Agents for treating disorders involving ryanodine receptors

Abstract

The present disclosure relates to 1,4-oxazepane and 1,4-thiazepane derivatives and their use to treat disorders and diseases associated with ryanodine receptors (RyRs) that regulate calcium channel signaling in cells. The present disclosure also discloses pharmaceutical compositions comprising these compounds and uses thereof to treat diseases and conditions associated with RyR dysfunction, in particular cardiac, musculoskeletal and central nervous system (CNS) disorders.

Description

AGENTS FOR TREATING DISORDERS INVOLVING RYANODINE RECEPTORSCROSS-REFERENCE TO RELATED APPLICATIONS

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

[0002] The sarcoplasmic reticulum (SR) is a structure in cells that functions, among other things, as a specialized intracellular calcium (Ca2+) store. Ryanodine receptors (RyRs) are channels in the SR that open and close to regulate the release of Ca2+from the SR into the intracellular cytoplasm of the cell. Release of Ca2+into the cytoplasm from the SR increases cytoplasmic Ca2+concentration. Open probability of RyRs refers to the likelihood that a RyR is open at any given moment, and therefore capable of releasing Ca2+into the cytoplasm from the SR. Three RyR isoforms are known. RyRl is the predominant isoform expressed in mammalian skeletal muscle, RyR2 is predominantly found in cardiac muscle, whereas RyR3 expression is low in skeletal muscle.

[0003] Mutations in RYR1 or RYR2 are characterized by inappropriate channel opening not related to contraction signals. This channel opening is further exacerbated by post-translational modifications such as PKA-phosphorylation, oxidation, or nitrosylation of the RyR channel. The resulting leaky channels exhibit a pathologic increase in the open probability under resting conditions. The SR Ca2+leak leads to a reduction in SR Ca2+content, with less Ca2+available for release and consequently weaker muscle contractions.INCORPORATION BY REFERENCE

[0004] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually.SUMMARY OF THE INVENTION

[0005] In some embodiments, the disclosure provides compounds of formula (I):ring A 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 CH2or C(O);Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen;R' and R" are each hydrogen, or together with the carbon atom to which R' and R" are bound form C(O);R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety; each R3is 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)Rb, C(O)NHRbor S(O)2Rb; or two adjacent R3groups, together with the carbon atoms to which they are bound, form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted;R4is alkyl that is unsubstituted or substituted, or hydrogen;Rais alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl, each of which is unsubstituted or substituted, or hydroxy, carboxy, or NHRC, wherein Rcis alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen;Rbis alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen; and n is 0, 1, 2, 3, 4 or 5; or a pharmaceutically-acceptable salt thereof.

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

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

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

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

[0010] The present disclosure further provides methods of making compounds of formula (I) and their intermediates.DETAILED DESCRIPTION

[0011] In some embodiments, the disclosure provides a compound of formula (I):wherein ring A 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 CH2or C(O);Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen;R' and R" are each hydrogen or together with the carbon atom to which R' and R" are bound form C(O);R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety; each R3is 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)Rb, C(O)NHRb, or S(O)2Rb;or two adjacent R3groups, together with the carbon atoms to which they are bound, form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; R4is alkyl that is unsubstituted or substituted, or hydrogen;Rais alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl, each of which is unsubstituted or substituted, or hydroxy, carboxy, or NHRC, wherein Rcis alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen;Rbis alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen; and n is 0, 1, 2, 3, 4 or 5; or a pharmaceutically-acceptable salt thereof.

[0012] In some embodiments, Z is a substituted alkyl. In some embodiments, Z is alkyl substituted with aryl. In some embodiments, Z is aryl(Ci-Ce)alkyl. In some embodiments, Z is (Ci-C6)alkyl.

[0013] In some embodiments, R1and R2are each independently (Ci-Ce)alkyl. In some embodiments, R1and R2are each independently alkyl substituted with aryl. In some embodiments, R1and R2are each independently aryl(Ci-Ce)alkyl. In some embodiments, R1and R2are each independently alkyl substituted with heteroaryl. In some embodiments, R1and R2are each independently heteroaryl(Ci-Ce)alkyl. In some embodiments, R1and R2are each independently alkyl substituted with cycloalkyl. In some embodiments, R1and R2are each independently cycloalkyl(Ci-C6)alkyl. In some embodiments, R1and R2are each independently alkyl substituted with heterocycloalkyl. In some embodiments, R1and R2are each independently heterocycloalkyl(Ci-C6)alkyl.

[0014] In some embodiments, each R3is independently (Ci-Ce)alkyl. In some embodiments, each R3is independently (Ci-Ce)alkoxy. In some embodiments, each R3is substituted alkoxy. In some embodiments, each R3is independently alkoxy substituted with aryl. In some embodiments, each R3is independently aryl(Ci-Ce)alkoxy. In some embodiments, each R3is independently phenyl(Ci-Ce)alkoxy. In some embodiments, each R3is independently (Ci- Cejalkylamino. In some embodiments, each R3is independently alkylamino substituted with aryl. In some embodiments, each R3is independently aryl(Ci-C6)alkylamino. In some embodiments, each R3is independently aryloxy that is optionally substituted.

[0015] In some embodiments, R4is (Ci-Ce)alkyl.

[0016] In some embodiments, Rais (Ci-Ce)alkyl. In some embodiments, Rcis (Ci-Ce)alkyl.

[0017] In some embodiments, Rbis (Ci-Ce)alkyl.

[0018] Several moieties described herein can be substituted or unsubstituted. Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, ureido groups, epoxy groups, and ester groups. Other non-limiting examples of optional substituents include halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, amido, alkylamido, dialkylamido, nitro, amino, cyano, azido, oxo, alkylamino, dialkylamino, carboxyl, thio, thioalkyl and thioaryl.

[0019] Non-limiting examples of alkyl groups include straight, branched, and cyclic alkyl groups. An alkyl group can be, for example, a Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. In some embodiments, each alkyl is independently (Ci-Ce)alkyl.

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

[0021] Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, secbutyl, and t-butyl. Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1 -chloroethyl, 2 -hydroxy ethyl, 1,2-difluoroethyl, and 3 -carboxypropyl.

[0022] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups. Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl-cycloprop-l-yl, cycloprop-2-en-l-yl, cyclobutyl, 2,3-dihydroxycyclobut-l-yl, cyclobut-2-en-l-yl, cyclopentyl, cyclopent-2-en-l-yl, cyclopenta-2,4-dien-l-yl, cyclohexyl, cyclohex-2-en-l-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopent-l-yl, 3,5-dichlorocyclohex-l-yl, 4-hydroxycyclohex-l-yl, 3,3,5-trimethylcyclohex-l-yl, octahydropentalenyl, octahydro- 177-indenyl, 3a, 4, 5, 6, 7,7a- hexahydro-3Z7-inden-4-yl, decahydroazulenyl, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, andbicyclo[3.3.3]undecanyl. In some embodiments, each cycloalkyl is independently (C3- Cio)cycloalkyl.

[0023] Non-limiting examples of alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups. The olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. An alkenyl or alkenylene group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, c25, C26, C27, C28, C29, C30, C31, C32, C33, C34, c35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. Non-limiting examples of alkenyl and alkenylene groups include ethenyl, prop-l-en-l-yl, isopropenyl, but-l-en-4-yl; 2- chloroethenyl, 4-hydroxybuten-l-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7-hydroxy-7- methyloct-3 , 5 -dien-2-yl .

[0024] Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups. The triple bond of an alkylnyl or alkynylene group can be internal or terminal. An alkylnyl or alkynylene group can be, for example, a C2, C3, C4, C5, Ce, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. Non-limiting examples of alkynyl or alkynylene groups include ethynyl, prop-2-yn-l-yl, prop-l-yn-l-yl, and 2-methyl-hex-4-yn-l-yl; 5-hydroxy- 5-methylhex-3-yn-l-yl, 6-hydroxy-6-methylhept-3-yn-2-yl, and 5-hydroxy-5-ethylhept-3-yn-l- yi.

[0025] A halo group can be, for example, a chloro, bromo, fluoro, or iodo. A haloalkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. A haloalkenyl group can be any alkenyl group substituted with any number of halogen atoms. A haloalkynyl group can be any alkynyl group substituted with any number of halogen atoms. Non-limiting examples of a haloalkyl group are trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 1,1 -difluoroethyl bromomethyl, chloromethyl, fluoromethyl, and iodomethyl.

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

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

[0028] An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be monocyclic or polycyclic. An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Nonlimiting 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- / c / 7-butyl phenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4- (trifluoromethyl)phenyl, 4-(difluoromethoxy)-phenyl, 4-(trifluoromethoxy)phenyl, 3- chlorophenyl, 4-chlorophenyl, 3, 4-di chlorophenyl, 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-di chlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3 -methoxyphenyl, 4- methoxyphenyl, 2,3 -dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5- trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4- di chlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3, 4-di chlorophenyl, 2,3,4- tri chlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5- tri chlorophenyl, 2,4,6-trichlorophenyl, 2,3 -dimethylphenyl, 2,4-dimethylphenyl, 2,5- dimethylphenyl, 2,6-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6- trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 3 -ethylphenyl, 4- ethylphenyl, 2,3 -di ethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2, 3, 4-tri ethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5- triethylphenyl, 2,4,6-triethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, and 4- isopropylphenyl. In some embodiments, each aryl is independently phenyl, naphthyl, or biphenyl. In some embodiments, each aryl is independently (C4-Cio)aryl.

[0029] A heterocycloalkyl group can be a non-aromatic ring or ring system, which may optionally contain one or more double bonds as part of the ring structure, and which has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus. In some embodiments, each heterocycloalkyl is a mono- or bi-cyclic non-aromatic ring or ring system containing 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. In some embodiments, each heterocycloalkyl is independently (C i -C9)heterocy cloalkyl .

[0030] Non-limiting examples of substituted aryl groups include 2-aminophenyl, 2-(N- methylamino)phenyl, 2-(7V,7V-dimethylamino)phenyl, 2-(7V-ethylamino)phenyl, 2-(N,N- diethylamino)phenyl, 3 -aminophenyl, 3-(A-methylamino)phenyl, 3-(N,N- dimethylamino)phenyl, 3-(7V-ethylamino)phenyl, 3-(A,A-diethylamino)phenyl, 4-aminophenyl, 4-(7V-methylamino)phenyl, 4-(7V,7V-dimethylamino)phenyl, 4-(7V-ethylamino)phenyl, and 4-(N,N- di ethyl amino)pheny 1.

[0031] An aryloxy group can be, for example, an oxygen atom substituted with any aryl group. An ether or an ether group comprises an aryloxy group. The aryloxy group can be substituted or unsubstituted. An aryloxy group can be substituted, for example, with amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. For example, a halogen or hydrogen group of a haloalkoxy group can be optionally replaced by amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, each aryloxy is independently -0-(C4-Cio)aryl.

[0032] A heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms. A heterocycle can 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 (Ci-C9)heterocyclyl. In some embodiments, each heterocyclyl is independently (C3-C9)heterocyclyl. In some embodiments, each heterocyclyl is independently(Cs-C9) heterocyclyl.

[0033] Non-limiting examples of heterocycles (heterocyclyl) include: heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-l / Z-azepinyl, 2,3 -dihydro- l / Z-indole, and 1, 2,3,4- tetrahydroquinoline; and ii) heterocyclic units having 2 or more rings one of which is a heterocyclic ring, non-limiting examples of which include hexahydro- I / / -pyrrol izinyl, 3a,4,5,6,7,7a-hexahydro-l / / -benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-l / 7-indolyl, 1, 2,3,4- tetrahydroquinolinyl, and decahydro- l / / -cycloocta[b]pyrrolyl.

[0034] Non-limiting examples of heteroaryl include: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, triazinyl, thiazolyl, 1 / 7-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, nonlimiting examples of which include: 7 / / -purinyl, 9 / / -purinyl, 6-amino-9 / 7-purinyl, 5H- pyrrolo[3,2-t ]pyrimidinyl, 7 / 7-pyrrolo[2,3-t ]pyrimidinyl, pyrido[2,3-t ]pyrimidinyl, 4, 5,6,7- tetrahydro-l-77-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl. In some embodiments, each heteroaryl is independently a mono- or bi-cyclic group composed of from 5 to 10 ring members, and having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. In some embodiments, each heteroaryl is independently (C3-C9)heteroaryl. In some embodiments, each heteroaryl is a 5- or 6-membered heteroaryl.

[0035] In some embodiments, a compound exists in a population of tautomeric forms. All such tautomeric forms are contemplated herein as part of the present disclosure.

[0036] In some embodiments, a compound of the present disclosure is substituted with a protecting group. Protecting groups can be selected on the basis of the atom(s) to which the protecting group is attached. Nitrogen protecting groups include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0037] For example, nitrogen protecting groups such as amide groups include, but are not limited to, formamide, acetamide, chloroacetamide, tri chloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3 -pyridyl carb oxami de, N- benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenyl acetamide, o-nitrophenoxyacetamide, acetoacetamide, (N' dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0038] Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2, 2, 2 -tri chloroethyl carbamate (TCBOC), 1- methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N- hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o- nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1- methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(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] Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p- toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy- 4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0040] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N- benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2, 3 -diphenylmal eimide, N-2,5-dimethylpyrrole, N- 1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3 -acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5- dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fem), N-2-picolylamino N'- oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N — (N',N'-dimethylaminomethylene)amine, N,N'- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N- diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N- copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0041] Oxygen protecting groups include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Example oxygen protecting groups include, but are not limited to, 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 (TEIP), 3 -bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxy cyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-di oxide, l-[(2-chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), l,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 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- l-benzyloxy-2-fluoroethyl, 2, 2, 2-tri chloroethyl, 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- di chlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a- 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(levulinoyloxyphenyl)methyl, 4, 4', 4"- tris(benzoyloxyphenyl)methyl, 3-(imidazol-l-yl)bis(4',4"-dimethoxyphenyl)methyl, 1, 1 -bis(4- methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, l,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethyl silyl (TMS), triethylsilyl (TES), triisopropyl silyl (TIPS), dimethylisopropyl silyl (IPDMS),diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethyl silyl (DPMS), t-butylmethoxyphenyl silyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, di chloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3 -phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2- tri chloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenyl sulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o- nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-l- napththyl carbonate, methyl dithiocarb onate, 2-iodobenzoate, 4 -azidobutyrate, 4-nitro-4- methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- ( 1 , 1 ,3 , 3 -tetramethylbutyl)phenoxy acetate, 2,4-bi s( 1 , 1 -dimethylpropyl)phenoxy acetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0042] Any compound herein can be purified. A compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, atleast 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.

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

[0044] In some embodiments, the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups, each appearing alone or as part of another moiety in the foregoing definitions of R1, R2, R3, R4, Ra, Rb, and Rcis substituted by from 1 to 4 groups selected from the group consisting of alkyl (e.g., (Ci-Ce)alkyl), alkoxy (e.g., (Ci-Ce)alkoxy), hydroxy, oxo, nitro, cyano, amino, - C(O)-Rd, -C(O)-ORd, -O-C(O)-Rd, -C(O)-NRdRe, -NRdRe, haloalkyl (e.g., (Ci-C6)haloalkyl), haloalkyloxy (e.g., (Ci-Ce)haloalkoxy, or trifluoromethoxy), or halogen, wherein Rdand Reare independently hydrogen or alkyl.

[0045] In some embodiments, one or more of the carbon atoms of the preceding possible substituents are isotopically enriched in deuterium.

[0046] In some embodiments, the compounds disclosed herein comprise their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

[0047] In some embodiments, X is sulphur.

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

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

[0050] In some embodiments, the compound is of formula (Ia):wherein R1, R2, R3, R4, R', R", X, Y, Z, and n are as defined in formula (I)

[0051] In some embodiments, Z is hydrogen.

[0052] In some embodiments, the compound is of formula (lb):wherein R1, R2, R3, R4, R', R", and n are as defined in formula (I).

[0053] In some embodiments, n is 1.

[0054] In some embodiments, R' and R" each are hydrogen.

[0055] In some embodiments, R1and R2each are hydrogen.

[0056] In some embodiments, R1is hydrogen.

[0057] In some embodiments, R2is hydrogen.

[0058] In some embodiments, R1is hydrogen or methyl.

[0059] In some embodiments, R2is hydrogen, alkyl, or C(O)Ra, wherein Rais as defined in formula (I).

[0060] In some embodiments, R2is hydrogen, C(O)Ra, benzyl, (Ci-Cio)alkyl, (C3- Cio)cycloalkyl, -(Ci-Cio)alkyl-(Ci-C9)heterocyclyl, (Ci-C9)heterocyclyl, (Ci-Cio)alkylsulfonyl, (C4-Cio)arylsulfonyl, (C4-Cio)heteroarylsulfonyl, 5- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein each benzyl, (Ci-Cio)alkyl, (C3-Cio)cycloalkyl, -(Ci-Cio)alkyl-(Ci- C9)heterocyclyl, (Ci-C9)heterocyclyl, (Ci-Cio)alkylsulfonyl, (C4-Cio)arylsulfonyl, (C4- Cio)heteroarylsulfonyl, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl is independently substituted or unsubstituted.

[0061] In some embodiments, R2is hydrogen, C(O)Ra, benzyl, (Ci-Cio)alkyl, (C3- Cio)cycloalkyl, -(Ci-Cio)alkyl-(Ci-C9)heterocyclyl, (Ci-C9)heterocyclyl, (Ci-Cio)alkylsulfonyl, (C4-Cio)arylsulfonyl, (C4-Cio)heteroarylsulfonyl, 5- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein each Rais -(Ci-Cio)alkyl-(Ci-C9)heterocyclyl, (Ci-C9)heterocyclyl, (Ci- Cio)alkyl, (C3-Cio)cycloalkyl, benzyl, NH-(Ci-Cio)alkyl, -CH2-(Ci-C9)heterocyclyl, -CH2-(CI- C5)heterocyclyl-(C4-Cio)aryl; wherein each benzyl, (Ci-Cio)alkyl, (C3-Cio)cycloalkyl, -(Ci- Cio)alkyl-(Ci-C9)heterocyclyl, (Ci-C9)heterocyclyl, (Ci-Cio)alkylsulfonyl, (C4-Cio)arylsulfonyl, (C4-Cio)heteroarylsulfonyl, NH-(Ci-Cio)alkyl, -CH2-(Ci-C9)heterocyclyl, -CH2-(CI- C5)heterocyclyl-(C4-Cio)aryl, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl is independently unsubstituted or substituted with one or more groups independently selected from halogen, -NH2, (Ci-Cio)alkyl, -ORX, oxo, C(O)RX, and -CO2RX, wherein each Rxis independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.

[0062] In some embodiments, R2is C(O)Ra. In some embodiments, R2is C(O)Ra, wherein Rais aryl or heteroaryl, each of which is unsubstituted or substituted. In some embodiments, R2is C(O)Ra, wherein Rais 5- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted. In some embodiments, Rais optionally substituted by from 1 to 4 groups selected from the group consisting of (Ci-Ce)alkyl, (Ci-Ce)alkoxy, hydroxy, oxo, nitro, cyano, amino, -C(O)-Rd, -C(O)-ORd, -O-C(O)-Rd, -C(O)-NRdRe, -NRdRe, (Ci-C6)haloalkyl, (Ci- Ce)haloalkyloxy (e.g., trifluoromethoxy), and halogen atom, wherein Rdand Reare independently hydrogen or (Ci-Ce)alkyl.

[0063] In some embodiments, R2is C(O)Ra, wherein Rais selected from the group consisting of pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridazinyl, triazolyl, oxadiazolyl, and pyrazinyl, each of which is unsubstituted or substituted. In some embodiments, Rais optionally substituted by from 1 to 4 groups selected from the group consisting of (Ci-Ce)alkyl, (Ci-Ce)alkoxy, hydroxy, oxo, nitro, cyano, amino, - C(O)-Rd, -C(O)-ORd, -O-C(O)-Rd, -C(O)-NRdRe, -NRdRe, (Ci-C6)haloalkyl, (Ci- Ce)haloalkyloxy (e.g., trifluoromethoxy), and halogen, wherein Rdand Reare independently hydrogen or (Ci-Ce)alkyl.

[0064] In some embodiments, R2is C(O)Ra, wherein Rais pyrimidin-2-yl, pyrimidin-5-yl, 5- amino-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, l / f-pyrazol-3-yl, 2-methyl-l / 7-pyrazole-3-yl, pyridin-2-yl, 2-chloro-pyridin-2-yl, 6-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl, 6-hydroxy- pyridin-2-yl, pyri din-3 -yl, 6-amino-pyri din-3 -yl, 2-chl oro-pyri din-3 -yl, pyridin-4-yl, 3-phenyl- l / Z-pyrazol-5-yl, l / f-imidazol-4-yl, lJ7-imidazol-2-yl, 1 -methyl- l / f-imidazol-4-yl, 1-methyl-l / Z-imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, 4-methyl-l,2,3-thiadiazol-5-yl, 5-phenylisoxazol-3- yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5-methyl-3-phenylisoxazol-4-yl, 4-phenylthiazol-2-yl, 1H- tetrazol-5-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin- 4-yl, 3-hydroxy-pyrazinyl, 4-isopropyl-l,2,3-thiadiazolyl, 3-methyl-isoxazole-5-yl, 4,4-difluoro- piperidin-l-yl, l,2,4-triazin-3-yl, 4-methylpyrid-2-ylamino, 3 -oxopiperazin- 1-yl, 5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl, or piperazin- 1-yl.

[0065] In some embodiments, R2is C(O)Ra, wherein Rais pyridin-2-yl.

[0066] In some embodiments, R2is C(O)Ra, wherein Rais 2-chloro-pyridin-2-yl.

[0067] In some embodiments, R2is C(O)Ra, wherein Rais 6-chloro-pyridin-2-yl.

[0068] In some embodiments, R2is C(O)Ra, wherein Rais 5-chloro-pyridin-2-yl.

[0069] In some embodiments, R2is C(O)Ra, wherein Rais 6-hy droxy-pyri din-2 -yl.

[0070] In some embodiments, R2is C(O)Ra, wherein Rais pyridin-3-yl.

[0071] In some embodiments, R2is C(O)Ra, wherein Rais 6-amino-pyridin-3-yl.

[0072] In some embodiments, R2is C(O)Ra, wherein Rais 2-chloro-pyridin-3-yl.

[0073] In some embodiments, R2is C(O)Ra, wherein Rais pyridin-4-yl.

[0074] In some embodiments, R2is C(O)Ra, wherein Rais pyrimidin-2-yl.

[0075] In some embodiments, R2is C(O)Ra, wherein Rais pyrimidin-5-yl.

[0076] In some embodiments, R2is C(O)Ra, wherein Rais 5-amino-pyrimidin-2-yl.

[0077] In some embodiments, R2is C(O)Ra, wherein Rais 5-methoxy-pyrimidin-2-yl.

[0078] In some embodiments, R2is C(O)Ra, wherein Rais lZZ-pyrazol-3-yl.

[0079] In some embodiments, R2is C(O)Ra, wherein Rais 2-methyl-lZ7-pyrazole-3-yl.

[0080] In some embodiments, R1and R2are each independently hydrogen, methyl, 2,2,2- trifluoroethyl, cyclopropyl, cyclobutyl, 3 -hydroxy cyclobutyl, 3,3-difluorocyclobutyl, cyclohexyl, 2-hydroxycyclohexyl, 3 -hydroxy cyclohexyl, 4-hydroxycyclohexyl, pyrimidin-2-yl, pyrimidin-2-ylmethyl, pyrimidin-3-ylmethyl, pyrimidin-4-ylmethyl, oxalyl, 2-methoxy ethyl, benzyl, 4-carboxybenzyl, 4-carboxymethylbenzyl, tetrahydro-27 / -pyran-4-yl, oxetan-3-yl, 1,2,4- thiadiazol-5-yl, 4-aminomethyl- 1,2, 3 -triazol- 1-ylmethyl, 4-methyl-l,2,3-thiadiazolyl-5- ylmethyl, benzo[d]thiazol-2-yl, 4-carboxylethyl-l,2,3-thiadiazolyl-5-ylmethyl, 4-carboxy- 1,2,3- thiadiazolyl-5-ylmethyl, isoindoline- 1, 3-dion-2-yl, or acetyl.

[0081] In some embodiments, R1and R2together with the nitrogen atom to which they are bound form an optionally substituted heterocycle or heteroaryl, wherein the optionally substituted heterocycle or heteroaryl is pyrazolidinonyl, piperazinyl, 2-oxopiperazinyl, triazolyl, benzotri azolyl, morpholinyl, pyrrolidinyl, or piperidinyl.

[0082] In some embodiments, R1and R2together with the nitrogen atom to which they are bound form an optionally substituted heterocycle, wherein the optionally substituted heterocycle is 1 / 7-1,2,3-triazol-l-yl, l / Z-benzo[d][l,2,3]triazol-l-yl, morpholinyl, 3,3-difluoropyrrolidin-l- yl, 4,4-difluoropiperidin-l-yl, pyrazolidin-4-one, and 4-benzylpiperidin-l-yl.

[0083] In some embodiments, R3is halogen, an alkoxy group, a cycloalkyloxy group, or an aryloxy group, each of which is optionally substituted by from 1 to 4 groups, wherein each group is independently alkyl, alkoxy, hydroxy, oxo, nitro, cyano, amino, -C(O)-Rd, -C(O)-ORd, - O-C(O)-Rd, -C(O)-NRdRe, -NRdRe, haloalkyl, haloalkyloxy (e.g., trifluoromethoxy), or halogen, wherein Rdand Reare independently hydrogen or alkyl.

[0084] In some embodiments, R3is halogen, an alkoxy group, a cycloalkyloxy group, or an aryloxy group, each of which is optionally substituted by from 1 to 4 groups, wherein each group is independently (Ci-Ce)alkyl, (Ci-Ce)alkoxy, hydroxy, oxo, nitro, cyano, amino, -C(O)- Rd, -C(O)-ORd, -O-C(O)-Rd, -C(O)-NRdRe, -NRdRe, (Ci-C6)haloalkyl, (Ci-C6)haloalkyloxy (e.g., trifluoromethoxy), or halogen, wherein Rdand Reare independently hydrogen or (Ci- Ce)alkyl.

[0085] In some embodiments, R3is halogen, a (Ci-Ce)alkoxy group, a cycloalkyloxy group, or an aryloxy group, each of which is optionally substituted by from 1 to 4 groups, wherein each group is independently (Ci-Ce)alkyl, (Ci-Ce)alkoxy, hydroxy, oxo, nitro, cyano, amino, -C(O)- Rd, -C(O)-ORd, -O-C(O)-Rd, -C(O)-NRdRe, -NRdRe, (Ci-C6)haloalkyl, (Ci-C6)haloalkyloxy (e.g., trifluoromethoxy), or halogen, wherein Rdand Reare independently hydrogen or (Ci- Ce)alkyl.

