Agents for the treatment of disorders involving ryanodine receptors

Abstract

This disclosure relates to 1,4-oxazolidinyl heptane and 1,4-thioazolidinyl heptane derivatives, and their use in treating conditions and diseases associated with the lanodid receptor (RyR), which regulates calcium channel signaling in cells. This disclosure also discloses pharmaceutical compositions comprising these compounds and their use in treating diseases and conditions associated with RyR dysfunction, particularly cardiovascular, musculoskeletal, and central nervous system (CNS) disorders.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 523,439, filed June 27, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0002] The sarcoplasmic reticulum (SR) is a structure in cells whose function includes serving as a specialized source of intracellular calcium (Ca). 2+ ) reservoir. The lanodidogen receptor (RyR) is a channel in SR that opens and closes to regulate Ca2+. 2+ SR is released into the intracellular cytoplasm of the cell. Ca is released from the cytoplasm of SR. 2+ Increase cytoplasmic calcium 2+ Concentration. The opening probability of RyR refers to the likelihood that RyR is open at any given moment, and therefore, it is possible to convert Ca... 2+ Released from SR into the cytoplasm. Three RyR isoforms are known. RyR1 is the major isoform expressed in mammalian skeletal muscle, RyR2 is mainly found in cardiac muscle, while RyR3 is expressed at a lower rate in skeletal muscle.

[0003] RYR1 or RYR2 mutations are characterized by inappropriate channel opening unrelated to contraction signals. This channel opening is further exacerbated by post-translational modifications such as PKA phosphorylation, oxidation, or nitrosation of RyR channels. The resulting leaky channels exhibit a pathologically increased probability of opening under resting conditions. SR Ca 2+ Leakage leads to SR Ca 2+ The reduced content allows for the release of Ca. 2+ The number of muscles decreases, resulting in weaker muscle contractions. Incorporation

[0004] Each patent, publication and non-patent document cited in this application is hereby incorporated in its entirety by reference, as if each were individually incorporated by reference. Summary of the Invention

[0005] In some embodiments, this disclosure provides compounds of formula (I): , in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; -X is O, S, S(O) or S(O)2; -Y is CH2 or C(O); -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); -R 1 and R 2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each being unsubstituted or substituted, or hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds to, it forms a heterocyclic alkyl moiety; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ; or two adjacent R 3 The group and the carbon atom it is bonded to form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; -R 4 It is an unsubstituted or substituted alkyl group, or hydrogen; -R a It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydroxyl, carboxyl, or NHR. c , where R c It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydrogen; -R b It is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group, each of which is unsubstituted or substituted, or hydrogen; and -n is 0, 1, 2, 3, 4 or 5; Or its pharmaceutically acceptable salt.

[0006] This disclosure further provides pharmaceutical compositions comprising a combination of a compound of formula (I) and one or more pharmaceutically acceptable excipients or carriers.

[0007] This disclosure further relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for the treatment of or reduction of the likelihood of the occurrence of a condition.

[0008] This disclosure further provides a method of treating a condition, the method comprising administering a pharmaceutical composition comprising a compound of formula (I) and a combination of one or more pharmaceutically acceptable excipients or carriers.

[0009] In some implementations, the condition is cardiac disease or illness, muscle fatigue, musculoskeletal disease or illness, CNS disease or illness, cognitive impairment, neuromuscular disease or illness, bone disease or illness, cancer cachexia, malignant hyperthermia, diabetes, sudden cardiac death and sudden infant death syndrome, or cognitive impairment.

[0010] This disclosure further provides methods for preparing compounds of formula (I) and intermediates thereof. Detailed Implementation

[0011] In some embodiments, this disclosure provides compounds of formula (I): , in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; -X is O, S, S(O) or S(O)2; -Y is CH2 or C(O); -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); -R 1 and R 2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each being unsubstituted or substituted, or hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds to, it forms a heterocyclic alkyl moiety; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ; or two adjacent R 3 The group and the carbon atom it is bonded to form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; -R 4 It is an unsubstituted or substituted alkyl group, or hydrogen; -R a It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydroxyl, carboxyl, or NHR. c , where R c It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydrogen; -R b It is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group, each of which is unsubstituted or substituted, or hydrogen; and -n is 0, 1, 2, 3, 4 or 5; Or its pharmaceutically acceptable salt.

[0012] In some embodiments, Z is a substituted alkyl group. In some embodiments, Z is an aryl-substituted alkyl group. In some embodiments, Z is an aryl (C1-C6) alkyl group. In some embodiments, Z is a (C1-C6) alkyl group.

[0013] In some implementation schemes, R 1 and R 2 Each is independently a (C1-C6) alkyl group. In some embodiments, R 1 and R 2 Each is an aryl-substituted alkyl group. In some embodiments, R 1 and R 2 Each is independently an aryl (C1-C6) alkyl group. In some embodiments, R 1 and R 2 Each is independently a heteroaryl-substituted alkyl group. In some embodiments, R 1 and R 2 Each is independently a heteroaryl (C1-C6) alkyl group. In some embodiments, R 1 and R 2 Each is independently a cycloalkyl-substituted alkyl group. In some embodiments, R 1 and R 2 Each is independently a cycloalkyl (C1-C6) alkyl group. In some embodiments, R 1 and R 2 Each is independently a heterocyclic alkyl-substituted alkyl group. In some embodiments, R 1 and R 2 Each is independently a heterocyclic alkyl (C1-C6) alkyl.

[0014] In some implementations, each R 3 Independently, it is a (C1-C6) alkyl group. In some embodiments, each R...3 Independently, it is a (C1-C6)alkoxy group. In some embodiments, each R... 3 It is a substituted alkoxy group. In some embodiments, each R 3 It is independently an aryl-substituted alkoxy group. In some embodiments, each R 3 Independently, it is an aryl (C1-C6) alkoxy group. In some embodiments, each R 3 Independently, it is a phenyl (C1-C6)alkoxy group. In some embodiments, each R... 3 Independently, it is a (C1-C6) alkylamino group. In some embodiments, each R 3 It is independently an aryl-substituted alkylamino group. In some embodiments, each R 3 Independently, it is an aryl (C1-C6) alkylamino group. In some embodiments, each R 3 Independently, it is an aryl group that is optionally substituted.

[0015] In some implementation schemes, R 4 It is a (C1-C6) alkyl group.

[0016] In some implementation schemes, R a It is a (C1-C6) alkyl group. In some embodiments, R c It is a (C1-C6) alkyl group.

[0017] In some implementation schemes, R b It is a (C1-C6) alkyl group.

[0018] Several parts described herein may be substituted or unsubstituted. Non-limiting examples of optional substituents include hydroxyl groups, mercapto groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azide groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, formaldehyde groups, imine groups, alkyl groups, haloalkyl groups, alkenyl groups, haloalkenyl groups, alkynyl groups, haloalkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclic groups, acyl groups, acyloxy groups, carbamate groups, amide groups, urea groups, epoxy groups, and ester groups. Other non-limiting examples of optional substituents include halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, amide, alkylamide, dialkylamide, nitro, amino, cyano, azide, oxo, alkylamide, dialkylamide, carboxyl, thio, thioalkyl, and thioaryl.

[0019] Non-limiting examples of alkyl groups include straight-chain, branched, and cyclic alkyl groups. Alkyl groups can be, for example, substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C16, C17, C18, C19, C18, C19, C19, C106, C116, C116, C126, C136, C146, C1 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20 C 21 C 22 C 23 C 24 C 25 C 26 C 27 C 28 C 29 C 30 C 31 C 32 C 33 C 34 C 35 C 36 C 37 C 38 C 39 C 40 C 41 C 42 C 43 C 44 C 45 C 46 C 47 C 48 C 49 Or C 50 Group. In some embodiments, each alkyl group is independently (C1-C6) alkyl.

[0020] Non-limiting examples of straight-chain alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0021] Branched alkyl groups include any straight-chain alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and tert-butyl. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl.

[0022] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cyclic alkyl groups also include fused, bridged, and spirobicyclic systems, as well as more advanced fused, bridged, and spiro systems. Cyclic alkyl groups can be substituted with any number of straight-chain, branched, or cyclic alkyl groups. Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl-cyclopropyl-1-yl, cyclopropyl-2-en-1-yl, cyclobutyl, 2,3-dihydroxycyclobut-1-yl, cyclobut-2-en-1-yl, cyclopentyl, cyclopent-2-en-1-yl, cyclopent-2,4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctyl, 2,5-dimethylcyclopentyl-1-yl, 3,5-dichlorocyclohexyl-1-yl, 4-hydroxycyclohexyl-1-yl, 3,3,5-trimethylcyclohexyl-1-yl, octahydrocyclopentadienyl, octahydro-1 H -Indene, 3a,4,5,6,7,7a-hexahydro-3 H -indene-4-yl, decahydroazine, bicyclo-[2.1.1]hexyl, bicyclo-[2.2.1]heptyl, bicyclo-[3.1.1]heptyl, 1,3-dimethyl[2.2.1]heptane-2-yl, bicyclo-[2.2.2]octyl, and bicyclo-[3.3.3]undecyl. In some embodiments, each cycloalkyl group is independently (C3-C4). 10 )cycloalkyl.

[0023] Non-limiting examples of alkenyl and alkenyl groups include straight-chain, branched, and cyclic alkenyl groups. The alkene in an alkenyl group can be, for example, E , Z cis, trans, terminal, or ex-methylene. The alkenyl or alkenyl group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C6, C7, C8, C9, C9, C10 ... 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20 C 21 C 22 C 23 C 24 C 25 C 26 C 27 C 28 C 29 C 30 C 31 C 32 C 33 C34 C 35 C 36 C 37 C 38 C 39 C 40 C 41 C 42 C 43 C 44 C 45 C 46 C 47 C 48 C 49 Or C 50 Groups. Non-limiting examples of alkenyl and alkenyl groups include vinyl, propen-1-yl, isopropenyl, buten-4-yl; 2-chlorovinyl, 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7-hydroxy-7-methyloct-3,5-dien-2-yl.

[0024] Non-limiting examples of alkynyl or ynylene groups include straight-chain, branched, and cyclic alkynyl groups. The triple bond of the alkynyl or ynylene group can be internal or terminal. The alkynyl or ynylene group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C16, C17, C8, C9, C16, C18, C19 ... 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20 C 21 C 22 C 23 C 24 C 25 C 26 C 27 C 28 C 29 C 30 C 31 C 32 C 33 C 34 C 35 C 36 C 37 C 38 C 39 C 40 C 41 C 42 C 43 C44 C 45 C 46 C 47 C 48 C 49 Or C 50 Group. Non-limiting examples of ynyl or ynylene groups include ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl and 2-methyl-hex-4-yn-1-yl; 5-hydroxy-5-methylhex-3-yn-1-yl, 6-hydroxy-6-methylhept-3-yn-2-yl and 5-hydroxy-5-ethylhept-3-yn-1-alkyl.

[0025] The halogen group can be, for example, chlorine, bromine, fluorine, or iodine. The haloalkyl group can be any alkyl group substituted with any number of halogen atoms (e.g., fluorine, chlorine, bromine, and iodine atoms). The haloalkenyl group can be any alkenyl group substituted with any number of halogen atoms. The haloalkynyl group can be any alkynyl group substituted with any number of halogen atoms. Non-limiting examples of haloalkyl groups are trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 1,1-difluoroethylbromomethyl, chloromethyl, fluoromethyl, and iodomethyl.

[0026] The alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. Ethers or ether groups include alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy. The alkoxy group can be, for example, substituted or unsubstituted. The alkoxy group can be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups. In some embodiments, each alkoxy group is independently (C1-C1). 10 )alkoxy.

[0027] A haloalkoxy group is an alkoxy group substituted with one or more halogen atoms (i.e., F, Cl, Br, or I). Non-limiting examples of haloalkoxy groups include trifluoromethoxy, trichloromethoxy, tribromomethoxy, triiodomethoxy, trifluoroethoxy, trichloroethoxy, tribromoethoxy, triiodoethoxy, trifluoropropoxy, trichlorompropoxy, tribromopropoxy, triiodopropoxy, trifluoroisopropoxy, trichloromisopropoxy, tribromoisopropoxy, triiodoisopropoxy, trifluoroisobutoxy, trichloromisobutoxy, tribromoixobutoxy, and triiodoisobutoxy. The haloalkoxy group can be substituted with, for example, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. For example, the halogen or hydrogen group of the haloalkoxy group can optionally be substituted with amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some implementations, each haloalkoxy group is independently (C1-C1). 10 ) Haloalkoxy groups.

[0028] The aryl group can be heterocyclic or non-heterocyclic. The aryl group can be monocyclic or polycyclic. The aryl group can be substituted by any number of substituents described herein, such as hydrocarbon groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophene, and furanyl. Non-limiting examples of substituted aryl groups include 3,4-dimethylphenyl, 4-tert-butylphenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-(difluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- 3-Difluorophenyl, 3,4-Difluorophenyl, 3,5-Difluorophenyl, 2,3-Dichlorophenyl, 3,4-Dichlorophenyl, 3,5-Dichlorophenyl, 2-Hydroxyphenyl, 3-Hydroxyphenyl, 4-Hydroxyphenyl, 2-Methoxyphenyl, 3-Methoxyphenyl, 4-Methoxyphenyl, 2,3-Dimethoxyphenyl, 3,4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 2,4-Difluorophenyl, 2,5-Difluorophenyl, 2,6-Difluorophenyl, 2,3,4-Trifluorophenyl, 2,3,5-Trifluorophenyl, 2,3,6-Trifluorophenyl 2,4,5-Trifluorophenyl, 2,4,6-Trifluorophenyl, 2,4-Dichlorophenyl, 2,5-Dichlorophenyl, 2,6-Dichlorophenyl, 3,4-Dichlorophenyl, 2,3,4-Trichlorophenyl, 2,3,5-Trichlorophenyl, 2,3,6-Trichlorophenyl, 2,4,5-Trichlorophenyl, 3,4,5-Trichlorophenyl, 2,4,6-Trichlorophenyl, 2,3-Dimethylphenyl, 2,4-Dimethylphenyl, 2,5-Dimethylphenyl, 2,6-Dimethylphenyl, 2,3,4-Trimethylphenyl, 2,3,5-Trimethylphenyl, 2 3,6-Trimethylphenyl, 2,4,5-Trimethylphenyl, 2,4,6-Trimethylphenyl, 2-Ethylphenyl, 3-Ethylphenyl, 4-Ethylphenyl, 2,3-Diethylphenyl, 2,4-Diethylphenyl, 2,5-Diethylphenyl, 2,6-Diethylphenyl, 3,4-Diethylphenyl, 2,3,4-Triethylphenyl, 2,3,5-Triethylphenyl, 2,3,6-Triethylphenyl, 2,4,5-Triethylphenyl, 2,4,6-Triethylphenyl, 2-Isopropylphenyl, 3-Isopropylphenyl, and 4-Isopropylphenyl. In some embodiments, each aryl group is independently phenyl, naphthyl, or biphenyl. In some embodiments, each aryl group is independently (C4-C5). 10 Aryl.

[0029] The heterocyclic alkyl group can be a non-aromatic ring or ring system, which may optionally contain one or more double bonds as part of the ring structure, and has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus. In some embodiments, each heterocyclic alkyl group is a monocyclic or bicyclic non-aromatic ring or ring system containing 3 to 10 ring members and containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. In some embodiments, each heterocyclic alkyl group is independently a (C1-C9) heterocyclic alkyl group.

[0030] Non-limiting examples of substituted aryl groups include: 2-aminophenyl, 2-( N -methylamino)phenyl, 2-( N , N -dimethylamino)phenyl, 2-( N -Ethylamino)phenyl, 2-( N , N -diethylamino)phenyl, 3-aminophenyl, 3-( N -methylamino)phenyl, 3-( N , N -dimethylamino)phenyl, 3-( N -Ethylamino)phenyl, 3-( N , N -diethylamino)phenyl, 4-aminophenyl, 4-( N -methylamino)phenyl, 4-( N , N -dimethylamino)phenyl, 4-( N -Ethylamino)phenyl and 4-( N , N -Diethylamino)phenyl.

[0031] The aryloxy group can be, for example, an oxygen atom substituted with any aryl group. Ethers or ether groups include aryloxy groups. The aryloxy group can be substituted or unsubstituted. The aryloxy group can be substituted, for example, with amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. For example, the halogen or hydrogen group of a haloalkoxy group can optionally be substituted with amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, each aryloxy group is independently -O-(C4-C) 10 Aryl.

[0032] The heterocycle can be any ring containing a non-carbocyclic atom, such as N, O, S, P, Si, B, or any other heteroatom. The heterocycle can be substituted with any number of substituents, such as alkyl groups and halogen atoms. The heterocycle can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include piperazine, pyrrole, pyrrolidine, pyridine, succinimide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran. In some embodiments, each heterocyclic group is independently (C1-C9) heterocyclic group. In some embodiments, each heterocyclic group is independently (C3-C9) heterocyclic group. In some embodiments, each heterocyclic group is independently (C5-C9) heterocyclic group.

[0033] Non-limiting examples of heterocycles (heterocyclic groups) include: heterocyclic units having a single ring containing one or more heteroatoms, including: diazacyclopropenyl, azacyclopropane, azacyclobutane, pyrazolyl, imidazoalkyl, oxazolyl, isoxazolinyl, thiazoalkyl, isothiazolinyl, oxathiazolidinone, oxazolone, hydantoin, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-one, 2,3,4,5-tetrahydro-1 H -azapyridine, 2,3-dihydro-1 H -Indole and 1,2,3,4-tetrahydroquinoline; and ii) a heterocyclic unit having two or more rings, one of which is a heterocyclic ring, non-limiting examples of which include: hexahydro-1 H -pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1 H -benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1 H -Indole, 1,2,3,4-tetrahydroquinolinyl and decahydro-1 H -Cyclooctatetraen[b]pyrroleyl.

[0034] Non-limiting examples of heteroaryl groups include: i) heteroaryl rings containing a single ring, such as 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazine, thiazolyl, 1 H -Imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) a heteroaryl ring containing two or more fused rings, one of which is a heteroaryl ring, non-limiting examples of which include: 7 H -Purinyl, 9 H -Puryl group, 6-amino-9 H -Puryl group, 5 H -pyrrolo[3,2-d ]Pyrimidinyl, 7 H -pyrrolo[2,3- d ]pyrimidinyl, pyrido[2,3- d ]Pyrimidinyl, 4,5,6,7-tetrahydro-1 H -Indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxyquinolinyl, and isoquinolinyl. In some embodiments, each heteroaryl group is independently a monocyclic or bicyclic group consisting of 5 to 10 ring members and has at least one aromatic moiety and contains 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. In some embodiments, each heteroaryl group is independently a (C3-C9) heteroaryl group. In some embodiments, each heteroaryl group is independently a 5- or 6-membered heteroaryl group.

[0035] In some embodiments, the compounds exist in groups of tautomers. All such tautomers are contemplated herein as part of this disclosure.

[0036] In some embodiments, the compounds of this disclosure are substituted with protecting groups. Protecting groups can be selected based on the atoms to which they are attached. Nitrogen protecting groups include those described in detail in *Protecting Groups in Organic Synthesis*, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0037] For example, nitrogen-protecting groups such as amide groups include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridinecarboxamide, 3-pyridylcarboxamide, N-benzoylphenylalanine derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylated methionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0038] Nitrogen-protecting groups, such as urethane groups, include but are not limited to methyl urethane, ethyl urethane, 9-fluorenylmethyl urethane (Fmoc), 9-(2-sulfonyl)fluorenylmethyl urethane, 9-(2,7-dibromo)fluorenylmethyl urethane, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothiophene)]methyl urethane (DBD-Tmoc), 4-methoxyphenylacetyl urethane (Phenoc), 2,2,2-trichloroethyl urethane (Troc), 2-trimethylsilylethyl urethane (Teoc), and 2-phenylethylamino urethane. Carbamates (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-methyl-1-(4-biphenyl)ethylcarbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethylcarbamate (t-Bumeoc), 2-(2' and 4'-pyridyl)ethylcarbamate (Pyoc), 2-(N,N-dicyclohexylmethylcarbamate) Acylamino)ethyl carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate Ester, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthraylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithionylhexyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphoniumylethyl carbamate (Peoc), 2-triphenylphosphoniumylisopropyl carbamate (Ppoc), 1,1-Dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromone methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) Methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyylvinyl carbamate, o-(N,N-dimethylformamide)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamide)propyl carbamate Ester, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl 1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-tert-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,6-trimethylbenzylcarbamate.

[0039] Nitrogen protecting groups, such as sulfonamide groups, include but are not limited to p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylsomn-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilyl ethyl sulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzyl sulfonamide, trifluoromethyl sulfonamide, and benzoylmethyl sulfonamide.

[0040] Other nitrogen-protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylated methionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazopentanyl adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, and 5-substituted... 1,3-Dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptaylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro... -9-fluorenylmethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylamine, N-salicylamine, N-5-chlorosalicylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N - Diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkylaminophosphate, dibenzylaminophosphate, diphenylaminophosphate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylbenzenesulfenamide, and 3-nitropyridinebenzenesulfenamide (Npys).

[0041] Oxygen protecting groups include those described in detail in *Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999*, which are incorporated herein by reference. Examples of oxygen protecting groups include, but are not limited to, methyl, tert-butyloxycarbonyl (BOC or Boc), methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethyl... Silyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-bridged methylenebenzofuran-2-yl, 1 -Ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenoethyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl N -Oxides, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzocycloheptanyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromobenzoylmethyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthaliminophenyl)methyl, 4,4',4''-tris(acetylpropionyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-Bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-m-xylylsilyl, triphenylsilyl, diphenylmethyl Silyl ester (DPMS), tert-butylmethoxyphenylsilyl ester (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxovalerate (acetylpropionate), 4,4-(ethylidene dithio)valerate (acetylpropionic acid dithioacetal), tertylvalerate, adamantyl ester, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (trimethylbenzene ester), alkylmethyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkylethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphino)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (Dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, dichlorophenylacetic acid, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyyl)benzoate, α-naphthyl ester, nitrate, alkyl N,N,N',N'-tetramethyldiaminophosphate, alkyl N-phenylcarbamate, borate, dimethylthiophosphino, alkyl 2,4-Dinitrophenyl sulfenate, sulfate ester, methanesulfonate (methanesulfonate), benzyl sulfonate, and p-toluenesulfonate (Ts).

[0042] Any compound described herein can be purified. Compounds described herein may have a purity of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, and at least 2% purity. 8% purity, at least 29% purity, at least 30% purity, at least 31% purity, at least 32% purity, at least 33% purity, at least 34% purity, at least 35% purity, at least 36% purity, at least 37% purity, at least 38% purity, at least 39% purity, at least 40% purity, at least 41% purity, at least 42% purity, at least 43% purity, at least 44% purity, at least 45% purity, at least 46% purity, at least 47% purity, at least 48% purity, at least 49% purity, at least 50% purity, at least 51% purity, at least 52% purity, at least 53% purity, at least 54% purity, at least 55% purity. At least 56% purity, at least 57% purity, at least 58% purity, at least 59% purity, at least 60% purity, at least 61% purity, at least 62% purity, at least 63% purity, at least 64% purity, at least 65% purity, at least 66% purity, at least 67% purity, at least 68% purity, at least 69% purity, at least 70% purity, at least 71% purity, at least 72% purity, at least 73% purity, at least 74% purity, at least 75% purity, at least 76% purity, at least 77% purity, at least 78% purity, at least 79% purity, at least 80% purity, at least 81% purity, at least 82% purity, at least 83% purity. Purity: at least 84% purity, at least 85% purity, at least 86% purity, at least 87% purity, at least 88% purity, at least 89% purity, at least 90% purity, at least 91% purity, at least 92% purity, at least 93% purity, at least 94% purity, at least 95% purity, at least 96% purity, at least 97% purity, at least 98% purity, at least 99% purity, at least 99% purity, at least 99.1% purity, at least 99.2% purity, at least 99.3% purity, at least 99.4% purity, at least 99.5% purity, at least 99.6% purity, at least 99.7% purity, at least 99.8% purity, or at least 99.9% purity.

[0043] After preparation, the compounds disclosed herein can be isolated and purified to obtain a composition containing at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the compound or a salt thereof by weight.

[0044] In some implementations, in the aforementioned R 1 R 2 R 3 R 4 R a R b and R c In the definition, alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups, whether occurring independently or as part of another part, are substituted with 1 to 4 groups selected from the following: alkyl (e.g., (C1-C6)alkyl), alkoxy (e.g., (C1-C6)alkoxy), hydroxy, oxo, nitro, cyano, amino, -C(O)-R d -C(O)-OR d -OC(O)-R d -C(O)-NR d R e -NR d R e , a haloalkyl (e.g., (C1-C6) haloalkyl), a haloalkyloxy (e.g., (C1-C6) haloalkoxy or trifluoromethoxy) or a halogen, wherein R d and R e It is either hydrogen or alkyl.

[0045] In some implementations, one or more carbon isotopes of the aforementioned possible substituents are enriched with deuterium.

[0046] In some embodiments, the compounds disclosed herein include their enantiomers, diastereomers, and addition salts with pharmaceutically acceptable acids or bases.

[0047] In some implementations, X is sulfur.

[0048] In some implementations, Y is C(O).

[0049] In some embodiments, ring A is a six-membered aryl or heteroaryl group, each of which is unsubstituted or substituted.

[0050] In some embodiments, the compound has the formula (I a ):

[0051] Where R 1 R2 R 3 R 4 R', R'', X, Y, Z and n are as defined in equation (I).

[0052] In some implementations, Z is hydrogen.

[0053] In some embodiments, the compound has the formula (I b ): , Where R 1 R 2 R 3 R 4 R', R'' and n are as defined in equation (I).

[0054] In some implementations, n is 1.

[0055] In some implementations, R' and R'' are each hydrogen.

[0056] In some implementation schemes, R 1 and R 2 Each is hydrogen.

[0057] In some implementation schemes, R 1 It is hydrogen.

[0058] In some implementation schemes, R 2 It is hydrogen.

[0059] In some implementation schemes, R 1 It is either hydrogen or methyl.

[0060] In some implementation schemes, R 2 It is hydrogen, alkyl, or C(O)R a , where R a As defined in equation (I).

[0061] In some implementation schemes, R 2 It is hydrogen, C(O)R a , benzyl, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, -(C1-C 10 )alkyl-(C1-C9)heterocyclic group, (C1-C9)heterocyclic group, (C1-C 10 )alkylsulfonyl, (C4-C 10 ) arylsulfonyl, (C4-C 10 ) heteroarylsulfonyl, 5 to 10 aryl or 5 to 10 heteroaryl; wherein each benzyl, (C1-C 10 )alkyl, (C3-C 10)cycloalkyl, -(C1-C 10 )alkyl-(C1-C9)heterocyclic group, (C1-C9)heterocyclic group, (C1-C 10 )alkylsulfonyl, (C4-C 10 ) arylsulfonyl, (C4-C 10 The heteroarylsulfonyl, 5- to 10-membered aryl and 5- to 10-membered heteroaryl groups are independently substituted or unsubstituted.

