, unsubstituted arylene, and / or unsubstituted heteroarylene). In embodiments, the substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted Kill, substituted alkenyl, substituted alkynyl, substituted heteroalkyl, substituted heteroalkenyl, substituted heteroalkynyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl , substituted heteroaryl, substituted alkylene, substituted alkenylene, substituted alkynylene, substituted he teroalkylene, substituted heteroalkenylene, substituted heteroalkynylene, substituted cycloalki lene, substituted heterocycloalkyl, substituted arylene, and / or substituted heteroarylene (where present).

[0071] In embodiments, the substituted moiety (e.g., substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heteroalkyl, substituted heteroalkenyl, substituted heteroalkynyl, substituted cycloalki l, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted alkenylene, substituted alkynylene, substituted heteroalkylene, substituted heteroalkenylene , substituted heteroalkynylene, substituted cycloalkylene, substituted heterocycloalkyl, substituted a ryl, and / or substituted heteroarylene) is substituted with at least one substituent, and when the substituted moiety is substituted with a plurality of substituents, each substituent may optionally be different . In embodiments, when the substituted moiety is substituted with a plurality of substituents, each substituent is different.

[0072] In embodiments, the substituted moiety (e.g., substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heteroalkyl, substituted heteroalkenyl, substituted heteroalkynyl, substituted cycloalki l, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted alkenylene, substituted alkynylene, substituted heteroalkylene, substituted heteroalkenylene , substituted heteroalkynylene, substituted cycloalkylene, substituted heterocycloalkyl, substituted a rylene, and / or substituted heteroarylene) is substituted with at least one size-limiting substituent and, when the substituted moiety is substituted with a plurality of size-limiting substituents, each size-limiting substitut ent may optionally be different. In embodiments, when the substituted moiety is substituted with a plurality of size-limiting substituents , each size-limiting substituent is different.

[0073] In embodiments, the substituted moiety (e.g., substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heteroalkyl, substituted heteroalkenyl, substituted heteroalkynyl, substituted cycloalkyl , substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted alkenylene, substituted alkynylene, substituted heteroalkylene, substituted heteroalkenylene , substituted heteroalkynylene, substituted cycloalkylene, substituted heterocycloalkyl, substituted a rylene, and / or substituted heteroarylene) is substituted with at least one lower substituent and, when the substituted moiety is substituted with a plurality of lower substituents, each lower substituent may optionally be different . In embodiments, when the substituted moiety is substituted with a plurality of lower substituents, each lower substitut ent is different.

[0074] In embodiments, the substituted moiety (e.g., substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heteroalkyl, substituted heteroalkenyl, substituted heteroalkynyl, substituted cycloalkyl , substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted alkenylene, substituted alkynylene, substituted heteroalkylene, substituted heteroalkenylene , substituted heteroalkynylene, substituted cycloalkylene, substituted heterocycloalkyl, substituted a Rylene, and / or substituted heteroarylene) has at least one substituent, size restriction Substituted with a substituent, or a lower substituent, and the substituted moiety is a substituent, size-restricted substituent, and When substituted with a plurality of groups selected from lower substituents, each substituent, size-restricted substituent , and / or lower substituent may optionally be different. In an embodiment, the substituted moiety When substituted with a plurality of groups selected from substituents, size-restricted substituents, and lower substituents Case, each substituent, size-restricted substituent, and / or lower substituent is different.

[0075] "Tautomer" refers to a molecule in which a proton shift from one atom of the molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors including the physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria are as follows: In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors including the physical state, temperature, solvent, and pH. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors including the physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria are as follows: In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors including the physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria are as follows:

Chemical formula

[0076] "Pharmaceutically acceptable salts" include both acid and base addition salts. Any pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any pharmaceutically suitable salt form. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Any pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any pharmaceutically suitable salt form. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0077] "Pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effects and properties of the free base Salts that are not biologically or otherwise undesirable. Also, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid It refers to salts formed with inorganic acids such as aliphatic mono- and di-carboxylic acids, phenyl-substituted aryl acids, etc. Alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfo acids. Also included are salts formed with organic acids such as acetic acid, trifluoroacetic acid, and proton. Pionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, Malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanoic acid, Examples include toluenesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Examples of suitable salts include sulfates, pyrosulfates, bisulfates, sulfites, hydrogen sulfites, nitrates, and phosphorus salts. Phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide Iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate Salt, oxalate, malonate, succinate, suberate, sebacate, fumarate, Maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dibenzoate Torobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenyl Examples include acetate, citrate, lactate, malate, tartrate, and methanesulfonate. Salts of amino acids such as arginate, gluconate, and galacturonate are also contemplated. (For example, Berge SM et al., "Pharmaceutic al Salts,”Journal of Pharmaceutical Science (See, e.g., J. N. C., 66:1-19 (1997)). Acid addition salts of basic compounds are It is prepared by contacting the basic form with a sufficient amount of the desired acid to form a salt.

[0078] The term "pharmaceutically acceptable basic addition salt" refers to a salt that retains the biological effects and properties of the free acid and is not biologically undesirable or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, the pharmaceutically acceptable basic addition salts are formed with a metal or an amine, such as an alkali metal and an alkaline earth metal or an organic amine. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, ferrous lead, copper, manganese, aluminum salts, etc. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines containing naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methyl glucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, pi peridine, N-ethylpiperidine, polyamine resins, etc., but are not limited to these. See Berge et al., supra.

[0079] As used in some embodiments, a “prodrug” refers to a compound that is converted into a biologically active compound described herein under physiological conditions or upon solvolysis. Accordingly, the term “prodrug” refers to a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs are typically inactive when administered to a subject but are converted to an active compound in vivo, e.g., by hydrolysis. Prodrug compounds often provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs, Amsterdam: Elsevier, 1985). Discussions of prodrugs can also be found in Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and Roche, E.B., ed. Bioreversible Carriers in Drug Design, Oxford: Pergamon Press, 1987. The term “prodrug” also means any covalently attached carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. As described herein, a prodrug of an active compound can be prepared by modifying a functional group that is present in the active compound in such a way that the modification is cleaved to the parent active compound either by a predetermined operation or in vivo. Prodrugs include prodrugs of active compounds (See also Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and Roche, E.B., ed. Bioreversible Carriers in Drug Design, Oxford: Pergamon Press, 1987.) The discussion of prodrugs can also be found in Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and Roche, E.B., ed. Bioreversible Carriers in Drug Design, Oxford: Pergamon Press, 1987. The term “prodrug” also means any covalently attached carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. As described herein, a prodrug of an active compound can be prepared by modifying a functional group that is present in the active compound in such a way that the modification is cleaved to the parent active compound either by a predetermined operation or in vivo. Prodrugs include prodrugs of active compounds

[0080] The term “prodrug” also means that such prodrug includes any covalently attached carrier that releases an active compound in vivo when administered to a mammalian subject. As described herein, a prodrug of an active compound can be prepared by modifying a functional group present in the active compound such that the modification is cleaved to the parent active compound either by a predetermined operation or in vivo. Prodrugs include prodrugs of active compounds As described herein, a prodrug of an active compound can be prepared by modifying a functional group present in the active compound such that the modification is cleaved to the parent active compound either by a predetermined operation or in vivo. Prodrugs include prodrugs of active compounds compound can be prepared by modifying a functional group present in the active compound such that the modification is cleaved to the parent active compound either by a predetermined operation or in vivo. Prodrugs include prodrugs of active compounds ​When administered to a mammalian subject, a hydroxy group, an amino group, or a mercapto group binds to any group to form a free hydroxy group, a free amino group, or a free mercapto group, respectively A compound that cleaves as such is included. Examples of prodrugs include acetate, formate, and benzoate derivatives of alcohols in active compounds and the like, but are not limited thereto.

[0081] "Pharmaceutically acceptable solvate" refers to a substance composition in a solvent-added form. In some embodiments, the solvate contains either a stoichiometric or non-stoichiometric amount of solvent and is formed during the manufacturing process using a pharmaceutically acceptable solvent such as water, ethanol. When the solvent is water, a "hydrate" is formed, or when the solvent is alcohol, an alcoholate is formed. The solvates of the compounds described herein are prepared or formed as appropriate during the processes described herein. The compounds provided herein optionally exist in either non-solvated or solvated forms.

[0082] The terms "allosteric site" and "allosteric binding site" refer to ligand binding sites that are locally distinct from the orthosteric binding site.

[0083] The terms "orthosteric site" and "orthosteric binding site" refer to the primary binding site of a receptor that is recognized by an endogenous ligand or agonist of the receptor. For example, the orthosteric site of the muscarinic acetylcholine M1 receptor is the site where acetylcholine binds.

[0084] The term "ligand" binds or associates with a receptor to form a complex and exhibits a Refers to a natural or synthetic molecule that can mediate, prevent, or modify an effect. The term " ligand" is meant to include allosteric modifiers, inhibitors, activators, agonists, antagonists, natural substrates, and analogs of natural substrates.

[0085] The terms "natural ligand" and "endogenous ligand" refer to ligands that occur naturally and bind to a receptor.

[0086] In embodiments, with respect to protein-inhibitor interactions, the terms "inhibitor", "inhibit", "inhibiting", "inhibits", etc. mean to adversely affect (e.g., decrease) the activity or function of a protein as compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means adversely affecting (e.g., decreasing) the protein concentration or level as compared to the protein concentration or level in the absence of the inhibitor. In embodiments, inhibition refers to a reduction in a disease or symptoms of a disease. In embodiments, inhibition refers to a reduction in the activity of a specific protein target. Thus, inhibition includes, at least in part, partially or completely blocking a stimulus, decreasing signal transduction or enzyme activity or the amount of a protein, preventing, or delaying activation or inactivating, desensitizing, or downregulating. In embodiments, inhibition refers to a reduction in the activity of a target protein due to a direct (Binds to a protein that activates a quality, thereby preventing activation of the target protein) .

[0087] In embodiments, the terms "inhibitor", "suppressor", "antagonist", or "downregulator" refer synonymously to a substance capable of detectably reducing the expression or activity of a given gene or protein. An antagonist reduces expression or activity by 10%, 20%, 30%, 40%, 50%, 60% compared to a control in the absence of the antagonist, 70%, 80%, 90%, or more. In certain examples, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more lower than the expression or activity in the absence of the antagonist.

[0088] In embodiments, the term "expression" includes any stage involved in polypeptide production, including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression is detected using conventional techniques for detecting proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.). It can be obtained.

[0089] The term "mAChR M1 receptor antagonist" refers to any exogenously administered compound or agent that can partially or completely inhibit the effect of an agonist (e.g., acetylcholine) on the mAChR M1 receptor or reverse it. This term includes compounds or agents characterized or described as antagonists, partial antagonists, and negative allosteric modulators. For example, m An AChR M1 receptor antagonist can mediate its effects by binding to an orthosteric site or an allosteric site, or can interact with a unique binding site that is not normally involved in the biological regulation of receptor activity. Thus, an mAChR M1 receptor antagonist directly or indirectly inhibits the activity of the mAChR M1 receptor in an animal, particularly a mammal, such as a human, in the presence or absence of acetylcholine or another agonist. In various embodiments, an mAChR M1 receptor antagonist reduces the activity of the intracellular mAChR M1 receptor in the presence of extracellular acetylcholine. In some embodiments, a compound that is an "mAChR M1 receptor antagonist" includes a compound that is an "mAChR M1 receptor competitive antagonist", an "mAChR M1 receptor non-competitive antagonist", an "mAChR M1 receptor partial antagonist", or a "negative allosteric modulator of the mAChR M1 receptor". The term "mAChR M1 receptor competitive antagonist" refers to any exogenously administered compound or agent that can bind to the orthosteric site of the mAChR M1 receptor without activating the receptor. Thus, a competitive antagonist can interact with the mAChR M1 receptor, compete with acetylcholine, an endogenous ligand, for binding to the receptor, and reduce the ability of the receptor to transmit an intracellular signal in response to binding of the endogenous ligand.