[0086] In some embodiments, R3is phenyloxy, which is un substituted. In some embodiments, R3is phenyloxy which is substituted. In some embodiments, R3is phenyloxy which is optionally substituted by from 1 to 4 groups, wherein each group is independently alkyl, alkoxy, hydroxy, oxo, nitro, cyano, amino, -C(O)-Rd, -C(O)-ORd, -O-C(O)-Rd, -C(O)-NRdRe, -NRdRe, haloalkyl, haloalkyloxy (e.g., trifluoromethoxy), and halogen, wherein Rdand Reare independently hydrogen or alkyl. In some embodiments, R3is phenyloxy which is substituted by one or more halogen atoms.

[0087] In some embodiments, R3is phenyloxy which is optionally substituted by from 1 to 4 groups selected from the group consisting of (Ci-Ce)alkyl, (Ci-Ce)alkoxy, hydroxy, oxo, nitro, cyano, amino, -C(O)-Rd, -C(O)-ORd, -O-C(O)-Rd, -C(O)-NRdRe, -NRdRe, (Ci-C6)haloalkyl, (Ci- Ce)haloalkyloxy (e.g., trifluoromethoxy), and halogen, wherein Rdand Reare independently hydrogen or (Ci-Ce)alkyl.

[0088] In some embodiments, R3is optionally substituted by one or two substituents, identical or different, selected from the group consisting of hydroxy, fluorine, chlorine, bromine, iodide, CF3, CHF2, methoxy, S(O)2Me, cyano, and C(O)Me.

[0089] In some embodiments, R3is phenoxy which is optionally substituted by one or two substituents, identical or different, selected from the group consisting of hydroxy, fluorine, chlorine, bromine, iodide, CF3, CHF2, methoxy, S(O)2Me, cyano, and C(O)Me.

[0090] In some embodiments, R3is independently at each occurrence selected from the group consisting of alkyl, cyclohexyl, haloalkyl, alkyloxy, hydroxyalkyloxy, haloalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, arylsulfonyl, alkylsulfonyl, phenyl, phenoxy, benzo[d][l,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 halogen.

[0091] In some embodiments, R3is independently at each occurrence selected from the group consisting of alkyl, cyclohexyl, halo(Ci-Ce)alkyl, alkyloxy, hydroxy(Ci-Ce)alkyloxy, halo(Ci- Ce)alkyloxy, cycloalkyloxy, cycloalkyl(Ci-C6)alkyloxy, aryl(Ci-Ce)alkyloxy, arylsulfonyl, alkylsulfonyl, phenyl, phenoxy, benzo[d][l,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 halogen.

[0092] In some embodiments, R3is independently at each occurrence (Ci-Cio)alkyl, cyclohexyl, (C3-Cio)cycloalkyl, (Ci-Cio)alkoxy, (Ci-Cio)cycloalkyloxy, (C4-Cio)arylsulfonyl, (Ci- Cio)alkylsulfonyl, phenyl, benzyl, phenoxy, benzo[d][l,3]dioxol-5-yloxy)phenyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(0)-NH-(Ci-Cio)cycloalkyl, -NH-C(0)-(Ci-Cio)cycloalkyl, (C3- C9)heteroaryl, (Ci-C9)heterocyclyl, or naphthalenyl, each of which is substituted or unsubstituted, or halogen.

[0093] In some embodiments, R3is independently at each occurrence halogen, (Ci-Cio)alkyl, (Ci-Cio)haloalkyl, cyclohexyl, (Ci-Cio)alkoxy, (Ci-Cio)cycloalkyloxy, (C4-Cio)aryl sulfonyl, (Ci-Cio)alkylsulfonyl, phenyl, phenoxy, benzo[d][l,3]dioxol-5-yloxy)phenyl, benzyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(0)-NH-(Ci-Cio)cycloalkyl, -NH-C(O)-(Ci- Cio)cycloalkyl, (C3-C9)heteroaryl, (Ci-C9)heterocyclyl, or naphthalenyl, wherein each (Ci- Cio)alkyl, cyclohexyl, (Ci-Cio)alkoxy, (Ci-Cio)cycloalkyloxy, (C4-Cio)arylsulfonyl, (Ci- Cio)alkylsulfonyl, phenyl, phenoxy, benzo[d][l,3]dioxol-5-yloxy)phenyl, benzyl, phenylamino, -C(O)-NHPh, -NH-C(O)Ph, -C(0)-NH-(Ci-Cio)cycloalkyl, -NH-C(0)-(Ci-Cio)cycloalkyl, (C3- C9)heteroaryl, (Ci-C9)heterocyclyl, and naphthalenyl is independently unsubstituted or substituted with halogen, oxo, cyano, -NH2, (Ci-Cio)alkyl, (Ci-Cio)alkoxy, (Ci-Cio)haloalkyl,(Ci-Cio)alkylsulfonyl, C(O)RX, NH-C(O)-RX, -CO2RX, -CO2NRXRY, -OCH2CO2RX, -ORX, or - CH2ORX, wherein each Rxand RYare independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.

[0094] In some embodiments, R3is independently at each occurrence methyl, ethyl, propyl, n- butyl, ec-butyl, / -butyl, pentan- 1-yl, pentan-2 -yl, pentan-3 -yl, cyclohexyl, hydroxy cyclohexyl, trifluoromethyl, methoxy, neopentyloxy, 2,4-dimethylpentan-3-yloxy, 2-hydroxy-2- methylpropoxy, (adamantan-l-yl)methoxy, (adamantan-2-yl)methoxy, (adamantan-l-yl)oxy, (adamantan-2-yl)oxy, cyclopentyloxy, cyclohexyloxy, fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethoxy, trifluoroethoxy, phenyl, 2-chlorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3 -bromophenyl, 4-bromophenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 4-bromophenyl, 2-methoxyphenyl, 3 -methoxyphenyl, 4- methoxyphenyl, 2-m ethylphenyl, 3 -methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3- trifluorom ethylphenyl, 4-trifluorom ethylphenyl, 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][l,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- (trifluorom ethoxy )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, IH-indol-l-yl, 4- methyl sulfonylphenoxy, -C(O)-NHPh, -NH-C(O)Ph, -C(O)-NHcyclohexyl, -NH- C(O)cyclohexyl, 2-(acetamido)phenyl, 2-carboxyphenyl, 3 -carboxyphenyl, 4-carboxyphenyl, 2- carb oxami dophenyl, 3 -carb oxami dophenyl, 4-carboxamidophenyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 2-(2-oxy acetic acid phenyl), 3-(2-oxyacetic acid phenyl), 4- (2-oxyacetic acid phenyl), 2-oxopyrrolidin-l-yl, 3 -(trifluoromethyl)- IH-pyrazol -4-yl, pyridyl, naphthal ene-l-yl, naphthalene-2-yl, -S(O)2Ph, 2-oxopyridin-l(2H)-yl, indolyl, phenylsulfonyl, 2-hydroxymethylpyrrolidiny-l-yl, or hydroxypiperidine- 1-yl.

[0095] In some embodiments, R3is phenoxy substituted by one to five groups independently selected from halogen and (Ci-Cio)haloalkyl. In some embodiments, R3is phenoxy substituted by one to five halogen.

[0096] In some embodiments, R3is 2-(trifluoromethyl)phenoxy. In some embodiments, R3is 3- (trifluoromethyl)phenoxy. In some embodiments, R3is 4-(trifluoromethyl)phenoxy. In someembodiments, R3is 2-(trifluoromethoxy)phenoxy. In some embodiments, R3is 3-(trifluorom ethoxy )phenoxy. In some embodiments, R3is 4-(trifluoromethoxy)phenoxy. In some embodiments, R3is 2-chlorophenoxy.

[0097] In some embodiments, R3is phenoxy.

[0098] In some embodiments, R3is 3-chlorophenoxy.

[0099] In some embodiments, R3is 4-chlorophenoxy.

[0100] In some embodiments, R3is 2-fluorophenoxy.

[0101] In some embodiments, R3is 3 -fluorophenoxy.

[0102] In some embodiments, R3is 4-fluorophenoxy.

[0103] In some embodiments, R3is 2,4-dichlorophenoxy.

[0104] In some embodiments, R3is 3, 5 -difluorophenoxy.

[0105] In some embodiments, two adjacent R3groups, together with the carbon atoms to which they are bound, form a fused cycloalkyl or heterocycloalkyl ring, e.g., a benzofuranyl ring.

[0106] In some embodiments, R4is methyl.

[0107] In some embodiments, R4is 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.Compounds

[0109] Non-limiting examples of compounds of formula (I) are:(2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-phenylphenyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-bromophenyl)-5-(dimethylaminomethyl)-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-2-(4-bromophenyl)-5-(morpholinomethyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-bromophenyl)-5-(morpholinomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-bromophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-[(4-benzyl-l-piperidyl)methyl]-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[(4-benzyl-l-piperidyl)methyl]-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-bromophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-methoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(trifluoromethyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-benzyloxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(trifluoromethyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-phenylphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenoxy)phenyl]-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,2,2-trifluoroethoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)-lH-pyrazol-4-yl]phenyl]-l,4-thiazepan-3- one;(2R,5S)-5-(aminomethyl)-2-(3-iodophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-l,4-thiazepan-3-one;3-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;3-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;4-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;4-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;(2S,5R)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(l,3-benzodioxol-5-yl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(l,3-benzodioxol-5-yl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-bromo-5-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-naphthyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(l -naphthyl)- l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(benzenesulfonyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2-methoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(o-tolyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(l-ethylpropyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenyl]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenyl]phenyl]-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(3-amino-4-chloro-phenyl)phenyl]-5-(aminomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,4-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-chloro-3-iodo-phenyl)phenyl]-l,4-thiazepan-3-one;N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzamide;N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]cyclohexanecarboxamide;(2R,5S)-5-(aminomethyl)-2-[3-(4-fluorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-cyclohexylphenyl)-l,4-thiazepan-3-one;3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]-N-phenyl-benzamide;(2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-l,4-thiazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4-thiazepan-3- one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4-thiazepan-3- one;(2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4-thiazepan-3- one;N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]phenyl]acetamide;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(4,4-difluoro-l-piperidyl)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(4,4-difluoro-l-piperidyl)methyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,3-dimethoxyphenyl)phenyl]-l,4-thiazepan-3-one;2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzoic acid;2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzamide;(2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxyphenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;2-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]phenoxy]acetic acid;(2R,5 S)-5-(aminomethyl)-2-[3 -(2-oxopyrrolidin- 1 -yl)phenyl]- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-(2-oxo-l-pyridyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]phenyl]-l,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-(4-hydroxy-l-piperidyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,2-dimethylpropoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-(((3R,5R,7R)-adamantan-l-yl)methoxy)phenyl)-5-(aminomethyl)-l,4-thiazepan-3- one;(2R,5S)-2-(3-(((lR,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-5-(aminomethyl)-l,4-thiazepan-3- one;(2R,5S)-5-(aminomethyl)-2-[3-(cyclohexoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(l-isopropyl-2-methyl-propoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2 -hydroxy -2-methyl-propoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-l,4-thiazepan-3-one;(2R,5 S)-5-(aminomethyl)-2-(4-phenoxy-3 -propyl -phenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-(3-chloro-4-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R, 5 S)-5 -(aminomethyl)-2-(4-indol- 1 -ylphenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[4-(2-methoxyphenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2,4-dichlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[3-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[2-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-fluorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-l,4-thiazepan-3-one;4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]benzonitrile;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(methylaminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(cyclohexoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-l,4-thiazepan-3-one;(2R,5 S)-5-(aminomethyl)-2-(2-methyl-4-phenoxy-phenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-dibenzofuran-2-yl-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-methylsulfonylphenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;2-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]benzonitrile;(2R,5S)-2-[4-(4-acetylphenoxy)phenyl]-5-(aminomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(l,3-benzodioxol-5-yloxy)phenyl]-l,4-thiazepan-3-one;3-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]-5-chloro-benzonitrile;(2R,5S)-5-(aminomethyl)-2-(4-anilinophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-chloro-4-phenoxy-phenyl)-l,4-thiazepan-3-one;4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]-3-chloro-benzonitrile;(2R,5S)-5-(aminomethyl)-2-(2-methoxy-4-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)-2-methoxy-phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-(triazol-l-ylmethyl)-l,4-thiazepan-3-one;(2R,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[[4-(aminomethyl)triazol-l-yl]methyl]-2-[4-(4-fluorophenoxy)phenyl]-l,4-thiazepan-3 -one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-5-[(pyrimidin-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-l,4- thiazepan-3-one;(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-5-[(l,3-benzothiazol-2-ylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(l,2,4-thiadiazol-5-ylamino)methyl]-l,4-thiazepan-3-one;N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide;2-oxo-2-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methylamino]acetate;N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide;4-(aminomethyl)-N-[[(2R,5S)-2-(3-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]benzamide;N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-2H-tetrazole-5- carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]thiazole-4- carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-4-methyl- thiadiazole-5-carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH-pyrazole-3- carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-5- carboxamide;6-amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-3 -carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]thiazole-2- carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-5-phenyl-isoxazole-3- carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-5-methyl-3-phenyl- isoxazole-4-carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-4-phenyl-thiazole-2- carboxamide;N-[[(2R, 5 S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-3 -phenyl- lH-pyrazole-5- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carb oxami de;1-methyl-N-[[(2S,5R)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]imidazole-4- carboxamide;4-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiadiazole-5- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-5-carboxamide6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-3- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]methanesulfonamide4-isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiadiazole-5- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-lH-imidazole-4- carboxamide;2-morpholino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]acetamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-lH-pyrazole-3- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]morpholine-4-sulfonamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridazine-3-carboxamide;5-isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiadiazole-4- carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-3-sulfonamide;4-fluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]benzenesulfonamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2-sulfonamide; l-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]imidazole-4- sulfonamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiazole-2-carboxamide;3.3-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]cyclobutanecarboxamide;4.4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]cyclohexanecarboxamide;N-[[(2R,5S)-2-[3-(2-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-3-oxo-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-(((2R,5S)-2-(3-(((lR,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-l,4-thiazepan-5- yl)methyl)pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-2-pyrimidin-2-yl- acetamide;1 -benzyl-3 -[[(2R,5 S)-3 -oxo-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-5-yl]methyl]urea;3-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]isoxazole-5- carboxamide;N-[[(2R,5S)-2-[3-(cyclohexoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;4.4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]piperidine-l- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-l,2,4-triazine-3- carboxamide;N-[[(2R,5S)-2-[4-(2-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrazine-2-carboxamide;6-chloro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- carboxamide;2-[5-(4-chlorophenyl)isoxazol-3-yl]-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]acetamide;6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- carboxamide;5-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;5-methoxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide; l-(4-methyl-2-pyridyl)-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]ureaN-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH-pyrazole-3- carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-2-morpholino- acetamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH-pyrazole-3- carboxamide;N-[[(2R, 5 S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l -methyl- imidazole-4-carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridazine-3- carboxamide;6-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-3-carboxamide;6-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-3 -carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridazine-3- carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-2-morpholino- acetamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-2- sulfonamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-2- sulfonamide;2-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]benzamide;4-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]benzamide;(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-5-[(l,2,4-thiadiazol-5-ylamino)methyl]-l,4-thiazepan-3 -one;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;5-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;5-chloro-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-2-carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-5-methoxy- pyrimidine-2-carboxamide;5-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-5-methoxy- pyrimidine-2-carboxamide;3-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrazine-2- carboxamide;3-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- carboxamide;N-[[(2S,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2S,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-l,4-thiazepan-5- yl]methyl]-l,3,4-oxadiazole-2-carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-5-(4-fluorophenyl)-l,3,4- oxadiazole-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]piperazine-l-carboxamide;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-l,4-thiazepan-3-one; methyl 4-[[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5- yl]methylamino]methyl]benzoate;(2R,5S)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;4-[[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methylamino]methyl]benzoic acid;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(cyclopropylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-5-[(cyclopropylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[(cyclobutylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(tetrahydropyran-4-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-5-[(oxetan-3-ylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[[bis(oxetan-3-yl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-((((lr,3S)-3-hydroxycyclobutyl)amino)methyl)-2-(4-phenoxyphenyl)-l,4-thiazepan- 3 -one;(2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[[(3,3-difluorocyclobutyl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[[(4-methylthiadiazol-5-yl)methylamino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3 -one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-4-ylmethylamino)methyl]-l,4-thiazepan-3-one;4-[[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methylamino]methyl]benzoic acid;4-[[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methylamino]methyl]benzoic acid;(2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-bromophenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-2-[3-(2,4-dichlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan- 3 -one;(2R,5S)-5-[(2,2,2-trifluoroethylamino)methyl]-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-l,4- thiazepan-3-one;(2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R, 5 S)-5-[(2-m ethoxy ethylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,l-dioxo-l,4-thiazepan-3-one;(2R,5 S)-5-(aminom ethyl)- 1 , 1 -di oxo-2-(3 -phenoxyphenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-l,l-dioxo-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-5-[(2-oxopiperazin-l-yl)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-l,4-oxazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-l,4-oxazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-(dimethylaminomethyl)-l,4-oxazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(2 -methoxy ethylamino)methyl]-l,4-oxazepan-3-one;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyrimidine-2- carboxamide;6-amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine- 3 -carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-2- carboxamide;6-chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine- 2-carboxamide;2-chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-3 -carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]-l-methyl- imidazole-2-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-3- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-4- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridazine-3- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridazine-4- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]thiazole-4- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]thiazole-2- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyrazine-2- carboxamide;(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2 trifluoroethyl amino) methyl]-l,4-oxazepan-3- one;(2R,5 S)-2-(4-phenoxyphenyl)-5-(piperazine- 1 -carbonyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-l,4-oxazepan-3-one;(2R,5 S)-5-(benzotriazol- 1 -ylmethyl)-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(S)-5-(aminomethyl)-2,2-diphenyl-l,4-thiazepan-3-one;(2R,5S)-5-[(3-oxopiperazin-l-yl)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one; and their enantiomers, diastereoisomers, addition salts thereof with a pharmaceutically acceptable acid or base, and deuterated derivatives.

[0110] In some embodiments, the compound of formula (I) is:(2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(25.55)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;(25.55)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-oxazepan-3-one, or a pharmaceutically- acceptable salt thereof;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-oxazepan-3- one, or a pharmaceutically-acceptable salt thereof;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]thiazole-2- carboxamide, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide, or a pharmaceutically-acceptable salt thereof;N-[[(2R,5S)-2-[4-(3,5-difhrorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide, or a pharmaceutically-acceptable salt thereof;N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide, or a pharmaceutically-acceptable salt thereof;N-[[(2R, 5 S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-3 -phenyl- lH-pyrazole-5- carboxamide, or a pharmaceutically-acceptable salt thereof;N-(((2R,5S)-2-(3-(((lR,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-l,4-thiazepan-5- yl)methyl)pyrimidine-2-carboxamide, or a pharmaceutically-acceptable salt thereof;(2R,5 S)-2-(4-phenoxyphenyl)-5-(piperazine- 1 -carbonyl)- 1 ,4-thiazepan-3 -one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5 S)-5-(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl]- 1 , 1 -di oxo- 1 ,4-thiazepan-3 -one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-[(2-oxopiperazin-l-yl)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(3-(((3R,5R,7R)-adamantan-l-yl)methoxy)phenyl)-5-(aminomethyl)-l,4-thiazepan-3- one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof; or (S)-5-(aminomethyl)-2,2-diphenyl-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

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

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

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

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

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

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

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

[0118] The present disclosure also relates to a process for the preparation of compounds of formula (I) and its intermediates.

[0119] A starting material can comprise a compound of formula (II):wherein A, R3, Z, and n are as defined in formula (I).

[0120] The starting material can be esterified to yield a compound of formula (III):wherein A, R3, Z, and n are as defined in formula (I), and Aik is an alkyl group. In some embodiments, Aik is (Ci-Ce)alkyl.

[0121] The compound of formula (III) can be subsequently subjected to a bromination reaction to yield a compound of formula (IV):wherein A, R3, Z, and n are as defined in formula (I), and Aik is as defined above. Other halogens (e.g., Cl, I) can be incorporated instead of Br.

[0122] The compound of formula (IV) can be reacted with a compound of formula (V):wherein X, R', and R" are as defined in formula (I) and P is a protecting group, to yield a compound of formula (VI):wherein A, R3, Z, X, R', R", and n are as defined in formula (I), and Aik and P are as defined above.

[0123] The compound of formula (VI) can be deprotected to form a compound of formulawherein A, R3, Z, X, R', R", and n are as defined in formula (I), and Aik is as defined above.

[0124] The compound of formula (VII) can be cyclized to yield a compound of formula (VIII):wherein A, R3, Z, X, R', R", and n are as defined in formula (I).

[0125] The hydroxyl group of the compound of formula (VIII) can be protected to yield a compound of formula (IX):wherein A, R3, Z, X, R', R", and n are as defined in formula (I), and P is a protecting group.

[0126] The compound of formula (IX) can be subjected to a reaction with a compound of formula (X): X'R4', wherein X' is halogen and R4' is alkyl that is unsubstituted or substituted, to yield a compound of formula (XI):wherein A, R3, Z, X, R', R", and n are as defined in formula (I), and R4and P are as defined above.

[0127] The compounds of formula (IX) and (XI) together, represent the compound of formula (XII):wherein A, R3, R4, Z, X, R', R", and n are as defined in formula (I), and P is as defined above.

[0128] The compound of formula XII can be subjected to a reaction with a compound of formula (XIII): HNR'R2, wherein R1and R2are as defined in formula (I), to yield a compound of formula (I / a), a particular case of compound of formula (I):wherein A, R1, R2, R3, R4, Z, X, R', R", and n are as defined in formula (I), which can be subjected to a reduction to yield a compound of formula (I / b), a particular case of compound of formula (I):wherein A, R1, R2, R3, R4, Z, X, R', R", and n are as defined in formula (I).

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

[0130] In some embodiments, the compound of formula (I) can be purified according to a separation technique, such as, for example, column chromatography, thin-layer chromatography, sublimation, recrystallization, liquid-liquid extraction, or trituration.

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

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

[0133] In should be understood that at any moment considered appropriate during the course of the process described above, some groups (e.g., hydroxy, amino) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

[0134] In some embodiments, the compound of formula (I) is obtained using an alternative process, for example, the compound of formula (I) can be synthesized starting from a compound of formula (VI) as described above, wherein the hydroxyl moiety is activated, then contacted with an azide derivative to form a compound of formula (XIV):wherein A, R3, Z, X, R', R", and n are as defined in formula (I).

[0135] The compound of formula (XIV) can be cyclized to form a compound of formula (XV):wherein A, R3, Z, X, R', R", and n are as defined in formula (I).

[0136] The compound of formula (XV) can be subjected to a reaction with a compound of formula (X): X'R4', as defined above, to yield a compound of formula (XVI):wherein A, R3, Z, X, R', R", and n are as defined in formula (I), and R4is as defined above.

[0137] Compound of formula (XV) and compound of formula (XVI) together, represent a compound of formula (XVII):wherein A, R3, R4, Z, X, R', R", and n are as defined in formula (I).

[0138] The compound of formula (XVII) can be subjected to reducing conditions to yield a compound of formula (I / c), a particular case of compound of formula (I):wherein A, R3, R4, Z, X, R', R", and n are as defined in formula (I).

[0139] The compound of formula (I / c) can be further reduced to form a compound of formula(I / d), a particular case of compound of formula (I):wherein A, R3, R4, Z, X, R', R", and n are as defined in formula (I).

[0140] Compounds of formula (I / c) and (I / d) together, represent a compound of formula (I / e), a particular case of compound of formula (I):wherein A, R3, R4, Y, Z, X, R', R", and n are as defined in formula (I).

[0141] The compound of formula (I / e) can be subjected to a reaction with the compound of formula (XVIII): X''Rb, wherein X" is halogen and R1' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted, or C(O)Ra, C(O)ORa, or S(O)2Rb, to yield a compound of formula (I / f), a particular case of compound of formula (I):wherein A, R3, R4, Y, Z, X, R', R", and n are as defined in formula (I), and R1' is as defined above.

[0142] In some embodiments, R1' is aryl(Ci-Ce)alkyl.

[0143] In some embodiments, R1' is (Ci-Ce)alkyl.

[0144] The compound of formula (I / f) can be subjected to a reaction with a compound of formula (XIX): X"R2', wherein X" is halogen and R2' is alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl, each of which is unsubstituted or substituted, or C(O)Ra, C(O)ORa, or S(O)2Rb, to yield the compound of formula (I / g), a particular case of compound of formula (I):wherein A, R3, R4, Y, Z, X, R', R", and n are as defined in formula (I), and R1' and R2' are as defined above. In some embodiments, R2' is (Ci-Ce)alkyl. In some embodiments, R2' is aryl(Ci- Ce)alkyl.

[0145] In some embodiments, the present disclosure provides a process for the synthesis of a compound of formula (I):, comprising:(a) esterifying a compound of formula (II):to generate a compound of formula (III):wherein ring A is aryl or a 5- or 6- membered heteroaryl, each of which is unsubstituted or substituted;each R3is 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)Rb, C(O)NHRbor S(O)2Rb; optionally wherein two adjacent R3groups, together with the carbon atoms to which they are bound, form an optionally fused cycloalkyl or heterocycloalkyl ring;- Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen; n is 0, 1, 2, 3, 4 or 5; andAik is an alkyl group;(b) subjecting the compound of formula (III) to a bromination reaction to yield a compound of formula (IV):(c) reacting the compound of formula (IV) with a compound of formula (V):to yield a compound of formula (VI):wherein- 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 bound form C(O); and- P is a protecting group;(d) deprotecting the compound of formula (VI) to generate a compound of formula (VII):(e) cyclizing the compound of formula (VII) to yield a compound of formula (VIII):(f) protecting the hydroxyl group to yield a compound of formula (IX):wherein P is a protecting group;(g) reacting the compound of formula (IX) with a compound of formula (X): X'R4', wherein X' is halogen and R4' is alkyl that is unsubstituted or substituted, to yield a compound of formula (XI):the compounds of formula (IX) and (XI) representing a compound of formula (XII):wherein A, R3, Z, X, R', R", n, and P are as defined above, and R4is alkyl that is unsubstituted or substituted, or hydrogen;(h) reacting the compound of formula (XII) with a compound of formula (XIII): HNR1R2, wherein R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety, to yield a compound of formula (I / a):(i) optionally, reducing the compound of formula (I / a) to yield a compound of formula (I / b):the compound of formula (I / a) and the compound of formula (I / b) representing the compound of formula (I); and(j) optionally purifying the resulting compound and / or optionally converting the resulting compound into its addition salts with a pharmaceutically acceptable acid or base and / or optionally separating the resulting compound into its isomers.

[0146] In some embodiments, the present disclosure provides a process for the synthesis of a compound of formula (I), comprising the steps of:(a) reacting the compound of formula (VI)wherein- 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 bound form C(O); and- P is a protecting group; with an azide derivative to yield a compound of formula (XIV):(b) cyclizing the compound of formula (XIV) to yield a compound of formula (XV):(c) reacting the compound of formula (XV) with a compound of formula (X): X'R4' as defined above, to yield a compound of formula (XVI):the compound of formula (XV) and the compound of formula (XVI) representing a compound of formula (XVII):(d) reducing the compound of formula (XVII) to yield a compound of formula (I / c):(e) optionally further reducing the compound of formula (I / c) to yield a compound of formula (I / d):the compound of formula (I / c) and the compound of formula (I / d) representing a compound of(f) optionally reacting the compound of formula (I / e) with a compound of formula (XVIII): X''Rb, wherein X" is halogen and Rbis alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted, or C(O)Ra, C(O)ORb, or S(O)2Rb, to yield a compound of(g) optionally reacting the compound of formula (I / f) with a compound of formula (XIX): X"R2', wherein X" is halogen and R2' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted, or C(O)Ra, C(O)ORb, or S(O)2Rb, to yield a compound of formula (I / g):(h) optionally purifying the resulting compound, and / or optionally converting the resulting compound into its addition salts with a pharmaceutically acceptable acid or base, and / or optionally separating the resulting compound into its isomers.