[0062] In some implementation schemes, R 2 It is hydrogen, C(O)R a , benzyl, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, -(C1-C 10 )alkyl-(C1-C9)heterocyclic group, (C1-C9)heterocyclic group, (C1-C 10 )alkylsulfonyl, (C4-C 10 ) arylsulfonyl, (C4-C 10 ) heteroarylsulfonyl, 5 to 10 aryl or 5 to 10 heteroaryl, wherein each R a Yes - (C1-C 10 )alkyl-(C1-C9)heterocyclic group, (C1-C9)heterocyclic group, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, benzyl, NH-(C1-C 10 )alkyl, -CH2-(C1-C9)heterocyclic, -CH2-(C1-C5)heterocyclic-(C4-C 10 ) aryl; wherein each benzyl group, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, -(C1-C 10 )alkyl-(C1-C9)heterocyclic group, (C1-C9)heterocyclic group, (C1-C 10 )alkylsulfonyl, (C4-C 10 ) arylsulfonyl, (C4-C 10 ) heteroarylsulfonyl, NH-(C1-C 10 )alkyl, -CH2-(C1-C9)heterocyclic, -CH2-(C1-C5)heterocyclic-(C4-C 10 ) aryl, 5 to 10 aryl and 5 to 10 heteroaryl groups are independently unsubstituted or independently selected from one or more halogens, -NH2, (C1-C 10 )alkyl, -OR X , oxo, C(O)R X and -CO2R X The groups are substituted, wherein each R group is replaced by a group. XIt is independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.

[0063] In some implementation schemes, R 2 It is C(O)R a In some implementations, R 2 It is C(O)R a , where R a It is an aryl or heteroaryl group, each of which may be unsubstituted or substituted. In some embodiments, R 2 It is C(O)R a , where R a It is a 5- to 10-membered aryl or a 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted. In some embodiments, R a Optionally substituted with 1 to 4 groups selected from the following: (C1-C6)alkyl, (C1-C6)alkoxy, hydroxyl, oxo, nitro, cyano, amino, -C(O)-R d -C(O)-OR d -OC(O)-R d -C(O)-NR d R e -NR d R e (C1-C6) haloalkyl, (C1-C6) haloalkoxy (e.g., trifluoromethoxy) and halogen atoms, wherein R d and R e It is either hydrogen or (C1-C6) alkyl.

[0064] In some implementation schemes, R 2 It is C(O)R a , where R a The group is selected from pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridazinyl, triazolyl, oxadiazolyl, or pyrazinyl, each of which may be unsubstituted or substituted. In some embodiments, R a Optionally substituted with 1 to 4 groups selected from the following: (C1-C6)alkyl, (C1-C6)alkoxy, hydroxyl, oxo, nitro, cyano, amino, -C(O)-R d -C(O)-OR d -OC(O)-R d -C(O)-NR d R e -NR d R e (C1-C6) haloalkyl, (C1-C6) haloalkoxy (e.g., trifluoromethoxy) and halogen, wherein Rd and R e It is either hydrogen or (C1-C6) alkyl.

[0065] In some implementation schemes, R 2 It is C(O)R a , where R a It is pyrimidin-2-yl, pyrimidin-5-yl, 5-amino-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, 1 H -pyrazole-3-yl, 2-methyl-1 H -Pyrazol-3-yl, pyridin-2-yl, 2-chloro-pyridin-2-yl, 6-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl, 6-hydroxy-pyridin-2-yl, pyridin-3-yl, 6-amino-pyridin-3-yl, 2-chloro-pyridin-3-yl, pyridin-4-yl, 3-phenyl-1 H -pyrazole-5-yl, 1 H -imidazol-4-yl, 1 H -imidazol-2-yl, 1-methyl-1 H -imidazol-4-yl, 1-methyl-1 H -imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, 4-methyl-1,2,3-thiadiazol-5-yl, 5-phenylisoxazole-3-yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5-methyl-3-phenylisoxazole-4-yl, 4-phenylthiazol-2-yl, 1 H -Tetrazole-5-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, 3-hydroxypyrazinyl, 4-isopropyl-1,2,3-thiadiazolyl, 3-methyl-isoxazolyl-5-yl, 4,4-difluoro-piperidin-1-yl, 1,2,4-triazin-3-yl, 4-methylpyridin-2-ylamino, 3-oxopiperazin-1-yl, 5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl or piperazin-1-yl.

[0066] In some implementation schemes, R 2 It is C(O)R a , where R a It is pyridin-2-yl.

[0067] In some implementation schemes, R 2 It is C(O)R a , where R a It is 2-chloro-pyridin-2-yl.

[0068] In some implementation schemes, R 2 It is C(O)R a , where R a It is 6-chloro-pyridin-2-yl.

[0069] In some implementation schemes, R 2 It is C(O)R a , where R a It is 5-chloro-pyridin-2-yl.

[0070] In some implementation schemes, R 2 It is C(O)Ra, where R a It is 6-hydroxy-pyridin-2-yl.

[0071] In some implementation schemes, R 2 It is C(O)R a , where R a It is pyridin-3-yl.

[0072] In some implementation schemes, R 2 It is C(O)R a , where R a It is 6-amino-pyridin-3-yl.

[0073] In some implementation schemes, R 2 It is C(O)R a , where R a It is 2-chloro-pyridin-3-yl.

[0074] In some implementation schemes, R 2 It is C(O)R a , where R a It is pyridin-4-yl.

[0075] In some implementation schemes, R 2 It is C(O)R a , where R a It is pyrimidin-2-yl.

[0076] In some implementation schemes, R 2 It is C(O)R a , where R a It is pyrimidin-5-yl.

[0077] In some implementation schemes, R 2 It is C(O)R a , where R a It is 5-amino-pyrimidin-2-yl.

[0078] In some implementation schemes, R 2 It is C(O)R a , where R a It is 5-methoxy-pyrimidin-2-yl.

[0079] In some implementation schemes, R 2 It is C(O)Ra , where R a It is 1 H -pyrazole-3-yl.

[0080] In some implementation schemes, R 2 It is C(O)R a , where R a It is 2-methyl-1 H -pyrazole-3-yl.

[0081] In some implementation schemes, R 1 and R 2 Each of the following is independently hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3-hydroxycyclobutyl, 3,3-difluorocyclobutyl, cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, pyrimidin-2-yl, pyrimidin-2-methyl, pyrimidin-3-methyl, pyrimidin-4-methyl, oxalyl, 2-methoxyethyl, benzyl, 4-carboxybenzyl, 4-carboxymethylbenzyl, tetrahydro-2-yl H -pyran-4-yl, oxetane-3-yl, 1,2,4-thiadiazol-5-yl, 4-aminomethyl-1,2,3-triazol-1-ylmethyl, 4-methyl-1,2,3-thiadiazol-5-ylmethyl, benzo[d]thiazol-2-yl, 4-carboxyethyl-1,2,3-thiadiazol-5-ylmethyl, 4-carboxy-1,2,3-thiadiazol-5-ylmethyl, isoindoline-1,3-dione-2-yl or acetyl.

[0082] In some implementation schemes, R 1 and R 2 Together with the nitrogen atoms they bind, they form optionally substituted heterocycles or heteroaryl groups, wherein the optionally substituted heterocycles or heteroaryl groups are pyrazolidinone, piperazine, 2-oxopiperazine, triazolyl, benzotriazolyl, morpholino, pyrrolidinyl, or piperidinyl.

[0083] In some implementation schemes, R 1 and R 2 Together with the nitrogen atoms they bind to, they form optionally substituted heterocycles, wherein the optionally substituted heterocycle is 1 H -1,2,3-triazol-1-yl, 1 H -Benz[d][1,2,3]triazol-1-yl, morpholino, 3,3-difluoropyrrolidone-1-yl, 4,4-difluoropiperidin-1-yl, pyrazolidine-4-one and 4-benzylpiperidin-1-yl.

[0084] In some implementation schemes, R 3It is a halogen, alkoxy, cycloalkyloxy, or aryloxy group, each optionally substituted by one to four groups, wherein each group is independently alkyl, alkoxy, hydroxy, oxo, nitro, cyano, amino, -C(O)-R d -C(O)-OR d -OC(O)-R d -C(O)-NR d R e -NR d R e , haloalkyl, haloalkyloxy (e.g., trifluoromethoxy) or halogen, wherein R d and R e Each is either hydrogen or alkyl.

[0085] In some implementation schemes, R 3 It is a halogen, alkoxy, cycloalkyloxy, or aryloxy group, each optionally substituted by one to four groups, wherein each group is independently (C1-C6)alkyl, (C1-C6)alkoxy, hydroxyl, oxo, nitro, cyano, amino, -C(O)-R d -C(O)-OR d -OC(O)-R d -C(O)-NR d R e -NR d R e (C1-C6) haloalkyl, (C1-C6) haloalkyloxy (e.g., trifluoromethoxy) or halogen, wherein R d and R e It is either hydrogen or (C1-C6) alkyl.

[0086] In some implementation schemes, R 3 It is a halogen, (C1-C6)alkoxy, cycloalkyloxy, or aryloxy group, each optionally substituted by one to four groups, wherein each group is independently (C1-C6)alkyl, (C1-C6)alkoxy, hydroxyl, oxo, nitro, cyano, amino, -C(O)-R d -C(O)-OR d -OC(O)-R d -C(O)-NR d R e -NR d R e (C1-C6) haloalkyl, (C1-C6) haloalkyloxy (e.g., trifluoromethoxy) or halogen, wherein R d and R e It is either hydrogen or (C1-C6) alkyl.

[0087] In some implementation schemes, R 3 It is an unsubstituted phenyloxy group. In some embodiments, R 3 It is a substituted phenyloxy group. In some embodiments, R 3 It is a phenyloxy group optionally substituted with 1 to 4 groups, wherein each group is independently alkyl, alkoxy, hydroxyl, oxo, nitro, cyano, amino, -C(O)-R d -C(O)-OR d -OC(O)-R d -C(O)-NR d R e -NR d R e , haloalkyl, haloalkyloxy (e.g., trifluoromethoxy) or halogen, wherein R d and R e It is independently hydrogen or alkyl. In some embodiments, R 3 It is a phenyloxy group that has been substituted with one or more halogen atoms.

[0088] In some implementation schemes, R 3 It is a phenyloxy group optionally substituted with 1 to 4 groups selected from the following: (C1-C6)alkyl, (C1-C6)alkoxy, hydroxyl, oxo, nitro, cyano, amino, -C(O)-R d -C(O)-OR d -OC(O)-R d -C(O)-NR d R e -NR d R e (C1-C6) haloalkyl, (C1-C6) haloalkyloxy (e.g., trifluoromethoxy) and halogen, wherein R d and R e It is either hydrogen or (C1-C6) alkyl.

[0089] In some implementation schemes, R 3 Optionally substituted with one or two identical or different substituents selected from hydroxyl, fluorine, chlorine, bromine, iodine, CF3, CHF2, methoxy, S(O)2Me, cyano and C(O)Me.

[0090] In some implementation schemes, R 3 It is a phenoxy group optionally substituted with one or two identical or different substituents selected from hydroxyl, fluorine, chlorine, bromine, iodine, CF3, CHF2, methoxy, S(O)2Me, cyano and C(O)Me.

[0091] In some implementation schemes, R3 Each time it appears, it is independently selected from alkyl, cyclohexyl, haloalkyl, alkoxy, hydroxyalkyloxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, arylsulfonyl, alkylsulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxacyclopenten-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NHcycloalkyl, -NH-C(O)cycloalkyl, heteroaryl, heterocyclic and naphthyl, each of which is substituted or unsubstituted, or halogen.

[0092] In some implementation schemes, R 3 Each time it appears, it is independently selected from alkyl, cyclohexyl, halo(C1-C6)alkyl, alkoxy, hydroxy(C1-C6)alkyloxy, halo(C1-C6)alkyloxy, cycloalkyloxy, cycloalkyl(C1-C6)alkyloxy, aryl(C1-C6)alkyloxy, arylsulfonyl, alkylsulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxacyclopenten-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NHcycloalkyl, -NH-C(O)cycloalkyl, heteroaryl, heterocyclic and naphthyl, each of which is substituted or unsubstituted, or halogen.

[0093] In some implementation schemes, R 3 It is (C1-C) independently each time it appears. 10 )alkyl, cyclohexyl, (C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy, (C1-C 10 )cycloalkyloxy, (C4-C 10 )arylsulfonyl, (C1-C 10 )alkylsulfonyl, phenyl, benzyl, phenoxy, benzo[d][1,3]dioxacyclopenten-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NH-(C1-C 10 )cycloalkyl, -NH-C(O)-(C1-C 10 (C1-C9)cycloalkyl, (C3-C9)heteroaryl, (C1-C9)heterocyclic or naphthyl, each of which is substituted or unsubstituted, or halogen.

[0094] In some implementation schemes, R 3 Each time it appears, it is independently a halogen, (C1-C) 10 )alkyl, (C1-C 10 ) Haloalkyl, cyclohexyl, (C1-C 10 )alkoxy, (C1-C 10)cycloalkyloxy, (C4-C 10 )arylsulfonyl, (C1-C 10 )alkylsulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxane-5-yloxy)phenyl, benzyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NH-(C1-C 10 )cycloalkyl, -NH-C(O)-(C1-C 10 )cycloalkyl, (C3-C9)heteroaryl, (C1-C9)heterocyclic or naphthyl; wherein each (C1-C 10 )alkyl, cyclohexyl, (C1-C 10 )alkoxy, (C1-C 10 )cycloalkyloxy, (C4-C 10 )arylsulfonyl, (C1-C 10 )alkylsulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxane-5-yloxy)phenyl, benzyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NH-(C1-C 10 )cycloalkyl, -NH-C(O)-(C1-C 10 Cycloalkyl, (C3-C9)heteroaryl, (C1-C9)heterocyclic and naphthyl groups are independently unsubstituted or substituted by: halogen, oxo, cyano, -NH2, (C1-C9)-hydroxyl, -NH2 ... 10 )alkyl, (C1-C 10 )alkoxy, (C1-C 10 ) Haloalkyl, (C1-C 10 )alkylsulfonyl, C(O)R X NH-C(O)-R X -CO2R X -CO2NR X R Y -OCH2CO2R X -OR X or -CH2OR X , where each R X and R Y It is independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.

[0095] In some implementation schemes, R 3Each time it appears independently, it is methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, pentan-1-yl, pentan-2-yl, pentan-3-yl, cyclohexyl, hydroxycyclohexyl, trifluoromethyl, methoxy, neopentyloxy, 2,4-dimethylpentan-3-yloxy, 2-hydroxy-2-methylpropoxy, (adamantane-1-yl)methoxy, (adamantane-2-yl)methoxy, (adamantane-1-yl)oxy, (adamantane-2-yl)oxy, cyclopentyloxy, cyclohexyloxy, fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethoxy, trifluoroethoxy, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4- Fluorophenyl, 4-bromophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-amino-4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3-iodo-4-chlorophenyl, benzo[d][1,3]dioxacyclopenten-5-yloxy)phenyl, phenylamino, phenoxy, 2-methoxyphenoxy, 3-methoxyphenoxy, 4-methoxyphenoxy, 2- (trifluoromethyl)phenoxy, 3-(trifluoromethyl)phenoxy, 4-(trifluoromethyl)phenoxy, 2-(trifluoromethoxy)phenoxy, 3-(trifluoromethoxy)phenoxy, 4-(trifluoromethoxy)phenoxy, 2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2,4-dichlorophenoxy, 3,5-difluorophenoxy, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 2-acetylphenoxy, 3-acetylphenoxy, 4-acetylphenoxy, 3-chloro-5-cyanophenoxy, 2-chloro-4-cyanophenoxy, 1H-indol-1-yl, 4-methylsulfonylphenoxy, -C(O)-NHPh, -NH-C(O) Ph, -C(O)-NHcyclohexyl, -NH-C(O)cyclohexyl, 2-(acetamido)phenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 2-formamidophenyl, 3-formamidophenyl, 4-formamidophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-(2-oxoacetic acid phenyl), 3-(2-oxyacetic acid phenyl), 4-(2-oxyacetic acid phenyl), 2-oxopyrrolidone-1-yl, 3-(trifluoromethyl)-1H-pyrazole-4-yl, pyridyl, naphth-1-yl, naphth-2-yl, -S(O)2Ph, 2-oxopyridin-1(2H)-yl, indole, phenylsulfonyl, 2-hydroxymethylpyrrolidone-1-yl or hydroxypiperidin-1-yl.

[0096] In some implementation schemes, R 3 It is selected independently from one to five halogens and (C1-C2) 10 The phenoxy group is substituted with a haloalkyl group. In some embodiments, R 3 It is a phenoxy group substituted with one to five halogens.

[0097] In some implementation schemes, R 3 It is 2-(trifluoromethyl)phenoxy. In some embodiments, R 3 It is 3-(trifluoromethyl)phenoxy. In some embodiments, R 3 It is 4-(trifluoromethyl)phenoxy. In some embodiments, R 3 It is 2-(trifluoromethoxy)phenoxy. In some embodiments, R 3 It is 3-(trifluoromethoxy)phenoxy. In some embodiments, R 3 It is 4-(trifluoromethoxy)phenoxy. In some embodiments, R 3 It is 2-chlorophenoxy.

[0098] In some implementation schemes, R 3 It is a phenoxy group.

[0099] In some implementation schemes, R 3 It is 3-chlorophenoxy.

[0100] In some implementation schemes, R 3 It is 4-chlorophenoxy.

[0101] In some implementation schemes, R 3 It is 2-fluorophenoxy.

[0102] In some implementation schemes, R 3 It is 3-fluorophenoxy.

[0103] In some implementation schemes, R 3 It is 4-fluorophenoxy.

[0104] In some implementation schemes, R 3 It is 2,4-dichlorophenoxy.

[0105] In some implementation schemes, R 3 It is 3,5-difluorophenoxy.

[0106] In some implementations, two adjacent R 3 The groups, together with the carbon atoms they are bonded to, form fused cycloalkyl or heterocycloalkyl rings, such as benzofuranyl rings.

[0107] In some implementation schemes, R4 It is a methyl group.

[0108] In some implementation schemes, R 4 It is hydrogen.

[0109] In some embodiments, the compound is provided as a free base. In some embodiments, the compound is provided as a free acid. In some embodiments, the compound is provided as a salt of a pharmaceutically acceptable acid. In some embodiments, the compound is provided as a salt of a pharmaceutically acceptable base.

[0110] compound Non-limiting examples of compounds of formula (I) are: (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenylphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-bromophenyl)-5-(dimethylaminomethyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-[(4-benzyl-1-piperidinyl)methyl]-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(4-benzyl-1-piperidinyl)methyl]-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-methoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(trifluoromethyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-benzyloxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(trifluoromethyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenylphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-iodophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; 3-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; 3-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; 4-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; 4-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; (2S,5R)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one); (2R,5S)-5-(aminomethyl-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one); (2S,5R)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(1,3-benzodioxacyclopenten-5-yl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1,3-benzodioxacyclopenten-5-yl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromo-5-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-naphthyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(1-naphthyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(benzenesulfonyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-methoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(o-tolyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-ethylpropyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(3-amino-4-chloro-phenyl)phenyl]-5-(aminomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,4-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chloro-3-iodo-phenyl)phenyl]-1,4-thiazacycloheptane-3-one; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzamide; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]cyclohexaneformamide; (2R,5S)-5-(aminomethyl)-2-[3-(4-fluorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-cyclohexylphenyl)-1,4-thiazacycloheptane-3-one; 3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]-N-phenyl-benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidone-1-yl)methyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidone-1-yl)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidone-1-yl)methyl]-1,4-thiazacycloheptane-3-one; N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]phenyl]acetamide; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidinyl)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidinyl)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,3-dimethoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzoic acid; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; 2-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]phenoxy]acetic acid; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxopyrrolidone-1-yl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxo-1-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-hydroxy-1-piperidinyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-(((3R,5R,7R)-adamantane-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazacycloheptan-3-one; (2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantane-2-yl)oxy)phenyl)-5-(aminomethyl)-1,4-thiazacycloheptan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(cyclohexyloxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-isopropyl-2-methyl-propoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxy-2-methyl-propoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxy-3-propyl-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-chloro-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-indol-1-ylphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-methoxyphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,4-dichlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[2-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(methylaminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclohexyloxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-methyl-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-dibenzofuran-2-yl-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methylsulfonylphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; 2-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[4-(4-acetylphenoxy)phenyl]-5-(aminomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(1,3-benzodioxacyclopenten-5-yloxy)phenyl]-1,4-thiazacycloheptane-3-one; 3-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]-5-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(4-phenylaminophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-chloro-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]-3-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(2-methoxy-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)-2-methoxy-phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(triazol-1-ylmethyl)-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[4-(aminomethyl)triazol-1-yl]methyl]-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(pyrimidin-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(1,3-benzothiazo-2-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(1,2,4-thiadiazol-5-ylamino)methyl]-1,4-thiazacycloheptane-3-one; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; 2-O-2-[[(2R,5S)-3-O-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methylamino]acetate; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]thiazolyl-2-carboxamide; 4-(aminomethyl)-N-[[(2R,5S)-2-(3-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]benzamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]-2H-tetrazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]thiazolyl-4-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazolyl-5-yl]methyl]-4-methyl-thiadiazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-5-carboxamide; 6-Amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazolyl-5-yl]methyl]thiazolyl-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]-5-phenyl-isoxazol-3-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]-5-methyl-3-phenyl-isoxazol-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazolyl-5-yl]methyl]-4-phenyl-thiazolyl-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 1-Methyl-N-[[(2S,5R)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]imidazol-4-carboxamide; 4-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyrimidin-5-carboxamide 6-Amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]methanesulfonamide 4-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]-1H-imidazol-4-carboxamide; 2-Morpholino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]acetamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]morpholine-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyridazine-3-carboxamide; 5-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]thiadiazole-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-sulfonamide; 4-Fluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]benzenesulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-sulfonamide; 1-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]imidazol-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]thiazolyl-2-carboxamide; 3,3-Difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]cyclobutane formamide; 4,4-Difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]cyclohexaneformamide; N-[[(2R,5S)-2-[3-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantane-2-yl)oxy)phenyl)-3-oxo-1,4-thiazacycloheptane-5-yl)methyl)pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]-2-pyrimidin-2-ylacetamide; 1-Benzyl-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]urea; 3-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]isoxazole-5-carboxamide; N-[[(2R,5S)-2-[3-(cyclohexyloxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 4,4-Difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]piperidine-1-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]-1,2,4-triazine-3-carboxamide; N-[[(2R,5S)-2-[4-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrazine-2-carboxamide; 6-Chloro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; 2-[5-(4-chlorophenyl)isoxazo-3-yl]-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]acetamide; 6-Amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; 5-Amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; 5-Methoxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; 1-(4-methyl-2-pyridyl)-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]urea N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridazine-3-carboxamide; 6-Amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; 6-Amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-sulfonamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-sulfonamide; 2-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]benzamide; 4-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]benzamide; (2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-5-[(1,2,4-thiadiazol-5-ylamino)methyl]-1,4-thiazacycloheptane-3-one; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 5-Amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; 5-Chloro-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-5-methoxy-pyrimidin-2-carboxamide; 5-Amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-5-methoxy-pyrimidin-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrazine-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; N-[[(2S,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2S,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-1,4-thiazolyl-5-yl]methyl]-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazolyl-5-yl]methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]piperazine-1-carboxamide; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-1,4-thiazacycloheptane-3-one; 4-[[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoate; (2R,5S)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; 4-[[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoic acid; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(cyclopropylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(cyclopropylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(cyclobutylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(tetrahydropyran-4-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(oxetane-3-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[bis(oxetane-3-yl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-((((1r,3S)-3-hydroxycyclobutyl)amino)methyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[(3,3-difluorocyclobutyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[(4-methylthiadiazol-5-yl)methylamino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-4-ylmethylamino)methyl]-1,4-thiazacycloheptane-3-one; 4-[[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoic acid; 4-[[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoic acid; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-bromophenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2,4-dichlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(2,2,2-trifluoroethylamino)methyl]-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-1,1-dioxo-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-1,1-dioxo-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(2-oxopiperazin-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazetane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-oxazetane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-1,4-oxazetane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-oxazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(dimethylaminomethyl)-1,4-oxazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-oxazetane-3-one; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 6-Amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; 6-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridine-2-carboxamide; 2-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]-1-methyl-imidazol-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridazine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]thiazolyl-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]thiazolyl-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyrazine-2-carboxamide; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazetane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazacycloheptane-3-one; (2R,5S)-5-(benzotriazol-1-ylmethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(3-oxopiperazin-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; And their enantiomers, diastereomers, their addition salts with pharmaceutically acceptable acids or bases, and deuterated derivatives.

[0111] In some embodiments, the compound of formula (I) is: (2R,5S)-5-(aminomethyl)-2-[4-(3,5-dimethylphenoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazetane-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazetane-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]thiazolyl-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide, or a pharmaceutically acceptable salt thereof; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantane-2-yl)oxy)phenyl)-3-oxo-1,4-thiazacycloheptane-5-yl)methyl)pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-[(2-oxopiperazin-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-(((3R,5R,7R)-adamantane-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; or (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazocycloheptan-3-one, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compound of formula (I) is (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound of formula (I) is (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the compound of formula (I) is (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the compound of formula (I) is (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the compound of formula (I) is (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the compound of formula (I) is N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the compound of formula (I) is (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0119] Synthesis method This disclosure also relates to a method for preparing compounds of formula (I) and intermediates thereof.

[0120] Starting materials may include compounds of formula (II): , Among them, A and R 3 Z and n are as defined in equation (I).

[0121] The starting material can be esterified to generate a compound of formula (III): , Among them, A and R 3 Z and n are as defined in formula (I), and Alk is an alkyl group. In some embodiments, Alk is a (C1-C6) alkyl group.

[0122] Compound (III) can then undergo bromination to produce compound (IV): , Among them, A and R 3Z and n are as defined in equation (I), and Alk is as defined above. Other halogens (e.g., Cl, I) can be introduced to replace Br.

[0123] Compound (IV) can react with compound (V): , Where X, R', and R'' are as defined in formula (I) and P is a protecting group, to generate compound of formula (VI): , Among them, A and R 3 Z, X, R', R'' and n are as defined in equation (I), and Alk and P are as defined above.

[0124] Compounds of formula (VI) can be deprotected to form compounds of formula (VII): , Among them, A and R 3 Z, X, R', R'' and n are as defined in equation (I), and Alk is as defined above.

[0125] Compound (VII) can be cyclized to generate compound (VIII): , Among them, A and R 3 Z, X, R', R'' and n are as defined in equation (I).

[0126] The hydroxyl group of compound (VIII) can be protected to generate compound (IX): , Among them, A and R 3 Z, X, R', R'' and n are as defined in formula (I), and P is a protecting group.

[0127] Compounds of formula (IX) and (X) can be combined: X'R 4 'The reaction proceeds, where X' is a halogen and R...' 4 ' is an unsubstituted or substituted alkyl group, forming a compound of formula (XI): , Among them, A and R 3 Z, X, R', R'' and n are as defined in equation (I), and R 4’ P is as defined above.

[0128] Compounds of formula (IX) and (XI) together represent compound (XII): , Among them, A and R 3 R 4 Z, X, R', R'' and n are as defined in equation (I), and P is as defined above.