[0090]

[0091] ​​​​​​​​​​​​​​​​​Any exogenously administered compound or agent that binds to a site other than the orthosteric binding site of the receptor, which can partially or completely inhibit or reverse the effect of an agonist (e.g., acetylcholine) on the mAChR M1 receptor. Thus, a non-competitive antagonist interacts with the mAChR M1 receptor, reducing the binding of the endogenous ligand acetylcholine to the receptor and / or reducing the ability of the receptor to transmit intracellular signals in response to the binding of the endogenous ligand. The term "mAChR M1 partial antagonist" refers to any exogenously administered compound or agent that can bind to the orthosteric or allosteric site, but the effect of the binding only partially blocks the effect of the mAChR M1 receptor response to an agonist, e.g., acetylcholine. Thus, a partial antagonist can interact with the mAChR M1 receptor but cannot completely inhibit the response of the mAChR M1 receptor to an agonist, e.g., acetylcholine. The term "negative allosteric modulator of mAChR M1" refers to any exogenously administered compound or agent that binds to an allosteric site that directly or indirectly inhibits the activity of the mAChR M1 receptor in the presence of acetylcholine or another agonist in an animal, particularly a mammalian animal, e.g., a human. For example, without intending to be limited to the present disclosure, a selective muscarinic M1 negative allosteric modulator preferentially binds to the muscarinic M1 receptor and acts as a non-competitive antagonist.

[0092]

[0093] It can reduce muscarinic M1 signal transduction. In one aspect, mAChR A negative allosteric modulator of the M1 receptor reduces intracellular the activity of mAChR M1 receptor in the presence of extracellular acetylcholine.

[0094] In embodiments, terms such as "selective" or "selectivity" with respect to a compound or agent refer to the ability of a compound or agent to preferentially increase or decrease the activity of a particular molecular target (e.g., protein, enzyme, etc.) over one or more different molecular targets (e.g., a compound having selectivity for the muscarinic acetylcholine M1 receptor (mAChR M1) preferentially inhibits mAChR M1 over other muscarinic receptors). In embodiments, a "muscarinic acetylcholine M1 receptor selective compound" or "mAChR M1 selective compound" refers to a compound having selectivity for the muscarinic acetylcholine M1 receptor (mAChR M1) (e.g., a compound described herein). In embodiments, a compound (e.g., a compound described herein) is about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or about 100-fold more selective for the muscarinic acetylcholine M1 receptor (mAChR M1) than one or more mAChR M2, M3, M4, or M 5 receptors. In embodiments, a compound (e.g., a compound described herein) is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or at least 100-fold more selective for the muscarinic acetylcholine M1 receptor (mAChR M1) than one or more mAChR M2 , M3, M4, or M5 receptors. The term "subject" or "patient" includes mammals. Examples of mammals include one or more mAChR M2, M3, M4, or M5 receptors, the compound (e.g., a compound described herein) is about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or about 100-fold more selective for the muscarinic acetylcholine M1 receptor (mAChR M1). In embodiments, the compound (e.g., a compound described herein) is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or at least 100-fold more selective for the muscarinic acetylcholine M1 receptor (mAChR M1) than one or more mAChR M2, M3, M4, or M5 receptors. In embodiments, the compound (e.g., a compound described herein) is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or M3, M4, or M5 receptors, the compound (e.g., a compound described herein) is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or at least 100-fold more selective for the muscarinic acetylcholine M1 receptor (mAChR M1) than one or more mAChR M2, M3, M4, or M5 receptors. is at least 100-fold more selective.

[0095] The terms "subject" or "patient" include mammals. Examples of mammals include Any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; experimental animals including rodents such as rats, mice, and guinea pigs, etc., but

[0096] not limited thereto. In one aspect, the subject is a human. As used herein, "treat" or "treating" or "alleviate" or "improve " are used interchangeably herein. These terms refer to an approach to obtain beneficial or desired results, including but not limited to therapeutic and / or preventive benefits. "Therapeutic benefit" means the eradication or improvement of the underlying disease being treated. Also, a therapeutic benefit is achieved by the eradication or alleviation of one or more physiological symptoms associated with the underlying disease such that improvement is observed in the patient, even though the patient may still be afflicted with the underlying disease. For preventive benefits, the composition is administered to patients

[0097] at risk of developing a particular disease, or to patients reporting one or more physiological 50 symptoms of the disease, even in the absence of a diagnosis of the disease. As used herein, "EC " is intended to refer to the concentration of a substance (e.g., a compound or drug) required to activate or enhance by 50% the components of a biological process, or a process including 50 proteins, subunits, organelles, ribonucleoproteins, etc. For example, EC In an embodiment, the in vitro assay system endogenously expresses the target of interest or is a cell line transfected with an appropriate expression vector that directs recombinant expression of the target. is utilized.

[0098] As used herein, "IC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process or a component of a process, such as a protein, subunit, organelle, ribonucleoprotein, etc., by 50%. For example, IC is intended to refer to the inhibitory concentration (IC) that is half (50%) of the maximum value of the substance determined in an appropriate assay. For example, the IC 50 of the mAChR M1 receptor can be determined in an in vitro assay system. of the mAChR M1 receptor can be determined in an in vitro assay system. 50 is the in vitro assay system.

[0099] II. Compounds The present disclosure provides compounds that are antagonists of the muscarinic acetylcholine M1 receptor (mAChR M1). These compounds, and compositions containing these compounds, are useful for the treatment or prevention of neuropathy. In some embodiments, the compounds described herein are useful for treating multiple sclerosis. are useful for treating multiple sclerosis.

[0100] In one aspect, a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IA-1) or (IB-1),

Chemical formula

Chemical formula

Chemical formula

[0101] In one aspect, a compound of formula (IA) or (IB), wherein

Chemical formula

Chemical formula

[0102] In one aspect, a compound of formula (IIA) or (IIB),

Chemical formula

Chemical formula

[0103] In another aspect, a compound of formula (III) wherein,

Chemical formula

Chem.

[0104] In embodiments of the compounds described herein (e.g., formula (IA-1), (IB-1), (IA), (IB ), (IIA), (IIB), or (III)), or their pharmaceutically acceptable salts or solvates, X is a bond, -C(R 9 )(R 10 )-, -N(R 11 )-, or -O-. In some embodiments, X is a bond, -N(R 11 ) -, or -O-.

[0105] In some embodiments of the compounds of formula (IA), (IB), (IIA), (IIB), or (III), or their pharmaceutically acceptable salts or solvates, X is a bond, -C(R )(R )(R 9 )-, -N(R 10 )-, or -O-. In some embodiments, X is a bond, -N(R 11 )-, or -O-. In embodiments, substituted X (e.g., substituted alkylene, substituted alkenylene, substituted alkynylene, substituted heteroalkylene, substituted heteroalkenylene, and / or substituted heteroalki 11 )-, or -O-.

[0106] ylene, substituted heteroalkenylylene, and / or substituted heteroalkynylylene), wherein, Nylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent , when the substitution X is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents , each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, when X is substituted, it is substituted with at least one substituent . In embodiments, when X is substituted, it is substituted with at least one size-limiting substituent . In embodiments, when X is substituted, it is substituted with at least one lower substituent .

[0107] In embodiments, substitution Y (e.g., substituted alkylene, substituted alkenylene, and / or substituted heteroalkylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substitution Y is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents , each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, when Y is substituted, it is substituted with at least one substituent . In embodiments, when Y is substituted, it is substituted with at least one size-limiting substituent . In embodiments, when Y is substituted, it is substituted with at least one lower substituent .

[0108] In embodiments, ring A may be substituted with hydroxyl in addition to the recited substituents

[0109] . In embodiments of the compounds described herein (e.g., formula (IA-1), (IB-1), (IA), (IB ), (IIA), (IIB), or (III)), or their pharmaceutically acceptable salts or solvates, R 1 is​​ [Chemical formula] is. In some embodiments, R 1 is [Chemical formula] is.

[0110] Compounds of formula (IA), (IB), (IIA), (IIB), or (III), or in some embodiments of their pharmaceutically acceptable salts or solvates, R 1 is [Chemical formula] is. In some embodiments, R 1 is [Chemical formula] is.

[0111] In embodiments, R 2 is hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1- 6 haloalkyl, substituted or unsubstituted C 1-6 haloalkoxy, substituted or unsubstituted C1 -6 cycloalkyl, substituted or unsubstituted C 1-6 cycloalkoxy, substituted or unsubstituted C 1-6 halocycloalkyl, substituted or unsubstituted C 1-6 halocycloalkoxy, substituted or unsubstituted C alkylhydroxyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 1-6

[0112] In an embodiment, the substituent R 2 (e.g., substituted alkyl, substituted alkoxy, substituted haloalkyl , substituted haloalkoxy, substituted cycloalkyl, substituted cycloalkoxy, substituted halocyclo alkyl, substituted halocycloalkoxy, substituted alkyl hydroxyl, substituted heterocycloalkyl , substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent , size-limiting substituent, or lower substituent, and when the substituent R 2 is substituted with a plurality of groups selected from substituents, size-limiting substituents , and lower substituents, each substituent, size -limiting substituent, and / or lower substituent may optionally be different. In an embodiment , when R 2 is substituted, R 2 is substituted with at least one substituent. In an embodiment , when R 2 is substituted, it is substituted with at least one size-limiting substituent. In an embodiment , when R 2 is substituted, it is substituted with at least one lower substituent.

[0113] In an embodiment, the substituent R 3 (e.g., substituted alkyl, substituted alkoxy, substituted haloalkyl , substituted haloalkoxy, substituted cycloalkyl, substituted cycloalkoxy, substituted halocyclo alkyl, substituted halocycloalkoxy, substituted alkyl hydroxyl, substituted heterocycloalkyl , substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent , size-limiting substituent, or lower substituent, and when the substituent R 3 is substituted with a plurality of groups selected from substituents, size-limiting substituents , and lower substituents, each substituent, size The group-limiting substituents and / or lower substituents may optionally be different. In an embodiment , when R 3 is substituted, it is substituted with at least one substituent. In an embodiment, when R 3 is substituted, it is substituted with at least one size-limiting substituent. In an embodiment, when R 3 is substituted, it is substituted with at least one lower substituent.

[0114] In an embodiment, substituted R 4 (e.g., substituted alkyl) is substituted with at least one substituent, size -limiting substituent, or lower substituent, and when substituted R 4 is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent group, and / or lower substituent may optionally be different. In an embodiment, when R 4 is sub stituted, it is substituted with at least one substituent. In an embodiment, when R 4 is substituted it is substituted with at least one size-limiting substituent. In an embodiment, when R 4 is substituted, it is substituted with at least one lower substituent.

[0115] In an embodiment, substituted R 5 (e.g., substituted alkyl) is substituted with at least one substituent, size -limiting substituent, or lower substituent, and when substituted R 5 is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent group, and / or lower substituent may optionally be different. In an embodiment, when R 5 is sub stituted, it is substituted with at least one substituent. In an embodiment, when R 5is replaced in the case of, is replaced with at least one size-limiting substituent. In an embodiment, R 5 is replaced in the case of, is replaced with at least one lower substituent.

[0116] In an embodiment, substitution R 6 (e.g., substituted alkyl) is replaced with at least one substituent, size -limiting substituent, or lower substituent, and substitution R 6 is replaced with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents, and each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In an embodiment, R 6 is replaced in the case of, is replaced with at least one substituent. In an embodiment, R 6 is replaced in the case of, is replaced with at least one size-limiting substituent. In an embodiment, R 6 is replaced in the case of, is replaced with at least one lower substituent.

[0117] In an embodiment, substitution R 7 (e.g., substituted alkyl) is replaced with at least one substituent, size -limiting substituent, or lower substituent, and substitution R 7 is replaced with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents, and each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In an embodiment, R 7 is replaced in the case of, is replaced with at least one substituent. In an embodiment, R 7 is replaced in the case of, is replaced with at least one size-limiting substituent. In an embodiment, R 7 is replaced in the case of, is replaced with at least one lower substituent.

