Agents for treating disorders involving ryanodine receptors

Abstract

The present disclosure relates treating skeletal muscle weakness associated with heart failure by administering a compound that binds to leaky ryanodine receptors (RyRs). Compounds of the present disclosure can bind to and repair the leak in both RyR1 and RyR2 to improve skeletal muscle and cardiac function, respectively.

Description

WSGR Docket No. 59915-715.601AGENTS FOR TREATING DISORDERS INVOLVING RYANODINE RECEPTORS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 689,261, filed August 30, 2024; and U.S. Provisional Application No. 63 / 737,012, filed December 20, 2024, each of which are incorporated herein by reference.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 (Ry Rs) 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] Provided herein is a method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I):WSGR Docket No. 59915-715.601 wherein: n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R1is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R2is arylalkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, -SO2R7, - P(=O)R8R9, or -(CH2)m-R10;R3is acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or substituted; or H, -CO2Y, or -C(=O)NHY ;Y is alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R4is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H; each R5is acyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or - NR15R16, -(CH2)tNR15R16, -NHNR15R16, -NHOH, -OR15, -C(=O)NHNR15R16, -CO2R15, - C(=O)NR15R16, or -CH2X; each R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NHNR15R16, -NHOH, -NR15R16, or -CH2X; each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X; each R8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH;- each R10is -NR15R16, OH, -SO2R11, -NHSO2R11, -C(=O)(R12), -NHC=O(R12), -OC=O(R12), or -P(=O)R13R14; each R11, R12, R13, and R14is independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or H, OH, NH2, -NHNH2, or -NHOH;WSGR Docket No. 59915-715.601 each X is independently halogen, -CN, -CO2R15, -C(=O)NR15R16, -NR15R16, -OR15, -SO2R7, or -P(=O)R8R9; each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the N to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted; t is 1, 2, 3, 4, 5, or 6; and m is 1, 2, 3, or 4; or a pharmaceutically-acceptable salt thereof.

[0006] In some embodiments, the compound is:wherein R is COOH, or a pharmaceutically-acceptable salt thereof.

[0007] In some embodiments, the compound is:or a pharmaceutically-acceptable salt thereof.

[0008] In some embodiments, the compound is the pharmaceutically-acceptable salt.

[0009] In some embodiments, the pharmaceutically-acceptable salt is a hemifumarate salt.

[0010] In some embodiments, the treating decreases skeletal muscle weakness in the subject.

[0011] In some embodiments, the treating improves skeletal muscle function in the subject.

[0012] In some embodiments, the treating improves skeletal muscle strength in the subject.

[0013] In some embodiments, the treating improves grip strength in the subject.

[0014] In some embodiments, the treating improves pinch strength in the subject.

[0015] In some embodiments, the treating improves pulmonary function in the subject.

[0016] In some embodiments, the treating improves forced vital capacity in the subject.WSGR Docket No. 59915-715.601

[0017] In some embodiments, the treating improves maximum oxygen consumption (VO2 max) in the subject.

[0018] In some embodiments, the treating improves endurance in the subject.

[0019] In some embodiments, the treating improves exercise capacity in the subject.

[0020] In some embodiments, the treating improves exercise tolerance in the subject.

[0021] In some embodiments, the skeletal muscle weakness comprises weakness in a proximal muscle of the subject.

[0022] In some embodiments, the proximal muscle is a deltoid muscle.

[0023] In some embodiments, the proximal muscle is a shoulder muscle.

[0024] In some embodiments, the proximal muscle is an upper arm muscle.

[0025] In some embodiments, the proximal muscle is a hip muscle.

[0026] In some embodiments, the proximal muscle is a thigh muscle.

[0027] In some embodiments, the proximal muscle is a quadricep muscle.

[0028] In some embodiments, the proximal muscle is a core muscle.

[0029] In some embodiments, the skeletal muscle weakness comprises weakness in a distal muscle of the subject.