[0129] Compounds of formula XII and (XIII) can be combined: HNR 1 R 2 The reaction proceeds, where R 1 and R 2 As defined in formula (I), to generate a compound of formula (I / a), a special case of a compound of formula (I): , Among them, A and R 1 R 2 R 3 R 4 Z, X, R', R'' and n, as defined in formula (I), can be reduced to produce a compound of formula (I / b), a special case of compound (I): , Among them, A and R 1 R 2 R 3 R 4 R', R'' and n are as defined in equation (I).

[0130] Compound (I / a) and compound (I / b) together represent compound (I).

[0131] In some implementations, the compound of formula (I) can be purified according to separation techniques such as column chromatography, thin-layer chromatography, sublimation, recrystallization, liquid-liquid extraction or grinding.

[0132] In some implementations, the compound of formula (I) can be converted into its addition salt using a pharmaceutically acceptable acid or base.

[0133] In some implementations, the compound of formula (I) may be optionally isolated into its isomers according to separation techniques.

[0134] It should be understood that during the process described above, at any point deemed appropriate, some groups (e.g., hydroxyl, amino) of the starting reagent or synthetic intermediate can be protected as needed for the synthesis, followed by deprotection and functionalization.

[0135] In some embodiments, the compound of formula (I) is obtained using an alternative method; for example, the compound of formula (I) can be synthesized starting from the compound of formula (VI) as described above, wherein the hydroxyl moiety is activated and then contacted with an azide derivative to form the compound of formula (XIV): , Among them, A and R 3 Z, X, R', R'' and n are as defined in equation (I).

[0136] Compounds of formula (XIV) can be cyclized to form compounds of formula (XV): , Among them, A and R 3 Z, X, R', R'' and n are as defined in equation (I).

[0137] Compounds of formula (XV) can be combined with compounds of formula (X) as defined above: X'R 4’ The reaction proceeds to produce a compound of formula (XVI): , Among them, A and R 3 Z, X, R', R'' and n are as defined in equation (I), and R 4’ As defined above.

[0138] Compounds of formula (XV) and (XVI) together represent compounds of formula (XVII): , Among them, A and R 3 R 4 Z, X, R', R'' and n are as defined in equation (I).

[0139] Compounds of formula (XVII) can be subjected to reducing conditions to produce compounds of formula (I / c), a special case of compounds of formula (I): , Among them, A and R 3 R 4 Z, X, R', R'' and n are as defined in equation (I).

[0140] Compounds of formula (I / c) can be further reduced to form compounds of formula (I / d), a special case of compounds of formula (I): , Among them, A and R 3 R 4 Z, X, R', R'' and n are as defined in equation (I).

[0141] Compounds of formula (I / c) and formula (I / d) together represent compounds of formula (I / e), a special case of compounds of formula (I): , Among them, A and R 3 R 4 Y, Z, X, R', R'' and n are as defined in equation (I).

[0142] Compounds of formula (I / e) and (XVIII) can be combined: X''R 1 'The reaction proceeds, where X'' is a halogen and R 1 'Is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is unsubstituted or substituted, or C(O)R a C(O)OR a or S(O)2R b To generate compounds of formula (I / f), a special case of compounds of formula (I): , Among them, A and R 3 R 4 , Y, Z, X, R', R'' and n are as defined in equation (I), and R 1 As defined above.

[0143] In some implementation schemes, R 1 It is an aryl (C1-C6) alkyl group.

[0144] In some implementation schemes, R 1 It is a (C1-C6) alkyl group.

[0145] Compounds of formula (I / f) and (XIX) can be combined: X''R 2 'The reaction proceeds, where X'' is a halogen and R 2 'Is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is unsubstituted or substituted, or C(O)R a C(O)OR a or S(O)2R b To produce compounds of formula (I / g), a special case of compounds of formula (I): , Among them, A and R 3 R 4 , Y, Z, X, R', R'' and n are as defined in equation (I), and R 1’ and R 2 As defined above. In some implementations, R 2 It is a (C1-C6) alkyl group. In some embodiments, R 2 It is an aryl (C1-C6) alkyl group.

[0146] In some embodiments, this disclosure provides a method for synthesizing compounds of formula (I): The methods include: (a) Esterified (II) compounds: , Compounds of formula (III): , in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ;Optionally, two adjacent R 3 The group and the carbon atom it is bonded to form a fused cycloalkyl or heterocycloalkyl ring; -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -n is 0, 1, 2, 3, 4, or 5; and -Alk is an alkyl group; (b) subjecting compound (III) to bromination to produce compound (IV): ; (c) Reacting compound (IV) with compound (V):

[0147] Compounds of formula (VI): , in -X is O, S, S(O) or S(O)2; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); and -P is a protecting group; (d) Deprotecting compound (VI) to generate compound (VII): ; (e) Cycling of compound (VII) to generate compound (VIII): ; (f) Protecting the hydroxyl group to form a compound of formula (IX): , Where P is a protecting group; (g) Making compound of formula (IX) and compound of formula (X): X'R 4 'Reaction, where X' is a halogen and R 4 ' is an unsubstituted or substituted alkyl group, forming a compound of formula (XI): , Compounds of formula (IX) and (XI) represent compounds of formula (XII):

[0148] Among them, A and R 3 Z, X, R', R'', n, and P are as defined above, and R 4 It is an unsubstituted or substituted alkyl group, or hydrogen; (h) To make compound (XII) and compound (XIII): HNR 1 R 2 The reaction, in which R 1 and R 2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each being unsubstituted or substituted, or hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds to, it forms a heterocyclic alkyl moiety to generate the (I / a) compound: ; (i) Optionally, the compound of formula (I / a) is reduced to produce the compound of formula (I / b): , Compounds of formula (I / a) and (I / b) represent compounds of formula (I); and (i) Optionally, purify the resulting compound; and / or, optionably, convert the resulting compound into its addition salt using a pharmaceutically acceptable acid or base; and / or, optionably, isolate the resulting compound into its isomers.

[0149] In some embodiments, this disclosure provides a method for synthesizing compound (I). The method includes the following steps: (a) Make compound of formula (VI)

[0150] in -X is O, S, S(O) or S(O)2; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); and -P is a protecting group; Reacts with azide derivatives to produce compounds of formula (XIV): ; (b) Cycling of compound (XIV) to generate compound (XV): ; (c) Reacting compound (XV) with compound (X) as defined above: X'R4' to generate compound (XVI): , Compounds of formula (XV) and formula (XVI) represent compounds of formula (XVII): ; (d) Reduction of compound (XVII) to produce compound (I / c): ; (e) Optionally, the compound of formula (I / c) is further reduced to generate the compound of formula (I / d): , Compounds of formula (I / c) and formula (I / d) represent compounds of formula (I / e): ; (f) Optionally, make the compound of formula (I / e) with the compound of formula (XVIII): X''R 1 'Reaction, where X'' is a halogen and R 1 'Is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is unsubstituted or substituted, or C(O)R a C(O)OR b or S(O)2R b Compounds with formula (I / f): ; (g) Optionally, make the compound of formula (I / f) and the compound of formula (XIX): X''R 2 'Reaction, where X'' is a halogen and R 2 'Is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is unsubstituted or substituted, or C(O)R a C(O)ORb or S(O)2R b Compounds with formula (I / g): ;as well as (h) Optionally, purify the resulting compound; and / or, optionably, convert the resulting compound into its addition salt using a pharmaceutically acceptable acid or base; and / or, optionably, isolate the resulting compound into its isomers.

[0151] In some embodiments, this disclosure provides a method for synthesizing compounds of formula (I): The method, include: (a) Esterified (II) compounds:

[0152] Compounds of formula (III): , in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ;Optionally, two adjacent R 3 The group, together with the carbon atom it is bonded to, forms an optionally fused cycloalkyl or heterocycloalkyl ring; -R 4 It is hydrogen; -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -n is 0, 1, 2, 3, 4, or 5; and -Alk is an alkyl group; (b) subjecting compound (III) to bromination to produce compound (IV): ; (c) Reacting compound (IV) with compound (V):

[0153] Compounds of formula (VI): , in -X is O, S, S(O) or S(O)2; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); and -P is a protecting group; (d) Deprotecting compound (VI) to generate compound (VII): ; (e) Cycling of compound (VII) to generate compound (VIII): ; (f) Reacting a compound of formula (VIII) with a compound of formula RSO2LG or a compound of formula (R-SO2-)2O, wherein R is an alkyl or aryl group and LG is a leaving group (e.g., chlorine). Compounds of formula (IX): , Among them, A and R 3 Z, X, R, R', R'' and n are as defined above; (g) Make compound (IX) react with compound R 10 The reaction of N3 compounds, in which R 10 It is a metal cation (e.g., Li) + Na + or K + ) or N + Alk4, where Alk is an alkyl group, to form compound (X): ;as well as (h) To convert compound (X) into compound (I'): , Where R 1 and R 2 Each is a hydrogen atom. Compound (I') can be further reacted to produce compound (I), where R... 1 and R 2 As stated above.

[0154] The conversion of compound (X) into compound (I) can be achieved by several methods through the reduction of azides to the corresponding amines, including but not limited to catalytic hydrogenation, reduction via hydride donors (such as LiAlH4, NaBH4), silanes in the presence of metals, phosphine / water, etc.

[0155] In some embodiments, this disclosure provides a method for synthesizing compounds of formula (I): The method, include: (a) Esterified (II) compounds:

[0156] Compounds of formula (III): , in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ;Optionally, two adjacent R 3 The group, together with the carbon atom it is bonded to, forms an optionally fused cycloalkyl or heterocycloalkyl ring; -R 4 It is hydrogen; -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -n is 0, 1, 2, 3, 4, or 5; and -Alk is an alkyl group; (b) subjecting compound (III) to bromination to produce compound (IV): ; (c) Reacting compound (IV) with compound (V):

[0157] Compounds of formula (VI): , in -X is O, S, S(O) or S(O)2; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); and -P is a protecting group; (d) Deprotecting compound (VI) to generate compound (VII): ; (e) Cycling of compound (VII) to generate compound (VIII): ; (f) In the presence of a phosphine (e.g., alkyl, O-alkyl, aryl, or heteroarylphosphine) and an azodicarboxylic acid ester such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP), or tetramethylazodicarboxamide (DMAD), a compound of formula (VIII) is reacted with a compound of formula NH(P)2, wherein P is a nitrogen protecting group, to generate a compound of formula (IX): , Among them, A and R 3 Z, X, R', R'', P, and n are as defined above; and (g) Converting compound (IX) into compound (I).

[0158] Where R 1 and R 2 Each is a hydrogen atom. The compound can further react to form another compound, where R... 1 and R 2 As described above, for example, where R 1 and R 2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, and each is either unsubstituted or substituted, with hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds with, it forms a heterocyclic alkyl moiety.

[0159] In some implementations, compounds of formulas (I / c), (I / d), (I / e), (I / f), and / or (I / g) can be purified using separation techniques.

[0160] In some implementations, compounds of formulas (I / c), (I / d), (I / e), (I / f), and / or (I / g) can be converted into their addition salts using pharmaceutically acceptable acids or bases.

[0161] In some embodiments, compounds of formula (I / c), (I / d), (I / e), (I / f) and / or (I / g) may optionally be isolated into their isomers according to separation techniques.

[0162] It should be understood that during the process described above, at any point deemed appropriate, some groups (e.g., hydroxyl, amino) of the starting reagent or synthetic intermediate can be protected as needed for the synthesis, followed by deprotection and functionalization.

[0163] All stereoisomers of the compounds disclosed herein (e.g., those that may exist due to asymmetric carbons on various substituents), including enantiomers and diastereomers, are considered within the scope of this disclosure. For example, individual stereoisomers of the compounds disclosed may be substantially free of other isomers (e.g., as pure or substantially pure optical isomers with specific activities), or may be mixed, for example, as racemates, or as mixtures rich in one stereoisomer. The chiral center of this disclosure may have an S or R configuration as defined in IUPAC 1974 Recommendations. Racemate forms may be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers may be obtained from racemates by any suitable method, including but not limited to methods such as forming a salt with an optically active acid or base and then crystallizing.

[0164] Pharmaceutically acceptable salts Any compound described herein may be provided as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to the compound to form an acid addition salt may be an organic or inorganic acid. The base added to the compound to form a base addition salt may be an organic or inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt.

[0165] Metal salts can be generated by adding an inorganic base to the compounds disclosed herein. The inorganic base consists of a metal cation paired with a basic counterion, such as hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0166] In some implementations, the metal salt is a lithium salt, sodium salt, potassium salt, cesium salt, cerium salt, magnesium salt, manganese salt, iron salt, calcium salt, strontium salt, cobalt salt, titanium salt, aluminum salt, copper salt, cadmium salt, or zinc salt.

[0167] Ammonium salts can be generated by adding ammonia or an organic amine to the compounds disclosed herein. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, etc. N methylmorpholine, piperidine, N -methylpiperidine, N -Ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.

[0168] In some implementations, the ammonium salt is a triethylamine salt, a trimethylamine salt, a diisopropylamine salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, or a morpholine salt. N 2-Methylmorpholine salt, piperidine saltN 2-methylpiperidine salt, N -Ethylpiperidine salt, dibenzylamine salt, piperazine salt, pyridine salt, pyrazole salt, pyridazine salt, pyrimidine salt, imidazole salt, or pyrazine salt.

[0169] Acid addition salts can be generated by adding an acid to the compounds disclosed herein. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentian acid, phosphonic acid, pyruvic acid, malonic acid, camphoric acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0170] In some embodiments, the salt is a hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentianate, phosphonate, pyruvate, malonate, camphorate, trifluoroacetate, gluconate, glucuronate, glycoside, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, hemifumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate.

[0171] In some embodiments, one or more compounds of this disclosure exist as protonated salts at the nitrogen atom, including salts formed with organic and inorganic anions and cations discussed herein. Non-limiting examples of such acids include hydrochloric acid, hydrofluoric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, palmitic acid, cholic acid, pamoic acid, mucoic acid, D-glutamic acid, D-camphoric acid, glutaric acid, phthalic acid, tartaric acid, lauric acid, stearic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, sorbic acid, picric acid, benzoic acid, and cinnamic acid.

[0172] Therapeutic uses In some embodiments, this disclosure provides a compound for treating conditions, symptoms, and diseases associated with the ranodin receptor (RyR).

[0173] In some embodiments, this disclosure provides compounds, such as Rycal compounds, as RyR modulators. For example, the compounds of this disclosure can bind to leaking RyR subunits, restore Calstabin binding, and repair channel leakage. In some embodiments, the compounds of this disclosure bind to leaking RyR channels, restore Calstabin binding, and repair channel leakage without blocking the RyR channels. In some embodiments, the compounds of this disclosure are capable of repairing leakage in RyR channels, such as RyR1, RyR2, and / or RyR3 channels. In some embodiments, the compositions of this disclosure enhance the association of RyR and Calstabin (e.g., RyR1 and Calstabin1; RyR2 and Calstabin2; and RyR3 and Calstapin1) and / or inhibit their dissociation.

[0174] Non-limiting examples of conditions, symptoms, and diseases associated with RyR include those that can be treated and / or prevented by regulating RyR, including, for example, heart disease or disorders, musculoskeletal disorders or diseases, cancer-related muscle weakness, malignant hyperthermia, and diabetes. The compounds described herein may also reduce the likelihood of such conditions occurring.

[0175] In some embodiments, this disclosure provides a method for treating or reducing the occurrence of a condition by administering a therapeutically effective amount of a compound disclosed herein, such as a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, to a subject in need. In some embodiments, the compound is administered in the form of a pharmaceutical composition. In some embodiments, the compound is in a unit dosage form. In some embodiments, the unit dosage form is a solid dosage form. In some embodiments, the pharmaceutical composition is in a unit dosage form suitable for oral administration.

[0176] In some embodiments, this disclosure provides a method for treating or reducing the likelihood of a condition by using a compound, such as a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, this disclosure provides a compound, such as a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, for the preparation of a medicament.

[0178] In some implementations, the condition, symptom, or disease is associated with abnormal function of RyR1. In some implementations, the condition, symptom, or disease is associated with abnormal function of RyR2. In some implementations, the condition, symptom, or disease is associated with abnormal function of RyR3. In some implementations, the condition is cardiology or a disease. In some implementations, the condition is a musculoskeletal disorder or disease. In some implementations, the condition is cancer-related muscle weakness. In some implementations, the condition is malignant hyperthermia. In some implementations, the condition is diabetes.

[0179] In some embodiments, this disclosure provides a method for regulating the binding of RyR and Calstabins in a target, comprising administering to the target an amount of a compound, such as a compound of formula (I) described herein or a salt thereof, which effectively regulates the amount of Calstabin bound to RyR. In some embodiments, the compound is used at a dose sufficient to restore or enhance the binding of Calstabin2 to RyR2. In some embodiments, the compound is used at a dose sufficient to restore or enhance the binding of Calstabin2 to RyR2. In some embodiments, the compound is used at a dose sufficient to restore or enhance the binding of Calstabin1 to RyR1. In other embodiments, the compound is used at a dose sufficient to restore or enhance the binding of Calstabin1 to RyR1.

[0180] The methods disclosed herein can be practiced in vitro (e.g., cultured cells or tissues) or in vivo (e.g., in non-human animals or humans).

[0181] In some embodiments, the compounds of this disclosure are not selective for specific RyR isotypes. In some embodiments, the compounds of this disclosure can bind to and / or repair Ca in RyR1 and RyR2. +2 Leakage. In some embodiments, the compounds of this disclosure can prevent pressure-induced dissociation of Calstabin2 from RyR2 and Calstabin1 from RyR1, thereby reducing RyR-mediated SR Ca. 2+ Leakage leads to improved cardiac and skeletal muscle function.

[0182] Therefore, in some embodiments, the compounds disclosed herein can be used to treat skeletal muscle (RyR1) and myocardial (RyR2) calcium deficiency. +2 Diseases characterized by leakage. For example, the compounds disclosed herein can be used to treat myocardial and skeletal muscle dysfunction in heart failure. In other embodiments, the compounds disclosed herein can be used to treat myocardial and skeletal muscle dysfunction in muscular dystrophy, such as Duchenne muscular dystrophy.

[0183] In some embodiments, the compounds of this disclosure are selective for RyR1, meaning they are more effective at repairing calcium leakage in RyR1 compared to RyR2. In some embodiments, the compounds of this disclosure are selective for RyR2, meaning they are more effective at repairing calcium leakage in RyR2 compared to RyR1.

[0184] Lanodine receptor: Excitation-contraction coupling (ECC) process The sarcoplasmic reticulum (SR) is a structure in cells whose function includes serving as a specialized source of intracellular calcium (Ca). 2+ ) reservoir. The lanodidogen receptor (RyR) is a channel in SR that regulates Ca2+ by opening and closing. 2+ Ca is released from SR into the cytoplasm of the cell. Ca is released from SR into the cytoplasm. 2+ Increase cytoplasmic calcium 2+ Concentration. The opening probability of RyR refers to the likelihood that RyR is open at any given moment, and therefore, it is possible to convert Ca... 2+ Released from SR into the cytoplasm.

[0185] RyR is the main Ca on SR. 2+ Release channels are responsible for excitation-contraction coupling (ECC) in skeletal muscle. Of the three known RyR isoforms (RyR1, RyR2, and RyR3), RyR1 is widely expressed and is the predominant isoform expressed in mammalian skeletal muscle. RyR2 is also widely expressed and is the predominant form found in cardiac muscle. RyR3 is expressed at lower levels in adult skeletal muscle. The RyR isoforms exhibit high structural and functional homology. This isoform forms a large sarcoplasmic membrane complex composed of four monomers, which constitute the protein-associated Ca2+. 2+ Release channels, such as kinases, phosphatases, phosphodiesterases, and other regulatory subunits.

[0186] Ca released from SR is regulated by several RyR-binding proteins. 2+ Calmodulin is a calcium-based protein. 2+ The key mediators of signal transduction exert both positive and negative influences on the opening probability of RyR. Calstabin1 (FKBP12) and Calstabin2 (FKBP12.6) stabilize the closure states of RyR1 and RyR2, respectively. Calstabin1 is primarily associated with skeletal muscle RyR1, while cardiac RyR2 has the highest affinity for Calstabin2.

[0187] RYR1 or RYR2The mutation is characterized by inappropriate channel opening unrelated to contraction signals. This channel opening is further exacerbated by post-translational modifications, including PKA phosphorylation, oxidation, or nitrosation of RyR channels. The resulting leaky channels exhibit a pathologically increased probability of opening under resting conditions. SR Ca 2+ Leakage caused SR Ca in the lumen 2+ The reduced content allows for the release of Ca. 2+ Reduced, resulting in weaker muscle contraction. Intracellular calcium leakage has different pathological consequences depending on the tissue involved.

[0188] Lanodine receptor 2 and heart disease In some implementations, conditions associated with RyR are cardiac disorders or diseases involving lanodidone receptor 2 (RyR2). The RyR2 channel regulates Ca2+ in the sarcoplasmic reticulum (SR) of cardiomyocytes required for endocrine disruption (ECC) in the myocardium. 2+ The release of RyR2 plays a crucial role in intracellular calcium processing. The RyR2 channel is a macromolecular complex comprising four identical RyR2 subunits, each binding one Calstabin2 (FKBP12.6) and other interacting proteins, such as phosphatases and kinases. Calstabin2 binding stabilizes the channel in a closed state during the cardiac resting phase (diastole), preventing diastolic calcium leakage from the SR, and functionally couples the RyR2 channel group to allow synchronous opening during excitation-contraction coupling.

[0189] Phosphorylation of RyR2 by protein kinase A (PKA) is a crucial part of the fight-or-flight response. Phosphorylation increases the release of Ca2+ by a given trigger. 2+ This increases cardiac EC coupling gain. This process strengthens muscle contraction and improves exercise capacity. This signaling pathway provides a mechanism by which activation of the sympathetic nervous system (SNS) in the stress response leads to increased cardiac output. PKA phosphorylation of RyR2 increases the channel's sensitivity to calcium-dependent activation. This increased sensitivity leads to an increased opening probability and an increased release of calcium from the SR into the intracellular cytoplasm.

[0190] Heart failure (HF) is characterized by a persistent hyperadrenergic state, in which serum catecholamine levels are chronically elevated. One consequence of this chronic hyperadrenergic state is persistent PKA hyperphosphorylation of RyR2, resulting in the chronic phosphorylation of 3-4 of the four Ser2808 molecules in each homotetrameric RyR2 channel. This chronic PKA hyperphosphorylation of RyR2 is associated with the depletion of the channel-stabilizing subunit Calstabin2 in the RyR2 channel macromolecular complex. Calstabin2 depletion leads to diastolic SR Ca2+ in the RyR2 complex. 2+Leakage occurs, leading to impaired contractility. This diastolic SR Ca is affected by the activation of the inward depolarization current. 2+ Leaks are also linked to fatal heart arrhythmias.

[0191] Mice engineered with RyR2 lacking PKA phosphorylation sites (RyR-S2808A) were protected from the progression of heart failure (HF) after myocardial infarction (MI). Furthermore, chronic PKA hyperphosphorylation of RyR2 in HF is associated with remodeling of the RyR2 macromolecular complex. This remodeling includes the depletion of phosphatases PP1 and PP2a (which impair Ser2808 dephosphorylation) and the depletion of cAMP-specific phosphodiesterase type 4 (PDE4D3) within the RyR2 complex. Depletion of PDE4D3 within the RyR2 complex leads to a sustained increase in local cAMP levels.

[0192] Therefore, diastolic SR Ca 2+ Leakage leads to the progression of heart failure (HF) and arrhythmias. Additional post-translational modifications (oxidation and nitrosation) of RyR channels further promote leakage. Single-channel imaging of heart failure cardiomyocytes showed a significantly increased probability of RyR2 opening compared to normal cardiomyocytes, indicating leakage channels. This is due to the diastolic SRCa of RyR2 via phosphorylation / oxidation. 2+ Leakage, RyR channel, large lumen SR Ca available under normal conditions 2+ Cardiac reserves are rapidly depleted in heart failure. Lanodine receptor channel modulators can improve cardiac function in mouse or rat models of heart failure by stabilizing ejection fraction through repair of calcium leakage.

[0193] RyR2 leakage is associated with various cardiac conditions, illnesses, and diseases. In some implementations, cardiac conditions are due to... RYR2 Caused by gene mutation. In some implementations, the cardiac condition is due to post-translational modification of RyR2.

[0194] Heart failure In some embodiments, the heart condition or disease is heart failure. In some embodiments, the heart condition or disease is myocardial infarction (MI). In some embodiments, the heart failure is congestive heart failure. In some embodiments, the heart failure is chronic heart failure. In some embodiments, the heart failure is systolic heart failure. In some embodiments, the heart failure is diastolic heart failure. In some embodiments, the heart failure is acute decompensated heart failure. In some embodiments, the heart failure is heart failure with reduced ejection fraction (HFrEF). In some embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart failure is acute heart failure, for example, preserving cardiac function after myocardial infarction or cardiomyopathy. In some embodiments, the heart failure is right ventricular failure (RHF). In some embodiments, the heart failure is left ventricular failure (LHF).

[0195] In some implementations, the cardiac condition or disease includes cardiac ischemia / reperfusion (I / R) injury. I / R injury may occur after coronary angioplasty or thrombolysis used to treat myocardial infarction (MI), or during / after coronary artery bypass surgery or heart transplantation, or after a drop in blood pressure (e.g., a sudden drop in blood pressure).

[0196] In some embodiments, the cardiac condition or disease is characterized by an irregular heartbeat or arrhythmia. In some embodiments, the cardiac condition or disease is catecholamine-sensitive polymorphic ventricular tachycardia (CPVT). In some embodiments, the cardiac condition or disease is type 1 catecholamine-sensitive polymorphic ventricular tachycardia (CPVT1). In some embodiments, the cardiac condition or disease is atrial arrhythmia, or is characterized by it. In some embodiments, the cardiac condition or disease is ventricular arrhythmia, or is characterized by it. In some embodiments, the cardiac condition or disease is atrial fibrillation, or is characterized by it. In some embodiments, the cardiac condition or disease is ventricular fibrillation, or is characterized by it. In some embodiments, the cardiac condition or disease is atrial tachyarrhythmia, or is characterized by it. In some embodiments, the cardiac condition or disease is ventricular tachyarrhythmia, or is characterized by it. In some embodiments, the cardiac condition or disease is atrial tachycardia, or is characterized by it. In some embodiments, the cardiac condition or disease is ventricular tachycardia, or is characterized by it. In some embodiments, the cardiac condition or disease is premature contractions (PC), or is characterized by it. In some embodiments, the cardiac condition or disease is ventricular premature contractions (PVC), or is characterized by it. In some embodiments, the cardiac condition or disease is bigeminy, or is characterized by it. In some embodiments, the cardiac condition or disease is sick sinus syndrome, or is characterized by it. In some embodiments, the cardiac condition or disease is paired ventricular premature contractions, or is characterized by it. In some embodiments, the cardiac condition or disease is sudden cardiac death (SCD), or is characterized by it. In some embodiments, the cardiac condition or disease is sudden infant death syndrome (SDIS), or is characterized by it. In some embodiments, the cardiac condition or disease is sudden death of unknown cause (SUD), or is characterized by it.

