A agonist for treating disorders involving ryanodine receptors

Abstract

This disclosure relates to 1,4-oxazepane and 1,4-thiazepane derivatives and their use to treat disorders and diseases associated with ryanodine receptor (RyR) that modulate calcium channel signaling in cells. This disclosure also discloses pharmaceutical compositions comprising these compounds and their use to treat diseases and conditions associated with RyR dysfunction, particularly cardiac, musculoskeletal, and central nervous system (CNS) disorders.

Description

[Technical Field]

[0001] Cross-reference of related applications

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

[0002]

[0002] The sarcoplasmic reticulum (SR) is particularly specialized in intracellular calcium (Ca 2+ It is a cellular structure that functions as a store. The ryanodine receptor (RyR) is a structure that transmits Ca from the cellular SR to the intracellular cytoplasm. 2+ It is a channel in the SR that opens and closes to regulate the release of Ca from the SR to the cytoplasm. 2+ Release causes cytoplasmic Ca 2+ The concentration increases. The probability that RyR is open is that RyR is open at any given time, and therefore Ca 2+ This refers to the possibility of releasing RyR from SR into the cytoplasm. Three RyR isoforms are known. RyR1 is the main isoform expressed in mammalian skeletal muscle, RyR2 is mainly found in cardiac muscle, while RyR3 expression is low in skeletal muscle.

[0003]

[0003] Mutations in RYR1 or RYR2 are characterized by improper channel opening unrelated to contractile signals. This channel opening is further exacerbated by post-translational modifications of the RyR channel, such as PKA-phosphorylation, oxidation, or nitrosylation. The resulting leaky channels exhibit a pathological increase in the probability of opening under resting conditions. SR Ca 2+ The leak is SR Ca 2+ This reduces the amount of calcium that can be released. 2+ This decreases, resulting in weaker muscle contraction.

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

Summary of the Invention

Means for Solving the Problems

[0005]

[0005] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0006]

Chemical Formula

[0007] [wherein, - The A ring is aryl or a 5- or 6-membered heteroaryl (each of which is unsubstituted or substituted), - X is O, S, S(O), or S(O)2, - Y is CH2 or C(O), - Z is alkyl or aryl (each of which is unsubstituted or substituted), or hydrogen, - R’ and R’’ are each hydrogen, or R’ and R’’ together with the carbon atom to which they are attached form C(O), - R 1 and R 2 are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is 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 to which they are attached form a heterocycloalkyl moiety, - R 3Each is independently 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 groups together with the carbon atom to which they are attached form a fused cycloalkyl or heterocycloalkyl ring (each of which is unsubstituted or substituted), - R 4 is unsubstituted or substituted alkyl, or hydrogen, - R a is alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl (each of which is unsubstituted or substituted), or hydroxy, carboxy, or NHR c [where R c is alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl (each of which is unsubstituted or substituted)], or hydrogen, - R b is alkyl, aryl, cycloalkyl, heterocyloalkyl, or heteroaryl (each of which is unsubstituted or substituted), or hydrogen, - n is 0, 1, 2, 3, 4 or 5].

[0008]

[0006] The present disclosure further provides a pharmaceutical composition comprising the compound of formula (I) in combination with one or more pharmaceutically acceptable excipients or carriers.

[0007] The disclosure further relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound, for use in treating a condition or reducing the likelihood of a condition occurring.

[0009]

[0008] The Disclosure further provides a method for treating a condition, comprising the step of administering a pharmaceutical composition comprising a compound of formula (I) in combination with one or more pharmaceutically acceptable excipients or carriers.

[0010]

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

[0011]

[0010] The present disclosure further provides methods for producing compounds of formula (I) and intermediates thereof. [Modes for carrying out the invention]

[0012] Detailed explanation

[0011] In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0013] [ka]

[0014] [In the formula, - The A ring is an aryl or a 5-membered or 6-membered heteroaryl (each of which is either unsubstituted or substituted), - X is O, S, S(O), or S(O)², - Y is either CH2 or C(O), - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - R 1 and R 2 Each of these can independently be alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydrogen, C(O)R a , C(O)OR b , or S(O)2R b And, or R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form a heterocycloalkyl moiety. - R 3 Each of these independently consists of alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being 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 groups, together with the carbon atoms to which they are bonded, form condensed cycloalkyl or heterocycloalkyl rings (each of which is either unsubstituted or substituted). - R 4 is an unsubstituted or substituted alkyl group, or hydrogen. - R a This includes alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydroxy, carboxy, or NHR. c [Here, R c[is alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of these being unsubstituted or substituted)], or hydrogen, - R b is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl (each of which is unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5.

[0015]

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

[0016]

[0013] In some embodiments, R 1 and R 2 Each of these is independently a (C1-C6) alkyl group. In some embodiments, R 1 and R 2 Each of these is an alkyl group that is independently substituted with an aryl group. In some embodiments, R 1 and R 2 Each of these is independently an aryl(C1-C6)alkyl. In some embodiments, R 1 and R 2 Each of these is an alkyl group independently substituted with a heteroaryl group. In some embodiments, R 1 and R 2 Each of these is independently a heteroaryl (C1-C6) alkyl. In some embodiments, R 1 and R 2 Each of these is an alkyl group independently substituted with a cycloalkyl group. In some embodiments, R 1 and R 2 Each of these is independently a cycloalkyl(C1-C6)alkyl. In some embodiments, R 1 and R 2Each of these is an alkyl group independently substituted with a heterocycloalkyl group. In some embodiments, R 1 and R 2 Each of these is independently a heterocycloalkyl (C1-C6) alkyl group.

[0017]

[0014] In some embodiments, R 3 Each of these is independently a (C1-C6) alkyl group. In some embodiments, R 3 Each of these is independently a (C1-C6)alkoxy. In some embodiments, R 3 Each of these is a substituted alkoxy. In some embodiments, R 3 Each of these is an aryl-substituted alkoxy. In some embodiments, R 3 Each of these is independently an aryl(C1-C6)alkoxy. In some embodiments, R 3 Each of these is independently a phenyl(C1-C6) alkoxy. In some embodiments, R 3 Each of these is independently a (C1-C6) alkylamino. In some embodiments, R 3 Each of these is independently an aryl-substituted alkylamino. In some embodiments, R 3 Each of these is independently an aryl(C1-C6)alkylamino. In some embodiments, R 3 These are aryloxy compounds that are independently and arbitrarily substituted.

[0018]

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

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

[0019]

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

[0018] Some of the parts described in this specification may be substituted or unsubstituted. Non-limiting examples of optional substituents include hydroxyl group, sulfhydryl group, halogen, amino group, nitro group, nitroso group, cyano group, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halo-alkyl group, alkenyl group, halo-alkenyl group, alkynyl group, halo-alkynyl group, alkoxy group, aryl group, aryloxy group, aralkyl group, arylalkoxy group, heterocyclyl group, acyl group, acyloxy group, carbamate group, amide group, ureido group, epoxy group, and ester group. Other non-limiting examples of optional substituents include halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, amide, alkylamide, dialkylamide, nitro, amino, cyano, azide, oxo, alkylamino, dialkylamino, carboxyl, thio, thioalkyl and thioaryl.

[0020]

[0019] Non-limiting examples of alkyl groups include linear, branched, and cyclic alkyl groups. The alkyl group may be, for example, a substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C 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 can be based on. In some embodiments, each alkyl is independently (C1-C6) alkyl.

[0021]

[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.

[0022]

[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 t-butyl. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl.

[0023]

[0022] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cyclocyclic alkyl groups also include condensed, crosslinked, and spirodicyclic groups as well as higher condensed, crosslinked, and spiro systems. Cyclocyclic alkyl groups may be substituted with any number of linear, branched, or cyclic alkyl groups. Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methylcyclopropane-1-yl, cyclopropane-2-en-1-yl, cyclobutyl, 2,3-dihydroxycyclobuta-1-yl, cyclobuta-2-en-1-yl, cyclopentyl, cyclopenta-2-en-1-yl, cyclopenta-2,4-dien-1-yl, cyclohexyl, cyclohexa-2-en-1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopenta-1-yl, 3,5-dichlorocyclohexa-1-yl, 4- Examples include hydroxycyclohexa-1-yl, 3,3,5-trimethylcyclohexa-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazlenyl, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. In some embodiments, each cycloalkyl is independently (C 3- C 10 It is a cycloalkyl compound.

[0024]

[0023] Non-limiting examples of alkenyl and alkenylene groups include linear, branched, and cyclic alkenyl groups. The olefin(s) of the alkenyl group can be, for example, E, Z, cis, trans, terminal, or exomethylene. The alkenyl or alkenylene group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C 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 It can be a group. Non-limiting examples of alkenyl and alkenylene groups include ethenyl, propa-1-en-1-yl, isopropenyl, buta-1-en-4-yl; 2-chloroethenyl, 4-hydroxybuten-1-yl, 7-hydroxy-7-methylocta-4-en-2-yl, and 7-hydroxy-7-methylocta-3,5-dien-2-yl.

[0025]

[0024] Non-limiting examples of alkynyl or alkynylene groups include linear, branched, and cyclic alkynyl groups. The triple bond of the alkynyl or alkynylene group can be internal or terminal. The alkynyl or alkynylene group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C15 , 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 It can be a group. Non-limiting examples of alkynyl or alkynylene groups include ethinyl, propa-2-in-1-yl, propa-1-in-1-yl, and 2-methylhexa-4-in-1-yl; 5-hydroxy-5-methylhexa-3-in-1-yl, 6-hydroxy-6-methylhepta-3-in-2-yl, and 5-hydroxy-5-ethylhepta-3-in-1-yl.

[0026]

[0025] The halo group can be, for example, chloro, bromo, fluoro, or iodine. The haloalkyl group may be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. The haloalkenyl group may be any alkenyl group substituted with any number of halogen atoms. The haloalkynyl group may 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.

[0027]

[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 may be substituted or unsubstituted, for example. The alkoxy group may be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. In some embodiments, each alkoxy is independently (C 1- C 10 It is an alkoxy.

[0028]

[0027] A haloalkoxy group is an alkoxy group substituted with one or more halogen atoms, namely 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 triiodoixobutoxy. The haloalkoxy group may be substituted with, for example, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. For example, the halogen or hydrogen group of the haloalkoxy group may be optionally replaced with amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, each haloalkoxy is independently (C 1- C 10 It is a haloalkoxy.

[0029]

[0028] The aryl group may be heterocyclic or nonheterocyclic. The aryl group may be monocyclic or polycyclic. The aryl group may be substituted with any number of substituents described herein, such as hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl. 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-hydro Xyphenyl, 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,Examples include 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, the aryls are each independently phenyl, naphthyl, or biphenyl. In some embodiments, the aryls are each independently (C4-C, 10 ) It is Ariel.

[0030]

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

[0031]

[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.

[0032]

[0031] The aryloxy group can be, for example, an oxygen atom substituted with any aryl group. The ether or ether group contains the aryloxy group. The aryloxy group may be substituted or unsubstituted. The aryloxy group may 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 may be optionally replaced with amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, each aryloxy is independently -O-(C4-C 10 ) It is Ariel.

[0033]

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

[0034]

[0033] Non-limiting examples of heterocyclics include i) heterocyclic units having a monocycle containing one or more heteroatoms (non-limiting examples include diazilinyl, azilidinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinyl, oxazolidinyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidine-2-onyl, 2,3,4,5-te Examples include trahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline; and ii) heterocyclic units having two or more rings, one of which is a heterocyclic ring (non-limiting examples include hexahydro-1H-pyrrolidinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro-1H-cycloocta[b]pyrrolyl).

[0035]

[0034] Non-limiting examples of heteroaryls include i) heteroaryl rings containing monocyclic rings (non-limiting examples include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl); and ii Examples include heteroaryl rings comprising two or more fused rings, one of which is a heteroaryl ring (non-limiting examples include 7H-prinyl, 9H-prinyl, 6-amino-9H-prinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-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 is independently a monocyclic or bicyclic group consisting of 5 to 10 ring members, having at least one aromatic moiety, and containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. In some embodiments, each heteroaryl is independently a (C3-C9) heteroaryl. In some embodiments, each heteroaryl is a 5-membered or 6-membered heteroaryl.

[0036]

[0035] In some embodiments, the compound exists as a group of tautomers. All such tautomers are contemplated herein as part of the present disclosure.

[0036] In some embodiments, the compounds of this disclosure are substituted with protecting groups. Protecting groups may be selected based on the atom to which the protecting group is bonded. Examples of nitrogen protecting groups are described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0037]

[0037] Examples of nitrogen protecting groups such as amide groups include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolineamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazofenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrosinamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0038]

[0038] Examples of nitrogen protecting groups such as carbamate groups include methyl carbamate, ethyl carbamate, 9-fluorenyl methyl carbamate (Fmoc), 9-(2-sulfo)fluorenyl methyl carbamate, 9-(2,7-dibromo)fluorenyl methyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxantyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate ( Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethylsilylethylcarbamate (Teoc), 2-phenylethylcarbamate (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-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'-and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamide)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (All oc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-Dichlorobenzylcarbamate, 4-Methylsulfinylbenzylcarbamate (Msz), 9-Anthrylmethylcarbamate, Diphenylmethylcarbamate, 2-Methylthioethylcarbamate, 2-Methylsulfonylethylcarbamate, 2-(p-Toluenesulfonyl)ethylcarbamate, [2-(1,3-Dithianyl)]methylcarbamate (Dmoc), 4-Methylthiophenylcarbamate (Mtpc), 2,4-Dimethylthiophenylcarbamate (Bmpc), 2-Phosonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzoisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6 - Nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamide)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamide) Samide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,Examples include, but are not limited to, 5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0039]

[0039] Examples of nitrogen protecting groups such as sulfonamide groups include 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), and 2,4,6-trimethylbenzenesulfonamide. Examples include, but are not limited to, (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0040]

[0040] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilyl Zacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroline (pyroolin) )-3-yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylamine N-Tylthiomethyleneamine, N-Benzylideneamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-Pyridyl)Mesityl]methyleneamine, N-(N',N'-Dimethylaminomethylene)amine, N,N'-Isopropylidenediamine, Np-Nitrobenzylideneamine, N-Salicylideneamine, N-5-Chlorosalicylideneamine, N-(5-Chloro-2-Hydroxyphenyl)phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,Examples include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboric acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramide, dibenzylphosphoramide, diphenylphosphoramide, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0041]

[0041] Examples of 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 methyl, t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)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-methoxypiperidine-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxy Siethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-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-Picolyl, 4-Picolyl, 3-Methyl-2-Picolyl N-oxide, Diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-Dibenzosberyl, Triphenylmethyl, α-Naphthyldiphenylmethyl, p-Methoxyphenyldiphenylmethyl, Di(p-Methoxyphenyl)phenylmethyl, Tri(p-Methoxyphenyl)methyl, 4-(4'-Bromophenacyloxyphenyl)diphenylmethyl, 4,4',4”-Tris(4,5- Dichlorophthalimidophenyl)methyl, 4,4',4”-Tris(levrinoyloxyphenyl)methyl, 4,4',4”-Tris(benzoyloxyphenyl)methyl, 3-(imidazole-1-yl)bis(4',4”-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzoisothiazolyl S,S-dioxide, Trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyltexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, Acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (rebrinate), 4,4-(ethylenedithio)pentanoate (rebrinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-Trimethylbenzoate (mesitoate), 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-(triphenylphosphonio)ethyl carbonate (Peoc), alkylisobutyl carbonate, alkylvinyl carbonate, Alkylallyl 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-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitrate 4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyl Examples include, but are not limited to, phosphates, monosuccinoates, (E)-2-methyl-2-butenoates, o-(methoxyacyl)benzoates, α-naphthoates, nitrates, alkyl N,N,N',N'-tetramethylphosphodiamides, alkyl N-phenylcarbamates, borates, dimethylphosphintioyls, alkyl 2,4-dinitrophenyl sulfenates, sulfates, methanesulfonates (mesylates), benzylsulfonates, and tosylates (Ts).

[0042]

[0042] Any compound in this specification may be purified. The compounds in this specification may be purified to 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%, and at least 20%. Purity, at least 21% purity, at least 22% purity, at least 23% purity, at least 24% purity, at least 25% purity, at least 26% purity, at least 27% purity, at least 28% 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 Degrees of purity, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% , 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,It can have a purity of at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

[0043]

[0043] After preparation, the compounds of the present disclosure can be isolated and purified to obtain compositions containing the compound or a salt thereof in an amount of at least about 90% by mass, at least about 91% by mass, at least about 92% by mass, at least about 93% by mass, at least about 94% by mass, at least about 95% by mass, at least about 96% by mass, at least about 97% by mass, at least about 98% by mass, at least about 99% by mass, or about 100% by mass.

[0044]

[0044] In some embodiments, alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are used individually or R 1 , R 2 , R 3 , R 4 , R a , R b , and R c Appearing as part of another part of the above definition, 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 Re , -NR d R e , haloalkyl (e.g., (C1-C6) haloalkyl), haloalkyloxy (e.g., (C1-C6) haloalkoxy or trifluoromethoxy), or halogen [where R d and R e Each is independently substituted by 1 to 4 groups selected from the group consisting of hydrogen or alkyl.

[0045]

[0045] In some embodiments, one or more carbon atoms of the immediately preceding possible substituent are isotope enriched with deuterium.

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

[0046]

[0047] In some embodiments, X is sulfur.

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

[0049] In some embodiments, A is a 6-membered aryl or heteroaryl (each of which is either unsubstituted or substituted).

[0047]

[0050] In some embodiments, the compound is of formula (I a It is a compound of )

[0048] [ka]

[0049] [In the formula, R 1 , R 2 , R 3 , R 4 R', R'', X, Y, Z, and n are as defined in equation (I).

[0051] In some embodiments, Z is hydrogen.

[0050]

[0052] In some embodiments, the compound is of formula (I b It is a compound of )

[0051] [ka]

[0052] [In the formula, R 1 , R 2 , R 3 , R 4 R', R'', and n are as defined in equation (I).

[0053] In some embodiments, n is 1.

[0053]

[0054] In some embodiments, R' and R'' are hydrogen atoms, respectively.

[0055] In some embodiments, R 1 and R 2 Each of these is hydrogen.

[0056] In some embodiments, R 1 It is hydrogen.

[0054]

[0057] In some embodiments, R 2 It is hydrogen.

[0058] In some embodiments, R 1 It is either hydrogen or methyl.

[0059] In some embodiments, R 2 is hydrogen, alkyl, or C(O)R a [Here, R a This is as defined in equation (I).

[0055]

[0060] In some embodiments, R 2 is hydrogen, C(O)R a , benzyl, (C1-C 10 )alkyl, (C3-C 10 )Cycloalkyl, -(C1-C 10)alkyl-(C1-C9) heterocyclyl, (C1-C9) heterocyclyl, (C1-C 10 ) Alkyl sulfonyl, (C4-C 10 ) Aryl sulfonyl, (C4-C 10 ) Heteroarylsulfonyl, 5-10 membered aryl, or 5-10 membered heteroaryl, benzyl, (C1-C 10 )alkyl, (C3-C 10 )Cycloalkyl, -(C1-C 10 )alkyl-(C1-C9) heterocyclyl, (C1-C9) heterocyclyl, (C1-C 10 ) Alkyl sulfonyl, (C4-C 10 ) Aryl sulfonyl, (C4-C 10 Heteroarylsulfonyls, 5-10 membered aryls, and 5-10 membered heteroaryls are each independently substituted or unsubstituted.

[0056]

[0061] In some embodiments, R 2 is hydrogen, C(O)R a , benzyl, (C1-C 10 )alkyl, (C3-C 10 )Cycloalkyl, -(C1-C 10 )alkyl-(C1-C9) heterocyclyl, (C1-C9) heterocyclyl, (C1-C 10 ) Alkyl sulfonyl, (C4-C 10 ) Aryl sulfonyl, (C4-C 10 ) Heteroarylsulfonyl, 5-10 membered aryl, or 5-10 membered heteroaryl [where R a These are -(C1-C 10 )alkyl-(C1-C9) heterocyclyl, (C1-C9) heterocyclyl, (C1-C 10 )alkyl, (C3-C 10 )Cycloalkyl, benzyl, NH-(C1-C 10 )alkyl, -CH2-(C1-C9)heterocyclyl, -CH2-(C1-C5)heterocyclyl-(C4-C 10 )aryl; benzyl, (C1-C 10 )alkyl, (C3-C10 )Cycloalkyl, -(C1-C 10 )alkyl-(C1-C9) heterocyclyl, (C1-C9) heterocyclyl, (C1-C 10 ) Alkyl sulfonyl, (C4-C 10 ) Aryl sulfonyl, (C4-C 10 ) Heteroarylsulfonyl, NH-(C1-C 10 )alkyl, -CH2-(C1-C9)heterocyclyl, -CH2-(C1-C5)heterocyclyl-(C4-C 10 )aryl, 5-10 membered aryl, and 5-10 membered heteroaryl are each independently unsubstituted or halogen, -NH2, (C1-C 10 ) alkyl, -OR X , oxo, C(O)R X , and -CO2R X It is substituted with one or more groups independently selected from R X Each of these is independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.

[0057]

[0062] In some embodiments, R 2 is C(O)R a In some embodiments, R 2 C(O)R a [Here, R a [is aryl or heteroaryl (each of which is unsubstituted or substituted)]. In some embodiments, R 2 C(O)R a [Here, R a [is a 5-10 member aryl or 5-10 member heteroaryl (each of which is unsubstituted or substituted)]. In some embodiments, R a (C1-C6)alkyl, (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 , (C1-C6)haloalkyl, (C1-C6)haloalkyloxy (e.g., trifluoromethoxy), and halogen atoms [where R d and R e Each is independently optionally substituted with 1 to 4 groups selected from the group consisting of hydrogen or (C1-C6) alkyl groups.

[0058]

[0063] In some embodiments, R 2 C(O)R a [Here, R a [The compound is selected from the group consisting of pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridadinyl, triazolyl, oxadiazolyl, and pyrazinyl (each of these being unsubstituted or substituted). In some embodiments, R a (C1-C6)alkyl, (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 , (C1-C6)haloalkyl, (C1-C6)haloalkyloxy (e.g., trifluoromethoxy), and halogen [where R d and R e Each is independently optionally substituted with 1 to 4 groups selected from the group consisting of hydrogen or (C1-C6) alkyl groups.

[0059]

[0064] In some embodiments, R 2 C(O)R a [Here, R aThese include pyrimidine-2-yl, pyrimidine-5-yl, 5-aminopyrimidine-2-yl, 5-methoxypyrimidine-2-yl, 1H-pyrazole-3-yl, 2-methyl-1H-pyrazole-3-yl, pyridine-2-yl, 2-chloropyridine-2-yl, 6-chloropyridine-2-yl, 5-chloropyridine-2-yl, 6-hydroxypyridine-2-yl, and pyridine-3-yl. , 6-amino-pyridine-3-yl, 2-chloro-pyridine-3-yl, pyridine-4-yl, 3-phenyl-1H-pyrazole-5-yl, 1H-imidazole-4-yl, 1H-imidazole-2-yl, 1-methyl-1H-imidazole-4-yl, 1-methyl-1H-imidazole-2-yl, thiazole-2-yl, thiazole-4-yl, 4-methyl-1,2,3-thiadiazole- [5-yl, 5-phenylisoxazole-3-yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5-methyl-3-phenylisoxazole-4-yl, 4-phenylthiazol-2-yl, 1H-tetrazole-5-yl, pyridazine-2-yl, pyridazine-3-yl, pyridazine-4-yl, pyrazine-2-yl, pyrazine-3-yl, pyrazine-4-yl, 3-hydroxypyrazineyl, 4-isopropyl-1,2,3-thiadiazolyl, 3-methylisoxazole-5-yl, 4,4-difluoropiperidine-1-yl, 1,2,4-triazine-3-yl, 4-methylpyrido-2-ylamino, 3-oxopiperazine-1-yl, 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-yl, or piperazine-1-yl].

[0060]

[0065] In some embodiments, R 2 C(O)R a [Here, R a It is pyridine-2-yl.

[0066] In some embodiments, R 2 C(O)R a [Here, R a It is 2-chloropyridine-2-yl.

[0061]

[0067] In some embodiments, R 2 C(O)R a [Here, R a It is 6-chloropyridine-2-yl.

[0068] In some embodiments, R 2 C(O)R a [Here, R a It is 5-chloropyridine-2-yl.

[0062]

[0069] In some embodiments, R 2 C(O)R a [Here, R a It is 6-hydroxypyridine-2-yl.

[0070] In some embodiments, R 2 C(O)R a [Here, R a It is pyridine-3-yl.

[0063]

[0071] In some embodiments, R 2 C(O)R a [Here, R a It is 6-aminopyridine-3-yl.

[0072] In some embodiments, R 2 C(O)R a [Here, R a It is 2-chloropyridine-3-yl.

[0064]

[0073] In some embodiments, R 2 C(O)R a [Here, R a It is pyridine-4-yl.

[0074] In some embodiments, R 2 C(O)R a [Here, R a It is pyrimidine-2-yl.

[0065]

[0075] In some embodiments, R 2 C(O)R a [Here, R a It is pyrimidine-5-yl.

[0076] In some embodiments, R 2 C(O)R a [Here, R a It is 5-aminopyrimidine-2-yl.

[0066]

[0077] In some embodiments, R 2 C(O)R a [Here, R a It is 5-methoxypyrimidine-2-yl.

[0078] In some embodiments, R 2 C(O)R a [Here, R a It is 1H-pyrazole-3-yl.

[0067]

[0079] In some embodiments, R 2 C(O)R a [Here, R a It is 2-methyl-1H-pyrazole-3-yl.

[0080] In some embodiments, R 1 and R 2Each of these is independently hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3-hydroxycyclobutyl, 3,3-difluorocyclobutyl, cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, pyrimidine-2-yl, pyrimidine-2-ylmethyl, pyrimidine-3-ylmethyl, pyrimidine-4-ylmethyl, oxalyl, 2-methoxyethyl, benzyl, 4-carboxybenzyl, 4-carboxymethyl Rubenzyl, tetrahydro-2H-pyran-4-yl, oxetan-3-yl, 1,2,4-thiadiazole-5-yl, 4-aminomethyl-1,2,3-triazole-1-ylmethyl, 4-methyl-1,2,3-thiadiazolyl-5-ylmethyl, benzo[d]thiazol-2-yl, 4-carboxylethyl-1,2,3-thiadiazolyl-5-ylmethyl, 4-carboxy-1,2,3-thiadiazolyl-5-ylmethyl, isoindoline-1,3-dione-2-yl, or acetyl.