[0147] In some embodiments, the present disclosure provides a process for the synthesis of a compound of formula (I):comprising:(a) esterifying a compound of formula (II):to generate a compound of formula (III):wherein ring A is aryl or a 5- or 6- membered heteroaryl, each of which is unsubstituted or substituted; each R3is 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)Rb, C(O)NHRbor S(O)2Rb; optionally wherein two adjacent R3groups, together with the carbon atoms to which they are bound, form an optionally fused cycloalkyl or heterocycloalkyl ring;- R4is hydrogen;- Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen; n is 0, 1, 2, 3, 4 or 5; andAik is an alkyl group;(b) subjecting the compound of formula (III) to a bromination reaction to yield a compound of formula (IV):(c) reacting the compound of formula (IV) with a compound of formula (V):to yield a compound of formula (VI):wherein- 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 bound form C(O); and- P is a protecting group;(d) deprotecting the compound of formula (VI) to generate a compound of formula (VII):(e) cyclizing the compound of formula (VII) to yield a compound of formula (VIII):(f) reacting the 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 yield a compound of formula (IX):wherein A, R3, Z, X, R, R', R", and n are as defined above;(g) reacting the compound of formula (IX) with a compound of the formula R10N3, wherein R10is a metal cation (e.g., Li+, Na+or K+) or N+Alk4, wherein Aik is alkyl, to generate a compound of formula (X):; and(h) converting the compound of formula (X) to a compound of formula (I’):wherein each of R1and R2are a hydrogen atom. The compound of formula (I’) may be further reacted to generate compounds of formula (I) wherein R1and R2are as described above.

[0148] Conversion of compound (X) to compound (I) can be effectuated by reduction of the azide to the corresponding amine by several methods, including but not limited to catalytic hydrogenation, reduction by hydride donors (e.g., Li AIH4, NaBFL), a silane in the presence of a metal, phosphine / water, and the like.

[0149] In some embodiments, the present disclosure provides a process for the synthesis of a compound of formula (I):comprising:(a) esterifying a compound of formula (II):to generate a compound of formula (III):wherein ring A is aryl or a 5- or 6- membered heteroaryl, each of which is unsubstituted or substituted; each R3is 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)Rb, C(O)NHRbor S(O)2Rb; optionally wherein two adjacent R3groups, together with the carbon atoms to which they are bound, form an optionally fused cycloalkyl or heterocycloalkyl ring;- R4is hydrogen;- Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen; n is 0, 1, 2, 3, 4 or 5; andAik is an alkyl group;(b) subjecting the compound of formula (III) to a bromination reaction to yield a compound of formula (IV):(c) reacting the compound of formula (IV) with a compound of formula (V):to yield a compound of formula (VI):wherein- 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 bound form C(O); and- P is a protecting group;(d) deprotecting the compound of formula (VI) to generate a compound of formula (VII):(e) cyclizing the compound of formula (VII) to yield a compound of formula (VIII):(f) reacting the compound of formula (VIII) with a compound of formula NH(P)2 wherein P is a nitrogen protecting group, in the presence of a phosphine (e.g., an alkyl, O-Alkyl, aryl or heteroaryl phosphine) and an azodicarboxylate such as diethyl azodi carb oxy late (DEAD, diisopropyl azodi carb oxy late (DIAD), 1,1'-(Azodicarbonyl)dipiperidine (ADDP), or tetramethyl azodi carb oxmi de (DM AD) to yield a compound of formula (IX):wherein A, R3, Z, X, R', R", P and n are as defined above; and(g) converting the compound of formula (IX) to a compound of formula (I)wherein R1and R2are each a hydrogen atom. The compound may be further reacted generate compounds wherein R1and R2are as described above, for example wherein R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety.

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

[0151] In some embodiments, compounds of formula (I / c), (I / d), (I / e), (I / f), and / or (I / g) can be converted into their addition salts with a pharmaceutically acceptable acid or base.

[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 a separation technique.

[0153] It should be understood that at any moment considered appropriate during the course of the process described above, some groups (e.g., hydroxy, amino) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

[0154] All stereoisomers of the compounds of the present disclosure (for example, those which can exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this present disclosure. Individual stereoisomers of the compounds of the present disclosure can, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or can be admixed, for example, as racemates, or as mixtures enriched by one stereoisomer. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, methods, such as, for example, salt formation with an optically active acid or base, followed by crystallization.Pharmaceutically Acceptable Salts

[0155] Any compound herein can be provided as a pharmaceutically-acceptable salt. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt.

[0156] Metal salts can arise from the addition of an inorganic base to a compound of the present disclosure. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0157] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0158] Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, 7V-methylpiperidine, 7V-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.

[0159] In some embodiments, an ammonium salt is a triethyl amine salt, a trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an 7V-methylmorpholine salt, a piperidine salt, an 7V-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.

[0160] Acid addition salts can arise from the addition of an acid to a compound of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, phosphonic acid, pyruvic acid, malonic acid, camphoric acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

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

[0162] In some embodiments, one or more of the compounds of the disclosure is in the form of a salt protonated on a nitrogen atom, including salts formed with organic and inorganic anions and cations discussed herein. Non-limiting examples of such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, and cinnamic acid.Therapeutic Uses

[0163] In some embodiments, the present disclosure provides a compound that treats conditions, disorders, and diseases associated with Ryanodine Receptors (RyRs).

[0164] In some embodiments, the present disclosure provides compounds that are RyR modulators, for example, a Rycal compound. Compounds of the present disclosure can, for example, bind to leaky RyR subunits, restore Calstabin binding, and repair the channel leak. In some embodiments, compounds of the present disclosure bind to leaky RyR channels, restore Calstabin binding, and fix the channel leak without blocking the RyR channel. In some embodiments, compounds of the present disclosure are capable of fixing a leak in RyR channels, for example, RyRl, RyR2, and / or RyR3 channels. In some embodiments, the compositions of the present disclosure enhance association and / or inhibit dissociation of RyR and Calstabin (e.g., RyRl and Calstabinl; RyR2 and Calstabin2; and RyR3 and Calstabinl).

[0165] Non-limiting examples of conditions, disorders, and diseases associated with RyRs include disorders and diseases that can be treated and / or prevented by modulating RyRs and include, for example, a cardiac disorder or disease, a musculoskeletal disorder or disease, cancer associated muscle weakness, malignant hyperthermia, and diabetes. A compound herein can also lessen the likelihood of the occurrence of such a condition.

[0166] In some embodiments, the present disclosure provides a method of treating or reducing a likelihood of occurrence of a condition by administering to a subject in need thereof a therapeutically-effective amount of a compound disclosed herein, e.g., a compound of formula (I) as described herein, or a pharmaceutically-acceptable salt thereof. In some embodiments, the compound is administered in a pharmaceutical composition. In some embodiments, the compound is in a unit dosage form. In some embodiments, the unit dosage form is a solid dosage form. In some embodiments, the pharmaceutical composition is in a unit dosage form suitable for oral administration.

[0167] In some embodiments, the present disclosure provides a compound, e.g., a compound of formula (I) as described herein, or a pharmaceutically-acceptable salt thereof, for use in a method of treating or reducing a likelihood of occurrence of a condition.

[0168] In some embodiments, the present disclosure provides a compound, e.g., a compound of formula (I) as described herein, or a pharmaceutically-acceptable salt thereof, for use in the manufacture of a medicament.

[0169] In some embodiments, the condition, disorder, or disease is associated with an abnormal function of RyRl. In some embodiments, the condition, disorder, or disease is associated with an abnormal function of RyR2. In some embodiments, the condition, disorder or disease is associated with an 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 associated muscle weakness. In someembodiments, the condition is malignant hyperthermia. In some embodiments, the condition is diabetes.

[0170] In some embodiments, the present disclosure provides a method of modulating the binding of RyRs and Calstabins in a subject, including administering to the subject an amount of a compound, e.g., a compound of formula (I) as described herein, or a salt thereof, effective to modulate the amount of RyR-bound Calstabin. In some embodiments, the compound is used at a dose sufficient to restore or enhance binding of Calstabin2 to RyR2. In some embodiments, the compound is used at a dose sufficient to restore or enhance binding of Calstabin2 to RyR2. In some embodiments, the compound is used at a dose sufficient to restore or enhance binding of Calstabinl to RyRl. In other embodiments, the compound is used at a dose sufficient to restore or enhance binding of Calstabinl to RyRl.

[0171] Methods of the disclosure can be practiced on an in vitro system (e.g., cultured cells or tissues) or in vivo (e.g., in a non-human animal or a human).

[0172] In some embodiments, a compound of the present disclosure is not selective towards a particular RyR isoform. In some embodiments, a compound present disclosure can bind to and / or fix Ca+2leak in both RyRl and RyR2. In some embodiments, a compound of the disclosure can prevent stress-induced dissociation of Calstabin2 from RyR2 and Calstabinl from RyRl, thereby reducing RyR-mediated SR Ca2+leak, resulting in improved cardiac and skeletal muscle function.

[0173] Therefore, in some embodiments, compounds of the present disclosure can be used to treat conditions that are characterized by both skeletal muscle (RyRl) and cardiac muscle (RyR2) Ca+2leak. For example, a compound of the present disclosure can be used to treat both cardiac and skeletal muscle dysfunction in heart failure. In other embodiments, a compound of the present disclosure can be used to treat both cardiac and skeletal muscle dysfunction in muscular dystrophy, e.g., Duchenne Muscular Dystrophy.

[0174] In some embodiments, a compound of the present disclosure is selective towards RyRl, i.e., it is more potent at fixing calcium leak in RyRl than RyR2. In some embodiments, a compound of the present disclosure is selective towards RyR2, i.e., it is more potent at fixing calcium leak in RyR2 than RyRl .Ryanodine Receptors: Excitation-contraction coupling (ECC) process

[0175] The sarcoplasmic reticulum (SR) is a structure in cells that functions, among other things, as a specialized intracellular calcium (Ca2+) store. Ryanodine receptors (RyRs) are channels in the SR, which open and close to regulate the release of Ca2+from the SR into theintracellular cytoplasm of the cell. Release of Ca2+into the cytoplasm from the SR increases cytoplasmic Ca2+concentration. Open probability of RyRs refers to the likelihood that a RyR is open at any given moment, and therefore capable of releasing Ca2+into the cytoplasm from the SR.

[0176] The RyR is the major Ca2+release channel on the SR responsible for excitationcontraction coupling (ECC) in striated muscle. Among the three known RyR isoforms (RyRl, RyR2 and RyR3), RyRl is widely expressed and is the predominant isoform expressed in mammalian skeletal muscle. RyR2 is also widely expressed and is the predominant form found in cardiac muscle. RyR3 expression is low in adult skeletal muscle. RyR subtypes exhibit a high degree of structural and functional homology. The subtypes form a large sarcoplasmic membrane complex, consisting of four monomers that constitute a Ca2+release channel associated with proteins, such as kinases, phosphatases, phosphodiesterases, and other regulatory subunits.

[0177] Ca2+release from the SR is modulated by several RyR binding proteins. Calmodulin, a key mediator of Ca2+signaling, exerts both positive and negative effects on RyR open probability. Calstabinl (FKBP12) and calstabin2 (FKBP12.6) stabilize the closed state of RyRl and RyR2, respectively. Calstabinl associates predominantly with skeletal muscle RyRl, while cardiac muscle RyR2 has the highest affinity for Calstabin2.

[0178] Mutations in RYR1 or RYR2 are characterized by inappropriate channel opening not related to contraction signals. This channel opening is further exacerbated by post-translational modifications such as PKA-phosphorylation, oxidation, or nitrosylation of the RyR channel. The resulting leaky channels exhibit a pathologic increase in the open probability under resting conditions. The SR Ca2+leak leads to a reduction in luminal SR Ca2+content, with less Ca2+available for release and consequently weaker muscle contractions The intracellular calcium leak has distinct pathological consequences depending on which tissue is involved.Ryanodine Receptor 2 and Cardiac Diseases

[0179] In some embodiments, the RyR-associated condition is a cardiac disorder or disease that implicates the Ryanodine Receptor 2 (RyR2). The RyR2 channel plays a major role in intracellular calcium handling by regulating the release of Ca2+from the sarcoplasmic reticulum (SR) in cardiac myocytes required for ECC in cardiac muscle. The RyR2 channel is a macromolecular complex, which includes four identical RyR2 subunits, each of which binds one Calstabin2 (FKBP12.6), and other interacting proteins such as phosphatases and kinases. Binding of Calstabin2 stabilizes the channel in the closed state during the resting phase of theheart (diastole), thereby preventing diastolic calcium leak from the SR, and functionally couples groups of RyR2 channels to allow synchronous opening during excitation-contraction coupling.

[0180] Phosphorylation of RyR2 by protein kinase A (PKA) is an important part of the fight- or-flight response. Phosphorylation increases cardiac EC coupling gain by augmenting the amount of Ca2+released for a given trigger. The process strengthens muscle contraction and improves exercise capacity. This signaling pathway provides a mechanism by which activation of the sympathetic nervous system (SNS), in response to stress, results in increased cardiac output. Phosphorylation of RyR2 by PKA increases the sensitivity of the channel to calciumdependent activation. The increased sensitivity leads to increased open probability and increased calcium release from the SR into the intracellular cytoplasm.

[0181] Heart failure (HF) is characterized by a sustained hyperadrenergic state in which serum catecholamine levels are chronically elevated. One consequence of this chronic hyperadrenergic state is persistent PKA hyperphosphorylation of RyR2, such that 3-4 out of the four Ser2808 in each homotetrameric RyR2 channel are chronically phosphorylated. Chronic PKA hyperphosphorylation of RyR2 is associated with depletion of the channel-stabilization subunit Calstabin2 from the RyR2 channel macromolecular complex. Depletion of Calstabin2 results in a diastolic SR Ca2+leak from the RyR complex and contributes to impaired contractility. Due to the activation of inward depolarizing currents, this diastolic SR Ca2+leak also is associated with fatal cardiac arrhythmias.

[0182] Mice engineered with RyR2 lacking the PKA phosphorylation site (RyR-S2808A) are protected from HF progression after myocardial infarction (MI). In addition, chronic PKA hyperphosphorylation of RyR2 in HF is associated with remodeling of the RyR2 macromolecular complex. The remodeling includes depletion of phosphatases PPI and PP2a (impairing dephosphorylation of Ser2808) and the cAMP-specific type 4 phosphodiesterase (PDE4D3) from the RyR2 complex. Depletion of PDE4D3 from the RyR2 complex causes sustained elevation of local cAMP levels.

[0183] Thus, diastolic SR Ca2+leak contributes to HF progression and arrhythmias. Additional post-translational modifications of the RyR channel (oxidation and nitrosylation) further drive the leak. Single-channel tracings of heart failure cardiomyocytes show a dramatic increase in open probability in RyR2 as compared with normal cardiomyocytes, indicating leaky channels. The large luminal SR Ca2+stores available in the normal state of the RyR channel are dramatically depleted in heart failure due to diastolic SR Ca2+leak via phosphorylated / oxidized RyR2. Ryanodine receptor channel modulators can stabilize ejection fraction by repairing calcium leak and thereby improve cardiac function in a mouse or rat heart failure model.

[0184] RyR2 leak is associated with a variety of cardiac disorders, conditions, and diseases. In some embodiments, the cardiac condition is due to mutation in an RYR2 gene. In some embodiments, the cardiac condition is due to a post-translationally modified RyR2.Heart Failure

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

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

[0187] In some embodiments, the cardiac disorder or disease is characterized by an irregular heartbeat or an arrhythmia. In some embodiments, the cardiac disorder or disease is catecholaminergic polymorphic ventricular tachycardia (CPVT). In some embodiments, the cardiac disorder or disease is catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1). In some embodiments, the cardiac disorder or disease is, or is characterized by, an atrial arrhythmia. In some embodiments, the cardiac disorder or disease is, or is characterized by, a ventricular arrhythmia. In some embodiments, the cardiac disorder or disease is, or is characterized by, atrial fibrillation. In some embodiments, the cardiac disorder or disease is, or is characterized by, ventricular fibrillation. In some embodiments, the cardiac disorder or disease is, or is characterized by, atrial tachyarrhythmia. In some embodiments, the cardiac disorder or disease is, or is characterized by, ventricular tachyarrhythmia. In some embodiments, the cardiac disorder or disease is, or is characterized by, atrial tachycardia. In some embodiments, the cardiac disorder or disease is, or is characterized by, ventricular tachycardia. In someembodiments, the cardiac disorder or disease is, or is characterized by, a premature contraction (PC). In some embodiments, the cardiac disorder or disease is, or is characterized by, a premature ventricular contraction (PVC). In some embodiments, the cardiac disorder or disease is, or is characterized by, bigeminy. In some embodiments, the cardiac disorder or disease is, or is characterized by, sick sinus syndrome. In some embodiments, the cardiac disorder or disease is, or is characterized by, a premature ventricular contraction couplet. In some embodiments, the cardiac disorder or disease is, or is characterized by, sudden cardiac death (SCD). In some embodiments, the cardiac disorder or disease is, or is characterized by Sudden infant death syndrome (SDIS). In some embodiments, the cardiac disorder or disease is, or is characterized by, sudden unexplained death (SUD).

[0188] In heart failure, Ca2+concentration in the sarcoplasmic reticulum (SR) can be abnormally regulated. Diastolic leak of Ca2+from the SR through modified leaky RyR2 Ca2+release channels can result in delayed after depolarizations (DADs). When the amplitude of a DAD is above a certain threshold (a suprathreshold DAD), it can trigger an action potential (AP) called triggered activity (TA), which can lead to a premature ventricular contraction (PVC). Ryanodine receptor channel modulators (e.g., a compound of formula (I), or any other compound encompassed by such formula, or otherwise described herein) can preferentially bind to leaky RyR2 channels and induce a conformation change that can shift the open probability of the RyR2 channel towards a closed (resting) state, repairing the channel leak, thereby restoring normal RyR2 function. In some embodiments, repairing the channel leak results in a reduction in calcium flow (e.g., calcium sparks).

[0189] In some embodiments, Ryanodine receptor channel modulators as described herein can be effective at treating heart failure that is characterized by high burden of PVCs. A PVC burden can be determined by monitoring a subject (e.g., a heart failure patient) during a defined time period, using electrocardiographic monitoring or any other system that detects and stores the measured electrical activity of the heart (e.g., a continuous cardiac monitoring system). In some embodiments, the PVC burden is calculated as the percentage of total PVCs in a given time period divided by the total number of beats during that same time period.

[0190] In some embodiments, the PVC burden is at least about 1% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 5% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 10% of all heartbeats within a time period. In some embodiments, the PVC burden ranges from about 5% of all heartbeats to about 20% of all heartbeats. In some embodiments, the PVC burden ranges from about 5% of all heartbeats to about 15 % of all heartbeats within a time period. In someembodiments, the PVC burden ranges from about 5% of all heartbeats to about 10 % of all heartbeats within a time period. In some embodiments, the heart rate preceding the PVC is at least about 60 beats per minute, at least about 70 beats per minute, at least about 80 beats per minute, at least about 90 beats per minute, or at least about 100 beats per minute.

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

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

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

[0194] A common symptom of heart failure is pronounced muscle fatigue and exercise intolerance, which lead to limitations in activities of daily living and affects quality of life. Heart failure is associated with maladaptive remodeling of the skeletal muscle RyRl complex, and this may play a role in the characteristic exercise intolerance and limitation in activities seen in heart failure patients.

[0195] For example, skeletal muscle RyRl from human heart failure patients is post- translationally modified (e.g., phosphorylated, oxidized and / or nitrosylated) and depleted of Calstabin 1, implicating pathological Ca+2release as a potential mechanism behind skeletal muscle weakness and impaired exercise tolerance in patients with heart failure, and suggesting potential target for pharmacological intervention.

[0196] In some embodiments, compounds of the disclosure can prevent stress-induced dissociation of the channel stabilizing subunit calstabin2 from RyR2 and calstabinl from RyRl, thereby reducing RyR-mediated SR Ca2+leak, resulting in improved cardiac and skeletal muscle function in a heart failure patient. Thus, in some embodiments, compounds of the present disclosure can treat both skeletal and cardiac muscle weakness in a heart failure patient. A compound of the present disclosure can therefore be uniquely positioned to treat both cardiac and skeletal muscle dysfunction in heart failure.

[0197] Provided herein is a method of treating skeletal muscle weakness in a heart failure patient, the method comprising administering to 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) fixes calcium leak in RyRl and / or RyR2 channel of the subject.

[0198] Improvement in skeletal muscle function can be measured by a variety of methods, including measuring maximal oxygen consumption (VO2 max), exercise capacity, distance walked, muscle strength, cardiopulmonary exercise test, and the like.Cardiac Arrhythmias

[0199] In some embodiments, the cardiac disorder or disease is characterized by an irregular heartbeat or an arrhythmia. In some embodiments, the cardiac disorder or disease is characterized by an ectopy, such as, for example, ventricular ectopy. In some embodiments, an ectopy (e.g., ventricular ectopy) associated with the cardiac disease or disorder (e.g., CPVT) can be induced by stress, such as catecholaminergic stress. In some embodiments, the ectopy (e.g., ventricular ectopy) is exercise-induced. In some embodiments, the ectopy (e.g., ventricular ectopy) is induced by an elevated heart rate. In some embodiments, the ectopy (e.g., ventricular ectopy) occurs when the subject has an elevated heart rate relative to baseline heart rate of the subject. In some embodiments, the elevated heart rate is a rate at least about 100 beats per minute, at least about 105 beats per minute, at least about 110 beats per minute, at least about 115 beats per minute, at least about 120 beats per minute, at least about 125 beats per minute, at least about 130 beats per minute, at least about 135 beats per minute, at least about 140 beats per minute, at least about 145 beats per minute, at least about 150 beats per minute, at least about 155 beats per minute, at least about 160 beats per minute, at least about 165 beats per minute, at least about 170 beats per minute, at least about 175 beats per minute, at least about 180 beats per minute, at least about 185 beats per minute, at least about 190 beats per minute, at least about 195 beats per minute, or at least about 200 beats per minute. In some embodiments, the elevated heart rate is from about 100 beats per minute to about 200 beats per minute, from about 125beats per minute to about 200 beats per minute, from about 150 beats per minute to about 200 beats per minute, from about 100 beats per minute to about 125 beats per minute, from about 100 beats per minute to about 150 beats per minute, or from about 100 beats per minute to about 175 beats per minute. In some embodiments, the elevated heart rate is induced by stress. In some embodiments, the stress is catecholaminergic stress. In some embodiments, the elevated heart rate is induced by exercise.Catecholaminergic Polymorphic Ventricular Tachycardia

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

[0201] In some embodiments, the present disclosure provides a method of treating catecholaminergic polymorphic ventricular tachycardia (CPVT), comprising administering to a subject in need thereof a therapeutically-effective amount of a ryanodine receptor channel modulator, wherein the treating the catecholaminergic polymorphic ventricular tachycardia (CPVT) reduces a likelihood of atrial fibrillation in the subject.

[0202] Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is one of the most lethal inherited arrhythmogenic disorders. CPVT occurs in the absence of structural heart disease and is characterized by adrenergically mediated ventricular arrhythmias associated with a high incidence of Sudden Cardiac Death (SCD). CPVT is a life-threatening disease that is a major cause of unexplained sudden death, particularly in children and young adults. The typical newly diagnosed patient with CPVT is a child or young adult free of structural cardiac disease, with a normal resting electrocardiogram, who presents with stress (e.g., exercise or emotional)- induced palpitations or syncope. If not managed, CPVT is a highly lethal disease with an untreated mortality rate of 30-50% by the age of 40 years.

[0203] CPVT is associated with mutations in two genes that code for proteins associated with the sarcoplasmic reticulum (SR) of the cardiomyocyte. The most frequently observed form is CPVT type 1 (CPVT1), 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 leaky RyR2 channels that can be associated with decreased binding of the Calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. Mice heterozygous for theR2474S mutation (which occurs in humans with CPVT1) in RyR2 (RyR2-R2474S mice) can exhibit exercise-induced ventricular arrhythmias and sudden cardiac death.

[0204] Under normal physiological conditions, SR Ca2+flux is tightly regulated, and RyR2 interacting proteins contribute to this regulation. For example, Calstabin2 modulates SR Ca2+release by stabilizing the RyR2 closed state. In patients with CPVT1, decreased RyR2- Calstabin2 binding can be associated with RyR2 Ca2+leak.

[0205] RyR2-R2474S, a mutant channel harboring a point mutation causing CPVT in humans, adopts a primed state as compared to non-mutated RyR2. The primed state is a transition between the closed and open conformations of these channels. In the primed state, the mutant channel is susceptible to transition to the open conformation. Wild type RyR2 channels open during systole, which is the appropriate phase of the cardiac cycle for calcium release. In contrast, the primed, mutant channel can be open in both systole and diastole with exercise or catecholaminergic stress. This inappropriate opening during diastole can lead to the ventricular arrythmias characteristic of CPVT. These observations were made under conditions that resemble the channel status during diastole under exercise-induced beta-adrenergic stimulation, e.g., PKA phosphorylation and low calcium concentration.

[0206] In some embodiments, the mutant RyR2 protein associated with CPVT is in primed state. In some embodiments, an RyR2 protein in primed state comprises a higher distribution of open probability (Po) as compared to an RyR2 protein in a resting (closed) state. In some embodiments, an RyR2 protein in primed state is a leaky RyR2 protein, which is characterized by an abnormal Ca+2leak from the RyR2 channel. In some embodiments, a RyR2 protein in primed state is a leaky RyR2 protein, which is characterized by a higher distribution of open probability (Po) as compared to an RyR2 protein in a resting (closed) state. In some embodiments, a primed state RyR2 comprises about 30% to about 60% of the RyR2 channel in an open state. In some embodiments, a primed state RyR2 comprises about 30%, about 35%, about 40%, about 45%, about 50%, about 55% or about 60% of the RyR channel in an open state.

[0207] Ryanodine receptor channel modulators offer an innovative approach to the treatment of CPVT1. Ryanodine receptor channel modulators can preferentially bind to leaky RyR2 channels and induce a conformation change that can shift the open probability of the RyR channel towards a closed (resting) state, restore Calstabin 2 binding and repair the channel leak, thereby restoring normal RyR2 function.

[0208] In some embodiments, the present disclosure provides a method of treating catecholaminergic polymorphic ventricular tachycardia (CPVT), comprising administering to asubject in need thereof a therapeutically-effective amount of a ryanodine receptor channel modulator. In some embodiments, the present disclosure provides a method of treating CPVT, comprising administering to a subject in need thereof a therapeutically-effective amount of a compound as described herein, or a pharmaceutically-acceptable salt thereof. In some embodiments, the administering is once daily. In some embodiments, the CPVT is CPVT type 1.