[0197] In heart failure, calcium in the sarcoplasmic reticulum (SR) 2+ The concentration can be abnormally adjusted. This is achieved through improved leakage RyR2Ca. 2+ Release channel from SR diastolic Ca 2+ Leakage can lead to delayed depolarization (DAD). When the amplitude of DAD exceeds a certain threshold (overthreshold DAD), it can trigger an action potential (AP) called triggered activity (TA), which can lead to premature ventricular contractions (PVCs). Lanodine receptor channel modulators (e.g., compounds of formula (I), or any other compounds contained in that formula, or compounds otherwise described herein) can preferentially bind to leaked RyR2 channels and induce a conformational change that shifts the open probability of the RyR2 channel to a closed (resting) state, repairing the channel leakage and restoring normal RyR2 function. In some embodiments, repairing the channel leakage results in a reduction in calcium flux (e.g., calcium spark).

[0198] In some implementations, lanodine receptor channel modulators, as described herein, are effective in treating heart failure characterized by high PVC load. PVC load can be determined by monitoring subjects (e.g., patients with heart failure) over a defined time period using electrocardiography or any other system (e.g., a continuous cardiac monitoring system) that monitors or detects and stores measured cardiac electrical activity. In some implementations, PVC load is calculated as the percentage of total PVC over a given time period divided by the total number of beats within the same time period.

[0199] In some embodiments, the PVC load is at least about 1% of all heartbeats within a time period. In some embodiments, the PVC load is at least about 5% of all heartbeats within a time period. In some embodiments, the PVC load is at least about 10% of all heartbeats within a time period. In some embodiments, the PVC load ranges from about 5% to about 20% of all heartbeats. In some embodiments, the PVC load ranges from about 5% to about 15% of all heartbeats within a time period. In some embodiments, the PVC load ranges from about 5% to about 10% of all heartbeats within a time period. In some embodiments, the heart rate before the PVC is at least about 60 beats / min, at least about 70 beats / min, at least about 80 beats / min, at least about 90 beats / min, or at least about 100 beats / min.

[0200] In some embodiments, heart failure is characterized by elevated levels of N-terminal pro-β-natriuretic peptide (NTproBNP). In some embodiments, the N-terminal pro-β-natriuretic peptide level is greater than about 600 pg / mL, greater than about 700 pg / mL, greater than about 800 pg / mL, greater than about 900 pg / mL, greater than about 1,000 pg / mL, or greater than about 1,500 pg / mL.

[0201] In some embodiments, the time period is from about 1 minute to about 24 hours. In some embodiments, the time period is from about 1 minute to about 12 hours. In some embodiments, the time period is from about 1 minute to about 10 hours. In some embodiments, the time period is from about 1 minute to about 5 hours. In some embodiments, the time period is from about 1 minute to about 1 hour. In some embodiments, the time period is from about 1 minute to about 30 minutes. In some embodiments, the time period is from about 5 minutes to about 30 minutes. In some embodiments, the time period is about 1 minute. In some embodiments, the time period is about 60 minutes. In some embodiments, the time period is about 24 hours.

[0202] In some implementations, the subject has heart failure with a reduced ejection fraction (HFrEF). In some implementations, the subject's ejection fraction is less than about 40%. In some implementations, the subject's ejection fraction is less than about 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, or even lower.

[0203] A common symptom of heart failure is significant muscle fatigue and exercise intolerance, which leads to limited daily activities and affects quality of life. Heart failure is associated with maladaptive remodeling of the skeletal muscle RyR1 complex, and this may play a role in the exercise intolerance and activity limitation characteristic of patients with heart failure.

[0204] For example, skeletal muscle RyR1 from human patients with heart failure is post-translationally modified (e.g., phosphorylation, oxidation, and / or nitrosation), and Calstabin 1 is depleted, indicating pathological calcium deficiency. +2 Release is a potential mechanism behind skeletal muscle weakness and impaired exercise tolerance in patients with heart failure, and suggests potential targets for pharmacological interventions.

[0205] In some embodiments, the compounds of this disclosure can prevent the pressure-induced dissociation of the channel-stabilizing subunits calstabin2 from RyR2 and calstabin1 from RyR1, thereby reducing RyR-mediated SR Ca2+. 2+ Leakage leads to improved myocardial and skeletal muscle function in patients with heart failure. Therefore, in some embodiments, the compounds of this disclosure can treat skeletal and myocardial weakness in patients with heart failure. Thus, the compounds of this disclosure can be uniquely targeted to treat myocardial and skeletal muscle dysfunction in heart failure.

[0206] This article provides a method for treating skeletal muscle weakness in patients with heart failure, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) repairs calcium leakage in the subject's RyR1 and / or RyR2 channels.

[0207] Improvements in skeletal muscle function can be measured in a variety of ways, including measuring maximum oxygen consumption (VO2 max), exercise capacity, walking distance, muscle strength, and cardiopulmonary exercise tests.

[0208] arrhythmia In some embodiments, the cardiac condition or disease is characterized by an irregular heartbeat or arrhythmia. In some embodiments, the cardiac condition or disease is characterized by ectopic heart disease, such as ventricular ectopic heart disease. In some embodiments, ectopic heart disease or condition (e.g., CPVT) associated with a heart condition (e.g., ventricular ectopic heart disease) may be induced by pressure, such as catecholamine stress. In some embodiments, ectopic heart disease (e.g., ventricular ectopic heart disease) is exercise-induced. In some embodiments, ectopic heart disease (e.g., ventricular ectopic heart disease) is induced by an elevated heart rate. In some embodiments, ectopic heart disease (e.g., ventricular ectopic heart disease) occurs when the subject has a heart rate that is elevated relative to the subject's baseline heart rate. In some implementations, an elevated heart rate is defined as a heart rate of at least approximately 100 beats per minute, at least approximately 105 beats per minute, at least approximately 110 beats per minute, at least approximately 115 beats per minute, at least approximately 120 beats per minute, at least approximately 125 beats per minute, at least approximately 130 beats per minute, at least approximately 135 beats per minute, at least approximately 140 beats per minute, at least approximately 145 beats per minute, at least approximately 150 beats per minute, at least approximately 155 beats per minute, at least approximately 160 beats per minute, at least approximately 165 beats per minute, at least approximately 170 beats per minute, at least approximately 175 beats per minute, at least approximately 180 beats per minute, at least approximately 185 beats per minute, at least approximately 190 beats per minute, at least approximately 195 beats per minute, or at least approximately 200 beats per minute. In some embodiments, the elevated heart rate is approximately 100 beats / min to approximately 200 beats / min, approximately 125 beats / min to approximately 200 beats / min, approximately 150 beats / min to approximately 200 beats / min, approximately 100 beats / min to approximately 125 beats / min, approximately 100 beats / min to approximately 150 beats / min, or approximately 100 beats / min to approximately 175 beats / min. In some embodiments, the elevated heart rate is stress-induced. In some embodiments, the stress is catecholamine stress. In some embodiments, the elevated heart rate is exercise-induced.

[0209] Catecholamine-sensitive polymorphic ventricular tachycardia In some embodiments, this disclosure provides a method for treating catecholamine-sensitive polymorphic ventricular tachycardia (CPVT), comprising administering a therapeutically effective amount of a lanodilator receptor channel modulator to a subject in need, wherein treatment of catecholamine-sensitive polymorphic ventricular tachycardia (CPVT) reduces the likelihood of the subject developing ectopic ventricular tachycardia.

[0210] In some embodiments, this disclosure provides a method for treating catecholamine-sensitive polymorphic ventricular tachycardia (CPVT), comprising administering a therapeutically effective amount of a lanodilator receptor channel modulator to a subject in need, wherein treatment of catecholamine-sensitive polymorphic ventricular tachycardia (CPVT) reduces the likelihood of atrial fibrillation in the subject.

[0211] Catecholamine-sensitive polymorphic ventricular tachycardia (CPVT) is one of the most deadly inherited arrhythmias. CPVT occurs in the absence of structural heart disease and is characterized by adrenergic-mediated ventricular arrhythmias, associated with a high incidence of sudden cardiac death (SCD). CPVT is a life-threatening condition and a leading cause of unexplained sudden death, particularly in children and young adults. A typical newly diagnosed CPVT patient is a child or young adult without structural heart disease, with a normal resting electrocardiogram, who presents with stress-induced palpitations or syncope. If left untreated, CPVT is a highly fatal condition, with an untreated mortality rate of 30-50% by age 40.

[0212] CPVT is associated with mutations in two genes that encode proteins related to the sarcoplasmic reticulum (SR) of cardiomyocytes. The most commonly observed form is type 1 CPVT (CPVT1), an autosomal dominant form caused by mutations in the RYR2 gene. RYR2 encodes an intracellular SR calcium release channel. CPVT-associated RyR2 mutations lead to leakage of the RyR2 channel, which may be related to reduced binding of the Calstabin2 (FKBP12.6) subunit in the stable closure state of the channel. Heterozygous mice with the R2474S mutation in RyR2 (which occurs in humans with CPVT1) (RyR2-R2474S mice) can exhibit exercise-induced ventricular arrhythmias and sudden cardiac death.

[0213] Under normal physiological conditions, SR Ca 2+ Flux is tightly regulated, and RyR2 interacting proteins are involved in this regulation. For example, Calstabin2 regulates SR Ca by stabilizing the RyR2 closed state. 2+ Release. In CPVT1 patients, reduced RyR2-Calstabin2 binding may be related to RyR2-Ca 2+ Related to leakage.

[0214] RyR2-R2474S is a mutant channel carrying a point mutation that causes CPVT in humans. Compared to unmutated RyR2, it is in a primed state. The primed state is the transition between the closed and open conformations of these channels. In the primed state, mutant channels readily transition to the open conformation. Wild-type RyR2 channels are open during systole, which is the appropriate phase for calcium release during the cardiac cycle. In contrast, under exercise or catecholamine stress, primed mutant channels can be open during both systole and diastole. This inappropriate opening during diastole can lead to ventricular arrhythmias specific to CPVT. These observations were made under conditions similar to the channel state during diastole under exercise-induced β-adrenergic stimulation (e.g., PKA phosphorylation and low calcium concentration).

[0215] In some embodiments, the CPVT-related mutant RyR2 protein is in a ready-to-launch state. In some embodiments, the ready-to-launch RyR2 protein contains a higher probability of opening (Po) distribution compared to the resting (closed) RyR2 protein. In some embodiments, the ready-to-launch RyR2 protein is a leaky RyR2 protein characterized by an aberrant Ca2+ channel. +2 Leakage. In some embodiments, the RyR2 protein in the ready-to-be-released state is a leaking RyR2 protein compared to the RyR2 protein in the resting (closed) state, characterized by a higher probability of opening (Po) distribution. In some embodiments, the ready-to-be-released RyR2 comprises about 30% to about 60% of the RyR2 channels in the open state. In some embodiments, the ready-to-be-released RyR2 comprises about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% of the RyR2 channels in the open state.

[0216] Lanorodin receptor channel modulators offer an innovative approach to treating CPVT1. These modulators preferentially bind to leaking RyR2 channels and induce conformational changes that shift the opening probability of RyR channels to a closed (resting) state, restoring Calstabin 2 binding and repairing channel leakage, thereby restoring normal RyR2 function.

[0217] In some embodiments, this disclosure provides a method for treating catecholamine-sensitive polymorphic ventricular tachycardia (CPVT), comprising administering a therapeutically effective amount of a lanodilator receptor channel modulator to a subject in need. In some embodiments, this disclosure provides a method for treating CPVT, comprising administering a therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need. In some embodiments, administration is once daily. In some embodiments, the CPVT is type 1 CPVT.

[0218] In some embodiments, this disclosure provides a method for treating CPVT, comprising administering a therapeutically effective amount of a lanodilator receptor channel modulator to a subject in need, wherein treating CPVT reduces the likelihood of sudden cardiac death in the subject. In some embodiments, the CPVT is type 1 CPVT.

[0219] In some embodiments, the compound is administered as a single therapy. In some embodiments, the compound is administered in combination with one or more additional therapies. In some embodiments, the compound is administered in combination with a beta-blocker. In some embodiments, the compound is administered in combination with a sodium channel blocker (also referred to herein as a sodium channel inhibitor). In some embodiments, the compound is administered in combination with both a beta-blocker and a sodium channel inhibitor.

[0220] In some embodiments, the subject is receiving a treatment regimen for CPVT, wherein the CPVT treatment regimen includes a beta-blocker. In some embodiments, the compound described herein is administered in combination with a beta-blocker. In some embodiments, the compound is administered in combination with a beta-blocker, wherein the beta-blocker is administered at an amount effective for treating the subject's CPVT in the absence of the compound described herein or its pharmaceutically acceptable salt. In some embodiments, the compound is administered in combination with a beta-blocker, wherein the beta-blocker is administered in a reduced amount, wherein the reduced amount is approximately less than the amount of CPVT used to treat the subject in the absence of the compound. In some embodiments, the compound is administered in combination with a beta-blocker, wherein the beta-blocker is administered in a reduced amount, wherein the reduced amount is approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95% of the amount of CPVT used to treat the subject in the absence of the compound.

[0221] The amount of beta-blocker used to treat CPVT in the absence of a compound can be less than the maximum tolerated dose of the beta-blocker, for example, it can be about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% lower than the maximum tolerated dose of the beta-blocker.

[0222] The amount of beta-blocker less than the amount used to treat CPVT without the compound can be less than the dose of a beta-blocker effective for treating CPVT without the compound or its pharmaceutically acceptable salt. For example, it can be about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% lower than the dose of a beta-blocker effective for treating CPVT without the compound.

[0223] Non-limiting examples of beta-blockers include acebutolol, atenolol, betaxolol, bisoprolol, bucindolol, butaxamine, carteolol, carvedilol, celiprolol, esmolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, and their pharmaceutically acceptable salts.

[0224] In some embodiments, the beta-blocker is a non-selective beta-blocker. Non-selective beta-blockers inhibit β-1 receptors primarily located in the myocardium and β-2 receptors primarily located in the bronchial and vasomotor systems. In some embodiments, the non-selective beta-blocker is naldolol, pentbuprofen, indolol, propranolol, sotalol, or timolol, or a pharmaceutically acceptable salt thereof. In one embodiment, the non-selective beta-blocker is naldolol or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the beta-blocker is a selective beta-blocker. Selective beta-blockers (such as metoprolol) preferentially inhibit β1 receptors (cardiac selectivity). At very high concentrations, this selectivity may decrease, and some β2 inhibition may occur. This selectivity is demonstrated by the inability to reverse the β2-mediated vasodilation of adrenaline. This contrasts with the effect of non-selective beta-blockers, which are able to reverse the vasodilation of adrenaline. In one embodiment, the beta-blocker is metoprolol or a pharmaceutically acceptable salt thereof.

[0226] In some implementations, the subject is receiving a treatment regimen for CPVT, which includes a sodium channel inhibitor. In some implementations, the compound is administered in combination with a sodium channel inhibitor. Non-limiting examples of sodium channel inhibitors include flecainide, quinidine, procainamide, disopyramide, lidocaine, mexiletine, tocainide, phenytoin, moricizine, propafenone, lacosamide, rufinamide, fosphenytoin, ethotoin, and carbamazepine. e) eslicarbazepine, pilsicainide, tetrodoxin, apririndine, ajmaline, encainide, propafenone, amiodarone, procainamide, quinidine, oxcarbazepine, moricizine, amiloride, lamotrigine, triamterene, mexiletine, phenytoin, and ranolazine, or pharmaceutically acceptable salts thereof. In some embodiments, the sodium channel inhibitor is flecainide or a pharmaceutically acceptable salt thereof. In some embodiments, the sodium channel inhibitor is flecainide acetate.

[0227] In some embodiments, the subject is receiving a treatment regimen for CPVT, wherein the CPVT treatment regimen includes a sodium channel inhibitor. In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is administered in combination with a sodium channel inhibitor. In some embodiments, the compound is administered in combination with a sodium channel inhibitor, wherein the sodium channel inhibitor is administered at an amount effective for treating the subject's CPVT in the absence of the compound. In some embodiments, the compound is administered in combination with a beta-blocker, wherein the sodium channel inhibitor is administered at a reduced amount, wherein the reduced amount is approximately less than the amount of CPVT used to treat the subject in the absence of the compound. In some embodiments, the compound is administered in combination with a sodium channel inhibitor, wherein the sodium channel inhibitor is administered at a reduced amount, wherein the reduced amount is approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95% of the amount of CPVT used to treat the subject in the absence of the compound.

[0228] The amount of sodium channel inhibitor used to treat CPVT in the absence of a compound can be less than the maximum tolerated dose of the sodium channel inhibitor. For example, it can be about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% lower than the maximum tolerated dose of the sodium channel inhibitor.

[0229] The amount of sodium channel inhibitor less than that used to treat CPVT without the compound can be less than the dose of a sodium channel inhibitor that is effective for treating CPVT without the compound. For example, it can be about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% lower than the dose of a sodium channel inhibitor that is effective for treating CPVT without the compound.

[0230] In some implementations, the sodium channel inhibitor is flecainide or a pharmaceutically acceptable salt thereof. The amount of flecainide or a pharmaceutically acceptable salt thereof less than the amount used to treat CPVT without the compound can be less than the dose of flecainide or a pharmaceutically acceptable salt thereof that is effective for treating CPVT without the compound, for example, it can be about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% lower than the dose of flecainide or a pharmaceutically acceptable salt thereof that is effective for treating CPVT without the compound.

[0231] In some embodiments, left ventricular sympathectomy may be used as part of a treatment regimen for CPVT. In some embodiments, the method of treating CPVT includes using a combination of a beta-blocker and cardiac sympathectomy. In some embodiments, the method of treating CPVT includes using a combination of a sodium channel inhibitor and cardiac sympathectomy. In some embodiments, the method of treating CPVT includes using a combination of a sodium channel inhibitor and a beta-blocker and cardiac sympathectomy. In some embodiments, the method of treating CPVT includes using a combination of the compounds described herein or pharmaceutically acceptable salts thereof with cardiac sympathectomy. In some embodiments, the method of treating CVPT includes using a combination of a compound and a beta-blocker with cardiac sympathectomy. In some embodiments, the method of treating CPVT includes using a combination of a compound and a sodium channel inhibitor with cardiac sympathectomy. In some embodiments, the method of treating CPVT includes using a combination of a compound, a sodium channel inhibitor, and a beta-blocker with cardiac sympathectomy. In some embodiments, the subject has an implantable cardioverter defibrillator (ICD).

[0232] Lanorodin receptor 1 and musculoskeletal diseases In some implementations, RyR-related conditions are musculoskeletal disorders or diseases involving lanodine receptor 1 (RyR1). The RyR1 macromolecular complex consists of a tetramer of 560-kDa RyR1 subunits that form a scaffold for proteins that regulate channel function, including PKA and phosphodiesterase 4D3 (PDE4D3), protein phosphatase 1 (PP1), and Calstabin1. A kinase-anchored protein (mAKAP) targets PKA and PDE4D3 to RyR1, while a spinin targets PP1 to the channel. The catalytic and regulatory subunits of PKA, PP1, and PDE4D3 regulate PKA-mediated phosphorylation of RyR1 at Ser2843 (Ser2844 in mice). PKA-mediated phosphorylation of RyR1 at Ser2844 increases the channel's response to cytoplasmic calcium. 2+ This reduces the sensitivity of Calstabin1 to RyR1 binding affinity and destabilizes the closed state of the channel.

[0233] The concentration of Calstabin1 in skeletal muscle can be approximately 200 nM. PKA phosphorylation of RyR1 can reduce the binding affinity of Calstabin1 to RyR1 from approximately 100-200 nM to over 600 nM. Therefore, under physiological conditions, the reduction in the binding affinity of Calstabin1 to RyR1 due to PKA phosphorylation of RyR1 at Ser2843 is sufficient to significantly reduce the amount of Calstabin1 present in the RyR1 complex. Chronic PKA hyperphosphorylation of RyR1 at Ser2843 leads to channel leakage (i.e., channels that are easily opened at rest), which results in skeletal muscle dysfunction associated with a persistent hyperadrenergic state, such as in individuals with heart failure.

[0234] Furthermore, RyR1 can be modulated through post-translational modifications other than phosphorylation, such as nitrosation of free thiol groups on cysteine ​​residues. S Nitrification and channel oxidation can increase the activity of RyR1 channels. RyR1's... S - Nitrification and oxidation can both reduce the binding of Calstabin1 to RyR1.

[0235] In some implementations, the musculoskeletal disorder or disease is a congenital myopathy, that is, a myopathy present at birth. In some implementations, the congenital myopathy is caused by a mutation. RYR1 Genetic causes. In some implementations, congenital myopathy is caused by post-translational modifications of RyR1.

[0236] In some implementations, musculoskeletal disorders are classified as congenital muscular dystrophy (CMD). CMD is present at birth. CMD is classified based on gene mutations: 1) genes encoding proteins that encode the basement membrane or extracellular matrix structure of skeletal muscle fibers; 2) genes encoding putative or confirmed glycosyltransferases that affect the glycosylation of dystrophic proteoglycans (outer membrane proteins of the basement membrane); and 3) others. Non-limiting examples of CMD include RYR1-related myopathy (RYR1-RM), laminin-α2-deficient CMD (MDC1A), Ullrich CMG (UCMD 1, 2, and 3), Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama CMD (FCMD), CMD plus secondary laminin deficiency 1 (MDC1B), CMD plus secondary laminin deficiency 2 (MDC1C), CMD with intellectual disability and hypertrophic gyri (MDC1D), and rigid spine with type 1 muscular dystrophy (RSMD1).

[0237] RYR1-related myopathy In some implementations, the musculoskeletal disease is RYR1-related myopathy (RYR1-RM). RYR1-related myopathy (RYR1-RM) is a heterogeneous group of monogenic neuromuscular diseases caused by pathogenic variants of the RYR1 gene. RYR1-RM can be classified into two main phenotypic categories based on clinical and histological characteristics: 1) a phenotype with dynamic and sporadic presentations, without myopathy intervening between exacerbations, including susceptibility to malignant hyperthermia (MH), potentially fatal hypermetabolic crises to certain environmental and drug triggers, exertional rhabdomyolysis, and atypical periodic paralysis. 2) a phenotype with overt myopathy of varying severity, including severe fetal akinesis, late-onset axial myopathy, and congenital myopathy. Based on histological characteristics, the latter can be further subdivided into central nucleoid myopathy, multiple micronucleoid myopathy, congenital fibrous disproportionate myopathy, and central nucleoid myopathy.

[0238] Affected individuals typically exhibit delayed motor milestones, muscle weakness, and gait disturbances. In severe cases, they may also present with scoliosis, oculomotor palsy, and respiratory distress, all of which are caused by skeletal muscle weakness. The primary calcium (Ca) encoding skeletal muscle... 2+ Release channel RYR1 The pathogens in these cells have varying effects on the RYR1 channel. These variants typically disrupt the normal calcium channel between the sarcoplasmic reticulum (SR) and the myocyte cytoplasm. 2+ Flow, and often leads to excessive Ca. 2+ It leaks into the cytoplasm. Continuous Ca... 2+ Leakage will reduce the SR Ca required for ECC. 2+In addition, chronic SR Ca 2+ Leakage leads to mitochondrial calcium overload, which impairs mitochondrial function, manifesting as reduced oxidative load and ATP production. SR Ca 2+ Leakage can also activate the calcium-activated protease caloplasmin, potentially leading to cell damage. In turn, oxidative stress can further lead to RyR1 Ca2+ oxidation and nitrosation via channel oxidation. 2+ leakage.

[0239] It has been reported that both autosomal dominant (monolecular, including de novo pathogenic variants) and recessive (biale) inheritance patterns result in RYR1-RM. Classical central nervous system disease is dominantly inherited and typically reflects the relatively milder end of the clinical spectrum, although clinical severity and penetrance range widely. Recessive RYR1-RM can be more severe, particularly in individuals carrying complex heterozygous attenuated alleles with one or more missense variants, and may manifest as severe muscle weakness, respiratory failure requiring ventilatory support, oculomotor palsy, and sometimes feeding difficulties requiring feeding tubes in very young children. RYR1-RM can be severely disabling and worsens with age, accumulating significant disability over time.

[0240] In some embodiments, the compounds of this disclosure can be used to treat RYR1-RM in autosomal dominant individuals. In some embodiments, the compounds of this disclosure can be used to treat RYR1-RM in recessive individuals. In some embodiments, the compounds of this disclosure can be used to treat RYR1-RM in compound heterozygous individuals.

[0241] In some implementations, RYR1-related myopathy is congenital, meaning the subject has... RYR1 At least one genetic mutation in the gene. In some implementations, RyR1-related myopathy is caused by... RyR1 Caused by de novo mutation of the gene.

[0242] Muscular dystrophy In some implementations, the musculoskeletal disorder or disease is muscular dystrophy. Non-limiting examples of muscular dystrophy include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Limb-Girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy, myotonic dystrophy (DM), including myotonic dystrophy 1 (DM-1) and myotonic dystrophy 2 (DM2), myotonic dystrophy, congenital muscular dystrophy (CMD), distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, and oculopharyngeal muscular dystrophy.

[0243] In some embodiments, the compounds disclosed herein can be used to treat subjects (e.g., patients) suffering from Duchenne muscular dystrophy (DMD). DMD is one of the leading fatal genetic diseases in children. Mutations in the dystrophin gene (more than 4,700 have been identified) result in the absence of dystrophin or dysfunctional expression of dystrophin, leading to muscle weakness and wasting, depletion of muscle regeneration capacity, chronic local inflammation, and replacement of muscle fibers with connective and adipose tissue. Patients with DMD suffer from a progressive decline in muscle function, leading to loss of the ability to walk by approximately 10–12 years of age. Cardiac dysfunction usually occurs after loss of the ability to walk. Death is usually due to respiratory failure and / or heart failure, occurring by age 30.

[0244] Mutations in dystrophin associated with DMD disrupt the connection between the subarctic cytoskeleton and the extracellular matrix. This connection is crucial for protecting and stabilizing muscle from contractile damage. The sarcoplasmic instability caused by dystrophin mutations has a cascade effect. One major impact is on cytoplasmic calcium... 2+ The increase in concentration leads to Ca 2+- Activation of calpains (dependent proteases). Another effect is inflammation and increased iNOS activity, which can lead to the oxidation / nitrosation of proteins, lipids, and DNA.

[0245] Intracellular Ca 2+ It is a mediator of several regulatory processes in skeletal muscle. From a DMD mouse model ( mdx The RyR1 channel isolated in mice is highly nitrite-prone, a potential consequence of altered downstream nitric oxide signaling due to dystrophin loss, leading to increased Ca2+ in SR. 2+ Increased ion leakage. Excessive oxidation or nitrosation of RyR1 can disrupt the interaction between Calstabin1 and the RyR1 complex, leading to RyR1 leakage and muscle weakness. In some embodiments, the compounds of this disclosure prevent Calstabin1 depletion of RyR1 and inhibit SR Ca 2+ Leakage reduces biochemical and histological evidence of muscle damage, improves muscle function, and enhances athletic performance.

[0246] In some embodiments, the compounds of this disclosure can repair Ca in RyR1 and RyR2. 2+ Leakage. Therefore, these compounds can be effectively used to treat skeletal muscle and cardiopulmonary dysfunction in DMD. Cardiomyopathy is the most common cause of death in affected populations. Compounds targeting skeletal and cardiac dysfunction can be uniquely positioned to provide improvement in myocardial and skeletal muscle dysfunction in DMD.