[0068]

[0081] In some embodiments, R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form an optionally substituted heterocycle or heteroaryl, which is pyrazolidinol, piperazinyl, 2-oxopiperazinyl, triazolyl, benzotriazolyl, morpholinyl, pyrrolidinyl, or piperidinyl.

[0069]

[0082] In some embodiments, R 1 and R 2 These, together with the nitrogen atoms to which they are bonded, form an optionally substituted heterocycle, the optionally substituted heterocycles being 1H-1,2,3-triazole-1-yl, 1H-benzo[d][1,2,3]triazole-1-yl, morpholinyl, 3,3-difluoropyrrolidine-1-yl, 4,4-difluoropiperidine-1-yl, pyrazolidine-4-one, and 4-benzylpiperidine-1-yl.

[0070]

[0083] In some embodiments, R 3 The group is a halogen, alkoxy group, cycloalkyloxy group, or aryloxy group, each of which is optionally substituted with 1 to 4 groups, each independently of the alkyl, alkoxy, hydroxy, oxo, nitro, cyano, amino, or -C(O)-R group. 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 [where R d and R e [These are independently hydrogen or alkyl.]

[0071]

[0084] In some embodiments, R 3 The group is a halogen, alkoxy group, cycloalkyloxy group, or aryloxy group, each of which is optionally substituted with 1 to 4 groups, each independently being (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, oxo, nitro, cyano, amino, or -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 [where R d and R e [These are independently hydrogen or (C1-C6) alkyl.]

[0072]

[0085] In some embodiments, R 3The group is a halogen, a (C1-C6) alkoxy group, a cycloalkyloxy group, or an aryloxy group, each of which is optionally substituted with 1 to 4 groups, each independently of being (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy, oxo, nitro, cyano, amino, or -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 [where R d and R e [These are independently hydrogen or (C1-C6) alkyl.]

[0073]

[0086] In some embodiments, R 3 R is an unsubstituted phenyloxy compound. In some embodiments, R 3 is a substituted phenyloxy. In some embodiments, R 3 This is a phenyloxy compound that is optionally substituted with 1 to 4 groups, each of which is independently alkyl, alkoxy, hydroxy, oxo, nitro, cyano, amino, or -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), and halogen [where R d and R e R is independently hydrogen or alkyl. In some embodiments, 3 This is a phenyloxy compound substituted with one or more halogen atoms.

[0074]

[0087] In some embodiments, R 3(C1-C6)alkyl, (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 , (C1-C6)haloalkyl, (C1-C6)haloalkyloxy (e.g., trifluoromethoxy), and halogen [where R d and R e The phenyloxy is independently substituted with 1 to 4 groups selected from the group consisting of hydrogen or (C1-C6) alkyl groups.

[0075]

[0088] In some embodiments, R 3 It is optionally substituted with one or two identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, bromine, iodide, CF3, CHF2, methoxy, S(O)2Me, cyano, and C(O)Me.

[0076]

[0089] In some embodiments, R 3 This is a phenoxy molecule that is optionally substituted with one or two identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, bromine, iodide, CF3, CHF2, methoxy, S(O)2Me, cyano, and C(O)Me.

[0077]

[0090] In some embodiments, R 3Each is independently selected from the group consisting of alkyl, cyclohexyl, haloalkyl, alkyloxy, hydroxyalkyloxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, arylsulfonyl, alkylsulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxol-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NH cycloalkyl, -NH-C(O) cycloalkyl, heteroaryl, heterocyclyl, and naphthalenyl (each of which is substituted or unsubstituted), or halogens.

[0078]

[0091] In some embodiments, R 3 Each is independently selected from the group consisting of alkyl, cyclohexyl, halo(C1-C6)alkyl, alkyloxy, 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]dioxol-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NHcycloalkyl, -NH-C(O)cycloalkyl, heteroaryl, heterocyclyl, and naphthalenyl (each of which is substituted or unsubstituted), or halogens.

[0079]

[0092] In some embodiments, R 3 These are independent, in their respective appearances (C1-C 10 )alkyl, cyclohexyl, (C3-C 10 )Cycloalkyl, (C1-C 10 )alkoxy, (C1-C 10 )Cycloalkyloxy, (C4-C 10 ) Aryl sulfonyl, (C1-C 10)Alkyl sulfonyl, phenyl, benzyl, phenoxy, benzo[d][1,3]dioxol-5-yloxy)phenyl, 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) heterocyclyl, or naphthalenyl (each of these being substituted or unsubstituted), or halogen.

[0080]

[0093] In some embodiments, R 3 They are independent of each other, and in their respective appearances, halogen, (C1-C 10 )alkyl, (C1-C 10 ) Haloalkyl, cyclohexyl, (C1-C 10 )alkoxy, (C1-C 10 )Cycloalkyloxy, (C4-C 10 ) Aryl sulfonyl, (C1-C 10 )Alkyl sulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxol-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)heterocyclyl, or naphthalenyl, (C1-C 10 )alkyl, cyclohexyl, (C1-C 10 )alkoxy, (C1-C 10 )Cycloalkyloxy, (C4-C 10 ) Aryl sulfonyl, (C1-C 10 )Alkyl sulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxol-5-yloxy)phenyl, benzyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NH-(C1-C 10 )Cycloalkyl, -NH-C(O)-(C1-C 10Cycloalkyl, (C3-C9) heteroaryl, (C1-C9) heterocyclyl, and naphthalenyl are each independently unsubstituted or halogen, oxo, cyano, -NH2, (C1-C 10 )alkyl, (C1-C 10 )alkoxy, (C1-C 10 ) Haloalkyl, (C1-C 10 ) Alkyl sulfonyl, C(O)R X NH-C(O)-R X , -CO2R X , -CO2NR X R Y ,-OCH2CO2R X , -OR X , or -CH2OR X [Here, R X and R Y [is independently substituted with hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.]

[0081]

[0094] In some embodiments, R 3These are independently present in their respective appearances: methyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl, pentan-1-yl, pentan-2-yl, pentan-3-yl, cyclohexyl, hydroxycyclohexyl, trifluoromethyl, methoxy, neopentyloxy, 2,4-dimethylpentan-3-yloxy, 2-hydroxy-2-methylpropoxy, (adamantan-1-yl)methoxy, (adamantan-2-yl)methoxy, (adamantan-1-yl)oxy, (adamantan-2-yl)oxy, cy Clopentyloxy, 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]dioxol-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-Indole-1-yl, 4-Methylsulfonylphenoxy, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NHCyclohexyl, -NH-C(O)Cyclohexyl, 2-(Acetamide)phenyl, 2-Carboxyphenyl, 3-Carboxyphenyl, 4-Carboxyphenyl, 2-Carboxamidephenyl, 3-Carboxamidephenyl, 4-Carboxamidephenyl These are boxamidephenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-(2-oxyacetate phenyl), 3-(2-oxyacetate phenyl), 4-(2-oxyacetate phenyl), 2-oxopyrrolidine-1-yl, 3-(trifluoromethyl)-1H-pyrazole-4-yl, pyridyl, naphthalen-1-yl, naphthalen-2-yl, -S(O)2Ph, 2-oxopyridine-1(2H)-yl, indolyl, phenylsulfonyl, 2-hydroxymethylpyrrolidiny-1-yl, or hydroxypiperidine-1-yl.

[0082]

[0095] In some embodiments, R 3 These are independently halogen and (C1-C 10 ) A phenoxy substituted with 1 to 5 groups selected from haloalkyl groups. In some embodiments, R 3 It is a phenoxy compound substituted with 1 to 5 halogens.

[0083]

[0096] In some embodiments, R 3 is 2-(trifluoromethyl)phenoxy. In some embodiments, R 3 R is 3-(trifluoromethyl)phenoxy. In some embodiments, R 3 R is 4-(trifluoromethyl)phenoxy. In some embodiments, R 3R is 2-(trifluoromethoxy)phenoxy. In some embodiments, R 3 R is 3-(trifluoromethoxy)phenoxy. In some embodiments, R 3 R is 4-(trifluoromethoxy)phenoxy. In some embodiments, R 3 It is 2-chlorophenoxy.

[0084]

[0097] In some embodiments, R 3 It is phenoxy.

[0098] In some embodiments, R 3 It is 3-chlorophenoxy.

[0099] In some embodiments, R 3 It is 4-chlorophenoxy.

[0085]

[0100] In some embodiments, R 3 It is 2-fluorophenoxy.

[0101] In some embodiments, R 3 It is 3-fluorophenoxy.

[0102] In some embodiments, R 3 It is 4-fluorophenoxy.

[0086]

[0103] In some embodiments, R 3 It is 2,4-dichlorophenoxy.

[0104] In some embodiments, R 3 It is 3,5-difluorophenoxy.

[0105] In some embodiments, two adjacent R 3 The groups, together with the carbon atoms to which they are bonded, form a condensed cycloalkyl or heterocycloalkyl ring, such as a benzofuranyl ring.

[0087]

[0106] In some embodiments, R 4 It is methyl.

[0107] In some embodiments, R 4 It is hydrogen.

[0108] 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 in the form of a salt with a pharmaceutically acceptable acid. In some embodiments, the compound is provided in the form of a salt with a pharmaceutically acceptable base.

[0088] compound

[0109] Non-limiting examples of compounds of formula (I) are: (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenylphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-bromophenyl)-5-(dimethylaminomethyl)-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-[(4-benzyl-1-piperidyl)methyl]-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[(4-benzyl-1-piperidyl)methyl]-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-methoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(trifluoromethyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-benzyloxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(trifluoromethyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenylphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenoxy)phenyl]-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)-1H-pyrazole-4-yl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-iodophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazepan-3-one; 3-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; 3-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; 4-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; 4-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; (2S,5R)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(1,3-benzodioxol-5-yl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1,3-benzodioxol-5-yl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromo-5-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-naphthyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(1-naphthyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(benzenesulfonyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-methoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(o-tolyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-ethylpropyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(3-amino-4-chlorophenyl)phenyl]-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,4-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chloro-3-iodophenyl)phenyl]-1,4-thiazepan-3-one; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzamide; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]cyclohexanecarboxamide; (2R,5S)-5-(aminomethyl)-2-[3-(4-fluorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-cyclohexylphenyl)-1,4-thiazepan-3-one; 3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]-N-phenyl-benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidine-1-yl)methyl]-1,4-thiazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidine-1-yl)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidine-1-yl)methyl]-1,4-thiazepan-3-one; N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]phenyl]acetamide; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidyl)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidyl)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,3-dimethoxyphenyl)phenyl]-1,4-thiazepan-3-one; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzoic acid; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxyphenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; 2-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]phenoxy]acetic acid; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxopyrrolidine-1-yl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxo-1-pyridyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-hydroxy-1-piperidyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-(((3R,5R,7R)-adamantan-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(cyclohexoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-isopropyl-2-methylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxy-2-methylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxy-3-propyl-phenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-chloro-4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-indole-1-ylphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-methoxyphenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,4-dichlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[2-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1,4-thiazepan-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(methylaminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclohexoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-methyl-4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-dibenzofuran-2-yl-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methylsulfonylphenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; 2-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[4-(4-acetylphenoxy)phenyl]-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(1,3-benzodioxol-5-yloxy)phenyl]-1,4-thiazepan-3-one; 3-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]-5-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(4-anilinophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-chloro-4-phenoxyphenyl)-1,4-thiazepan-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]-3-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(2-methoxy-4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)-2-methoxyphenyl]-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(triazole-1-ylmethyl)-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[4-(aminomethyl)triazole-1-yl]methyl]-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(pyrimidine-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(1,3-benzothiazole-2-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(1,2,4-thiadiazole-5-ylamino)methyl]-1,4-thiazepan-3-one; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; 2-Oxo-2-[[(2R,5S)-3-Oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methylamino]acetate; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide; 4-(aminomethyl)-N-[[(2R,5S)-2-(3-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]benzamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-2H-tetrazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]thiazole-4-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-4-methyl-thiadiazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-5-carboxamide; 6-amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-5-phenyl-isoxazole-3-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-4-phenyl-thiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 1-Methyl-N-[[(2S,5R)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]imidazole-4-carboxamide; 4-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-5-carboxamide 6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]methanesulfonamide 4-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-1H-imidazole-4-carboxamide; 2-Morpholino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]acetamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]morpholine-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide; 5-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiadiazole-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-3-sulfonamide; 4-Fluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]benzenesulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; 1-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]imidazole-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide; 3,3-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]cyclobutanecarboxamide; 4,4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]cyclohexanecarboxamide; N-[[(2R,5S)-2-[3-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-1,4-thiazepan-5-yl)methyl)pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-2-pyrimidine-2-ylacetamide; 1-Benzyl-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]urea; 3-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]isoxazole-5-carboxamide; N-[[(2R,5S)-2-[3-(cyclohexoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 4,4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]piperidine-1-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-1,2,4-triazine-3-carboxamide; N-[[(2R,5S)-2-[4-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrazine-2-carboxamide; 6-Chloro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; 2-[5-(4-chlorophenyl)isoxazole-3-yl]-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]acetamide; 6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; 5-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-Methoxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 1-(4-methyl-2-pyridyl)-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]urea N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide; 6-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; 6-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; 2-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]benzamide; 4-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]benzamide; (2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-5-[(1,2,4-thiadiazole-5-ylamino)methyl]-1,4-thiazepan-3-one; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-Chloro-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-5-methoxypyrimidine-2-carboxamide; 5-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-5-methoxypyrimidine-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrazine-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; N-[[(2S,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2S,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-1,4-thiazepan-5-yl]methyl]-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]piperazine-1-carboxamide; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylmethylamino)methyl]-1,4-thiazepan-3-one; Methyl 4-[[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methylaminomethyl]benzoate; (2R,5S)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; 4-[[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methylaminomethyl]benzoic acid; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(cyclopropylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(cyclopropylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[(cyclobutylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(tetrahydropyran-4-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(oxetane-3-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[bis(oxetan-3-yl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-((((1r,3S)-3-hydroxycyclobutyl)amino)methyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[(3,3-difluorocyclobutyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[(4-methylthiadiazole-5-yl)methylamino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-4-ylmethylamino)methyl]-1,4-thiazepan-3-one; 4-[[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methylaminomethyl]benzoic acid; 4-[[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methylaminomethyl]benzoic acid; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-bromophenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2,4-dichlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(2,2,2-trifluoroethylamino)methyl]-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-1,1-dioxo-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-1,1-dioxo-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(2-oxopiperazine-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-oxazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(dimethylaminomethyl)-1,4-oxazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-oxazepan-3-one; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyrimidine-2-carboxamide; 6-amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-2-carboxamide; 6-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-2-carboxamide; 2-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]-1-methylimidazole-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridazine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]thiazole-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]thiazole-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyrazine-2-carboxamide; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazepan-3-one; (2R,5S)-5-(benzotriazole-1-ylmethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazepan-3-one; (2R,5S)-5-[(3-oxopiperazine-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; Also included are their enantiomers, diastereomers, their addition salts with pharmaceutically acceptable acids or bases, and deuterated derivatives.

[0089]

[0110] In some embodiments, the compound of formula (I) is (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]thiazole-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-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-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide, or a pharmaceutically acceptable salt thereof; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-1,4-thiazepan-5-yl)methyl)pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylmethylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-[(2-oxopiperazine-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-(((3R,5R,7R)-adamantan-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; or (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazepan-3-one, or its pharmaceutically acceptable salt. That is the case.

[0090]

[0111] In some embodiments, the compound of formula (I) is (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof.

[0091]

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

[0092]

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

[0093]

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

[0094]

[0115] In some embodiments, the compound of formula (I) is (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof.

[0095]

[0116] In some embodiments, the compound of formula (I) is N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0096]

[0117] In some embodiments, the compound of formula (I) is (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one or a pharmaceutically acceptable salt thereof.

[0097] Synthesis method

[0118] This disclosure also relates to methods for preparing compounds of formula (I) and their intermediates.

[0119] The starting material may include the compound of formula (II).

[0098] [ka]

[0099] [In the formula, A, R 3 Z and n are as defined in equation (I).

[0120] The starting material can be esterified to obtain the compound of formula (III).

[0100] [ka]

[0101] [In the formula, A, R 3 Z, n, and n are as defined in formula (I), and Alk is an alkyl group. In some embodiments, Alk is a (C1-C6) alkyl group.

[0102]

[0121] The compound of formula (III) can then be subjected to a bromination reaction to obtain the compound of formula (IV).

[0103] [ka]

[0104] [In the formula, A, R 3 Z, n, and n are as defined in equation (I), and Alk is as defined above. Other halogens (e.g., Cl, I) can be incorporated in place of Br.

[0105]

[0122] The compound of formula (IV) and the compound of formula (V)

[0106] [ka]

[0107] [wherein X, R', and R'' are as defined in formula (I), and P is a protecting group] reacted with the compound of formula (VI) to form the compound of formula (VI).

[0108] [ka]

[0109] [In the formula, A, R 3 Z, X, R', R'', and n are as defined in equation (I), and Alk and P are as defined above. You can obtain this.

[0110]

[0123] Deprotect the compound of formula (VI) to obtain the compound of formula (VII).

[0111] [ka]

[0112] [In the formula, A, R 3 Z, X, R', R'', and n can be formed as defined in equation (I), and Alk can be formed as defined above.

[0124] The compound of formula (VII) is cyclized to obtain the compound of formula (VIII).

[0113] [ka]

[0114] [In the formula, A, R 3 Z, X, R', R'', and n are as defined in equation (I). You can obtain this.

[0115]

[0125] Protect the hydroxyl group of the compound of formula (VIII) and the compound of formula (IX)

[0116] [ka]

[0117] [In the formula, A, R 3 Z, X, R', R'', and n are as defined in formula (I), and P is a protecting group. You can obtain this.

[0118]

[0126] The compound of formula (IX) is given by formula (X):X'R 4 ' Compound [wherein X' is a halogen, R 4 ' is an unsubstituted or substituted alkyl group' and reacts with the compound of formula (XI).

[0119] [ka]

[0120] [In the formula, A, R 3 Z, X, R', R'', and n are as defined in equation (I), and R 4’ And P is as defined above. You can obtain this.

[0121]

[0127] Compounds of formula (IX) and (XI) are both compounds of formula (XII).

[0122] [ka]

[0123] [In the formula, A, R 3 , R 4 Z, X, R', R'', and n are as defined in equation (I), and P is as defined above.

[0128] The compound of formula XII is given by formula (XIII):HNR 1 R 2 Compounds of [wherein R 1 and R 2 [As defined in formula (I)], the compound of formula (I / a), which is a specific case of the compound of formula (I), is subjected to a reaction.

[0124] [ka]

[0125] [In the formula, A, R 1 , R2 , R 3 , R 4 [where Z, X, R', R'', and n are as defined in formula (I)] can be obtained, and subject to reduction, a compound of formula (I / b) which is a specific case of the compound of formula (I) can be obtained.

[0126] [ka]

[0127] [In the formula, A, R 1 , R 2 , R 3 , R 4 Z, X, R', R'', and n are as defined in equation (I). You can obtain this.

[0128]

[0129] Both the compound of formula (I / a) and the compound of formula (I / b) represent the compound of formula (I).

[0130] In some embodiments, the compound of formula (I) may be purified according to separation techniques such as column chromatography, thin-layer chromatography, sublimation, recrystallization, liquid-liquid extraction, or tritulation.

[0129]

[0131] In some embodiments, the compound of formula (I) can be converted to its addition salt with a pharmaceutically acceptable acid or base.

[0132] In some embodiments, the compound of formula (I) can be selectively separated into its isomers according to a separation technique.

[0130]

[0133] As required by the synthesis, it should be understood that at any time deemed appropriate during the course of the above method, some groups (e.g., hydroxyl, amino) of the starting reagent or synthetic intermediate can be protected, followed by deprotection and functionalization.

[0131]

[0134] In some embodiments, the compound of formula (I) is obtained using alternative methods. For example, the compound of formula (I) can be synthesized from the compound of formula (VI) described above. The hydroxyl moiety is activated and then contacted with an azide derivative to obtain the compound of formula (XIV).

[0132] [ka]

[0133] [In the formula, A, R 3 Z, X, R', R'', and n form the equation as defined in equation (I).

[0135] The compound of formula (XIV) is cyclized to obtain the compound of formula (XV).

[0134] [ka]

[0135] [In the formula, A, R 3 Z, X, R', R'', and n can form as defined in equation (I).

[0136] The compound of formula (XV) is defined above as formula (X):X'R 4 When subjected to a reaction with the compound of formula (XVI), the compound of formula (XVI)

[0136] [ka]

[0137] [In the formula, A, R 3 Z, X, R', R'', and n are as defined in equation (I), and R 4’ [This is defined above.] You can obtain this.

[0138]

[0137] Both the compound of formula (XV) and the compound of formula (XVI) are compounds of formula (XVII)

[0139] [ka]

[0140] [In the formula, A, R 3 , R 4 Z, X, R', R'', and n represent the values ​​as defined in equation (I).

[0138] When the compound of formula (XVII) is subjected to reducing conditions, the compound of formula (I / c), which is a specific case of the compound of formula (I), is obtained.

[0141] [ka]

[0142] [In the formula, A, R 3 , R 4 Z, X, R', R'', and n are as defined in equation (I). You can obtain this.

[0143]

[0139] Further reduction of the compound of formula (I / c) yields the compound of formula (I / d), which is a specific case of the compound of formula (I).

[0144] [ka]

[0145] [In the formula, A, R 3 , R 4 Z, X, R', R'', and n can form as defined in equation (I).

[0140] Compounds of formula (I / c) and (I / d) are both specific cases of compound (I) of formula (I / e).

[0146] [ka]

[0147] [In the formula, A, R 3 , R 4Y, Z, X, R', R'', and n represent the values ​​as defined in equation (I).

[0141] Compound of formula (I / e), formula (XVIII):X''R 1 ' Compound [wherein X'' is a halogen, R 1 ' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of these being unsubstituted or substituted), or C(O)R a , C(O)OR a , or S(O)2R b The compound of formula (I / f), which is a specific case of the compound of formula (I), is subjected to the reaction with [the compound of formula (I / f)].

[0148] [ka]

[0149] [In the formula, A, R 3 , R 4 Y, Z, X, R', R'', and n are as defined in equation (I), and R 1 ' is defined as above.' You can obtain this.

[0150]

[0142] In some embodiments, R 1 ' is an aryl (C1-C6) alkyl.

[0143] In some embodiments, R 1 ' is an (C1-C6) alkyl group.

[0151]

[0144] Compounds of formula (I / f), formula (XIX):X''R 2 ' Compound [wherein X'' is a halogen, R 2 ' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of these being unsubstituted or substituted), or C(O)R a , C(O)OR a , or S(O)2R bThe compound of formula (I / g), which is a specific case of the compound of formula (I), is subjected to the reaction with [the compound of formula (I / g)].

[0152] [ka]

[0153] [In the formula, A, R 3 , R 4 Y, Z, X, R', R'', and n are as defined in equation (I), and R 1 'and R 2 ' is defined as above.' In some embodiments, R 2 ' is (C1-C6) alkyl. In some embodiments, R 2 ' is an aryl (C1-C6) alkyl.

[0154]

[0145] In some embodiments, the present disclosure relates to compounds of formula (I).

[0155] [ka]

[0156] A method for synthesizing, (a) Compound of formula (II)

[0157] [ka]

[0158] Esterilize to obtain the compound of formula (III)

[0159] [ka]

[0160] [In the formula, - The A ring is an aryl or a 5-membered or 6-membered heteroaryl (each of which is either unsubstituted or substituted), - R 3 Each of these independently consists of alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being unsubstituted or substituted), or hydrogen, halogen, NHC(O)R b C(O)NHR b Alternatively, S(O)2R b And, by choice, two adjacent R 3 The groups, together with the carbon atoms to which they are bonded, optionally form condensed cycloalkyl or heterocycloalkyl rings. - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5. - Alk is an alkyl group. The steps to generate, (b) The compound of formula (III) is subjected to a bromination reaction to obtain the compound of formula (IV).

[0161] [ka]

[0162] Steps to obtain, (c) Compound of formula (IV) to compound of formula (V)

[0163] [ka]

[0164] Reacting with it, the compound of formula (VI)

[0165] [ka]

[0166] [In the formula, - X is O, S, S(O) or S(O)2, - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - P is a protecting group. Steps to obtain, (d) Deprotect the compound of formula (VI) to obtain the compound of formula (VII)

[0167] [ka]

[0168] The steps to generate, (e) Cyclizing the compound of formula (VII) to obtain the compound of formula (VIII)

[0169] [ka]

[0170] Steps to obtain, (f) Protect the hydroxyl group to form the compound of formula (IX)

[0171] [ka]

[0172] [In the formula, P is a protecting group.] Steps to obtain, (g) Compound of formula (IX) is given formula (X):X'R 4 ' Compound [wherein X' is a halogen, R 4 ' is reacted with an unsubstituted or substituted alkyl to form the compound of formula (XI).

[0173] [ka]

[0174] The step of obtaining the compound of formula (IX) and (XI) is the compound of formula (XII).

[0175] [ka]

[0176] [In the formula, A, R 3 Z, X, R', R'', n, and P are as defined above, and R 4 [These are unsubstituted or substituted alkyl groups, or hydrogen atoms.] Steps represent, (h) Compounds of formula (XII) are given by formula (XIII): HNR 1 R 2 Compounds of [wherein R 1 and R 2 Each of these can independently be alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydrogen, C(O)R a , C(O)OR b , or S(O)2R b And, or R 1 and R 2 [These react with the nitrogen atoms to which they are bonded to form a heterocycloalkyl moiety] to form the compound of formula (I / a).

[0177] [ka]

[0178] Steps to obtain, (i) Optionally, reduce the compound of formula (I / a) to obtain the compound of formula (I / b).

[0179] [ka]

[0180] A step to obtain, wherein the compound of formula (I / a) and the compound of formula (I / b) represent the compound of formula (I), and (j) The steps of optionally purifying the obtained compound and / or optionally converting the obtained compound to an addition salt thereof with a pharmaceutically acceptable acid or base and / or optionally separating the obtained compound into its isomers. This provides a method that includes [something].

[0181]

[0146] In some embodiments, the present disclosure relates to compounds of formula (I).

[0182] [ka]

[0183] A method for synthesizing, (a) Compounds of formula (VI)

[0184] [ka]

[0185] [In the formula, - X is O, S, S(O) or S(O)2, - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - P is a protecting group. The compound of formula (XIV) is obtained by reacting it with an azide derivative.