[0030] In some embodiments, the distal muscle is a hand muscle.

[0031] In some embodiments, the distal muscle is a lower arm muscle.

[0032] In some embodiments, the distal muscle is a lower leg muscle.

[0033] In some embodiments, the distal muscle is a foot muscle.

[0034] In some embodiments, the heart failure is congestive heart failure.

[0035] In some embodiments, the heart failure is chronic heart failure.

[0036] In some embodiments, the heart failure is heart failure with reduced ejection fraction.

[0037] In some embodiments, the heart failure is heart failure with preserved ejection fraction.

[0038] In some embodiments, the subject is a heart failure patient having an implantable cardioverterdefibrillator, wherein the implantable cardioverter-defibrillator is implanted in the patient.

[0039] In some embodiments, the heart failure is acute heart failure.

[0040] In some embodiments, the heart failure is right heart failure.

[0041] In some embodiments, the heart failure is left heart failure.

[0042] In some embodiments, the heart failure comprises myocardial infarction.

[0043] In some embodiments, the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

[0044] In some embodiments, the heart failure comprises cardiac ischemia / reperfusion injury.

[0045] In some embodiments, the treating decreases calcium leak from a RyRl channel in the subject.

[0046] In some embodiments, the treating decreases calcium leak from a RyR2 channel in the subject.

[0047] In some embodiments, the treating decreases open probability (Po) of RyRl protein in the subject.

[0048] In some embodiments, the treating decreases open probability (Po) of RyR2 protein in the subject.

[0049] In some embodiments, the administering is oral.WSGR Docket No. 59915-715.601

[0050] In some embodiments, the administering is once per day.

[0051] In some embodiments, the administering is twice per day.

[0052] In some embodiments, the compound is 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof.

[0053] In some embodiments, the compound is provided in a solid dosage form.

[0054] In some embodiments, the solid dosage form is suitable for oral administration.

[0055] In some embodiments, the solid dosage form comprises a pharmaceutically-acceptable excipient.

[0056] In some embodiments, the therapeutically-effective amount is about 50 mg to about 400 mg.

[0057] In some embodiments, the therapeutically-effective amount is about 200 mg. In some embodiments, the therapeutically-effective amount is administered once daily at the dose of 200 mg. In some embodiments, the therapeutically-effective amount is administered twice daily, in two daily doses of 100 mg.

[0058] In some embodiments, the therapeutically-effective amount is about 300 mg. In some embodiments, the therapeutically-effective amount is administered once daily at the dose of 300 mg. In some embodiments, the therapeutically-effective amount is administered twice daily, in two daily doses of 150 mg.

[0059] In some embodiments, the therapeutically-effective amount is about 400 mg. In some embodiments, the therapeutically-effective amount is administered once daily at the dose of 400 mg. In some embodiments, the therapeutically-effective amount is administered twice daily, in two daily doses of 200 mg.

[0060] In some embodiments, the subject is an adult.

[0061] In some embodiments, the subject is a child.

[0062] In some embodiments, the subject is 50 years or older.

[0063] In some embodiments, the subject is 60 years or older.

[0064] In some embodiments, the subject is 70 years or older.

[0065] In some embodiments, the subject is 80 years or older.

[0066] In some embodiments, the compound or pharmaceutically-acceptable salt thereof is administered to the subject as a pharmaceutical composition in unit dosage form, wherein the unit dosage form further comprises a pharmaceutically-acceptable excipient.

[0067] In some embodiments, the unit dosage form is a tablet.

[0068] In some embodiments, the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 to about 200 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0069] In some embodiments, the unit dosage form comprises about 23.5 to about 235 mg of 4-[(7- methoxy-2, 3 -dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0070] In some embodiments, the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 mg of 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.WSGR Docket No. 59915-715.601

[0071] In some embodiments, the unit dosage form comprises 23.5 mg of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0072] In some embodiments, the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 50 mg of 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0073] In some embodiments, the unit dosage form comprises about 58.75 mg of 4-[(7-methoxy-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate .

[0074] In some embodiments, the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 100 mg of 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0075] In some embodiments, the unit dosage form comprises about 117.5 mg of 4-[(7-methoxy-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate .

[0076] Provided herein is a method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a solid dosage form comprising a therapeutically-effective amount of a compound of Formula (I):wherein: n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R1is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R2is alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, - SO2R7, -P(=O)R8R9, or -(CH2)m-R10;R3is acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or substituted; or H, -CO2Y, or -C(=O)NHY ;Y is alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;WSGR Docket No. 59915-715.601R4is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H; each R5is acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -NR15R16, -(CH2)tNR15R16, -NHNR15R16, -NHOH, -OR15, - C(=O)NHNR15R16, -CO2R15, -C(=O)NR15R16, or -CH2X; each R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NHNR15R16, -NHOH, -NR15R16, or -CH2X; each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X; each R8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH;- each R10is -NR15R16, OH, -SO2Rn, -NHSO2Rn, -C(=O)(R12), -NHC=O(R12), -OC=O(R12), or -P(=O)R13R14; each R11, R12, R13, and R14is independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or H, OH, NH2, -NHNH2, or -NHOH; each X is independently halogen, -CN, -CO2R15, -C(=O)NR15R16, -NR15R16, -OR15, -SO2R7, or -P(=O)R8R9; each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the N to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted; t is 1, 2, 3, 4, 5, or 6; and m is 1, 2, 3, or 4; or a pharmaceutically-acceptable salt thereof.

[0077] In some embodiments, the compound is the pharmaceutically-acceptable salt.

[0078] In some embodiments, the pharmaceutically-acceptable salt is a hemifumarate salt.

[0079] In some embodiments, the treating decreases skeletal muscle weakness in the subject.

[0080] In some embodiments, the treating improves skeletal muscle function in the subject.

[0081] In some embodiments, the treating improves skeletal muscle strength in the subject.

[0082] In some embodiments, the treating improves grip strength in the subject.

[0083] In some embodiments, the treating improves pinch strength in the subject.

[0084] In some embodiments, the treating improves pulmonary function in the subject.

[0085] In some embodiments, the treating improves forced vital capacity in the subject.WSGR Docket No. 59915-715.601

[0086] In some embodiments, the treating improves maximum oxygen consumption (VO2 max) in the subject.

[0087] In some embodiments, the treating improves endurance in the subject.

[0088] In some embodiments, the treating improves exercise capacity in the subject.

[0089] In some embodiments, the treating improves exercise tolerance in the subject.

[0090] In some embodiments, the skeletal muscle weakness comprises weakness in a proximal muscle of the subject.

[0091] In some embodiments, the proximal muscle is a deltoid muscle.

[0092] In some embodiments, the proximal muscle is a shoulder muscle.

[0093] In some embodiments, the proximal muscle is an upper arm muscle.

[0094] In some embodiments, the proximal muscle is a hip muscle.

[0095] In some embodiments, the proximal muscle is a thigh muscle.

[0096] In some embodiments, the proximal muscle is a quadricep muscle.

[0097] In some embodiments, the proximal muscle is a core muscle.

[0098] In some embodiments, the skeletal muscle weakness comprises weakness in a distal muscle of the subject.

[0099] In some embodiments, the distal muscle is a hand muscle.

[0100] In some embodiments, the distal muscle is a lower arm muscle.

[0101] In some embodiments, the distal muscle is a lower leg muscle.

[0102] In some embodiments, the distal muscle is a foot muscle.

[0103] In some embodiments, the heart failure is congestive heart failure.

[0104] In some embodiments, the heart failure is chronic heart failure.

[0105] In some embodiments, the heart failure is heart failure with reduced ejection fraction.