[0247] This article provides a method for treating DMD, which involves administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0248] This article provides a method for treating skeletal muscle weakness in patients with DMD, which involves administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject in need.

[0249] This article provides a method for treating cardiomyopathy in patients with DMD, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0250] In some embodiments, the compounds of this disclosure can treat or improve muscle weakness in patients with DMD. In some embodiments, the compounds of this disclosure can treat or improve muscle weakness in DMD patients who are able to walk. In some embodiments, the compounds of this disclosure can treat or improve muscle weakness in DMD patients who are unable to walk. In some embodiments, the compounds of this disclosure can treat or improve cardiac dysfunction in DMD patients who are unable to walk. In some embodiments, the compounds of this disclosure can treat or improve respiratory dysfunction in DMD patients who are unable to walk. In some embodiments, the compounds of this disclosure can treat or improve skeletal muscle, respiratory, and / or cardiac dysfunction in DMD patients (such as DMD patients who are unable to walk). A DMD patient who is able to walk can be a patient capable of walking. A DMD patient who is unable to walk can be a patient who has lost the ability to walk.

[0251] In some embodiments, the musculoskeletal condition or disease is cancer cachexia, i.e., cancer-related muscle weakness. In some embodiments, cancer-related muscle weakness is, for example, cancer cachexia caused by cancer with bone metastases. Muscle weakness and muscle atrophy (cachexia) are common paraneoplastic diseases in cancer patients. These conditions lead to significant fatigue and greatly reduce the patient's quality of life. In some cancers, such as prostate cancer and breast cancer with bone metastases, RyR1 is oxidized and induced to become leaky. Muscle function is improved by applying Rycal compounds to repair the leak. Non-limiting examples of cachexia-related cancers that can be treated with the compounds described herein include breast cancer, prostate cancer, bone cancer, pancreatic cancer, lung cancer, colon cancer, and gastrointestinal cancer. These conditions lead to significant fatigue and greatly reduce the patient's quality of life. This disclosure provides a method for treating, preventing, and reducing the likelihood of cancer patients developing muscle weakness, for example based on the presence of a modified state (e.g., the oxidized state of RyR1) that induces RyR1 to become leaky. Muscle function can be improved by applying Rycal compounds to prevent or reduce the likelihood of leakage.

[0252] In some implementations, musculoskeletal conditions or diseases are age-related losses of muscle mass and strength (sarcopenia). Sarcopenia leads to increased disability and mortality. Compared to RyR1 from younger (3–6 months) adult mice, RyR1 from older mice can be oxidized, cysteine-nitrosated, and depleted of Calstabin1. Treatment of older mice with Rycals stabilizes the binding of Calstabin1 to RyR1, reduces intracellular calcium leakage, reduces reactive oxygen species (ROS), and enhances tetanic calcium absorption. 2+ Release, muscle-specific strength and athletic ability.

[0253] In some embodiments, the compositions of this disclosure can be used to treat pancreatic conditions such as diabetes. In some embodiments, the compositions of this disclosure can be used to treat type II diabetes by reducing the likelihood of intracellular calcium leakage via leaked RyR2. This leakage leads to mitochondrial calcium overload and reduces ATP production, thereby reducing K+. ATP Channel activation. Reduced channel activation blocks plasma membrane depolarization. This blockage reduces the activation of voltage-gated calcium channels, which are the primary source of calcium required for insulin secretion.

[0254] Lanodine receptors and central nervous system disorders In some embodiments, the pharmaceutical composition described herein is administered to a subject in need. In some embodiments, the subject in need suffers from a condition or disease. In some embodiments, the pharmaceutical composition described herein is administered to treat a subject suffering from a condition or disease, wherein the pharmaceutical composition herein relieves one or more symptoms of the condition or disease.

[0255] In some embodiments, the condition associated with RyR is a central nervous system (CNS) condition or disease involving lanodin receptor 1 (RyR1). In some embodiments, the condition associated with RyR is a central nervous system (CNS) condition or disease involving lanodin receptor 2 (RyR2). In some embodiments, the condition associated with RyR is a central nervous system (CNS) condition or disease involving lanodin receptor 3 (RyR3). In some embodiments, the condition is a peripheral central nervous system condition, symptom, or disease. In some embodiments, the condition is a neurological condition, symptom, or disease. In some embodiments, the condition is a neurodegenerative disease. In some embodiments, the condition is cognitive impairment. In some embodiments, the compounds of this disclosure can be used to improve cognitive function. In some embodiments, the disclosed compounds can be used to treat cognitive impairment. In some embodiments, the compounds of this disclosure can be used to slow the progression of cognitive impairment. In some embodiments, the compounds of this disclosure can be used to reduce the likelihood of cognitive impairment.

[0256] In some embodiments, this disclosure relates to a method of treating or reducing the likelihood of developing neurological conditions, symptoms, and diseases by administering to a subject in need an amount of a compound described herein, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound.

[0257] In some embodiments, this disclosure relates to the use of compounds described herein, such as compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for the treatment or reduction of the likelihood of the occurrence of neurological conditions, symptoms, and diseases.

[0258] In another embodiment, this disclosure relates to compounds described herein, such as compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for the treatment of or reduction of the likelihood of the occurrence of neurological conditions, symptoms, and diseases.

[0259] In some embodiments, conditions, disorders, and diseases that can be treated or prevented by the compounds disclosed herein include Alzheimer's disease, post-traumatic stress disorder (PTSD), Huntington's disease, neuropathy, seizure disorders, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), spinocerebellar ataxia, and Parkinson's disease.

[0260] In some embodiments, the disclosed compounds can be used to treat movement disorders. Non-limiting examples of movement disorders include ataxia, dystonia, chorea, Huntington's disease, functional movement disorders, multiple system atrophy, Parkinson's disease, movement disorders caused by Alzheimer's disease, progressive supranuclear palsy, restless legs syndrome, tardive dyskinesia, Tourette syndrome, tremor, and Wilson's disease.

[0261] In some implementations, the movement disorder is tremor or is characterized by tremor. Non-limiting examples of tremor include essential tremor, Parkinson's tremor, dystonia tremor, cerebellar tremor, psychogenic tremor, orthostatic tremor, and physiological tremor.

[0262] In some implementations, the movement disorder is essential tremor. Essential tremor is a tremor that primarily occurs in both upper limbs and is less common in other areas such as the head, neck, vocal cords, or lower limbs. Essential tremor is one of the most common movement disorders and tends to worsen with age. Essential tremor is more noticeable when attempting to use the upper limbs than at rest. Therefore, difficulties with writing or drawing are often identified.

[0263] Other examples of neurodegenerative diseases include: Parkinson's disease, multiple sclerosis, autoimmune diseases, Pick disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multiple system degeneration (Shy-Drager syndrome), motor neuron disease, amyotrophic lateral sclerosis (ALS), degenerative ataxia, corticobasal ganglia degeneration, Guam-type ALS-Parkinson-dementia complex, subacute sclerosing panencephalitis, synucleinopathies, primary progressive aphasia, striatal substantia nigra degeneration, Machado-Joseph disease / spinocerebellar ataxia type 3 and olivopontocerebellar degeneration, Gilles de La Tourette disease, medullary and pseudobulbar palsy, spinal cord and spinobulbar muscular atrophy (Kennedy disease). Diseases including primary lateral sclerosis, hereditary spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach disease, Sandhoff disease, familial spastic diseases, Wohlfart-Kugelberg-Welander disease, spastic paraplegia, progressive multifocal leukoencephalopathy, prions (including Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, Kuru disease, and fatal familial insomnia).

[0264] Neurodegenerative diseases also include ischemic and hemorrhagic stroke, spinal cord injury, brain injury, schizophrenia, autism, ataxia, amyotrophic lateral sclerosis (ALS), Lou Gehrig's disease, Lyme disease, meningitis, migraine, motor neuron disease, pain, brain injury, brain dysfunction, spinal cord disorders, peripheral nervous system disorders, cranial nerve disorders, autonomic nervous system disorders, sleep disorders, headache, lower back and neck pain, neuropathic pain, dementia, delirium and dementia dizziness and vertigo, stupor and coma, head injury, stroke, nervous system tumors, brain or spinal cord infections, prions, depression, and drug addiction.

[0265] Dementia is a decline in cognitive function beyond the expected range of normal aging caused by damage or disease of the brain or central nervous system. Dementia typically affects cognitive functions such as learning, memory, attention, language skills, and problem-solving abilities. Types and causes of dementia include Alzheimer's disease, vascular dementia (also known as multi-infarct dementia), Binswanger's disease, Lewy body dementia (DLB), alcohol-induced persistent dementia, frontotemporal degeneration (FTLD), Pick's disease, frontotemporal dementia (or frontal lobe degeneration FTLD), semantic dementia (or temporal lobe degeneration FTLD), progressive nonfluent aphasia, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, and AIDS-related dementia complex.

[0266] Amyotrophic lateral sclerosis (ALS), or ALS, is a progressive neurodegenerative disease that affects upper motor neurons (motor neurons in the brain) and / or lower motor neurons (motor neurons in the spinal cord), leading to the death of motor neurons. Non-limiting examples of ALS include classic ALS (which typically affects both lower and upper motor neurons), primary lateral sclerosis (PLS, which typically affects only upper motor neurons), progressive bulbar palsy (PBP or medullary seizures, a form of ALS that typically begins with difficulty swallowing, chewing, and speaking), progressive muscular atrophy (PMA, which typically involves only lower motor neurons), and familial ALS (the inherited form of ALS).

[0267] Multiple sclerosis, or MS, is a progressive neurodegenerative disease that causes the destruction of myelin, the lipid that covers nerve cells, particularly in the brain and spinal cord. Non-limiting examples of multiple sclerosis include relapsing-remitting MS (RRMS) (typically characterized by partial or complete recovery following an episode (also known as a relapse, exacerbation, or seizure), secondary progressive MS (SPMS) (typically characterized by fewer relapses, but with increasing disability and symptoms), and primary progressive MS (PPMS) (typically characterized by symptom progression and no relief of disability).

[0268] Alzheimer's disease, or AD, is a progressive neurodegenerative disease characterized by dementia and is defined by the American Psychiatric Association (in DSM IV) as the development of multiple cognitive deficits, including memory impairment.

[0269] Parkinson's disease is a neurodegenerative disorder. Many signs and symptoms associated with Parkinson's disease may precede typical Parkinson's symptoms, in some cases many years earlier. Involvement of the dopaminergic substantia nigra, which forms the basis of the disease's primary motor features, occurs when the disease is progressing well at the neuropathological level. The motor features of Parkinson's disease are characterized by muscle rigidity, tremors, gait and postural abnormalities, bradykinesia (slowing of body movement), and, in extreme cases, loss of movement (amaurosis). The primary symptoms result from reduced stimulation of the basal ganglia to the motor cortex and other areas of the brain, usually caused by insufficient dopamine production and action by dopaminergic neurons in the brain. The motor features of Parkinson's disease are only one component of a broader spectrum of symptoms that can lead to a large number of nonmotor signs and symptoms, including olfactory dysfunction, REM sleep behavior disorder (RBD), constipation, depression, and cognitive deficits. Many of these signs and symptoms may precede motor symptoms by years to a decade or more.

[0270] Parkinsonian-like disorders: Several other disorders that share characteristics with Parkinson's disease can be interchangeably referred to as Parkinsonian-like disorders, secondary Parkinsonism, Parkinsonian syndromes, or atypical Parkinsonism. These neurological syndromes can be characterized by tremor, bradykinesia, rigidity, and postural instability. Several causes can lead to similar symptoms, including some toxins, metabolic disorders, and non-Parkinsonian neurological conditions. A common cause is medication side effects, primarily from neuroleptic antipsychotics, especially phenothiazines (such as perphenazine and chlorpromazine), thioxanthates (such as flupentixol and zuclothiasol), butyrophenones (such as haloperidol (Haldol)), piperazines (such as ziprasidone), and less commonly, antidepressants. Other causes include, but are not limited to, olivopontocerebellar degeneration; progressive supranuclear palsy; corticobasal degeneration; temporal-frontal dementia; drug-induced lesions caused by antipsychotics, prochlorperazine, or metoclopramide; carbon monoxide poisoning; head trauma; and Huntington's disease-related Parkinsonism. In some cases, alpha-synucleinopathy can lead to Parkinsonian disease, secondary Parkinson's disease, Parkinsonian syndrome, or atypical Parkinson's disease. In some implementations, the methods described herein are used to diagnose Parkinsonian disease, secondary Parkinson's disease, and Parkinsonian syndrome.

[0271] Cognitive impairment In some embodiments, the compounds of this disclosure can be used to treat cognitive impairment. In some embodiments, this disclosure relates to a method of treating or reducing the likelihood of developing or improving cognitive impairment by administering to a subject in need an amount of a compound described herein, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound.

[0272] In some embodiments, this disclosure relates to the use of compounds described herein, such as compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for the treatment or reduction of the likelihood of the occurrence of cognitive impairment, or for the improvement of cognitive function.

[0273] In some embodiments, this disclosure relates to compounds described herein, such as compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for the treatment or reduction of the likelihood of cognitive impairment, or for the improvement of cognitive function.

[0274] In some implementations, cognitive impairment is associated with stress-related cognitive impairment or age-related cognitive impairment, or a combination thereof. In some implementations, cognitive impairment is associated with a disease. Non-limiting examples of diseases associated with cognitive impairment are post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, generalized anxiety disorder, obsessive-compulsive disorder, schizophrenia, bipolar disorder, Parkinson's disease, and major depressive disorder.

[0275] In some embodiments, the compounds of this disclosure improve cognitive functions such as short-term memory, long-term memory, attention, learning, and any combination thereof.

[0276] The compounds disclosed herein can be used to treat various conditions in subjects (e.g., patients). In some embodiments, the subject is a newborn. In some embodiments, the subject is 1 year or older. In some embodiments, the subject is 2 years or older. In some embodiments, the subject is 3 years or older. In some embodiments, the subject is 4 years or older. In some embodiments, the subject is 5 years or older. In some embodiments, the subject is about 5 years to about 12 years old. In some embodiments, the subject is no more than 5 years, no more than 6 years, no more than 7 years, no more than 8 years, no more than 9 years, no more than 10 years, no more than 11 years, no more than 12 years, no more than 13 years, no more than 14 years, or no more than 15 years old. In some implementations, the subject's age is at least 5 years old, at least 6 years old, at least 7 years old, at least 8 years old, at least 9 years old, at least 10 years old, at least 11 years old, at least 12 years old, at least 13 years old, at least 14 years old, at least 15 years old, at least 20 years old, at least 25 years old, at least 30 years old, at least 40 years old, at least 50 years old, at least 60 years old, at least 70 years old, at least 80 years old, or at least 90 years old. In some implementations, the subject's age is approximately 4 years to approximately 12 years old, approximately 5 years to approximately 12 years old, approximately 6 years to approximately 12 years old, approximately 7 years to approximately 12 years old, approximately 8 years to approximately 12 years old, approximately 9 years to approximately 12 years old, approximately 10 years to approximately 12 years old, approximately 10 years to approximately 16 years old, approximately 12 years to approximately 16 years old, approximately 14 years to approximately 16 years old, approximately 10 years to approximately 18 years old, approximately 12 years to approximately 18 years old, approximately 14 years to approximately 18 years old, or approximately 16 years to approximately 18 years old. In some implementations, the subject's age is approximately 10 to approximately 120 years, approximately 11 to approximately 120 years, approximately 12 to approximately 120 years, approximately 13 to approximately 120 years, approximately 14 to approximately 120 years, approximately 15 to approximately 120 years, approximately 16 to approximately 120 years, approximately 17 to approximately 120 years, or approximately 18 to approximately 120 years.

[0277] Pharmaceutical Composition The compounds of this disclosure are formulated into pharmaceutical compositions for administration to human subjects in a biocompatible form suitable for in vivo administration. According to another aspect, this disclosure provides a pharmaceutical composition comprising a mixture of the disclosed compounds with a pharmaceutically acceptable diluent and / or carrier. The pharmaceutically acceptable carrier is preferably acceptable in the sense of compatibility with the other components of the composition and harmlessness to their receptors.

[0278] The compound may be administered alone, but is preferably administered in combination with one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers as used herein may be selected from a variety of organic or inorganic materials used in pharmaceutical formulations and incorporated as one or more of the following forms: fillers, diluents, binders, disintegrants, buffers, colorants, emulsifiers, flavor enhancers, gelling agents, flow aids, preservatives, solubilizers, stabilizers, suspending agents, sweeteners, tension agents, wetting agents, emulsifiers, dispersants, swelling agents, flame retardants, lubricants, absorbents, and thickeners.

[0279] The compounds disclosed herein can be administered, either in their pure form or as pharmaceutical compositions, to human or animal subjects in a biocompatible form suitable for in vivo administration. Subjects may include, for example, elderly individuals, adults, adolescents, pre-pubescent children, children, toddlers, infants, newborns, and non-human animals. In some embodiments, the subject is a patient.

[0280] The compounds of this disclosure may be administered to human or animal subjects via procedures including, but not limited to, oral, sublingual, buccal, parenteral (intravenous, intramuscular, or subcutaneous), transdermal, percutaneous, intranasal, intravaginal, rectal, ocular, and inhalation (administered via inhalation). The compounds of this disclosure may also be administered to subjects by delivery to the muscles of the subject (including, but not limited to, the subject's heart or skeletal muscle). In one embodiment, the compounds are administered to the subject by targeted delivery to cardiomyocytes via a catheter inserted into the subject's heart. In some embodiments, the compounds may be administered directly into the CNS, for example, by direct intraspinal injection or intraventricular infusion of the compound into cerebrospinal fluid (CSF), or by intraventricular, intrathecal, or interstitial administration. Administration may be to the muscles of the subject, such as the subject's heart or skeletal muscle. In some embodiments, the compounds are administered to the subject by targeted delivery to cardiomyocytes via a catheter inserted into the subject's heart. In some embodiments, the compounds are administered orally.

[0281] According to this disclosure, pharmaceutical compositions for solid oral administration include, in particular, tablets or sugar-coated pills, sublingual tablets, orally disintegrating tablets, sachets, capsules (including gelatin capsules), powders, lozenges, and granules, as well as those for liquid oral, nasal, buccal, or ocular administration, in particular including emulsions, solutions, oils, suspensions, drops, syrups, and aerosols. These compounds may also be administered in suspension or solution form via drinking water or with food. Examples of acceptable pharmaceutical carriers include, but are not limited to, cellulose derivatives, including carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, and microcrystalline cellulose; sugars such as mannitol, sucrose, or lactose; glycerin, gum arabic, magnesium stearate, sodium stearoyl fumarate, saline, sodium alginate, starch, talc, and water, etc.

[0282] According to this disclosure, pharmaceutical compositions for parenteral injection particularly include sterile solutions, which may be aqueous or non-aqueous dispersions, suspensions, or emulsions, as well as sterile powders for reconstituted injectable solutions or dispersions. The compounds of this disclosure can be combined with sterile aqueous solutions isotonic with the blood of the recipient. Such formulations are prepared by dissolving a solid active ingredient in water containing physiologically compatible substances (such as sodium chloride, glycine, etc.) and having a buffered pH compatible with physiological conditions, thereby producing an aqueous solution, which is then sterilized. The formulations are presented in single or multi-dose containers, such as sealed ampoules or vials. The formulations are delivered by any injection method, including but not limited to suprafascial, intracapsular, intracranial, intradermal, intrasheathal, intramuscular, intraorbital, intraperitoneal, intraspinal, intrasternal, intravascular, intravenous, parenchymal, subcutaneous, or sublingual administration, or via catheter into the recipient's heart.

[0283] Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and those for transdermal administration particularly include powders, aerosols, creams, ointments, gels, and patches.

[0284] For transdermal application, the compounds of this disclosure are combined with skin penetration enhancers such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, etc. N -Methylpyrrolidone, etc., which increase the skin's permeability to the compounds disclosed herein and allow the compounds to penetrate through the skin and enter the bloodstream. The compound / reinforcing agent composition may also be further combined with a polymer, such as ethyl cellulose, hydroxypropyl cellulose, ethylene / vinyl acetate, polyvinylpyrrolidone, etc., to provide a composition in gel form, which is dissolved in a solvent, evaporated to the desired viscosity, and then applied to a backing material to provide a patch.

[0285] Non-limiting examples of pharmaceutically acceptable excipients or carriers include organic or inorganic materials used as materials in pharmaceutical formulations and incorporated as one or more of the following forms: fillers, diluents, binders, disintegrants, buffers (pH adjusters), colorants, emulsifiers, flavor enhancers, gelling agents, flow aids, surfactants (wetting agents), preservatives, solubilizers, stabilizers, suspending agents, sweeteners, tensioning agents, emulsifiers, dispersants, swelling agents, flame retardants, lubricants, absorbents, plasticizers, and thickeners.

[0286] Pharmaceutically acceptable excipients may be present in the pharmaceutical composition at a mass of about 0.1% to about 99% of the composition mass. For example, pharmaceutically acceptable excipients may be present in the pharmaceutical composition in amounts ranging from about 0.1% to about 95%, from about 0.11% to about 90%, from about 0.1% to about 85%, from about 0.1% to about 80%, from about 0.1% to about 75%, from about 0.1% to about 70%, from about 0.1% to about 65%, from about 0.1% to about 60%, from about 0.1% to about 55%, from about 0.1% to about 50%, from about 0.1% to about 45%, from about 0.11% to about 40%, from about 0.1% to about 35%, from about 0.1% to about 30%, from about 0.1% to about 25%, from about 0.1% to about 20%, from about 0.1% to about 15%, from about 0.1% to about 10%, from about 0.1% to about 5%, and from about 0.1% to about 1% by mass.

[0287] Pharmaceutically acceptable excipients may be present in quantities of approximately 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, and 1% of the formulation mass. 9%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 31%, approximately 32%, approximately 33%, approximately 34%, approximately 35%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50% %, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81% Approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 99.1%, approximately 99.2%, approximately 99.3%, approximately 99.4%, approximately 99.5%, approximately 99.6%, approximately 99.7%, approximately 99.8%, or approximately 99.9% exist.

[0288] The compounds disclosed herein can be formulated into pharmaceutical compositions intended for immediate release. The compounds disclosed herein can also be formulated into pharmaceutical compositions intended for prolonged release.

[0289] In some embodiments, the compound is formulated to provide a prolonged release of the compound. In some embodiments, the compound is formulated to provide a controlled release of the compound. In some embodiments, the compound is formulated to provide a sustained release of the compound.

[0290] In some embodiments, the compound is formulated to provide immediate release of the compound. The release of the active ingredient can be based on an immediate release profile, for example, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the active ingredient is released within 1 hour after application.

[0291] In some embodiments, the compound is formulated to provide an extended release of the compound. The term "extended release" can refer to a slower release of the active ingredient compared to an immediately released formulation. The sustained-release characteristics of the composition are typically measured by in vitro dissolution assays and confirmed by in vivo blood concentration-time profiles (i.e., pharmacokinetic profiles). For example, a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof in a unit dosage form, wherein the unit dosage form is an extended-release dosage form, can release the compound or a pharmaceutically acceptable salt thereof in a controlled manner such that, in a study (e.g., a controlled study), if the unit dosage form is administered to a study subject, a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is present in the subject for a period of time, wherein this period occurs after administration and is at least about 12 hours. In some embodiments, the compound is released from the composition in a controlled manner such that, in a study (e.g., a controlled study), if the unit dosage form is administered to a study subject, a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is present in the subject for a period of time, wherein this period occurs after administration and is at least about 24 hours. In some implementations, this period is at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, or at least about 24 hours after application.

[0292] In some embodiments, the compound is formulated to provide a delayed release of the compound. In some embodiments, the delayed-release formulation releases the compound after a lag time, which may be, for example, about 1 hour to about 6 hours, about 1 hour to about 2 hours, about 2 hours to about 4 hours, or about 4 hours to about 6 hours after administration. In some embodiments, the delayed-release formulation releases the compound after a lag time, which may be, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours after administration. After the lag time, the formulation can release the active compound according to an immediate release profile as described herein or according to an extended or controlled release profile as described herein.

[0293] In some embodiments, the delayed-release formulation is a gastric resistance formulation. In some embodiments, the delayed-release formulation is a gastric resistance formulation in unit dosage form. In some embodiments, the delayed-release formulation is a gastric resistance formulation in unit solid dosage form. In some embodiments, the gastric resistance formulation is a gastric resistance tablet.

[0294] Gastric resistance tablets are delayed-release tablets that resist acidic gastric juices and release their active substance in intestinal fluids. Gastric resistance tablets can be prepared from particles or microparticles already coated with a gastric resistance coating, or by coating tablets with a gastric resistance coating (e.g., enteric-coated tablets). The pH range of fluids in different segments of the gastrointestinal tract provides an environmental stimulus for reactive drug release.

[0295] In some embodiments, the enteric-coated gastric-resistant tablet consists of two layers: (1) a drug-containing core (for immediate release); and (2) an enteric coating layer containing an enteric polymer that substantially covers the core. Due to the acid resistance of the enteric coating layer, the tablet substantially does not release the drug in the stomach. The enteric coating layer dissolves rapidly after gastric emptying, and the drug is rapidly released from the tablet core.

[0296] In some embodiments, the enteric-coated gastric-resistant tablet consists of three layers: (1) a drug-containing core (immediate release function); (2) a sub-coating layer substantially covering the core, which may include a swellable hydrophobic polymer layer (e.g., hydroxypropyl cellulose or hydroxypropyl methylcellulose (hydroxypropyl methylcellulose)) (time-release function); and (3) an enteric coating layer containing an enteric polymer that substantially covers the sub-coating layer (acid-resistant function). Due to the acid resistance of the outer enteric coating layer, the tablet essentially does not release the drug in the stomach. The enteric coating layer dissolves rapidly after gastric emptying, and intestinal fluid begins to erode the sub-coating polymer layer. After gastric emptying, the drug is rapidly released once the erosion front reaches the tablet core. The time required for the tablet core to become accessible through the dissolution of the erosion layer is a lag phase, the duration of which can be controlled by the quality or composition of the polymer in the sub-coating layer.

[0297] In some embodiments, gastric resistant formulations are delayed-release formulations resulting from, for example, the sensitivity of enteric coatings to pH, and modified-release formulations resulting from, for example, the presence of polymers in the sub-coating layer. In some embodiments, the formulation is characterized by a delayed-release profile such that all or substantially all of the formulation passes through the stomach and is released in the small intestine. Furthermore, due to the presence of polymers in the sub-coating layer, the slow erosion (hysteresis phase) of the formulation can result in a prolonged release of the active ingredient relative to an immediately released formulation. In some embodiments, the release profile of the gastric resistant formulation is a combination of a delayed-release profile (e.g., due to the presence of enteric coatings) and a prolonged-release profile (e.g., due to the presence of polymers, such as those in the sub-coating layer).