[0186] [ka]

[0187] Steps to obtain, (b) Cyclizing the compound of formula (XIV) to obtain the compound of formula (XV)

[0188] [ka]

[0189] Steps to obtain, (c) Compounds of formula (XV) defined above: formula (X):X'R 4 Reacting with the compound of ' to form the compound of formula (XVI)

[0190] [ka]

[0191] The step of obtaining the compound of formula (XV) and the compound of formula (XVI) is the compound of formula (XVII)

[0192] [ka]

[0193] Steps represent, (d) Reduce the compound of formula (XVII) to obtain the compound of formula (I / c)

[0194] [ka]

[0195] Steps to obtain, (e) The compound of formula (I / c) is optionally further reduced to obtain the compound of formula (I / d).

[0196] [ka]

[0197] The step of obtaining the compound of formula (I / c) and the compound of formula (I / d) is the compound of formula (I / e)

[0198] [ka]

[0199] Steps represent, (f) Compound of formula (I / e) of formula (XVIII):X''R 1 ' Compound [wherein X'' is a halogen, R 1 ' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of these being unsubstituted or substituted), or C(O)R a , C(O)OR b , or S(O)2R b The compound of formula (I / f) is formed by reacting it with [the compound of formula (I / f)] at any choice.

[0200] [ka]

[0201] Steps to obtain, (g) Compound of formula (I / f) formula (XIX):X''R 2 ' Compound [wherein X'' is a halogen, R 2 ' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of these being unsubstituted or substituted), or C(O)R a , C(O)OR b , or S(O)2R b The compound of formula (I / g) is formed by reacting it with [the compound of formula (I / g)] at any choice.

[0202] [ka]

[0203] Steps to obtain, (h) The steps of optionally purifying the obtained compound and / or optionally converting the obtained compound to an addition salt thereof with a pharmaceutically acceptable acid or base and / or optionally separating the obtained compound into its isomers. This provides a method that includes [something].

[0204]

[0147] In some embodiments, the present disclosure relates to compounds of formula (I).

[0205] [ka]

[0206] A method for synthesizing, (a) Compound of formula (II)

[0207] [ka]

[0208] Esterilize to obtain the compound of formula (III)

[0209] [ka]

[0210] [In the formula, - The A ring is an aryl or a 5-membered or 6-membered heteroaryl (each of which is either unsubstituted or substituted), - R 3 Each of these independently consists of alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being unsubstituted or substituted), or hydrogen, halogen, NHC(O)R b C(O)NHR b Alternatively, S(O)2R b And, by choice, two adjacent R 3 The groups, together with the carbon atoms to which they are bonded, optionally form condensed cycloalkyl or heterocycloalkyl rings. - R 4 It is hydrogen, - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5. - Alk is an alkyl group. The steps to generate, (b) The compound of formula (III) is subjected to a bromination reaction to obtain the compound of formula (IV).

[0211] [ka]

[0212] Steps to obtain, (c) Compound of formula (IV) to compound of formula (V)

[0213] [ka]

[0214] Reacting with it, the compound of formula (VI)

[0215] [ka]

[0216] [In the formula, - X is O, S, S(O) or S(O)2, - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - P is a protecting group. Steps to obtain, (d) Deprotect the compound of formula (VI) to obtain the compound of formula (VII)

[0217] [ka]

[0218] The steps to generate, (e) Cyclizing the compound of formula (VII) to obtain the compound of formula (VIII)

[0219] [ka]

[0220] Steps to obtain, (f) Reacting a compound of formula (VIII) with a compound of formula RSO2LG or a compound of formula (R-SO2-)2O [wherein R is alkyl or aryl and LG is a leaving group (e.g., chloride)] to obtain a compound of formula (IX)

[0221] [ka]

[0222] [In the formula, A, R 3 Z, X, R, R', R'', and n are as defined above. Steps to obtain, (g) Compound of formula (IX) 10 Compound N3 [wherein R 10 is a metal cation (for example, Li + kaNa + or K + ) or N + Reacting with Alk4 (where Alk is alkyl) yields the compound of formula (X).

[0223] [ka]

[0224] The steps to generate, (h) Compound of formula (X) is compound of formula (I')

[0225] [ka]

[0226] [In the formula, R 1 and R 2 Each of these is a hydrogen atom. Steps to convert and The present invention provides a method comprising further reacting the compound of formula (I') to obtain the compound of formula (I) [wherein R 1 and R 2 It is possible to generate the above.

[0227]

[0148] The conversion from compound (X) to compound (I) can be achieved by reduction of the azide to the corresponding amine by several methods, including but not limited to catalytic hydrogenation in the presence of a metal or phosphine / water, reduction with a hydride donor (e.g., LiAlH4, NaBH4), or reduction with a silane.

[0228]

[0149] In some embodiments, the present disclosure relates to compounds of formula (I).

[0229] [ka]

[0230] A method for synthesizing, (a) Compound of formula (II)

[0231] [ka]

[0232] Esterilize to obtain the compound of formula (III)

[0233] [ka]

[0234] [In the formula, - The A ring is an aryl or a 5-membered or 6-membered heteroaryl (each of which is either unsubstituted or substituted), - R 3Each of these independently consists of alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being unsubstituted or substituted), or hydrogen, halogen, NHC(O)R b C(O)NHR b Alternatively, S(O)2R b And, by choice, two adjacent R 3 The groups, together with the carbon atoms to which they are bonded, optionally form condensed cycloalkyl or heterocycloalkyl rings. - R 4 It is hydrogen, - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5. - Alk is an alkyl group. The steps to generate, (b) The compound of formula (III) is subjected to a bromination reaction to obtain the compound of formula (IV).

[0235] [ka]

[0236] Steps to obtain, (c) Compound of formula (IV) to compound of formula (V)

[0237] [ka]

[0238] Reacting with it, the compound of formula (VI)

[0239] [ka]

[0240] [In the formula, - X is O, S, S(O) or S(O)2, - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - P is a protecting group. Steps to obtain, (d) Deprotect the compound of formula (VI) to obtain the compound of formula (VII)

[0241] [ka]

[0242] The steps to generate, (e) Cyclizing the compound of formula (VII) to obtain the compound of formula (VIII)

[0243] [ka]

[0244] Steps to obtain, (f) A compound of formula (VIII) is reacted with a compound of formula NH(P)2 [wherein P is a nitrogen protecting group] in the presence of a phosphine (e.g., alkyl, O-alkyl, aryl, or heteroarylphosphine) and an azodicarboxylate such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1'-(azodicarbonyl)dipiperidine (ADDP), or tetramethyl azodicarbboxamide (azodicarboxmide) (DMAD) to obtain a compound of formula (IX).

[0245] [ka]

[0246] [In the formula, A, R 3Z, X, R', R'', P, and n are as defined above. Steps to obtain, (g) Compound of formula (IX) is a compound of formula (I)

[0247] [ka]

[0248] [In the formula, R 1 and R 2 Each of these is a hydrogen atom. Steps to convert and The present invention provides a method that includes further reacting the compound to form a compound [where R 1 and R 2 As stated above, for example, R 1 and R 2 Each of these independently consists of alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is either unsubstituted or substituted), hydrogen, and C(O)R. a , C(O)OR b , or S(O)2R b is, or R 1 and R 2 These can combine with the nitrogen atom to which they are bonded to form a heterocycloalkyl moiety.

[0249]

[0150] In some embodiments, compounds of formula (I / c), (I / d), (I / e), (I / f), and / or (I / g) may be purified according to separation techniques.

[0151] In some embodiments, the compounds of formula (I / c), (I / d), (I / e), (I / f), and / or (I / g) can be converted to their addition salts with pharmaceutically acceptable acids or bases.

[0250]

[0152] In some embodiments, compounds of formula (I / c), (I / d), (I / e), (I / f), and / or (I / g) can be optionally separated into their isomers according to separation techniques.

[0251]

[0153] As required by the synthesis, it should be understood that at any time deemed appropriate during the course of the above method, some groups (e.g., hydroxyl, amino) of the starting reagent or synthetic intermediate can be protected, followed by deprotection and functionalization.

[0252]

[0154] All stereoisomers of the compounds of this disclosure, including enantiomer and diastereomer forms (e.g., stereoisomers that may exist due to the chiral carbons in various substituents), are intended within the scope of this disclosure. Individual stereoisomers of the compounds of this disclosure may be substantially free of other isomers (e.g., pure or substantially pure optical isomers with specified activity), or they may be miscible, for example, as a racemate or as a mixture enriched by one stereoisomer. The chiral centers of this disclosure may have S or R configurations as defined by the IUPAC 1974 Recommendations. Racemates may be separated by physical methods, such as fractional crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography. Individual optical isomers may be obtained from racemates by any preferred method, including, but not limited to, salt formation with an optically active acid or base, followed by crystallization.

[0253] Pharmaceutically acceptable salts

[0155] Any compound described herein may be provided as a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include acid addition salts and base addition salts. The acid added to the compound to form an acid addition salt may be an organic acid or an inorganic acid. The base added to the compound to form a base addition salt may be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt.

[0254]

[0156] Metal salts may be obtained by adding an inorganic base to a compound of the disclosure. The inorganic base consists of a metal cation paired with a basic counterion, such as a hydroxide, carbonate, bicarbonate, or phosphate. The metal may be an alkali metal, alkaline earth metal, transition metal, or typical metal. In some embodiments, the metal may be lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0255]

[0157] In some embodiments, 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.

[0256]

[0158] Ammonium salts may be obtained by adding ammonia or an organic amine to the compounds of the present disclosure. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.

[0257]

[0159] In some embodiments, the ammonium salt is triethylamine salt, trimethylamine salt, diisopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, morpholine salt, N-methylmorpholine salt, piperidine salt, N-methylpiperidine salt, N-ethylpiperidine salt, dibenzylamine salt, piperazine salt, pyridine salt, pyrazole salt, pyridazine salt, pyrimidine salt, imidazole salt, or pyrazine salt.

[0258]

[0160] Acid addition salts may be obtained by adding an acid to a compound of the present disclosure. In some embodiments, the acid is an organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrite, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, phosphonic acid, pyruvate, malonic acid, camphoric acid, gluconic acid, glucuronic acid, sugar 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.

[0259]

[0161] In some embodiments, the salt is hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentisinate, phosphonate, pyruvate, malonate, camphorate, trifluoroacetate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, hemifumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate.

[0260]

[0162] In some embodiments, one or more of the compounds of the Disclosure take the form of a salt in which the nitrogen atom is protonated, 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.

[0261] therapeutic use

[0163] In some embodiments, the present disclosure provides compounds for treating ryanodine receptor (RyR)-related conditions, disorders, and diseases.

[0262]

[0164] In some embodiments, the Disclosure provides compounds that are RyR modulators, e.g., Rycal compounds. Compounds of the Disclosure can, for example, bind to a leaky RyR subunit, restore calstabine binding, and repair channel leakage. In some embodiments, compounds of the Disclosure bind to a leaky RyR channel, restore calstabine binding, and repair channel leakage without blocking the RyR channel. In some embodiments, compounds of the Disclosure can repair leakage in RyR channels, e.g., RyR1, RyR2, and / or RyR3 channels. In some embodiments, compositions of the Disclosure enhance the association of RyR and calstabine (e.g., RyR1 and calstabine 1; RyR2 and calstabine 2; and RyR3 and calstabine 1) and / or inhibit dissociation.

[0263]

[0165] Non-limiting examples of conditions, disorders, and diseases associated with RyR include disorders and diseases that can be treated and / or prevented by modulating RyR, such as cardiac disorders or diseases, musculoskeletal disorders or diseases, cancer-related muscle weakness, malignant hyperthermia, and diabetes. The compounds described herein can also reduce the likelihood of such conditions occurring.

[0264]

[0166] In some embodiments, the Disclosure provides a method for treating a condition or reducing the likelihood of its occurrence by administering a therapeutically effective amount of a compound disclosed herein, for example, a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, to a subject requiring treatment of the condition or reduction of its likelihood of occurrence. In some embodiments, the compound is administered in a pharmaceutical composition. In some embodiments, the compound is in unit dosage form. In some embodiments, the unit dosage form is a solid dosage form. In some embodiments, the pharmaceutical composition is in unit dosage form suitable for oral administration.

[0265]

[0167] In some embodiments, the Disclosure provides compounds, for example, compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, for use in methods of treating a condition or reducing the likelihood thereof.

[0266]

[0168] In some embodiments, the Disclosure provides compounds, for example, compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, for use in the manufacture of pharmaceuticals.

[0267]

[0169] In some embodiments, the condition, disorder, or disease is associated with abnormal function of RyR1. In some embodiments, the condition, disorder, or disease is associated with abnormal function of RyR2. In some embodiments, the condition, disorder, or disease is associated with abnormal function of RyR3. In some embodiments, the condition is a cardiac disorder or disease. In some embodiments, the condition is a musculoskeletal disorder or disease. In some embodiments, the condition is cancer-related muscle weakness. In some embodiments, the condition is malignant hyperthermia. In some embodiments, the condition is diabetes mellitus.

[0268]

[0170] In some embodiments, the Disclosure provides a method for modulating the binding of RyR and calstabine in a subject, comprising the step of administering to the subject an amount of a compound effective in modulating the amount of RyR-bound calstabine, for example, a compound of formula (I) described herein or a salt thereof. In some embodiments, the compound is used in a dose sufficient to restore or enhance the binding of calstabine 2 to RyR2. In some embodiments, the compound is used in a dose sufficient to restore or enhance the binding of calstabine 2 to RyR2. In some embodiments, the compound is used in a dose sufficient to restore or enhance the binding of calstabine 1 to RyR1. In other embodiments, the compound is used in a dose sufficient to restore or enhance the binding of calstabine 1 to RyR1.

[0269]

[0171] The methods of the present disclosure may be carried out in vitro (e.g., in cultured cells or tissues) or in vivo (e.g., in non-human animals or humans).

[0172] In some embodiments, the compounds of the Disclosure are not selective to a particular RyR isoform. In some embodiments, the compounds of the Disclosure bind to both RyR1 and RyR2, and / or Ca +2 Leakage can be repaired. In some embodiments, the compounds of the present disclosure can prevent stress-induced dissociation of calstabine 2 from RyR2 and calstabine 1 from RyR1, thereby preventing RyR-mediated SR Ca 2+ Leakage is reduced, and cardiac and skeletal muscle function is improved.

[0270]

[0173] Accordingly, in some embodiments, the compounds of the present disclosure are used to reduce both skeletal muscle (RyR1) and cardiac muscle (RyR2) Ca +2Conditions characterized by leakage can be treated. For example, the compounds of this disclosure can be used to treat both cardiac and skeletal muscle dysfunction in heart failure. In other embodiments, the compounds of this disclosure can be used to treat both cardiac and skeletal muscle dysfunction in muscular dystrophy, such as Duchenne muscular dystrophy.

[0271]

[0174] In some embodiments, the compounds of the disclosure are selective to RyR1, that is, they are more effective at repairing calcium leakage in RyR1 than in RyR2. In some embodiments, the compounds of the disclosure are selective to RyR2, that is, they are more effective at repairing calcium leakage in RyR2 than in RyR1.

[0272] Lyanodine receptor: Excitation-contraction coupling (ECC) process

[0175] The sarcoplasmic reticulum (SR) is particularly specialized in intracellular calcium (Ca 2+ It is a cellular structure that functions as a store. The ryanodine receptor (RyR) is a structure that transmits Ca from the cellular SR to the intracellular cytoplasm. 2+ It is a channel in the SR that opens and closes to regulate the release of Ca from the SR to the cytoplasm. 2+ Release causes cytoplasmic Ca 2+ The concentration increases. The probability that RyR is open is that RyR is open at any given time, and therefore Ca 2+ This refers to the possibility of releasing SR into the cytoplasm.

[0273]

[0176] RyR is the major Ca of SR, which is responsible for excitation-contraction coupling (ECC) in striated muscle. 2+It is a release channel. Of the three known RyR isoforms (RyR1, RyR2, and RyR3), RyR1 is widely expressed and is the dominant isoform expressed in mammalian skeletal muscle. RyR2 is also widely expressed and is the dominant form found in cardiac muscle. RyR3 expression is low in adult skeletal muscle. RyR subtypes show a high degree of structural and functional homology. Subtypes are related to proteins such as kinases, phosphatases, phosphodiesterases, and other regulatory subunits. 2+ It forms a large sarcoplasmic membrane complex consisting of four monomers that make up the release channel.

[0274]

[0177] Ca from SR 2+ Release is modulated by several RyR-binding proteins. Ca 2+ Calmodulin, a key mediator in signal transduction, exerts both positive and negative effects on RyR opening probability. Calstabine 1 (FKBP12) and Calstabine 2 (FKBP12.6) stabilize the closed state of RyR1 and RyR2, respectively. Calstabine 1 predominantly associates with skeletal muscle RyR1, while cardiac muscle RyR2 has the highest affinity for Calstabine 2.

[0275]

[0178] Mutations in RYR1 or RYR2 are characterized by improper channel opening unrelated to contractile signaling. This channel opening is further exacerbated by post-translational modifications of the RyR channel, such as PKA-phosphorylation, oxidation, or nitrosylation. The resulting leaky channels exhibit a pathological increase in opening probability under resting conditions. SR Ca 2+ Leakage is due to tubular SR Ca 2+ This reduces the amount of calcium that can be released. 2+ This decreases, resulting in weakened muscle contraction. Intracellular calcium leakage leads to different pathological consequences depending on which tissues are involved.

[0276] Lyanodine receptor 2 and heart disease

[0179] In some embodiments, a RyR-related condition is a cardiac disorder or disease involving ryanodine receptor 2 (RyR2). The RyR2 channel is required for ECC in the cardiomyocyte to release Ca from the sarcoplasmic reticulum (SR) in cardiomyocytes. 2+ By regulating release, it plays a major role in intracellular calcium manipulation. The RyR2 channel is a macromolecular complex containing four identical RyR2 subunits, each of which binds to one calstabin 2 (FKBP12.6) and other interacting proteins such as phosphatases and kinases. The binding of calstabin 2 stabilizes the closed channel during the resting (relaxing) phase of the heart, thereby preventing relaxation-induced calcium leakage from the SR and functionally coupling the RyR2 channel cluster to enable synchronous opening during excitation-contraction coupling.

[0277]

[0180] Phosphorylation of RyR2 by protein kinase A (PKA) is a crucial part of the fight-or-flight response. Phosphorylation is a reaction in which Ca2+2 is released in response to a given trigger. 2+ By increasing the amount of [substance], the gain of cardiac EC coupling is increased. This method enhances muscle contraction and improves exercise capacity. This signaling pathway provides a mechanism by which cardiac output increases through sympathetic nervous system (SNS) activation in response to stress. Phosphorylation of RyR2 by PKA increases the channel's sensitivity to calcium-dependent activation. This increased sensitivity leads to an increased probability of opening and increased calcium release from SR into the intracellular cytoplasm.

[0278]

[0181] Heart failure (HF) is characterized by a persistent hyperadrenergic state with chronically elevated serum catecholamine levels. One consequence of this chronic hyperadrenergic state is persistent PKA hyperphosphorylation of RyR2, in which 3-4 of the 4 Ser2808 in each homotetrameric RyR2 channel are chronically phosphorylated. Chronic PKA hyperphosphorylation of RyR2 is associated with the depletion of the channel-stabilizing subunit calstabin 2 from the RyR2 channel macromolecular complex. Depletion of calstabin 2 leads to the depletion of relaxing SR Ca from the RyR complex. 2+ This leads to leakage and causes contractile impairment. Due to the activation of inward depolarization current, this relaxation phase SR Ca 2+ Leakage is also associated with fatal cardiac arrhythmias.

[0279]

[0182] Mice modified with RyR2 lacking a PKA phosphorylation site (RyR-S2808A) are protected from HF progression after myocardial infarction (MI). Furthermore, chronic PKA hyperphosphorylation of RyR2 in HF is associated with remodeling of the RyR2 macromolecular complex. Remodeling involves depletion of phosphatases PP1 and PP2a (impairing dephosphorylation of Ser2808) and cAMP-specific phosphodiesterase 4 (PDE4D3) from the RyR2 complex. Depletion of PDE4D3 from the RyR2 complex leads to persistent elevation of local cAMP levels.

[0280]

[0183] Therefore, sarcoholic SRCa 2+ Leakage is a contributing factor to HF progression and arrhythmias. Additional post-translational modifications (oxidation and nitrosylation) of RyR channels further drive leakage. Tracing single channels in cardiomyocytes of heart failure cells shows a dramatically increased open probability in RyR2 compared to normal cardiomyocytes, suggesting a leaky channel. Large luminal SR Ca available in normal RyR channels 2+ The store is mediated by phosphorylated / oxidized RyR2 during the sacral phase of SR Ca 2+Calcium is dramatically depleted in heart failure due to leakage. Rianodine receptor channel modulators can stabilize ejection fraction by repairing calcium leakage, thereby improving cardiac function in mouse or rat models of heart failure.

[0281]

[0184] RyR2 leakage is associated with a variety of cardiac disorders, conditions, and diseases. In some embodiments, the cardiac conditions are caused by mutations in the RYR2 gene. In some embodiments, the cardiac conditions are caused by post-translational modified RyR2.

[0282] heart failure

[0185] In some embodiments, the heart disorder or disease is heart failure. In some embodiments, the heart disorder or disease is myocardial infarction (MI). In some embodiments, heart failure is congestive heart failure. In some embodiments, heart failure is chronic heart failure. In some embodiments, heart failure is systolic heart failure. In some embodiments, heart failure is diastolic heart failure. In some embodiments, heart failure is acute decompensated heart failure. In some embodiments, heart failure is heart failure with reduced ejection fraction (HFrEF). In some embodiments, heart failure is heart failure with preserved ejection fraction (HFpEF). In some embodiments, heart failure is acute heart failure, for example, to preserve cardiac function after myocardial infarction or cardiomyopathy. In some embodiments, heart failure is right heart failure (RHF). In some embodiments, heart failure is left heart failure (LHF).

[0283]

[0186] In some embodiments, the cardiac injury or disease includes myocardial ischemia / reperfusion (I / R) injury. I / R injury may occur after coronary angioplasty or thrombolysis for the treatment of myocardial infarction (MI), or during / after cardiac bypass surgery or heart transplantation, or after a drop in blood pressure (e.g., a transient drop in blood pressure).

[0284]

[0187] In some embodiments, the heart disorder or disease is characterized by an irregular heartbeat or arrhythmia. In some embodiments, the heart disorder or disease is catecholamine-induced polymorphic ventricular tachycardia (CPVT). In some embodiments, the heart disorder or disease is catecholamine-induced polymorphic ventricular tachycardia type 1 (CPVT1). In some embodiments, the heart disorder or disease is or is characterized by an atrial arrhythmia. In some embodiments, the heart disorder or disease is or is characterized by a ventricular arrhythmia. In some embodiments, the heart disorder or disease is atrial fibrillation. In some embodiments, the heart disorder or disease is ventricular fibrillation. In some embodiments, the heart disorder or disease is atrial tachyarrhythmia. In some embodiments, the heart disorder or disease is ventricular tachyarrhythmia. In some embodiments, the heart disorder or disease is atrial tachycardia. In some embodiments, the heart disorder or disease is ventricular tachycardia or characterized by it. In some embodiments, the heart disorder or disease is premature contractions (PCs) or characterized by it. In some embodiments, the heart disorder or disease is ventricular premature contractions (PVCs) or characterized by it. In some embodiments, the heart disorder or disease is bigeminy or characterized by it. In some embodiments, the heart disorder or disease is sick sinus syndrome or characterized by it. In some embodiments, the heart disorder or disease is ventricular premature contraction caplets or characterized by it. In some embodiments, the heart disorder or disease is sudden cardiac death (SCD) or characterized by it. In some embodiments, the heart disorder or disease is sudden infant death syndrome (SDIS) or characterized by it. In some embodiments, the heart disorder or disease is sudden death of unknown cause (SUD) or characterized by it.

[0285]

[0188] In heart failure, Ca in the sarcoplasmic reticulum (SR) 2+ The concentration may be abnormally controlled. Modified leaky RyR2 Ca 2+ Relaxation Ca from SR through release channels 2+ Leakage can result in delayed depolarization (DAD). If the amplitude of the DAD exceeds a certain threshold (over-threshold DAD), it can trigger an action potential (AP) called a triggering activity (TA), which can lead to ventricular premature contractions (PVCs). Ryanodine receptor channel modulators (e.g., compounds of formula (I), or any other compounds incorporated by such formula or otherwise described herein) can preferentially bind to leaky RyR2 channels and induce structural changes that can shift the RyR2 channel's open probability towards the closed (resting) state, repairing channel leakage and thereby restoring normal RyR2 function. In some embodiments, repairing channel leakage reduces calcium flow (e.g., calcium sparks).

[0286]

[0189] In some embodiments, the ryanodine receptor channel modulators described herein may be effective in treating heart failure characterized by a high PVC load. The PVC load may be determined by monitoring a subject (e.g., a heart failure patient) for a defined period of time using electrocardiogram monitoring or any other system (e.g., a continuous cardiac monitoring system) that detects and stores the measured electrical activity of the heart. In some embodiments, the PVC load is calculated as the percentage obtained by dividing the total PVCs in a given time by the total number of beats in the same time.

[0287]

[0190] In some embodiments, the PVC load is at least about 1% of all heartbeats in time. In some embodiments, the PVC load is at least about 5% of all heartbeats in time. In some embodiments, the PVC load is at least about 10% of all heartbeats in time. 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 in time. In some embodiments, the PVC load ranges from about 5% to about 10% of all heartbeats in time. In some embodiments, the heart rate preceding 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.

[0288]

[0191] In some embodiments, heart failure is characterized by elevated levels of N-terminal pro b-type natriuretic peptide (NTproBNP). In some embodiments, N-terminal pro b-type natriuretic peptide levels are greater than approximately 600 pg / mL, greater than approximately 700 pg / mL, greater than approximately 800 pg / mL, greater than approximately 900 pg / mL, greater than approximately 1,000 pg / mL, or greater than approximately 1,500 pg / mL.

[0289]

[0192] In some embodiments, the time ranges from approximately 1 minute to approximately 24 hours. In some embodiments, the time ranges from approximately 1 minute to approximately 12 hours. In some embodiments, the time ranges from approximately 1 minute to approximately 10 hours. In some embodiments, the time ranges from approximately 1 minute to approximately 5 hours. In some embodiments, the time ranges from approximately 1 minute to approximately 1 hour. In some embodiments, the time ranges from approximately 1 minute to approximately 30 minutes. In some embodiments, the time ranges from approximately 5 minutes to approximately 30 minutes. In some embodiments, the time ranges from approximately 1 minute. In some embodiments, the time ranges from approximately 60 minutes. In some embodiments, the time ranges from approximately 24 hours.