[0106] In some embodiments, the heart failure is heart failure with preserved ejection fraction.

[0107] In some embodiments, the subject is a heart failure patient having an implantable cardioverterdefibrillator, wherein the implantable cardioverter-defibrillator is implanted in the patient.

[0108] In some embodiments, the wherein the heart failure is acute heart failure.

[0109] In some embodiments, the heart failure is right heart failure.

[0110] In some embodiments, the heart failure is left heart failure.[oni] In some embodiments, the heart failure comprises myocardial infarction.

[0112] In some embodiments, the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

[0113] In some embodiments, the heart failure comprises cardiac ischemia / reperfusion injury.

[0114] In some embodiments, the treating decreases calcium leak from a RyRl channel in the subject.

[0115] In some embodiments, the treating decreases calcium leak from a RyR2 channel in the subject.

[0116] In some embodiments, the treating decreases open probability (Po) of RyRl protein in the subject.

[0117] In some embodiments, the treating decreases open probability (Po) of RyR2 protein in the subject.

[0118] In some embodiments, the administering is oral.WSGR Docket No. 59915-715.601

[0119] In some embodiments, the administering is once per day.

[0120] In some embodiments, the administering is twice per day.

[0121] In some embodiments, the compound is 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof.

[0122] In some embodiments, the compound is provided in the solid dosage form.

[0123] In some embodiments, the solid dosage form is suitable for oral administration.

[0124] In some embodiments, the solid dosage form comprises a pharmaceutically-acceptable excipient.

[0125] In some embodiments, the therapeutically-effective amount is about 50 mg to about 400 mg.

[0126] In some embodiments, the therapeutically-effective amount is about 200 mg. In some embodiments, the therapeutically-effective amount is administered once daily at the dose of 200 mg. In some embodiments, the therapeutically-effective amount is administered twice daily, in two daily doses of 100 mg.

[0127] In some embodiments, the therapeutically-effective amount is about 300 mg. In some embodiments, the therapeutically-effective amount is administered once daily at the dose of 300 mg. In some embodiments, the therapeutically-effective amount is administered twice daily, in two daily doses of 150 mg.

[0128] In some embodiments, the therapeutically-effective amount is about 400 mg. In some embodiments, the therapeutically-effective amount is administered once daily at the dose of 400 mg. In some embodiments, the therapeutically-effective amount is administered twice daily, in two daily doses of 200 mg.

[0129] In some embodiments, the subject is an adult.

[0130] In some embodiments, the subject is 50 years or older.

[0131] In some embodiments, the subject is 60 years or older.

[0132] In some embodiments, the subject is 70 years or older.

[0133] In some embodiments, the subject is 80 years or older.

[0134] In some embodiments, the subject is a child.

[0135] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered to the subject as a pharmaceutical composition in unit dosage form, wherein the unit dosage form further comprises a pharmaceutically acceptable excipient.

[0136] In some embodiments, the unit dosage form is a tablet.

[0137] In some embodiments, the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 to about 200 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0138] In some embodiments, the unit dosage form comprises about 23.5 to about 235 mg of 4-[(7- methoxy-2, 3 -dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0139] In some embodiments, the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 mg of 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.WSGR Docket No. 59915-715.601

[0140] In some embodiments, the unit dosage form comprises 23.5 mg of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0141] In some embodiments, the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 50 mg of 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0142] In some embodiments, the unit dosage form comprises about 58.75 mg of 4-[(7-methoxy-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate .

[0143] In some embodiments, the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 100 mg of 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0144] In some embodiments, the unit dosage form comprises about 117.5 mg of 4-[(7-methoxy-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate .

[0145] Provided herein is a method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (V):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 withWSGR Docket No. 59915-715.601 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.

[0146] In some embodiments, the compound is the pharmaceutically-acceptable salt.

[0147] In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.

[0148] In some embodiments, the treating decreases skeletal muscle weakness in the subject.