[0118] In embodiments of the compounds described herein (e.g., of formula (IA-1), (IB-1), (IA), (IB ), (IIA), (IIB), or (III)), or their pharmaceutically acceptable salts or solvates, R 8 is

Chemical formula

Chemical formula

[0119] In some embodiments of the compounds of formula (IA), (IB), (IIA), (IIB), or (III), or their pharmaceutically acceptable salts or solvates, R is 8 is

Chemical formula

Chemical formula

[0120] In embodiments, the substituted R 9 (e.g., substituted alkyl, substituted alkoxy, substituted haloalkyl , substituted haloalkoxy, substituted cycloalkyl, substituted cycloalkoxy, substituted halocyclo alkyl, substituted halocycloalkoxy, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 9 is from substituents, size-limiting substituents, and lower substituents When substituted with a plurality of selected groups, each substituent, size-limiting substituent, and / or the lower substituents may optionally be different. In an embodiment, when R 9 is substituted, it is substituted with at least one substituent. In an embodiment, when R 9 is substituted, it is substituted with at least one size-limiting substituent. In an embodiment, when R 9 is substituted, it is substituted with at least one lower substituent.

[0121] In an embodiment, substituted R 10 (e.g., substituted alkyl, substituted alkoxy, substituted haloalkyl alkyl, substituted haloalkoxy, substituted cycloalkyl, substituted cycloalkoxy, substituted halocyclo alkyl, substituted halocycloalkoxy, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when substituted R 10 is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents , each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In an embodiment, when R 10 is substituted, it is substituted with at least one substituent. In an embodiment, when R is substituted, it is substituted with at least 10 one size-limiting substituent. In an embodiment, when R is substituted, it is substituted with at least 10 one lower substituent when R is substituted.

[0122] In an embodiment, substituted R 11 (e.g., substituted alkyl, substituted haloalkyl, substituted cyclo alkyl, substituted halocycloalkyl, substituted heterocycloalkyl, substituted aryl. And / or or a substituted heteroaryl) is substituted with at least one substituent, a size-limiting substituent, or a lower level substituent, and substituted R 11 When is substituted with a substituent, a size-limiting substituent, and a lower-level substituent When selected from a plurality of groups, each substituent, size-limiting substituent, and / or The lower-level substituent may optionally be different. In an embodiment, R 11 When is substituted, It is substituted with at least one substituent. In an embodiment, R 11 When is substituted, at least It is substituted with one size-limiting substituent. In an embodiment, R 11 When is substituted, at least It is substituted with one lower-level substituent.

[0123] In an embodiment, substituted R 12 (e.g., substituted alkyl, substituted alkoxy, substituted haloalkyl l, substituted haloalkoxy, substituted cycloalkyl, substituted cycloalkoxy, substituted halocyclo alkyl, substituted halocycloalkoxy, substituted alkyl hydroxyl, substituted heterocycloalkyl l, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, a size-limiting substituent, or a lower-level substituent, and substituted R 12 When is substituted with a substituent, a size-limited substituent, and a plurality of groups selected from lower-level substituents, each substituent, size-limiting substituent, and / or lower-level substituent may optionally be different. In an embodiment In, R 12 When is substituted, it is substituted with at least one substituent. In an embodiment, R 12 When is substituted, it is substituted with at least one size-limiting substituent. In an embodiment Is, when R 12 Is substituted, it is substituted with at least one lower-level substituent.

[0124] In an embodiment, substituted R 13 (for example, substituted alkyl, substituted haloalkyl, substituted cyclo alkyl, substituted halocycloalkyl, substituted heterocycloalkyl, substituted aryl. And / or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower class substituent, and when substituted R 13 is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower class substituents, each substituent, size-limiting substituent, and / or lower class substituent may optionally be different. In an embodiment, when R 13 is substituted, it is substituted with at least one substituent. In an embodiment, when R 13 is substituted, at least one size-limiting substituent. In an embodiment, when R 13 is substituted, at least one lower class substituent.

[0125] In an embodiment, substituted R 14 (for example, substituted alkyl, substituted haloalkyl, substituted cyclo alkyl, substituted halocycloalkyl, substituted heterocycloalkyl, substituted aryl. And / or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower class substituent, and when substituted R 14 is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower class substituents, each substituent, size-limiting substituent, and / or lower class substituent may optionally be different. In an embodiment, when R 14 is substituted, it is substituted with at least one substituent. In an embodiment, when R 14 is substituted, at least is substituted with at least one size-limiting substituent. In an embodiment, when R 14 is substituted, it is substituted with at least one lower-level substituent.

[0126] In an embodiment, substituted R 15 (e.g., substituted alkyl, substituted haloalkyl, substituted cycloalkyl, substituted halocycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower-level substituent, and when substituted R 15 is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower-level substituents, each substituent, size-limiting substituent, and / or lower-level substituent may optionally be different. In an embodiment, when R 15 is substituted, it is substituted with at least one substituent. In an embodiment, when R 15 is substituted, it is substituted with at least one size-limiting substituent. In an embodiment, when R 15 is substituted, it is substituted with at least one lower-level substituent.

[0127] In an embodiment, substituted R 16 (e.g., substituted alkyl, substituted haloalkyl, substituted cycloalkyl, substituted halocycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower-level substituent, and when substituted R 16 is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower-level substituents, each substituent, size-limiting substituent, and / or lower-level substituent may optionally be different. In an embodiment, when R 16 is substituted,​ is substituted with at least one substituent. In embodiments, R 16 , when substituted, is substituted with at least one size-restricted substituent. In embodiments, R 16 , when substituted, is substituted with at least one lower substituent.

[0128] Any combination of the groups described above or below for the various variable parts is contemplated herein. Throughout this specification, those groups and substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0129] In some embodiments, a compound selected from the following, or a pharmaceutically acceptable salt or solvate thereof is provided:

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[0130] In an embodiment, the compound is

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[0131] In an embodiment, the compound is useful as a comparative compound. In an embodiment, the comparative compound is , an assay (e.g., as described herein, e.g., in the Examples section, figures, or tables It can be used to evaluate the activity of a test compound in an assay such as

[0132] In embodiments, the compound is a compound described herein (e.g., in the compound section , the examples section, the methods section, or the claims, tables, or figures).

[0133] III. Further Forms of Compounds Isomers The compounds described herein include all tautomers possible within the scope of the formulas described herein. Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some situations, the compound exists as a tautomer.

[0134] In some situations, the compounds described herein have one or more chiral centers, and each center exists in the (R) configuration or the (S) configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, enantiomers and / or di astereoisomeric mixtures resulting from a single preparative step, combination, or interconversion are useful for the uses described herein. In some embodiments, the compounds described herein are obtained by chiral chromatography resolution of a racemic mixture. ​​​, are prepared as optically pure enantiomers. In some embodiments, the compounds described herein are prepared by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereo isomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer -s as their individual stereoisomers. In some embodiments a dissociable complex is preferred (e.g., a crystalline diastereomeric salt). In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility , reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments the diastereomers are separated by chiral chromatography or preferably by separation / resolution techniques based on differences in solubility . In some embodiments, the optically pure enantiomer is then recovered from the resolving agent by any practical means that does not result in racemization .

[0135] The term "geometric isomers" refers to the E or Z geometric isomers of an alkene double bond (e.g., c is or trans). The term "positional isomers" refers to structural isomers around the central ring, e.g., ortho-, meta-, and para isomers around a benzene ring .

[0136] Labeled Compounds The compounds disclosed herein are, in some embodiments, used in different enriched isotopic forms, e.g ., 2 H, 3 H, 11 C, 13 C and / or 14 C in enriched forms. In one particular embodiment, the compound is deuterated at at least one position . Yes. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334, ,997. As described in U.S. Patent Nos. 5,846,51 4 and 6,334,997, deuteration can improve metabolic stability and / or efficacy and thus increase the duration of action of the drug. .

[0137] Unless otherwise specified, the structures shown herein are intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, a compound having this structure is within the scope of the present disclosure except that hydrogen is replaced with deuterium or tritium, or carbon is replaced with C- or C-enriched carbon. 13 1 4

[0138] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes in one or more of the atoms that make up such compounds. For example, the compounds can be labeled with isotopes such as, for example, deuterium ( H), tritium ( 2 H), 3 iodine-125 ( I) or carbon-14 ( 125 C). 14 . 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 17 O, 18 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S,​​​​35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 Isotope substitution with I is contemplated for all. All isotopic modifications of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0139] In certain embodiments, the compounds disclosed herein have some or all of the H atoms 1 replaced by 2 H atoms. Methods for synthesizing deuterium-containing compounds are known in the art. In some embodiments, deuterium-substituted compounds are synthesized using various methods as described below: Dean, D.C.; “Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development,” Curr. Pharm. Des., 2000, 6(10); George W.; Varma, R.S., “The Synthesis of Radiolabeled Compounds via Organometallic Intermediates,” Tetrahedron, 1989, 45(21), 6601-21; and Evans, E.A., “Synthesis of radiolabeled compounds,” J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0140] In some embodiments, the compounds described herein are labeled by chromophores or fluorescent moieties, bioluminescent labels, or other means including, but not limited to, the use of chemiluminescent labels.

[0141] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0142] In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of several inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ by reacting, during the final isolation and purification of the compounds of the present disclosure, or by reacting the purified compound separately with a suitable acid or base and isolating the thus formed salt.

[0143] Solvates In some embodiments, the compounds described herein exist as solvates. The present disclosure provides methods of treating a disease by administering such solvates. The present disclosure further provides methods of treating a disease by administering such solvates as a pharmaceutical composition.

[0144] ​​​​​​​​​​​​​​The solvate includes either a stoichiometric or non-stoichiometric amount of solvent and, in some embodiments, is formed during the crystallization process using a pharmaceutically acceptable solvent such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. The solvates of the compounds described herein are prepared or formed as appropriate during the processes described herein. As just one example, the hydrates of the compounds described herein are prepared as appropriate by recrystallization from an aqueous / organic solvent mixture using an organic solvent including but not limited to dioxane, tetrahydrofuran or methanol. Further, the compounds provided herein exist not only in the unsolvated form but also in the solvated form. Generally, the solvated form is considered equivalent to the unsolvated form for the purposes of the compounds and methods provided herein. In some embodiments, the compounds described herein exist in the form of prodrugs. The present disclosure provides methods of treating a disease by administering such prodrugs. The present disclosure further provides methods of treating a disease by administering such prodrugs as a pharmaceutical composition. In some embodiments, the prodrug includes a compound in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3 or 4) amino acid residues, is covalently bonded to a free amino group, hydroxy group or carboxylic acid group of the compound of the present disclosure via an amide bond or an ester bond. Amino acid residues include the 20 naturally occurring amino acids.

[0145] Prodrug In some embodiments, the compounds described herein exist in the form of prodrugs. The present disclosure provides methods of treating a disease by administering such prodrugs. The present disclosure further provides methods of treating a disease by administering such prodrugs as a pharmaceutical composition.

[0146] In some embodiments, the prodrug includes a compound in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3 or 4) amino acid residues, is covalently bonded to a free amino group, hydroxy group or carboxylic acid group of the compound of the present disclosure via an amide bond or an ester bond. ​​​​​​​​​​Although these are exemplified, they are not limited thereto, and also include 4-hydroxyproline, hydroxylysine, democine, isodemocine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. In other embodiments, the prodrug is a nucleic acid residue, or two or more (e.g., 2, 3 or 4) oligonucleotides of nucleic acid residues covalently bonded to the compounds of the present disclosure .