[0290]

[0193] In some embodiments, subjects have heart failure with reduced ejection fraction (HFrEF). In some embodiments, subjects have an ejection fraction of less than about 40%. In some embodiments, subjects have an ejection fraction of less than about 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, less than 20%, or even less.

[0291]

[0194] Common symptoms of heart failure include obvious muscle fatigue and exercise intolerance, which limit daily living activities and affect quality of life. Heart failure is associated with maladaptive remodeling of the skeletal muscle RyR1 complex, which may play a role in the characteristic exercise intolerance and activity limitations seen in patients with heart failure.

[0292]

[0195] For example, skeletal muscle RyR1 from human heart failure patients is post-translationally modified (e.g., phosphorylation, oxidation and / or nitrosylation), leading to calstabine 1 depletion and pathological Ca +2 This study interprets the release as a potential mechanism underlying skeletal muscle weakness and reduced exercise tolerance in heart failure patients, suggesting a potential target for pharmacological intervention.

[0293]

[0196] In some embodiments, the compounds of the present disclosure can prevent stress-induced dissociation of the channel-stabilizing subunit calstabine 2 from RyR2 and calstabine 1 from RyR1, thereby preventing RyR-mediated SR Ca 2+ Leakage is reduced, and cardiac and skeletal muscle function is improved in patients with heart failure. Therefore, in some embodiments, the compounds of the Disclosure can treat both skeletal and cardiac muscle weakness in patients with heart failure. Thus, the compounds of the Disclosure can be independently positioned to treat both cardiac and skeletal muscle dysfunction in heart failure.

[0294]

[0197] The foregoing provides a method for treating skeletal muscle weakness in patients with heart failure, comprising the step of administering to a 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 RyR1 and / or RyR2 channels of the subject.

[0295]

[0198] Improvements in skeletal muscle function can be measured by various methods, including measurements of maximum oxygen uptake (VO2 max), exercise capacity, walking distance, muscle strength, and cardiopulmonary exercise testing.

[0296] Cardiac arrhythmia

[0199] In some embodiments, cardiac disorders or diseases are characterized by arrhythmias or arrhythmias. In some embodiments, cardiac disorders or diseases are characterized by ectopic excitations, such as ectopic ventricular excitations. In some embodiments, ectopic excitations (e.g., ectopic ventricular excitations) associated with cardiac diseases or disorders (e.g., CPVT) can be induced by stress, such as catecholamine stress. In some embodiments, ectopic excitations (e.g., ectopic ventricular excitations) are exercise-induced. In some embodiments, ectopic excitations (e.g., ectopic ventricular excitations) are induced by elevated heart rate. In some embodiments, ectopic excitations (e.g., ectopic ventricular excitations) occur when a subject has an elevated heart rate compared to the subject's baseline heart rate. In some embodiments, the elevated heart rate is at least about 100 beats / min, at least about 105 beats / min, at least about 110 beats / min, at least about 115 beats / min, at least about 120 beats / min, at least about 125 beats / min, at least about 130 beats / min, at least about 135 beats / min, at least about 140 beats / min, at least about 145 beats / min, at least about 150 beats / min, at least about 155 beats / min, at least about 160 beats / min, at least about 165 beats / min, at least about 170 beats / min, at least about 175 beats / min, at least about 180 beats / min, at least about 185 beats / min, at least about 190 beats / min, at least about 195 beats / min, or at least about 200 beats / min. In some embodiments, the elevated heart rate is approximately 100 to 200 beats / min, 125 to 200 beats / min, 150 to 200 beats / min, 100 to 125 beats / min, 100 to 150 beats / min, or 100 to 175 beats / min. In some embodiments, the elevated heart rate is induced by stress. In some embodiments, the stress is catecholamine stress. In some embodiments, the elevated heart rate is induced by exercise.

[0297] Catecholamine-induced polymorphic ventricular tachycardia

[0200] In some embodiments, the present disclosure provides a method for treating catecholamine-induced polymorphic ventricular tachycardia (CPVT), comprising the step of administering a therapeutically effective amount of a ryanodine receptor channel modulator to a subject in need of treatment for CPVT, wherein the treatment of catecholamine-induced polymorphic ventricular tachycardia (CPVT) reduces the likelihood of ectopic excitation developing in the subject.

[0298]

[0201] In some embodiments, the present disclosure provides a method for treating catecholamine-induced polymorphic ventricular tachycardia (CPVT), comprising the step of administering a therapeutically effective amount of a ryanodine receptor channel modulator to a subject in need of treatment for CPVT, wherein the likelihood of atrial fibrillation in the subject is reduced by treating the catecholamine-induced polymorphic ventricular tachycardia (CPVT).

[0299]

[0202] Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is one of the most fatal hereditary arrhythmogenic disorders. 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 disorder that is 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 with no structural heart disease, a normal resting electrocardiogram, and presents with stress-induced palpitations or syncope (e.g., exercise or emotional). If left untreated, CPVT is a highly fatal disorder with an untreated mortality rate of 30–50% by age 40.

[0300]

[0203] CPVT is associated with mutations in two genes encoding proteins related to the sarcoplasmic reticulum (SR) of cardiomyocytes. The most frequently observed form is type 1 CPVT (CPVT1), which is an autosomal dominant form due to mutations in the RYR2 gene. RYR2 encodes an intracellular SR calcium release channel. CPVT-associated RyR2 mutations result in a leaky RyR2 channel, which may be associated with reduced binding of the calstabin 2 (FKBP12.6) subunit that stabilizes the channel's closed state. Mice heterozygous for the R2474S mutation in RyR2 (which occurs in humans with CPVT1) (RyR2-R2474S mice) can exhibit exercise-induced ventricular arrhythmias and sudden cardiac death.

[0301]

[0204] Under normal physiological conditions, SR Ca 2+ Flux is strictly regulated, and RyR2-interacting proteins contribute to this regulation. For example, calstabine 2 stabilizes the closed state of SR Ca by stabilizing the RyR2 state. 2+ It modulates release. In CPVT1 patients, a decrease in RyR2-calstabine 2 binding is associated with RyR2Ca 2+ It may be related to leakage.

[0302]

[0205] The RyR2-R2474S mutant channel, which carries a point mutation that causes CPVT in humans, adopts a primed state compared to non-mutant RyR2. The primed state is a transition between the closed and open structures of these channels. In the primed state, the mutant channel is more susceptible to the transition to the open structure. Wild-type RyR2 channels open during systole, a phase of the cardiac cycle suitable for calcium release. In contrast, primed mutant channels may remain open during both systole and diastole under exercise or catecholamine-mediated stress. This inappropriate opening during diastole can lead to ventricular arrhythmias, which are characteristic of CPVT. These observations were made under conditions similar to the channel status during diastole under exercise-induced β-adrenergic stimulation, e.g., PKA phosphorylation and low calcium concentrations.

[0303]

[0206] In some embodiments, the CPVT-related mutant RyR2 protein is in a primed state. In some embodiments, the primed RyR2 protein has a higher open probability (P) compared to the resting (closed) RyR2 protein. o ) Includes distribution. In some embodiments, primed RyR2 protein abnormal Ca from RyR2 channel +2 It is a leaky RyR2 protein characterized by leakage. In some embodiments, the primed RyR2 protein has a higher opening probability (P) compared to the resting (closed) RyR2 protein. o It is a leaky RyR2 protein characterized by its distribution. In some embodiments, primed RyR2 contains about 30% to about 60% open RyR2 channels. In some embodiments, primed RyR2 contains about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% open RyR channels.

[0304]

[0207] The ryanodine receptor channel modulator provides an innovative approach to treating CPVT1. The ryanodine receptor channel modulator can preferentially bind to leaky RyR2 channels, shifting the RyR channel's open probability towards the closed (resting) state, thereby inducing a structural change that can restore calstabine 2 binding and repair channel leakage, thereby restoring normal RyR2 function.

[0305]

[0208] In some embodiments, the Disclosure provides a method for treating catecholamine-induced polymorphic ventricular tachycardia (CPVT), comprising the step of administering a therapeutically effective amount of a ryanodine receptor channel modulator to a subject requiring treatment for CPVT. In some embodiments, the Disclosure provides a method for treating CPVT, comprising the step of administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a subject requiring treatment for CPVT. In some embodiments, the administration is once daily. In some embodiments, the CPVT is type 1 CPVT.

[0306]

[0209] In some embodiments, the present disclosure provides a method for treating CPVT, comprising the step of administering a therapeutically effective amount of a ryanodine receptor channel modulator to a subject in need of treatment for CPVT, wherein the treatment of CPVT reduces the likelihood of sudden cardiac death in the subject. In some embodiments, the CPVT is type 1 CPVT.

[0307]

[0210] In some embodiments, the compound is administered as monotherapy. 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 a beta-blocker and a sodium channel inhibitor.

[0308]

[0211] In some embodiments, the subject is receiving a treatment regimen for CPVT, which 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, and the beta-blocker is administered in a therapeutically effective amount for treating CPVT in the subject in the absence of the compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is administered in combination with a beta-blocker, and the beta-blocker is administered in a reduced amount, which is approximately less than the amount used to treat CPVT in the subject in the absence of the compound. In some embodiments, the compound is administered in combination with a beta-blocker, which is administered in a reduced amount, the reduced amount being 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% of the amount used to treat CPVT in a subject in the absence of the compound.

[0309]

[0212] An amount of beta-blocker less than the amount used to treat CPVT in the absence of the compound may be less than the maximum tolerated dose of the beta-blocker, for example, about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the maximum tolerated dose of the beta-blocker.

[0310]

[0213] An amount of beta-blocker less than the amount used to treat CPVT in the absence of the compound may be less than the dose of beta-blocker that is therapeutically effective for CPVT in the absence of the compound or a pharmaceutically acceptable salt thereof, for example, 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% of a dose of beta-blocker that is therapeutically effective for CPVT in the absence of the compound.

[0311]

[0214] Non-limiting examples of beta-blockers include acebutolol, atenolol, betaxolol, bisoprolol, bucindolol, butaxamine, carteolol, carvedilol, ceriprolol, esmolol, labetalol, metoprolol, nadolol, nebibolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, and pharmaceutically acceptable salts thereof.

[0312]

[0215] In some embodiments, the β-blocker is a non-selective β-blocker. A non-selective β-blocker inhibits both β-1 receptors, which are mainly located in the myocardium, and β-2 receptors, which are mainly located in the bronchial and vascular muscular systems. In some embodiments, the non-selective β-blocker is nadolol, pembutolol, pindolol, propranolol, sotalol, or timolol, or a pharmaceutically acceptable salt thereof. In embodiments, the non-selective β-blocker is nadolol or a pharmaceutically acceptable salt thereof.

[0313]

[0216] In some embodiments, the β-blocker is a selective β-blocker. Selective β-blockers (such as metoprolol) can preferentially inhibit β-1 receptors (cardiac selectivity). At very high concentrations, this selectivity may be reduced, and some β-2 inhibition may occur. Selectivity is confirmed by the inability to reverse the β-2 mediated vasodilatory effect of epinephrine. This is in contrast to the effect of non-selective β-blockers, which can reverse the vasodilatory effect of epinephrine. In some embodiments, the selective β-blocker is metoprolol or a pharmaceutically acceptable salt thereof.

[0314]

[0217] In some embodiments, subjects receive a treatment regimen for CPVT that includes a sodium channel inhibitor. In some embodiments, 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, tokainide, phenytoin, moriscidine, propafenone, lacosamide, rufinamide, fosphenytoin, etotoin, carbamazepine, eslicarbazepine, pilsicainide, tetrodotoxin, aprindine, ajumaline, encainide, propafenone, amiodarone, procainamide, quinidine, oxcarbazepine, moriscidine, amiloride, lamotrigine, triamterene, mexiletine, phenytoin, and lanolazine, 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.

[0315]

[0218] In some embodiments, the subject is receiving a treatment regimen for CPVT, which includes a sodium channel inhibitor. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are administered in combination with a sodium channel inhibitor. In some embodiments, the compounds are administered in combination with a sodium channel inhibitor, and the sodium channel inhibitor is administered in a therapeutically effective amount for treating CPVT in the subject in the absence of the compound. In some embodiments, the compounds are administered in combination with a beta-blocker, and the sodium channel inhibitor is administered in a reduced amount, which is approximately less than the amount used to treat CPVT in the subject in the absence of the compound. In some embodiments, the compound is administered in combination with a sodium channel inhibitor, the sodium channel inhibitor is administered in a reduced amount, the reduced amount being 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% of the amount used to treat CPVT in a subject in the absence of the compound.

[0316]

[0219] An amount of sodium channel inhibitor less than the amount used to treat CPVT in the absence of the compound may be less than the maximum tolerated dose of the sodium channel inhibitor, for example, about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the maximum tolerated dose of the sodium channel inhibitor.

[0317]

[0220] The amount of sodium channel inhibitor less than the amount used to treat CPVT in the absence of the compound may be less than the amount of sodium channel inhibitor therapeutically effective for CPVT in the absence of the compound, for example, 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% of the amount of sodium channel inhibitor therapeutically effective for CPVT in the absence of the compound.

[0318]

[0221] In some embodiments, the sodium channel inhibitor is flecainide or a pharmaceutically acceptable salt thereof. An amount of flecainide or a pharmaceutically acceptable salt less than the amount used to treat CPVT in the absence of the compound can be an amount less than the dose of flecainide or a pharmaceutically acceptable salt thereof that is therapeutically effective for CPVT in the absence of the compound, for example, 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% of a dose of flecainide or a pharmaceutically acceptable salt that is therapeutically effective for CPVT in the absence of the compound.

[0319]

[0222] In some embodiments, left sympathetic denervation can be used as part of a treatment regimen for CPVT. In some embodiments, a method for treating CPVT includes the use of a beta-blocker in combination with sympathetic denervation. In some embodiments, a method for treating CPVT includes the use of a sodium channel inhibitor in combination with sympathetic denervation. In some embodiments, a method for treating CPVT includes the use of a sodium channel inhibitor and a beta-blocker in combination with sympathetic denervation. In some embodiments, a method for treating CPVT includes the use of a compound described herein or a pharmaceutically acceptable salt thereof in combination with sympathetic denervation. In some embodiments, a method for treating CVPT includes the use of a compound and a beta-blocker in combination with sympathetic denervation. In some embodiments, a method for treating CPVT includes the use of a compound and a sodium channel inhibitor in combination with sympathetic denervation. In some embodiments, a method for treating CPVT includes the use of a compound, a sodium channel inhibitor, and a beta-blocker in combination with sympathetic denervation. In some embodiments, the subject has an implantable cardioverter-defibrillator (ICD).

[0320] Lyanodine receptor 1 and musculoskeletal diseases

[0223] In some embodiments, the RyR-related condition is a musculoskeletal disorder or disease involving ryanodine receptor 1 (RyR1). The RyR1 macromolecular complex consists of a tetramer of 560-kDa RyR1 subunits that forms a scaffold for proteins that modulate channel function, including PKA and phosphodiesterase 4D3 (PDE4D3), protein phosphatase 1 (PP1), and calstabine 1. The A kinase anchor protein (mAKAP) targets RyR1 with PKA and PDE4D3, and spinophilin targets PP1 as the channel. The catalytic and regulatory subunits of PKA, PP1, and PDE4D3 modulate PKA-mediated phosphorylation of RyR1 at Ser2843 (Ser2844 in mice). PKA-mediated phosphorylation of RyR1 at Ser2844 is linked to cytoplasmic Ca 2+This increases the channel's sensitivity, reduces the binding affinity of calstabine 1 to RyR1, and destabilizes the channel's closed state.

[0321]

[0224] The calstabine 1 concentration in skeletal muscle can be set to approximately 200 nM. PKA phosphorylation of RyR1 can reduce the binding affinity of calstabine 1 to RyR1 from approximately 100-200 nM to over 600 nM. Therefore, under physiological conditions, the reduction in the binding affinity of calstabine 1 to RyR1 due to PKA phosphorylation of RyR1 at Ser2843 is sufficient to substantially reduce the amount of calstabine 1 present in the RyR1 complex. Chronic PKA hyperphosphorylation of RyR1 at Ser2843 leads to the creation of leaky channels (i.e., channels that are easily opened at rest), which contribute to skeletal muscle dysfunction associated with persistent hyperadrenergic states, such as those in individuals with heart failure.

[0322]

[0225] Furthermore, regulation of RyR1 by post-translational modifications other than phosphorylation, such as nitrosylation (S-nitrosylation) of the free sulfhydryl group of cysteine ​​residues and channel oxidation, can increase RyR1 channel activity. S-nitrosylation and oxidation of RyR1 can reduce the binding of carstabine 1 to RyR1, respectively.

[0323]

[0226] In some embodiments, the musculoskeletal disorder or disease is a congenital myopathy, i.e., a myopathy present at birth. In some embodiments, the congenital myopathy is caused by a mutated RYR1 gene. In some embodiments, the congenital myopathy is caused by a post-translationally modified RyR1.

[0324]

[0227] In some embodiments, the musculoskeletal disorder is congenital muscular dystrophy (CMD). Congenital muscular dystrophy is present at birth. CMD is classified based on gene mutations: 1) genes encoding structural proteins of the basement membrane or extracellular matrix of skeletal muscle fibers; 2) genes encoding putative or indicated glycosyltransferases that affect the glycosylation of dystroglycans, which are outer membrane proteins of the basement membrane; and 3) others. Non-limiting examples of CMD include RYR1-associated myopathy (RYR1-RM), laminin-α2 deficiency CMD (MDC1A), Ulrich-type CMG (UCMD 1, 2, and 3), Walker-Warburg syndrome (WWS), myo-ophthalmopathy (MEB), Fukuyama-type CMD (FCMD), CMD plus secondary laminin deficiency 1 (MDC1B), CMD plus secondary laminin deficiency 2 (MDC1C), CMD with intellectual disability and pachygyrus (MDC1D), and spinal rigidity with muscular dystrophy type 1 (RSMD1).

[0325] RYR1-related myopathy

[0228] In some embodiments, the musculoskeletal disorder is RYR1-associated myopathy (RYR1-RM). RYR1-associated myopathy (RYR1-RM) is a heterogeneous group of monogenic neuromuscular disorders caused by pathogenic variants in the RYR1 gene. RYR1-RM can be broadly classified into two phenotypic categories based on clinical and histological features: 1) A phenotype having dynamic and incidental symptoms without myopathy mediation between exacerbations, including susceptibility to malignant hyperthermia (MH), potentially lethal hypermetabolic crises in response to certain environmental and pharmacological triggers, exertional rhabdomyolysis, and atypical periodic paralysis. 2) A phenotype having myopathy with apparent variable severity, including severe fetal akinesia, late-onset axial myopathy, and congenital myopathy. The latter can be further subdivided based on histological characteristics into central core disease, multi-minicore disease, congenital fibrous type disproportion, and central nucleus myopathy.

[0326]

[0229] Individuals affected generally exhibit delayed motor milestones, muscle weakness, and gait disturbances, while severe cases all present with scoliosis, ophthalmoplegia, and respiratory distress due to skeletal muscle weakness. Major calcium (Ca) in skeletal muscle 2+ Causative variants in RYR1, which encodes the release channel, have different effects on the RyR1 channel. Variants generally affect the normal Ca between the sarcoplasmic reticulum (SR) and myocyte cytosol. 2+ This disrupts the flow and usually leads to excessive Ca into the cytosol. 2+ Leakage occurs. Persistent Ca 2+ Leakage is necessary for ECC, SR Ca 2+ It reduces chronic SR Ca 2+ Leakage leads to mitochondrial calcium overload, impairing mitochondrial function and manifesting as oxidative overload and reduced ATP production. SR Ca 2+ Leakage can also activate the calcium-activated protease calpain, potentially causing cytotoxicity. Oxidative stress can further contribute to RyR1 Ca through channel oxidation and nitrosylation. 2+ This could be a factor in causing leakage.

[0327]

[0230] Both autosomal dominant (single allele, including de novo pathogenic variants) and recessive (two alleles) patterns of inheritance have been reported to cause RYR1-RM. Classical central core disease is predominantly inherited and typically reflects the relatively mild end of the clinical spectrum, although with a wide range of clinical severity and penetrance. Recessive RYR1-RM can be more severe, especially with one or more missense variants, and may present with compound heterozygotes and lower morphological alleles, presenting with severe muscle weakness, respiratory failure requiring ventilatory support, ophthalmoplegia, and sometimes feeding difficulties requiring the use of a feeding tube in very young children. RYR1-RM significantly impairs function, worsens with age, and may lead to a significant spontaneous increase in disability over time.

[0328]

[0231] In some embodiments, the compounds of the Disclosure can be used to treat RYR1-RM in autosomal dominant subjects. In some embodiments, the compounds of the Disclosure can be used to treat RYR1-RM in recessive subjects. In some embodiments, the compounds of the Disclosure can be used to treat RYR1-RM in compound heterozygous subjects.

[0329]

[0232] In some embodiments, RYR1-related myopathy is congenital, meaning the subject has at least one hereditary mutation in the RyR1 gene. In some embodiments, RYR1-related myopathy is caused by a de novo mutation in the RYR1 gene.

[0330] Muscular dystrophy

[0233] In some embodiments, the musculoskeletal disorder or disease is a 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 1 (DM-1) and myotonic dystrophy 2 (DM2), as well as myotonic muscular dystrophy (DM), congenital muscular dystrophy (CMD), distal muscular dystrophy, Emery-Drefusch muscular dystrophy, and oculopharyngeal muscular dystrophy.

[0331]

[0234] In some embodiments, the compounds of the present disclosure can be used to treat subjects (e.g., patients) with Duchenne muscular dystrophy (DMD). DMD is one of the leading fatal childhood genetic disorders. Mutations in the dystrophin gene (over 4700 identified) result in the absence of dystrophin or the expression of dysfunctional dystrophin, leading to muscle weakness and wasting, exhaustion of muscle regeneration capacity, chronic local inflammation, and replacement of muscle fibers by connective and adipose tissue. Patients with DMD experience progressive decline in muscle function and lose the ability to walk at around 10–12 years of age. Cardiac failure typically appears after the loss of the ability to walk. Death, usually due to respiratory and / or heart failure, occurs by age 30.

[0332]

[0235] Mutations in dystrophin associated with DMD disrupt the junction between the submembrane cytoskeleton and the extracellular matrix. This junction is essential for protecting and stabilizing muscle against contraction-induced injury. Myocyte membrane instability caused by mutations in dystrophin has a cascading effect. One major effect is cytosolic Ca 2+ This is an increase in concentration, Ca 2+ It leads to the activation of the dependent protease (calpain). Another effect is increased inflammation and iNOS activity, which can cause oxidation / nitrosylation of proteins, lipids, and DNA.

[0333]

[0236] Intracellular Ca 2+ It is a mediator of several regulatory processes in skeletal muscle. RyR1 channels isolated from the mouse DMD model (mdx mouse) are hypernitrosylated as a potential consequence of altered nitric oxide downstream signaling due to dystrophin loss, and Ca from SR 2+ Ion leakage increases. Excessive oxidation or nitrosylation of RyR1 may interfere with the interaction between calstabine 1 and the RyR1 complex, leading to RyR1 leakage and muscle weakness. In some embodiments, the compounds of this disclosure prevent calstabine 1 depletion from RyR1 and SR Ca 2+It inhibits leakage, reduces biochemical and histological evidence of muscle damage, improves muscle function, and increases athletic performance.

[0334]

[0237] In some embodiments, the compounds of the present disclosure are Ca in both RyR1 and RyR2. 2+ Leakage can be repaired. Therefore, these compounds may be effective in treating dysfunction in both skeletal muscle and cardiac and pulmonary dysfunction in DMD. Cardiomyopathy is the leading cause of death in the affected population. Compounds targeting dysfunction in both skeletal and cardiac dysfunction may be independently configured to improve both cardiac and skeletal muscle dysfunction in DMD.

[0335]

[0238] The foregoing provides a method for treating DMD, comprising the step of administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject requiring treatment for DMD.

[0336]

[0239] The present invention provides a method for treating skeletal muscle weakness in DMD patients, comprising the step of administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject requiring treatment for skeletal muscle weakness.

[0337]

[0240] The foregoing provides a method for treating cardiomyopathy in a DMD patient, comprising the step of administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject requiring treatment for cardiomyopathy.

[0338]

[0241] In some embodiments, the compounds of the Disclosure can treat or improve muscle weakness in DMD patients. In some embodiments, the compounds of the Disclosure can treat or improve muscle weakness in DMD patients who are able to walk. In some embodiments, the compounds of the Disclosure can treat or improve muscle weakness in DMD patients who are unable to walk. In some embodiments, the compounds of the Disclosure treat or improve cardiac dysfunction in DMD patients who are unable to walk. In some embodiments, the compounds of the Disclosure treat or improve respiratory dysfunction in DMD patients who are unable to walk. In some embodiments, the compounds of the Disclosure treat or improve skeletal muscle, respiratory, and / or cardiac dysfunction in DMD patients, e.g., DMD patients who are unable to walk. A DMD patient who is able to walk may be a patient who has the ability to walk. A DMD patient who is unable to walk may be a patient who has lost the ability to walk.

[0339]

[0242] In some embodiments, the musculoskeletal disorder or disease is cancer cachexia, i.e., cancer-related muscle weakness. In some embodiments, cancer-related muscle weakness is cancer cachexia, for example, cancer cachexia caused by cancer with bone metastases. Muscle weakness and muscle atrophy (cachexia) are common paraneoplastic conditions in cancer patients. These conditions cause significant fatigue and dramatically reduce the patient's quality of life. In certain cancers, such as prostate cancer and breast cancer with bone metastases, RyR1 is oxidized and induced to become leaky. Restoration of leakiness by administration of Rycal compounds improves muscle function. Non-limiting examples of cachexia-related cancers that can be treated with the compounds herein include breast cancer, prostate cancer, bone cancer, pancreatic cancer, lung cancer, colon cancer, and gastrointestinal cancer. These conditions cause significant fatigue and dramatically reduce the patient's quality of life. This disclosure provides a method for treating, preventing, and reducing the likelihood of muscle weakness in cancer patients, based, for example, on the presence of a modified state (e.g., an oxidized state of RyR1) that induces RyR1 to become leaky. Prevention of leakage or reduction of its likelihood by administration of a Rycal compound can improve muscle function.

[0340]

[0243] In some embodiments, the musculoskeletal condition or disease is age-related loss of muscle mass and strength (sarcopenia). Sarcopenia is a contributing factor to disability and increased mortality. RyR1 from aging mice is oxidized, cysteine-nitrosylated, and can deplete calstabine 1 compared to RyR1 from young adults (3-6 months). Treatment of aging mice with Rycal stabilizes the binding of calstabine 1 to RyR1, reduces intracellular calcium leakage, decreases reactive oxygen species (ROS), and reduces tetanic Ca 2+ It can enhance muscle release, muscle-specific strength, and athletic performance.