[0298] In some embodiments, the gastric resistance formulation exhibits disintegration resistance in gastric juice. For example, in some embodiments, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the active ingredient is released from the formulation in gastric juice or at a pH simulating gastric juice. The pH of gastric juice varies with the presence or absence of food and is generally in the range of about 1.5 to about 3.5. In some embodiments, the gastric resistance formulation is substantially non-disintegrating for at least about 15 minutes after exposure to gastric juice. For example, the gastric resistance formulation is substantially non-disintegrating for at least about 30 minutes, or at least about 45 minutes, or at least about 60 minutes, or at least about 75 minutes, or at least about 90 minutes, or at least about 120 minutes, or at least about 180 minutes or even longer after exposure to gastric juice. In some embodiments, the gastric resistance formulation exhibits disintegration resistance in gastric juice in the absence of food. In some implementations, the gastric resistance agent has disintegration resistance in gastric juice in the presence of food.

[0299] In some embodiments, the gastric resistance formulation (e.g., gastric resistance tablets) substantially does not disintegrate at a pH of 5.5 or lower. For example, the gastric resistance formulation (e.g., gastric resistance tablets) releases less than about 10% of the active ingredient at a pH of 5.5 or lower. For example, the gastric resistance formulation (e.g., gastric resistance tablets) releases less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the active ingredient at a pH of 5.5 or lower.

[0300] In some embodiments, the gastric resistance agent does not substantially disintegrate upon exposure to a pH equal to or below about 5.5, such as a pH equal to or below about 4.5, about 4.0, about 3.5, about 3.0, about 2.5, about 2.0, or lower. In some embodiments, the gastric resistance agent does not substantially disintegrate for at least about 15 minutes after exposure to a pH equal to or below about 5.5. For example, the gastric resistance agent does not substantially disintegrate for at least about 30 minutes, or at least about 45 minutes, or at least about 60 minutes, or at least about 75 minutes, or at least about 90 minutes, or at least about 120 minutes, or at least about 180 minutes, or even longer after exposure to a pH equal to or below about 5.5.

[0301] In some embodiments, the gastric resistance formulation (e.g., gastric resistance tablets) decomposes substantially at a neutral pH (pH=7) or near-neutral pH (e.g., pH 6.8 or higher). In some embodiments, the delayed-release formulation releases at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% at a pH of about 6.8 or higher. Such release can occur rapidly within 30 minutes, or 40 minutes, or 50 minutes, or 60 minutes, or 120 minutes, or 180 minutes after the enteric coating and / or sub-coating are eroded and the drug-containing core is exposed.

[0302] In some embodiments, gastric resistance formulations (e.g., tablets) include an enteric coating. Enteric-coated tablets are solid oral dosage forms designed to pass through the stomach and release the drug in the small intestine. In some embodiments, the enteric coating prevents the release of the active ingredient before the tablet reaches the small intestine.

[0303] Once the formulation reaches the small intestine, the enteric coating dissolves, and the active ingredient is released. The release of the active ingredient can be based on an immediate release profile, for example, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the active ingredient is released within 1 hour of reaching the small intestine.

[0304] In some embodiments, disintegration is determined by measuring the solubility of the gastric resistant agent in a medium with a pH less than 5.5, such as a pH between about 1.0 and about 2.0, or a pH between about 4.0 and 5.0, such as a pH of about 4.5. In some embodiments, disintegration is determined by measuring the solubility of the gastric resistant agent in a medium with a pH between about 6.5 and about 7.0, such as a pH of about 6.8.

[0305] In some embodiments, the medium with a pH below 5.5 is an HCl solution with a pH of approximately 1.2. In some embodiments, the medium with a pH below 5.5 is a 0.1N HCl solution with a pH of approximately 1.2. In some embodiments, the medium with a pH of 6.8 is a phosphate buffer.

[0306] In some embodiments, the enteric coating dissolves rapidly after gastric emptying, and intestinal fluid begins to erode the sub-coating polymer layer. After gastric emptying, the erosion front reaches the tablet core, and the drug is rapidly released. The time required for the tablet core to become accessible through the dissolution of the erosion layer is referred to as the "lag phase." In some embodiments, the duration of the lag phase can be controlled by changing the quality of the polymer in the sub-coating layer. In some embodiments, the duration of the lag phase can be controlled by changing the properties of the polymer in the sub-coating layer. In some embodiments, the duration of the lag phase can be controlled by changing the quality and composition of the polymer in the sub-coating layer. In some embodiments, the polymer is hydroxypropyl cellulose. In some embodiments, the polymer is hydroxypropyl methylcellulose (hydroxypropyl methylcellulose).

[0307] In some embodiments, the gastric resistance pharmaceutical composition of this disclosure is administered to a subject in a feeding state (e.g., during or after a meal, up to about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or about 7 hours). In some embodiments, the gastric resistance pharmaceutical composition of this disclosure is administered to a subject in a fasting state (e.g., at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours, or longer, after a meal). In some embodiments, the meal is a high-fat meal. In some embodiments, the meal is a low-fat meal.

[0308] In some embodiments, the gastric resistance pharmaceutical composition of this disclosure is administered in combination with a gastric acid reducer. For example, a regimen in which the subject receiving the gastric resistance composition also receives a gastric acid reducer. In some embodiments, the gastric acid reducer is administered simultaneously with the gastric resistance pharmaceutical composition. In some embodiments, the gastric acid reducer is administered sequentially before or after the gastric resistance pharmaceutical composition. In some embodiments, the gastric acid reducer is administered at most about 1 hour, or at most about 2 hours, or at most about 3 hours, or at most about 4 hours, or at most about 5 hours, or at most about 6 hours, or at most about 7 hours, or at most about 8 hours, or at most about 9 hours, or at most about 10 hours, or at most about 11 hours, or at most about 12 hours before the gastric resistance preparation. In some implementations, the gastric acid reducer is administered at most about 1 hour, or at most about 2 hours, or at most about 3 hours, or at most about 4 hours, or at most about 5 hours, or at most about 6 hours, or at most about 7 hours, or at most about 8 hours, or at most about 9 hours, or at most about 10 hours, or at most about 11 hours, or at most about 12 hours after the gastric resistance agent.

[0309] Non-limiting examples of pharmaceutically acceptable fillers / diluents include cellulose derivatives, including microcrystalline cellulose, silicified microcrystalline cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, starch, sugars such as mannitol, sucrose, lactose, sorbitol, dextrin (e.g., maltodextrin), amino sugars, alginate, sodium alginate, and water.

[0310] Non-limiting examples of pharmaceutically acceptable adhesives include microcrystalline cellulose, tragacanth gum, gum arabic, gelatin, polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose, and starch.

[0311] Non-limiting examples of pharmaceutically acceptable disintegrants include croscarmellose sodium, carboxymethyl starch sodium, and crospovidone.

[0312] Non-limiting examples of pharmaceutically acceptable lubricants include stearates such as magnesium stearate or zinc stearate, stearic acid, sodium fumarate stearate, talc, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol, and hydrogenated vegetable oils.

[0313] Non-limiting examples of pharmaceutically acceptable gliding agents include colloidal silica, talc, tricalcium phosphate, calcium silicate, cellulose, magnesium silicate, magnesium trisilicate, starch, magnesium stearate, talc, and mineral oil. Non-limiting examples of moisture-blocking agents include stearic acid.

[0314] Non-limiting examples of pharmaceutically acceptable plasticizers include triethyl citrate.

[0315] Non-limiting examples of pharmaceutically acceptable surfactants include sodium dodecyl sulfate or polysorbate, polyvinyl alcohol (PVA), polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers known as "poloxam", polyglycerol fatty acid esters such as glyceryl monolaurate and glyceryl monomyristate, sorbitol fatty acid esters such as sorbitol monostearate, polyoxyethylene sorbitol fatty acid esters such as polyoxyethylene sorbitol monostearate (Tween), polyoxyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil and hardened castor oil such as polyoxyethylene hardened castor oil.

[0316] Non-limiting examples of pharmaceutically acceptable flavoring agents include sweeteners such as sucralose and synthetic flavor oils, as well as flavoring aromatics, natural oils, extracts of plants, leaves, flowers, and fruits, and combinations thereof. Non-limiting examples of flavoring agents include cinnamon oil, wintergreen oil, peppermint oil, clover oil, hay oil, fennel oil, eucalyptus, peppermint, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, and fruit flavorings including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0317] Non-limiting examples of pharmaceutically acceptable pigments or colorants include aluminum oxide (dried aluminum hydroxide), annatto extract, calcium carbonate, canthaxanthin, caramel, beta-carotene, cochineal extract, carmine, sodium copper potassium chlorophyll (chlorophyll-copper complex), dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ferric ammonium ferrocyanide, ferric ferrocyanide, chromium hydroxide green, chromium oxide green, guanine, mica-based pearlescent pigments, pyrophyllite, mica, dental cleaning agents, talc, titanium dioxide, aluminum powder, bronze powder, copper powder, and zinc oxide.

[0318] Non-limiting examples of buffers or pH adjusters include acidic buffers such as short-chain fatty acids, citric acid, acetic acid, hydrochloric acid, sulfuric acid, and fumaric acid; and basic buffers such as tris, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and magnesium hydroxide.

[0319] Non-limiting examples of tension enhancers include ionic and nonionic agents such as alkali metal or alkaline earth metal halides, urea, glycerol, sorbitol, mannitol, propylene glycol, and dextrose.

[0320] Non-limiting examples of wetting agents include glycerin, cetyl alcohol, and glyceryl monostearate.

[0321] Non-limiting examples of preservatives include benzalkonium chloride, benzo[a]chloromethyl chloride, thimerosal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, benzoyl alcohol, chlorhexidine, and polyhexamethylene biguanide.

[0322] Non-limiting examples of antioxidants include sorbic acid, ascorbic acid, ascorbate, glycine, α-tocopherol, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

[0323] In some embodiments, the solid dosage form is encapsulated. In some embodiments, the solid dosage form comprises a core, a sub-coating substantially surrounding the core, and a coating substantially surrounding the sub-coating.

[0324] In some embodiments, the sub-coating includes an expandable polymer, such as an expandable hydrophobic polymer layer (e.g., hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose (HPMC)).

[0325] In some embodiments, the coating comprises an enteric polymer. Non-limiting examples of enteric polymers include hydroxypropyl methylcellulose acetate succinate (HPMC-AS), cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, methacrylic acid / methacrylate copolymers (e.g., poly(methacrylic acid-co-methacrylate), methacrylic acid / acrylate copolymers, shellac (aloe ester).

[0326] In some embodiments, pharmaceutically acceptable carriers or excipients are used to formulate liquids, gels, syrups, elixirs, pastes, or suspensions for oral ingestion by a subject. Non-limiting examples of solvents used in oral soluble formulations may include water, ethanol, isopropanol, saline, physiological saline, DMSO, potassium phosphate buffer, phosphate-buffered saline (PBS), sodium phosphate buffer, 4-2-hydroxyethyl-1-piperazine ethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC). Non-limiting examples of solubilizers used in oral soluble formulations may include sucrose, urea, cremaphore, and potassium phosphate buffer.

[0327] Preparation method The pharmaceutical formulations disclosed herein are prepared using methods well-known in the pharmaceutical field, including but not limited to wet and dry granulation methods, or by direct compression. The choice of carrier is determined based on the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0328] The pharmaceutical compositions described herein can be manufactured using suitable pharmacological techniques. Suitable pharmacological techniques include, for example, one or a combination of the following methods: (1) wet granulation; (2) dry granulation; (3) dry mixing; (4) direct compression; (5) grinding; (6) rolling; or (7) fusion. Other methods include, for example, spray drying, disc coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, and extrusion, including hot melt extrusion.

[0329] In some embodiments, the tablets disclosed herein are prepared by a wet granulation process. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid (e.g., water) to agglomerate the powder into granules. The granules are dried and then sieved and / or ground to the desired particle size. The granules are then tableted, or other excipients, such as glidants and / or lubricants, are added prior to tableting.

[0330] In some embodiments, the active ingredient is dissolved with one or more pharmaceutically acceptable excipients, and the resulting mixture is granulated in the presence of a suitable solvent (e.g., water). Wet granules are obtained, which may be dried and optionally sieved to obtain dry granules. The dry granules may optionally be mixed with one or more additional pharmaceutically acceptable excipients, optionally sieved, and compressed into tablets.

[0331] In some embodiments, the tablets disclosed herein are prepared by a dry granulation process. In some embodiments, the dry granulation process is a slugging process. Slugging is a dry granulation method in which an active ingredient (optionally in combination with one or more excipients) is first compressed to form a slug, which is then ground to form granules suitable for further processing. For example, a blend of the active ingredient and a pharmaceutically acceptable excipient can be compressed into a slug or tablet and then ground into compacted granules. The compacted granules can then be compressed into tablets.

[0332] In some implementations, the granulation of the active ingredient can be achieved through dry granulation.

[0333] In other embodiments, direct compression technology can be used to directly compress the blend composition into a compacted dosage form. Direct compression can produce more uniform, particle-free tablets.

[0334] In some embodiments, the granulation method includes a rolling process, which increases the particle size of the powder by feeding the active ingredient (optionally in combination with one or more wet or dry excipients) into a rolling device, followed by drying (if necessary), grinding, and size adjustment of the compacted mixture to form particles with the desired particle size.

[0335] In some implementations, the capsules described herein may comprise any of the blends and particles described above with reference to tableting.

[0336] In some embodiments, the compounds of this disclosure have poor solubility in water. In some embodiments, techniques such as particle size reduction, preparation of the compound in an amorphous state, or certain formulation techniques can be used to improve the solubility of the compounds of this disclosure.

[0337] In some embodiments, the compounds of this disclosure are incorporated into the pharmaceutical composition as solid dispersions (SDs). In some embodiments, the compounds of this disclosure are incorporated into the pharmaceutical composition as amorphous solid dispersions (ASDs). In one embodiment, this disclosure provides a method for preparing any one of solid dispersions or amorphous solid dispersions by spray drying, hot melt extrusion, lyophilization, co-milling, co-grinding, evaporation, and any combination thereof. Pharmaceutical compositions comprising the compounds of this disclosure may comprise compounds in a substantially amorphous state. “Substantially” amorphous means that at least 90%, at least 95%, or at least 97% of the compound is amorphous. A “solid dispersion” of a compound herein may include a composition in which at least 90%, at least 95%, or at least 97% of the compound is uniformly molecularly dispersed in a solid polymer matrix.

[0338] In some embodiments, the solid dispersions of this disclosure (e.g., spray-dried dispersions) comprise a polymer. Any suitable polymer known in the art may be used in this disclosure. Exemplary suitable polymers include polymers selected from: cellulose-based polymers, polyoxyethylene-based polymers, polyethylene glycol-propylene glycol copolymers, vinyl-based polymers, PEO-polyvinylcaprolactam-based polymers, and polymethacrylate-based polymers.

[0339] In some embodiments, the composition is a lipid-based formulation comprising the compounds of this disclosure in the form of a solution, dispersion, or suspension containing at least one lipid. The composition may be in the form of lipid nanoparticles.

[0340] Cellulose-based polymers include methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate succinate, and their copolymers. Polyoxyethylene-based polymers include polyethylene glycol-propylene glycol, polyethylene glycol, poloxamer, and their copolymers. Vinyl-based polymers include polyvinylpyrrolidone (PVP) and PVP / VA. PEO-polyvinylcaprolactam-based polymers include polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam-based graft copolymers (such as Soluplus®). Polymethacrylate-based polymers are cationic and anionic polymers synthesized from dimethylaminoethyl methacrylate, methacrylic acid, and methacrylates in varying proportions. Several types are commercially available and can be obtained as dry powders, aqueous dispersions, or organic solutions.

[0341] Examples of such polymethacrylate-based polymers include poly(methacrylate, ethyl acrylate) (1:1), dimethylaminoethyl methacrylate-methyl methacrylate copolymer, and Eudragit®.

[0342] In some embodiments, the cellulose-based polymers are hydroxypropyl methylcellulose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate or HMPCAS) and hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose or HPMC), or a combination of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose.

[0343] HPMCAS is available in various grades based on the content (wt%) of acetyl and succinyl groups and particle size in the HPMCAS molecule. For example, HPMCAS is available in grades L, M, and H. HPMCAS-H is a grade containing approximately 10-14 wt% acetyl groups and approximately 4-8 wt% succinyl groups. Each HPMCAS grade is available in two particle sizes, F (fine) and G (granular). HPMC is available in various types (e.g., HPMC E, F, J, and K types). HPMC type E means approximately 28-30% methoxy groups and approximately 7-12% hydroxypropoxy groups. Various E grades are available, ranging from low to high viscosity. For example, E3 means that the viscosity of HPMC measured at 20°C and in 2% water is approximately 2.4–3.6 mPa·s; E15 means that the viscosity of HPMC measured at 20°C and in 2% water is approximately 12–18 mPa·s; and E50 means that the viscosity of HPMC measured at 20°C and in 2% water is approximately 40–60 mPa·s.

[0344] In some embodiments, the cellulose-based polymer is hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, or a combination of hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose.

[0345] In some embodiments, the cellulose-based polymer is hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose acetate succinate L, or hydroxypropyl methylcellulose acetate succinate H.

[0346] In some implementations, the polyethylene oxide-based polymer or polyethylene glycol-propylene glycol copolymer is polyethylene glycol or pluronic.

[0347] In some implementations, the polyethylene oxide-based polymer or polyethylene glycol-propylene glycol copolymer is polyethylene glycol 3350 or poloxamer 407.

[0348] In some implementations, the vinyl-based polymer is a vinyl-based polyvinylpyrrolidone polymer, such as polyvinylpyrrolidone K30 or vinylpyrrolidone VA 64.

[0349] In some embodiments, the polymethacrylate polymer is Eudragit L100-55 or Eudragit® EPO.

[0350] In some embodiments, the polymer is selected from cellulose polymers, such as HPMC and / or HPMC AS.

[0351] In some embodiments, the polymer is one or more water-soluble or partially water-soluble polymers. Water-soluble or partially water-soluble polymers include, but are not limited to: cellulose derivatives (such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC)) or ethyl cellulose; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA); acrylates, such as polymethacrylates (e.g., Eudragit® E); cyclodextrins (such as β-cyclodextrin) and their copolymers and derivatives, including, for example, PVP-VA (polyvinylpyrrolidone-vinyl acetate).

[0352] In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC), such as HPMC E50, HPMC E15, or HPMC E3.

[0353] The polymer can be a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (such as cellulose acetate phthalate (CAP)), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HMPCAS), carboxymethyl cellulose (CMC) or salts thereof (e.g., sodium salts, such as (CMC-Na)), cellulose acetate trimellitate (CAT), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), or polymethacrylates (such as Eudragit® S).

[0354] In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate HG grade (HPMCAS-HG).

[0355] In some embodiments, the polymer is a polyvinylpyrrolidone copolymer, such as a vinylpyrrolidone / vinyl acetate copolymer (PVP / VA).

[0356] In some embodiments, the compounds of this disclosure are incorporated into the pharmaceutical composition as a spray-dried dispersion (SSD). In some embodiments, the compounds of this disclosure are incorporated into the pharmaceutical composition as an amorphous spray-dried dispersion (ASSD).

[0357] The pharmaceutical compositions mentioned above illustrate this disclosure, but do not limit this disclosure in any way.

[0358] According to the methods of this disclosure, any of these compounds can be applied to a subject (or brought into contact with the subject's cells) in an amount that effectively limits or prevents a reduction in the level of RyR-bound Calstabin in the subject (particularly in the subject's cells). This amount can be determined, for example, by analyzing an in vivo titration curve and the methods and assays disclosed herein. Suitable amounts of the disclosed compounds that effectively limit or prevent a reduction in the level of RyR-bound Calstabin in the subject range from about 0.01 mg / kg / day to about 100 mg / kg / day (e.g., 1, 2, 5, 10, 20, 25, 50, or 100 mg / kg / day), and / or amounts sufficient to achieve plasma levels ranging from about 300 ng / ml to about 5000 ng / ml. Alternatively, the amount of the disclosed compounds ranges from about 1 mg / kg / day to about 50 mg / kg / day. Alternatively, the amount of the disclosed compounds ranges from about 10 mg / kg / day to about 20 mg / kg / day. It also includes doses that can be administered from about 0.01 mg / kg / day or 0.05 mg / kg / day to about 5 mg / kg / day or about 10 mg / kg / day.

[0359] Dosage and Dosing Regimen According to the methods of this disclosure, any of these compounds may be applied in an amount to a subject (or brought into contact with the subject's cells) in an amount that effectively limits or prevents a reduction in the level of Calstabin, which binds to RyR, in the subject, particularly in the subject's cells. Alternatively, the methods of this disclosure may involve administering an amount of the compound that is effective in treating or preventing the RyR-related conditions described herein.

[0360] In some implementations, the appropriate amount of the compound that effectively limits or prevents the reduction of Calstabin levels bound to RyR in the subject and / or effectively treats or reduces the likelihood of RyR-related conditions ranges from about 1 to about 2000 mg / day, for example, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day, about 400 mg / day, etc. mg / day, approximately 420 mg / day, approximately 440 mg / day, approximately 460 mg / day, approximately 480 mg / day, approximately 500 mg / day, approximately 600 mg / day, approximately 700 mg / day, approximately 800 mg / day, approximately 900 mg / day, approximately 1000 mg / day, approximately 1100 mg / day, approximately 1200 mg / day, approximately 1300 mg / day, approximately 1400 mg / day, approximately 1500 mg / day, approximately 1600 mg / day, approximately 1700 mg / day, approximately 1800 mg / day, approximately 1900 mg / day, or approximately 2000 mg / day.

[0361] The compounds described herein may be available in quantities ranging from about 1 mg to about 2000 mg; from about 1 mg to about 1000 mg; from about 1 mg to about 500 mg; from about 5 mg to about 1000 mg; from about 5 mg to about 500 mg; from about 5 mg to about 100 mg; from about 10 mg to about 50 mg; from about 50 mg to about 250 mg; from about 100 mg to about 200 mg; from about 1 mg to about 50 mg; from about 50 mg to about 100 mg; from about 100 mg to about 150 mg; from about 150 mg to about 200 mg; from about 200 mg to about 250 mg; from about 250 mg to about 300 mg; from about 300 mg to about 350 mg; from about 350 mg to about 400 mg; from about 400 mg to about 450 mg; from about 450 mg to about 500 mg; from about 500 mg to about 550 mg; from about 550 mg to about 600 mg. The present composition contains mg, ranging from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg.

[0362] The compounds described herein may be available in doses of approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg. The composition is present in amounts of approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, approximately 1500 mg, approximately 1550 mg, approximately 1600 mg, approximately 1650 mg, approximately 1700 mg, approximately 1750 mg, approximately 1800 mg, approximately 1850 mg, approximately 1900 mg, approximately 1950 mg, or approximately 2000 mg.

[0363] In some implementations, the dosage can be expressed as the amount of drug divided by the mass of the subject, for example, the number of milligrams of drug per kilogram of the subject's body weight. In some embodiments, the dosage range of the compound is from about 0.01 mg / kg to about 2000 mg / kg, about 0.01 mg / kg to about 1000 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.01 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.5 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.01 mg / kg to about 0.05 mg / kg, about 1 mg / kg to about 1000 mg / kg, about 1 mg / kg to about 500 mg / kg, about 1 mg / kg to about 250 mg / kg, about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, about 5 mg / kg to about 50 mg / kg, about 5 mg / kg to about 10 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 50 mg / kg, about 10 mg / kg to about 20 mg / kg, about 250 mg / kg to about 2000 mg / kg, about 10 mg / kg to about 800 mg / kg, about 50 mg / kg to about 400 mg / kg, about 100 mg / kg to about 300 mg / kg, or about 150 mg / kg to about 200 mg / kg. In some embodiments, the compound is administered in amounts of about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about 900 mg / kg, about 950 mg / kg, or about 1000 mg / kg of the subject's body weight.

[0364] In some implementations, the dosage can be expressed as the amount of drug per day divided by the mass of the subject, for example, the number of milligrams of drug per kilogram of the subject's body weight per day (mg / kg / day / day). In some embodiments, the dosage range of the compound is from about 0.01 mg / kg / day to about 2000 mg / kg / day, about 0.01 mg / kg / day to about 1000 mg / kg / day, about 0.01 mg / kg / day to about 100 mg / kg / day, about 0.01 mg / kg / day to about 10 mg / kg / day, about 0.01 mg / kg / day to about 5 mg / kg / day, about 0.01 mg / kg / day to about 1 mg / kg / day, about 0.01 mg / kg / day to about 0.5 mg / kg / day, about 0.01 mg / kg / day to about 0.1 mg / kg / day, about 0.01 mg / kg / day to about 0.05 mg / kg / day, about 1 mg / kg / day to about 1000 mg / kg / day, about 1 mg / kg / day to about 500 mg / kg / day, about 1 mg / kg / day to about 250 mg / kg / day. mg / kg / day, about 1 mg / kg / day to about 100 mg / kg / day, about 1 mg / kg / day to about 50 mg / kg / day, about 5 mg / kg / day to about 50 mg / kg / day, about 5 mg / kg / day to about 10 mg / kg / day, about 5 mg / kg / day to about 20 mg / kg / day, about 10 mg / kg / day to about 50 mg / kg / day, about 10 mg / kg / day to about 20 mg / kg / day, about 250 mg / kg / day to about 2000 mg / kg / day, about 10 mg / kg / day to about 800 mg / kg / day, about 50 mg / kg / day to about 400 mg / kg / day, about 100 mg / kg / day to about 300 mg / kg / day, or about 150 mg / kg / day to about 200 mg / kg / day.In some embodiments, the compound is administered at a daily dose of approximately 1 mg / kg / day, approximately 2 mg / kg / day, approximately 5 mg / kg / day, approximately 10 mg / kg / day, approximately 20 mg / kg / day, approximately 50 mg / kg / day, approximately 100 mg / kg / day, approximately 150 mg / kg / day, approximately 200 mg / kg / day, approximately 250 mg / kg / day, approximately 300 mg / kg / day, approximately 350 mg / kg / day, approximately 400 mg / kg / day, approximately 450 mg / kg / day, approximately 500 mg / kg / day, approximately 550 mg / kg / day, approximately 600 mg / kg / day, approximately 650 mg / kg / day, approximately 700 mg / kg / day, approximately 750 mg / kg / day, approximately 800 mg / kg / day, approximately 850 mg / kg / day, approximately 900 mg / kg / day, approximately 950 mg / kg / day, or approximately 1000 mg / kg / day of the subject's body weight. Administer at a dose of mg / kg / day.

[0365] In some embodiments, the compounds of this disclosure are administered in an amount sufficient to achieve the maximum plasma concentration (e.g., steady state) of the subject, which is about 1 ng / ml to about 5000 ng / ml, such as about 50 ng / ml to about 5000 ng / ml, about 100 ng / ml to about 5000 ng / ml, about 200 ng / ml to about 5000 ng / ml, about 300 ng / ml to about 5000 ng / ml, about 400 ng / ml to about 5000 ng / ml, about 500 ng / ml to about 5000 ng / ml, about 50 ng / ml to about 500 ng / ml, about 100 ng / ml to about 500 ng / ml, about 150 ng / ml to about 500 ng / ml, about 200 ng / ml to about 500 ng / ml, or about 250 ng / ml to about 500 ng / ml.