[0147] Pharmaceutically acceptable prodrugs of the compounds described herein include esters, carbonic acid esters, thiocarbonic acid esters, N-acyl derivatives, N-acyl oxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphoric acid esters, metal salts and sulfonic acid esters, but are not limited thereto. In some embodiments, compounds having a free amino group, amide group, hydroxy group or carboxylic acid group are converted to prodrugs. For example, a free carboxyl group is derivatized as an amide or an alkyl ester. In certain examples, all of these prodrug moieties incorporate groups including, but not limited to, ether, amine and carboxylic acid functional groups.

[0148] Hydroxy prodrugs include esters such as, but not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyl oxyalkyl esters, alkyl esters, aryl esters, phosphoric acid esters, sulfonic acid esters, sulfuric acid esters and disulfide-containing esters; Ter, amide, carbamate, hemisuccinate, dimethylaminoacetate and phospho contain a phorolyloxymethyloxycarbonyl, which are described in Fleisher, D.et al., “Improved oral drug delivery: solubi lity limitations overcome by the use of prodrugs,” Advanced Drug Delivery Reviews , 1996, 19, 115-130.

[0149] Prodrugs derived from amines include the following groups and combinations thereof:

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[0150] IV. Pharmaceutical Compositions In embodiments, the compounds described herein (e.g., of formula (IA-1), (IB-1), ( IA), (IB), (IIA), (IIB), or (III)) are administered as pure chemical substances. In embodiments, the compounds described herein (e.g., of formula (IA-1), ( IB-1), (IA), (IB), (IIA), (IIB), or (III)) are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) pharmaceutical additive, a physiologically suitable (or acceptable) pharmaceutical additive, or a physiologically suitable (or acceptable) carrier) selected based on a selected route of administration and standard pharmaceutical practice, which is, for example, described in Gennaro, A .R., “Remington: The Science and Practice of Pharmacy,” 20th ed., Lippincott Williams & Wilkins, 2000. of Pharmacy,” 20th ed., Lippincott Williams & Wilkins, 2000. of Pharmacy,” 20th ed., Lippincott Williams & Wilkins, 2000. .R., “Remington: The Science and Practice of Pharmacy,” 21 st ed., Easton: Lippincott Williams & Wilkins, 2005, as described therein.

[0151] In certain embodiments, the compounds of formulas (IA), (IB), (IIA), (I IB), or (III) described herein are administered as pure chemical substances. In some embodiments, the compounds of formulas (IA), (IB), (IIA), (IIB), or (III) described herein are selected based on the chosen route of administration and standard pharmaceutical practice to be combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) pharmaceutical additive, a physiologically suitable (or acceptable) pharmaceutical additive, or a physiologically suitable (or acceptable) carrier), which is described, for example, in Gennaro, A.R., “Remington: The Science and Practice of Pharmacy,” 21 ed., East on: Lippincott Williams & Wilkins, 2005. Thus, provided herein is a pharmaceutical composition comprising at least one compound of formulas (IA-1), (IB-1), (IA), (IB), (IIA), of Pharmacy,” 21 st ed., East on: Lippincott Williams & Wilkins, 2005, as described therein.

[0152] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound of formulas (IA-1), (IB-1), (IA), (IB), (IIA), of Pharmacy,” 21 (IIB), or (III) described herein, in combination with one or more pharmaceutically acceptable carriers, or a pharmaceutically acceptable salt or solvate thereof. The carrier(s) (or pharmaceutical additive(s)) is / are such that the carrier is compatible with the other components of the composition and the recipient of the composition (i.e., the carrier is non-toxic and does not interfere with the activity of the other components of the composition or the physiological response of the recipient to the composition). (IIB), or (III) described herein, in combination with one or more pharmaceutically acceptable carriers, or a pharmaceutically acceptable salt or solvate thereof. The carrier(s) (or pharmaceutical additive(s)) is / are such that the carrier is compatible with the other components of the composition and the recipient of the composition (i.e., That is, when it is not harmful to the subject), it is acceptable or appropriate.

[0153] Accordingly, provided herein is a combination of one or more pharmaceutically acceptable carriers and at least one compound of formula (IA), (IB), (IIA), (IIB), or (III) as described herein or a pharmaceutically acceptable salt or solvate thereof. The carrier(s) (or pharmaceutical additive(s)) is such that the carrier is compatible with the other components of the composition and is not harmful to the recipient of the composition (i.e., the subject), and is acceptable or appropriate. In a case where it is compatible with the other components of the composition and is not harmful to the recipient of the composition (i.e., the subject), it is acceptable or appropriate.

[0154] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable pharmaceutical additive and a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof.

[0155] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable pharmaceutical additive and a compound of formula (IB-1), or a pharmaceutically acceptable salt thereof.

[0156] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable pharmaceutical additive and a compound of formula (IA), or a pharmaceutically acceptable salt thereof.

[0157] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable pharmaceutical additive and a compound of formula (IB), or a pharmaceutically acceptable salt thereof.

[0158] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable pharmaceutical additive and a compound of formula (IIA), or a pharmaceutically acceptable salt thereof.

[0159] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable pharmaceutical additive and a compound of formula (IIB), or a pharmaceutically acceptable salt thereof.

[0160] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable pharmaceutical additive and a compound of formula (III), or a pharmaceutically acceptable salt thereof.

[0161] In embodiments, the pharmaceutical composition comprises a compound selected from Compound List 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0162] In embodiments, the compounds described herein (e.g., of formula (IA-1), (IB-1), (IA), (IB), (IIA), (IIB), or (III)) are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other organic low molecular weight substances, such as contaminating intermediates or by-products generated in one or more steps of the synthesis method.

[0163] In certain embodiments, the compounds of formula (IA), (IB), (IIA), (IIB), or (III) described herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0 .1% of other organic low molecular weight substances, such as contaminating intermediates or by-products generated in one or more steps of the synthesis method.

[0164] These pharmaceutical compositions include those suitable for oral administration, rectal administration, topical administration, buccal administration, parenteral administration (e.g., subcutaneous administration, intramuscular administration, intradermal administration, or intravenous administration), vaginal administration, ophthalmic administration, or aerosol administration.

[0165] Exemplary pharmaceutical compositions are, for example, in solid, semi-solid or liquid form, for external use, enteral or parenteral use, in a mixture with an organic or inorganic carrier or pharmaceutical additive suitable therefor, and are used in the form of pharmaceutical preparations containing one or more of the disclosed compounds as active ingredients. In some embodiments, the active ingredient is, for example, tablets, pellets, capsules, suppositories, solvents, emulsions, suspensions, and other conventional non-toxic pharmaceutical pharmaceutically acceptable carriers for any other suitable form of use. The active compound is contained in the pharmaceutical composition in an amount sufficient to produce a desired effect on the disease process or condition.

[0166] In some embodiments for preparing solid compositions such as tablets, the major active ingredient is a solid preformulation composition comprising a homogeneous mixture of the disclosed compound or its non-toxic pharmaceutically acceptable salt, and is mixed with a pharmaceutical carrier, such as corn starch lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate cium, dicalcium phosphate or gums, and other pharmaceutical diluents, such as water. When these preformulation compositions are referred to as being homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. For solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject composition is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers

[0167] acceptable carriers, and / or mixed with any of the following: (1) fillers Agents or bulking agents, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid;( 2) Binders, such as carboxymethyl cellulose, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia, etc.; (3) Humectants such as glycerol; (4) Disintegrants, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5 ) Dissolution retardants, such as paraffin; (6) Absorption promoters, such as quaternary ammonium compounds ; (7) Wetting agents, such as sodium docusate, cetyl alcohol and glycerol monostearate, etc.; (8) Absorbents, such as kaolin clay and bentonite clay;( 9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof and (1 ) Colorants. In the case of capsules, tablets and pills, in some embodiments, the composition contains buffers. In some embodiments, similar types of solid compositions are also used as fillers for soft -hard gelatin capsules using pharmaceutical additives such as lactose or milk sugar, and high molecular weight polyethylene glycol. In some embodiments, tablets are optionally made by compression or molding using one or more auxiliary components. In some embodiments, compressed tablets are made with binders (e.g., gelatin also ), etc. In some embodiments, the composition is a buffer. In some embodiments, similar types of solid compositions are also used as fillers for soft -hard gelatin capsules using pharmaceutical additives such as lactose or milk sugar, and high molecular weight polyethylene glycol. In some embodiments, tablets are optionally made by compression or molding using one or more auxiliary components. In some embodiments, compressed tablets are made with binders (e.g., gelatin also

[0168] In some embodiments, tablets are made by compression or molding, optionally using one or more secondary components. In some embodiments, compressed tablets are made with binders (e.g., gelatin also Or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (For example, sodium starch glycolate or cross-linked sodium carboxymethylcellulose Sodium) is prepared using surfactants or dispersants. In some embodiments, The molded tablets are formed from a mixture of the target composition moistened with an inert liquid diluent using a suitable machine And in some embodiments, tablets, as well as other solid dosage forms, such as sugar-coated Agents, capsules, pills and granules are scored or prepared with coatings and shells, such as enteric coatings Gums and other coatings.

[0169] Compositions for inhalation or aerosol delivery include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include Pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and Elixirs are included. In addition to the target composition, in some embodiments, the liquid dosage form is An inert diluent, such as water or other solvents, solubilizers and emulsifiers, such as ethyl a Alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed Oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol Alcohol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan Cyclodextrin and mixtures thereof. In some embodiments, the suspension, in addition to the target composition, for example, ethoxylated iso

[0170] In some embodiments, the suspension, in addition to the target composition, for example, ethoxylated iso Stearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose Crystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, etc. as well as suspending agents as mixtures thereof.

[0171] In some embodiments, formulations for rectal or vaginal administration are presented as suppositories, This may involve the subject composition being coated with, for example, cocoa butter, polyethylene glycol, a suppository wax or or salicylates, and is a solid at room temperature but a liquid at body temperature, and thus It dissolves in the body cavity and releases the active agent.

[0172] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, and the like. In some embodiments, the active ingredient is an ointment, gel, solution, patch, or inhalant. The components are mixed under sterile conditions with a pharma- ceutically acceptable carrier and, optionally, with preservatives, buffers, etc. , or mixed with a propellant.

[0173] In some embodiments, ointments, pastes, creams and gels are provided in addition to the subject compositions. Pharmaceutical excipients, such as animal and vegetable fats, oils, waxes, paraffins, denaturants, Pun, tragacanth, cellulose derivatives, polyethylene glycol, silicone, vent The silicate may be selected from the group consisting of talc, zinc oxide, silicate, talc and zinc oxide, or mixtures thereof.

[0174] In some embodiments, powders and sprays contain, in addition to the subject composition, excipients. For example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polysaccharides. In some embodiments, the spray comprises a tertiary amide powder, a tertiary amide powder, or a mixture of these materials. Further, conventional propellants, such as chlorofluorohydrocarbons as well as volatile unsubstituted carbonyl compounds, Hydrogen includes, for example, butane and propane.

[0175] In some embodiments, the compounds described herein are formulated as eye drops for administration to the eye. will be done.

[0176] Alternatively, the compositions and compounds disclosed herein may be administered by aerosol. This can be done by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. In some embodiments, this is accomplished by using a non-aqueous (e.g., fluorocarbon propellant) In some embodiments, a sonic nebulizer is used. These are due to the exposure of the drug to shear, which can result in degradation of compounds contained in the subject compositions. Generally, aqueous aerosols are used to minimize the impact of the aqueous solubility of the target composition. The solution or suspension can be formulated with conventional pharma- ceutically acceptable carriers and stabilizers. Carriers and stabilizers will vary depending on the requirements of the particular subject composition, but typically include Typically, non-ionic surfactants (e.g., Tween, Pluronic, or poly Ethylene glycol), serum albumin, sorbitan ester, oleic acid, lecithin, Harmless proteins such as amino acids like glycine, buffers, salts, sugars or sugar alcohols Aerosols are generally prepared from isotonic solutions.