[0341]

[0244] In some embodiments, the compositions of the present disclosure are useful in treating pancreatic conditions, such as diabetes mellitus. In some embodiments, the compositions of the present disclosure are useful in treating type II diabetes mellitus by reducing the likelihood of intracellular calcium leakage via leaky RyR2. This leakage causes mitochondrial calcium overload and decreased ATP production, and K ATP Channel activation is reduced. This reduction in channel activation blocks plasma membrane depolarization. This blockage reduces the activation of plasma membrane potential-opening calcium channels, which are the primary source of calcium needed for insulin secretion.

[0342] Lyanodine receptor and central nervous system disorders

[0245] In some embodiments, the pharmaceutical compositions described herein are administered to subjects in need. In some embodiments, subjects in need have a condition or disease. In some embodiments, the pharmaceutical compositions described herein are administered to treat subjects in need of a condition or disease, and the pharmaceutical compositions herein reduce the symptoms(s) of the condition or disease.

[0343]

[0246] In some embodiments, the RyR-associated condition is a central nervous system (CNS) disorder or disease involving ryanodine receptor 1 (RyR1). In some embodiments, the RyR-associated condition is a central nervous system (CNS) disorder or disease involving ryanodine receptor 2 (RyR2). In some embodiments, the RyR-associated condition is a central nervous system (CNS) disorder or disease involving ryanodine receptor 3 (RyR3). In some embodiments, the condition is a peripheral central nervous system condition, disorder, or disease. In some embodiments, the condition is a neurological condition, disorder, 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 the Disclosure are useful in improving cognitive function. In some embodiments, the compounds of the Disclosure are useful in treating cognitive impairment. In some embodiments, the compounds of the Disclosure are useful in slowing the progression of cognitive impairment. In some embodiments, the compounds of the Disclosure are useful in reducing the likelihood of developing cognitive impairment.

[0344]

[0247] In some embodiments, the Disclosure relates to a method for treating or reducing the likelihood of a nervous system condition, disorder, or disease by administering a certain amount of a compound described herein, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such a compound, to a subject who requires treatment of such a condition, disorder, or disease of the nervous system or reduction of the likelihood of such a condition occurring.

[0345]

[0248] In some embodiments, the disclosure relates to the use of compounds described herein, for example, compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for treating or reducing the likelihood of the occurrence of nervous system conditions, disorders, and diseases.

[0346]

[0249] In another embodiment, the present disclosure relates to a compound described herein, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound, for use in treating or reducing the likelihood of nervous system conditions, disorders, and diseases.

[0347]

[0250] In some embodiments, conditions, disorders, and diseases that can be treated or prevented by the compounds of the Disclosure include Alzheimer's disease, post-traumatic stress disorder (PTSD), Huntington's disease, neuropathy, paroxysmal disorders, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), spinocerebellar ataxia, and Parkinson's disease.

[0348]

[0251] In some embodiments, the compounds of the present disclosure are useful for treating motor disorders. Non-limiting examples of motor disorders include ataxia, dystonia, chorea, Huntington's disease, functional motor disorders, multiple system atrophy, Parkinson's disease, parkinsonism, motor disorders caused by Alzheimer's disease, progressive supranuclear palsy, restless legs syndrome, tardive dyskinesia, Tourette's syndrome, tremor, and Wilson's disease.

[0349]

[0252] In some embodiments, the motor disorder is or is characterized by a tremor. Non-limiting examples of tremors include essential tremor, parkinsonist tremor, dystonic tremor, cerebellar tremor, psychogenic tremor, orthostatic tremor, and physiological tremor.

[0350]

[0253] In some embodiments, the motor impairment is essential tremor. Essential tremor is a tremor that is predominantly located in both upper limbs, or less frequently in other locations such as the head, neck, vocal cords, or lower limbs. Essential tremor is one of the most common motor impairments and tends to worsen with age. Characteristically, essential tremor is more apparent at rest after attempts to use the upper limbs. Therefore, difficulty with handwriting or drawing is often pronounced.

[0351]

[0254] Other examples of neurodegenerative diseases include Parkinsonian disease, multiple sclerosis, autoimmune disorders, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multiple system degeneration (Schey-Drager syndrome), motor neuron disease, amyotrophic lateral sclerosis, ataxia, corticobasal degeneration, ALS-Parkinson's-dementia complex in Guam, subacute sclerosing panencephalitis, synuclein disease, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease / spinocerebellar ataxia type 3, and olivopont. Examples of prion diseases include cerebellar degeneration, Gildela Tourette's disease, medullary and pseudobulbar palsy, spinal and bulbar muscular atrophy (Kennedy disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sack disease, Sandhoff disease, familial spastic disorder, Wohlfahrt-Kugelberg-Welander disease, spastic paraplegia, progressive multifocal leukoencephalopathy, Creutzfeldt-Jakob disease, Gerstmann-Streussler-Scheinker disease, Kuru, and fatal familial insomnia.

[0352]

[0255] Neurodegenerative diseases include ischemic and hemorrhagic stroke, spinal cord injury, brain injury, schizophrenia, autism, ataxia, amyotrophic lateral sclerosis, Lou Gehrig's disease, Lyme disease, meningitis, migraine, motor neuron disease, pain, brain injury, brain dysfunction, spinal cord injury, peripheral nervous system disorders, cranial nerve disorders, autonomic nervous system disorders, sleep disorders, headaches, back pain and neck pain, neuropathic pain, dementia, delirium and dementia, dizziness and vertigo, stupor and coma, head trauma, stroke, tumors of the nervous system, infections of the brain or spinal cord, prion diseases, depression, and drug addiction.

[0353]

[0256] Dementia refers to a decline in cognitive function that exceeds the decline expected from 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 skills. Types and causes of dementia include Alzheimer's disease, vascular dementia (also known as polyinfarct dementia), Binswanger's disease, Lewy body dementia (DLB), persistent alcoholic dementia, frontotemporal dementia (FTLD), Pick's disease, frontotemporal dementia (or frontal FTLD), semantic dementia (or temporal FTLD), progressive non-fluent aphasia, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, and AIDS-dementia complex.

[0354]

[0257] Amyotrophic lateral sclerosis, 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 motor neuron death. Non-specific examples of ALS include classical ALS (typically affecting both lower and upper motor neurons), primary lateral sclerosis (PLS, typically affecting only upper motor neurons), progressive bulbar palsy (PBP, or a bulbar palsy-type version of ALS that typically begins with difficulty swallowing, chewing, and speaking), progressive muscular atrophy (PMA, typically affecting only lower motor neurons), and familial ALS (a genetic version of ALS).

[0355]

[0258] Multiple sclerosis, or MS, is a progressive neurodegenerative disease that leads to the destruction of the myelin sheath of nerve cells, particularly those in the brain and spinal cord. Non-specific examples of multiple sclerosis include relapsing-remitting multiple sclerosis (RRMS), typically characterized by partial or complete recovery (also called exacerbation, relapse, or flare) after an attack; secondary progressive multiple sclerosis (SPMS), generally characterized by fewer relapses and increasing disability and symptoms; and primary progressive multiple sclerosis (PPMS), generally characterized by progression of symptoms and disability without remission.

[0356]

[0259] Alzheimer's disease, or AD, is a progressive neurodegenerative disorder characterized by dementia and defined by the American Psychiatric Association (in DSM-IV) as the appearance of a variety of cognitive deficits, including memory impairment.

[0357]

[0260] Parkinson's disease is a neurodegenerative disease. Many of the signs and symptoms associated with Parkinson's disease may precede typical Parkinson's disease by several years, in some cases. The involvement of the substantia nigra, which underlies the main motor features of the disease, occurs when the disease has progressed sufficiently to a neuropathological level. The motor features of Parkinson's disease are characterized by muscle rigidity, tremors, gait and postural abnormalities, slowing of physical movement (bradykinesia), and, in extreme cases, loss of physical movement (akinegy). The primary symptoms are a result of reduced stimulation of the motor cortex and other areas of the brain by the basal ganglia, usually caused by insufficient formation and action of dopamine produced in the brain's dopaminergic neurons. The motor features of Parkinson's disease are only one component of a much more widespread disorder that causes a wealth of non-motor 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 several years to more than 10 years.

[0358]

[0261] Parkinson's disease-like disorders: Several other conditions exhibit features of Parkinson's disease and are referred to synonymously as Parkinson's disease-like disorders, secondary parkinsonism, Parkinsonian syndromes, or atypical Parkinson's disease. These neurological syndromes may be characterized by tremors, hypokinesia, rigidity, and postural instability. Several etiologies can lead to similar symptoms, including certain toxins, metabolic disorders, and non-PD neurological conditions. Common causes include medications, primarily neuroleptic antipsychotics, especially phenothiazines (such as perphenazine and chlorpromazine), thioxanthenes (such as flupentixol and zuclopentixol), and butyrophenones (such as haloperidol (Haldol)), piperazines (such as ziprasidone), and rarely, side effects of antidepressants. Other causes include, but are not limited to, olivopontocerebellar degeneration; progressive supranuclear palsy; corticobasal degeneration; temporal-frontal dementia; drug-induced causes by antipsychotics, prochlorperazine, or metoclopromide; carbon monoxide poisoning; head trauma; and Huntington's disease parkinsonism. In some cases, alpha-synuclein disease may result in parkinson's disease-like disorders, secondary parkinsonism, parkinsonian syndromes, or atypical parkinsonism. In some embodiments, the methods described herein are used to diagnose parkinson's disease-like disorders, secondary parkinsonism, and parkinsonian syndromes.

[0359] Cognitive dysfunction

[0262] In some embodiments, the compounds of the Disclosure are useful in treating cognitive impairment. In some embodiments, the Disclosure relates to a method for treating cognitive impairment, reducing its likelihood of occurrence, or improving cognitive function by administering a certain amount of a compound described herein, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such a compound, to a subject who requires treatment of cognitive impairment or reduction of its likelihood of occurrence, or improvement of cognitive function.

[0360]

[0263] In some embodiments, the disclosure relates to the use of compounds described herein, for example, compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, for treating cognitive impairment, reducing its likelihood of occurrence, or improving cognitive function.

[0361]

[0264] In some embodiments, the present disclosure relates to a compound described herein, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound, for use in treating cognitive impairment or reducing its likelihood of occurrence, or for improving cognitive function.

[0362]

[0265] In some embodiments, cognitive impairment is related to stress-related cognitive impairment, age-related cognitive impairment, or a combination thereof. In some embodiments, cognitive impairment is related to a disease. Non-exclusive examples of diseases associated with cognitive impairment include 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.

[0363]

[0266] In some embodiments, the compounds of the present disclosure improve cognitive functions, such as short-term memory, long-term memory, attention, learning, and any combination thereof.

[0267] The compounds of this disclosure are useful as treatments for various conditions in subjects, for example, patients. In some embodiments, the subjects are neonates. In some embodiments, the subjects are 1 year of age or older. In some embodiments, the subjects are 2 years of age or older. In some embodiments, the subjects are 3 years of age or older. In some embodiments, the subjects are 4 years of age or older. In some embodiments, the subjects are 5 years of age or older. In some embodiments, the subjects are approximately 5 to approximately 12 years of age. In some embodiments, the subjects are 5 years or younger, 6 years or younger, 7 years or younger, 8 years or younger, 9 years or younger, 10 years or younger, 11 years or younger, 12 years or younger, 13 years or younger, 14 years or younger, or 15 years or younger. In some embodiments, the subjects are 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 embodiments, the subjects are about 4 to about 12 years old, about 5 to about 12 years old, about 6 to about 12 years old, about 7 to about 12 years old, about 8 to about 12 years old, about 9 to about 12 years old, about 10 to about 12 years old, about 10 to about 16 years old, about 12 to about 16 years old, about 14 to about 16 years old, about 10 to about 18 years old, about 12 to about 18 years old, about 14 to about 18 years old, or about 16 to about 18 years old. In some embodiments, the target age group is approximately 10 to 120 years old, 11 to 120 years old, 12 to 120 years old, 13 to 120 years old, 14 to 120 years old, 15 to 120 years old, 16 to 120 years old, 17 to 120 years old, or 18 to 120 years old.

[0364] Pharmaceutical composition

[0268] The compounds of the present disclosure are formulated into pharmaceutical compositions for administration to human subjects in a biocompatible form suitable for in vivo administration. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the compounds of the present disclosure mixed with a pharmaceutically acceptable diluent and / or carrier. The pharmaceutically acceptable carrier is preferably compatible with the other components of the composition and is not harmful to the recipient.

[0365]

[0269] The compound may be administered alone, but preferably with one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carriers used herein may be selected from a variety of organic or inorganic materials used as materials for pharmaceutical formulations and incorporated as one or more of the following: fillers, diluents, binders, disintegrants, buffers, colorants, emulsifiers, flavor enhancers, gelling agents, flowing agents, preservatives, solubilizers, stabilizers, suspending agents, sweeteners, isotonic agents, wetting agents, emulsifiers, dispersants, swelling agents, retarders, lubricants, absorbents, and thickeners.

[0366]

[0270] The compounds of this disclosure may be administered as pharmaceutical compositions for administration in a neat or biocompatible form suitable for in vivo administration to human or animal subjects. Subjects may be, for example, the elderly, adults, adolescents, preadolescents, children, infants, neonates, and non-human animals. In some embodiments, the subject is a patient.

[0367]

[0271] The compounds of the Disclosure may be administered to human or animal subjects by procedures including, but not limited to, oral, sublingual, buccal, parenteral (intravenous, intramuscular, or subcutaneous), transdermal, transdermal, intranasal, vaginal, rectal, ocular, and respiratory (via inhalation). The compounds of the Disclosure may also be administered to subjects by delivery to the subject's muscles, including, but not limited to, the subject's heart or skeletal muscle. In one embodiment, the compound is administered to the subject by targeted delivery to cardiomyocytes via a catheter inserted into the subject's heart. In some embodiments, the compound may be administered directly to the CNS, for example, by intralumbar injection or intraventricular infusion into the cerebrospinal fluid (CSF), or by intraventricular, intrathecal, or intrastitious administration. Administration may be to the subject's muscles, for example, the subject's heart or skeletal muscle. In some embodiments, the compound is administered to the subject by targeted delivery to cardiomyocytes via a catheter inserted into the subject's heart. In some embodiments, the compound is administered orally.

[0368]

[0272] Pharmaceutical compositions according to this disclosure for solid oral administration include, in particular, tablets or dragees, sublingual tablets, orally disintegrating tablets, sachets, capsules including gelatin capsules, powders, lozenges, and granules, and for liquid oral, nasal, buccal, or ocular administration, in particular, emulsions, solutions, oils, suspensions, drops, syrups, and aerosols. Compounds may also be administered as suspensions or solutions via drinking water or food. Examples of acceptable pharmaceutical carriers include, in particular, cellulose derivatives including carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, and microcrystalline cellulose; sugars such as mannitol, sucrose, or lactose; glycerin, acacia gum, magnesium stearate, sodium stearyl fumarate, physiological saline, sodium alginate, starch, talc, and water.

[0369]

[0273] Pharmaceutical compositions according to the present disclosure for parenteral injection include sterile solutions, dispersions, suspensions or emulsions, which may be aqueous or non-aqueous, and also sterile powders for reconstitution of injection solutions or dispersions. The compounds of the present disclosure can be combined with sterile aqueous solutions that are isotonic with the blood of the subject. Such formulations are prepared by dissolving a solid active ingredient in water containing a physiologically compatible substance such as sodium chloride or glycine and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and then sterilizing the solution. The formulations are provided in unit or multi-dose containers such as sealed ampoules or vials. The formulations are delivered to the heart of the subject by any mode of injection, including but not limited to fascial, intracapsular, intracranial, intradermal, intrathecal, intramuscular, intraorbital, intraperitoneal, intraspinal, intrasternal, intravascular, intravenous, intraparenchymal, subcutaneous, or sublingual, or via catheter.

[0370]

[0274] Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and pharmaceutical compositions for transdermal administration include powders, aerosols, creams, ointments, gels, and patches.

[0371]

[0275] In transdermal administration, the compounds of the present disclosure are combined with skin penetration enhancers such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, and N-methylpyrrolidone to increase the skin's permeability to the compounds of the present disclosure, allowing the compounds to penetrate the skin into the bloodstream. The compound / enhancing agent composition can be further combined with polymeric substances such as ethylcellulose, hydroxypropylcellulose, ethylene / vinyl acetate, and polyvinylpyrrolidone to produce the composition in gel form. It is dissolved in a solvent, evaporated to the desired viscosity, and then applied to a base material to produce a patch.

[0372]

[0276] Non-limiting examples of pharmaceutically acceptable excipients or carriers include organic or inorganic materials used as materials for pharmaceutical formulations, which are incorporated as one or more of the following: fillers, diluents, binders, disintegrants, buffers (pH adjusters), colorants, emulsifiers, flavor enhancers, gelling agents, fluidizing agents, surfactants (wetting agents), preservatives, solubilizers, stabilizers, suspending agents, sweeteners, isotonic agents, emulsifiers, dispersants, swelling agents, retarders, lubricants, absorbents, plasticizers, and thickeners.

[0373]

[0277] Pharmaceutically acceptable excipients may be present in a pharmaceutical composition in an amount of approximately 0.1% to approximately 99% by mass of the composition. For example, pharmaceutically acceptable excipients may be present in a pharmaceutical composition in amounts of approximately 0.1% to approximately 95% by mass, approximately 0.11% to approximately 90% by mass, approximately 0.1% to approximately 85% by mass, approximately 0.1% to approximately 80% by mass, approximately 0.1% to approximately 75% by mass, approximately 0.1% to approximately 70% by mass, approximately 0.1% to approximately 65% ​​by mass, approximately 0.1% to approximately 60% by mass, approximately 0.1% to approximately 55% by mass, and approximately 0.1% by mass. Mass% to approximately 50 mass%, approximately 0.1 mass% to approximately 45 mass%, approximately 0.11 mass% to approximately 40 mass%, approximately 0.1 mass% to approximately 35 mass%, approximately 0.1 mass% to approximately 30 mass%, approximately 0.1 mass% to approximately 25 mass% %, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 1% by weight.

[0374]

[0278] Pharmaceutically acceptable excipients are 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 10% of the formulation. 19%, 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 It may exist as 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% by mass.

[0375]

[0279] The compounds of this disclosure may be formulated in pharmaceutical compositions for immediate release. The compounds of this disclosure may be formulated in pharmaceutical compositions for extended release.

[0280] In some embodiments, the compound is formulated to provide a long-lasting 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.

[0376]

[0281] In some embodiments, the compound is formulated to result in the immediate release of the compound. The release of the active ingredient may occur according to 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 may be released within one hour after administration.

[0377]

[0282] In some embodiments, the compound is formulated to result in an extended release of the compound. The term “extended release” can refer to the release of the active ingredient being slower than that from an immediate-release dosage form. The sustained-release properties of a composition are typically measured by an in vitro dissolution method and supported by an in vivo blood concentration-time profile (i.e., a pharmacokinetic profile). For example, a pharmaceutical composition comprising the compound herein or a pharmaceutically acceptable salt thereof in a unit dosage form that is an extended-release dosage form can release the compound or a pharmaceutically acceptable salt thereof in a controlled manner such that, when the unit dosage form is administered to a study subject in a study (e.g., a comparative study with a control group), a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is present in the subject for a period of time, which 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, when a unit dosage form is administered to a study subject in a study (e.g., a comparative study with a control group), a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is present in the subject for a period of time, which occurs after administration and is at least about 24 hours. In some embodiments, the time 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 administration.

[0378]

[0283] In some embodiments, the compound is formulated to result in a delayed release of the compound. In some embodiments, the delayed-release formulation releases the compound after a lag time, which can be, for example, about 1 to 6 hours, about 1 to 2 hours, about 2 to 4 hours, or about 4 to 6 hours after administration. In some embodiments, the delayed-release formulation releases the compound after a lag time, which can 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 the immediate-release profile or the extended or controlled-release profile described herein.

[0379]

[0284] In some embodiments, the delayed-release formulation is a gastric-resistant formulation. In some embodiments, the delayed-release formulation is a gastric-resistant formulation in unit dosage form. In some embodiments, the delayed-release formulation is a gastric-resistant formulation in unit solid dosage form. In some embodiments, the gastric-resistant formulation is a gastric-resistant tablet.

[0380]

[0285] Gastric-resistant tablets are delayed-release tablets that resist acidic gastric juices and release their active substances in intestinal fluids. Gastric-resistant tablets can be prepared from granules or particles already coated with a gastric-resistant coating, or by coating tablets with a gastric-resistant coating (e.g., enteric-coated tablets). The pH range of fluids in various segments of the gastrointestinal tract provides environmental stimuli for responsive drug release.

[0381]

[0286] In some embodiments, an enteric-coated gastric-resistant tablet comprises two layers: (1) a drug-containing core (with immediate release function); and (2) an enteric coating layer containing an enteric polymer that substantially covers the core. The tablet substantially does not release the drug in the stomach due to the acid resistance of the enteric coating layer. The enteric coating layer dissolves rapidly after gastric emptying, resulting in rapid drug release from the tablet core.

[0382]

[0287] In some embodiments, an enteric-coated gastric-resistant tablet comprises three layers: (1) a drug-containing core (immediate-release function); (2) a subcoat layer substantially covering the core, which may include a swellable hydrophobic polymer layer (e.g., hydroxypropylcellulose or hypromellose (hydroxypropylmethylcellulose) (time-release function)); and (3) an enteric coating layer containing an enteric polymer substantially covering the subcoat layer (acid-resistant function). The tablet substantially does not release the drug in the stomach due to the acid resistance of the outer enteric coating layer. The enteric coating layer dissolves rapidly after gastric emptying, and the enteric fluid begins to erode the subcoat polymer layer. Rapid drug release occurs after gastric emptying when the front of the erosion reaches the tablet core. The time required for the tablet core to become accessible by the dissolution of the erosion layer is the delay phase, which can be controlled by the mass or composition of the polymer in the subcoat layer.

[0383]

[0288] In some embodiments, gastric-resistant formulations are delayed-release formulations due to pH sensitivity resulting from, for example, an enteric coating, and modified-release formulations due to, for example, the presence of polymers in a subcoat 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, the presence of polymers in the undercoat layer can result in a longer-lasting release of the active ingredient compared to an immediate-release formulation due to the slow erosion (delay phase) of the formulation. In some embodiments, gastric-resistant formulations have a release profile that is a combination of a delayed-release profile due to, for example, the presence of an enteric coating and a long-lasting release profile due to, for example, the presence of polymers, for example, in a subcoat layer.

[0384]

[0289] In some embodiments, gastric-resistant formulations are resistant to disintegration in gastric juice. For example, in some embodiments, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the active ingredient is released from the formulation in gastric juice or at a pH that mimics the pH of gastric juice. The pH of gastric juice varies with the presence or absence of food and typically ranges from about 1.5 to about 3.5. In some embodiments, gastric-resistant formulations do not substantially disintegrate for at least about 15 minutes after exposure to gastric juice. For example, gastric-resistant formulations do 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 longer, after exposure to gastric juice. In some embodiments, gastric-resistant formulations are resistant to disintegration in gastric juice in the absence of food. In some embodiments, gastric-resistant formulations are resistant to disintegration in gastric juice in the presence of food.

[0385]

[0290] In some embodiments, gastric-resistant formulations (e.g., gastric-resistant tablets) do not substantially disintegrate at pH 5.5 or lower. For example, gastric-resistant formulations (e.g., gastric-resistant tablets) release less than about 10% of the active ingredient at pH 5.5 or lower. For example, gastric-resistant formulations (e.g., gastric-resistant tablets) release 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 1% of the active ingredient at pH about 5.5 or lower.

[0386]

[0291] In some embodiments, the gastric-resistant formulation remains substantially undisintegrated after exposure to a pH of about 5.5 or less, for example, about 4.5 or less, about 4.0, about 3.5, about 3.0, about 2.5, about 2.0, or less. In some embodiments, the gastric-resistant formulation remains substantially undisintegrated for at least about 15 minutes after exposure to a pH of about 5.5 or less. For example, the gastric-resistant formulation remains substantially undisintegrated 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 of about 5.5 or less.

[0387]

[0292] In some embodiments, gastric-resistant formulations (e.g., gastric-resistant tablets) substantially disintegrate at a neutral pH (pH=7) or near-neutral pH, for example, pH 6.8 or higher. In some embodiments, delayed-release formulations release 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 pH about 6.8 or higher. Such release may occur rapidly, for example, within 30 minutes, or 40 minutes, or 50 minutes, or 60 minutes, or 120 minutes, or 180 minutes, after the enteric coating and / or subcoat layers have been eroded and the drug-containing core has been exposed.

[0388]

[0293] In some embodiments, gastric-resistant formulations (e.g., tablets) include an enteric coating layer. 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.

[0389]

[0294] When the formulation reaches the small intestine, the enteric coating dissolves and the active ingredient is released. The release of the active ingredient may occur according to an immediate release profile. Within one hour of reaching the small intestine, 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 may be released.

[0390]

[0295] In some embodiments, disintegration is determined by measuring the dissolution of the gastric-resistant formulation in a medium having a pH less than 5.5, for example, a pH of about 1.0 to about 2.0, or a pH of about 4.0 to 5.0, for example, a pH of about 4.5. In some embodiments, disintegration is determined by measuring the dissolution of the gastric-resistant formulation in a medium having a pH of about 6.5 to about 7.0, for example, a pH of about 6.8.

[0391]

[0296] In some embodiments, a medium having a pH less than 5.5 is an HCl solution having a pH of about 1.2. In some embodiments, a medium having a pH less than 5.5 is a 0.1N HCl solution having a pH of about 1.2. In some embodiments, a medium having a pH of 6.8 is a phosphate buffer.

[0392]

[0297] In some embodiments, the enteric coating layer dissolves rapidly after gastric emptying, and the intestinal fluid begins to erode the subcoat polymer layer. Rapid drug release occurs after the front of the erosion reaches the tablet core after gastric emptying. The time required for the tablet core to become accessible due to the dissolution of the erosion layer is called the "delay phase". In some embodiments, the delay phase can be controlled by changing the mass of the polymer in the subcoat layer. In some embodiments, the delay phase can be controlled by changing the properties of the polymer in the subcoat layer. In some embodiments, the delay phase can be controlled by changing the mass and composition of the polymer in the subcoat layer. In some embodiments, the polymer is hydroxypropyl cellulose. In some embodiments, the polymer is hypromellose (hydroxypropyl methylcellulose).