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

[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 betablocker. 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.

[0211] In some embodiments, the subject is undergoing a treatment regimen for CPVT, wherein the treatment regimen for CPVT comprises a beta-blocker. In some embodiments, a compound as described herein is administered in combination with a beta-blocker. In some embodiments, the compound is administered in combination with a beta-blocker, wherein the beta-blocker is administered in an amount that is therapeutically-effective to treat CPVT in the subject in absence of a compound as described herein, or a pharmaceutically-acceptable salt thereof. In some embodiments, the compound is administered in combination with a betablocker, wherein the beta-blocker is administered in a reduced amount, wherein the reduced amount is about less than an amount used to treat CPVT in the subject in absence of the compound. In some embodiments, the compound is administered in combination with a betablocker, wherein the beta-blocker is administered in a reduced amount, wherein the reduced amount is 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 amount used to treat CPVT in the subject in absence of the compound.

[0212] An amount of beta-blocker that is less than an amount that is used to treat CPVT in absence of the compound can be less than a maximum tolerated dose of the beta blocker, which can be, 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% less than a maximum tolerated dose of the beta blocker.

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

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

[0215] In some embodiments the beta-blocker is a non-selective beta-blocker. A non-selective beta-blocker inhibits both beta-1 receptors located primarily in cardiac muscle, and beta-2 receptors located primarily in the bronchial and vascular musculature. In some embodiments, a non-selective beta-blocker is nadolol, penbutolol, pindolol, propranolol, sotalol, or timolol, or pharmaceutically acceptable-salts thereof. In an embodiment, a non-selective beta-blocker is nadolol or a pharmaceutically-acceptable salt thereof.

[0216] In some embodiments, the beta-blocker is a selective beta-blocker. Selective beta blockers (such as metoprolol) can preferentially inhibit beta 1 receptors (cardio-selective). At very high concentrations, this selectivity can be reduced and some beta 2 inhibition can occur. Selectivity is confirmed by the inability to reverse the beta 2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which can be capable of reversing the vasodilating effects of epinephrine. In some embodiments, a selective betablocker is metoprolol or a pharmaceutically-acceptable salt thereof.

[0217] In some embodiments, the subject is undergoing a treatment regimen for CPVT, wherein the treatment regimen for CPVT comprises 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, tocainide, phenytoin, moricizine, propafenone, lacosamide, rufmamide, fosphenytoin, ethotoin, carbamazepine, eslicarbazepine, pilsicainide, tetrodoxin, aprindine, ajmaline, encainide, propafenone, amiodarone, procainamide,quinidine, oxcarbazepine, moricizine, amiloride, lamotrigine, triamterene, mexiletine, phenytoin, and ranolazine, or a pharmaceutically-acceptable salt 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.

[0218] In some embodiments, the subject is undergoing a treatment regimen for CPVT, wherein the treatment regimen for CPVT comprises a sodium channel inhibitor. In some embodiments, a compound as described herein, or a pharmaceutically-acceptable salt thereof, is administered in combination with a sodium channel inhibitor. In some embodiments, the compound is administered in combination with a sodium channel inhibitor, wherein the sodium channel inhibitor is administered in an amount that is therapeutically-effective to treat CPVT in the subject in absence of the compound. In some embodiments, the compound is administered in combination with a beta-blocker, wherein the sodium channel inhibitor is administered in a reduced amount, wherein the reduced amount is about less than an amount used to treat CPVT in the subject in absence of the compound. In some embodiments, the compound is administered in combination with a sodium channel inhibitor, wherein the sodium channel inhibitor is administered in a reduced amount, wherein the reduced amount is 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 amount used to treat CPVT in the subject in absence of the compound.

[0219] An amount sodium channel inhibitor that is less than an amount that is used to treat CPVT in the absence of the compound can be less than a maximum tolerated dose of the sodium channel inhibitor, which can be, 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% less than a maximum tolerated dose of the sodium channel inhibitor.

[0220] An amount of sodium channel inhibitor that is less than an amount that is used to treat CPVT in absence of the compound can be an amount that is less than a dose of the sodium channel inhibitor that is therapeutically effective for CPVT in absence of the compound, which can be, 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% less than a dose of the sodium channel inhibitor that is therapeutically effective for CPVT in absence of the compound.

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

[0222] In some embodiments, left cardiac sympathetic denervation can be used as part of a treatment regimen for CPVT. In some embodiments, a method for treating CPVT comprises use of a beta-blocker in combination with cardiac sympathetic denervation. In some embodiments, a method for treating CPVT comprises use of a sodium channel inhibitor in combination with cardiac sympathetic denervation. In some embodiments, a method for treating CPVT comprises use of a sodium channel inhibitor and a beta-blocker in combination with cardiac sympathetic denervation. In some embodiments, a method for treating CPVT comprises use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in combination with cardiac sympathetic denervation. In some embodiments, a method for treating CVPT comprises use of the compound and a beta-blocker in combination with cardiac sympathetic denervation. In some embodiments, a method for treating CPVT comprises use of the compound and a sodium channel inhibitor in combination cardiac sympathetic denervation. In some embodiments, a method for treating CPVT comprises use of the compound, a sodium channel inhibitor, and a beta-blocker in combination cardiac sympathetic denervation. In some embodiments, the subject has an Implantable Cardioverter Defibrillator (ICD).Ryanodine Receptor 1 and Musculoskeletal Diseases

[0223] In some embodiments, the RyR-associated condition is a musculoskeletal disorder or disease that implicates the Ryanodine Receptor 1 (RyRl). The RyRl macromolecular complex consists of a tetramer of the 560-kDa RyRl subunit that forms a scaffold for proteins that regulate channel function including PKA and the phosphodiesterase 4D3 (PDE4D3), protein phosphatase 1 (PPI) and Calstabinl. A-kinase anchor protein (mAKAP) targets PKA and PDE4D3 to RyRl, whereas spinophilin targets PPI to the channel. The catalytic and regulatory subunits of PKA, PPI, and PDE4D3 regulate PKA-mediated phosphorylation of RyRl at Ser2843 (Ser2844 in the mouse). PKA-mediated phosphorylation of RyRl at Ser2844 increases the sensitivity of the channel to cytoplasmic Ca2+, reduces the binding affinity of Calstabinl for RyRl, and destabilizes the closed state of the channel.

[0224] Calstabinl concentrations in skeletal muscle can be approximately 200 nM. PKA phosphorylation of RyRl can reduce the binding affinity of Calstabinl for RyRl from approximately 100-200 nM to more than 600 nM. Thus, under physiologic conditions, reduction in the binding affinity of Calstabinl for RyRl, resulting from PKA phosphorylation of RyRl at Ser2843, is sufficient to reduce substantially the amount of Calstabinl present in the RyRl complex. Chronic PKA hyperphosphorylation of RyRl at Ser2843) results in leaky channels (i.e., channels prone to opening at rest), which contribute to the skeletal muscle dysfunction that is associated with persistent hyperadrenergic states such as those in individuals with heart failure.

[0225] Moreover, regulation of RyRl by posttranslational modifications other than phosphorylation, such as by nitrosylation of free sulfhydryl groups on cysteine residues (5- nitrosylation), and channel oxidation, can increase RyRl channel activity. 5-nitrosylation and oxidation of RyRl each can reduce Calstabinl binding to RyRl.

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

[0227] In some embodiments, the musculoskeletal disorder is a congenital muscular dystrophy (CMD). Congenital muscular dystrophy is present at birth. CMD is classified based on genetic mutations: 1) genes encoding for structural proteins of the basal membrane or extracellular matrix of the skeletal muscle fibers; 2) genes encoding for putative or demonstrated glycosyltransferases, that in turn affect the glycosylation of dystroglycan, an external membrane protein of the basal membrane; and 3) other. Non-limiting examples of CMD include RYR1- related myopathies (RYR1-RM), Laminin-a2-deficient CMD (MDC1A), Ullrich CMG (UCMDs 1, 2 and 3), Walker- Warburg syndrome (WWS), Muscle-eye-brain disease (MEB), Fukuyama CMD (FCMD), CMD plus secondary laminin deficiency 1 (MDC1B), CMD plus secondary laminin deficiency 2 (MDC1C), CMD with mental retardation and pachygyria (MDC1D), and Rigid spine with muscular dystrophy Type 1 (RSMD1).RYRl-Related Myopathy

[0228] In some embodiments, the musculoskeletal disease is RYR1 -related myopathy (RYR1- RM). RYR1 -related myopathies (RYR1-RM) are a heterogenous group of monogenic neuromuscular disorders caused by pathogenic variants in the RYR1 gene. RYR1-RM can be categorized based on clinical and histological features into two main phenotypic categories: 1)Phenotypes with dynamic and episodic manifestations without interceding myopathy between exacerbations, including susceptibility to malignant hyperthermia (MH), a potentially fatal hypermetabolic crisis in response to certain environmental and pharmacologic triggers, exertional rhabdomyolysis, and atypical periodic paralysis. 2) Phenotypes with frank myopathy of variable severity including severe fetal akinesia, late-onset axial myopathy, and congenital myopathies. The latter can be further subclassified into central core disease, multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy based on histological features.

[0229] Affected individuals generally present with delayed motor milestones, muscle weakness, impaired ambulation, and, in severe cases, scoliosis, ophthalmoplegia, and respiratory distress all due to skeletal muscle weakness. Causative variants in RYRL which encodes the major calcium (Ca2+) release channel in skeletal muscle, exert different effects on the RyRl channel. The variants generally disrupt the normal Ca2+flow between the sarcoplasmic reticulum (SR) and muscle cell cytosol and commonly result in excessive Ca2+leak into the cytosol. Persistent Ca2+leak decreases SR Ca2+that is necessary for ECC. Additionally, chronic SR Ca2+leak results in mitochondrial calcium overload, which impairs mitochondrial function manifested as oxidative overload and reduced ATP production. SR Ca2+leak can also activate the calcium-activated protease calpain, which can cause cellular injury. The oxidative stress, in turn, can further contribute to RyRl Ca2+leak by channel oxidation and nitrosylation.

[0230] Both autosomal dominant (monoallelic, including de novo pathogenic variants) and recessive (biallelic) patterns of inheritance are reported to cause RYR1-RM. Classic central core disease is dominantly inherited and typically reflects the relatively milder end of the clinical spectrum, albeit with a wide range of clinical severity and penetrance. Recessive RYR1-RM can be more severe, particularly in those carrying a hypomorphic allele in compound heterozygosity with one or more missense variants, and can present with profound muscle weakness, respiratory insufficiency, necessitating ventilatory support, ophthalmoplegia, and at times, feeding difficulties, requiring the use of a feeding tube in very young children. RYR1-RM can be quite disabling and further worsen with aging and result in accrual of notable disability over time.

[0231] In some embodiments, the compounds of the present disclosure can be used to treat RYR1-RM in an autosomal dominant subject. In some embodiments, the compounds of the present disclosure can be used to treat RYR1-RM in a recessive subject. In some embodiments, the compounds of the present disclosure can be used to treat RYR1-RM in a compound heterozygous subject.

[0232] In some embodiments, the RYRl-related myopathy is congenital, i.e., subject has at least one inherited mutation of RyRl gene. In some embodiments, the RyRl -related myopathy results from de novo mutations in the RYR1 gene.Muscular Dystrophy

[0233] In some embodiments, the musculoskeletal disorder or disease is muscular dystrophy. Non-limiting examples of muscular dystrophy include Duchenne Muscular Dystrophy (DMD), Becker’s Muscular Dystrophy (BMD), Limb-Girdle Muscular Dystrophy (LGMD), facioscapulohumeral dystrophy, myotonic dystrophy (DM), including myotonic dystrophy 1 (DM-1) and myotonic dystrophy 2 (DM2), myotonic muscular dystrophy, congenital muscular dystrophy (CMD), distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, and oculopharyngeal muscular dystrophy.

[0234] In some embodiments, compounds of the present disclosure can be used to treat a subject (e.g., a patient) with Duchenne muscular dystrophy (DMD). DMD is one of the leading lethal childhood genetic diseases. Mutations in the dystrophin gene (more than 4700 identified) result in the absence of dystrophin or in the expression of a dysfunctional dystrophin leading to muscle weakness and wasting, exhaustion of muscular regenerative capacity, chronic local inflammation and substitution of myofibers by connective and adipose tissue. DMD patients suffer progressive deterioration of muscle function that results in loss of ambulation at approximately 10-12 years of age. Cardiac dysfunction typically emerges after loss of ambulation. Death, usually due to respiratory and / or cardiac failure, occurs by the age of 30.

[0235] Mutations in dystrophin associated with DMD disrupts the link between the subsarcolemma cytoskeleton and the extracellular matrix. This link is essential for protecting and stabilizing the muscle against contraction induced injury. Sarcolemmal instability due to mutations in dystrophin has a cascade effect. One major effect is increased cytosolic Ca2+concentration, which leads to activation of Ca2+'dependent proteases (calpains). Another effect is inflammation and elevated iNOS activity, which can cause oxidation / nitrosylation of proteins, lipids, and DNA.

[0236] Intracellular Ca2+is a mediator of several regulatory processes in skeletal muscle. RyRl channels isolated from a DMD mouse model (mdx mice) are hypernitrosylated as a potential consequence of altered nitric oxide signaling downstream of dystrophin loss, resulting in an increase leak of Ca2+ions from the SR. Excessive oxidation or nitrosylation of RyRl can disrupt the interaction of Calstabinl with the RyRl complex, leading to RyRl leakiness and muscle weakness. In some embodiments, compounds of the present disclosure prevent Calstabinldepletion from RyRl, inhibit SR Ca2+leak, reduce biochemical and histological evidence of muscle damage, improve muscle function and increase exercise performance.

[0237] In some embodiments, compounds of the present disclosure can fix Ca2+leak in both RyRl and RyR2. Therefore, these compounds can be effective at treating both skeletal muscle as well as cardiac and pulmonary dysfunction in DMD. Cardiomyopathy is the most common cause of death in the affected population. Compounds that target both skeletal and cardiac dysfunction can be uniquely positioned to provide improvement in both cardiac and skeletal muscle dysfunction in DMD.

[0238] Provided herein is a method for treating DMD, the method comprising administering to a subject in need thereof a compound of formula (I), or a pharmaceutically-acceptable salt thereof.

[0239] Provided herein is a method for treating skeletal muscle weakness in a DMD patient, the method comprising administering to a subject in need thereof a compound of formula (I), or a pharmaceutically-acceptable salt thereof.

[0240] Provided herein is a method for treating cardiomyopathy in a DMD patient, the method comprising administering to a subject in need thereof a compound of formula (I), or a pharmaceutically-acceptable salt thereof.

[0241] In some embodiments, compounds of the present disclosure can treat or improve muscle weakness in a DMD patient. In some embodiments, compounds of the present disclosure can treat or improve muscle weakness in an ambulatory DMD patient. In some embodiments, compounds of the present disclosure can treat or improve muscle weakness in a non-ambulatory DMD patient. In some embodiments, compounds of the present disclosure treat or improve cardiac dysfunction in a non-ambulatory DMD patient. In some embodiments, compounds of the present disclosure treat or improve respiratory dysfunction in a non- ambulatory DMD patient. In some embodiments, compounds of the present disclosure treat or improve skeletal muscle, respiratory, and / or cardiac dysfunction in a DMD patient, e.g., a non-ambulatory DMD patient. An ambulatory DMD patient can be a patient who has the ability to walk. A non-ambulatory DMD patient can be a patient who has lost the ability to walk.

[0242] In some embodiments, the musculoskeletal disorder or disease is cancer cachexia, i.e., cancer associated muscle weakness. In some embodiments, the cancer associated muscle weakness is cancer cachexia, for example, due to a cancer having bone metastases. Muscle weakness and muscle atrophy (cachexia) are common paraneoplastic conditions in cancer patients. These conditions cause significant fatigue and dramatically reduce patients’ quality of life. In certain cancers, e.g., prostate and breast cancer with bone metastases, RyRl is oxidizedand induced to become leaky. Repairing the leak by administration of Rycal compounds improves muscle function. Non-limiting examples of cancers associated with cachexia that can be treated with a compound 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 patients’ quality of life. The present disclosure provides a method for treating, preventing, and reducing a likelihood of developing muscle weakness in a cancer patient, based, for example, on the presence of a modified (e.g., an oxidized state of RyRl), which state induces RyRl to become leaky. Prevention or reducing a likelihood of occurrence of the leak by administration of Rycal compounds can improve muscle function.

[0243] In some embodiments, the musculoskeletal condition or disease is age-related loss of muscle mass and force (sarcopenia). Sarcopenia contributes to disability and increased mortality. RyRl from aged mice can be oxidized, cysteine-nitrosylated, and depleted of Calstabinl, compared to RyRl from younger (3-6 months) adults. Treating aged mice with Rycals can stabilize the binding of Calstabinl to RyRl, reduce intracellular calcium leak, decrease reactive oxygen species (ROS), and enhance tetanic Ca2+release, muscle-specific force, and exercise capacity.

[0244] In some embodiments, the compositions of the present disclosure are useful in treating a condition of the pancreas, for example diabetes. In some embodiments, the compositions of the present disclosure are useful in treating Type II diabetes by reducing a likelihood of occurrence of intracellular calcium leak via leaky RyR2. This leak causes mitochondrial calcium overload, and decreased ATP production, which reduces activation of KATP channels. Reduced activation of the channels blocks depolarization of the plasma membrane. This blocking decreases activation of the plasma membrane voltage-gated calcium channel, which is the primary source of calcium required for insulin secretion.Ryanodine Receptors and Disorders of the Central Nervous System

[0245] In some embodiments, the pharmaceutical composition described herein is administered to a subject in need thereof. In some embodiments, the subject in need thereof has a condition or disease. In some embodiments, the pharmaceutical composition described herein is administered to treat a subject in need thereof with a condition or disease, wherein the pharmaceutical composition herein reduces a symptom or symptoms of the condition or disease.

[0246] In some embodiments, the RyR-associated condition is a central nervous system (CNS) disorder or disease that implicates the Ryanodine Receptor 1 (RyRl). In some embodiments, theRyR-associated condition is a central nervous system (CNS) disorder or disease that implicates the Ryanodine Receptor 2 (RyR2). In some embodiments, the RyR-associated condition is a central nervous system (CNS) disorder or disease that implicates the 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 dysfunction. In some embodiments, compounds of the disclosure are useful in improving cognitive function. In some embodiments, compounds of the disclosure are useful in treatment of cognitive dysfunction. In some embodiments, compounds of the disclosure are useful in slowing progression of cognitive dysfunction. In some embodiments, compounds of the disclosure are useful in reducing likelihood of occurrence of cognitive dysfunction.

[0247] In some embodiments, the present disclosure relates to a method of treating or reducing the likelihood of occurrence of conditions, disorders, and diseases of the nervous system, by administering to a subject in need thereof an amount of a compound described herein, e.g., a compound of formula (I) or a pharmaceutically-acceptable salt thereof, or a pharmaceutical composition comprising such compound.

[0248] In some embodiments, the present disclosure relates to the use of a compound described herein, e.g., a compound of formula (I) or a pharmaceutically-acceptable salt thereof, or a pharmaceutical composition comprising such compound, for treating or reducing the likelihood of occurrence of conditions, disorders, and diseases of the nervous system.

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

[0250] In some embodiments, conditions, disorders, and diseases treatable or preventable by the compounds of the present disclosure include Alzheimer's disease, post-traumatic stress disorder (PTSD), Huntington’s Disease, neuropathy, seizure disorders, Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Spinocerebellar ataxia, and Parkinson’s Disease.

[0251] In some embodiments, compounds of the present disclosure are useful for treating a movement disorder. Non-limiting examples of movement disorders include ataxia, dystonia, chorea, Huntington’s disease, functional movement disorder, multiple system atrophy, Parkinson’s disease, Parkinsonism, a movement disorder due to Alzheimer’s disease,progressive supranuclear palsy, restless legs syndrome, tardive dyskinesia, Tourette syndrome, tremors, and Wilson’s disease.

[0252] In some embodiments, the movement disorder is or is characterized by a tremor. Nonlimiting examples of tremors include essential tremor, Parkinsonism tremor, dystonic tremor, cerebellar tremor, psychogenic tremor, orthostatic tremor, and physiologic tremor.

[0253] In some embodiments, the movement disorder is essential tremor. Essential tremor is a tremor predominantly present in bilateral upper extremities, or less commonly in other locations, such as the head, neck, vocal cords, or lower limbs. Essential tremor is one of the most common movement disorders and tends to worsen with age. Characteristically, essential tremor is more pronounced upon attempts to use the upper extremities, rather than at rest. Consequently, handwriting or drawing difficulties are often marked.

[0254] Other examples of neurodegenerative diseases include Parkinson-like Disease, Multiple Sclerosis, autoimmune disorders, Pick Disease, diffuse Lewy body Disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases, amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson-Dementia complex of Guam, subacute sclerosing panencephalitis, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado- Joseph disease / spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette Disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy Disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig- Hoffmann Disease, Kugelberg- Welander Disease, Tay-Sach Disease, Sandhoff Disease, familial spastic disease, Wohlfart-Kugelberg-Welander Disease, spastic paraparesis, progressive multifocal leukoencephalopathy, prion diseases, including Creutzfeldt-Jakob Disease, Gerstmann-Straussler-Scheinker Disease, Kuru, and fatal familial insomnia.

[0255] Neurodegenerative diseases also 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 Diseases, pain, brain damage, brain dysfunction, spinal cord disorders, peripheral nervous system disorders, cranial nerve disorders, autonomic nervous system disorders, sleep disorders, headaches, lower back and neck pain, neuropathic pain, dementia, delirium and dementia dizziness and vertigo, stupor and coma, head injury, stroke, tumors of the nervous system, infections of the brain or spinal cord, prion diseases, depression, and drug addiction.

[0256] Dementia refers to decline in cognitive function due to damage or disease in the brain or central nervous system beyond that which might be expected from normal aging. Dementiastypically affect 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 multiinfarct dementia), Binswanger's disease, dementia with Lewy bodies (DLB), alcohol-induced persisting dementia, frontotemporal lobar degenerations (FTLD), Pick's disease, frontotemporal dementia (or frontal variant FTLD), semantic dementia (or temporal variant FTLD), progressive non-fluent aphasia, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's di and AIDS dementia complex.

[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) and results in motor neuron death. Non-limiting examples of ALS include classical ALS (typically affecting both lower and upper motor neurons), Primary Lateral Sclerosis (PLS, typically affecting only the upper motor neurons), Progressive Bulbar Palsy (PBP or Bulbar Onset, a version of ALS that typically begins with difficulties swallowing, chewing and speaking), Progressive Muscular Atrophy (PMA, typically affecting only the lower motor neurons), and familial ALS (a genetic version of ALS).

[0258] “Multiple sclerosis” or “MS” is a progressive neurodegenerative disease resulting in destruction of the myelin covering of nerve cells, particularly of the brain and spinal cord. Nonlimiting examples of multiple sclerosis include Relapsing-remitting (RRMS) (typically characterized by partial or total recovery after attacks (also called exacerbations, relapses, or flares)), Secondary progressive (SPMS) (generally characterized by fewer relapses, with an increase in disability and symptoms), and Primary progressive (PPMS) (generally characterized by progression of symptoms and disability without remission).

[0259] “Alzheimer’s disease” or “AD” is a progressive neurodegenerative disease characterized by dementia and defined by the American Psychiatric Association (in DSM IV) as the development of multiple cognitive deficits that includes memory impairment.

[0260] Parkinson's disease is a neurodegenerative disease. Many of the signs and symptoms associated with Parkinson's disease can precede typical Parkinson's disease, in some cases by many years. Involvement of the dopaminergic substantia nigra, which underlies the primary motor features of the disease, occurs at a time when the disease is well advanced at a neuropathological level. The motor features of Parkinson's disease are characterized by muscle rigidity, tremor, gait and postural abnormalities, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex and other areas of the brain by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which isproduced in the dopaminergic neurons of the brain. The motor features of Parkinson's disease are just one component of a much more wide-spread disorder that causes an abundance of nonmotor signs and symptoms, including olfactory dysfunction, REM sleep behavioral disorder (RBD), constipation, depression, and cognitive deficits. Many of these signs and symptoms can precede the motor symptoms by years to a decade or more.

[0261] Parkinson' s-Like Diseases: several other conditions have the features of Parkinson's disease and are interchangeably referred to as Parkinson' s-like disease, secondary Parkinsonism, Parkinson's syndrome, or atypical Parkinson's. These neurological syndromes can be characterized by tremor, hypokinesia, rigidity, and postural instability. Several etiologies can lead to similar symptoms, including some toxins, metabolic diseases, and non-PD neurological conditions. A common cause is as a side effect of medications, mainly neuroleptic antipsychotics, especially the phenothiazines (such as perphenazine and chlorpromazine), thioxanthenes (such as flupenthixol and zuclopenthixol) and butyrophenones (such as haloperidol (Haldol)), piperazines (such as ziprasidone), and rarely, antidepressants. Other causes include but are not limited to olivopontocerebellar degeneration; progressive supranuclear palsy; corticobasal degeneration; temporo-frontal dementia; drug-induced by antipsychotics, prochlorperazine, or metoclopromide; poisoning with carbon monoxide; head trauma; and Huntington's disease Parkinsonism. In some cases, alpha-synucleinopathies can result in Parkinson' s-like disease, secondary Parkinsonism, Parkinson's syndrome, or atypical Parkinson's. In some embodiments, the methods described herein are used to diagnose Parkinson' s-like disease, secondary Parkinsonism, and Parkinson's syndrome.Cognitive Dysfunction

[0262] In some embodiments, compounds of the present disclosure are useful in treating cognitive dysfunction. In some embodiments, the present disclosure relates to a method of treating or reducing the likelihood of occurrence cognitive dysfunction, or for improving cognitive function, by administering to a subject in need thereof an amount of a compound described herein, e.g., a compound of formula (I) or a pharmaceutically -acceptable salt thereof, or a pharmaceutical composition comprising such compound.

[0263] In some embodiments, the present disclosure relates to the use of a compound described herein, e.g., a compound of formula (I) or a pharmaceutically-acceptable salt thereof, or a pharmaceutical composition comprising such compound, for treating or reducing the likelihood of occurrence of cognitive dysfunction, or for improving cognitive function.

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

[0265] In some embodiments, cognitive dysfunction is associated with stress-related cognitive dysfunction or age-related cognitive dysfunction or a combination thereof. In some embodiments, cognitive dysfunction is associated with a disease. Non-limiting examples of diseases implicated with cognitive dysfunction are post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, generalized anxiety disorder, obsessive compulsive disorder, Schizophrenia, Bipolar disorder, Parkinson’s disease, and major depression.

[0266] In some embodiments, the compounds of the present disclosure improve cognitive function, for example, short term memory, long term memory, attention, learning, and any combination thereof.