[0149] In some embodiments, the treating improves skeletal muscle function in the subject.

[0150] In some embodiments, the treating improves skeletal muscle strength in the subject.

[0151] In some embodiments, the treating improves grip strength in the subject.

[0152] In some embodiments, the treating improves pinch strength in the subject.

[0153] In some embodiments, the treating improves pulmonary function in the subject.

[0154] In some embodiments, the treating improves forced vital capacity in the subject.

[0155] In some embodiments, the treating improves maximum oxygen consumption (VO2 max) in the subject.

[0156] In some embodiments, the treating improves endurance in the subject.

[0157] In some embodiments, the treating improves exercise capacity in the subject.

[0158] In some embodiments, the treating improves exercise tolerance in the subject.

[0159] In some embodiments, the skeletal muscle weakness comprises weakness in a proximal muscle of the subject.

[0160] In some embodiments, the proximal muscle is a deltoid muscle.

[0161] In some embodiments, the proximal muscle is a shoulder muscle.

[0162] In some embodiments, the proximal muscle is an upper arm muscle.

[0163] In some embodiments, the proximal muscle is a hip muscle.

[0164] In some embodiments, the proximal muscle is a thigh muscle.

[0165] In some embodiments, the proximal muscle is a quadricep muscle.

[0166] In some embodiments, the proximal muscle is a core muscle.

[0167] In some embodiments, the skeletal muscle weakness comprises weakness in a distal muscle of the subject.

[0168] In some embodiments, the distal muscle is a hand muscle.

[0169] In some embodiments, the distal muscle is a lower arm muscle.

[0170] In some embodiments, the distal muscle is a lower leg muscle.WSGR Docket No. 59915-715.601

[0171] In some embodiments, the distal muscle is a foot muscle.

[0172] In some embodiments, the heart failure is congestive heart failure.

[0173] In some embodiments, the heart failure is chronic heart failure.

[0174] In some embodiments, the heart failure is heart failure with reduced ejection fraction.

[0175] In some embodiments, the heart failure is heart failure with preserved ejection fraction.

[0176] In some embodiments, the subject is a heart failure patient having an implantable cardioverterdefibrillator, wherein the implantable cardioverter-defibrillator is implanted in the patient.

[0177] In some embodiments, the wherein the heart failure is acute heart failure.

[0178] In some embodiments, the heart failure is right heart failure.

[0179] In some embodiments, the heart failure is left heart failure.

[0180] In some embodiments, the heart failure comprises myocardial infarction.

[0181] In some embodiments, the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

[0182] In some embodiments, the heart failure comprises cardiac ischemia / reperfusion injury.

[0183] In some embodiments, the treating decreases calcium leak from a RyRl channel in the subject.

[0184] In some embodiments, the treating decreases calcium leak from a RyR2 channel in the subject.

[0185] In some embodiments, the treating decreases open probability (Po) of RyRl protein in the subject.

[0186] In some embodiments, the treating decreases open probability (Po) of RyR2 protein in the subject.

[0187] In some embodiments, the administering is oral.

[0188] In some embodiments, the administering is once per day.

[0189] In some embodiments, the administering is twice per day.

[0190] In some embodiments, the pharmaceutical composition is provided in a solid dosage form.

[0191] In some embodiments, the solid dosage form is suitable for oral administration.

[0192] In some embodiments, the solid dosage form comprises a pharmaceutically-acceptable excipient.

[0193] In some embodiments, the subject is an adult.

[0194] In some embodiments, the subject is 50 years or older.

[0195] In some embodiments, the subject is 60 years or older.

[0196] In some embodiments, the subject is 70 years or older.

[0197] In some embodiments, the subject is 80 years or older.

[0198] In some embodiments, the subject is a child.

[0199] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered to the subject as a pharmaceutical composition in unit dosage form, wherein the unit dosage form further comprises a pharmaceutically acceptable excipient.