[0177] Pharmaceutical compositions suitable for parenteral administration are prepared by reconstituting sterile injectable solutions or dispersions immediately prior to use. One or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, comprising the subject composition in combination with a liquid or emulsion, or a sterile powder, which in some embodiments, include antioxidants, buffers, bacteriostats, solutes or suspending or thickening agents to render the formulation isotonic with the blood of the intended recipient .

[0178] Examples of suitable aqueous and non-aqueous carriers used in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc. ), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Suitable fluidity is maintained, for example, by the use of coating materials such as lecithin, maintenance of the required particle size in the case of dispersions , and the use of surfactants.

[0179] Enteral pharmaceutical formulations comprising the disclosed compounds and enteric substances; as well as pharmaceutically acceptable carriers or pharmaceutical additives thereof are also contemplated. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and mainly soluble in intestinal fluids at a specific pH. The small intestine is part of the digestive tract (intestine) between the stomach and the large intestine, which includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5. Thus, enteric materials are, for example, at a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0 . is not soluble until. Exemplary enteric materials include cellulose acetate phthalate (CA P), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropylmethyl cellulose succinate, cellulose acetate succinate, cellulose acetate to hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate , copolymers of methyl methacrylate and methyl methacrylate, methyl acrylate and meth lum methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethylmethyl acrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins , such as zein, shellac and copal colophonium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit F S30D, Eudragit L100, Eudragit S100, Kollico at EMM30D, Estacryl 30D, Coateric, and Aquat eric) are included. The solubility of each of the above materials is known or can be readily determined in vitro .

[0180] The dosage of a composition comprising at least one compound described herein (e.g., of formula (IA-1), (IB-1), (IA), (IB), (IIA), (IIB), or (III)) varies according to the condition of the patient (e.g., human), i.e., the stage of the disease, general health, age, and other factors.

[0181] The dosage of a composition comprising at least one compound of formula (IA), (IB), (IIA), (IIB), or (III) described herein varies according to the condition of the patient (e.g., human), i.e., the stage of the disease, general health, age, and other factors.

[0182] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). Appropriate dosages and appropriate administration periods and frequencies are determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, appropriate dosages and treatment regimens provide a therapeutically and / or prophylactically beneficial (e.g., more frequent complete or partial remission, or longer disease - free and / or overall survival periods, or improvement in clinical outcomes such as reduction in symptom severity) amount of the composition ( plural available) to provide. Optimal dosages are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dosage depends on the patient's body mass, weight, or blood volume.

[0183] Oral dosages are typically in the range of about 1.0 mg to about 1000 mg, once to 4 times a day, or more.

[0184] The disclosed compounds are administered to subjects or patients (animals and humans) in need of such treatment at a dosage that provides optimal pharmaceutical efficacy. The dosage required for use in any particular application is , not only the specific compound or composition selected, but also the route of administration, the nature of the condition being treated, the age and condition of the patient, concomitant drug therapy or special diet and subsequent patient compliance, as well as other factors, will vary from patient to patient and ultimately the appropriate volume is left to the discretion of the attending physician. To treat the clinical conditions and diseases described above, the compounds contemplated herein are formulated in dosage unit form with conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients and are administered orally, subcutaneously, topically, parenterally, by inhalation spray, rectally. Parenteral administration includes subcutaneous injection, intravenous injection or intramuscular injection or infusion methods.

[0185] V. Methods of Using Compounds and Compositions Antagonists of mAChR M1 The muscarinic acetylcholine receptor M1 (mAChR M1) is found in both the central and peripheral nervous systems, particularly in the cerebral cortex and sympathetic ganglia. In particular, M1 is expressed in oligodendrocyte progenitor cells (OPCs) of the central nervous system. Over time, OPCs differentiate into myelin-producing oligodendrocytes. Myelin is essential for the conduction of action potentials along axons, and its loss is responsible for neurodegenerative disorders, particularly multiple sclerosis. In some embodiments, selective mAChR M1 antagonists promote the differentiation of OPCs into oligodendrocytes. In some embodiments, selective mAChR M1 antagonists are useful for the treatment of demyelinating disorders such as multiple sclerosis. In some embodiments, selective mACh R M1 antagonists are useful for treating epileptic disorders as well as certain movement disorders including Parkinson's disease, dystonia, and fragile X syndrome.

[0186] In one aspect, the compounds disclosed herein are selective antagonists of the muscarinic acetylcholine M1 receptor (mAChR M1). In some embodiments, the compounds disclosed herein are selective antagonists of the muscarinic acetylcholine M1 receptor (mAChR M1) with respect to one or more of the mAChR M2, M3, M4, or M5 receptors In some embodiments, the compounds disclosed herein are selective antagonists of the muscarinic acetylcholine M1 receptor (mAChR M1) with respect to one or more of the mAChR M2, M3, M4, or M5 receptors In some embodiments, the compounds disclosed herein are selective antagonists of the muscarinic acetylcholine M1 receptor (mAChR M1) with respect to one or more of the mAChR M2, M3, M4, or M5 receptors In some embodiments, the compounds disclosed herein are selective antagonists of the muscarinic acetylcholine M1 receptor (mAChR M1) with respect to one or more of the mAChR M2, M3, M4, or M5 receptors In some embodiments, the compounds disclosed herein exhibit an IC 50 for the mAChR M1 response, which is about one-fifth, about one-tenth, about one-twentieth, about one-thirtieth, about one-fiftieth, about one-hundredth, or about one-hundredth or more than that of mAChR M2 In some embodiments, the compounds disclosed herein exhibit an IC for the mAChR M1 response, which is about one-fifth, about one-tenth, about one-twentieth, about one-thirtieth, about one-fiftieth, about one-hundredth, or about one-hundredth or more than that of mAChR M2 In some embodiments, the compounds disclosed herein exhibit an IC 50 for the mAChR M1 response, which is about one-fifth, about one-tenth, about one-twentieth, about one-thirtieth, about one-fiftieth, about one-hundredth, or about one-hundredth or more than that of mAChR M3 In some embodiments, the compounds disclosed herein exhibit an IC for the mAChR M1 response, which is about one-fifth, about one-tenth, about one-twentieth, about one-thirtieth, about one-fiftieth, about one-hundredth, or about one-hundredth or more than that of mAChR M3 In some embodiments, the compounds disclosed herein exhibit an IC 50 for the mAChR M1 response, which is about one-fifth for the mAChR M1 response, which is about one-fifth, about one-tenth, about one-twentieth, about one-thirtieth, about one-fiftieth, about one-hundredth, or about one-hundredth or more than that of mAChR M4 In some embodiments, the compounds disclosed herein exhibit an IC for the mAChR M1 response, which is about one-fifth, about one-tenth, about one-twentieth, about one-thirtieth, about one-fiftieth, about one-hundredth, or about one-hundredth or more than that of mAChR M4 50 for the mAChR M1 response, which is about one-fifth, about one-tenth, about one-twentieth, about one-thirtieth, about one-fiftieth, about one-hundredth, or about one-hundredth or more than that of mAChR M5 In some embodiments, the compounds disclosed herein exhibit an IC for the mAChR M1 response, which is about one-fifth, about one-tenth, about one-twentieth, about one-thirtieth, about one-fiftieth, about one-hundredth, or about one-hundredth or more than that of mAChR M5 In some embodiments, the compounds disclosed herein exhibit an IC 50is shown, which is about one-fifth, about one-tenth, about one- twentieth, about one-thirtieth, about one-fiftieth, about one- hundredth, or more than about one-hundredth of that of mAChR M2, M3, M4,

[0187] Therapy The compounds disclosed herein are useful for the treatment, prevention, amelioration, control or reduction of risk of various disorders, where the patient or subject would benefit from

[0188] antagonism of the muscarinic acetylcholine M1 receptor. In one aspect, the therapy may include selective M1 receptor antagonism to an extent effective to affect cholinergic action. Accordingly, disorders for which the compounds disclosed herein are useful may be associated with cholinergic action, such as cholinergic hyperfunction. In some embodiments,

[0189] provided herein is a method of treating or preventing a disorder in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein, in an effective dose and amount to treat the

[0190] Some embodiments provided herein are methods of doing so in a subject in need of treating a neurodegenerative disorder, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., , of formula (IA-1), (IB-1), (IA), (IB), (IIA), (IIB), or , or (III)), or a pharmaceutically acceptable salt or solvate thereof.

[0191] Some embodiments provided herein are methods of doing so in a subject in need of treating a neurodegenerative disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA ), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0192] In an embodiment, the method of doing so in a subject in need of treating a neurodegenerative disorder comprises administering an effective amount of a compound selected from Compound List 1, or a pharmaceutically acceptable salt or solvate thereof.

[0193] Some embodiments provided herein are methods of doing so in a subject in need of treating a neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., of formula (IA-1), (IB-1), (IA), (IB), (IIA), (IIB), or ( III)), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments are methods of doing so in a subject in need of treating a neuropathy comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., of formula (I A-1), (IB-1), (IA), (IB), (IIA), (IIB), or (III)), or a pharmaceutically acceptable salt or solvate thereof, administering to a subject , wherein the neuropathy is peripheral neuropathy. Some embodiments are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., of formula (IA-1), (IB-1), (IA), (IB), (IIA ), (IIB), or (III)), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy. Some embodiments provided herein are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA ), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA ), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is peripheral neuropathy. Some embodiments are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy.

[0194] Some embodiments provided herein are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA ), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA ), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is peripheral neuropathy. Some embodiments are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy. Some embodiments are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA ), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is peripheral neuropathy. Some embodiments are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy. Some embodiments are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is peripheral neuropathy. Some embodiments are methods of doing so in a subject in need of treating neuropathy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neuropathy is diabetic neuropathy. ). .

[0195] In an embodiment, a method of doing so in a subject in need of treating a neuropathy comprises administering an effective amount of a compound selected from Compound List 1, or a pharmaceutically acceptable salt or solvate thereof.

[0196] Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., of formula (IA-1), (I B-1), (IA), (IB), (IIA), (IIB), or (III)), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., of formula (IA-1), (IB -1), (IA), (IB), (IIA), (IIB), or (III)), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is a demyelinating disease of the central nervous system. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., of formula (IA-1), (IB-1), (IA), (IB), (IIA) ), (IIB), or (III)), or a pharmaceutically acceptable salt or solvate thereof, wherein the demyelinating disease is multiple sclerosis. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., of formula (IA-1), (IB-1), (IA), (IB), (IIA) ), (IIB), or (III)), or a pharmaceutically acceptable salt or solvate thereof wherein the demyelinating disease is multiple sclerosis. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., of formula (IA-1), (IB-1) ), wherein the demyelinating disease is multiple sclerosis. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method , (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, and administering to a subject in need thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.

[0197] Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering a therapeutically effective amount of a compound of formula (IA), (IB), ( IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the demyelinating disease is a demyelinating disease of the central nervous system. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), ( IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the demyelinating disease is multiple sclerosis. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system. (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), ( IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the demyelinating disease is multiple sclerosis. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system. Some embodiments are methods of doing so in a subject in need of treating a demyelinating disease, the method comprising administering a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system. (III), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.

[0198] In an embodiment, a method of doing so in a subject in need of treating a demyelinating disease comprises administering an effective amount of a compound selected from Compound List 1, or a pharmaceutically acceptable salt or solvate thereof.

[0199] Some embodiments are methods of modulating muscarinic acetylcholine receptor M1 activity in a subject, comprising administering to the subject a compound described herein (e.g., of formula (IA-1), (IB-1) , (IA), (IB), (IIA), (IIB), or (III)), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments, a compound described herein (e.g., of formula (IA-1), (IB-1) , (IA), (IB), (IIA), (IIB), or (III)), or a pharmaceutically acceptable salt or solvate thereof acts as a selective M1 antagonist.

[0200] Some embodiments are methods of modulating muscarinic acetylcholine receptor M1 activity in a subject, comprising administering to the subject a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof. Some embodiments, a compound of formula (IA), (IB), (IIA), (IIB), or (III), or a pharmaceutically acceptable salt or solvate thereof acts as a selective M1 antagonist.