[0393]

[0298] In some embodiments, the gastric-tolerant pharmaceutical compositions of the Disclosure are administered to subjects in a fed state (e.g., during a meal or within approximately 1, 2, 3, 4, 5, 6, or 7 hours after a meal). In some embodiments, the gastric-tolerant pharmaceutical compositions of the Disclosure are administered to subjects in a fasted state (e.g., at least approximately 8, 9, 10, 11, or 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.

[0394]

[0299] In some embodiments, the gastric resistance pharmaceutical compositions of the present disclosure are administered in combination with an acid inhibitor. For example, a subject administered with the gastric resistance composition is also administered with an acid inhibitor regimen. In some embodiments, the acid inhibitor is administered simultaneously with the gastric resistance pharmaceutical composition. In some embodiments, the acid inhibitor is administered sequentially before or after the gastric resistance pharmaceutical composition. In some embodiments, the acid inhibitor is administered at most about 1 hour, at most about 2 hours, at most about 3 hours, at most about 4 hours, at most about 5 hours, at most about 6 hours, at most about 7 hours, at most about 8 hours, at most about 9 hours, at most about 10 hours, at most about 11 hours, or at most about 12 hours before the gastric resistance preparation. In some embodiments, the gastric acid inhibitor is administered at a maximum of approximately 1 hour, or at a maximum of approximately 2 hours, or at a maximum of approximately 3 hours, or at a maximum of approximately 4 hours, or at a maximum of approximately 5 hours, or at a maximum of approximately 6 hours, or at a maximum of approximately 7 hours, or at a maximum of approximately 8 hours, or at a maximum of approximately 9 hours, or at a maximum of approximately 10 hours, or at a maximum of approximately 11 hours, or at a maximum of approximately 12 hours after the gastric-resistant preparation.

[0395]

[0300] Non-limiting examples of pharmaceutically acceptable fillers / diluents include cellulose derivatives, including microcrystalline cellulose, silicified microcrystalline cellulose, carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and ethylcellulose, starch, sugars, such as mannitol, sucrose, lactose, sorbitol, dextrin (e.g., maltodextrin), amino sugars, alginic acid, sodium alginate, and water.

[0396]

[0301] Non-limiting examples of pharmaceutically acceptable binders include microcrystalline cellulose, tragacanth gum, acacia gum, gelatin, polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose, and starch.

[0397]

[0302] Non-limiting examples of pharmaceutically acceptable disintegrants include roscarmellose sodium, carboxymethyl starch sodium, and crospovidone.

[0398]

[0303] Non-limiting examples of pharmaceutically acceptable lubricants include stearates such as magnesium stearate or zinc stearate, stearic acid, sodium stearyl fumarate, talc, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol, and hydrogenated vegetable oils.

[0399]

[0304] Non-limiting examples of pharmaceutically acceptable fluidizing agents include colloidal silicon dioxide, talc, tricalcium phosphate, calcium silicate, cellulose, magnesium silicate, magnesium trisilicate, starch, magnesium stearate, talc, and mineral oil. Non-limiting examples of moisture-proofing agents include stearic acid.

[0400]

[0305] A non-limiting example of a pharmaceutically acceptable plasticizer is triethyl citrate.

[0306] Examples of pharmaceutically acceptable surfactants include sodium lauryl sulfate or polysorbate, polyvinyl alcohol (PVA), polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymer called "poloxamer," polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate (Tween), polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, and hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil.

[0401]

[0307] Non-limiting examples of pharmaceutically acceptable flavorings include sweeteners, such as sucralose, as well as synthetic flavoring oils and aromatic compounds, natural oils, extracts derived from plants, leaves, flowers, and fruits, and combinations thereof. Non-limiting examples of flavorings include cinnamon oil, wintergreen oil, peppermint oil, clover oil, hay oil, anise oil, eucalyptus, peppermint, vanilla, citrus oils, such as lemon oil, orange oil, grape and grapefruit oil, as well as fruit essences, including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0402]

[0308] Non-limiting examples of pharmaceutically acceptable pigments or colorants include alumina (dried aluminum hydroxide), annat extract, calcium carbonate, canthaxanthin, caramel, β-carotene, cochineal extract, carmine, sodium potassium copper chlorophyllin (chlorophyllin-copper complex), dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ammonium ferric ferrocyanide, iron ferrocyanide, chromium hydroxide green, chromium oxide green, guanine, mica-based pearlescent pigments, pyrophyllite, mica, toothpaste, talc, titanium dioxide, aluminum powder, bronze powder, copper powder, and zinc oxide.

[0403]

[0309] 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.

[0404]

[0310] Non-limiting examples of isotonic enhancers include alkali metal halides or alkaline earth metals, urea, glycerol, sorbitol, mannitol, propylene glycol, and ionic and nonionic activators such as dextrose.

[0405]

[0311] Non-limiting examples of wetting agents include glycerin, cetyl alcohol, and glycerol monostearate.

[0312] Non-limiting examples of preservatives include benzalkonium chloride, benzoxonium chloride, thiomersal, phenylmercury nitrate, phenylmercury acetate, phenylmercury borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl alcohol, chlorohexidine, and polyhexamethylene biguanide.

[0406]

[0313] Non-limiting examples of antioxidants include sorbic acid, ascorbic acid, ascorbate, glycine, α-tocopherol, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

[0407]

[0314] In some embodiments, the solid dosage form is coated. In some embodiments, the solid dosage form includes a core, a base layer substantially surrounding the core, and a coating layer substantially surrounding the base layer.

[0408]

[0315] In some embodiments, the undercoat layer includes a swellable polymer such as a swellable hydrophobic polymer layer (e.g., hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC)).

[0409]

[0316] In some embodiments, the coating layer includes an enteric polymer. Non-limiting examples of enteric polymers include hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate, HPMC-AS), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, methacrylic acid / methacrylic acid ester copolymer (e.g., poly(methacrylate-co-methylmethacrylate), methacrylic acid / acrylic acid ester copolymer, shellac (ester of aleuric acid)).

[0410]

[0317] In some embodiments, a pharmaceutically acceptable carrier or excipient is used to formulate a liquid, gel, syrup, elixir, slurry, or suspension for oral administration by the subject. Non-limiting examples of solvents used in orally soluble formulations include water, ethanol, isopropanol, saline, DMSO, potassium phosphate buffer, phosphate-buffered saline (PBS), sodium phosphate buffer, 4-2-hydroxyethyl-1-piperazineethanesulfonic 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 cosolvents used in orally soluble formulations include sucrose, urea, cremafoll, and potassium phosphate buffer.

[0411] Preparation method

[0318] The pharmaceutical formulations of this disclosure are prepared by methods known in pharmaceutical technology, including but not limited to wet and dry granulation methods, or by direct compression. The choice of carrier is determined by the solubility and chemical properties of the compound, the selected route of administration, and standard pharmaceutical practices.

[0412]

[0319] The pharmaceutical compositions described herein may be manufactured by preferred pharmacological techniques. Preferred 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) milling; (6) roller compression; or (7) fusion. Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Ulster coating), tangential coating, top spray, tableting, and hot melt extrusion.

[0413]

[0320] In some embodiments, the tablets disclosed herein are prepared by a wet granulation method. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, such as water, to agglomerate the powder into granules. The granules are dried, then screened and / or milled to a desired particle size. The granules are then made into tablets, or other excipients, such as fluidizers and / or lubricants, may be added before tableting.

[0414]

[0321] 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, such as water. A wet granule is obtained, which can be dried and optionally sieved to obtain a dry granule. The dry granule can be mixed with one or more additional pharmaceutically acceptable excipients, optionally sieved, and compressed into a tablet.

[0415]

[0322] In some embodiments, the tablets disclosed herein are prepared by a dry granulation method. In some embodiments, the dry granulation method is a slugging method. Slugging is a dry granulation method in which an active ingredient, in combination with one or more excipients of choice, is first compressed to form a slag, and then milled to form fine particles suitable for further processing. For example, a blend composition of an active ingredient and pharmaceutically acceptable excipients can be condensed into a slag or sheet and then ground into condensed granules. The condensed granules can then be compressed into tablets.

[0416]

[0323] In some embodiments, granulation of the active ingredient can be achieved by a dry granulation method.

[0324] In other embodiments, the blended composition may be compressed directly into a compacted dosage form using a direct compression technique. Direct compression produces a more uniform tablet without granules.

[0417]

[0325] In some embodiments, the granulation method includes a roller compression method in which powder size expansion is achieved by supplying an active ingredient in combination with one or more wet or dry excipients of choice through a roller device, and then drying, milling, and sizing the compacted mixture (if necessary) to form granules having a desired particle size.

[0418]

[0326] In some embodiments, the capsules described herein may include any of the above blends and granules described relating to tablet manufacturing.

[0327] In some embodiments, the compounds of the Disclosure are poorly soluble in water. In some embodiments, the solubility of the compounds of the Disclosure can be improved by using techniques such as particle size reduction to prepare the compounds in an amorphous state, or by using certain formulation techniques.

[0419]

[0328] In some embodiments, the compounds of the Disclosure are incorporated into a pharmaceutical composition in the form of a solid dispersion (SD). In some embodiments, the compounds of the Disclosure are incorporated into a pharmaceutical composition in the form of an amorphous solid dispersion (ASD). In embodiments, the Disclosure provides methods for preparing either a solid dispersion or an amorphous solid dispersion by spray drying, hot melt extrusion, freeze-drying, co-grinding, co-milling, evaporation, and any combination thereof. A pharmaceutical composition comprising the compounds of the Disclosure may contain the 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 as used herein may include a composition in which at least 90%, at least 95%, or at least 97% of the compound is homogeneously molecularly dispersed in a solid polymer matrix.

[0420]

[0329] In some embodiments, the solid dispersions of the Disclosure (e.g., spray-dried dispersions) include polymers. Any suitable polymer known in the Art may be used in the Disclosure. Exemplary suitable polymers include those selected from cellulosic polymers, polyoxyethylene polymers, polyethylene-propylene glycol copolymers, vinyl polymers, PEO-polyvinylcaprolactam polymers, and polymethacrylate polymers.

[0421]

[0330] In some embodiments, the composition is a lipid-based formulation comprising the compound of the Disclosure in the form of a solution, dispersion, or suspension having at least one lipid. The composition may take the form of lipid nanoparticles.

[0422]

[0331] Examples of cellulosic polymers include methylcellulose, hydroxypropyl methylcellulose (HPMC) (hypromellose), hypromellose phthalate (HPMC-P), hypromellose acetate succinate, and copolymers thereof. Examples of polyoxyethylene polymers include polyethylene-propylene glycol, polyethylene glycol, poloxamer, and copolymers thereof. Examples of vinyl polymers include polyvinylpyrrolidone (PVP) and PVP / VA. Examples of PEO-polyvinylcaprolactam polymers include polyethylene glycol, polyvinyl acetate, and polyvinylcaprolactam graft copolymers (e.g., Soluplus®). Polymethacrylate polymers are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylate, methacrylic acid, and methacrylic acid esters in various ratios. Several types are commercially available and can be obtained as dry powder, aqueous dispersion, or organic solution.

[0423]

[0332] Examples of such polymethacrylate polymers include poly(methacrylic acid, ethyl acrylate) (1:1), dimethylaminoethyl methacrylate-methyl methacrylate copolymer, and Eudragit®.

[0424]

[0333] In some embodiments, the cellulosic polymer is hypromellose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate or HMPCAS) and hypromellose (also known as hydroxypropyl methylcellulose or HPMC), or a combination of hypromellose acetate succinate and hypromellose.

[0425]

[0334] HPMCAS is available in various grades based on the content (weight %) of acetyl and succinoyl groups in the HPMCAS molecule and particle size. For example, HPMCAS grades L, M, and H are available. HPMCAS-H is a grade containing about 10-14% by weight of acetyl groups and about 4-8% by weight of succinoyl groups. Each HPMCAS grade is available in two particle sizes: F (fine) and G (granular). HPMC appears in various types (e.g., HPMC E, F, J, and K types). HPMC type E means that it contains about 28-30% methoxy groups and about 7-12% hydroxypropoxy groups. There are various E grades ranging from low to high viscosity. For example, E3 means that the viscosity of HPMC measured at 2% in water at 20°C is about 2.4-3.6 millipascals·seconds (mPa·s). E15 means that the viscosity of HPMC measured at 2% in water at 20°C is approximately 12-18 mPa·s. E50 means that the viscosity of HPMC measured at 2% in water at 20°C is approximately 40-60 mPa·s.

[0426]

[0335] In some embodiments, the cellulosic polymer is hypromellose acetate succinate and hypromellose, or a combination of hypromellose acetate succinate and hypromellose.

[0427]

[0336] In some embodiments, the cellulosic polymer is hypromellose E15, hypromellose acetate succinate L, or hypromellose acetate succinate H.

[0428]

[0337] In some embodiments, the polyoxyethylene polymer or polyethylene-propylene glycol copolymer is polyethylene glycol or Pluronic®.

[0429]

[0338] In some embodiments, the polyoxyethylene polymer or polyethylene-propylene glycol copolymer is polyethylene glycol 3350 or poloxamer 407.

[0430]

[0339] In some embodiments, the vinyl polymer is a vinyl-polyvinylpyrrolidine polymer such as polyvinylpyrrolidone K30 or polyvinylpyrrolidone VA 64.

[0431]

[0340] In some embodiments, the polymethacrylate polymer is Eudragit L100-55 or Eudragit® E PO.

[0341] In some embodiments, the polymer is selected from cellulosic polymers such as HPMC and / or HPMC AS.

[0432]

[0342] In some embodiments, the polymer is one or more water-soluble polymers or partially water-soluble polymers. Examples of water-soluble or partially water-soluble polymers include, but are not limited to, cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC)) or ethylcellulose; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA); acrylates such as polymethacrylate (e.g., Eudragit® E); cyclodextrin (e.g., β-cyclodextrin), and copolymers and derivatives thereof, including, for example, PVP-VA (polyvinylpyrrolidone-vinyl acetate).

[0433]

[0343] In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC), such as HPMC E50, HPMC E15, or HPMC E3.

[0344] The polymer can be a pH-dependent enteric polymer. Examples of such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or their salts (e.g., sodium salts such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), or polymethacrylate (e.g., Eudragit® S).

[0434]

[0345] 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).

[0435]

[0346] In some embodiments, the polymer is a polyvinylpyrrolidone copolymer, for example, a vinylpyrrolidone / vinyl acetate copolymer (PVP / VA).

[0347] In some embodiments, the compounds of the Disclosure are incorporated into a pharmaceutical composition in the form of a spray-dried dispersion (SSD). In some embodiments, the compounds of the Disclosure are incorporated into a pharmaceutical composition in the form of an amorphous spray-dried dispersion (ASSD).

[0436]

[0348] The above pharmaceutical compositions are illustrative examples of this disclosure, but are not intended to limit this disclosure.

[0349] According to the methods of the present disclosure, any of these compounds may be administered to (or brought into contact with) a subject in an amount effective to limit or reduce the potential decrease in RyR-bound callustabine levels in the subject, particularly in the cells of the subject. This amount may be determined, for example, by the analyses, methods and assays disclosed herein of titration curves established in vivo. Preferred amounts of the compounds of the present disclosure that are effective to limit or prevent the decrease in RyR-bound callustabine levels in a 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 are sufficient to achieve plasma levels ranging from about 300 ng / ml to about 5,000 ng / ml. Alternatively, amounts of the compounds from the present disclosure range from about 1 mg / kg / day to about 50 mg / kg / day. Alternatively, amounts of the compounds from the present disclosure range from about 10 mg / kg / day to about 20 mg / kg / day. This also includes doses of approximately 0.01 mg / kg / day or 0.05 mg / kg / day to approximately 5 mg / kg / day or approximately 10 mg / kg / day that may be administered.

[0437] Administration and administration regimens

[0350] According to the methods of the present disclosure, any of these compounds may be administered to (or brought into contact with) a subject in an amount effective to limit or prevent a decrease in RyR-bound calstabine levels in the subject cells, in particular. Alternatively, the methods of the present disclosure may include the step of administering a compound in an amount effective to treat or prevent a RyR-related condition as described herein.

[0438]

[0351] In some embodiments, preferred amounts of the compound that are effective in limiting or preventing a decrease in the level of RyR-bound carstabin in the subject and / or treating or reducing the likelihood of a RyR-related condition are about 1 to about 2,000 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 The dosage ranges from approximately mg / day, 280 mg / day, 300 mg / day, 320 mg / day, 340 mg / day, 360 mg / day, 380 mg / day, 400 mg / day, 420 mg / day, 440 mg / day, 460 mg / day, 480 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1,000 mg / day, 1,100 mg / day, 1,200 mg / day, 1,300 mg / day, 1,400 mg / day, 1,500 mg / day, 1,600 mg / day, 1,700 mg / day, 1,800 mg / day, 1,900 mg / day, or approximately 2,000 mg / day.

[0439]

[0352] The compounds described herein contain approximately 1 mg to approximately 2000 mg; approximately 1 mg to approximately 1000 mg; approximately 1 mg to approximately 500 mg; approximately 5 mg to approximately 1000 mg, approximately 5 mg to approximately 500 mg, approximately 5 mg to approximately 100 mg, approximately 10 mg to approximately 50 mg, approximately 50 mg to approximately 250 mg, approximately 100 mg to approximately 200 mg, approximately 1 mg to approximately 50 mg, approximately 50 mg to approximately 100 mg, approximately 100 mg to approximately 150 mg, approximately 150 mg to approximately 200 mg, approximately 200 mg to approximately 250 mg, approximately 250 mg to approximately 300 mg It can exist in the range of mg, approximately 300mg to 350mg, approximately 350mg to 400mg, approximately 400mg to 450mg, approximately 450mg to 500mg, approximately 500mg to 550mg, approximately 550mg to 600mg, approximately 600mg to 650mg, approximately 650mg to 700mg, approximately 700mg to 750mg, approximately 750mg to 800mg, approximately 800mg to 850mg, approximately 850mg to 900mg, approximately 900mg to 950mg, or approximately 950mg to 1000mg.

[0440]

[0353] The compounds described herein are present in amounts of approximately 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, and 5 mg in the composition. It can be present in amounts of 50 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, 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.

[0441]

[0354] In some embodiments, the dose can be expressed as the quotient obtained by dividing the amount of drug by the mass of the target, for example, the number of milligrams of drug / the number of kilograms of the mass of the target. In some embodiments, the compound is approximately 0.01 mg / kg to approximately 2,000 mg / kg, approximately 0.01 mg / kg to approximately 1,000 mg / kg, approximately 0.01 mg / kg to approximately 100 mg / kg, approximately 0.01 mg / kg to approximately 10 mg / kg, approximately 0.01 mg / kg to approximately 5 mg / kg, approximately 0.01 mg / kg to approximately 1 mg / kg, approximately 0.01 mg / kg to approximately 0.5 mg / kg, approximately 0.01 mg / kg to approximately 0.1 mg / kg, approximately 0.01 mg / kg to approximately 0.05 mg / kg, approximately 1 mg / kg to approximately 1,000 mg / kg, approximately 1 mg / kg to approximately 500 mg / kg, approximately 1 mg It is administered in amounts ranging from approximately 250 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 5 mg / kg to 50 mg / kg, 5 mg / kg to 10 mg / kg, 5 mg / kg to 20 mg / kg, 10 mg / kg to 50 mg / kg, 10 mg / kg to 20 mg / kg, 250 mg / kg to 2000 mg / kg, 10 mg / kg to 800 mg / kg, 50 mg / kg to 400 mg / kg, 100 mg / kg to 300 mg / kg, or approximately 150 mg / kg to 200 mg / kg. In some embodiments, the compound is administered in amounts of approximately 1 mg / kg, approximately 2 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 20 mg / kg, approximately 50 mg / kg, approximately 100 mg / kg, approximately 150 mg / kg, approximately 200 mg / kg, approximately 250 mg / kg, approximately 300 mg / kg, approximately 350 mg / kg, approximately 400 mg / kg, approximately 450 mg / kg, approximately 500 mg / kg, approximately 550 mg / kg, approximately 600 mg / kg, approximately 650 mg / kg, approximately 700 mg / kg, approximately 750 mg / kg, approximately 800 mg / kg, approximately 850 mg / kg, approximately 900 mg / kg, approximately 950 mg / kg, or approximately 1,000 mg / kg of target mass (kg).

[0442]

[0355] In some embodiments, the dose can be expressed as the quotient obtained by dividing the amount of drug by the mass of the target body per day, for example, the number of milligrams of drug / the number of kilograms of the mass of the target body per day (mg / kg / day / day). In some embodiments, the compound is administered in doses of approximately 0.01 mg / kg / day to approximately 2,000 mg / kg / day, approximately 0.01 mg / kg / day to approximately 1,000 mg / kg / day, approximately 0.01 mg / kg / day to approximately 100 mg / kg / day, approximately 0.01 mg / kg to approximately 10 mg / kg / day, approximately 0.01 mg / kg to approximately 5 mg / kg / day, approximately 0.01 mg / kg / day to approximately 1 mg / kg / day, approximately 0.01 mg / kg / day to approximately 0.5 mg / kg / day, approximately 0.01 mg / kg / day to approximately 0.1 mg / kg / day, approximately 0.01 mg / kg / day to approximately 0.05 mg / kg / day, approximately 1 mg / kg / day to approximately 1,000 mg / kg / day, approximately 1 mg / kg / day to approximately 500 mg / kg / day, and approximately 1 mg / kg / day. The dosage is administered in amounts ranging from approximately 250 mg / kg / day to approximately 1 mg / kg / day to approximately 100 mg / kg / day, approximately 1 mg / kg / day to approximately 50 mg / kg / day, approximately 5 mg / kg / day to approximately 50 mg / kg / day, approximately 5 mg / kg / day to approximately 10 mg / kg / day, approximately 5 mg / kg / day to approximately 20 mg / kg / day, approximately 10 mg / kg / day to approximately 50 mg / kg / day, approximately 10 mg / kg / day to approximately 20 mg / kg / day, approximately 250 mg / kg / day to approximately 2000 mg / kg / day, approximately 10 mg / kg / day to approximately 800 mg / kg / day, approximately 50 mg / kg / day to approximately 400 mg / kg / day, approximately 100 mg / kg / day to approximately 300 mg / kg / day, or approximately 150 mg / kg / day to approximately 200 mg / kg / day.In some embodiments, the compound is administered at 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, and approximately 400 mg / kg / day. It is administered at doses of approximately 450 mg / kg / day, 500 mg / kg / day, 550 mg / kg / day, 600 mg / kg / day, 650 mg / kg / day, 700 mg / kg / day, 750 mg / kg / day, 800 mg / kg / day, 850 mg / kg / day, 900 mg / kg / day, 950 mg / kg / day, or 1,000 mg / kg of target body mass (kg) / day.

[0443]

[0356] In some morphological applications, the compounds of the present disclosure are administered in amounts sufficient to achieve a maximum plasma concentration in the subject (e.g., at steady state), such as about 1 ng / ml to about 5,000 ng / ml, for example, about 50 ng / ml to about 5,000 ng / ml, about 100 ng / ml to about 5,000 ng / ml, about 200 ng / ml to about 5,000 ng / ml, about 300 ng / ml to about 5,000 ng / ml, about 400 ng / ml to about 5,000 ng / ml, about 500 ng / ml to about 5,000 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.

[0444] Numbered embodiments

[0357] Embodiment 1. Compound of formula (I) or a pharmaceutically acceptable salt thereof

[0445] [ka]

[0446] [In the formula, - The A ring is an aryl or a 5-membered or 6-membered heteroaryl (each of which is either unsubstituted or substituted), - X is O, S, S(O), or S(O)², - Y is either CH2 or C(O), - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - R 1 and R 2 Each of these can independently be alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydrogen, C(O)R a , C(O)OR b , or S(O)2R b And, or R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form a heterocycloalkyl moiety. - R 3 Each of these independently consists of alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being 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 groups, together with the carbon atoms to which they are bonded, form condensed cycloalkyl or heterocycloalkyl rings (each of which is either unsubstituted or substituted). - R 4 is an unsubstituted or substituted alkyl group, or hydrogen. - R aThis includes alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydroxy, carboxy, or NHR. c [Here, R c [is alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of these being unsubstituted or substituted)], or hydrogen, - R b is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl (each of which is unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5.

[0447]

[0358] Embodiment 2. The compound according to Embodiment 1, wherein X is sulfur.

[0359] Embodiment 3. The compound according to Embodiment 1 or Embodiment 2, wherein Y is C(O).

[0448]

[0360] Embodiment 4. Formula (I a The compound described in Embodiment 1, which is a compound of ).

[0449] [ka]

[0450]

[0361] Embodiment 5. The compound according to any one embodiment of Embodiments 1 to 4, wherein Z is hydrogen.

[0362] Embodiment 6. Formula (I b The compound described in Embodiment 1, which is a compound of ).

[0451] [ka]

[0452]

[0363] Embodiment 7. A compound according to any one embodiment of Embodiments 1 to 6, wherein n is 1.

[0364] Embodiment 8. The compound according to any one embodiment of Embodiments 1 to 7, wherein R' and R'' are hydrogen.

[0453]

[0365] Embodiment 9. R 1 and R 2 A compound according to any one embodiment of Embodiments 1 to 8, wherein each of the atoms is hydrogen.

[0366] Embodiment 10. R 1 A compound according to any one embodiment of Embodiments 1 to 8, wherein the compound is hydrogen.

[0454]

[0367] Embodiment 11. R 1 A compound according to any one embodiment of Embodiments 1 to 8, wherein the compound is methyl.

[0368] Embodiment 12. R 2 A compound according to any one embodiment of Embodiments 1 to 11, wherein the compound is hydrogen.

[0455]

[0369] Embodiment 13. R 2 A compound according to any one embodiment of embodiments 1 to 8, 10, and 11, wherein the parent is alkyl.

[0370] Embodiment 14. R 2 C(O)R a The compound according to any one embodiment of embodiments 1 to 8, 10, and 11.

[0456]

[0371] Embodiment 15. R 2 However, C(O)R a [Here, R a The compound according to any one embodiment of Embodiments 1 to 8, 10 and 11, wherein is an aryl or heteroaryl compound (each of which is substituted or unsubstituted).

[0457]

[0372] Embodiment 16. R 2 However, C(O)R a [Here, R aThe compound according to any one embodiment of Embodiments 1 to 8, 10 and 11, wherein [the compound is pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridadinyl, triazolyl, oxadiazolyl, or pyrazinyl (each of these being substituted or unsubstituted).