[0267] Compounds of the present disclosure are useful as treatment for a variety of conditions in a subject, e.g., a patient. In some embodiments, the subject is a newborn. In some embodiments, the subject is age 1 year and above. In some embodiments, the subject is age 2 years and above. In some embodiments, the subject is age 3 years and above. In some embodiments, the subject is age 4 years and above. In some embodiments, the subject is age 5 years and above. In some embodiments, the subject is an age of about 5 years to about 12 years. In some embodiments, the subject is no more than 5 years, no more than 6 years, no more than 7 years, no more than 8 years, no more than 9 years, no more than 10 years, no more than 11 years, no more than 12 years, no more than 13 years, no more than 14 years, or no more than 15 years. In some embodiments, the subject is at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 11 years, at least 12 years, at least 13 years, at least 14 years, at least 15 years, at least 20 years, at least 25 years, at least 30 years, at least 40 years, at least 50 years, at least 60 years, at least 70 years, at least 80 years, or at least 90 years. In some embodiments, the subject is an age of about 4 years to about 12 years, about 5 years to about 12 years, about 6 years to about 12 years, about 7 years to about 12 years, about 8 years to about 12 years, about 9 years to about 12 years, about 10 years to about 12 years, about 10 years to 16 years, about 12 years to 16 years, about 14 years to about 16 years, about 10 years to about 18 years, about 12 years to about 18 years, about 14 years to about 18 years, or about 16 to about 18 years. In some embodiments, the subject is an age of about 10 to about 120 years, about 11 to about 120 years, about 12 to about 120 years, about 13 to about 120 years, about 14 to about 120years, about 15 to about 120 years, about 16 to about 120 years, about 17 to about 120 years, or about 18 to about 120 years.Pharmaceutical Compositions

[0268] The compounds of the present disclosure are formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. According to another aspect, the present disclosure provides a pharmaceutical composition comprising compounds of the present disclosure in admixture with a pharmaceutically acceptable diluent and / or carrier. The pharmaceutically-acceptable carrier is preferably acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0269] The compound can be administered alone but is preferably administered with one or more pharmaceutically acceptable carriers. The pharmaceutically-acceptable carrier employed herein can be selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated as any one or more of fillers, diluents, binders, disintegrants, buffers, colorants, emulsifiers, flavor-improving agents, gellants, glidants, preservatives, solubilizers, stabilizers, suspending agents, sweeteners, tonicity agents, wetting agents, emulsifiers, dispersing agents, swelling agents, retardants, lubricants, absorbents, and viscosity-increasing agents.

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

[0271] The compounds of the present disclosure are administered to a human or animal subject by procedures including, without limitation, oral, sublingual, buccal, parenteral (intravenous, intramuscular or subcutaneous), transdermal, per- or trans-cutaneous, intranasal, intra-vaginal, rectal, ocular, and respiratory (via inhalation administration). The compounds of the present disclosure can also be administered to the subject by way of delivery to the subject’s muscles including, but not limited to, the subject’s cardiac or skeletal muscles. In one embodiment, the compound is administered to the subject by way of targeted delivery to cardiac muscle cells via a catheter inserted into the subject's heart. In some embodiments, the compounds can be administered directly into the CNS, for example by intralumbar injection or intreventricular infusion of the compounds directly into the cerebrospinal-fluid (CSF), or by intraventricular,intrathecal or interstitial administration. Administration can be to the subject’s muscles, for example, the subject’s cardiac or skeletal muscles. In some embodiments, the compound is administered to the subject by targeted delivery to cardiac muscle cells via a catheter inserted into the subject's heart. In some embodiments, the compound is orally administered.

[0272] The pharmaceutical compositions according to the present disclosure for solid oral administration include especially tablets or dragees, sublingual tablets, orally disintegrating tablets, sachets, capsules including gelatin capsules, powders, lozenges, and granules, and those for liquid oral, nasal, buccal or ocular administration include especially emulsions, solutions, oils, suspensions, drops, syrups and aerosols. The compounds can also be administered as a suspension or solution via drinking water or with food. Examples of acceptable pharmaceutical carriers include, but are not limited to, cellulose derivatives including carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, ethyl cellulose and microcrystalline cellulose; sugars such as mannitol, sucrose, or lactose; glycerin, gum arabic, magnesium stearate, sodium stearyl fumarate, saline, sodium alginate, starch, talc and water, among others.

[0273] The pharmaceutical compositions according to the present disclosure for parenteral injections include especially sterile solutions, which can be aqueous or non-aqueous, dispersions, suspensions or emulsions and also sterile powders for the reconstitution of injectable solutions or dispersions. The compounds of the present disclosure can be combined with a sterile aqueous solution that is isotonic with the blood of the subject. Such a formulation is prepared by dissolving a solid active ingredient in water containing physiologically- compatible substances, such as sodium chloride, glycine and the like, and having a buffered pH compatible with physiological conditions, so as to produce an aqueous solution, then rendering said solution sterile. The formulation is presented in unit or multi-dose containers, such as sealed ampoules or vials. The formulation is delivered by any mode of injection, including, without limitation, epifascial, intracapsular, intracranial, intracutaneous, intrathecal, intramuscular, intraorbital, intraperitoneal, intraspinal, intrasternal, intravascular, intravenous, parenchymatous, subcutaneous, or sublingual or by way of catheter into the subject's heart.

[0274] The pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and those for per- or trans-cutaneous administration include especially powders, aerosols, creams, ointments, gels and patches.

[0275] For transdermal administration, the compounds of the present disclosure are combined with skin penetration enhancers, such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, A-methylpyrrolidone and the like, which increase the permeability of theskin to the compounds of the present disclosure and permit the compounds to penetrate through the skin and into the bloodstream. The compound / enhancer compositions also can be further combined with a polymeric substance, such as ethylcellulose, hydroxypropyl cellulose, ethylene / vinylacetate, polyvinyl pyrrolidone, and the like, to provide the composition in gel form, which is dissolved in a solvent, evaporated to the desired viscosity and then applied to backing material to provide a patch.

[0276] Non-limiting examples of pharmaceutically-acceptable excipients or carriers include organic or inorganic materials that are used as materials for pharmaceutical formulations and are incorporated as any one or more of fillers, diluents, binders, disintegrants, buffers (pH adjusting agents), colorants, emulsifiers, flavor-improving agents, gellants, glidants, surfactants (wetting agents), preservatives, solubilizers, stabilizers, suspending agents, sweeteners, tonicity agents, emulsifiers, dispersing agents, swelling agents, retardants, lubricants, absorbents, plasticizers, and viscosity-increasing agents.

[0277] A pharmaceutically-acceptable excipient can be present in a pharmaceutical composition at a mass of between about 0.1% and about 99% by mass of the composition. For example, a pharmaceutically-acceptable excipient can be present in a pharmaceutical composition at a mass of between about 0.1% and about 95%, between about 0.11% and about 90%, between about 0.1% and about 85%, between about 0.1% and about 80%, between about 0.1% and about 75%, between about 0.1% and about 70%, between about 0.1% and about 65%, between about 0.1% and about 60%, between about 0.1% and about 55%, between about 0.1% and about 50%, between about 0.1% and about 45%, between about 0.11% and about 40%, between about 0.1% and about 35%, between about 0.1% and about 30%, between about 0.1% and about 25%, between about 0.1% and about 20%, between about 0.1% and about 15%, between about 0.1% and about 10%, between about 0.1% and about 5%, between about 0.1% and about 1%, by mass of the formulation.

[0278] A pharmaceutically-acceptable excipient can be present at about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9% by mass of the formulation.

[0279] Compounds of the present disclosure can be formulated in pharmaceutical compositions intended for immediate release. Compounds of the present disclosure can be formulated in pharmaceutical compositions intended for extended release.

[0280] In some embodiments, the compound is formulated to provide a prolonged release of the compound. In some embodiments, the compound is formulated to provide controlled release of the compound. In some embodiments, the compound is formulated to provide sustained release of the compound.

[0281] In some embodiments, the compound is formulated to provide immediate release of the compound. Release of the active ingredient can be according to an immediate release profile, e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the active ingredient is released within 1 hour after administration.

[0282] In some embodiments, the compound is formulated to provide extended release of the compound. The term “extended release,” can refer to the release of the active ingredient more slowly than that from an immediate release dosage form. The sustained release property of a composition is typically measured by an in vitro dissolution method and confirmed by an in vivo blood concentration-time profile (i.e., a pharmacokinetic profile). For example, a pharmaceutical composition comprising in a unit dosage form a compound herein or a pharmaceutically- acceptable salt thereof, wherein the unit dosage form is an extended release dosage form, can release the compound or a pharmaceutically-acceptable salt thereof in a controlled manner such that, in a study (e.g., a controlled study), if the unit dosage form is administered to a study subject, then a therapeutically-effective amount of the compound or the pharmaceutically- acceptable salt thereof is present in the subject over a period of time, wherein the period of time occurs after administration, wherein the period of time is at least about 12 hours. In some embodiments, the compound is released from the composition in a controlled manner such that, in a study (e.g., a controlled study), if the unit dosage form is administered to a study subject,then a therapeutically-effective amount of the compound or the pharmaceutically-acceptable salt thereof is present in the subject over a period of time, wherein the period of time occurs after administration, wherein the period of time is at least about 24 hours. In some embodiments, the period of 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.

[0283] In some embodiments, the compound is formulated to provide delayed release of the compound. In some embodiments, a delayed release formulation releases the compound after a lag time which can be, e.g., from about 1 hour to about 6 hours, from about 1 hour to about 2 hours, from about 2 hours to about 4 hours, or from about 4 hours to about 6 hours after administration. In some embodiments, a delayed release formulation releases the compound after a lag time which can be, e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours after administration. After the lag time, the formulation can release the active compound according to an immediate release profile as described herein, or according to an extended or controlled release profile as described herein.

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

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

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

[0287] In some embodiments, enteric-coated gastro-resistant tablets are composed of three layers: (1) a drug-containing core (immediate release function); (2) a subcoat layer substantially covering the core, which subcoat layer can include a swellable, hydrophobic polymer layer (e.g., hydroxypropyl cellulose or hypromellose (hydroxypropylmethyl cellulose) (time release function)); and (3) an enteric coating layer comprising an enteric polymer, the enteric coating layer substantially covering the subcoat layer (acid resistance function). The tablet does not substantially release the drug in the stomach due to the acid resistance of the outer enteric coating layer. The enteric coating layer rapidly dissolves after gastric emptying and the intestinal fluid begins to erode the subcoat polymer layer. Rapid drug release occurs after the erosion front reaches the tablet core after gastric emptying. The time needed for the tablet core to become accessible by dissolution of the eroding layers is the lag phase, the duration of which can be controlled either by the mass or composition of the polymer in the subcoat layer.

[0288] In some embodiments, a gastro-resistant formulation is a delayed-release formulation due to, e.g., sensitivity to pH resulting from an enteric coating, and a modified-release formulation due to, e.g., the presence of a polymer in the subcoat layer. In some embodiments, a formulation is characterized by a delayed-release profile such that all or substantially all of the formulation transits the stomach and is released in the small intestine. In addition, due to the presence of a polymer in the subcoating layer, slow erosion of the formulation (lag phase) can result in prolonged-release of the active ingredient relative to an immediate release formulation. In some embodiments, a gastro-resistant formulation has a release profile that is a combination of delayed-release profile due, e.g., to presence of an enteric coating, and prolonged-release profile due, e.g., to presence of a polymer, for example due to the presence of a polymer in a subcoat layer.

[0289] In some embodiments, the gastro-resistant formulation is resistant to disintegration in gastric fluid. For example, in some embodiments, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the active ingredient is released from the formulation in gastric fluid or at a pH mimicking that of gastric fluid. A pH of gastric fluid varies with the presence or absence of food, and typically ranges from about 1.5 to about 3.5. In some embodiments, the gastro-resistant formulation does not substantially disintegrate for at least about 15 minutes after exposure to gastric fluid. For example, the gastro-resistant formulation does not substantially disintegrate for at least about 30 minutes or at least about 45 minutes or at least about 60 minutes or at least about 75 minutes or at least about 90 minutes or at least about 120 minutes or at least about 180 minutes or even longer after exposure to gastricfluid. In some embodiments, the gastro-resistant formulation is resistant to disintegration in gastric fluid in the absence of food. In some embodiments, the gastro-resistant formulation is resistant to disintegration in gastric fluid in the presence of food.

[0290] In some embodiments, the gastro-resistant formulation (e.g., a gastro-resistant tablet) does not substantially disintegrate at a pH at or below 5.5. For example, the gastro-resistant formulation (e.g., gastro-resistant tablet) releases less than about 10% of an active ingredient at a pH at or below 5.5. For example, the gastro-resistant formulation (e.g., gastro-resistant tablet) releases less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of an active ingredient at a pH at or below about 5.5.

[0291] In some embodiments, the gastro-resistant formulation does not substantially disintegrate after exposure to a pH at or below about 5.5, e.g., a pH at or below about 4.5, about 4.0, about 3.5, about 3.0, about 2.5, about 2.0, or lower. In some embodiments, the gastro- resistant formulation does not substantially disintegrate for at least about 15 minutes after exposure to a pH at or below about 5.5. For example, the gastro-resistant formulation does not substantially disintegrate for at least about 30 minutes or at least about 45 minutes or at least about 60 minutes or at least about 75 minutes or at least about 90 minutes or at least about 120 minutes or at least about 180 minutes or even longer after exposure to a at or below pH below about 5.5.

[0292] In some embodiments, the gastro-resistant formulation (e.g., gastro-resistant tablet) substantially disintegrates at neutral pH (pH=7), or a pH that is close to neutral, e.g., a pH 6.8, or higher. In some embodiments, delay ed-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 a pH about 6.8 or higher. Such release can occur rapidly, e.g., within 30 minutes, or 40 minutes, or 50 minutes, or 60 minutes, or 120 minutes, or 180 minutes after the enteric layer and / or the subcoat layer are eroded and the drug-containing core is exposed.

[0293] In some embodiments, the gastro-resistant formulation (e.g., tablet) comprises an enteric coating layer. Enteric coated tablets are solid, oral unit dosage forms that are designed to pass through the stomach and release the drug in the small intestine. In some embodiments, enteric coatings prevent release of the active ingredient before the tablet reaches the small intestine.

[0294] Once the formulation reaches the small intestine, the enteric coating dissolves and the active ingredient is released. Release of the active ingredient can be according to an immediate release profile, e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the active ingredient is released within 1 hour of reaching the small intestine.

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

[0296] In some embodiments, the medium having a pH below 5.5 is a HC1 solution having a pH of about 1.2. In some embodiments, the medium having a pH below 5.5 is a 0. IN HC1 solution having a pH of about 1.2. In some embodiments, the medium having a pH of 6.8 is a phosphate buffer.

[0297] In some embodiments, an enteric coating layer rapidly dissolves after gastric emptying and the intestinal fluid begins to erode the subcoat polymer layer. Rapid drug release occurs after the erosion front reaches the tablet core after gastric emptying. The time needed for the tablet core to become accessible by dissolution of the eroding layers is designated the “lag phase”. In some embodiments, duration of the lag phase may be controlled by varying the mass of the polymer in the subcoat layer. In some embodiments, duration of the lag phase is controlled by varying the nature of the polymer in the subcoat layer. In some embodiments, the duration of the lag phase is controlled by varying the mass and composition of the polymer in the subcoat layer. In some embodiments, the polymer is hydroxypropylcellulose. In some embodiments, the polymer is hypromellose (hydroxypropylmethyl cellulose).

[0298] In some embodiments, a gastro-resistant pharmaceutical composition of the present disclosure is administered to the subject in a fed state (e.g., during a meal or within at most about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or about 7 hours after a meal). In some embodiments, a gastro-resistant pharmaceutical composition of the present disclosure is administered to the subject in a fasted state (e.g., at least 8 about hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours after a meal, or longer). In some embodiments, a meal is a high fat meal. In some embodiments, a meal is a low fat meal.

[0299] In some embodiments, the gastro-resistant pharmaceutical composition of the present disclosure is administered in combination with a gastric acid-reducing agent. For example, the subject being administered the gastro-resistant composition is also administered a regimen of a gastric acid-reducing agent. In some embodiments, the gastric-acid reducing agent is administered concomitantly with the gastro-resistant pharmaceutical composition. In some embodiments, the gastric-acid reducing agent is administered sequentially, before or after the gastro-resistant pharmaceutical composition. In some embodiments, the gastric-acid reducing agent is administered at most about 1 hour, or at most about 2 hours, or at most about 3 hours, or at most about 4 hours, or at most about 5 hours, or at most about 6 hours, or at most about 7 hours, or at most about 8 hours, or at most about 9 hours, or at most about 10 hours, or at most about 11 hours, or at most about 12 hours before the gastro-resistant formulation. In some embodiments, the gastric-acid reducing agent is administered at most about 1 hour, or at most about 2 hours, or at most about 3 hours, or at most about 4 hours, or at most about 5 hours, or at most about 6 hours, or at most about 7 hours, or at most about 8 hours, or at most about 9 hours, or at most about 10 hours, or at most about 11 hours, or at most about 12 hours after the gastro- resistant formulation.

[0300] Non-limiting examples of pharmaceutically-acceptable fillers / diluents include cellulose derivatives including microcrystalline cellulose, silicified microcrystalline cellulose carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, starches, sugars such as mannitol, sucrose, lactose, sorbitol, dextrins (e.g., maltodextrin), amino-sugars, alginic acid, sodium alginate, and water.

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

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

[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 oil.

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

[0305] Non-limiting examples of pharmaceutically-acceptable plasticizers include triethyl citrate.

[0306] Non-limiting examples of pharmaceutically-acceptable surfactants include sodium laurylsulfate or polysorbates, polyvinyl alcohol (PVA), polyethylene glycols, polyoxyethylenepolyoxypropylene block copolymers known as “poloxamer”, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid ester such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate (Tween), polyethylene glycol fatty acid ester such as polyoxyethylene monostearate, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, and hardened castor oil such as polyoxyethylene hardened castor oil.

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

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

[0309] Non-limiting examples of buffering or pH adjusting agents include acidic buffering agents such as short chain fatty acids, citric acid, acetic acid, hydrochloric acid, sulfuric acid and fumaric acid; and basic buffering agents such as tris, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and magnesium hydroxide.

[0310] Non-limiting examples of tonicity enhancing agents include ionic and non-ionic agents such as, alkali metal or alkaline earth metal halides, urea, glycerol, sorbitol, mannitol, propylene glycol, and dextrose.

[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, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl alcohol, chlorohexidine, and polyhexamethylene biguanide.

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

[0314] In some embodiments, solid dosage forms are coated. In some embodiments, solid dosage forms contain a core, a subcoating layer substantially surrounding the core, and a coating layer substantially surrounding the subcoating layer.

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

[0316] In some embodiments, the coating layer comprises 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 copolymers (e.g., poly(methacrylic acid-co-methyl methacrylate), methacrylic acid / acrylic acid ester copolymers, shellac (esters of aleurtic acid).

[0317] In some embodiments, pharmaceutically-acceptable carriers or excipients are used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions for oral ingestion by a subject. Non-limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hy droxy ethyl- 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 co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremaphor, and potassium phosphate buffer.Methods of Preparation

[0318] The pharmaceutical formulations of the present disclosure are prepared by methods well-known in the pharmaceutical arts, 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 nature of the compounds, chosen route of administration and standard pharmaceutical practice.

[0319] Pharmaceutical compositions described herein can be manufactured by suitable pharmacological techniques. Suitable pharmacological techniques include, e.g., one or a combination of methods such as (1) wet granulation; (2) dry granulation; (3) dry mixing; (4) direct compression; (5) milling; (6) roller compaction; or (7) fusion. Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, and extruding, including hot melt extrusion.

[0320] In some embodiments, a tablet disclosed herein is prepared by a wet granulation process. In wet granulation, some or all of the active ingredient(s) and excipients in powder form are blended and then further mixed in the presence of a liquid, for example water, that causes the powders to clump into granules. The granulate dried and then screened and / or milled to the desired particle size. The granulate is then tableted, or other excipients can be added prior to tableting, such as a glidant and / or a lubricant.

[0321] In some embodiments, an active ingredient is dissolved with one or more pharmaceutically-acceptable excipients, and the resulting mixture is granulated in the presence of a suitable solvent, for example water. A wet granulate is obtained which can be dried and optionally sifted to obtain a dry granulate. The dry granulate can optionally be mixed with one or more additional pharmaceutically-acceptable excipients, optionally sifted, and compressed into tablets.

[0322] In some embodiments, a tablet disclosed herein is prepared by a dry granulation process. In some embodiments, a dry granulation process is a slugging process. Slugging is a dry granulation method in which an active ingredient, optionally in combination with one or more excipients, is first compressed to form a slug and is then milled to form particulates suitable for further processing. For example, a blended composition of the active ingredient(s) and pharmaceutically-acceptable excipients may be compacted into a slug or a sheet and then ground into compacted granules. The compacted granules may subsequently be compressed into a tablet.

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

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

[0325] In some embodiments, a granulation method comprises a roller compaction method, in which powder size enlargement is accomplished by feeding an active ingredient, optionally incombination with one or more wet or dry excipients, through a roller apparatus, followed by drying (if necessary), milling, and sizing the compacted mixture to form granules having a desired particle size.

[0326] In some embodiments, a capsule described herein can comprise any of the aforementioned blends and granulates described with reference to tableting.

[0327] In some embodiments, compounds of the disclosure are poorly soluble in water. In some embodiments, techniques such as particle size reduction, preparing the compound in an amorphous state, or certain formulation techniques can be used to improve the solubility of a compound of the disclosure.

[0328] In some embodiments, compounds of the present disclosure are incorporated in a pharmaceutical composition in the form of a solid dispersion (SD). In some embodiments, compounds of the present disclosure are incorporated in a pharmaceutical composition in the form of an amorphous solid dispersion (ASD). In an embodiment, the present disclosure provides a process for preparation of any of a solid dispersion or an amorphous solid dispersion by spray drying, hot melt extrusion, lyophilization, co-grinding, co-milling, evaporation, and any combinations thereof. Pharmaceutical compositions comprising a compound of the present disclosure can comprise the compound in a substantially amorphous state. “Substantially” amorphous denotes that at least 90%, at least 95%, or at least 97% of the compound is amorphous. A “solid dispersion” of a compound herein can include compositions where at least 90%, at least 95% or at least 97% of the compound is homogeneously molecularly dispersed in a solid polymer matrix.

[0329] In some embodiments, the solid dispersions (e.g., spray dried dispersions) of the disclosure comprise a polymer(s). Any suitable polymers known in the art can be used in the disclosure. Exemplary suitable polymers include polymers selected from cellulose-based polymers, polyoxyethylene-based polymers, polyethylene-propylene glycol copolymers, vinylbased polymers, PEO-polyvinyl caprolactam -based polymers, and polymethacrylate-based polymers.

[0330] In some embodiments, the composition is a lipid-based formulation comprising the compound of the disclosure, in the form a solution, dispersion or suspension with at least one lipid. The composition can be in the form of lipid nanoparticles.

[0331] The cellulose-based polymers include a methylcellulose, a hydroxypropyl methylcellulose (HPMC) (hypromellose), a hypromellose phthalate (HPMC-P), a hypromellose acetate succinate, and co-polymers thereof. The polyoxyethylene-based polymers include a polyethylene-propylene glycol, a polyethylene glycol, a poloxamer, and co-polymers thereof.The vinyl-based polymers include a polyvinylpyrrolidone (PVP), and PVP / VA.. The PEO- polyvinyl caprolactam-based polymers include a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer (e.g., Soluplus®). The polymethacrylate-based polymers are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Several types are commercially available and may be obtained as the dry powder, aqueous dispersion, or organic solution.

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

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

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

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

[0336] In some embodiments, the cellulose-based polymer is hypromellose El 5, hypromellose acetate succinate L or hypromellose acetate succinate H.

[0337] [In some embodiments, the polyoxyethylene-based polymer or polyethylene-propylene glycol copolymer is a polyethylene glycol or a pluronic.

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

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

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

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

[0342] In some embodiments, the polymer is one or more water-soluble polymer(s) or partially water-soluble polymer(s). Water-soluble or partially water-soluble polymers include but are not limited to, cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates, such as polymethacrylate (e.g., Eudragit® E); cyclodextrins (e.g., b-cyclodextrin) and copolymers and derivatives thereof, including for example PVP-VA (polyvinylpyrrolidone-vinyl acetate).

[0343] In some embodiments, the polymer is hydroxypropylmethylcellulose (HPMC), such as HPMC E50, HPMC El 5, or HPMC E3.

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

[0345] In some embodiments, the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS). In some embodiments, the polymer is hydroxypropyl methyl cellulose acetate succinate HG grade (HPMCAS -HG).

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

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

[0348] The pharmaceutical compositions mentioned above illustrate the present disclosure but do not limit it in any way.

[0349] In accordance with the methods of the present disclosure, any of these compounds can be administered to the subject (or are contacted with cells of the subject) in an amount effective to limit or reduce a likelihood of a decrease in the level of RyR-bound Calstabin in the subject,particularly in cells of the subject. This amount can be determined, for example, by analysis of titration curves established in vivo and methods and assays disclosed herein. A suitable amount of the compounds of the present disclosure effective to limit or prevent a decrease in the level of RyR-bound Calstabin in the subject ranges 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 is an amount sufficient to achieve plasma levels ranging from about 300 ng / ml to about 5,000 ng / ml. Alternatively, the amount of compounds from the present disclosure ranges from about 1 mg / kg / day to about 50 mg / kg / day. Alternatively, the amount of compounds from the present disclosure ranges from about 10 mg / kg / day to about 20 mg / kg / day. Also included are amounts of from about 0.01 mg / kg / day or 0.05 mg / kg / day to about 5 mg / kg / day or about 10 mg / kg / day which can be administered.Dosing and Dosing Regimens

[0350] In accordance with the methods of the present disclosure, any of these compounds can be administered to the subject (or contacted with cells of the subject) in an amount effective to limit or prevent a decrease in the level of RyR-bound Calstabin in the subject, particularly in cells of the subject. Alternatively, the methods of the present disclosure comprise administering a compound in an amount effective to treat or prevent a RyR-related condition as described herein.

[0351] In some embodiments, a suitable amount of the compounds effective to limit or prevent a decrease in the level of RyR-bound Calstabin in the subject and / or to treat or reduce a likelihood of conditions associated with RyR ranges from about 1 to about 2,000 mg per day, for example about 10 mg per day, about 20 mg per day, about 30 mg per day, about 40 mg per day, about 50 mg per day, about 60 mg per day, about 70 mg per day, about 80 mg per day, about 90 mg per day, about 100 mg per day, about 120 mg per day, about 140 mg per day, about 160 mg per day, about 180 mg per day, about 200 mg per day, about 220 mg per day, about 240 mg per day, about 260 mg per day, about 280 mg per day, about 300 mg per day, about 320 mg per day, about 340 mg per day, about 360 mg per day, about 380 mg per day, about 400 mg per day, about 420 mg per day, about 440 mg per day, about 460 mg per day, about 480 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, about 1,000 mg per day, about 1,100 mg per day, about 1,200 mg per day, about 1,300 mg per day, about 1,400 mg per day, about 1,500 mg per day, about 1,600 mg per day, about 1,700 mg per day, about 1,800 mg per day, about 1,900 mg per day, or about 2,000 mg per day.