[0201] solvate thereof.

[0201] In an embodiment, a method of modulating muscarinic acetylcholine receptor M1 activity in a subject comprises a compound selected from Compound List 1, or a pharmaceutically acceptable salt or It includes administering a solvate.

[0202] VI. Combination Therapy Also, herein, for the purpose of providing a beneficial effect from the interaction of these therapeutic agents as part of a specific treatment regimen, for example, combination therapies that co-administer the disclosed compounds and additional active agents are also contemplated. In some embodiments, the compounds described herein are administered in combination with one or more immunomodulatory agents. In some embodiments the compounds described herein are administered in combination with one or more immunomodulatory agents, and one or more of the immunomodulatory agents are selected from IFN-β1 molecule; corticosteroid; polymer of glutamic acid, lysine, alanine, and tyrosine or glatiramer; antibody against alpha-4 integrin or fragment thereof or natalizumab; anthraquinone molecule or mitoxantrone ; fingolimod or other S1P functional modifiers; dimethyl fumarate or other N RF2 functional modifiers; antibody against the alpha subunit of the IL-2 receptor (CD25) of T cells or daclizumab; antibody against CD52 or alemtuzumab; antibody against CD20 or ocrelizumab; and inhibitor of dihydroorotate dehydrogenase or teriflunomide. In some embodiments, the immunomodulatory agent is IF N-β1 molecule. In some embodiments, the immunomodulatory agent is a corticosteroid . In some embodiments, the immunomodulatory agent is a polymer of glutamic acid, lysine, alanine, and tyrosine or glatiramer. In some embodiments, the immunomodulatory agent is an antibody against alpha-4 integrin or fragment thereof or natalizumab. In some embodiments, the immunomodulatory agent is an anthraquinone molecule or mitoxantrone. In some embodiments, the immunomodulatory agent is fingolimod or another S1P1 functional modifier. In some embodiments, the immunomodulatory agent is dimethyl fumarate or another NRF2 functional modifier. In some embodiments, the immunomodulatory agent is an antibody or daclizumab against the alpha subunit of the IL-2 receptor (CD25) of T cells. In some embodiments, the immunomodulatory agent is an antibody or alemtuzumab against CD52. In some embodiments, the immunomodulatory agent is an antibody or ofatumumab against CD20. In some embodiments, the immunomodulatory agent is an inhibitor of dihydroorotate dehydrogenase or teriflunomide.

[0203] The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic interactions resulting from the combination of therapeutic agents. Administration of these combinations of therapeutic agents is typically carried out over a predetermined period (usually several weeks, months or years, depending on the selected combination). The combination therapy is intended to include not only administering the plurality of therapeutic agents sequentially, i.e., administering each therapeutic agent at different times, but also administering these therapeutic agents, or at least two of these therapeutic agents, substantially simultaneously.

[0204] Substantially simultaneous administration can be achieved, for example, by administering a single formulation or composition (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent), or a plurality of single formulations (e.g., capsules) of each therapeutic agent to the subject. Sequential or substantially Co - administration is effected by any suitable route including, but not limited to, oral, intravenous, intramuscular, and direct absorption routes via mucosal tissue. The therapeutic agents are administered by the same route or different routes. For example, the first therapeutic agent of a selected combination is administered by intravenous injection while the other therapeutic agent of the combination is administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0205] Combination therapies also include administration of the therapeutic agents as described above in further combination with other biologically active components and non - drug therapies. When the combination therapy further includes non - drug therapy, the non - drug therapy is performed at any appropriate time as long as a beneficial effect from the interaction of the combination of the therapeutic agent and the non - drug therapy is achieved. For example, in appropriate cases, beneficial effects can also be achieved when the non - drug therapy is temporarily removed, perhaps for several days or weeks, from the administration of the therapeutic agent.

[0206] The components of the combination are administered to the patient simultaneously or sequentially. The components are present in the same pharmaceutically acceptable carrier and thus it will be understood that they are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers such as conventional oral dosage forms which are administered simultaneously or sequentially.

[0207] The following examples are provided merely as illustrations of various embodiments and are not to be construed as limiting the invention in any way.

[0208] The examples and embodiments described herein are for illustrative purposes only and in view of them Various modifications or alterations will be suggested to those skilled in the art and should be within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0209] VII. Preparation of Compounds The compounds used in the reactions described herein are prepared according to known organic synthetic techniques starting from commercially available chemical substances and / or compounds described in the chemical literature. "Commercially available chemical substances" include Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL ), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K .), Chemservice Inc. (West Chester, PA), Com bi-blocks (San Diego, CA), Crescent Chemica l Co. (Hauppauge, NY), eMolecules (San Diego ), CA), Fisher Scientific Co. (Pittsburgh, PA ), Fisons Chemicals (Leicestershire, UK), Fr ontier Scientific (Logan, UT), ICN Biomedic als, Inc. (Costa Mesa, CA), Key Organics (Cor ), Fisher Scientific Co. (Pittsburgh, PA ), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cor wall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. (Cornwall, UK), Pierce Chemical Co. (Rockford, IL), Riedel de Haen (Seelze, Germany), Spectrum Quality Product nwall, U.K.), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Mayb ridge Chemical Co., Ltd. (Cornwall, U.K.), Pa rish Chemical Co. (Orem, UT), Pfaltz & Baue r, Inc. (Waterbury, CN), Polyorganix (Houston , TX), Pierce Chemical Co. (Rockford, IL), Ri edel de Haen AG (Hanover, Germany), Ryan Sc ientific, Inc. (Mount Pleasant, SC), Spectru m Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR ), Trans World Chemicals, Inc. (Rockville, M D), and WuXi (Shanghai, China) and obtained from standard commercial suppliers including these.

[0210] Appropriate reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described herein or provide references to articles describing the preparation include, for example, “ Synthetic Organic Chemistry,” New York: Jo hn Wiley & Sons, Inc., 1982; Sandler S. R. et al., “Organic Functional Group Preparati ons,” 2 nd Edition, Academic Press, 1983; “Comprehensive Organic Transformations,” Wiley-Interscience, 1989; Larock R. C., “Comprehensive Organic Transformations,” Wiley-VCH, 1999; Carey F. A. and Sundberg R. J., “Advanced Organic Chemistry,” Parts A and B, 4th Edition, Springer-Verlag, 2001; March J., “Advanced Organic Chemistry,” 5th Edition, Wiley-Interscience, 2001; and “Organic Chemistry,” Vollhardt K. P. C. and Schore N. E., 5th Edition, W. H. Freeman and Company, 2007. nd It should be noted that there seems to be some incomplete or incorrect information in the original text, especially in the citation part where the full details of some references are not properly presented. The above translation is based on the existing text as accurately as possible.ed., New York: Academic Press, 198 3; House, H. O., “Modern Synthetic Reactions ,” 2 nd ed., Menlo Park: W. A. Benjamin, Inc., 1 972; Gilchrist, T. L., “Heterocyclic Chemist ry,” 2 nd ed., New York: Wiley, 1992; March, J. , “Advanced Organic Chemistry: Reactions, M echanisms and Structure,” 4 th ed., New Yor k: Wiley, 1992 is included. Reactants useful for the preparation of the compounds described herein The synthesis is described in detail, or additional references to articles describing the preparation are provided Appropriate reference books and papers include, for example, Fuhrhop, J., Penzlin, G. , “Organic Synthesis: Concepts, Methods, Sta rting Materials,” 2 nd ed., New York: Wiley, 1994; Hoffman, R. V., “Organic Chemistry, An Intermediate Text,” Oxford: Oxford Univers ity Press, 1996; Larock, R. C., “Comprehensiv e Organic Transformations: A Guide to Fun ctional Group Preparations,” 2 nd ed., New York: Wiley, 1999; Otera, J., “Modern Carbony l Chemistry,”New York:Wiley,2000;Solomon s,TWG,“Organic Chemistry,”7 th ed.,New York: Wiley, 2000; Stowell, JC, “Intermedi "Cate Organic Chemistry," 2 nd ed., New York: Wiley,1993;“Industrial Organic Chemicals :Starting Materials and Intermediates:An Ullmann's Encyclopedia,”New York:Wiley, 8 volumes;“Organic Reactions,”New York:W iley, 55 volumes; and “Chemistry of Function "Nal Groups," New York: Wiley, 73 volumes. can be.

[0211] In addition, specific reactants and similar reactants can be found in the American Chemical Society's Chemical Information Search Service. Index of known chemicals compiled by the National Institute of Chemical Substances (which is available at most public libraries and available in university libraries) and identified through online databases (see details For more information, contact the American Chemical Society, Washington, DC. Chemicals that are not known in the catalogue but are still available in the market can be arbitrarily synthesized by custom chemical synthesis companies. It is prepared in advance and is available from many standard chemical suppliers (e.g., those listed above). We provide standard synthesis services for the preparation and selection of pharmaceutical salts of the compounds described herein. For references, see Stahl, PH, Wermuth, CG, “Handbook of “ook of Pharmaceutical Salts,” Zurich: Verl of Helvetica Chimica Acta, 2002.

[0212] List of Abbreviations As used throughout the foregoing and the entire description of this disclosure, the following abbreviations should be understood to have the following meanings, unless otherwise expressly stated: : [Table 1-1] [Table 1-2]

[0213] General Synthetic Scheme The compounds of formula (IA) or (IB) of this disclosure can be prepared, for example, from amine (1a) or (1b), or its corresponding ammonium salt, and carboxylic acid ( 2) in the presence of a suitable coupling reagent such as HATU, CDI, T3, etc., and a suitable base such as TEA, DIEA, etc. (Scheme 1). Alternatively, the acid can be pre-activated by conversion to the corresponding acid chloride using an agent such as thionyl chloride, oxalyl chloride, etc. The resulting amide (3a) or (3b) can itself be a compound of formula (IA) or (IB) and can be further functionalized using synthetic methodologies known to those skilled in the art to deliver another compound of formula (IA) or (IB). Examples of such transformations include, but are not limited to: : (a) Reduction of alkenes or alkynes in the presence of a catalyst such as Pd / C, Pd(OH)2, etc., and a reducing agent such as hydrogen gas, deuterium gas, etc. ​​​​​​​(b) Cyclopropanation of alkenes in the presence of a methylene source such as trimethylsulfonium iodide, diazomethane, and a promoter such as potassium tert-butoxide, palladium(II) acetate, etc. (c) Oxidation of sulfides in the presence of an oxidizing agent such as Oxone, mCPBA, etc. (d) Conversion of appropriately functionalized 2- or 4-methoxypyridine to its corresponding 1-methylpyridin-2(1H)-one or 1-methylpyridin-4(1H)-one in the presence of a methyl source such as iodomethane, dimethyl sulfate, etc., and a promoter such as sodium iodide, potassium iodide, etc. (e) Conversion of appropriately functionalized (hetero)aryl halide to its corresponding (hetero)aryl cyanide in the presence of an appropriate palladium ligand complex as a catalyst and a cyanide source such as zinc cyanide, etc. (f) Separation of a mixture of stereoisomers into its stereochemically enriched components using an appropriate chiral column such as Chiral PAK OD, Chiral PAK AD, etc.

Chemical formula

[0214] Alternatively, instead, the first coupling of an appropriate protected amine (4a) or (4b) with a carboxylic acid (2), followed by removal of the protecting group (PG) in amide (5a) or (5b) using conditions known to those skilled in the art (i.e., when N-PG is tert-butyl carbamate, by treatment with HCl, TFA, etc.), and finally, heating the resulting amine (6a) or (6b) under, for example, standard aromatic electrophilic substitution conditions (i.e., by heating the reactants in a polar aprotic solvent in the presence of an appropriate base). ​ uses Buchwald-Hartwig coupling conditions (i.e., coupling in the presence of a suitable palladium ligand complex as catalyst and a metal alkoxide as base) and reacts with a suitable functionalized (hetero)aryl halide, and it may be more advantageous to prepare a compound of formula (IA) or (IB) via a 3-step sequence (Scheme 2). It may be more advantageous.