[0366] Implementation plan with numbering Implementation Scheme 1. A compound of formula (I): , in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; -X is O, S, S(O) or S(O)2; -Y is CH2 or C(O); -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); -R 1 and R2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each being unsubstituted or substituted, or hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds to, it forms a heterocyclic alkyl moiety; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ; or two adjacent R 3 The group and the carbon atom it is bonded to form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; -R 4 It is an unsubstituted or substituted alkyl group, or hydrogen; -R a It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydroxyl, carboxyl, or NHR. c , where R c It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydrogen; -R b It is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group, each of which is unsubstituted or substituted, or hydrogen; and -n is 0, 1, 2, 3, 4 or 5; Or its pharmaceutically acceptable salt.

[0367] Implementation Scheme 2. The compound of Implementation Scheme 1, wherein X is sulfur.

[0368] Implementation Scheme 3. The compound of Implementation Scheme 1 or Implementation Scheme 2, wherein Y is C(O).

[0369] Implementation Scheme 4. The compound of Implementation Scheme 1, wherein the compound has the formula (I a ): .

[0370] Implementation Scheme 5. A compound of any one of Implementation Schemes 1-4, wherein Z is hydrogen.

[0371] Implementation Scheme 6. The compound of Implementation Scheme 1, wherein the compound has the formula (I b ): .

[0372] Implementation Scheme 7. A compound of any one of Implementation Schemes 1-6, where n is 1.

[0373] Implementation Scheme 8. A compound of any one of Implementation Schemes 1-7, wherein R' and R'' are each hydrogen.

[0374] Implementation Scheme 9. A compound of any one of Implementation Schemes 1-8, wherein R 1 and R 2 Each is hydrogen.

[0375] Implementation Scheme 10. A compound of any one of Implementation Schemes 1-8, wherein R 1 It is hydrogen.

[0376] Implementation Scheme 11. A compound of any one of Implementation Schemes 1-8, wherein R 1 It is a methyl group.

[0377] Implementation Scheme 12. A compound of any one of Implementation Schemes 1-11, wherein R 2 It is hydrogen.

[0378] Implementation Scheme 13. A compound of any one of Implementation Schemes 1-8, 10 and 11, wherein R 2 It is an alkyl group.

[0379] Implementation Scheme 14. A compound of any one of Implementation Schemes 1-8, 10 and 11, wherein R 2 It is C(O)R a .

[0380] Implementation Scheme 15. A compound of any one of Implementation Schemes 1-8, 10 and 11, wherein R 2 It is C(O)R a , where R a It is an aryl or heteroaryl group, each of which is substituted or unsubstituted.

[0381] Implementation Scheme 16. A compound of any one of Implementation Schemes 1-8, 10 and 11, wherein R 2 It is C(O)R a , where R a It is pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridazinyl, triazolyl, oxadiazolyl or pyrazinyl, each of which is substituted or unsubstituted.

[0382] Implementation Scheme 17. A compound of any one of Implementation Schemes 1-8, 10 and 11, wherein R 2 It is C(O)R a , where R a It is pyrimidin-2-yl, pyrimidin-5-yl, 5-aminopyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 1 H -pyrazole-3-yl, 2-methyl-1 H -Pyrazol-3-yl, pyridin-2-yl, 2-chloro-pyridin-2-yl, 6-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl, 6-hydroxy-pyridin-2-yl, pyridin-3-yl, 6-amino-pyridin-3-yl, 2-chloro-pyridin-3-yl, pyridin-4-yl, 3-phenyl-1 H -pyrazole-5-yl, 1 H -imidazol-4-yl, 1 H -imidazol-2-yl, 1-methyl-1 H -imidazol-4-yl, 1-methyl-1 H -imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, 4-methyl-1,2,3-thiadiazol-5-yl, 5-phenylisoxazole-3-yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5-methyl-3-phenylisoxazole-4-yl, 4-phenylthiazol-2-yl, 1 H -Tetrazole-5-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, 3-hydroxypyrazinyl, 4-isopropyl-1,2,3-thiadiazolyl, 3-methyl-isoxazolyl-5-yl, 4,4-difluoro-piperidin-1-yl, 1,2,4-triazin-3-yl, 4-methylpyridin-2-ylamino, 3-oxopiperazin-1-yl, 5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl or piperazin-1-yl.

[0383] Implementation Scheme 18. A compound of any one of Implementation Schemes 1-8, wherein R 1 and R 2 Each of the following is independently hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3-hydroxycyclobutyl, 3,3-difluorocyclobutyl, cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, pyrimidin-2-yl, pyrimidin-2-methyl, pyrimidin-3-methyl, pyrimidin-4-methyl, oxalyl, 2-methoxyethyl, benzyl, 4-carboxybenzyl, 4-carboxymethylbenzyl, tetrahydro-2-yl H-pyran-4-yl, oxetane-3-yl, 1,2,4-thiadiazol-5-yl, 4-aminomethyl-1,2,3-triazol-1-ylmethyl, 4-methyl-1,2,3-thiadiazol-5-ylmethyl, benzo[d]thiazol-2-yl, 4-carboxyethyl-1,2,3-thiadiazol-5-ylmethyl, 4-carboxy-1,2,3-thiadiazol-5-ylmethyl, isoindoline-1,3-dione-2-yl and acetyl; or wherein R1 and R2 together with the nitrogen atom to which they are bonded form an optionally substituted heterocyclic or heteroaryl group selected from pyrazolidine ketone, piperazinyl, 2-oxopiperazinyl, triazolyl, benzotriazolyl, morpholinyl, pyrrolidinyl or piperidinyl.

[0384] Implementation Scheme 19. A compound of any one of Implementation Schemes 1-18, wherein R 3 It is an alkoxy, cycloalkyloxy, or aryloxy group, which may be substituted or unsubstituted, or a halogen.

[0385] Implementation Scheme 20. A compound of any one of Implementation Schemes 1-18, wherein R 3 It is either a substituted or unsubstituted phenyloxy group.

[0386] Implementation Scheme 21. A compound of any one of Implementation Schemes 1-18, wherein R 3 It is substituted by one or two substituents selected from hydroxyl, fluorine, chlorine, bromine, iodine, CF3, CHF2, methoxy, SO2Me, cyano and C(O)Me.

[0387] Implementation Scheme 22. A compound of any one of Implementation Schemes 1-18, wherein R 3 Each time it appears independently of alkyl, cyclohexyl, alkoxy, cycloalkyloxy, arylsulfonyl, alkylsulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxacyclopenten-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NHcycloalkyl, -NH-C(O)cycloalkyl, heteroaryl, heterocyclic or naphthyl, each of which is substituted or unsubstituted, or halogen.

[0388] Implementation Scheme 23. A compound of any one of Implementation Schemes 1-22, wherein R 4 It is hydrogen.

[0389] Implementation Scheme 24. A compound of any one of Implementation Schemes 1-23, wherein the compound is a pharmaceutically acceptable salt.

[0390] Implementation Scheme 25. A compound, namely: (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenylphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-bromophenyl)-5-(dimethylaminomethyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-[(4-benzyl-1-piperidinyl)methyl]-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(4-benzyl-1-piperidinyl)methyl]-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-methoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(trifluoromethyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-benzyloxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(trifluoromethyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenylphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-iodophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; 3-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; 3-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; 4-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; 4-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; (2S,5R)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one); (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(1,3-benzodioxacyclopenten-5-yl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1,3-benzodioxacyclopenten-5-yl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromo-5-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-naphthyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(1-naphthyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(benzenesulfonyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-methoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(o-tolyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-ethylpropyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(3-amino-4-chloro-phenyl)phenyl]-5-(aminomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,4-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chloro-3-iodo-phenyl)phenyl]-1,4-thiazacycloheptane-3-one; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzamide; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]cyclohexaneformamide; (2R,5S)-5-(aminomethyl)-2-[3-(4-fluorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-cyclohexylphenyl)-1,4-thiazacycloheptane-3-one; 3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]-N-phenyl-benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidone-1-yl)methyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidone-1-yl)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidone-1-yl)methyl]-1,4-thiazacycloheptane-3-one; N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]phenyl]acetamide; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidinyl)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidinyl)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,3-dimethoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzoic acid; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; 2-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]phenoxy]acetic acid; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxopyrrolidone-1-yl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxo-1-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-hydroxy-1-piperidinyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-(((3R,5R,7R)-adamantane-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazacycloheptan-3-one; (2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantane-2-yl)oxy)phenyl)-5-(aminomethyl)-1,4-thiazacycloheptan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(cyclohexyloxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-isopropyl-2-methyl-propoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxy-2-methyl-propoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxy-3-propyl-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-chloro-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-indol-1-ylphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-methoxyphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,4-dichlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[2-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(methylaminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclohexyloxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-methyl-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-dibenzofuran-2-yl-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methylsulfonylphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; 2-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[4-(4-acetylphenoxy)phenyl]-5-(aminomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(1,3-benzodioxacyclopenten-5-yloxy)phenyl]-1,4-thiazacycloheptane-3-one; 3-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]-5-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(4-phenylaminophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-chloro-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]-3-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(2-methoxy-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)-2-methoxy-phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(triazol-1-ylmethyl)-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[4-(aminomethyl)triazol-1-yl]methyl]-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(pyrimidin-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(1,3-benzothiazo-2-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(1,2,4-thiadiazol-5-ylamino)methyl]-1,4-thiazacycloheptane-3-one; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; 2-O-2-[[(2R,5S)-3-O-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methylamino]acetate; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]thiazolyl-2-carboxamide; 4-(aminomethyl)-N-[[(2R,5S)-2-(3-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]benzamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]-2H-tetrazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]thiazolyl-4-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazolyl-5-yl]methyl]-4-methyl-thiadiazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-5-carboxamide; 6-Amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazolyl-5-yl]methyl]thiazolyl-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]-5-phenyl-isoxazol-3-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]-5-methyl-3-phenyl-isoxazol-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazolyl-5-yl]methyl]-4-phenyl-thiazolyl-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 1-Methyl-N-[[(2S,5R)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]imidazol-4-carboxamide; 4-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyrimidin-5-carboxamide 6-Amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]methanesulfonamide 4-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]-1H-imidazol-4-carboxamide; 2-Morpholino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]acetamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]morpholine-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyridazine-3-carboxamide; 5-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]thiadiazole-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-sulfonamide; 4-Fluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]benzenesulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-sulfonamide; 1-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]imidazol-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]thiazolyl-2-carboxamide; 3,3-Difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]cyclobutane formamide; 4,4-Difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]cyclohexaneformamide; N-[[(2R,5S)-2-[3-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantane-2-yl)oxy)phenyl)-3-oxo-1,4-thiazacycloheptane-5-yl)methyl)pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]-2-pyrimidin-2-ylacetamide; 1-Benzyl-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]urea; 3-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]isoxazole-5-carboxamide; N-[[(2R,5S)-2-[3-(cyclohexyloxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 4,4-Difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]piperidine-1-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]-1,2,4-triazine-3-carboxamide; N-[[(2R,5S)-2-[4-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrazine-2-carboxamide; 6-Chloro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; 2-[5-(4-chlorophenyl)isoxazo-3-yl]-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]acetamide; 6-Amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; 5-Amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; 5-Methoxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; 1-(4-methyl-2-pyridyl)-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]urea N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridazine-3-carboxamide; 6-Amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; 6-Amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-sulfonamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-sulfonamide; 2-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]benzamide; 4-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]benzamide; (2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-5-[(1,2,4-thiadiazol-5-ylamino)methyl]-1,4-thiazacycloheptane-3-one; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 5-Amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; 5-Chloro-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-5-methoxy-pyrimidin-2-carboxamide; 5-Amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-5-methoxy-pyrimidin-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrazine-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; N-[[(2S,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2S,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-1,4-thiazolyl-5-yl]methyl]-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazolyl-5-yl]methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]piperazine-1-carboxamide; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-1,4-thiazacycloheptane-3-one; 4-[[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoate; (2R,5S)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; 4-[[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoic acid; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(cyclopropylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(cyclopropylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(cyclobutylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(tetrahydropyran-4-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(oxetane-3-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[bis(oxetane-3-yl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-((((1r,3S)-3-hydroxycyclobutyl)amino)methyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[(3,3-difluorocyclobutyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[(4-methylthiadiazol-5-yl)methylamino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-4-ylmethylamino)methyl]-1,4-thiazacycloheptane-3-one; 4-[[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoic acid; 4-[[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoic acid; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-bromophenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2,4-dichlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(2,2,2-trifluoroethylamino)methyl]-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-1,1-dioxo-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-1,1-dioxo-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(2-oxopiperazin-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazetane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-oxazetane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-1,4-oxazetane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-oxazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(dimethylaminomethyl)-1,4-oxazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-oxazetane-3-one; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 6-Amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; 6-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridine-2-carboxamide; 2-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]-1-methyl-imidazol-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridazine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]thiazolyl-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]thiazolyl-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyrazine-2-carboxamide; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazetane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazacycloheptane-3-one; (2R,5S)-5-(benzotriazol-1-ylmethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazacycloheptane-3-one; or (2R,5S)-5-[(3-oxopiperazin-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; Or its enantiomers, diastereomers, pharmaceutically acceptable salts, or deuterated derivatives.

[0391] Implementation Scheme 26. A compound, namely: (2R,5S)-5-(aminomethyl)-2-[4-(3,5-dimethylphenoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazetane-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazetane-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]thiazolyl-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide, or a pharmaceutically acceptable salt thereof; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantane-2-yl)oxy)phenyl)-3-oxo-1,4-thiazacycloheptane-5-yl)methyl)pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-[(2-oxopiperazin-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-(((3R,5R,7R)-adamantane-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; or (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazacycloheptane-3-one, Or its pharmaceutically acceptable salt.

[0392] Implementation Scheme 27. A compound, namely (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0393] Implementation Scheme 28. A compound, namely (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0394] Implementation Scheme 29. A compound, namely (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0395] Implementation Scheme 30. A compound, namely (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0396] Implementation Scheme 31. A compound, namely (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

[0397] Implementation Scheme 32. A compound, namely N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0398] Implementation Scheme 33. A pharmaceutical composition comprising, in unit dosage form, a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1-32, and a pharmaceutically acceptable excipient.

[0399] Implementation Scheme 34. A method for treating a condition, the method comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need:

[0400] in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; -X is O, S, S(O) or S(O)2; -Y is CH2 or C(O); -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); -R 1 and R 2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each being unsubstituted or substituted, or hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds to, it forms a heterocyclic alkyl moiety; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ; or two adjacent R 3The group and the carbon atom it is bonded to form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; -R 4 It is an unsubstituted or substituted alkyl group, or hydrogen; -R a It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydroxyl, carboxyl, or NHR. c , where R c It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydrogen; -R b It is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group, each of which is unsubstituted or substituted, or hydrogen; and -n is 0, 1, 2, 3, 4 or 5; Or its pharmaceutically acceptable salt.

[0401] Implementation Plan 35. The method of Implementation Plan 34, wherein the condition is a heart condition.

[0402] Implementation scheme 36. The method of implementation scheme 34 or implementation scheme 35, wherein the condition is characterized by arrhythmia.

[0403] Implementation scheme 37. The method of any one of implementation schemes 34-36, wherein the condition is catecholamine-sensitive polymorphic ventricular tachycardia.

[0404] Implementation scheme 38. The method of any one of implementation schemes 34-36, wherein the condition is type 1 catecholamine-sensitive polymorphic ventricular tachycardia.

[0405] Implementation plan 39. The method of implementation plan 34 or implementation plan 35, wherein the condition is heart failure.

[0406] Implementation plan 40. The method of implementation plan 34 or implementation plan 35, wherein the condition is congestive heart failure.

[0407] Implementation plan 41. The method of implementation plan 34 or implementation plan 35, wherein the condition is chronic heart failure.

[0408] Implementation scheme 42. The method of implementation scheme 34 or implementation scheme 35, wherein the condition is heart failure with reduced ejection fraction.

[0409] Implementation scheme 43. The method of implementation scheme 34 or implementation scheme 35, wherein the condition is heart failure with preserved ejection fraction.

[0410] Implementation Scheme 44. The method of Implementation Scheme 34 or Implementation Scheme 35, wherein the subject is a heart failure patient with an implantable cardioverter defibrillator, wherein the implantable cardioverter defibrillator is implanted in the patient.

[0411] Implementation plan 45. The method of implementation plan 34 or implementation plan 35, wherein the condition is acute heart failure.

[0412] Implementation scheme 45a. The method of implementation scheme 34 or implementation scheme 35, wherein the condition is right heart failure.

[0413] Implementation scheme 45b. The method of implementation scheme 34 or implementation scheme 35, wherein the condition is left heart failure.

[0414] Implementation scheme 46. The method of implementation scheme 34, wherein the condition is skeletal muscle weakness associated with heart failure.

[0415] Implementation scheme 47. The method of implementation scheme 46, wherein the treatment improves skeletal muscle weakness in the subject.

[0416] Implementation scheme 48. The method of implementation scheme 46, wherein the treatment reduces calcium leakage from the RyR1 channel in the subject.

[0417] Implementation scheme 49. The method of implementation scheme 46, wherein the treatment reduces calcium leakage from the RyR2 channel in the subject.

[0418] Implementation scheme 50. The method of implementation scheme 34 or implementation scheme 35, wherein the subject is a heart failure patient who needs to preserve cardiac function after myocardial infarction.

[0419] Implementation plan 51. The method of implementation plan 34 or implementation plan 35, wherein the condition is myocardial infarction.

[0420] Implementation scheme 52. The method of implementation scheme 34 or implementation scheme 35, wherein the condition includes myocardial ischemia / reperfusion injury.

[0421] Implementation scheme 53. The method of implementation scheme 34, wherein the condition is a musculoskeletal condition.

[0422] Implementation scheme 54. The method of implementation scheme 34 or implementation scheme 53, wherein the condition is congenital myopathy.

[0423] Implementation scheme 55. The method of implementation scheme 34 or implementation scheme 53, wherein the condition is RYR1-related myopathy.

[0424] Implementation scheme 56. The method of implementation scheme 34 or implementation scheme 53, wherein the condition is congenital RYR1-related myopathy.

[0425] Implementation Plan 57. The method of Implementation Plan 34 or Implementation Plan 53, wherein the condition is caused by RYR1 RYR1-related myopathy caused by de novo gene mutation.

[0426] Implementation scheme 58. The method of implementation scheme 34 or implementation scheme 53, wherein the condition is muscular dystrophy.

[0427] Implementation scheme 59. The method of implementation scheme 34 or implementation scheme 53, wherein the condition is Duchenne muscular dystrophy.

[0428] Implementation Scheme 60. The method of Implementation Scheme 59, wherein the object is movable.

[0429] Implementation Plan 61. The method of Implementation Plan 59, in which the object cannot move.

[0430] Implementation scheme 62. The method of implementation scheme 59, wherein the treatment improves the skeletal muscle function of the subject.

[0431] Implementation scheme 63. The method of implementation scheme 59, wherein the treatment improves the myocardial function of the subject.

[0432] Implementation plan 64. The method of implementation plan 34 or implementation plan 53, wherein the condition is myotonic dystrophy.

[0433] Implementation plan 65. The method of implementation plan 34, wherein the condition is sarcopenia.

[0434] Implementation Scheme 66. The method of any one of Implementation Schemes 34-65, wherein the administration is oral.

[0435] Implementation Scheme 67. The method of any one of Implementation Schemes 34-66, wherein the treatment reduces calcium leakage from the RyR1 channel of the subject.

[0436] Implementation scheme 68. The method of any one of implementation schemes 34-67, wherein the treatment reduces calcium leakage from the RyR2 channel of the subject.

[0437] Implementation Scheme 69. The method of any one of Implementation Schemes 34-68, wherein the treatment reduces the open probability (P0) of the RyR1 protein in the subject. o ).

[0438] Implementation Scheme 70. The method of any one of Implementation Schemes 34-69, wherein the treatment reduces the open probability (P0) of the RyR2 protein in the subject. o ).

[0439] Implementation Scheme 71. The method of Implementation Scheme 34, wherein the compound reduces calcium leakage from the RyR1 and RyR2 channels of the object.

[0440] Implementation Scheme 72. A method for synthesizing compound (I) The methods include: (a) Esterified (II) compounds:

[0441] Compounds of formula (III): , in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ;Optionally, two adjacent R 3 The group, together with the carbon atom it is bonded to, forms an optionally fused cycloalkyl or heterocycloalkyl ring; -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -n is 0, 1, 2, 3, 4, or 5; and -Alk is an alkyl group; (b) subjecting compound (III) to bromination to produce compound (IV): ; (c) Reacting compound (IV) with compound (V):

[0442] Compounds of formula (VI): , in -X is O, S, S(O) or S(O)2; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); and -P is a protecting group; (d) Deprotecting compound (VI) to generate compound (VII): ; (e) Cycling of compound (VII) to generate compound (VIII): ; (f) Protecting the hydroxyl group to form a compound of formula (IX):

[0443] Where P is a protecting group; (g) Making compound of formula (IX) and compound of formula (X): X'R 4 'Reaction, where X' is a halogen and R 4 ' is an unsubstituted or substituted alkyl group, forming a compound of formula (XI): , Compounds of formula (IX) and (XI) represent compounds of formula (XII):

[0444] Among them, A and R 3 Z, X, R', R'', n, and P are as defined above, and R 4 It is an unsubstituted or substituted alkyl group, or hydrogen; (h) To make compound (XII) and compound (XIII): HNR 1 R 2 The reaction, in which R 1 and R 2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each being unsubstituted or substituted, or hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds to, a heterocyclic alkyl moiety is formed to generate a compound of formula (I / a): ; (i) Optionally, the compound of formula (I / a) is reduced to produce the compound of formula (I / b): , Compounds of formula (I / a) and (I / b) represent compounds of formula (I); and (i) Optionally, purify the resulting compound; and / or, optionably, convert the resulting compound into its addition salt using a pharmaceutically acceptable acid or base; and / or, optionably, isolate the resulting compound into its isomers.

[0445] Implementation Scheme 73. A method for synthesizing compound (I) The method includes the following steps: (a) Compound of formula (VI) of embodiment 72

[0446] Reacts with azide derivatives to produce compounds of formula (XIV): ; (b) Cycling of compound (XIV) to generate compound (XV): ; (c) Make compound of formula (XV) and compound of formula (X) as defined above: X'R 4 The reaction produces a compound of formula (XVI): , Compounds of formula (XV) and formula (XVI) represent compounds of formula (XVII): ; (d) Reduction of compound (XVII) to produce compound (I / c): ; (e) Optionally, the compound of formula (I / c) is further reduced to generate the compound of formula (I / d): , Compounds of formula (I / c) and formula (I / d) represent compounds of formula (I / e): ; (f) Optionally, make the compound of formula (I / e) with the compound of formula (XVIII): X''R 1 'Reaction, where X'' is a halogen and R 1 'Is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is unsubstituted or substituted, or C(O)R a C(O)OR b or S(O)2R b Compounds with formula (I / f): ; (g) Optionally, make the compound of formula (I / f) and the compound of formula (XIX): X''R 2 'Reaction, where X'' is a halogen and R 2 'Is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is unsubstituted or substituted, or C(O)R a C(O)OR b or S(O)2R b Compounds with formula (I / g): ;as well as (h) Optionally, purify the resulting compound; and / or, optionably, convert the resulting compound into its addition salt using a pharmaceutically acceptable acid or base; and / or, optionably, isolate the resulting compound into its isomers.

[0447] Implementation Scheme 74. A method for synthesizing compounds of formula (I):

[0448] include: (a) Esterified (II) compounds:

[0449] Compounds of formula (III): , in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ;Optionally, two adjacent R 3 The group and the carbon atom it is bonded to form a fused cycloalkyl or heterocycloalkyl ring; -R 4 It is hydrogen; -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -n is 0, 1, 2, 3, 4, or 5; and -Alk is an alkyl group; (b) subjecting compound (III) to bromination to produce compound (IV): ; (c) Reacting compound (IV) with compound (V):

[0450] Compounds of formula (VI): , in -X is O, S, S(O) or S(O)2; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); and -P is a protecting group; (d) Deprotecting compound (VI) to generate compound (VII): ; (e) Cycling of compound (VII) to generate compound (VIII): ; (f) Reacting a compound of formula (VIII) with a compound of formula RSO2LG or a compound of formula (RSO2)2O, wherein R is an alkyl or aryl group and LG is a leaving group, to generate a compound of formula (IX): , (g) Make compound (IX) react with compound R 10 The reaction of N3 compounds, in which R 10 It is a metal cation or N + Alk4, where Alk is an alkyl group, to form compound (X): ; (h) To convert compound (X) into compound (I'):

[0451] Where R 1 and R 2 Each is a hydrogen atom; and (i) Optionally, the compound of formula (I') is converted into the compound of formula (I). Example

[0452] Infrared spectra were recorded in ATR mode using a Fourier Bruker TENSOR 27 transform spectrometer.

[0453] NMR spectra of protons were recorded on a Bruker DPX 400-B or a 400 MHz Bruker Avance III N spectrometer. Chemical shifts are expressed in ppm and determined with respect to TMS used as a reference. The abbreviations used are: s: single peak d: double peak br: broad peak dd: Double double peak dt: Double triple peak t: triple peak td: Triple Double Peak quad: quadruple peak quint: five-peak m: multiple peaks The above definitions can be combined. For example, the ddd peak can be recorded as two doublets.

[0454] Mass spectra were recorded on a TSQ 7000 mass spectrometer. GC control was performed on a 0.53 x 15 m HPS-J&W Scientific column equipped with an Agilent 4890 flame ionization detection (FID) chromatograph.

[0455] Analytical UPLC-MS analysis was performed on a Waters Acquity Class H UPLC system equipped with a PDA detector, a Waters 3100 mass detector, and a CORTECS UPLC C18, 1.6µm, 2.1 mm x 50 mm column.

[0456] An Acquity UPLC BEHC18 1.7µm 2.1 x 30 mm column was examined by HPLC on an Agilent HPLC 1200 equipped with a diode array detector (DAD).

[0457] Enantiomer purity was analyzed on UPC2 (Waters).

[0458] Thin-layer chromatography (TLC) was performed on a MERCK 60F-254 silica gel plate.

[0459] Chromatography was performed using MERCK 60 silica gel (0.040–0.063 mm) or Interchim or Grace pre-packaged silica gel columns.

[0460] Reverse phase separation was performed on an Interchim FHP RP C18 15µm 275 x 60 mm column with UV detection.

[0461] Rapid column chromatography was performed on a Teledyne Isco CombiFlash Rf+ instrument equipped with a RediSep Rf Gold Silica (20-40µm) or RediSep Rf-Gold® reversed-phase C18 column.

[0462] The organic phase was filtered on a Millipore GVHP (0.22µm) filter, and the aqueous phase was filtered on a Whatman GF / Acat filter No. 1820-070.

[0463] Example 1: N Preparation of tert-butyl carbamate (1S)-1-(hydroxymethyl)-3-thioalkyl-propyl)carbamate.