[0352] A compound described herein can be present in a composition in a range of from about 1 mg to about 2000 mg; from about 1 mg to about 1000 mg; from about 1 mg to about 500 mg; from about 5 mg to about 1000 mg, from about 5 mg to about 500 mg, from about 5 mg to about 100 mg, from about 10 mg to about 50 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg.

[0353] A compound described herein can be present in a composition in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.

[0354] In some embodiments, a dose can be expressed in terms of an amount of the drug divided by the mass of the subject, for example, milligrams of drug per kilograms of subject body mass. In some embodiments, a compound is administered in an amount ranging from about 0.01 mg / kg to about 2,000 mg / kg, about 0.01 mg / kg to about 1,000 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.01 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.5 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.01 mg / kg to about 0.05 mg / kg, about 1 mg / kg to about 1,000 mg / kg, about 1 mg / kg to about 500 mg / kg, about 1 mg / kg to about 250 mg / kg, about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, about 5 mg / kg to about 50 mg / kg, about 5 mg / kgto about 10 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 50 mg / kg, about 10 mg / kg to about 20 mg / kg, about 250 mg / kg to about 2000 mg / kg, about 10 mg / kg to about 800 mg / kg, about 50 mg / kg to about 400 mg / kg, about 100 mg / kg to about 300 mg / kg, or about 150 mg / kg to about 200 mg / kg. In some embodiments, a compound is administered in an amount of about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about 900 mg / kg, about 950 mg / kg or about 1,000 mg / kg of subject body mass.

[0355] In some embodiments, a dose can be expressed in terms of an amount of the drug divided by the mass of the subject per day, for example, milligrams of drug per kilograms of subject body mass, per day (mg / kg / day / day). In some embodiments, a compound is administered in an amount ranging from about 0.01 mg / kg / day to about 2,000 mg / kg / day, about 0.01 mg / kg / day to about 1,000 mg / kg / day, about 0.01 mg / kg / day to about 100 mg / kg / day, about 0.01 mg / kg / day to about 10 mg / kg / day, about 0.01 mg / kg to about 5 mg / kg / day, about 0.01 mg / kg / day to about 1 mg / kg / day, about 0.01 mg / kg / day to about 0.5 mg / kg / day, about 0.01 mg / kg / day to about 0.1 mg / kg / day, about 0.01 mg / kg / day to about 0.05 mg / kg / day, about 1 mg / kg / day to about 1,000 mg / kg / day, about 1 mg / kg / day to about 500 mg / kg / day, about 1 mg / kg / day to about 250 mg / kg / day, about 1 mg / kg / day to about 100 mg / kg / day, about 1 mg / kg / day to about 50 mg / kg / day, about 5 mg / kg / day to about 50 mg / kg / day, about 5 mg / kg / day to about 10 mg / kg / day, about 5 mg / kg / day to about 20 mg / kg / day, about 10 mg / kg / day to about 50 mg / kg / day, about 10 mg / kg / day to about 20 mg / kg / day, about 250 mg / kg / day to about 2000 mg / kg / day, about 10 mg / kg / day to about 800 mg / kg / day, about 50 mg / kg / day to about 400 mg / kg / day, about 100 mg / kg / day to about 300 mg / kg / day, or about 150 mg / kg / day to about 200 mg / kg / day. In some embodiments, a compound is administered in an amount of about 1 mg / kg / day, about 2 mg / kg / day, about 5 mg / kg / day, about 10 mg / kg / day, about 20 mg / kg / day, about 50 mg / kg / day, about 100 mg / kg / day, about 150 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day, about 300 mg / kg / day, about 350 mg / kg / day, about 400 mg / kg / day, about 450 mg / kg / day, about 500 mg / kg / day, about 550 mg / kg / day, about 600 mg / kg / day, about 650 mg / kg / day, about 700 mg / kg / day, about 750 mg / kg / day, about 800 mg / kg / day, about 850 mg / kg / day, about 900 mg / kg / day, about 950 mg / kg / day or about 1,000 mg / kg / day of subject body mass per day.

[0356] In some embodiments, a compound of the present disclosure is administered in an amount sufficient to achieve a maximum plasma concentration in a subject (e.g., at steady state) of 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.NUMBERED EMBODIMENTS

[0357] Embodiment 1. A compound of Formula (I):wherein ring A 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 CH2or C(O);Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen;R' and R" are each hydrogen, or together with the carbon atom to which R' and R" are bound form C(O);R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety; each R3is independently alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroaryl amino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)Rb, C(O)NHRbor S(O)2Rb;or two adjacent R3groups, together with the carbon atoms to which they are bound, form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; R4is alkyl that is unsubstituted or substituted, or hydrogen;Rais alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl, each of which is unsubstituted or substituted, or hydroxy, carboxy, or NHRC, wherein Rcis alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen;Rbis alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen; and n is 0, 1, 2, 3, 4 or 5; or a pharmaceutically-acceptable salt thereof.

[0358] Embodiment 2. The compound of embodiment 1, wherein X is sulphur.

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

[0360] Embodiment 4. The compound of embodiment 1, wherein the compound is of formula (la):

[0361] Embodiment 5. The compound of any one of embodiments 1-4, wherein Z is hydrogen.

[0362] Embodiment 6. The compound of embodiment 1, wherein the compound is of formula (lb):

[0363] Embodiment 7. The compound of any one of embodiments 1-6, wherein n is 1.

[0364] Embodiment 8. The compound of any one of embodiments 1-7, wherein R' and R" are each hydrogen.

[0365] Embodiment 9. The compound of any one of embodiments 1-8, wherein R1and R2are each hydrogen.

[0366] Embodiment 10. The compound of any one of embodiments 1-8, wherein R1is hydrogen.

[0367] Embodiment 11. The compound of any one of embodiments 1-8, wherein R1is methyl.

[0368] Embodiment 12. The compound of any one of embodiments 1-11, wherein R2is hydrogen.

[0369] Embodiment 13. The compound of any one of embodiments 1-8, 10, and 11, wherein R2is alkyl.

[0370] Embodiment 14. The compound of any one of embodiments 1-8, 10, and 11, wherein R2is C(O)Ra.

[0371] Embodiment 15. The compound of any one of embodiments 1-8, 10, and 11, wherein R2is C(O)Ra, wherein Rais aryl or heteroaryl, each of which is substituted or unsubstituted.

[0372] Embodiment 16. The compound of any one of embodiments 1-8, 10, and 11, wherein R2is C(O)Ra, wherein Rais pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridazinyl, triazolyl, oxadiazolyl, or pyrazinyl, each of which is substituted or unsubstituted.

[0373] Embodiment 17. The compound of any one of embodiments 1-8, 10, and 11, wherein R2is C(O)Ra, wherein Rais pyrimidin-2-yl, pyrimidin-5-yl, 5-amino-pyrimidin-2-yl, 5-methoxy- pyrimidin-2-yl, lJT-pyrazol-3-yl, 2-methyl-17 / -pyrazole-3-yl, pyri din-2 -yl, 2-chloro-pyridin-2- yl, 6-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl, 6-hydroxy-pyridin-2-yl, pyridin-3-yl, 6-amino- pyridin-3-yl, 2-chl oro-pyri din-3 -yl, pyridin-4-yl, 3-phenyl-17 / -pyrazol-5-yl, lJ / -imidazol-4-yl, lJ / -imidazol-2-yl, 1 -methyl- lJ / -imidazol-4-yl, 1 -methyl- UT-imidazol -2 -yl, thiazol-2-yl, thiazol- 4-yl, 4-methyl-l,2,3-thiadiazol-5-yl, 5-phenylisoxazol-3-yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5- methyl-3-phenylisoxazol-4-yl, 4-phenylthiazol-2-yl, lH-tetrazol-5-yl, pyridazin-2-yl, pyridazin- 3-yl,pyridazin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, 3-hydroxy-pyrazinyl, 4-isopropyl- 1,2,3-thiadiazolyl, 3-methyl-isoxazole-5-yl, 4,4-difluoro-piperidin-l-yl, l,2,4-triazin-3-yl, 4- methylpyrid-2-ylamino, 3 -oxopiperazin- 1-yl, 5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl, or pi perazin- 1 -yl.

[0374] Embodiment 18. The compound of any one of embodiments 1-8, wherein R1and R2are each independently hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3- hydroxycyclobutyl, 3,3-difluorocyclobutyl, cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, pyrimidin-2-yl, pyrimidin-2-ylmethyl, pyrimidin-3- ylmethyl, pyrimidin-4-ylmethyl, oxalyl, 2-methoxyethyl, benzyl, 4-carboxybenzyl, 4- carboxymethylbenzyl, tetrahydro-2 / / -pyran-4-yl, oxetan-3-yl, l,2,4-thiadiazol-5-yl, 4- aminom ethyl- 1,2, 3 -triazol- 1-ylmethyl, 4-methyl-l,2,3-thiadiazolyl-5-ylmethyl, benzo[d]thiazol- 2-yl, 4-carboxylethyl-l,2,3-thiadiazolyl-5-ylmethyl, 4-carboxy- l,2,3-thiadiazolyl-5-ylmethyl, isoindoline- 1, 3-dion-2-yl, and acetyl; or wherein Ri and R2 together with the nitrogen atom to which they are bound form an optionally substituted heterocycle or heteroaryl selected from the group consisting of pyrazolidinonyl, piperazinyl, 2-oxopiperazinyl, triazolyl, benzotriazolyl, morpholinyl, pyrrolidinyl, or piperidinyl.

[0375] Embodiment 19. The compound of any one of embodiments 1-18, wherein R3is alkoxy, cycloalkyloxy, or aryloxy, each of which is substituted or unsubstituted, or halogen.

[0376] Embodiment 20. The compound of any one of embodiments 1-18, wherein R3is phenyloxy, which is substituted or unsubstituted.

[0377] Embodiment 21. The compound of any one of embodiments 1-18, wherein R3is substituted by one or two substituents selected from the group consisting of hydroxy, fluorine, chlorine, bromine, iodide, CF3, CHF2, methoxy, SCEMe, cyano, and C(O)Me.

[0378] Embodiment 22. The compound of any one of embodiments 1-18, wherein R3is independently at each occurrence alkyl, cyclohexyl, alkyloxy, cycloalkyloxy, arylsulfonyl, alkylsulfony, phenyl, phenoxy, benzo[d][l,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.

[0379] Embodiment 23. The compound of any one of embodiments 1-22, wherein R4is hydrogen.

[0380] Embodiment 24. The compound of any one of embodiments 1-23, wherein the compound is the pharmaceutically-acceptable salt.

[0381] Embodiment 25. A compound that is:(2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-phenylphenyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-bromophenyl)-5-(dimethylaminomethyl)-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-l,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-2-(4-bromophenyl)-5-(morpholinomethyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-bromophenyl)-5-(morpholinomethyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(3 -bromophenyl)- l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(3 -phenoxyphenyl)- l,4-thiazepan-3 -one;(2S,5R)-5-[(4-benzyl-l-piperidyl)methyl]-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-[(4-benzyl- 1 -piperidyl)methyl]-2-(4-bromophenyl)- 1 ,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-(2 -bromophenyl)- l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-methoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(trifluoromethyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-benzyloxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(trifluoromethyl)phenyl]-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(3 -phenylphenyl)- l,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(2-chlorophenyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl]- 1 ,4-thiazepan-3 -one;(2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(3 -phenoxyphenyl)- l,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenoxy)phenyl]-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R, 5R)-5 -(aminomethyl)-2-(3 -phenoxyphenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,2,2-trifluoroethoxy)phenyl]-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -[3 -(trifluoromethyl)- lH-pyrazol-4-yl]phenyl]- 1 ,4- thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-iodophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-l,4-thiazepan-3-one;3-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;3-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;4-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;4-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;(2S,5R)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,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]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(l,3-benzodioxol-5-yl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(l,3-benzodioxol-5-yl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-bromo-5-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-naphthyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(l -naphthyl)- l,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(benzenesulfonyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-(2-methoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(o-tolyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -( 1 -ethylpropyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenyl]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenyl]phenyl]-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(3-amino-4-chloro-phenyl)phenyl]-5-(aminomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,4-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-chloro-3-iodo-phenyl)phenyl]-l,4-thiazepan-3-one;N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzamide;N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2- yl]phenyl]cyclohexanecarboxamide;(2R,5S)-5-(aminomethyl)-2-[3-(4-fluorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-cyclohexylphenyl)-l,4-thiazepan-3-one;3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]-N-phenyl-benzamide;(2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-l,4-thiazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4- thiazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4- thiazepan-3-one;(2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4- thiazepan-3-one;N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]phenyl]acetamide;(2R, 5 S)-2- [3 -(4-chlorophenyl)phenyl]-5 -[(4,4-difluoro- 1 -piperidyl)methyl]- 1 ,4- thiazepan-3-one;(2R, 5 S)-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]-l,4-thiazepan-3-one;2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzoic acid;2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzamide;(2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxyphenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;2-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]phenoxy]acetic acid;(2R, 5 S)-5-(aminomethyl)-2-[3 -(2-oxopyrrolidin- 1 -yl)phenyl]- 1 ,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(2-oxo- 1 -pyridyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-[3 -[(2S)-2-(hydroxymethyl)pyrrolidin- 1 -yl]phenyl]- 1 ,4- thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(4-hydroxy- 1 -piperidyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-(2,2-dimethylpropoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-(((3R,5R,7R)-adamantan-l-yl)methoxy)phenyl)-5-(aminomethyl)-l,4- thiazepan-3-one;(2R,5S)-2-(3-(((lR,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-5-(aminomethyl)-l,4- thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(cyclohexoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(l-isopropyl-2-methyl-propoxy)phenyl]-l,4-thiazepan-3- one;(2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxy-2-methyl-propoxy)phenyl]-l,4-thiazepan-3- one;(2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(4-phenoxy-3 -propyl-phenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-(3-chloro-4-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-indol-l-ylphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2-methoxyphenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2,4-dichlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[3-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[2-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-fluorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-l,4-thiazepan-3- one;4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]benzonitrile;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(methylaminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(cyclohexoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-methyl-4-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-dibenzofuran-2-yl-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-methylsulfonylphenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;2-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]benzonitrile;(2R,5S)-2-[4-(4-acetylphenoxy)phenyl]-5-(aminomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(l,3-benzodioxol-5-yloxy)phenyl]-l,4-thiazepan-3-one;3-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]-5-chloro-benzonitrile;(2R,5S)-5-(aminomethyl)-2-(4-anilinophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-chloro-4-phenoxy-phenyl)-l,4-thiazepan-3-one;4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]-3-chloro-benzonitrile;(2R,5S)-5-(aminomethyl)-2-(2-methoxy-4-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)-2-methoxy-phenyl]-l,4-thiazepan-3- one;(2R,5S)-2-(4-phenoxyphenyl)-5-(triazol-l-ylmethyl)-l,4-thiazepan-3-one;(2R,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-[[4-(aminomethyl)triazol- 1 -yl]methyl]-2-[4-(4-fluorophenoxy)phenyl]- 1 ,4- thiazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-5-[(pyrimidin-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-l,4- thiazepan-3-one;(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan- 3 -one;(2R,5S)-5-[(l,3-benzothiazol-2-ylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3- one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(l,2,4-thiadiazol-5-ylamino)methyl]-l,4-thiazepan-3- one;N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l- methy 1 -imi dazol e-4-carb oxami de;2-oxo-2-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methylamino]acetate;N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiazole-2- carboxamide;4-(aminomethyl)-N-[[(2R,5S)-2-(3-bromophenyl)-3-oxo-l,4-thiazepan-5- yl]methyl]benzamide;N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-2H-tetrazole-5- carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine- 2-carboxamide;N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]thiazole-4- carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-4-methyl- thi adi azol e- 5 -carb oxami de;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH- pyrazole-3 -carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-5-carboxamide;6-amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-3-carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]thiazole-2- carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-5-phenyl-isoxazole-3- carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-5-methyl-3-phenyl- isoxazole-4-carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-4-phenyl-thiazole-2- carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-3-phenyl-lH- py razol e- 5 -carb oxami de;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;1-methyl-N-[[(2S,5R)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]imidazole-4-carboxamide;4-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiadiazole-5-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-5- carb oxami de6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-3- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]methanesulfonamide4-isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- y 1 ] methyl ] thi adi azol e- 5 -carb oxami de ;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-lH-imidazole-4- carboxamide;2-morpholino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]acetamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-lH-pyrazole-3- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]morpholine-4- sulfonamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridazine-3- carboxamide;5-isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- y 1 ] methyl ] thi adi azol e-4-carb oxami de ;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine- 2-carboxamide;N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-3- sulfonamide;4-fluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]benzenesulfonamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- sulfonamide; l-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]imidazole-4-sulfonamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiazole-2- carboxamide;3.3-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]cyclobutanecarboxamide;4.4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]cyclohexanecarboxamide;N-[[(2R,5S)-2-[3-(2-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-(((2R,5S)-2-(3-(((lR,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-l,4-thiazepan-5- yl)methyl)pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-2-pyrimidin-2-yl- acetamide; l-benzyl-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]urea;3-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]isoxazole-5-carboxamide;N-[[(2R,5S)-2-[3-(cyclohexoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;4,4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]piperidine-l -carboxamide;N-[[(2R,5 S)-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-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrazine-2- carboxamide;I l l6-chloro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- carboxamide;2-[5-(4-chlorophenyl)isoxazol-3-yl]-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4- thiazepan-5-yl]methyl]acetamide;6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- carboxamide;5-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide;5-methoxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide; l-(4-methyl-2-pyridyl)-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]ureaN-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH- pyrazole-3 -carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-2- morpholino-acetamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH- pyrazole-3 -carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridazine-3 -carboxamide;6-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-3-carboxamide;6-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-3-carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridazine- 3 -carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-2- morpholino-acetamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-2- sulfonamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-2- sulfonamide;2-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]benzamide;4-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]benzamide;(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-5-[(l,2,4-thiadiazol-5-ylamino)methyl]-l,4- thiazepan-3-one;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide;5-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;5-chloro-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-2-carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-5- methoxy-pyrimidine-2-carboxamide;5-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-5- methoxy-pyrimidine-2-carboxamide;3-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrazine-2-carboxamide;3-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine- 2-carboxamide;N-[[(2S,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2S,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-l,4-thiazepan-5- yl]methyl]-l,3,4-oxadiazole-2-carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-5-(4-fluorophenyl)- l,3,4-oxadiazole-2-carboxamide;N-[[(2R,5 S)-3 -oxo-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-5 -yl]methyl]piperazine- 1 - carboxamide;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-l,4-thiazepan-3- one; methyl 4-[[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5- yl]methylamino]methyl]benzoate;(2R,5S)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;4-[[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5- yl]methylamino]methyl]benzoic acid;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(cyclopropylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-5-[(cyclopropylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[(cyclobutylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(tetrahydropyran-4-ylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-5-[(oxetan-3-ylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[[bis(oxetan-3-yl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-((((lr,3S)-3-hydroxycyclobutyl)amino)methyl)-2-(4-phenoxyphenyl)-l,4- thiazepan-3-one;(2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3- one;(2R,5S)-5-[[(3,3-difluorocyclobutyl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3 -one;(2R,5S)-5-[[(4-methylthiadiazol-5-yl)methylamino]methyl]-2-(4-phenoxyphenyl)-l,4- thiazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-4-ylmethylamino)methyl]-l,4-thiazepan-3- one;4-[[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methylamino]methyl]benzoic acid;4- [[ [(2R, 5 S)-2- [3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 - yl]methylamino]methyl]benzoic acid;(2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-bromophenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R,5S)-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R,5S)-2-[3-(2,4-dichlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R,5S)-5-[(2,2,2-trifluoroethylamino)methyl]-2-[3-[2-(trifluoromethyl)phenyl]phenyl]- l,4-thiazepan-3-one;(2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R, 5 S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2 -methoxy ethylamino)methyl]-l,4-thiazepan- 3 -one;(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl]- 1 , 1 -di oxo- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-l,l-dioxo-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-l,l-dioxo-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R, 5 S)-5-[(2-oxopiperazin- 1 -yl)methyl]-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3 -one;(25.55)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-l,4-oxazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-l,4-oxazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-(dimethylaminomethyl)-l,4-oxazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-l,4-oxazepan-3- one;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyrimidine- 2-carboxamide;6-amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5- yl]methyl]pyridine-3-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-2- carboxamide;6-chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5- yl]methyl]pyridine-2-carboxamide;2-chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5- yl]methyl]pyridine-3-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]-l-methyl- imidazole-2-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-3- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-4- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridazine-3- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridazine-4- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]thiazole-4- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]thiazole-2- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyrazine-2- carboxamide;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2 trifluoroethyl amino) methyl]-l,4- oxazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-l-carbonyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl]-2-methyl- 1 ,4-oxazepan-3 -one;(2R, 5 S)-5-(benzotriazol- 1 -ylmethyl)-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3 -one; (2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(S)-5-(aminomethyl)-2,2-diphenyl-l,4-thiazepan-3-one; or(2R, 5 S)-5-[(3 -oxopiperazin- 1 -yl)methyl]-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3 -one; or an enantiomer, diastereoisomer, pharmaceutically-acceptable salt, or a deuterated derivative thereof.

[0382] Embodiment 26. A compound that is: (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(25.55)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;(25.55)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]thiazole-2- carboxamide, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;N-[[(2R,5S)-2-[4-(3,5-difhrorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically-acceptable salt thereof; N-[[(2R,5S)-2-[4-(3,5-difhrorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l- methyl-imidazole-4-carboxamide, or a pharmaceutically-acceptable salt thereof;N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically-acceptable salt thereof;N-[[(2R, 5 S)-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-(((lR,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-l,4-thiazepan-5- yl)methyl)pyrimidine-2-carboxamide, or a pharmaceutically-acceptable salt thereof; (2R,5 S)-2-(4-phenoxyphenyl)-5-(piperazine- 1 -carbonyl)- 1 ,4-thiazepan-3 -one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-l,4-thiazepan-3- one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3- one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,l-dioxo-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-[(2-oxopiperazin-l-yl)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(3-(((3R,5R,7R)-adamantan-l-yl)methoxy)phenyl)-5-(aminomethyl)-l,4- thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof; or (S)-5-(aminomethyl)-2,2-diphenyl-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

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

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

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

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

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

[0388] Embodiment 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.

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

[0390] Embodiment 34. A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I):wherein ring A 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 CH2or C(O);Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen;R' and R" are each hydrogen or together with the carbon atom to which R' and R" are bound form C(O);R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety; each R3is independently alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroaryl amino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)Rb, C(O)NHRbor S(O)2Rb; or two adjacent R3groups, together with the carbon atoms to which they are bound, form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted;R4is alkyl that is unsubstituted or substituted, or hydrogen;Rais alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl, each of which is unsubstituted or substituted, or hydroxy, carboxy, or NHRC, wherein Rcis alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen;Rbis alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen; and n is 0, 1, 2, 3, 4 or 5; or a pharmaceutically-acceptable salt thereof.

[0391] Embodiment 35. The method of embodiment 34, wherein the condition is a cardiac condition.

[0392] Embodiment 36. The method of embodiment 34 or embodiment 35, wherein the condition is characterized by an irregular heartbeat.

[0393] Embodiment 37. The method of any one of embodiments 34-36, wherein the condition is catecholaminergic polymorphic ventricular tachycardia.

[0394] Embodiment 38. The method of any one of embodiments 34-36, wherein the condition is catecholaminergic polymorphic ventricular tachycardia type 1.

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

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

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

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

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

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

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

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

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

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

[0405] Embodiment 47. The method of embodiment 46, wherein the treating improves skeletal muscle weakness in the subject.

[0406] Embodiment 48. The method of embodiment 46, wherein the treating decreases calcium leak from a RyRl channel in the subject.

[0407] Embodiment 49. The method of embodiment 46, wherein the treating decreases calcium leak from a RyR2 channel in the subject.

[0408] Embodiment 50. The method of embodiment 34 or embodiment 35, wherein the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

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

[0410] Embodiment 52. The method of embodiment 34 or embodiment 35, wherein the condition comprises cardiac ischemia / reperfusion injury.

[0411] Embodiment 53. The method of embodiment 34, wherein the condition is a musculoskeletal condition.

[0412] Embodiment 54. The method of embodiment 34 or embodiment 53, wherein the condition is a congenital myopathy.

[0413] Embodiment 55. The method of embodiment 34 or embodiment 53, wherein the condition is RYRl-related myopathy.

[0414] Embodiment 56. The method of embodiment 34 or embodiment 53, wherein the condition is congenital RYRl-related myopathy.

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

[0416] Embodiment 58. The method of embodiment 34 or embodiment 53, wherein the condition is a muscular dystrophy.

[0417] Embodiment 59. The method of embodiment 34 or embodiment 53, wherein the condition is Duchenne Muscular Dystrophy.

[0418] Embodiment 60. The method of embodiment 59, wherein the subject is an ambulatory.

[0419] Embodiment 61. The method of embodiment 59, wherein the subject is nonambulatory.

[0420] Embodiment 62. The method of embodiment 59, wherein the treating improves skeletal muscle function in the subject.

[0421] Embodiment 63. The method of embodiment 59, wherein the treating improves cardiac muscle function in the subject.

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

[0423] Embodiment 65. The method of embodiment 34, wherein the condition is sarcopenia.

[0424] Embodiment 66. The method of any one of embodiments 34-65, wherein the administering is oral.

[0425] Embodiment 67. The method of any one of embodiments 34-66, wherein the treating decreases calcium leak from a RyRl channel of the subject.

[0426] Embodiment 68. The method of any one of embodiments 34-67, wherein the treating decreases calcium leak from a RyR2 channel of the subject.

[0427] Embodiment 69. The method of any one of embodiments 34-68, wherein the treating decreases open probability (Po) of RyRl protein in the subject.

[0428] Embodiment 70. The method of any one of embodiments 34-69, wherein the treating decreases open probability (Po) of RyR2 protein in the subject.

[0429] Embodiment 71. The method of embodiment 34, wherein the compound decreases calcium leak from RyRl channel and RyR2 channel of the subject.

[0430] Embodiment 72. A process for the synthesis of a compound of formula (I)(a) esterifying a compound of formula (II):to generate a compound of formula (III):wherein ring A is aryl or a 5- or 6- membered heteroaryl, each of which is unsubstituted or substituted; each R3is 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)Rb, C(O)NHR:;' or S(O)2Rb; optionally wherein two adjacent R3groups, together with the carbon atoms to which they are bound, form an optionally fused cycloalkyl or heterocycloalkyl ring;- Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen; n is 0, 1, 2, 3, 4 or 5; andAik is an alkyl group;(b) subjecting the compound of formula (III) to a bromination reaction to yield a compound of formula (IV):(c) reacting the compound of formula (IV) with a compound of formula (V):to yield a compound of formula (VI):wherein- 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 bound form C(O); and- P is a protecting group;(d) deprotecting the compound of formula (VI) to generate a compound of formula (VII):(e) cyclizing the compound of formula (VII) to yield a compound of formula (VIII):(f) protecting the hydroxyl group to yield a compound of formula (IX):wherein P is a protecting group;(g) reacting the compound of formula (IX) with a compound of formula (X): X'R4', wherein X' is halogen and R4' is alkyl that is unsubstituted or substituted, to yield a compound of formula (XI):the compounds of formula (IX) and (XI) representing a compound of formula (XII):wherein A, R3, Z, X, R', R", n, and P are as defined above, and R4is alkyl that is unsubstituted or substituted, or hydrogen;(h) reacting the compound of formula (XII) with a compound of formula (XIII): HNR1R2, wherein R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety, to yield a compound of formula (I / a):(i) optionally, reducing the compound of formula (I / a) to yield a compound of formula (I / b):the compound of formula (I / a) and the compound of formula (I / b) representing the compound of formula (I); and(j) optionally purifying the resulting compound and / or optionally converting the resulting compound into its addition salts with a pharmaceutically acceptable acid or base and / or optionally separating the resulting compound into its isomers.