Chemical formula

[0215] In certain embodiments, one of ordinary skill in the art may also use the conditions described in the previously highlighted references and papers, and access a compound of formula (IA) or (IB) via direct nucleophilic substitution of the leaving group (LG) in (8a) or (8b) through the bond between the electrophile (9) and the electrophile (8a) or (8b) (Scheme 3). In certain cases, especially when the electrophile (9) is an amine, it may be beneficial if (9) is first activated by pretreatment with an agent such as a lithium chloride complex of isopropylmagnesium chloride. The electrophile (8a) or (8b) itself can be readily synthesized from an amine (1a) or (1b) and an acid chloride (7) in the presence of a suitable base such as, for example, TEA, DIEA, etc. It can be synthesized. It can be readily synthesized.

Chemical formula

[0216] In certain embodiments, the aforementioned direct nucleophilic substitution can be optimally achieved by using an amide (11a) or (11b) as the electrophile, which itself is an amine (1 a) or (1b) and an acid (10), for example, by a 2-step amide coupling-deprotection sequence and is suitably functionalized (12) as an electrophile ( Scheme 4).

Chemical Structure

[0217] For certain embodiments where X in formula (IA) or (IB) is NH, well-known to those skilled in the art under dehydration conditions, it may be proven more advantageous to use a ketone (14) and an amine (13a) or (13b) to form the necessary bond (Scheme 5). The resulting Schiff base (15a) or (15b) can be reduced using reagents such as lithium borohydride, sodium cyanoborohydride, or captured with organometallic compounds such as Grignard reagents, (hetero)aryl lithium reagents. When the organometallic compound is an organoiodine reagent, it may be beneficial to add a fluoride activator such as TBAF, cesium fluoride.

Chemical Structure

[0218] The above general synthetic scheme is described in an exemplary manner and is intended to have the described properties without limitation. It will also be understood that many of the reagents provided in the following examples can be replaced with other suitable reagents (e.g., Fieser, L ., et al., “Encyclopedia of Reagents for O rganic Synthesis,” 2 ed., New York: Wiley nd ​​​​​, see 2009). In addition, the selection of solvent, reaction temperature, volume and reaction time, etc. It will be understood that any conditions can still vary while producing the desired compound. The chemical structures, substituents, derivatives, intermediates and / or related to synthesis provided in this specification, including but not limited to such, can be made without departing from its spirit and scope.

[0219] VIII. Embodiments Embodiment P1. A compound, or a pharmaceutically acceptable salt or solvate thereof, which has a structure of formula (IA) or (IB),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical Structure

Chemical formula

Chemical Formula

[0220] IX. Additional Embodiments Embodiment PP1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IA-1) or (IB-1),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IA) or (IB), 【Chemical 1】 wherein, X is a bond, -C(R ９ )(R １０ )-, -N(R １１ )-, -O-, -S(O) ｎ - , -CH ２ N(R １１ ), or -CH ２ O-, and Y is -CH ２ -, -CH ２ CH ２ -, -CH=CH-, or -CH ２ OCH ２ - exists, R １ is 【Chemical 2】 and, wherein ring A is a 5- or 6-membered heteroaryl ring or optionally, Halogen, cyano, -N(R １４ )(R １５ ), C １－６ alkyl, C １－６ alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl, C ３－６ Si Chloroalkoxy, C ３－６ Halocycloalkyl, C ３－６ Halocycloalkoxy, hetero Cycloalkyl, aryl, heteroaryl, -S(O) ｎ (R １６ ) or -SF ５ is a 5- or 6-membered heterocycloalkyl ring substituted thereby, said heteroaryl or a heterocycloalkyl ring contains 1, 2, or 3 heteroatoms selected from the group consisting of O, N, or S, R ２ is hydrogen, deuterium, halogen, hydroxyl, C １－６ alkyl, C １－６ alkoxy Xy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl, C ３ －６ Cycloalkoxy, C ３－６ Halocycloalkyl, C ３－６ Halocycloalkoxy, C １－６ alkylhydroxyl, heterocycloalkyl, aryl, or heteroaryl is a radical, R ３ is halogen, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ３－６ cycloalkyl, C ３－６ cycloalkoxy, C ３－ ６ Halocycloalkyl, C ３－６ Halocycloalkoxy, C １－６ Alkylhydroxyl , heterocycloalkyl, aryl, or heteroaryl, or R ２ and R ３ is linked and optionally, halogen, C １－６ alkyl, or C ３－６ cycloalkyl forms a cycloalkyl or heterocycloalkyl ring substituted with a radical, R ４ and R ５ are each independently hydrogen, deuterium, halogen, and C １－３ alkyl selected from is selected, or R ３ and R ４ are linked, optionally with halogen, C １－６ alkyl, also or C ３－６ Cycloalkyl or heterocycloalkyl substituted with cycloalkyl Form a ring, or R ４ and R ５ are linked, optionally, halogen, C １－６ alkyl or C ３－６ cycloalkyl or heterocycloalkyl substituted with cycloalkyl forms a heterocycloalkyl ring, R ６ and R ７ each independently is hydrogen, deuterium, halogen, and C １－３ selected from alkyl is selected, or R ３ and R ７ are linked, optionally with halogen, C １－６ alkyl, also or C ３－６ cycloalkyl or heterocycloalkyl substituted with cycloalkyl Form a ring or R ４ and R ６ are connected, optionally with halogen, C １－６ alkyl or C ３－６ cycloalkyl or heterocycloalkyl substituted with cycloalkyl Form a kill ring or R ５ and R ７ are connected to form a bond R ８ is [Chemical Formula 3] is, R ９ and R １０ each independently represents hydrogen, deuterium, halogen, C １－６ alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl , C ３－６ Cycloalkoxy, C ３－６ Halocycloalkyl, C ３－６ Halocycloalko is selected from cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or optionally is R ３ and R １０ are linked and optionally, halogen, C １－６ alkyl, or C ３－ ６ forms a cycloalkyl or heterocycloalkyl ring substituted with cycloalkyl, Alternatively, R ４ and R １０ are linked, and optionally, halogen, C １－６ alkyl, or C ３－６ forms a cycloalkyl or heterocycloalkyl ring substituted with cycloalkyl formed, or R ６ and R １０ are linked, optionally with halogen, C １－６ alkyl, also or C ３－６ cycloalkyl or heterocycloalkyl substituted with cycloalkyl Form a ring or R ９ and R １０ are connected, optionally with halogen, C １－６ alkyl Ru, or C ３－６ Cycloalkyl or heterocycloalkyl substituted with cycloalkyl forms a cycloalkyl ring, R １１ is hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl , C ３－６ halocycloalkyl, heterocycloalkylaryl, or heteroaryl is R, or R ３ and R １１ are linked, optionally with halogen, C １－６ alkyl, or C ３－６ forms a heterocycloalkyl ring substituted with cycloalkyl, or R ４ and R １１ are linked, optionally with a halogen, C １－６ alkyl, or C ３－６ forms a heterocycloalkyl ring substituted with a cycloalkyl, or R ６ and R １１ are connected and optionally, halogen, C １－６ alkyl, or C ３－６ cycloalkyl forms a substituted heterocycloalkyl ring, Each R １２ is independently hydroxyl, halogen, cyano, -N(R １４ )(R １５ ), C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy Si, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, C ３－６ Halocycloalkyl , C ３－６ halocycloalkoxy, C １－６ alkylhydroxyl, heterocycloalkyl Ru, aryl, heteroaryl, -S(O) ｎ (R １６ ) or -SF ５ selected from or R ３ and one R １２ are linked, optionally with halogen, C １－６ alkyl or C ３－６ cycloalkyl or heterocycloalkyl substituted with cycloalkyl Form a kill ring, or R １０ and one R １２ are connected, optionally with halogen, C １－６ alkyl, or C ３－６ cycloalkyl or he substituted by cycloalkyl Form a terocycloalkyl ring, or R １１ and one R １２ are linked, optionally , halogen, C １－６ alkyl, or C ３－６ heterocyclyl substituted with cycloalkyl forms a heterocycloalkyl ring, R １３ is hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl , C ３－６ halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl is a radical, R １４ and R １５ are independently hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－６ Cycloalkyl, C ３－６ Halo cycloalkyl, heterocycloalkyl, aryl selected from heteroaryl or R １４ and R １５ are linked, optionally , halogen, C １－６ alkyl, or C ３－６ heterocyclyl substituted with cycloalkyl forms a heterocycloalkyl ring, R １６ is C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, C ３ －６ is halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein, m is 0 or 1, n is 0, 1, or 2, o is 0, 1, 2, or 3, a compound, or a pharmaceutically acceptable salt or solvate thereof.