[0458]

[0373] Embodiment 17. R 2 However, C(O)R a [Here, R aThese include pyrimidine-2-yl, pyrimidine-5-yl, 5-aminopyrimidine-2-yl, 5-methoxypyrimidine-2-yl, 1H-pyrazole-3-yl, 2-methyl-1H-pyrazole-3-yl, pyridine-2-yl, 2-chloropyridine-2-yl, 6-chloropyridine-2-yl, 5-chloropyridine-2-yl, 6-hydroxypyridine-2-yl, pyridine-3-yl, and 6-aminopyridine-2-yl. Lysine-3-yl, 2-chloropyridine-3-yl, pyridine-4-yl, 3-phenyl-1H-pyrazole-5-yl, 1H-imidazole-4-yl, 1H-imidazole-2-yl, 1-methyl-1H-imidazole-4-yl, 1-methyl-1H-imidazole-2-yl, thiazole-2-yl, thiazole-4-yl, 4-methyl-1,2,3-thiadiazole-5-yl, 5-phenylisoxane The compound according to any one embodiment of Embodiments 1 to 8, 10 and 11, which is [zole-3-yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5-methyl-3-phenylisoxazole-4-yl, 4-phenylthiazole-2-yl, 1H-tetrazole-5-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, 3-hydroxypyrazine, 4-isopropyl-1,2,3-thiadiazolyl, 3-methylisoxazole-5-yl, 4,4-difluoropiperidine-1-yl, 1,2,4-triazine-3-yl, 4-methylpyrido-2-ylamino, 3-oxopiperazine-1-yl, 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-yl, or piperazine-1-yl].

[0459]

[0374] Embodiment 18. R 1 and R 2Each of these independently consists of hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3-hydroxycyclobutyl, 3,3-difluorocyclobutyl, cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, pyrimidine-2-yl, pyrimidine-2-ylmethyl, pyrimidine-3-ylmethyl, pyrimidine-4-ylmethyl, oxalyl, 2-methoxyethyl, benzyl, 4-carboxybenzyl, 4-carboxymethylbenzyl, tetrahydro-2H-pyran-4-yl, oxetane-3-yl, 1,2,4-thiadiazole-5-yl, 4-aminomethyl-1,2,3-triazole-1-ylmethyl, 4 A compound according to any one embodiment of Embodiments 1 to 8, wherein R1 and R2 are optionally substituted together with the nitrogen atom to which they are bonded, forming a heterocycle or heteroaryl selected from the group consisting of pyrazolidinyl, piperazinyl, 2-oxopiperazinyl, triazolyl, benzotriazolyl, morpholinyl, pyrrolidinyl, or piperidinyl.

[0460]

[0375] Embodiment 19. R 3 The compound according to any one embodiment of Embodiments 1 to 18, wherein the compound is an alkoxy, cycloalkyloxy, or aryloxy (each of which is substituted or unsubstituted), or a halogen.

[0461]

[0376] Embodiment 20. R 3 The compound according to any one embodiment of Embodiments 1 to 18, wherein the compound is a substituted or unsubstituted phenyloxy compound.

[0377] Embodiment 21. R 3The compound according to any one embodiment of Embodiments 1 to 18, wherein the compound is substituted with one or two substituents selected from the group consisting of hydroxyl, fluorine, chlorine, bromine, iodide, CF3, CHF2, methoxy, SO2Me, cyano, and C(O)Me.

[0462]

[0378] Embodiment 22. R 3 The compound according to any one embodiment of Embodiments 1 to 18, wherein each of the elements is independently alkyl, cyclohexyl, alkyloxy, cycloalkyloxy, arylsulfonyl, alkylsulfonyl (alkylsulfony), phenyl, phenoxy, benzo[d][1,3]dioxol-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NH cycloalkyl, -NH-C(O) cycloalkyl, heteroaryl, heterocyclyl, or naphthalenyl (each of these being substituted or unsubstituted), or halogen.

[0463]

[0379] Embodiment 23. R 4 A compound according to any one embodiment of Embodiments 1 to 22, wherein the compound is hydrogen.

[0380] Embodiment 24. A compound according to any one embodiment of Embodiments 1 to 23, which is a pharmaceutically acceptable salt.

[0464]

[0381] Embodiment 25. (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenylphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-bromophenyl)-5-(dimethylaminomethyl)-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-[(4-benzyl-1-piperidyl)methyl]-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[(4-benzyl-1-piperidyl)methyl]-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-methoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(trifluoromethyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-benzyloxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(trifluoromethyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenylphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenoxy)phenyl]-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)-1H-pyrazole-4-yl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-iodophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazepan-3-one; 3-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; 3-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; 4-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; 4-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; (2S,5R)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(1,3-benzodioxol-5-yl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1,3-benzodioxol-5-yl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromo-5-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-naphthyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(1-naphthyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(benzenesulfonyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-methoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(o-tolyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-ethylpropyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(3-amino-4-chlorophenyl)phenyl]-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,4-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chloro-3-iodophenyl)phenyl]-1,4-thiazepan-3-one; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzamide; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]cyclohexanecarboxamide; (2R,5S)-5-(aminomethyl)-2-[3-(4-fluorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-cyclohexylphenyl)-1,4-thiazepan-3-one; 3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]-N-phenyl-benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidine-1-yl)methyl]-1,4-thiazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidine-1-yl)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidine-1-yl)methyl]-1,4-thiazepan-3-one; N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]phenyl]acetamide; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidyl)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidyl)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,3-dimethoxyphenyl)phenyl]-1,4-thiazepan-3-one; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzoic acid; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxyphenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; 2-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]phenoxy]acetic acid; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxopyrrolidine-1-yl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxo-1-pyridyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-hydroxy-1-piperidyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-(((3R,5R,7R)-adamantan-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(cyclohexoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-isopropyl-2-methylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxy-2-methylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxy-3-propyl-phenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-chloro-4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-indole-1-ylphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-methoxyphenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,4-dichlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[2-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1,4-thiazepan-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(methylaminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclohexoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-methyl-4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-dibenzofuran-2-yl-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methylsulfonylphenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; 2-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[4-(4-acetylphenoxy)phenyl]-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(1,3-benzodioxol-5-yloxy)phenyl]-1,4-thiazepan-3-one; 3-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]-5-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(4-anilinophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-chloro-4-phenoxyphenyl)-1,4-thiazepan-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]-3-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(2-methoxy-4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)-2-methoxyphenyl]-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(triazole-1-ylmethyl)-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[4-(aminomethyl)triazole-1-yl]methyl]-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(pyrimidine-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(1,3-benzothiazole-2-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(1,2,4-thiadiazole-5-ylamino)methyl]-1,4-thiazepan-3-one; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; 2-Oxo-2-[[(2R,5S)-3-Oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methylamino]acetate; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide; 4-(aminomethyl)-N-[[(2R,5S)-2-(3-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]benzamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-2H-tetrazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]thiazole-4-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-4-methyl-thiadiazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-5-carboxamide; 6-amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-5-phenyl-isoxazole-3-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-4-phenyl-thiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 1-Methyl-N-[[(2S,5R)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]imidazole-4-carboxamide; 4-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-5-carboxamide 6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]methanesulfonamide 4-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-1H-imidazole-4-carboxamide; 2-Morpholino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]acetamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]morpholine-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide; 5-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiadiazole-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-3-sulfonamide; 4-Fluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]benzenesulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; 1-Methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]imidazole-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide; 3,3-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]cyclobutanecarboxamide; 4,4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]cyclohexanecarboxamide; N-[[(2R,5S)-2-[3-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-1,4-thiazepan-5-yl)methyl)pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-2-pyrimidine-2-ylacetamide; 1-Benzyl-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]urea; 3-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]isoxazole-5-carboxamide; N-[[(2R,5S)-2-[3-(cyclohexoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 4,4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]piperidine-1-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-1,2,4-triazine-3-carboxamide; N-[[(2R,5S)-2-[4-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrazine-2-carboxamide; 6-Chloro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; 2-[5-(4-chlorophenyl)isoxazole-3-yl]-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]acetamide; 6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; 5-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-Methoxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 1-(4-methyl-2-pyridyl)-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]urea N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide; 6-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; 6-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; 2-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]benzamide; 4-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]benzamide; (2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-5-[(1,2,4-thiadiazole-5-ylamino)methyl]-1,4-thiazepan-3-one; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-Chloro-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-5-methoxypyrimidine-2-carboxamide; 5-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-5-methoxypyrimidine-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrazine-2-carboxamide; 3-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; N-[[(2S,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2S,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-1,4-thiazepan-5-yl]methyl]-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]piperazine-1-carboxamide; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylmethylamino)methyl]-1,4-thiazepan-3-one; Methyl 4-[[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methylaminomethyl]benzoate; (2R,5S)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; 4-[[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methylaminomethyl]benzoic acid; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(cyclopropylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(cyclopropylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[(cyclobutylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(tetrahydropyran-4-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(oxetane-3-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[bis(oxetan-3-yl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-((((1r,3S)-3-hydroxycyclobutyl)amino)methyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[(3,3-difluorocyclobutyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[(4-methylthiadiazole-5-yl)methylamino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-4-ylmethylamino)methyl]-1,4-thiazepan-3-one; 4-[[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methylaminomethyl]benzoic acid; 4-[[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methylaminomethyl]benzoic acid; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-bromophenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2,4-dichlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(2,2,2-trifluoroethylamino)methyl]-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-1,1-dioxo-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-1,1-dioxo-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(2-oxopiperazine-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-oxazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(dimethylaminomethyl)-1,4-oxazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-oxazepan-3-one; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyrimidine-2-carboxamide; 6-amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-2-carboxamide; 6-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-2-carboxamide; 2-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]-1-methylimidazole-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridazine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]thiazole-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]thiazole-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyrazine-2-carboxamide; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazepan-3-one; (2R,5S)-5-(benzotriazole-1-ylmethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazepan-3-one; or (2R,5S)-5-[(3-oxopiperazine-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; A compound that is either an enantiomer, diastereomer, pharmaceutically acceptable salt, or deuterated derivative thereof.

[0465]

[0382] Embodiment 26. (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]thiazole-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-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-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide, or a pharmaceutically acceptable salt thereof; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-1,4-thiazepan-5-yl)methyl)pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylmethylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-[(2-oxopiperazine-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-(((3R,5R,7R)-adamantan-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; or (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazepan-3-one, or its pharmaceutically acceptable salt. A compound that is

[0466]

[0383] Embodiment 27. A compound which is (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof.

[0467]

[0384] Embodiment 28. A compound which is (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof.

[0468]

[0385] Embodiment 29. A compound which is (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof.

[0469]

[0386] Embodiment 30. A compound which is (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof.

[0470]

[0387] Embodiment 31. A compound which is (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof.

[0471]

[0388] Embodiment 32. A compound which is N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0472]

[0389] Embodiment 33. A pharmaceutical composition comprising a compound described in any one embodiment of Embodiments 1 to 32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient in a unit dosage form.

[0473]

[0390] Embodiment 34. A method for treating a condition, comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject requiring treatment of the condition.

[0474] [ka]

[0475] [In the formula, - The A ring is an aryl or a 5-membered or 6-membered heteroaryl (each of which is either unsubstituted or substituted), - X is O, S, S(O), or S(O)², - Y is either CH2 or C(O), - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - R 1 and R 2 Each of these can independently be alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydrogen, C(O)R a , C(O)OR b , or S(O)2R b And, or R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form a heterocycloalkyl moiety. - R 3Each of these independently consists of alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being 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 groups, together with the carbon atoms to which they are bonded, form condensed cycloalkyl or heterocycloalkyl rings (each of which is either unsubstituted or substituted). - R 4 is an unsubstituted or substituted alkyl group, or hydrogen. - R a This includes alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydroxy, carboxy, or NHR. c [Here, R c [is alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of these being unsubstituted or substituted)], or hydrogen, - R b is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl (each of which is unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5] A method comprising the step of administering a drug.

[0476]

[0391] Embodiment 35. The method according to Embodiment 34, wherein the state is the state of the heart.

[0392] Embodiment 36. The method according to Embodiment 34 or Embodiment 35, wherein the state is characterized by an irregular heartbeat.

[0477]

[0393] Embodiment 37. The method according to any one embodiment of Embodiments 34 to 36, wherein the condition is catecholamine-induced polymorphic ventricular tachycardia.

[0394] Embodiment 38. The method according to any one embodiment of Embodiments 34 to 36, wherein the condition is type 1 catecholamine-induced polymorphic ventricular tachycardia.

[0478]

[0395] Embodiment 39. The method according to Embodiment 34 or Embodiment 35, wherein the condition is heart failure.

[0396] Embodiment 40. The method according to Embodiment 34 or Embodiment 35, wherein the condition is congestive heart failure.

[0479]

[0397] Embodiment 41. The method according to Embodiment 34 or Embodiment 35, wherein the condition is chronic heart failure.

[0398] Embodiment 42. The method according to Embodiment 34 or Embodiment 35, wherein the condition is heart failure with reduced ejection fraction.

[0480]

[0399] Embodiment 43. The method according to Embodiment 34 or Embodiment 35, wherein the condition is heart failure with preserved ejection fraction.

[0400] Embodiment 44. The method according to Embodiment 34 or Embodiment 35, wherein the subject is a heart failure patient having an implanted cardioverter-defibrillator, and the implanted cardioverter-defibrillator is implanted in the patient.

[0481]

[0401] Embodiment 45. The method according to Embodiment 34 or 35, wherein the condition is acute heart failure.

[0402] Embodiment 45a. The method according to Embodiment 34 or Embodiment 35, wherein the condition is right heart failure.

[0482]

[0403] Embodiment 45b. The method according to Embodiment 34 or Embodiment 35, wherein the condition is left heart failure.

[0404] Embodiment 46. The method according to Embodiment 34, wherein the condition is skeletal muscle weakness associated with heart failure.

[0483]

[0405] Embodiment 47. The method according to Embodiment 46, wherein the treatment improves skeletal muscle weakness in the subject.

[0406] Embodiment 48. The method according to Embodiment 46, wherein the treatment reduces calcium leakage from the RyR1 channel in the subject.

[0484]

[0407] Embodiment 49. The method according to Embodiment 46, wherein the treatment reduces calcium leakage from the RyR2 channel in the subject.

[0408] Embodiment 50. The method according to Embodiment 34 or Embodiment 35, wherein the subject is a heart failure patient who requires preservation of cardiac function after myocardial infarction.

[0485]

[0409] Embodiment 51. The method according to Embodiment 34 or Embodiment 35, wherein the condition is myocardial infarction.

[0410] Embodiment 52. The method according to Embodiment 34 or Embodiment 35, wherein the condition includes cardiac ischemia / reperfusion injury.

[0486]

[0411] Embodiment 53. The method according to Embodiment 34, wherein the state is a musculoskeletal state.

[0412] Embodiment 54. The method according to Embodiment 34 or Embodiment 53, wherein the condition is congenital myopathy.

[0487]

[0413] Embodiment 55. The method according to Embodiment 34 or Embodiment 53, wherein the condition is RYR1-related myopathy.

[0414] Embodiment 56. The method according to Embodiment 34 or Embodiment 53, wherein the condition is congenital RYR1-related myopathy.

[0488]

[0415] Embodiment 57. The method according to Embodiment 34 or Embodiment 53, wherein the condition is RYR1-related myopathy caused by a de novo mutation in the RYR1 gene.

[0489]

[0416] Embodiment 58. The method according to Embodiment 34 or Embodiment 53, wherein the condition is muscular dystrophy.

[0417] Embodiment 59. The method according to Embodiment 34 or Embodiment 53, wherein the condition is Duchenne muscular dystrophy.

[0490]

[0418] Embodiment 60. The method according to Embodiment 59, wherein the subject is a person capable of walking.

[0419] Embodiment 61. The method according to Embodiment 59, wherein the subject is a person who is unable to walk.

[0420] Embodiment 62. The method according to Embodiment 59, wherein the treatment improves skeletal muscle function in the subject.

[0491]

[0421] Embodiment 63. The method according to Embodiment 59, wherein the treatment improves myocardial function in the subject.

[0422] Embodiment 64. The method according to Embodiment 34 or 53, wherein the condition is myotonic dystrophy.

[0492]

[0423] Embodiment 65. The method according to claim 34, wherein the condition is sarcopenia.

[0424] Embodiment 66. The method according to any one embodiment of Embodiments 34 to 65, wherein the administration is by oral administration.

[0493]

[0425] Embodiment 67. The method according to any one embodiment of Embodiments 34 to 66, wherein the treatment reduces calcium leakage from the target RyR1 channel.

[0426] Embodiment 68. The method according to any one embodiment of Embodiments 34 to 67, wherein the treatment reduces calcium leakage from the target RyR2 channel.

[0494]

[0427] Embodiment 69. The treatment is the open probability (P) of the RyR1 protein in the subject. o The method according to any one embodiment of embodiments 34 to 68, which reduces ).

[0428] Embodiment 70. The treatment is the open probability (P) of the RyR2 protein in the subject. o A method according to any one embodiment of embodiments 34 to 69, which reduces ).

[0495]

[0429] Embodiment 71. The method according to Embodiment 34, wherein the compound reduces calcium leakage from the target RyR1 channel and RyR2 channel.

[0430] Embodiment 72. Compound of formula (I)

[0496] [ka]

[0497] A method for synthesizing, (a) Compound of formula (II)

[0498] [ka]

[0499] Esterilize to obtain the compound of formula (III)

[0500] [ka]

[0501] [In the formula, - The A ring is an aryl or a 5-membered or 6-membered heteroaryl (each of which is either unsubstituted or substituted), - R 3 Each of these independently consists of alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being unsubstituted or substituted), or hydrogen, halogen, NHC(O)R b C(O)NHR b Alternatively, S(O)2R b And, by choice, two adjacent R 3The groups, together with the carbon atoms to which they are bonded, optionally form condensed cycloalkyl or heterocycloalkyl rings. - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5. - Alk is an alkyl group. The steps to generate, (b) The compound of formula (III) is subjected to a bromination reaction to obtain the compound of formula (IV).

[0502] [ka]

[0503] Steps to obtain, (c) Compound of formula (IV) to compound of formula (V)

[0504] [ka]

[0505] Reacting with it, the compound of formula (VI)

[0506] [ka]

[0507] [In the formula, - X is O, S, S(O) or S(O)2, - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - P is a protecting group. Steps to obtain, (d) Deprotect the compound of formula (VI) to obtain the compound of formula (VII)

[0508] [ka]

[0509] The steps to generate, (e) Cyclizing the compound of formula (VII) to obtain the compound of formula (VIII)

[0510] [ka]

[0511] Steps to obtain, (f) Protect the hydroxyl group to form the compound of formula (IX)

[0512] [ka]

[0513] [In the formula, P is a protecting group.] Steps to obtain, (g) Compound of formula (IX) is given formula (X):X'R 4 ' Compound [wherein X' is a halogen, R 4 ' is reacted with an unsubstituted or substituted alkyl to form a compound of formula (XI).

[0514] [ka]

[0515] The step of obtaining the compound of formula (IX) and (XI) is the compound of formula (XII).

[0516] [ka]

[0517] [In the formula, A, R 3 Z, X, R', R'', n, and P are as defined above, and R 4 [These are unsubstituted or substituted alkyl groups, or hydrogen atoms.] Steps represent, (h) Compounds of formula (XII) are given by formula (XIII): HNR 1 R 2 Compounds of [wherein R 1 and R 2 Each of these can independently be alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydrogen, C(O)R a , C(O)OR b , or S(O)2Rb, or R 1 and R 2 [These react with the nitrogen atoms to which they are bonded to form a heterocycloalkyl moiety] to form the compound of formula (I / a).

[0518] [ka]

[0519] Steps to obtain, (i) Optionally, reduce the compound of formula (I / a) to obtain the compound of formula (I / b).

[0520] [ka]

[0521] A step to obtain, wherein the compound of formula (I / a) and the compound of formula (I / b) represent the compound of formula (I), and (j) The steps of optionally purifying the obtained compound and / or optionally converting the obtained compound to an addition salt thereof with a pharmaceutically acceptable acid or base and / or optionally separating the obtained compound into its isomers. A method that includes this.

[0522]

[0431] Embodiment 73. Compound of formula (I)

[0523] [ka]

[0524] A method for synthesizing, (a) Compound of formula (VI) as described in Embodiment 72

[0525] [ka]

[0526] The compound of formula (XIV) is obtained by reacting it with an azide derivative.

[0527] [ka]

[0528] Steps to obtain, (b) Cyclizing the compound of formula (XIV) to obtain the compound of formula (XV)

[0529] [ka]

[0530] Steps to obtain, (c) Compounds of formula (XV) defined above: formula (X):X'R 4 Reacting with the compound of ' to form the compound of formula (XVI)

[0531] [ka]

[0532] The step of obtaining the compound of formula (XV) and the compound of formula (XVI) is the compound of formula (XVII)

[0533] [ka]

[0534] Steps represent, (d) Reduce the compound of formula (XVII) to obtain the compound of formula (I / c)

[0535] [ka]

[0536] Steps to obtain, (e) The compound of formula (I / c) is optionally further reduced to obtain the compound of formula (I / d).

[0537] [ka]

[0538] The step of obtaining the compound of formula (I / c) and the compound of formula (I / d) is the compound of formula (I / e)

[0539] [ka]

[0540] Steps represent, (f) Compound of formula (I / e) of formula (XVIII):X''R 1 ' Compound [wherein X'' is a halogen, R 1 ' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of these being unsubstituted or substituted), or C(O)R a , C(O)OR b , or S(O)2R b The compound of formula (I / f) is formed by reacting it with [the compound of formula (I / f)] at any choice.

[0541] [ka]

[0542] Steps to obtain, (g) Compound of formula (I / f) formula (XIX):X''R 2' Compound [wherein X'' is a halogen, R 2 ' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of these being unsubstituted or substituted), or C(O)R a , C(O)OR b , or S(O)2R b The compound of formula (I / g) is formed by reacting it with [the compound of formula (I / g)] at any choice.

[0543] [ka]

[0544] Steps to obtain, (h) The steps of optionally purifying the obtained compound and / or optionally converting the obtained compound to an addition salt thereof with a pharmaceutically acceptable acid or base and / or optionally separating the obtained compound into its isomers. A method that includes this.

[0545]

[0432] Embodiment 74. Compound of formula (I)

[0546] [ka]

[0547] A method for synthesizing, (a) Compound of formula (II)

[0548] [ka]

[0549] Esterilize to obtain the compound of formula (III)

[0550] [ka]

[0551] [In the formula, - The A ring is an aryl or a 5-membered or 6-membered heteroaryl (each of which is either unsubstituted or substituted), - R 3 Each of these independently consists of alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being unsubstituted or substituted), or hydrogen, halogen, NHC(O)R b C(O)NHR b Alternatively, S(O)2R b And, by choice, two adjacent R 3 The groups, together with the carbon atoms to which they are bonded, optionally form condensed cycloalkyl or heterocycloalkyl rings. - R 4 It is hydrogen, - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5. - Alk is an alkyl group. The steps to generate, (b) The compound of formula (III) is subjected to a bromination reaction to obtain the compound of formula (IV).

[0552] [ka]

[0553] Steps to obtain, (c) Compound of formula (IV) to compound of formula (V)

[0554] [ka]

[0555] Reacting with it, the compound of formula (VI)

[0556] [ka]

[0557] [In the formula, - X is O, S, S(O) or S(O)2, - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - P is a protecting group. Steps to obtain, (d) Deprotect the compound of formula (VI) to obtain the compound of formula (VII)

[0558] [ka]

[0559] The steps to generate, (e) Cyclizing the compound of formula (VII) to obtain the compound of formula (VIII)

[0560] [ka]

[0561] Steps to obtain, (f) Reacting a compound of formula (VIII) with a compound of formula RSO2LG or a compound of formula (RSO2)2O [wherein R is alkyl or aryl and LG is a leaving group] to obtain a compound of formula (IX)

[0562] [ka]

[0563] Steps to obtain, (g) Compound of formula (IX) 10 Compound N3 [wherein R 10 is a metal cation or N +[Alk4, where Alk is alkyl] is reacted to form compound (X) of formula (X).

[0564] [ka]

[0565] The steps to generate, (h) Compound of formula (X) is compound of formula (I')

[0566] [ka]

[0567] [In the formula, R 1 and R 2 Each of these is a hydrogen atom. The steps to convert and (i) an optional step of converting a compound of formula (I') to a compound of formula (I), and A method that includes this. [Examples]

[0568]

[0433] The infrared spectrum was recorded using a Fourier Bruker tensor-27 transform spectrometer in ATR mode.

[0434] Proton NMR spectra were recorded using a Bruker DPX 400-B or 400 MHz Bruker Avance III N spectrometer. Chemical shifts are expressed in ppm and determined relative to the TMS used as the reference material. The abbreviations used are as follows: s: Single line d: double line Wide dd: double double line dt: tripled doublet t: Mie line td: triple double line quad: quadruple line quint:quintet m: multiplet

[0435] Combinations of the above definitions are possible. For example, ddd represents a double double double line.

[0569]

[0436] Mass spectra were recorded using a TSQ 7000 spectrometer. GC controls were prepared using a 0.53 × 15 m HPS-J&W Scientific column and a GC Agilent 4890 flame ionization detection (FID) chromatograph.

[0570]

[0437] Analytical UPLC-MS analysis was performed using a Waters Acquity H-Class UPLC system equipped with a PDA detector, Waters 3100 mass detector, and a CORTECS UPLC C18, 1.6 μm, 2.1 mm × 50 mm column.

[0571]

[0438] An HPLC check was performed using an HPLC 1200 Agilent equipped with a diode array detector (DAD) and an Acquity UPLC BEH C18 1.7 μm, 2.1 × 30 mm column.

[0572]

[0439] Enantiomer purity analysis was performed using UPC2 (Waters).

[0440] Thin-layer chromatography (TLC) was performed on a MERCK 60F-254 silica plate.

[0573]

[0441] Chromatography was performed using MERCK 60 silica gel (0.040~0.063 mm) or Interchim or Grace pre-packed silica columns.

[0574]

[0442] Reverse-phase separation was performed using UV detection with an Interchim FHP RP C18 15μm, 275×60mm column.

[0443] Flash column chromatography was performed using a Teledyne Isco CombiFlash Rf+ instrument equipped with a RediSep Rf Gold Silica (20-40 μm) or RediSep Rf Gold® reversed-phase C18 column.

[0575]

[0444] Filtration was performed using a GVHP type filter (0.22 μm) Millipore for the organic phase, and using Whatman GF / A catalog filter paper number 1820-070 for the aqueous phase.