[0431] Embodiment 73. A process for the synthesis of a compound of formula (I), comprising the steps of:(a) reacting the compound of formula (VI)of embodiment 72, with an azide derivative to yield a compound of formula (XIV):(b) cyclizing the compound of formula (XIV) to yield a compound of formula (XV):(c) reacting the compound of formula (XV) with a compound of formula (X): X'R4' as defined above, to yield a compound of formula (XVI):the compound of formula (XV) and the compound of formula (XVI) representing a compound of formula (XVII):(d) reducing the compound of formula (XVII) to yield a compound of formula (I / c):(e) optionally further reducing the compound of formula (I / c) to yield a compound of formula (I / d):the compound of formula (I / c) and the compound of formula (I / d) representing a compound of(f) optionally reacting the compound of formula (I / e) with a compound of formula (XVIII): X''Rb, wherein X" is halogen and Rbis alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each ofwhich is unsubstituted or substituted, or C(O)Ra, C(O)ORb, or S(O)2Rb, to yield a compound of(g) optionally reacting the compound of formula (I / f) with a compound of formula (XIX): X"R2', wherein X" is halogen and R2' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted, or C(O)Ra, C(O)ORb, or S(O)2Rb, to yield a compound of formula; and(h) optionally purifying the resulting compound, and / or optionally converting the resulting compound into its addition salts with a pharmaceutically acceptable acid or base, and / or optionally separating the resulting compound into its isomers.

[0432] Embodiment 74. A process for the synthesis of a compound of formula (I):comprising:(a) esterifying a compound of formula (II):to generate a compound of formula (III):wherein ring A is aryl or a 5- or 6- membered heteroaryl, each of which is unsubstituted or substituted; each R3is 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)Rb, C(O)NHRbor S(O)2Rb; optionally wherein two adjacent R3groups, together with the carbon atoms to which they are bound, form an optionally fused cycloalkyl or heterocycloalkyl ring;- R4is hydrogen;- Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen; n is 0, 1, 2, 3, 4 or 5; andAik is an alkyl group;(b) subjecting the compound of formula (III) to a bromination reaction to yield a compound of formula (IV):(c) reacting the compound of formula (IV) with a compound of formula (V):to yield a compound of formula (VI):wherein- 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 bound form C(O); and- P is a protecting group;(d) deprotecting the compound of formula (VI) to generate a compound of formula (VII):(e) cyclizing the compound of formula (VII) to yield a compound of formula (VIII):(f) reacting the compound of formula (VIII) with a compound of formula RSO2LG or a compound of formula (RSCh^O, wherein R is alkyl or aryl, and LG is a leaving group, to yield a compound of formula (IX):(g) reacting the compound of formula (IX) with a compound of the formula R10N3, wherein R10is a metal cation or N+Alk4, wherein Aik is alkyl, to generate a compound of formula (X):(h) converting the compound of formula (X) to a compound of formula (I’):wherein R1and R2are each a hydrogen atom; and(i) optionally, converting the compound of formula (I’) to a compound of formula (I).EXAMPLES

[0433] Infrared spectra were recorded using a Fourier Bruker TENSOR 27 transform spectrometer in ATR mode.

[0434] The NMR spectra of the proton were recorded on Bruker DPX 400-B or on 400 MHz Bruker Avance III N spectrometers. Chemical displacements are expressed in ppm and are determined in relation to the TMS used as a reference. The abbreviations used are: s : singlet d : doublet br: broad dd : double doublet dt : tripled doublet t : triplet td : triplet doublet quad : quadruplet quint : quintuplet m : multiplet

[0435] Combinations of the above definitions are possible. For example: ddd signifies double double doublet.

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

[0437] Analytical UPLC-MS analyses were performed on a Waters Acquity H-Class UPLC system equipped with a PDA detector, a Waters 3100 mass detector and a CORTECS UPLC C18, 1.6 pm, 2.1 mm x 50 mm column.

[0438] HPLC checks were performed on Acquity UPLC BEH C18 1.7 pm 2.1 x 30 mm columns on HPLC 1200 Agilent with diode array detector (DAD).

[0439] Enantiomeric purity analyses are performed on a UPC2 (Waters).

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

[0441] Chromatography was performed with MERCK 60 silica gel (0.040-0.063 mm) or Interchim or Grace prepackaged silica columns.

[0442] The reverse phase separations were performed on Interchim FHP RP C18 15 pm 275 x 60 mm columns with UV detection.

[0443] Flash column chromatography was performed on Teledyne Isco CombiFlash Rf+ instrument equipped with RediSep Rf Gold Silica (20-40 pm) or RediSep Rf Gold® Reversed- phase C18 columns.

[0444] Filtration was carried out on GVHP type filters (0.22 pm) Millipore for organic phases and on Whatman GF / A cat. filters. No. 1820-070 for aqueous phases.EXAMPLE 1: Preparation of tc / 7-Biityl \-|( 1 S)-l -(hydroxy methyl )-3-sulfanyl- propyl] carbamate.

[0445] Methyl (2S)-4-[[(3 S)-4-methoxy-3-methyl-4-oxo-butyl]disulfanyl]-2-methyl-butanoate (15.0 g, 30.2 mmol) prepared as described by Olivier Busnel et al. in “Synthesis and evaluation of new co-borono-a-amino acids as rat liver arginase inhibitors”, Bioorganic & Medicinal Chemistry 13 (2005) 2373-2379, content of which is herein incorporated by reference, was dissolved in tetrahydrofuran (150 mL) and methanol (30 mL), and the solution was cooled to 0 °C in an ice bath. To this solution were added calcium chloride (6.68 g, 60.2 mmol) and sodium borohydride (6.84 g, 181 mmol) in three equal portions over 1 hour. The reaction was carried out at room temperature for 6 h with stirring. Upon completion, the reaction was quenched by addition of saturated aqueous ammonium chloride followed by 1 M aqueous HC1, to achieve an acidic pH, and extracted with methylene chloride. The combined organic phase was dried over MgSO4, filtered and concentrated. The resulting colorless oil was dissolved in methylene chloride (180 mL), and water (0.544 mL) and tri-butyl phosphine (7.54 mL, 30.2 mmol) were added, and the mixture was stirred at room temperature for Ih. Upon completion, the reaction was concentrated under reduced pressure. The crude product containing terLButyl-7V-[(lS)-l- (hydroxymethyl)-3-sulfanyl-propyl]carbamate was used directly in the next step, or it was purified by silica gel flash chromatography. 'H NMR (400 MHz, dmso-d6) 5: 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. an (589nM) = -24.29 (c = 0,010 g / mL, MeOH) at 28 °C.EXAMPLE 2: Preparation of tert-Butyl / V-[(lR)-l-(hydroxymethyl)-3-sulfanyl- propyl] carbamate.

[0446] terLButyl A-[(lR)-l-(hydroxymethyl)-3-sulfanyl-propyl]carbamate was prepared with the same process as used in EXAMPLE 1 starting from methyl (2R)-4-[[(3R)-4-methoxy-3- methyl-4-oxo-butyl]disulfanyl]-2-methyl-butanoate. 'H NMR (400 MHz, dmso-d6) 5: 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. an (589nM) = +24.93 (c = 0,010 g / mL, MeOH) at 28 °C.EXAMPLE 3: General Method A for preparing phenylthiazepanones.NBS, CCI4orP = nitrogen protecting groupX = halogenX = R = leaving groupEXAMPLE 4: Preparation of (2R,5S)-5-(aminomethyl)-2-[4-(3,5- difluorophenoxy)phenyl]-l,4-thiazepan-3-one, hydrochloride (compound 103).

[0447] (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-l,4-thiazepan-3-one, hydrochloride was prepared in accordance with the method A of EXAMPLE 3.Step 1dioxane

[0448] 3, 5 -Difluorophenol (31.6 g, 243.2 mmol., 1.2 equiv.), cesium carbonate (138.6g, 425.6 mmol., 2.1 equiv.), copper(I) iodide (3.85g, 20.2 mmol., 0.1 equiv.), A,A-dimethylglycine hydrochloride (5.6g, 40.5 mmol., 0.2 equiv.) and methyl-4-bromophenyl acetate (A-l, 46.4g, 202.6 mmol., 1.0 equiv.) were added to a round bottom flask equipped with a magnetic stir bar. Anhydrous dioxane (250 mL) was then added and the reaction was run at 130 °C for 18 h. The reaction mixture was cooled to rt, filtered, and concentrated under vacuum. The crude product was purified by silica flash column chromatography (0— >5% methanol / dichloromethane) to afford the desired product as a colorless oil.JH NMR (400 MHz, Chloroform-t / ) 5 7.37 - 7.29 (m, 2H), 7.08 - 7.00 (m, 2H), 6.67 - 6.28 (m, 3H), 3.74 (s, 3H), 3.66 (s, 2H). MS: [M+H]+: did not ionize under conditions used.

[0449] Methyl 2-(4-(3, 5 -difluorophenoxy )phenyl)acetate (A-2, 24.0 g, 86.3 mmol, 1.0 equiv.) was dissolved in carbon tetrachloride (750 mL). A-bromosuccinimide (30.7 g, 172.6 mmol, 2 equiv.) was added, followed by hydrogen bromide solution (33% in acetic acid, 3.1 mL, 17.3 mmol, 0.2 equiv.). The reaction mixture was then refluxed for 17 h. After cooling to room temperature (rt.), the reaction mixture was concentrated, diluted with hexane (500 mL) filtered and concentrated under reduced pressure to afford the alkyl bromide (A-3) as a dark orange oil. 'HNMR (400 MHz, Chloroforms / ) 5 7.60 (d, 2H), 7.05 (d, 1H), 6.74 - 6.43 (m, 3H), 5.39 (s, 1H), 3.84 (s, 3H).Step 2'.

[0450] Methyl 2-bromo-2-(4-(3,5-difluorophenoxy)phenyl)acetate (A-3, 86.3 mmol, 1.0 equiv.) was dissolved in anhydrous acetonitrile (287 mL), and the solution was cooled to 0 °C. The thiol fragment (A-4, 23.6 g, 103.5 mmol, 1.2 equiv., Example 1) was added, followed by7V,7V-diisopropylethylamine (18.0 mL, 103.5 mmol, 1.2 equiv.), and the reaction mixture was stirred at 0 °C for 10-15 min. The reaction mixture was then concentrated directly and purified by silica gel flash column chromatography to afford the desired coupling product as a yellow oil and as a mixture of diastereomers. 'HNMR (400 MHz, Chloroform-t / ) 5 7.59 - 7.44 (m, 2H), 7.11 - 6.97 (m, 2H), 6.67 - 6.45 (m, 3H), 4.72 (d, 1H), 4.64 (d, 1H), 3.78 (d, 3H), 3.65 (m, 4H), 2.71 - 2.51 (m, 2H), 1.95 - 1.67 (m, 2H), 1.46 (s, 9H). MS: [M+H]+: 498.2.Step 3 :

[0451] Methyl-2-(((S)-3-((tert-butoxycarbonyl)amino)-4-hydroxybutyl)thio)-2-(4-(3,5- difluorophenoxy) phenyl)acetate (A-5, 42.9 g, 86.3 mmol, 1.0 equiv.) was dissolved in di chloromethane (400 mL), and hydrogen chloride solution (4.0 M in 1,4-di oxane, 215 mL, 863 mmol, 10 equiv.) was added. Vigorous gas evolution started within a few minutes and continued for approximately 30 min. The reaction mixture was stirred at ambient temperature for a total of 2 h. Upon completion, the solvent and the excess HC1 were removed by rotary evaporation. The crude product was used directly without further purification.

[0452] The crude hydrochloride salt (assumed to be 86.3 mmol, 1.0 equiv.) was dissolved in methanol (1700 mL), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 51.5 mL, 345.3 mmol, 4.0 equiv.) was added, and the reaction mixture was refluxed for 18 h. Upon completion, the reaction mixture was concentrated to near dryness, poured into 1 M aqueous HC1 and extracted with dichloromethane three times. The crude was purified by silica gel flash column chromatography (0-10% Methanol / di chloromethane) to afford the product as a mixture of diastereomers (A-6 and A-6’) (approximately 7: 1 d.r.).JH NMR (400 MHz, Chloroform-t / ) 5 7.60 (d, 1H), 7.37 (d, 2H), 7.06 (d, 2H), 6.70 - 6.40 (m, 3H), 4.69 (s, 1H), 3.84 - 3.71 (m, 1H), 3.70 - 3.58 (m, 2H), 3.18 (m, 1H), 3.04 (m, 1H), 2.94 (s, 2H), 2.00 (m, 1H), 1.80 (m, 1H). MS: [M+H]+: 366.1. The major diasteromer A-6 is shown in the above scheme. Compound A-6’ is shown below.

[0453] (2R,5S)-2-(4-(3,5-difluorophenoxy)phenyl)-5-(hydroxymethyl)-l,4-thiazepan-3-one (A-6, 21.78 g, 59.6 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (300 mL). The solution was cooled to 0 °C in an ice bath, and the following reagents were added sequentially: 4- dimethylaminepyridine (catalytic amount), triethylamine (10.0 mL, 71.5 mmol, 1.2 equiv.) and methanesulfonyl chloride (5.0 mL, 65.5 mmol, 1.1 equiv.). The reaction mixture was then stirred at 0 °C temperature for 30 min. Upon completion, the reaction mixture was poured into water and extracted with dichloromethane twice. The combined organic phase was dried over sodium sulfate, filtered and concentrated to afford the crude mesylate as a light yellow solid, which was taken forward without further purification.

[0454] ((2R,5S)-2-(4-(3,5-difluorophenoxy)phenyl)-3-oxo-l,4-thiazepan-5-yl)methyl methanesulfonate (assumed to be 59.6 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (125 mL). Tetrabutylammonium azide (18.65 g, 65.5 mmol, 1.1 equiv.) was then added and the reaction mixture was stirred at room temperature for 22 h. Upon completion, tetrahydrofuran was removed by rotary evaporation. The remaining oil was dissolved in ethyl acetate and washed with saturated aqueous ammonium chloride, water, and brine. The organic phase was then dried over sodium sulfate, filtered, and concentrated to afford the crude azide as a white solid, which was taken forward without further purification.

[0455] (2R, 5 S)-5 -(azidomethyl)-2-(4-(3 , 5 -difluorophenoxy )phenyl)- 1 ,4-thiazepan-3 -one (assumed to be 59.6 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (200 mL) and water (28 mL), and the solution was cooled to 0 °C in an ice bath. Triphenyl phosphine (20.3 g, 77.4 mmol, 1.3 equiv.) was added, and the reaction mixture was stirred at 23 °C for 1 h and at 40 °C for 15 h. Upon completion, tetrahydrofuran was removed by rotary evaporation, and the remaining oil was purified by silica gel chromatography (0-7% methanol / dichloromethane) toobtain the free amine as a white solid. This purification step separated the diastereomers, and the major cis product was taken forward. The pure cis amine was purified by Cl 8 reversed phase chromatography (water / acetonitrile with 0.1% formic acid mobile phase) to give the compound 1 as a white amorphous solid.

[0456] Free base: 'HNMR (400 MHz, DMSO-tL) 8 7.46 - 7.33 (m, 2H), 7.24 (d, 1H), 7.13 - 7.04 (m, 2H), 7.01 (tt, 1H), 6.77 - 6.65 (m, 2H), 5.03 (s, 1H), 3.66 (m, 1H), 3.20 (m, 1H), 2.89 (m, 1H), 2.65 (m, 2H), 2.12 - 1.95 (m, 1H), 1.46 (m, 1H). MS: [M+H]+: 365.1.Alternative Synthesis of Amine from Alcohol:A-6 1 (HCI)

[0457] A solution of (2R, 5 S)-2-(4-(3, 5 -difluorophenoxy)phenyl)-5 -(hydroxymethyl)- 1,4- thiazepan-3-one (A-6, 508 g, 1.39 mmol, 1.0 equiv.), B0C2NH (604 mg, 2.78 mmol, 2.0 equiv.), triphenylphosphine (548 mg, 2.09 mmol, 1.5 equiv.) were dissolved in anhydrous toluene (7 mL) under Ar, and the solution was cooled to 0 °C. DEAD solution (40 wt% in toluene, 948 pL, 2.09 mmol, 1.5 equiv.) was added dropwise, and the reaction was allowed to reach room temperature (r.t.) slowly and stirred over 3 days. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (0^40% hexane / ethyl acetate), followed by reverse phase (Cl 8) to obtain tert-butyl (tert- butoxycarbonyl)(((2R,5S)-2-(4-(3,5-difluorophenoxy)phenyl)-3-oxo-l,4-thiazepan-5- yl)methyl)carbamate. MS: [M+H]+: 565.4.

[0458] Tert-Butyl (tert-butoxycarbonyl)(((2R,5S)-2-(4-(3,5-difluorophenoxy)phenyl)-3-oxo- l,4-thiazepan-5-yl)methyl)carbamate (158 mg, 0.28 mmol, 1.0 equiv.) was dissolved in 1 mL of dichloromethane and hydrogen chloride solution (4.0 M in 1,4-dioxane, 1 mL, 4.0 mmol, 14 equiv.) was then added. The reaction mixture was stirred at ambient temperature for 1 h. Upon completion, the reaction mixture was diluted with diethyl ether, and the precipitated compound 1 (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-l,4-thiazepan-3-one hydrochloride was filtered off and dried.

[0459] Hydrochloride salt: 'HNMR (400 MHz, DMSO-t / 6) 6 8.12 (br s, 3H), 7.43 (d, 1H), 7.41 - 7.35 (m, 2H), 7.12 - 7.06 (m, 2H), 7.02 (tt, 1H), 6.77 - 6.69 (m, 2H), 5.12 (s, 1H), 4.16 (m, 1H), 3.19 (ddd, 1H), 3.12 - 2.81 (m, 3H), 2.10 - 1.94 (m, 1H), 1.66 - 1.45 (m, 1H). MS: [M+H]+: 365.2.

[0460] The following compounds in TABLE 1 were made in an analogous manner as Method A described above.TABLE 1EXAMPLE 5: General Method D.X= leaving groupEXAMPLE 6: Preparation of (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2- ylamino)methyl]-l,4-thiazepan-3-one (compound 129).

[0461] The compound 129 was prepared in accordance with Method A, followed by Method129

[0462] (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one hydrochloride (180 mg, 0.493 mmol, 1.0 equiv.), 2-chloropyrimidine (113 mg, 0.987 mmol, 2.0 equiv.) and DIPEA (215 pL, 1.23 mmol, 2.5 equiv.) were dissolved in ethanol (95%, 2 mL) in a microwave reaction vial. The reaction was run at 80 °C under microwave irradiation for 17h. Upon cooling to r.t., the product precipitated out of the reaction mixture as a white solid. The solid was collected by filtration, washed with diethyl ether and dried under vacuum to afford compound 129 (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one.JH NMR (400 MHz, DMSO-t / 6) 8 8.30 (d, 2H), 7.44 - 7.35 (m, 3H), 7.38 - 7.27 (m, 2H), 7.23 (t, 1H), 7.13 (td, 1H), 7.04 - 6.96 (m, 2H), 6.96 - 6.87 (m, 2H), 6.61 (t, 1H), 4.95 (s, 1H), 3.92 (t, 1H), 3.45 (tt, 2H), 3.26 - 3.15 (m, 1H), 2.88 (dt, 1H), 2.10 (d, 1H), 1.48 (q, 1H). MS: [M+H]+: 407.2.

[0463] The following compounds in TABLE 2 were made using Method A followed by Method D.TABLE 2EXAMPLE 7: General Method E.EXAMPLE 8: Preparation of N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4- thiazepan-5-yl]methyl]-l-methyl-imidazole-4-carboxamide (compound 137).

[0464] The compound 137 was prepared in accordance with Method A, followed by Method E:

[0465] To a solution of (2R,5S)-2-(4-(3,5-difhiorophenoxy)phenyl)-5-(hydroxymethyl)-l,4- thiazepan-3-one (587 mg, 1.61 mmol, 1.0 equiv.) in tetrahydrofuran (11 mL) cooled to 0 °C in an ice bath, were added: 4-dimethylaminepyridine (DMAP, catalytic amount), triethylamine (TEA, 290 pL, 2.09 mmol, 1.3 equiv.) and methanesulfonyl chloride (MsCI, 149 pL, 1.93 mmol, 1.2 equiv.). The reaction was then stirred at 0 °C temperature for approximately 1 hour, then diluted with water and extracted twice with dichloromethane. The combined organic phase was dried over sodium sulfate, filtered and concentrated to afford the crude mesylate, which was taken forward without further purification.

[0466] The crude from the first step was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium azide (nBu4NNs, 549 mg, 1.93 mmol, 1.2 equiv.) was added and the reaction was stirred at room temperature until completion. The tetrahydrofuran was removed by rotary evaporation and the remaining oil was dissolved in ethyl acetate and washed with saturated aqueous ammonium chloride, water and brine. The organic phase was then dried over sodium sulfate, filtered and concentrated to give the crude azide, which was taken forward without further purification.

[0467] The crude azide was dissolved in tetrahydrofuran (9 mL) and water (1.5 mL), the solution was cooled to 0 °C in an ice bath, triphenyl phosphine (PPhs, 548 mg, 2.09 mmol, 1.3 equiv.) was added, and the reaction was stirred at room temperature. Upon completion, tetrahydrofuran was removed by rotary evaporation, and the remaining oil was purified by silica gel chromatography (0-10% methanol / di chloromethane) to obtain the free amine as a white solid.

[0468] The amine was dissolved in DMF (5mL) and to this solution were added 3- methylimidazole-4-carboxylic acid (243 mg, 1.93 mmol, 1.2 equiv.), EDC-HC1 (370 mg, 1.93 mmol, 1.2 equiv.) and HOBt-TEO (25 mg, 0.16 mmol, 0.1 equiv.). The crude product was purified by reverse phase chromatography (Cl 8), followed by trituration with diethyl ether, to afford the target compound 137. 'H NMR (400 MHz, DMSO-t / 6) 8 8.31 (t, 1H), 7.72 - 7.62 (m, 2H), 7.59 (d, 1H), 7.41 - 7.31 (m, 2H), 7.08 - 6.94 (m, 3H), 6.74 - 6.62 (m, 2H), 5.00 (s, 1H), 3.91 (m, 1H), 3.68 (s, 3H), 3.52 (ddd, 1H), 3.29 - 3.13 (m, 2H), 2.88 (dt, 1H), 2.07 (m, 1H), 1.45 (m, 1H).MS: [M+H]+: 473.12

[0469] The following compounds in TABLE 3 were made using Method A, followed byMethod E.TABLE 3EXAMPLE 9: General Method F.EXAMPLE 10: Synthesis of (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2- ylmethylamino)methyl]-l,4-thiazepan-3-one, hydrochloride (compound 226)

[0470] (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-l,4-thiazepan-3- one, hydrochloride was prepared in accordance with Method A, followed by Method F:226

[0471] (2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one hydrochloride (347 mg, 0.951 mmol, 1.0 equiv.) and pyrimidine-2-carbaldehyde (123 mg, 1.14 mmol, 1.2 equiv.) were suspended in CH2Q2 (9 mL). Sodium triacetoxyborohydride (403 mg, 1.90 mmol, 2.0 equiv.) was added, and the reaction was stirred at r.t. for 1.5 h. The reaction was quenched with methanol (10 mL). After gas evolution ceased, the quenched reaction mixture was concentrated and purified by reversed phase Cis silica chromatography (150 g Cis silica, 10— >100% acetonitrile / water gradient). The free amine product was taken up in a small volume of methanol, and the solution was acidified with concentrated HC1. The mixture was concentrated to dryness.

[0472] The product hydrochloride salt was triturated with diethyl ether to obtain the (2R,5S)-2- (4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-l,4-thiazepan-3-one hydrochloride (compound 226) as a white solid. 'H NMR (400 MHz, DMSO-tL) 8 9.47 (s, 2H), 8.91 (d, 2H), 7.58 (t, 1H), 7.48 (d, 1H), 7.45 - 7.35 (m, 2H), 7.39 - 7.30 (m, 2H), 7.19 - 7.10 (m, 1H), 7.05 - 6.97 (m, 2H), 6.99 - 6.91 (m, 2H), 5.13 (s, 1H), 4.56 (d, 1H), 4.49 (d, 1H), 4.41 - 4.34 (m, 1H), 3.40 - 3.25 (m, 1H), 3.19 (ddd, 1H), 2.92 (ddd, 1H), 1.60 (q, 1H). MS: [M+H]+: 421.3.

[0473] The following compounds in TABLE 4 were made using Method A followed by Method F.TABLE 4EXAMPLE 11: General Method G.Y= halogenEXAMPLE 12: Preparation of (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2- trifluoroethylamino)methyl]-l,4-thiazepan-3-one (compound 243)

[0474] (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3- one was prepared in accordance with Method A, followed by Method G:

[0475] (2R,5S)-5-(Aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one hydrochloride (144 mg, 0.395 mmol, 1.0 equiv.) was suspended in a mixture of CH2CI2 / THF / DMF (4:4: 1, 4.5 mL). DIPEA (193 pL, 1.11 mmol, 2.8 equiv.) was added followed by trifluoroethyl tritiate (171 pL, 1.19 mmol, 3.0 equiv.), and the reaction was stirred at r.t. for 19 h then at 40 °C for 18 h. The reaction was concentrated and purified by reversed phase Cis silica chromatography (150 g Cis silica, 10— >100% acetonitrile / water gradient). The free amine product was taken up in a small volume of methanol, and the solution was acidified with concentrated HC1. The mixture was concentrated to dryness. (2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2- trifluoroethylamino)methyl]-l,4-thiazepan-3-one hydrochloride (compound 243) was triturated with diethyl ether to obtain as a white solid.'HNMR (400 MHz, DMSO-t / e) 8 7.44 - 7.35 (m, 2H), 7.39 - 7.29 (m, 2H), 7.29 - 7.23 (m, 1H), 7.19 - 7.10 (m, 1H), 7.05 - 6.98 (m, 2H), 6.98 - 6.90 (m, 2H), 5.06 (s, 1H), 4.00 (s, 1H), 3.23 - 3.11 (m, 1H), 2.89 (m, 3H), 2.02 (m, 1H), 1.49 (m, 1H). MS: [M+H]+: 411.3.

[0476] The following compounds in TABLE 5 were made using Method A followed by Method G.TABLE 5EXAMPLE 13: General Method H.EXAMPLE 14: Synthesis of (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,l- dioxo-l,4-thiazepan-3-one, hydrochloride (compound 254).