2. Having the structure of formula (IIA) or (IIB), 【Chemical Formula 4】 wherein, X is a bond, -C(R ９ )(R １０ )-, -N(R １１ )-, -O-, -S(O) ｎ - , -CH ２ N(R １１ ), or -CH ２ O-, and Y is -CH ２ -, -CH ２ CH ２ -, -CH=CH-, or -CH ２ OCH ２ - exists, R １ is 【Chemical Formula 5】 and, wherein ring A is a 5- or 6-membered heteroaryl ring or optionally, Halogen, cyano, -N(R １４ )(R １５ ), C １－６ alkyl, C １－６ alkoxy , C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, C ３－６ Halocycloalkyl, C ３－６ Halocycloalkoxy, hetero Rocycloalkyl, aryl, heteroaryl, -S(O) ｎ (R １６ ) or -S F ５ is a 5- or 6-membered heterocycloalkyl ring substituted with, and said heteroaryl or a heterocycloalkyl ring contains 1, 2, or 3 heteroatoms selected from the group consisting of O, N, or S, R ２ is hydrogen, deuterium, halogen, hydroxyl, C １－６ alkyl, C １－６ alkoxy Xy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl, C ３ －６ Cycloalkoxy, C ３－６ Halocycloalkyl, C ３－６ Halocycloalkoxy, C １－６ alkylhydroxyl, heterocycloalkyl, aryl, or heteroaryl is a radical, R ３ is halogen, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ３－６ cycloalkyl, C ３－６ cycloalkoxy, C ３－ ６ Halocycloalkyl, C ３－６ Halocycloalkoxy, C １－６ Alkylhydroxyl , heterocycloalkyl, aryl, or heteroaryl, or R ２ and R ３ is linked and optionally a halogen, C １－６ alkyl, or C ３－６ cycloalkyl forms a cycloalkyl or heterocycloalkyl ring substituted with a radical, R ８ is 【Chemical Formula 6】 is, R ９ and R １０ are each independently hydrogen, deuterium, halogen, C １－６ alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl , C ３－６ Cycloalkoxy, C ３－６ Halocycloalkyl, C ３－６ Halocycloalko is selected from cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or optionally is R ３ and R １０ are linked, optionally with halogen, C １－６ alkyl, or C ３－ ６ forms a cycloalkyl or heterocycloalkyl ring substituted with cycloalkyl, Alternatively, R ９ and R １０ are linked, optionally, to halogen, C １－６ alkyl, or C ３－６ forming a cycloalkyl or heterocycloalkyl ring substituted with cycloalkyl forms, R １１ is hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl , C ３－６ halocycloalkyl, heterocycloalkylaryl, or heteroaryl is or R ３ and R １１ are linked, optionally, to halogen, C １－６ alkyl, or C ３－６ forming a heterocycloalkyl ring substituted with cycloalkyl, Each R １２ independently is hydroxyl, halogen, cyano, -N(R １４ )(R １５ ), C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy Si, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, C ３－６ Halogencycloalkyl , C ３－６ halocycloalkoxy, C １－６ alkylhydroxyl, heterocycloalkyl Lu, aryl, heteroaryl, -S(O) ｎ (R １６ ), or -SF ５ selected from or R ３ and one R １２ are linked, optionally with halogen, C １－６ alkyl or C ３－６ cycloalkyl or heterocycloalkyl substituted with cycloalkyl Form a kill ring or R １０ and one R １２ are linked, optionally with halogen, C １－６ alkyl, or C ３－６ cycloalkyl or he substituted by cycloalkyl Form a terocycloalkyl ring or R １１ and one R １２ are linked, optionally , halogen, C １－６ alkyl, or C ３－６ heterocyclyl substituted with cycloalkyl forms a heterocycloalkyl ring, R １３ is hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl , C ３－６ halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl is a radical, R １４ and R １５ are independently hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－６ Cycloalkyl, C ３－６ Halocycloalkyl, heterocycloalkyl, aryl selected from heteroaryl or, or R １４ and R １５ are linked to optionally , halogen, C １－６ alkyl, or C ３－６ heterocyclyl substituted with cycloalkyl forms a heterocycloalkyl ring, R １６ is C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, C ３ －６ is a halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein, m is 0 or 1, n is 0, 1, or 2, o is 0, 1, 2, or 3, the compound according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. Having the structure of formula (III), 【Chemical 7】 wherein, X is a bond, -C(R ９ )(R １０ ), -N(R １１ ), -O-, -S(O) ｎ - , -CH ２ N(R １１ ), or -CH ２ O- and R １ is 【Chemical 8】 and, wherein ring A is a 5- or 6-membered heteroaryl ring or optionally, Halogen, cyano, -N(R １４ )(R １５ ), C １－６ alkyl, C １－６ alkoxy , C １－６ haloalkyl, C １－６ haloalkoxy, C ３－６ cycloalkyl, C ３－６ Cycloalkoxy, C ３－６ Halocycloalkyl, C ３－６ Halocycloalkoxy, hetero Cycloalkyl, aryl, heteroaryl, -S(O) ｎ (R １６ ) or -S F ５ is a 5- or 6-membered heterocycloalkyl ring substituted with, and the heteroaryl or a heterocycloalkyl ring contains 1, 2, or 3 heteroatoms selected from the group consisting of O, N, or S, R ２ is hydrogen, deuterium, halogen, hydroxyl, C １－６ alkyl, C １－６ alkoxy Xy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl, C ３ －６ Cycloalkoxy, C ３－６ Halocycloalkyl, C ３－６ Halocycloalkoxy, C １－６ alkylhydroxyl, heterocycloalkyl, aryl, or heteroaryl is a radical, R ３ is halogen, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ３－６ cycloalkyl, C ３－６ cycloalkoxy, C ３－ ６ halocycloalkyl, C ３－６ halocycloalkoxy, C １－６ alkylhydroxyl , heterocycloalkyl, aryl, or heteroaryl, or R ２ and R ３ is linked, optionally, to halogen, C １－６ alkyl, or C ３－６ cycloalkyl forms a cycloalkyl or heterocycloalkyl ring substituted with a radical, R ８ is 【Chemical Formula 9】 is, R ９ and R １０ each independently represents hydrogen, deuterium, halogen, C １－６ alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl , C ３－６ Cycloalkoxy, C ３－６ Halocycloalkyl, C ３－６ Halocycloalko is selected from cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or optionally is R ３ and R １０ are linked, optionally with halogen, C １－６ alkyl, or C ３－ ６ to form a cycloalkyl or heterocycloalkyl ring substituted with cycloalkyl Alternatively, R ９ and R １０ are linked, optionally, to halogen, C １－６ alkyl, or C ３－６ forms a cycloalkyl or heterocycloalkyl ring substituted with cycloalkyl forms, R １１ is hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl , C ３－６ halocycloalkyl, heterocycloalkylaryl, or heteroaryl is or R ３ and R １１ are linked, optionally with halogen, C １－６ alkyl, or C ３－６ forming a heterocycloalkyl ring substituted with cycloalkyl, Each R １２ is independently hydroxyl, halogen, cyano, -N(R １４ )(R １５ ), C １－６ alkyl, C １－６ alkoxy, C １－６ haloal Kill, C １－６ Haloalkoxy, C ３－６ Cycloalkyl, C ３－６ Cycloalkoxy, C ３－６ halocycloalkyl, C ３－６ halocycloalkoxy, C １－６ alkylhydro Xyl, heterocycloalkyl, aryl, heteroaryl, -S(O) ｎ (R １６ ) or -SF ５ selected from, or R ３ and one R １２ are linked, optionally, Halogen, C １－６ alkyl, or C ３－６ cycloalkyl substituted cycloal forms a kill or heterocycloalkyl ring, or R １０ and one R １２ are linked Optionally, with halogen, C １－６ alkyl, or C ３－６ substituted with cycloalkyl to form a cycloalkyl or heterocycloalkyl ring, or R １１ and one of R １２ is linked, optionally, to halogen, C １－６ alkyl, or C ３－６ cyclo a forms a heterocycloalkyl ring substituted with an alkyl, R １３ is hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl , C ３－６ halocycloalkyl, heterocycloalkyl, aryl, or heteroaryl is a radical, R １４ and R １５ are independently hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－６ Cycloalkyl, C ３－６ Halocycloalkyl, heterocycloalkyl, aryl selected from heteroaryl or, or R １４ and R １５ are linked, optionally , halogen, C １－６ alkyl, or C ３－６ heterocyclyl substituted with cycloalkyl forms a heterocycloalkyl ring, R １６ is C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, C ３ －６ is halo-cycloalkyl, hetero-cycloalkyl, aryl, or heteroaryl wherein, m is 0 or 1, n is 0, 1, or 2, The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein o is 0, 1, 2, or 3. **Claim 4** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond. **Claim 5** ... a pharmaceutically acceptable salt or solvate thereof. **Claim 6** X is -C(R ９ )(R １０ )-, the compound according to claim 1, or a pharmaceutically ... a pharmaceutically acceptable salt or solvate thereof. **Claim 7** X is -N(R １１ )-, the compound according to claim 1, or a pharmaceutically acceptable The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-. **Claim 8** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S-. **Claim 9** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S(O)-. **Claim 10** ... a pharmaceutically acceptable salt or solvate thereof. **Claim 11** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof... **Claim 12** The compound, or a pharmaceutically acceptable salt or solvate thereof. X is -S(O) ２ - is the compound according to claim 1, or a pharmaceutically acceptable **Claim 13** ... or a pharmaceutically acceptable salt or solvate thereof. R １ is 【Chemical 10】 **Claim 14** 。 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which forms... R ２ is hydrogen, -F, -CH ３ , -CH ２ CH ３ , -CF ２ H, -CF ３ , -CH ２ O H, -C(CH ３ ) ２ OH, phenyl, or cyclopropyl, according to claim 1 **Claim 15** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof. R ３ is -F, -CH ３ , -CH ２ CH ３ , -CF ２ H, -CF ３ , -CH ２ OH, - C(CH ３ ) ２ OH, phenyl, or cyclopropyl, the compound according to claim 1 **Claim 16** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. R ２ and R ３ are linked to form a cyclopropyl, cyclobutyl, or cyclopentyl ring **Claim 17** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. **Claim 18** R ２ and R ３ are linked to form an oxetanyl or tetrahydrofuran ring, claim The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein o is 0. **Claim 19** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein o is 1. **Claim 20** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein o is 2. **Claim 21** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein o is 3. **Claim 22** The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof... ... a compound selected therefrom, or a pharmaceutically acceptable salt thereof. **Claim 24** A pharmaceutical composition comprising the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. **Claim 25** ​ ​ ​ ​ ​ ​ ​ R ８ is 【Chemical Formula 11】 ​ 。

23. 【Fig. 12-1】 【Chemical Formula 12-2】 【Chemical Formula 12-3】 【Chemical Formula 12-4】 【Chemical Formula 12-5】 【Chemical 12-6】 【Chemical Formula 12-7】 【Chemical Formula 12-8】 ​ 【Chemical Formula 12-10】 【Chemical Formula 12-11】 【Chemical 12-12】 ​ ​ ​ ​ 。 ​ A method of doing so in a subject in need of treating a neurodegenerative disorder, the treatment comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof.

26. The method according to claim 25, further comprising administering one or more immunomodulators.

27. The one or more immunomodulators are IFN-β1 molecule; corticosteroid; glutamate , lysine, alanine, tyrosine polymer or glatiramer; antibody or fragment thereof against alpha-4 integrin or natalizumab; anthracenedione molecule or mitoxantrone; fingolimod or FTY720 or other S1P1 functional modulators ; dimethyl fumarate or other NRF2 functional modulators; antibody against the alpha subunit of the IL-2 receptor (CD25) of T cells or daclizumab; antibody against CD52 or alemtuzumab; antibody against CD20 or ocrelizumab; and inhibitor of dihydroorotate dehydrogenase or teriflunomide, selected from the group consisting of ; fingolimod or FTY720 or other S1P1 functional modulators ; dimethyl fumarate or other NRF2 functional modulators; antibody against the alpha subunit of the IL-2 receptor (CD25) of T cells or daclizumab; antibody against CD52 or alemtuzumab; antibody against CD20 or ocrelizumab; and inhibitor of dihydroorotate dehydrogenase or teriflunomide, the method according to claim 26 ; antibody against CD52 or alemtuzumab; antibody against CD20 or ocrelizumab; and inhibitor of dihydroorotate dehydrogenase or teriflunomide, the method according to claim 26 ; inhibitor of dihydroorotate dehydrogenase or teriflunomide, the method according to claim 26 .

28. A method of doing so in a subject in need of treating a demyelinating disease, the treatment being effective comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof.

29. The method according to claim 28, wherein the demyelinating disease is a demyelinating disease of the central nervous system.

30. The method according to claim 29, wherein the demyelinating disease is multiple sclerosis.

31. The method according to claim 28, wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.

32. The method according to claim 28, further comprising administering one or more immunomodulators.

33. The one or more immunomodulators are IFN-β1 molecule; corticosteroid; glutamate , lysine, alanine, tyrosine polymer or glatiramer; antibody or fragment thereof against alpha-4 integrin or natalizumab; anthracenedione molecule or mitoxantrone; fingolimod or FTY720 or other S1P1 functional modulators ; antibody or fragment thereof against alpha-4 integrin or natalizumab; anthracenedione molecule or mitoxantrone; fingolimod or FTY720 or other S1P1 functional modulators ; fingolimod or FTY720 or other S1P1 functional modulators ; dimethyl fumarate or other NRF2 functional modulators; antibody against the alpha subunit of the IL-2 receptor (CD25) of T cells An antibody against the alpha subunit of D25) or daclizumab; an antibody against CD52 or alemtuzumab; an antibody against CD20 or ofatumumab; and a method according to claim 32 selected from an inhibitor of dihydroorotate dehydrogenase or teriflunomide. **Claim 34** A method of treating a neuropathic disorder, optionally peripheral neuropathy, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof. **Claim 35** The method according to claim 34, wherein the neuropathic disorder is diabetic neuropathy. **Claim 36** The method according to claim 34, further comprising administering one or more immunomodulators. **Claim 37** The method according to claim 36, wherein the one or more immunomodulators are selected from IFN-β1 molecule; corticosteroid; a polymer of glutamic acid, lysine, alanine, tyrosine or glatiramer; an antibody or fragment thereof against alpha-4 integrin or natalizumab; an anthraquinone molecule or mitoxantrone; fingolimod or FTY720 or other S1P1 functional modifiers; dimethyl fumarate or other NRF2 functional modifiers; an antibody against the alpha subunit of the IL-2 receptor (CD25) of T cells or daclizumab; an antibody against CD52 or alemtuzumab; an antibody against CD20 or ofatumumab; and an inhibitor of dihydroorotate dehydrogenase or teriflunomide. **Claim 38** A method comprising administering to the subject a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof. **Claim 39** ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ A method for regulating the activity of muscarinic acetylcholine receptor M in a subject, comprising １ the step of ​ ​ ​ The method according to claim 38, wherein the compound acts as a selective M １ antagonist.

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