[0464]

[0465] Methyl (2S)-4-[[(3S)-4-methoxy-3-methyl-4-oxo-butyl]dithioalkyl]-2-methyl-butyrate (15.0 g, 30.2 mmol) was prepared according to the description by Oliver Busnel et al. in “Synthesis and evaluation of new ω-borono-α-amino acids as rat liver arginase inhibitors”, Bioorganic & MedicinalChemistry 13 (2005) 2373-2379 (the contents of which are incorporated herein by reference). The solution was then cooled to 0 °C in an ice bath. After 1 hour, calcium chloride (6.68 g, 60.2 mmol) and sodium borohydride (6.84 g, 181 mmol) were added to the solution in triplicate. The reaction was carried out at room temperature for 6 h with stirring. After completion, the reaction was quenched to an acidic pH by adding a saturated ammonium chloride aqueous solution followed by 1M HCl aqueous solution, and then extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, and concentrated. The resulting colorless oil was dissolved in dichloromethane (180 mL), and water (0.544 mL) and tributylphosphine (7.54 mL, 30.2 mmol) were added. The resulting mixture was stirred at room temperature for 1 h. After completion, the reaction was concentrated under reduced pressure. N The crude product of tert-butyl carbamate (1S)-1-(hydroxymethyl)-3-thioalkyl-propyl)carbamate can be used directly in the next step, or it can be purified by silica gel rapid chromatography. 1 H NMR (400 MHz, dmso-d6) δ: 6.5 (d, 1 H), 4.6 (t, 1 H), 3.5 (m, 1 H), 3.31 / 3.21 (m, 2 H), 2.45 (m, 2 H), 2.23 (t, 1 H),1.71 / 1.59 (m, 2 H), 1.39 (s, 9 H). MS: [M+H] + 221.0. D (589nM) = -24.29 (c = 0.010 g / mL, MeOH) at 28℃.

[0466] Example 2: NPreparation of tert-butyl carbamate (1R)-1-(hydroxymethyl)-3-thioalkyl-propyl]carbamate.

[0467] Using the same method as in Example 1, methyl (2R)-4-[[(3R)-4-methoxy-3-methyl-4-oxo-butyl]dithioalkyl]-2-methyl-butyrate was prepared from (2R)-4-[[(3R)-4-methoxy-3-methyl-4-oxo-butyl]dithioalkyl]-2-methyl-butyrate. N -[(1R)-1-(hydroxymethyl)-3-thioalkyl-propyl] tert-butyl carbamate. 1 H NMR (400 MHz, dmso-d6) δ: 6.5 (d, 1 H), 4.6 (t, 1 H), 3.5 (m, 1 H), 3.32 / 3.22 (m, 2 H), 2.45 (m, 2 H), 2.24 (t, 1 H), 1.73 / 1.56 (m, 2 H), 1.38(s, 9 H). MS: [M+H] + 221.0. D (589nM) = +24.93 (c = 0.010 g / mL, MeOH) at 28℃.

[0468] Example 3: General method A for preparing phenylthiazide heptaneone.

[0469]

[0470] Example 4: Preparation of (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one, hydrochloride (compound 103).

[0471] (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one, hydrochloride, was prepared according to method A in Example 3.

[0472] Step 1 :

[0473] 3,5-Difluorophenol (31.6 g, 243.2 mmol, 1.2 equivalents), cesium carbonate (138.6 g, 425.6 mmol, 2.1 equivalents), and cuprous iodide (3.85 g, 20.2 mmol, 0.1 equivalents) were added. N , N4-Dimethylglycine hydrochloride (5.6 g, 40.5 mmol, 0.2 equivalents) and methyl 4-bromophenylacetate (A-1, 46.4 g, 202.6 mmol, 1.0 equivalents) were added to a round-bottom flask equipped with a magnetic stir bar. Anhydrous dioxane (250 mL) was then added, and the reaction was run at 130 °C for 18 h. The reaction mixture was cooled to rt, filtered, and concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (0 → 5% methanol / dichloromethane) to give the desired product as a colorless oil. 1 H NMR (400 MHz, chloroform-) d ) δ 7.37 -7.29 (m, 2H), 7.08 - 7.00 (m, 2H), 6.67 - 6.28 (m, 3H), 3.74 (s, 3H), 3.66 (s, 2H). MS: [M+H] + It does not ionize under the conditions of use.

[0474] Methyl 2-(4-(3,5-difluorophenoxy)phenyl)acetate (A-2, 24.0 g, 86.3 mmol, 1.0 equivalent) was dissolved in carbon tetrachloride (750 mL). Add... N - Bromosuccinimide (30.7 g, 172.6 mmol, 2 equivalents) was added, followed by the addition of hydrobromic acid solution (33% in acetic acid, 3.1 mL, 17.3 mmol, 0.2 equivalents). The reaction mixture was then refluxed for 17 h. After cooling to room temperature (rt.), the reaction mixture was concentrated, diluted with hexane (500 mL), filtered, and concentrated under reduced pressure to give an alkyl bromide (A-3) as a deep orange oil. 1 H NMR (400 MHz, chloroform-) d ) δ 7.60 (d, 2H), 7.05 (d, 1H), 6.74 - 6.43 (m, 3H), 5.39 (s, 1H), 3.84 (s, 3H).

[0475] Step 2 :

[0476] Methyl 2-bromo-2-(4-(3,5-difluorophenoxy)phenyl)acetate (A-3, 86.3 mmol, 1.0 equivalent) was dissolved in anhydrous acetonitrile (287 mL), and the solution was cooled to 0°C. A thiol fragment (A-4, 23.6 g, 103.5 mmol, 1.2 equivalent, Example 1) was added, followed by... N,N- Diisopropylethylamine (18.0 mL, 103.5 mmol, 1.2 equivalents) was used, a...

Claims

1. Compound of formula (I): ， in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; -X is O, S, S(O) or S(O)2; -Y is CH2 or C(O); -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); -R 1 and R 2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each being unsubstituted or substituted, or hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds to, it forms a heterocyclic alkyl moiety; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ; or two adjacent R 3 The group and the carbon atom it is bonded to form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; -R 4 It is an unsubstituted or substituted alkyl group, or hydrogen; -R a It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydroxyl, carboxyl, or NHR. c , where R c It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydrogen; -R b It is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group, each of which is unsubstituted or substituted, or hydrogen; and -n is 0, 1, 2, 3, 4 or 5; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein X is sulfur.

3. The compound according to claim 1, wherein Y is C(O).

4. The compound according to claim 1, wherein the compound has the formula (I a ): 。 5. The compound according to claim 4, wherein Z is hydrogen.

6. The compound according to claim 1, wherein the compound has the formula (I b ): 。 7. The compound according to claim 1, wherein n is 1.

8. The compound according to claim 1, wherein R' and R'' are each hydrogen.

9. The compound according to claim 1, wherein R 1 and R 2 Each is hydrogen.

10. The compound according to claim 1, wherein R 1 It is hydrogen.

11. The compound according to claim 1, wherein R 1 It is a methyl group.

12. The compound according to claim 1, wherein R 2 It is hydrogen.

13. The compound according to claim 1, wherein R 2 It is an alkyl group.

14. The compound according to claim 1, wherein R 2 It is C(O)R a .

15. The compound according to claim 1, wherein R 2 It is C(O)R a , where R a It is an aryl or heteroaryl group, each of which is substituted or unsubstituted.

16. The compound according to claim 1, wherein R 2 It is C(O)R a , where R a It is pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridazinyl, triazolyl, oxadiazolyl or pyrazinyl, each of which is substituted or unsubstituted.

17. The compound according to claim 1, wherein R 2 It is C(O)R a , where R a It is pyrimidin-2-yl, pyrimidin-5-yl, 5-amino-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, 1 H -pyrazole-3-yl, 2-methyl-1 H -Pyrazol-3-yl, pyridin-2-yl, 2-chloro-pyridin-2-yl, 6-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl, 6-hydroxy-pyridin-2-yl, pyridin-3-yl, 6-amino-pyridin-3-yl, 2-chloro-pyridin-3-yl, pyridin-4-yl, 3-phenyl-1 H -pyrazole-5-yl, 1 H -imidazol-4-yl, 1 H -imidazol-2-yl, 1-methyl-1 H -imidazol-4-yl, 1-methyl-1 H -imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, 4-methyl-1,2,3-thiadiazol-5-yl, 5-phenylisoxazole-3-yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5-methyl-3-phenylisoxazole-4-yl, 4-phenylthiazol-2-yl, 1 H -Tetrazole-5-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, 3-hydroxypyrazinyl, 4-isopropyl-1,2,3-thiadiazolyl, 3-methyl-isoxazolyl-5-yl, 4,4-difluoro-piperidin-1-yl, 1,2,4-triazin-3-yl, 4-methylpyridin-2-ylamino, 3-oxopiperazin-1-yl, 5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl or piperazin-1-yl.

18. The compound according to claim 1, wherein R 1 and R 2 Each of the following is independently hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3-hydroxycyclobutyl, 3,3-difluorocyclobutyl, cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, pyrimidin-2-yl, pyrimidin-2-methyl, pyrimidin-3-methyl, pyrimidin-4-methyl, oxalyl, 2-methoxyethyl, benzyl, 4-carboxybenzyl, 4-carboxymethylbenzyl, tetrahydro-2-yl H -pyran-4-yl, oxetane-3-yl, 1,2,4-thiadiazol-5-yl, 4-aminomethyl-1,2,3-triazol-1-ylmethyl, 4-methyl-1,2,3-thiadiazol-5-ylmethyl, benzo[d]thiazol-2-yl, 4-carboxyethyl-1,2,3-thiadiazol-5-ylmethyl, 4-carboxy-1,2,3-thiadiazol-5-ylmethyl, isoindoline-1,3-dione-2-yl and acetyl; or wherein R1 and R2 together with the nitrogen atom to which they are bonded form an optionally substituted heterocycle or heteroaryl group, said heterocycle or heteroaryl group being selected from pyrazolidine ketone, piperazinyl, 2-oxopiperazinyl, triazolyl, benzotriazolyl, morpholinyl, pyrrolidinyl or piperidinyl.

19. The compound according to claim 1, wherein R 3 It is an alkoxy, cycloalkyloxy, or aryloxy group, which may be substituted or unsubstituted, or a halogen.

20. The compound according to claim 1, wherein R 3 It is a phenyloxy group, which can be substituted or unsubstituted.

21. The compound according to claim 1, wherein R 3 It is substituted with one or two substituents selected from hydroxyl, fluorine, chlorine, bromine, iodine, CF3, CHF2, methoxy, SO2Me, cyano and C(O)Me.

22. The compound according to claim 1, wherein R 3 Each time it appears independently of alkyl, cyclohexyl, alkoxy, cycloalkyloxy, arylsulfonyl, alkylsulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxacyclopenten-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NHcycloalkyl, -NH-C(O)cycloalkyl, heteroaryl, heterocyclic or naphthyl, each of which is substituted or unsubstituted, or halogen.

23. The compound according to claim 1, wherein R 4 It is hydrogen.

24. The compound of claim 1, wherein the compound is a pharmaceutically acceptable salt.

25. A compound, namely: (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenylphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-bromophenyl)-5-(dimethylaminomethyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-[(4-benzyl-1-piperidinyl)methyl]-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(4-benzyl-1-piperidinyl)methyl]-2-(4-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-methoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(trifluoromethyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-benzyloxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(trifluoromethyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenylphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-iodophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; 3-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; 3-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; 4-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; 4-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzonitrile; (2S,5R)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(1,3-benzodioxacyclopenten-5-yl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1,3-benzodioxacyclopenten-5-yl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromo-5-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-naphthyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(1-naphthyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(benzenesulfonyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-methoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(o-tolyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-ethylpropyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(3-amino-4-chloro-phenyl)phenyl]-5-(aminomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,4-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chloro-3-iodo-phenyl)phenyl]-1,4-thiazacycloheptane-3-one; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzamide; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]cyclohexaneformamide; (2R,5S)-5-(aminomethyl)-2-[3-(4-fluorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-cyclohexylphenyl)-1,4-thiazacycloheptane-3-one; 3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]-N-phenyl-benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidone-1-yl)methyl]-1,4-thiazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidone-1-yl)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidone-1-yl)methyl]-1,4-thiazacycloheptane-3-one; N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]phenyl]acetamide; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidinyl)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidinyl)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,3-dimethoxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzoic acid; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxyphenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one; 2-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenyl]phenoxy]acetic acid; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxopyrrolidone-1-yl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxo-1-pyridyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-hydroxy-1-piperidinyl)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-(((3R,5R,7R)-adamantane-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazacycloheptan-3-one; (2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantane-2-yl)oxy)phenyl)-5-(aminomethyl)-1,4-thiazacycloheptan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(cyclohexyloxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-isopropyl-2-methyl-propoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxy-2-methyl-propoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxy-3-propyl-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(3-chloro-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(4-indol-1-ylphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-methoxyphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,4-dichlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[2-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(methylaminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclohexyloxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-methyl-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-dibenzofuran-2-yl-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methylsulfonylphenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; 2-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[4-(4-acetylphenoxy)phenyl]-5-(aminomethyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(1,3-benzodioxacyclopenten-5-yloxy)phenyl]-1,4-thiazacycloheptane-3-one; 3-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]-5-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(4-phenylaminophenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-(2-chloro-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazacycloheptane-2-yl]phenoxy]-3-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(2-methoxy-4-phenoxy-phenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)-2-methoxy-phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(triazol-1-ylmethyl)-1,4-thiazacycloheptane-3-one; (2R,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[4-(aminomethyl)triazol-1-yl]methyl]-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(pyrimidin-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(1,3-benzothiazo-2-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(1,2,4-thiadiazol-5-ylamino)methyl]-1,4-thiazacycloheptane-3-one; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; 2-O-2-[[(2R,5S)-3-O-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methylamino]acetate; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]thiazolyl-2-carboxamide; 4-(aminomethyl)-N-[[(2R,5S)-2-(3-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]benzamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]-2H-tetrazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]thiazolyl-4-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazolyl-5-yl]methyl]-4-methyl-thiadiazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-5-carboxamide; 6-Amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazolyl-5-yl]methyl]thiazolyl-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]-5-phenyl-isoxazol-3-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]-5-methyl-3-phenyl-isoxazol-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazolyl-5-yl]methyl]-4-phenyl-thiazolyl-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazocycloheptan-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 1-Methyl-N-[[(2S,5R)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]imidazol-4-carboxamide; 4-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyrimidin-5-carboxamide 6-Amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]methanesulfonamide 4-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]-1H-imidazol-4-carboxamide; 2-Morpholino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]acetamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]morpholine-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]pyridazine-3-carboxamide; 5-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazolyl-5-yl]methyl]thiadiazole-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-sulfonamide; 4-Fluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]benzenesulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-sulfonamide; 1-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]imidazol-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]thiazolyl-2-carboxamide; 3,3-Difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]cyclobutane formamide; 4,4-Difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]cyclohexaneformamide; N-[[(2R,5S)-2-[3-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantane-2-yl)oxy)phenyl)-3-oxo-1,4-thiazacycloheptane-5-yl)methyl)pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]-2-pyrimidin-2-ylacetamide; 1-Benzyl-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]urea; 3-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]isoxazole-5-carboxamide; N-[[(2R,5S)-2-[3-(cyclohexyloxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 4,4-Difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]piperidine-1-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]-1,2,4-triazine-3-carboxamide; N-[[(2R,5S)-2-[4-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrazine-2-carboxamide; 6-Chloro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; 2-[5-(4-chlorophenyl)isoxazo-3-yl]-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]acetamide; 6-Amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; 5-Amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; 5-Methoxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; 1-(4-methyl-2-pyridyl)-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]urea N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridazine-3-carboxamide; 6-Amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; 6-Amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-sulfonamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-sulfonamide; 2-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]benzamide; 4-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]benzamide; (2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-5-[(1,2,4-thiadiazol-5-ylamino)methyl]-1,4-thiazacycloheptane-3-one; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 5-Amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; 5-Chloro-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-5-methoxy-pyrimidin-2-carboxamide; 5-Amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-5-methoxy-pyrimidin-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyrazine-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; N-[[(2S,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2S,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; N-[[(2R,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-1,4-thiazolyl-5-yl]methyl]-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazolyl-5-yl]methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazocycloheptan-5-yl]methyl]piperazine-1-carboxamide; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-1,4-thiazacycloheptane-3-one; 4-[[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoate; (2R,5S)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5R)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; 4-[[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoic acid; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(cyclopropylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(cyclopropylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(cyclobutylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(tetrahydropyran-4-ylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(oxetane-3-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[bis(oxetane-3-yl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-((((1r,3S)-3-hydroxycyclobutyl)amino)methyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[(3,3-difluorocyclobutyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[[(4-methylthiadiazol-5-yl)methylamino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-4-ylmethylamino)methyl]-1,4-thiazacycloheptane-3-one; 4-[[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoic acid; 4-[[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methylamino]methyl]benzoic acid; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-bromophenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2,4-dichlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(2,2,2-trifluoroethylamino)methyl]-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-1,1-dioxo-2-(3-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-1,1-dioxo-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one; (2R,5S)-5-[(2-oxopiperazin-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazetane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-oxazetane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-1,4-oxazetane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-oxazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-oxazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(dimethylaminomethyl)-1,4-oxazacycloheptane-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-oxazetane-3-one; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyrimidin-2-carboxamide; 6-Amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridine-2-carboxamide; 6-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridine-2-carboxamide; 2-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]-1-methyl-imidazol-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazetane-5-yl]methyl]pyridazine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]thiazolyl-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]thiazolyl-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]pyrazine-2-carboxamide; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazetane-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazacycloheptane-3-one; (2R,5S)-5-(benzotriazol-1-ylmethyl)-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazacycloheptane-3-one; or (2R,5S)-5-[(3-oxopiperazin-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one; Or its enantiomers, diastereomers, pharmaceutically acceptable salts, or deuterated derivatives.

26. A compound, namely: (2R,5S)-5-(aminomethyl)-2-[4-(3,5-dimethylphenoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazetane-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazetane-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazacycloheptane-5-yl]methyl]thiazolyl-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-1-methyl-imidazol-4-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide, or a pharmaceutically acceptable salt thereof; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantane-2-yl)oxy)phenyl)-3-oxo-1,4-thiazacycloheptane-5-yl)methyl)pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-[(2-oxopiperazin-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-(((3R,5R,7R)-adamantane-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof; or (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazacycloheptane-3-one, Or its pharmaceutically acceptable salt.

27. A compound, namely (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

28. A compound, namely (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

29. A compound, namely (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

30. A compound, namely (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

31. A compound, namely (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-1,4-thiazacycloheptane-3-one, or a pharmaceutically acceptable salt thereof.

32. A compound, namely N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazacycloheptane-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising, in unit dosage form, a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, and a pharmaceutically acceptable excipient.

34. A method of treating a condition, the method comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need: in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; -X is O, S, S(O) or S(O)2; -Y is CH2 or C(O); -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); -R 1 and R 2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each being unsubstituted or substituted, or hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds to, it forms a heterocyclic alkyl moiety; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ; or two adjacent R 3 The group and the carbon atom it is bonded to form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; -R 4 It is an unsubstituted or substituted alkyl group, or hydrogen; -R a It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydroxyl, carboxyl, or NHR. c , where R c It is an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each of which is unsubstituted or substituted, or hydrogen; -R b It is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group, each of which is unsubstituted or substituted, or hydrogen; and -n is 0, 1, 2, 3, 4 or 5; Or its pharmaceutically acceptable salt.

35. The method of claim 34, wherein the condition is a cardiac condition.

36. The method of claim 34, wherein the condition is characterized by arrhythmia.

37. The method of claim 34, wherein the condition is catecholamine-sensitive polymorphic ventricular tachycardia.

38. The method of claim 34, wherein the condition is type 1 catecholamine-sensitive polymorphic ventricular tachycardia.

39. The method of claim 34, wherein the condition is heart failure.

40. The method of claim 34, wherein the condition is congestive heart failure.

41. The method of claim 34, wherein the condition is chronic heart failure.

42. The method of claim 34, wherein the condition is heart failure with reduced ejection fraction.

43. The method of claim 34, wherein the condition is heart failure with preserved ejection fraction.

44. The method of claim 34, wherein the subject is a heart failure patient with an implantable cardioverter-defibrillator, wherein the implantable cardioverter-defibrillator is implanted in the patient.

45. The method of claim 34, wherein the condition is acute heart failure.

46. ​​The method of claim 34, wherein the condition is right heart failure.

47. The method of claim 34, wherein the condition is left ventricular failure.

48. The method of claim 34, wherein the condition is skeletal muscle weakness associated with heart failure.

49. The method of claim 48, wherein the treatment improves skeletal muscle weakness in the subject.

50. The method of claim 48, wherein the treatment improves the skeletal muscle function of the subject.

51. The method of claim 48, wherein the treatment reduces calcium leakage from the RyR1 channel of the object.

52. The method of claim 48, wherein the treatment reduces calcium leakage from the RyR2 channels of the object.

53. The method of claim 34, wherein the subject is a heart failure patient who needs to preserve cardiac function after myocardial infarction.

54. The method of claim 34, wherein the condition is myocardial infarction.

55. The method of claim 34, wherein the condition includes cardiac ischemia / reperfusion injury.

56. The method of claim 34, wherein the condition is a musculoskeletal condition.

57. The method of claim 34, wherein the condition is congenital myopathy.

58. The method of claim 34, wherein the condition is RYR1-related myopathy.

59. The method of claim 34, wherein the condition is congenital RYR1-related myopathy.

60. The method of claim 34, wherein the condition is RYR1-related myopathy caused by a de novo mutation in the RYR1 gene.

61. The method of claim 34, wherein the condition is muscular dystrophy.

62. The method of claim 34, wherein the condition is Duchenne muscular dystrophy.

63. The method of claim 62, wherein the object is movable.

64. The method of claim 62, wherein the object is immobile.

65. The method of claim 62, wherein the treatment improves the skeletal muscle function of the subject.

66. The method of claim 62, wherein the treatment improves myocardial function of the subject.

67. The method of claim 34, wherein the condition is myotonic dystrophy.

68. The method of claim 34, wherein the condition is sarcopenia.

69. The method of claim 34, wherein the administration is oral.

70. The method of claim 34, wherein the treatment reduces calcium leakage from the RyR1 channel of the object.

71. The method of claim 34, wherein the treatment reduces calcium leakage from the RyR2 channels of the object.

72. The method of claim 34, wherein the treatment reduces the open probability (P0) of the RyR1 protein in the subject. o ).

73. The method of claim 34, wherein the treatment reduces the open probability (P0) of the RyR2 protein in the object. o ).

74. The method of claim 34, wherein the compound reduces calcium leakage from the RyR1 and RyR2 channels of the object.

75. A method for synthesizing compound (I) The methods include: (a) Esterified (II) compounds: Compounds of formula (III): ， in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ;Optionally, two adjacent R 3 The group, together with the carbon atom it is bonded to, forms an optionally fused cycloalkyl or heterocycloalkyl ring; -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -n is 0, 1, 2, 3, 4, or 5; and -Alk is an alkyl group; (b) subjecting compound (III) to bromination to produce compound (IV): ； (c) Reacting compound (IV) with compound (V): Compounds of formula (VI): ， in -X is O, S, S(O) or S(O)2; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); and -P is a protecting group; (d) Deprotecting compound (VI) to generate compound (VII): ； (e) Cycling of compound (VII) to generate compound (VIII): ； (f) Protecting the hydroxyl group to form a compound of formula (IX): Where P is a protecting group; (g) Making compound of formula (IX) and compound of formula (X): X'R 4 'Reaction, where X' is a halogen and R 4 ' is an unsubstituted or substituted alkyl group, forming a compound of formula (XI): ， Compounds of formula (IX) and (XI) represent compounds of formula (XII): Among them, A and R 3 Z, X, R', R'', n, and P are as defined above, and R 4 It is an unsubstituted or substituted alkyl group, or hydrogen; (h) To make compound (XII) and compound (XIII): HNR 1 R 2 The reaction, in which R 1 and R 2 Each is independently an alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each being unsubstituted or substituted, or hydrogen, C(O)R a C(O)OR b or S(O)2R b ; or R 1 and R 2 Together with the nitrogen atom it bonds to, it forms a heterocyclic alkyl moiety to generate the (I / a) compound: ； (i) Optionally, the compound of formula (I / a) is reduced to produce the compound of formula (I / b): ， Compounds of formula (I / a) and (I / b) represent compounds of formula (I); as well as (j) Optionally, purify the resulting compound; and / or, optionably, convert the resulting compound into its addition salt using a pharmaceutically acceptable acid or base; and / or, optionably, isolate the resulting compound into its isomers.

76. A method for synthesizing compound (I) The method includes the following steps: (a) Using the compound of formula (VI) as claimed in claim 75 Reacts with azide derivatives to produce compounds of formula (XIV): ； (b) Cycling of compound (XIV) to generate compound (XV): ； (c) Make compound of formula (XV) and compound of formula (X) as defined above: X'R 4 The reaction produces a compound of formula (XVI): ， Compounds of formula (XV) and formula (XVI) represent compounds of formula (XVII): ； (d) Reduction of compound (XVII) to produce compound (I / c): ； (e) Optionally, the compound of formula (I / c) is further reduced to produce the compound of formula (I / d): ， Compounds of formula (I / c) and formula (I / d) represent compounds of formula (I / e): ； (f) Optionally, make the compound of formula (I / e) with the compound of formula (XVIII): X''R 1 'Reaction, where X'' is a halogen and R 1 'Is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is unsubstituted or substituted, or C(O)R a C(O)OR b or S(O)2R b Compounds with formula (I / f): ； (g) Optionally, make the compound of formula (I / f) and the compound of formula (XIX): X''R 2 'Reaction, where X'' is a halogen and R 2 'Is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is unsubstituted or substituted, or C(O)R a C(O)OR b or S(O)2R b Compounds with formula (I / g): ;as well as (h) Optionally, purify the resulting compound; and / or, optionably, convert the resulting compound into its addition salt using a pharmaceutically acceptable acid or base; and / or, optionably, isolate the resulting compound into its isomers.

77. A method for synthesizing compound (I) Method: include: (a) Esterified (II) compounds: Compounds of formula (III): ， in - Ring A is an aryl or a 5- or 6-membered heteroaryl group, each of which may be unsubstituted or substituted; - Each R 3 Independently, it is an alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b C(O)NHR b or S(O)2R b ;Optionally, two adjacent R 3 The group, together with the carbon atom it is bonded to, forms an optionally fused cycloalkyl or heterocycloalkyl ring; -R 4 It is hydrogen; -Z is an alkyl or aryl group, which is either unsubstituted or substituted, or hydrogen; -n is 0, 1, 2, 3, 4, or 5; and -Alk is an alkyl group; (b) subjecting compound (III) to bromination to produce compound (IV): ； (c) Reacting compound (IV) with compound (V): Compounds of formula (VI): ， in -X is O, S, S(O) or S(O)2; -R' and R'' are each hydrogen atoms, or together with carbon atoms bonded to R' and R'', they form C(O); and -P is a protecting group; (d) Deprotecting compound (VI) to generate compound (VII): ； (e) Cycling of compound (VII) to generate compound (VIII): ； (f) Reacting a compound of formula (VIII) with a compound of formula RSO2LG or a compound of formula (RSO2)2O, wherein R is an alkyl or aryl group and LG is a leaving group, to generate a compound of formula (IX): ， (g) Make compound (IX) react with compound R 10 The reaction of N3 compounds, in which R 10 It is a metal cation or N + Alk4, where Alk is an alkyl group, to form compound (X): ;as well as (h) To convert compound (X) into compound (I'): Where R 1 and R 2 Each is a hydrogen atom; and (i) Optionally, the compound of formula (I') is converted into the compound of formula (I).

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