[0477] (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,l-dioxo-l,4-thiazepan-3-one, hydrochloride was prepared in accordance with Method A, followed by Method H:

[0478] (2R,5S)-5-(Aminomethyl)-2-(4'-chloro-[l,r-biphenyl]-3-yl)-l,4-thiazepan-3-one hydrochloride (166 mg, 0.431 mmol, 1.0 equiv.) was dissolved in a mixture of methanol / water (8:1, 4.5 mL). mCPBA (77%, 251 mg, 1.12 mmol, 2.6 equiv.) was added, and the reaction was stirred at r.t. for 2 h. The reaction was concentrated and purified by reversed phase Cis silica chromatography (150 g Cis silica, 10—400% acetonitrile / water gradient). The free amine product was taken up in a small volume of methanol, and the solution was acidified with concentrated HC1. The mixture was concentrated to dryness. The product hydrochloride salt was triturated with diethyl ether to obtain (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]- l,l-dioxo-l,4-thiazepan-3-one hydrochloride (compound 254) as a white solid. *HNMR (400 MHz, DMSO ) 8 8.02 (d, 1H), 7.71 (m, 2H), 7.67 - 7.61 (m, 2H), 7.62 - 7.54 (m, 2H), 7.54 -7.42 (m, 2H), 6.15 (s, 1H), 4.30 (m, 1H), 3.94 - 3.78 (m, 1H), 3.60 (m, 1H), 3.09 (m, 2H), 2.21 (m, 1H), 2.05 (m, 1H). MS: [M+H]+: 379.1.

[0479] The compound 255 in TABLE 6 was made using Method A foll...

Claims

CLAIMSWhat is claimed is:

1. A compound of F ormula (I) :wherein ring A 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 CH2or C(O);Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen;R' and R" are each hydrogen, or together with the carbon atom to which R' and R" are bound form C(O);R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety; each R3is 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)Rb, C(O)NHRbor S(O)2Rb; or two adjacent R3groups, together with the carbon atoms to which they are bound, form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; R4is alkyl that is unsubstituted or substituted, or hydrogen;Rais alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl, each of which is unsubstituted or substituted, or hydroxy, carboxy, or NHRC, wherein Rcis alkyl, aryl,heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen;Rbis alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen; and n is 0, 1, 2, 3, 4 or 5; or a pharmaceutically-acceptable salt thereof.

2. The compound of claim 1, wherein X is sulphur.

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

4. The compound of claim 1, wherein the compound is of formula (Ia):The compound of claim 4, wherein Z is hydrogen.The compound of claim 1, wherein the compound is of formula (lb):The compound of claim 1, wherein n is 1.The compound of claim 1, wherein R' and R" are each hydrogen.

9. The compound of claim 1, wherein R1and R2are each hydrogen.

10. The compound of claim 1, wherein R1is hydrogen.

11. The compound of claim 1, wherein R1is methyl.

12. The compound of claim 1, wherein R2is hydrogen.

13. The compound of claim 1, wherein R2is alkyl.

14. The compound of claim 1, wherein R2is C(O)Ra.

15. The compound of claim 1, wherein R2is C(O)Ra, wherein Rais aryl or heteroaryl, each of which is substituted or unsubstituted.

16. The compound of claim 1, wherein R2is C(O)Ra, wherein Rais pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridazinyl, triazolyl, oxadiazolyl, or pyrazinyl, each of which is substituted or unsubstituted.

17. The compound of claim 1, wherein R2is C(O)Ra, wherein Rais pyrimidin-2-yl, pyrimidin-5-yl, 5-amino-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, lJT-pyrazol-3-yl, 2-methyl-lJT- pyrazole-3-yl, pyridin-2-yl, 2-chloro-pyridin-2-yl, 6-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl,6-hydroxy-pyridin-2-yl, pyridin-3-yl, 6-amino-pyri din-3 -yl, 2-chloro-pyridin-3-yl, pyridin-4-yl, 3-phenyl-17 / -pyrazol-5-yl, lJ / -imidazol-4-yl, lJ / -imidazol-2-yl, 1 -methyl- IJT-imidazol -4-yl, 1- methyl-lJT-imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, 4-methyl-l,2,3-thiadiazol-5-yl, 5- phenylisoxazol-3-yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5-methyl-3-phenylisoxazol-4-yl, 4- phenylthiazol-2-yl, lJT-tetrazol-5-yl, pyridazin-2-yl, pyridazin-3-yl,pyridazin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, 3 -hydroxy -pyrazinyl, 4-isopropyl-l,2,3-thiadiazolyl, 3-methyl- isoxazole-5-yl, 4,4-difluoro-piperidin-l-yl, l,2,4-triazin-3-yl, 4-methylpyrid-2-ylamino, 3- oxopiperazin-l-yl, 5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl, or piperazin- 1-yl.

18. The compound of claim 1, wherein R1and R2are each independently hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3 -hydroxy cyclobutyl, 3, 3 -difluorocyclobutyl,cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, pyrimidin-2-yl, pyrimidin-2-ylmethyl, pyrimidin-3-ylmethyl, pyrimidin-4-ylmethyl, oxalyl, 2-methoxy ethyl, benzyl, 4-carboxybenzyl, 4-carboxymethylbenzyl, tetrahydro-2 / / -pyran-4-yl, oxetan-3-yl, 1,2,4- thiadiazol-5-yl, 4-aminom ethyl- 1,2, 3 -triazol- 1-ylmethyl, 4-methyl-l,2,3-thiadiazolyl-5-ylmethyl, benzo[d]thiazol-2-yl, 4-carboxylethyl-l,2,3-thiadiazolyl-5-ylmethyl, 4-carboxy- 1,2,3- thiadiazolyl-5-ylmethyl, isoindoline- 1, 3-dion-2-yl, and acetyl; or wherein Ri and R2 together with the nitrogen atom to which they are bound form an optionally substituted heterocycle or heteroaryl selected from the group consisting of pyrazolidinonyl, piperazinyl, 2-oxopiperazinyl, triazolyl, benzotri azolyl, morpholinyl, pyrrolidinyl, or piperidinyl.

19. The compound of claim 1, wherein R3is alkoxy, cycloalkyloxy, or aryloxy, each of which is substituted or unsubstituted, or halogen.

20. The compound of claim 1, wherein R3is phenyloxy, which is substituted or unsubstituted.

21. The compound of claim 1, wherein R3is substituted by one or two substituents selected from the group consisting of hydroxy, fluorine, chlorine, bromine, iodide, CF3, CHF2, methoxy, SChMe, cyano, and C(O)Me.

22. The compound of claim 1, wherein R3is independently at each occurrence alkyl, cyclohexyl, alkyloxy, cycloalkyloxy, arylsulfonyl, alkyl sulfonyl, phenyl, phenoxy, benzo[d][l,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. The compound of claim 1, wherein R4is hydrogen.

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

25. A compound that is:(2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-bromophenyl)-l,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4-phenylphenyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-bromophenyl)-5-(dimethylaminomethyl)-l,4-thiazepan-3-one;(25.55)-5-(aminomethyl)-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-2-(4-bromophenyl)-5-(morpholinomethyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-bromophenyl)-5-(morpholinomethyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(3 -bromophenyl)- l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(3 -phenoxyphenyl)- l,4-thiazepan-3 -one;(2S,5R)-5-[(4-benzyl-l-piperidyl)methyl]-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-[(4-benzyl- 1 -piperidyl)methyl]-2-(4-bromophenyl)- 1 ,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-(2 -bromophenyl)- l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-methoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(trifluoromethyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-benzyloxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(trifluoromethyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-phenylphenyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(2-chlorophenyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl]- 1 ,4-thiazepan-3 -one;(25.55)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenoxy)phenyl]-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R, 5R)-5 -(aminomethyl)-2-(3 -phenoxyphenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(dimethylaminomethyl)-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2,2,2-trifluoroethoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,2,2-trifluoroethoxy)phenyl]-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -[3 -(trifluoromethyl)- lH-pyrazol-4-yl]phenyl]- 1 ,4- thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-iodophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(3-chlorophenyl)phenyl]-l,4-thiazepan-3-one;3-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;3-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;4-[3-[(2S,5R)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;4-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzonitrile;(2S,5R)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,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]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(3-pyridyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-pyridyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(3,4-dimethoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(l,3-benzodioxol-5-yl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(l,3-benzodioxol-5-yl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-bromo-5-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-naphthyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(l -naphthyl)- l,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(benzenesulfonyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-(2-methoxyphenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(o-tolyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -( 1 -ethylpropyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-[2-(trifluoromethyl)phenyl]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)phenyl]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenyl]phenyl]-l,4-thiazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(3-amino-4-chloro-phenyl)phenyl]-5-(aminomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,4-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-chloro-3-iodo-phenyl)phenyl]-l,4-thiazepan-3-one;N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzamide;N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2- yl]phenyl]cyclohexanecarboxamide;(2R,5S)-5-(aminomethyl)-2-[3-(4-fluorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(3-cyclohexylphenyl)-l,4-thiazepan-3-one;3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]-N-phenyl-benzamide;(2R,5S)-5-(aminomethyl)-2-[3-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-l,4-thiazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4- thiazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4- thiazepan-3-one;(2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4- thiazepan-3-one;N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]phenyl]acetamide;(2R, 5 S)-2- [3 -(4-chlorophenyl)phenyl]-5 -[(4,4-difluoro- 1 -piperidyl)methyl]- 1 ,4- thiazepan-3-one;(2R, 5 S)-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]-l,4-thiazepan-3-one;2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzoic acid;2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]benzamide;(2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxyphenyl)phenyl]-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;(2R,5R)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one;2-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]phenoxy]acetic acid;(2R, 5 S)-5-(aminomethyl)-2-[3 -(2-oxopyrrolidin- 1 -yl)phenyl]- 1 ,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(2-oxo- 1 -pyridyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R, 5 S)-5-(aminomethyl)-2-[3 -[(2S)-2-(hydroxymethyl)pyrrolidin- 1 -yl]phenyl]- 1 ,4- thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(4-hydroxy- 1 -piperidyl)phenyl]- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-[3-(2,2-dimethylpropoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-(((3R,5R,7R)-adamantan-l-yl)methoxy)phenyl)-5-(aminomethyl)-l,4- thiazepan-3-one;(2R,5S)-2-(3-(((lR,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-5-(aminomethyl)-l,4- thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(cyclohexoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(l-isopropyl-2-methyl-propoxy)phenyl]-l,4-thiazepan-3- one;(2R,5S)-5-(aminomethyl)-2-[3-(2-hydroxy-2-methyl-propoxy)phenyl]-l,4-thiazepan-3- one;(2R,5S)-5-(aminomethyl)-2-[4-(2-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-methoxyphenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(4-phenoxy-3 -propyl-phenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-(3-chloro-4-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(4-indol-l-ylphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2-methoxyphenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(2,4-dichlorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[3-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[2-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-fluorophenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-l,4-thiazepan-3- one;4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]benzonitrile;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(methylaminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(cyclohexoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-(2-methyl-4-phenoxy -phenyl)-!, 4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-dibenzofuran-2-yl-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-methylsulfonylphenoxy)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)phenyl]-l,4-thiazepan-3-one;2-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]benzonitrile;(2R,5S)-2-[4-(4-acetylphenoxy)phenyl]-5-(aminomethyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(l,3-benzodioxol-5-yloxy)phenyl]-l,4-thiazepan-3-one;3-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]-5-chloro-benzonitrile;(2R,5S)-5-(aminomethyl)-2-(4-anilinophenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-(2-chloro-4-phenoxy-phenyl)-l,4-thiazepan-3-one;4-[4-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenoxy]-3-chloro-benzonitrile;(2R,5S)-5-(aminomethyl)-2-(2-methoxy-4-phenoxy-phenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[4-(4-chlorophenoxy)-2-methoxy-phenyl]-l,4-thiazepan-3- one;(2R,5S)-2-(4-phenoxyphenyl)-5-(triazol-l-ylmethyl)-l,4-thiazepan-3-one;(2R,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5S)-5-(aminomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-(morpholinomethyl)-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-[[4-(aminomethyl)triazol- 1 -yl]methyl]-2-[4-(4-fluorophenoxy)phenyl]- 1 ,4- thiazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-5-[(pyrimidin-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-l,4- thiazepan-3-one;(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan- 3 -one;(2R,5S)-5-[(l,3-benzothiazol-2-ylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3- one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(l,2,4-thiadiazol-5-ylamino)methyl]-l,4-thiazepan-3- one;N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l- methy 1 -imi dazol e-4-carb oxami de;2-oxo-2-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methylamino]acetate;N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiazole-2- carboxamide;4-(aminomethyl)-N-[[(2R,5S)-2-(3-bromophenyl)-3-oxo-l,4-thiazepan-5- yl]methyl]benzamide;N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-2H-tetrazole-5- carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine- 2-carboxamide;N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]thiazole-4- carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-4-methyl- thi adi azol e- 5 -carb oxami de;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH- pyrazole-3 -carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-5-carboxamide;6-amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-3-carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]thiazole-2- carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-5-phenyl-isoxazole-3- carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-5-methyl-3-phenyl- isoxazole-4-carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-4-phenyl-thiazole-2- carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-3-phenyl-lH- py razol e- 5 -carb oxami de;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;1-methyl-N-[[(2S,5R)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]imidazole-4-carboxamide;4-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiadiazole-5-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-5- carb oxami de6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-3- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]methanesulfonamide4-isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- y 1 ] methyl ] thi adi azol e- 5 -carb oxami de ;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-lH-imidazole-4- carboxamide;2-morpholino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]acetamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-lH-pyrazole-3- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]morpholine-4- sulfonamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridazine-3- carboxamide;5-isopropyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- y 1 ] methyl ] thi adi azol e-4-carb oxami de ;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine- 2-carboxamide;N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-3- sulfonamide;4-fluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]benzenesulfonamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- sulfonamide; l-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]imidazole-4-sulfonamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]thiazole-2- carboxamide;3.3-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]cyclobutanecarboxamide;4.4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]cyclohexanecarboxamide;N-[[(2R,5S)-2-[3-(2-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-(((2R,5S)-2-(3-(((lR,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-l,4-thiazepan-5- yl)methyl)pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]-2-pyrimidin-2-yl- acetamide; l-benzyl-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]urea;3-methyl-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]isoxazole-5-carboxamide;N-[[(2R,5S)-2-[3-(cyclohexoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;4,4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]piperidine-l -carboxamide;N-[[(2R,5 S)-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-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrazine-2- carboxamide;6-chloro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- carboxamide;2-[5-(4-chlorophenyl)isoxazol-3-yl]-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4- thiazepan-5-yl]methyl]acetamide;6-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine-2- carboxamide;5-amino-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide;5-methoxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide; l-(4-methyl-2-pyridyl)-3-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]ureaN-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH- pyrazole-3 -carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-2- morpholino-acetamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH- pyrazole-3 -carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridazine-3 -carboxamide;6-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-3-carboxamide;6-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-3-carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridazine-3 -carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-2- morpholino-acetamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-2- sulfonamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-2- sulfonamide;2-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]benzamide;4-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5- yl]methyl]benzamide;(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-5-[(l,2,4-thiadiazol-5-ylamino)methyl]-l,4- thiazepan-3-one;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2-carboxamide;5-amino-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;5-chloro-N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyridine-2-carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-5- methoxy-pyrimidine-2-carboxamide;5-amino-N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-5- methoxy-pyrimidine-2-carboxamide;3-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyrazine-2-carboxamide;3-hydroxy-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-l,4-thiazepan-5-yl]methyl]pyridine- 2-carboxamide;N-[[(2S,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2S,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;N-[[(2R,5R)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide;5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-l,4-thiazepan-5- yl]methyl]-l,3,4-oxadiazole-2-carboxamide;N-[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-5-(4-fluorophenyl)- l,3,4-oxadiazole-2-carboxamide;N-[[(2R,5 S)-3 -oxo-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-5 -yl]methyl]piperazine- 1 - carboxamide;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-l,4-thiazepan-3- one; methyl 4-[[[(2R,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5- yl]methylamino]methyl]benzoate;(2R,5S)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2S,5R)-5-[(benzylamino)methyl]-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;4-[[[(2R,5S)-3-oxo-2-(3-phenoxyphenyl)-l,4-thiazepan-5- yl]methylamino]methyl]benzoic acid;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(cyclopropylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-5-[(cyclopropylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[(cyclobutylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(tetrahydropyran-4-ylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-5-[(oxetan-3-ylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-[[bis(oxetan-3-yl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-5-((((lr,3S)-3-hydroxycyclobutyl)amino)methyl)-2-(4-phenoxyphenyl)-l,4- thiazepan-3-one;(2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3- one;(2R,5S)-5-[[(3,3-difluorocyclobutyl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan- 3 -one;(2R,5S)-5-[[(4-methylthiadiazol-5-yl)methylamino]methyl]-2-(4-phenoxyphenyl)-l,4- thiazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-4-ylmethylamino)methyl]-l,4-thiazepan-3- one;4-[[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methylamino]methyl]benzoic acid;4- [[ [(2R, 5 S)-2- [3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 - yl]methylamino]methyl]benzoic acid;(2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-(3-bromophenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R,5S)-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3-one;(2R,5S)-2-[3-(2-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R,5S)-2-[3-(2,4-dichlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R,5S)-5-[(2,2,2-trifluoroethylamino)methyl]-2-[3-[2-(trifluoromethyl)phenyl]phenyl]- l,4-thiazepan-3-one;(2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R, 5 S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2 -methoxy ethylamino)methyl]- 1,4-thiazepan-3 -one;(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl]- 1 , 1 -di oxo- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-l,l-dioxo-2-(3-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5S)-l,l-dioxo-2-(3-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one;(2R, 5 S)-5-[(2-oxopiperazin- 1 -yl)methyl]-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3 -one;(25.55)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(4-methoxyphenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(25.55)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-l,4-oxazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-(methylaminomethyl)-l,4-oxazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-(dimethylaminomethyl)-l,4-oxazepan-3-one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-l,4-oxazepan-3- one;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyrimidine- 2-carboxamide;6-amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5- yl]methyl]pyridine-3-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-2- carboxamide;6-chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5- yl]methyl]pyridine-2-carboxamide;2-chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5- yl]methyl]pyridine-3-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]-l-methyl- imidazole-2-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]-l-methyl- imidazole-4-carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-3- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-4- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridazine-3- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridazine-4- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]thiazole-4- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]thiazole-2- carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyrazine-2- carboxamide;(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2 trifluoroethyl amino) methyl]-l,4- oxazepan-3-one;(2R,5S)-2-(4-phenoxyphenyl)-5-(piperazine-l-carbonyl)-l,4-thiazepan-3-one;(2R, 5 S)-5-(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl]-2-methyl- 1 ,4-oxazepan-3 -one;(2R, 5 S)-5-(benzotriazol- 1 -ylmethyl)-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3 -one;(2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(S)-5-(aminomethyl)-2,2-diphenyl-l,4-thiazepan-3-one; or(2R, 5 S)-5-[(3 -oxopiperazin- 1 -yl)methyl]-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3 -one; or an enantiomer, diastereoisomer, pharmaceutically-acceptable salt, or a deuterated derivative thereof.

26. A compound that is: (2R,5S)-5-(aminomethyl)-2-[4-(3,5-difluorophenoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(25.55)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;(25.55)-5-(aminomethyl)-2-(3-phenoxyphenyl)-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]thiazole-2- carboxamide, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(3-phenylphenyl)-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;N-[[(2R,5S)-2-[4-(3,5-difluorophenoxy)phenyl]-3-oxo-l,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-l,4-thiazepan-5-yl]methyl]-l- methyl-imidazole-4-carboxamide, or a pharmaceutically-acceptable salt thereof;N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-l,4-thiazepan-5- yl]methyl]pyrimidine-2-carboxamide, or a pharmaceutically-acceptable salt thereof; N-[[(2R, 5 S)-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-(((lR,3S,5R,7R)-adamantan-2-yl)oxy)phenyl)-3-oxo-l,4-thiazepan-5- yl)methyl)pyrimidine-2-carboxamide, or a pharmaceutically-acceptable salt thereof; (2R,5 S)-2-(4-phenoxyphenyl)-5-(piperazine- 1 -carbonyl)- 1 ,4-thiazepan-3 -one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-ylmethylamino)methyl]-l,4-thiazepan-3- one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4- thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(4-phenoxyphenyl)-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3- one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,l-dioxo-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-[(2-oxopiperazin-l-yl)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-2-(3-(((3R,5R,7R)-adamantan-l-yl)methoxy)phenyl)-5-(aminomethyl)-l,4- thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2-methyl-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof; or (S)-5-(aminomethyl)-2,2-diphenyl-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

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

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

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

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

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

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

34. A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I):wherein ring A 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 CH2or C(O);Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen;R' and R" are each hydrogen or together with the carbon atom to which R' and R" are bound form C(O);R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety; each R3is 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)Rb, C(O)NHRbor S(O)2Rb; or two adjacent R3groups, together with the carbon atoms to which they are bound, form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted;R4is alkyl that is unsubstituted or substituted, or hydrogen;Rais alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl, each of which is unsubstituted or substituted, or hydroxy, carboxy, or NHRC, wherein Rcis alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen;Rbis alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen; and n is 0, 1, 2, 3, 4 or 5; or a pharmaceutically-acceptable salt thereof.

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

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

37. The method of claim 34, wherein the condition is catecholaminergic polymorphic ventricular tachycardia.

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

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

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

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

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

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

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

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

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

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

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

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

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

51. The method of claim 48, wherein the treating decreases calcium leak from a RyRl channel in the subject.

52. The method of claim 48, wherein the treating decreases calcium leak from a RyR2 channel in the subject.

53. The method of claim 34, wherein the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

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

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

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

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

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

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

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

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

62. The method of claim 34, wherein the condition is Duchenne Muscular Dystrophy.

63. The method of claim 62, wherein the subject is an ambulatory.

64. The method of claim 62, wherein the subject is non-ambulatory.

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

66. The method of claim 62, wherein the treating improves cardiac muscle function in the subject.

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

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

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

70. The method of claim 34, wherein the treating decreases calcium leak from a RyRl channel of the subj ect.

71. The method of claim 34, wherein the treating decreases calcium leak from a RyR2 channel of the subj ect.

72. The method of claim 34, wherein the treating decreases open probability (Po) of RyRl protein in the subject.

73. The method of claim 34, wherein the treating decreases open probability (Po) of RyR2 protein in the subject.

74. The method of claim 34, wherein the compound decreases calcium leak from RyRl channel and RyR2 channel of the subject.

75. A process for the synthesis of a compound of formula (I), comprising:(a) esterifying a compound of formula (II):to generate a compound of formula (III):wherein ring A is aryl or a 5- or 6- membered heteroaryl, each of which is unsubstituted or substituted; each R3is 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)Rb, C(O)NHRbor S(O)2Rb; optionally wherein two adjacent R3groups, together with the carbon atoms to which they are bound, form an optionally fused cycloalkyl or heterocycloalkyl ring;- Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen; n is 0, 1, 2, 3, 4 or 5; andAik is an alkyl group;(b) subjecting the compound of formula (III) to a bromination reaction to yield a compound of formula (IV):(c) reacting the compound of formula (IV) with a compound of formula (V):to yield a compound of formula (VI):wherein- 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 bound form C(O); and- P is a protecting group;(d) deprotecting the compound of formula (VI) to generate a compound of formula (VII):(e) cyclizing the compound of formula (VII) to yield a compound of formula (VIII):(f) protecting the hydroxyl group to yield a compound of formula (IX):wherein P is a protecting group;(g) reacting the compound of formula (IX) with a compound of formula (X): X'R4', wherein X' is halogen and R4' is alkyl that is unsubstituted or substituted, to yield a compound of formula (XI):the compounds of formula (IX) and (XI) representing a compound of formula (XII):wherein A, R3, Z, X, R', R", n, and P are as defined above, and R4is alkyl that is unsubstituted or substituted, or hydrogen;(h) reacting the compound of formula (XII) with a compound of formula (XIII): HNR1R2, wherein R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1and R2together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety, to yield a compound of formula (I / a):the compound of formula (I / a) and the compound of formula (I / b) representing the compound of formula (I); and(j) optionally purifying the resulting compound and / or optionally converting the resulting compound into its addition salts with a pharmaceutically acceptable acid or base and / or optionally separating the resulting compound into its isomers.

76. A process for the synthesis of a compound of formula (I), comprising the steps of:(a) reacting the compound of formula (VI)of claim 75, with an azide derivative to yield a compound of formula (XIV):(b) cyclizing the compound of formula (XIV) to yield a compound of formula (XV):(c) reacting the compound of formula (XV) with a compound of formula (X): X'R4' as defined above, to yield a compound of formula (XVI):the compound of formula (XV) and the compound of formula (XVI) representing a compound of formula (XVII):(d) reducing the compound of formula (XVII) to yield a compound of formula (I / c):(e) optionally further reducing the compound of formula (I / c) to yield a compound of formula(I / d):the compound of formula (I / c) and the compound of formula (I / d) representing a compound of(f) optionally reacting the compound of formula (I / e) with a compound of formula (XVIII): X''Rb, wherein X" is halogen and Rbis alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each ofwhich is unsubstituted or substituted, or C(O)Ra, C(O)ORb, or S(O)2Rb, to yield a compound of(g) optionally reacting the compound of formula (I / f) with a compound of formula (XIX): X"R2', wherein X" is halogen and R2' is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted, or C(O)Ra, C(O)ORb, or S(O)2Rb, to yield a compound of formula; and(h) optionally purifying the resulting compound, and / or optionally converting the resulting compound into its addition salts with a pharmaceutically acceptable acid or base, and / or optionally separating the resulting compound into its isomers.

77. A process for the synthesis of a compound of formula (I):comprising:(a) esterifying a compound of formula (II):to generate a compound of formula (III):wherein ring A is aryl or a 5- or 6- membered heteroaryl, each of which is unsubstituted or substituted; each R3is 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)Rb, C(O)NHRbor S(O)2Rb; optionally wherein two adjacent R3groups, together with the carbon atoms to which they are bound, form an optionally fused cycloalkyl or heterocycloalkyl ring;- R4is hydrogen;- Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen; n is 0, 1, 2, 3, 4 or 5; andAik is an alkyl group;(b) subjecting the compound of formula (III) to a bromination reaction to yield a compound of formula (IV):(c) reacting the compound of formula (IV) with a compound of formula (V):to yield a compound of formula (VI):wherein- 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 bound form C(O); and- P is a protecting group;(d) deprotecting the compound of formula (VI) to generate a compound of formula (VII):(e) cyclizing the compound of formula (VII) to yield a compound of formula (VIII):(f) reacting the compound of formula (VIII) with a compound of formula RSO2LG or a compound of formula (RSCh^O, wherein R is alkyl or aryl, and LG is a leaving group, to yield a compound of formula (IX):(g) reacting the compound of formula (IX) with a compound of the formula R10N3, wherein R10is a metal cation or N+Alk4, wherein Aik is alkyl, to generate a compound of formula (X):; and(h) converting the compound of formula (X) to a compound of formula (I’):wherein R1and R2are each a hydrogen atom; and(i) optionally, converting the compound of formula (I’) to a compound of formula (I).

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