[0576] Example 1: Preparation of tert-butyl N-[(1S)-1-(hydroxymethyl)-3-sulfanyl-propyl]carbamate

[0577] [ka]

[0578]

[0445] Methyl(2S)-4-[[(3S)-4-methoxy-3-methyl-4-oxo-butyl]disulfanyl]-2-methyl-butanoate (15.0 g, 30.2 mmol) was prepared as described by Olivier Busnel et al. in "Synthesis and evaluation of new ω-borono-α-amino acids as rat liver arginase inhibitors," Bioorganic & Medicinal Chemistry 13 (2005) 2373-2379 (the contents of which are incorporated herein by reference), dissolved in tetrahydrofuran (150 mL) and methanol (30 mL), and the solution was cooled to 0°C in an ice bath. To this solution, calcium chloride (6.68 g, 60.2 mmol) and sodium borohydride (6.84 g, 181 mmol) were added in three equal parts over 1 hour. The reaction was carried out at room temperature for 6 hours with stirring. After completion, the reaction was quenched by adding saturated aqueous ammonium chloride, then acidic pH was achieved by adding 1 M aqueous HCl, and the mixture was extracted with methylene chloride. The combined organic phase was dehydrated with MgSO4, filtered, and concentrated. The resulting colorless oil was dissolved in methylene chloride (180 mL), water (0.544 mL) and tri-butylphosphine (7.54 mL, 30.2 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After completion, the reaction was concentrated under reduced pressure. The crude product containing tert-butyl-N-[(1S)-1-(hydroxymethyl)-3-sulfanyl-propyl]carbamate was used directly in the next step, or it was purified by silica gel flash 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. α at 28℃ D (589nM)=-24.29 (c=0.010g / mL, MeOH).

[0579] Example 2: Preparation of tert-butyl N-[(1R)-1-(hydroxymethyl)-3-sulfanyl-propyl]carbamate

[0446] tert-butyl N-[(1R)-1-(hydroxymethyl)-3-sulfanyl-propyl]carbamate was prepared starting from methyl(2R)-4-[[(3R)-4-methoxy-3-methyl-4-oxo-butyl]disulfanyl]-2-methyl-butanoate by the same method used in Example 1. 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. α at 28℃ D (589nM)=+24.93 (c=0,010g / mL, MeOH).

[0580] Example 3: General method A for preparing phenylthiazepanone

[0581] [ka]

[0582] Example 4: Preparation of (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazepan-3-one hydrochloride (compound 1...

Claims

1. Compound of formula (I): 【Chemistry 1】 [In the formula, - The A ring is an aryl or a 5-membered or 6-membered heteroaryl, each of which is either unsubstituted or substituted. - X is O, S, S(O), or S(O) ２ And, - Y is CH ２ or C(O), - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). -R １ and R ２ are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydrogen, C(O)R ａ , C(O)OR ｂ , or S(O) ２ R ｂ or R １ and R ２ together with the nitrogen atom to which they are attached form a heterocycloalkyl moiety - R ３ Each of these is independently alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being unsubstituted or substituted), or hydrogen, halogen, NHC(O)R ｂ , C(O)NHR ｂ , or S(O) ２ R ｂ or two adjacent R ３ The groups, together with the carbon atoms to which they are bonded, form a condensed cycloalkyl or heterocycloalkyl ring (each of which is either unsubstituted or substituted). - R ４ is an unsubstituted or substituted alkyl group, or hydrogen. - R ａ This includes alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of these being unsubstituted or substituted), or hydroxy, carboxy, or NHR ｃ [Here, R ｃ [is alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of these being unsubstituted or substituted)], or hydrogen, - R ｂ is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl (each of which is unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5. or a pharmaceutically acceptable salt thereof.

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

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

4. Equation (I ａ The compound according to claim 1, which is a compound of ). 【Chemistry 2】

5. The compound according to claim 4, wherein Z is hydrogen.

6. Equation (I ｂ The compound according to claim 1, which is a compound of ). 【Transformation 3】

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. R １ and R ２ The compound according to claim 1, wherein each of them is hydrogen.

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

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

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

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

14. R ２ ga C(O)R ａ The compound according to claim 1.

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

16. R ２ However, C(O)R ａ And here, R ａ The compound according to claim 1, wherein is pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridadinyl, triazolyl, oxadiazolyl, or pyrazinyl, each of which is substituted or unsubstituted.

17. R ２ However, C(O)R ａ And here, R ａ These include pyrimidine-2-yl, pyrimidine-5-yl, 5-aminopyrimidine-2-yl, 5-methoxypyrimidine-2-yl, 1H-pyrazole-3-yl, 2-methyl-1H-pyrazole-3-yl, pyridine-2-yl, 2-chloropyridine-2-yl, 6-chloropyridine-2-yl, 5-chloropyridine-2-yl, 6-hydroxypyridine-2-yl, pyridine-3-yl, 6 -aminopyridine-3-yl, 2-chloropyridine-3-yl, pyridine-4-yl, 3-phenyl-1H-pyrazole-5-yl, 1H-imidazole-4-yl, 1H-imidazole-2-yl, 1-methyl-1H-imidazole-4-yl, 1-methyl-1H-imidazole-2-yl, thiazole-2-yl, thiazole-4-yl, 4-methyl-1,2,3-thiadiazole-5-yl The compound according to claim 1, which is 5-phenylisoxazole-3-yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5-methyl-3-phenylisoxazole-4-yl, 4-phenylthiazole-2-yl, 1H-tetrazole-5-yl, pyridazine-2-yl, pyridazine-3-yl, pyridazine-4-yl, pyrazine-2-yl, pyrazine-3-yl, pyrazine-4-yl, 3-hydroxypyrazineyl, 4-isopropyl-1,2,3-thiadiazolyl, 3-methylisoxazole-5-yl, 4,4-difluoropiperidine-1-yl, 1,2,4-triazine-3-yl, 4-methylpyrido-2-ylamino, 3-oxopiperazine-1-yl, 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-yl, or piperazine-1-yl.

18. R １ and R ２ Each of these independently consists of hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3-hydroxycyclobutyl, 3,3-difluorocyclobutyl, cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, pyrimidine-2-yl, pyrimidine-2-ylmethyl, pyrimidine-3-ylmethyl, pyrimidine-4-ylmethyl, oxalyl, 2-methoxyethyl, benzyl, 4-carboxybenzyl, 4-carboxymethyl đonyl, tetrahydro-2H-pyran-4-yl, oxetan-3-yl, 1,2,4-thiadiazole-5-yl, 4-aminomethyl-1,2,3-triazole-1-ylmethyl, 4-methyl-1,2,3-thiadiazolyl-5-ylmethyl, benzo[d]thiazole-2-yl, 4-carboxylethyl-1,2,3-thiadiazolyl-5-ylmethyl, 4-carboxy-1,2,3-thiadiazolyl-5-ylmethyl, isoindoline-1,3-dione-2-yl, and acetyl, or R １ and R ２ The compound according to claim 1, wherein, together with the nitrogen atom to which they are bonded, they form a heterocycle or heteroaryl selected from the group consisting of pyrazolidinol, piperazinyl, 2-oxopiperazinyl, triazolyl, benzotriazolyl, morpholinyl, pyrrolidinyl, or piperidinyl, which are optionally substituted.

19. R ３ The compound according to claim 1, wherein the compound is an alkoxy, cycloalkyloxy, or aryloxy (each of which is substituted or unsubstituted), or a halogen.

20. R ３ The compound according to claim 1, wherein the compound is a substituted or unsubstituted phenyloxy.

21. R ３ However, hydroxy, fluorine, chlorine, bromine, iodide, CF ３ CHF ２ methoxy, SO ２ The compound according to claim 1, wherein it is substituted with one or two substituents selected from the group consisting of Me, cyano, and C(O)Me.

22. R ３ The compound according to claim 1, wherein each of the elements is independently alkyl, cyclohexyl, alkyloxy, cycloalkyloxy, arylsulfonyl, alkylsulfonyl, phenyl, phenoxy, benzo[d][1,3]dioxol-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NHcycloalkyl, -NH-C(O)cycloalkyl, heteroaryl, heterocyclyl, or naphthalenyl (each of which is substituted or unsubstituted), or halogen.

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

24. The compound according to claim 1, which is a pharmaceutically acceptable salt.

25. (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenylphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-bromophenyl)-5-(dimethylaminomethyl)-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-bromophenyl)-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-[(4-benzyl-1-piperidyl)methyl]-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[(4-benzyl-1-piperidyl)methyl]-2-(4-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-methoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(trifluoromethyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-benzyloxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(trifluoromethyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenylphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenoxy)phenyl]-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2,2-trifluoroethoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)-1H-pyrazole-4-yl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-iodophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-1,4-thiazepan-3-one; 3-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; 3-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; 4-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; 4-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzonitrile; (2S,5R)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(1,3-benzodioxol-5-yl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1,3-benzodioxol-5-yl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-bromo-5-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-naphthyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(1-naphthyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(benzenesulfonyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-methoxyphenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(o-tolyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-ethylpropyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(3-amino-4-chlorophenyl)phenyl]-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,4-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chloro-3-iodophenyl)phenyl]-1,4-thiazepan-3-one; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzamide; N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]cyclohexanecarboxamide; (2R,5S)-5-(aminomethyl)-2-[3-(4-fluorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-cyclohexylphenyl)-1,4-thiazepan-3-one; 3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]-N-phenyl-benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidine-1-yl)methyl]-1,4-thiazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidine-1-yl)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidine-1-yl)methyl]-1,4-thiazepan-3-one; N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]phenyl]acetamide; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidyl)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(4,4-difluoro-1-piperidyl)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,3-dimethoxyphenyl)phenyl]-1,4-thiazepan-3-one; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzoic acid; 2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]benzamide; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxyphenyl)phenyl]-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one; 2-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenyl]phenoxy]acetic acid; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxopyrrolidine-1-yl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-oxo-1-pyridyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-hydroxy-1-piperidyl)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-(((3R,5R,7R)-adamantan-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(cyclohexoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(1-isopropyl-2-methyl-propoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxy-2-methyl-propoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxy-3-propyl-phenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(3-chloro-4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-indole-1-ylphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2-methoxyphenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(2,4-dichlorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[3-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[2-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1,4-thiazepan-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(methylaminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclohexoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-methyl-4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-dibenzofuran-2-yl-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-methylsulfonylphenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)phenyl]-1,4-thiazepan-3-one; 2-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]benzonitrile; (2R,5S)-2-[4-(4-acetylphenoxy)phenyl]-5-(aminomethyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(1,3-benzodioxol-5-yloxy)phenyl]-1,4-thiazepan-3-one; 3-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]-5-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(4-anilinophenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(2-chloro-4-phenoxyphenyl)-1,4-thiazepan-3-one; 4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-1,4-thiazepan-2-yl]phenoxy]-3-chlorobenzonitrile; (2R,5S)-5-(aminomethyl)-2-(2-methoxy-4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)-2-methoxyphenyl]-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(triazole-1-ylmethyl)-1,4-thiazepan-3-one; (2R,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[4-(aminomethyl)triazole-1-yl]methyl]-2-[4-(4-fluorophenoxy)phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(pyrimidine-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(1,3-benzothiazole-2-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(1,2,4-thiadiazole-5-ylamino)methyl]-1,4-thiazepan-3-one; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; 2-oxo-2-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methylamino]acetate; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide; 4-(aminomethyl)-N-[[(2R,5S)-2-(3-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]benzamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-2H-tetrazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]thiazole-4-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-4-methyl-thiadiazole-5-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-5-carboxamide; 6-amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-5-phenyl-isoxazole-3-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-4-phenyl-thiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 1-methyl-N-[[(2S,5R)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]imidazole-4-carboxamide; 4-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-5-carboxamide 6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]methanesulfonamide 4-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiadiazole-5-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-1H-imidazole-4-carboxamide; 2-Morpholino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]acetamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]morpholine-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide; 5-Isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiadiazole-4-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-3-sulfonamide; 4-Fluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]benzenesulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; 1-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]imidazole-4-sulfonamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide; 3,3-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]cyclobutanecarboxamide; 4,4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]cyclohexanecarboxamide; N-[[(2R,5S)-2-[3-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-1,4-thiazepan-5-yl)methyl)pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-2-pyrimidine-2-ylacetamide; 1-benzyl-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]urea; 3-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]isoxazole-5-carboxamide; N-[[(2R,5S)-2-[3-(cyclohexoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 4,4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]piperidine-1-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]-1,2,4-triazine-3-carboxamide; N-[[(2R,5S)-2-[4-(2-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrazine-2-carboxamide; 6-Chloro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; 2-[5-(4-chlorophenyl)isoxazole-3-yl]-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]acetamide; 6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; 5-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-Methoxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 1-(4-methyl-2-pyridyl)-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]urea N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1H-pyrazole-3-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide; 6-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; 6-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-2-morpholinoacetamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; 2-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]benzamide; 4-Hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]benzamide; (2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-5-[(1,2,4-thiadiazole-5-ylamino)methyl]-1,4-thiazepan-3-one; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-Chloro-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-5-methoxypyrimidine-2-carboxamide; 5-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]-5-methoxypyrimidine-2-carboxamide; 3-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyrazine-2-carboxamide; 3-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide; N-[[(2S,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2S,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; N-[[(2R,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide; 5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-1,4-thiazepan-5-yl]methyl]-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxamide; N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-1,4-thiazepan-5-yl]methyl]piperazine-1-carboxamide; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylmethylamino)methyl]-1,4-thiazepan-3-one; Methyl 4-[[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methylaminomethyl]benzoate; (2R,5S)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5R)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; 4-[[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-1,4-thiazepan-5-yl]methylaminomethyl]benzoic acid; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(cyclopropylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(cyclopropylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[(cyclobutylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(tetrahydropyran-4-ylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(oxetane-3-ylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[bis(oxetan-3-yl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-((((1r,3S)-3-hydroxycyclobutyl)amino)methyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[(3,3-difluorocyclobutyl)amino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-[[(4-methylthiadiazole-5-yl)methylamino]methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-4-ylmethylamino)methyl]-1,4-thiazepan-3-one; 4-[[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methylaminomethyl]benzoic acid; 4-[[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methylaminomethyl]benzoic acid; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-bromophenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2,4-dichlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(2,2,2-trifluoroethylamino)methyl]-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-1,1-dioxo-2-(3-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-1,1-dioxo-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one; (2R,5S)-5-[(2-oxopiperazine-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-1,4-oxazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-1,4-oxazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(dimethylaminomethyl)-1,4-oxazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-1,4-oxazepan-3-one; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyrimidine-2-carboxamide; 6-amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-2-carboxamide; 6-Chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-2-carboxamide; 2-chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]-1-methylimidazole-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridazine-3-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyridazine-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]thiazole-4-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]thiazole-2-carboxamide; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]pyrazine-2-carboxamide; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazepan-3-one; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazepan-3-one; (2R,5S)-5-(benzotriazole-1-ylmethyl)-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazepan-3-one; or (2R,5S)-5-[(3-oxopiperazine-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one; A compound that is either an enantiomer, diastereomer, pharmaceutically acceptable salt, or deuterated derivative thereof.

26. (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-1,4-oxazepan-5-yl]methyl]thiazole-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-1,4-thiazepan-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-thiazepan-5-yl]methyl]-1-methylimidazole-4-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-1,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-1,4-thiazepan-5-yl]methyl]-3-phenyl-1H-pyrazole-5-carboxamide, or a pharmaceutically acceptable salt thereof; N-(((2R,5S)-2-(3-(((1R,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-1,4-thiazepan-5-yl)methyl)pyrimidine-2-carboxamide, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-1-carbonyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylmethylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-1,1-dioxo-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-[(2-oxopiperazine-1-yl)methyl]-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-2-(3-(((3R,5R,7R)-adamantan-1-yl)methoxy)phenyl)-5-(aminomethyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-1,4-oxazepan-3-one, or a pharmaceutically acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof; or (S)-5-(aminomethyl)-2,2-diphenyl-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof. A compound that is

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

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

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

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

31. A compound that is (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidine-2-ylamino)methyl]-1,4-thiazepan-3-one, or a pharmaceutically acceptable salt thereof.

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

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

34. A method for treating a condition, comprising administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject requiring treatment of the condition. 【Chemistry 4】 [In the formula, - Ring A is an aryl or a five-membered or six-membered heteroaryl (each of which is either unsubstituted or substituted), - X is O, S, S(O), or S(O) ２ And, - Y is CH ２ or C(O), - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - R １ and R ２ Each of these can independently be alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of these being either unsubstituted or substituted), or hydrogen, C(O)R ａ , C(O)OR ｂ , or S(O) ２ R ｂ And, or R １ and R ２ These, together with the nitrogen atom to which they are bonded, form a heterocycloalkyl moiety. - R ３ Each of these is independently alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being unsubstituted or substituted), or hydrogen, halogen, NHC(O)R ｂ , C(O)NHR ｂ , or S(O) ２ R ｂ or two adjacent R ３ The groups, together with the carbon atoms to which they are bonded, form a condensed cycloalkyl or heterocycloalkyl ring (each of which is either unsubstituted or substituted). - R ４ is an unsubstituted or substituted alkyl group, or hydrogen. - R ａ This includes alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of these being unsubstituted or substituted), or hydroxy, carboxy, or NHR ｃ (Here, R ｃ is alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydrogen. - R ｂ is an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl (each of which is unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5. A method comprising the step of administering a drug.

35. The method according to claim 34, wherein the state is the state of the heart.

36. The method according to claim 34, wherein the condition is characterized by an irregular heartbeat.

37. The method according to claim 34, wherein the condition is catecholamine-induced polymorphic ventricular tachycardia.

38. The method according to claim 34, wherein the condition is type 1 catecholamine-induced polymorphic ventricular tachycardia.

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

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

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

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

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

44. The method according to claim 34, wherein the subject is a heart failure patient having an implantable cardioverter-defibrillator, and the implantable cardioverter-defibrillator is implanted in the patient.

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

46. The method according to claim 34, wherein the condition is right heart failure.

47. The method according to claim 34, wherein the condition is left heart failure.

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

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

50. The method according to claim 48, wherein the treatment improves skeletal muscle function in the subject.

51. The method according to claim 48, wherein the treatment reduces calcium leakage from the RyR1 channel in the subject.

52. The method according to claim 48, wherein the treatment reduces calcium leakage from the RyR2 channel in the subject.

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

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

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

56. The method according to claim 34, wherein the state is a musculoskeletal state.

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

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

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

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

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

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

63. The method according to claim 62, wherein the subject is a person capable of walking.

64. The method according to claim 62, wherein the subject is a person who is unable to walk.

65. The method according to claim 62, wherein the treatment improves skeletal muscle function in the subject.

66. The method according to claim 62, wherein the treatment improves myocardial function in the subject.

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

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

69. The method according to claim 34, wherein the administration is by oral ingestion.

70. The method according to claim 34, wherein the treatment reduces calcium leakage from the target RyR1 channel.

71. The method according to claim 34, wherein the treatment reduces calcium leakage from the target RyR2 channel.

72. The treatment increases the open probability (P) of the RyR1 protein in the subject. ｏ The method according to claim 34, which reduces ).

73. The treatment increases the probability of RyR2 protein opening in the subject (P ｏ The method according to claim 34, which reduces ).

74. The method according to claim 34, wherein the compound reduces calcium leakage from the target RyR1 channel and RyR2 channel.

75. Compound of formula (I) 【Transformation 5】 A method for synthesizing, (a) Compound of formula (II) 【Transformation 6】 Esterilized to obtain the compound of formula (III) 【Transformation 7】 [In the formula, - Ring A is an aryl or a five-membered or six-membered heteroaryl (each of which is either unsubstituted or substituted), - R ３ Each of these is independently alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being unsubstituted or substituted), or hydrogen, halogen, NHC(O)R ｂ , C(O)NHR ｂ , or S(O) ２ R ｂ And, at will, two adjacent R ３ The groups, together with the carbon atoms to which they are bonded, optionally form condensed cycloalkyl or heterocycloalkyl rings. - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5. - Alk is an alkyl group. The steps to generate, (b) The compound of formula (III) is subjected to a bromination reaction to obtain the compound of formula (IV). 【Transformation 8】 Steps to obtain, (c) Compound of formula (IV) to compound of formula (V) 【Chemistry 9】 Reacting with it, the compound of formula (VI) 【Chemistry 10】 [In the formula, - X is O, S, S(O) or S(O) ２ And, - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - P is a protecting group. Steps to obtain, (d) Deprotect the compound of formula (VI) to obtain the compound of formula (VII) 【Chemistry 11】 The steps to generate, (e) Cyclizing the compound of formula (VII) to obtain the compound of formula (VIII) 【Chemistry 12】 Steps to obtain, (f) Protect the hydroxyl group to form a compound of formula (IX) 【Chemistry 13】 [In the formula, P is a protecting group.] Steps to obtain, (g) Compound of formula (IX) is formula (X): X'R ４ ' Compound of [wherein X' is a halogen, R ４ ' is reacted with an unsubstituted or substituted alkyl group to form the compound of formula (XI). 【Chemistry 14】 The step of obtaining the compound of formula (IX) and (XI) is the compound of formula (XII) 【Chemistry 15】 [In the formula, A, R ３ Z, X, R', R'', n, and P are as defined above, and R ４ [These are unsubstituted or substituted alkyl groups, or hydrogen.] Steps represent, (h) A compound of formula (XII) with a compound of formula (XIII): HNR １ R ２ [wherein R １ and R ２ are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl (each of which is unsubstituted or substituted), or hydrogen, C(O)R ａ , C(O)OR ｂ , or S(O) ２ R ｂ , or R １ and R ２ together with the nitrogen atom to which they are attached form a heterocycloalkyl moiety] to react to form a compound of formula (I / a) 【Chemistry 16】 Steps to obtain, (i) Optionally, reduce the compound of formula (I / a) to obtain the compound of formula (I / b). 【Chemistry 17】 A step to obtain, wherein the compound of formula (I / a) and the compound of formula (I / b) represent the compound of formula (I), and (j) The steps of optionally purifying the obtained compound and / or optionally converting the obtained compound to an addition salt thereof with a pharmaceutically acceptable acid or base and / or optionally separating the obtained compound into its isomers. A method that includes this.

76. Compound of formula (I) [Chemistry 18] A method for synthesizing, (a) The compound of formula (VI) as described in claim 75 【Chemistry 19】 The compound of formula (XIV) is obtained by reacting it with an azide derivative. 【Chemistry 20】 Steps to obtain, (b) Cyclizing the compound of formula (XIV) to obtain the compound of formula (XV) 【Chemistry 21】 Steps to obtain, (c) Reacting the compound of formula (XV) with the compound of formula (X) as defined above: X'R ４ ' to give a compound of formula (XVI) 【Chemistry 22】 The step of obtaining the compound of formula (XV) and the compound of formula (XVI) is the compound of formula (XVII) 【Chemistry 23】 Steps represent, (d) Reduce the compound of formula (XVII) to obtain the compound of formula (I / c) 【Chemistry 24】 Steps to obtain, (e) The compound of formula (I / c) is optionally further reduced to obtain the compound of formula (I / d). 【Chemistry 25】 The step of obtaining the compound of formula (I / c) and the compound of formula (I / d) is the compound of formula (I / e) 【Chemistry 26】 Steps represent, (f) Compound of formula (I / e) is given by formula (XVIII): X''R １ ' Compound [wherein X'' is a halogen, R １ ' is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of these being unsubstituted or substituted), or C(O)R ａ , C(O)OR ｂ , or S(O) ２ R ｂ The compound of formula (I / f) is formed by reacting it with [the compound of formula (I / f)] at any option. 【Chemistry 27】 Steps to obtain, (g) Compound of formula (I / f) is given by formula (XIX): X''R ２ ' Compound [wherein X'' is a halogen, R ２ ' is an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of these being unsubstituted or substituted), or C(O)R ａ , C(O)OR ｂ , or S(O) ２ R ｂ The compound of formula (I / g) is formed by reacting it with [the compound of formula (I / g)] at any option. 【Chemistry 28】 Steps to obtain, (h) The steps of optionally purifying the obtained compound and / or optionally converting the obtained compound to an addition salt thereof with a pharmaceutically acceptable acid or base and / or optionally separating the obtained compound into its isomers. A method that includes this.

77. Compound of formula (I) 【Chemistry 29】 A method for synthesizing, (a) Compound of formula (II) 【Transformation 30】 Esterilized to obtain the compound of formula (III) 【Chemistry 31】 [In the formula, - Ring A is an aryl or a five-membered or six-membered heteroaryl (each of which is either unsubstituted or substituted), - R ３ Each of these is independently alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino (each of these being unsubstituted or substituted), or hydrogen, halogen, NHC(O)R ｂ , C(O)NHR ｂ , or S(O) ２ R ｂ And, at will, two adjacent R ３ The groups, together with the carbon atoms to which they are bonded, optionally form condensed cycloalkyl or heterocycloalkyl rings. - R ４ It is hydrogen, - Z is an alkyl or aryl (each of which is either unsubstituted or substituted), or hydrogen. - n is 0, 1, 2, 3, 4, or 5. - Alk is an alkyl group] The steps to generate, (b) The compound of formula (III) is subjected to a bromination reaction to obtain the compound of formula (IV). 【Chemistry 32】 Steps to obtain, (c) Compound of formula (IV) to compound of formula (V) 【Transformation 33】 Reacting with it, the compound of formula (VI) 【Transformation 34】 [In the formula, - X is O, S, S(O) or S(O) ２ And, - R' and R'' are each hydrogen, or together with the carbon atom to which R' and R'' are bonded, they form C(O). - P is a protecting group] Steps to obtain, (d) Deprotect the compound of formula (VI) to obtain the compound of formula (VII) 【Chemistry 35】 The steps to generate, (e) Cyclizing the compound of formula (VII) to obtain the compound of formula (VIII) 【Transformation 36】 Steps to obtain, (f) Compound of formula (VIII) of formula RSO ２ LG compound or formula (RSO ２ ) ２ Reacting with a compound of O [wherein R is alkyl or aryl and LG is a leaving group] to form a compound of formula (IX) 【Chemistry 37】 Steps to obtain, (g) Compound of formula (IX) １０ N ３ Compounds of [wherein R １０ is a metal cation or N ＋ Alk ４ [and Alk is alkyl] is reacted with to form compound (X) of formula (X). 【Transformation 38】 The steps to generate, (h) Compound of formula (X) is compound of formula (I') 【Chemistry 39】 [In the formula, R １ and R ２ Each of these is a hydrogen atom. The steps to convert and (i) The optional step of converting a compound of formula (I') to a compound of formula (I) A method that includes this.

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