[0200] In some embodiments, the unit dosage form is a tablet.WSGR Docket No. 59915-715.601DETAILED DESCRIPTIONCompounds

[0201] Provided herein is a method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of the present disclosure.

[0202] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein: n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R1is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R2is arylalkyl, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, - SO2R7, -P(=O)R8R9, or -(CH2)m-R10;R3is acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or substituted; or H, -CO2Y, or -C(=O)NHY ;Y is alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R4is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H; each R5is acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -NR15R16, -(CH2)tNR15R16, -NHNR15R16, -NHOH, -OR15, - C(=O)NHNR15R16, -CO2R15, -C(=O)NR15R16, or -CH2X;WSGR Docket No. 59915-715.601 each R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NHNR15R16, -NHOH, -NR15R16, or -CH2X; each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X; each R8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH;- each R10is -NR15R16, OH, -SO2Rn, -NHSO2Rn, -C(=O)(R12), -NHC=O(R12), -OC=O(R12), or -P(=O)R13R14; each R11, R12, R13, and R14is independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or H, OH, NH2, -NHNH2, or -NHOH; each X is independently halogen, -CN, -CO2R15, -C(=O)NR15R16, -NR15R16, -OR15, -SO2R7, or -P(=O)R8R9; each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the N to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted; t is 1, 2, 3, 4, 5, or 6; and m is 1, 2, 3, or 4; or a pharmaceutically-acceptable salt thereof.

[0203] In some embodiments, the compound is 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof. The compound has the following chemical structure:

[0204] In some embodiments, 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid is provided in the form of a salt with a pharmaceutically-acceptable acid or base. Non-limiting examples of salts include sodium, potassium, magnesium, hemifumarate, hydrochloride, and hydrobromide salts. In some embodiments, the salt is a sodium salt. In some embodiments, the salt is a hemifumarate salt.WSGR Docket No. 59915-715.601

[0205] When present as a hemifumarate salt, the compound is herein designated Compound A.Compound A has an empirical formula possessing the following structure or an ionized form thereof:

[0206] For example, a compound of Formula (I) can be in ionized form, comprising two ionized molecules of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0207] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein R is COOH, or a pharmaceutically-acceptable salt thereof. In some embodiments, the calcium channel modulator is in the form of a salt with a pharmaceutically-acceptable acid or base. In some embodiments, the salt is selected from the group consisting of hemifumarate, sodium, potassium, magnesium, hydrochloride and hydrobromide, preferably wherein the salt is the sodium or the hemifumarate salt.

[0208] In some embodiments, the compound is:WSGR Docket No. 59915-715.601WSGR Docket No. 59915-715.601WSGR Docket No. 59915-715.601WSGR Docket No. 59915-715.601or a pharmaceutically-acceptable salt of any of the foregoing.

[0209] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein: n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R2is alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, -SO2R7, - P(=O)R8R9, or -(CH2)m-R10; each R5is acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -NR15R16, -NHNR15R16, -NHOH, -OR15, -C(=O)NHNR15R16, -CO2R15, - C(=O)NR15R16, -CH2X, or alkyl substituted by at least one labeling group, selected from a fluorescent group, a bioluminescent group, a chemiluminescent group, a colorimetric group, and a radioactive labeling group; each R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NHNR15R16, -NHOH, -NR15R16, or -CH2X; each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X;WSGR Docket No. 59915-715.601 each R8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH;- each R10is -NR15R16, OH, -SO2R11, -NHSO2R11, -C(=O)R12, -NH(C=O)R12, -O(C=O)R12, or -P(=O)R13R14; m is 0, 1, 2, 3, or 4; each R11, R12, R13, and R14is independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or H, OH, NH2, -NHNH2, or -NHOH;- each X is halogen, -CN, -CO2R15, -C(=O)NR15R16, -NR15R16, -OR15, -SO2R7, or -P(=O)R8R9; and each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the N to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted; or a pharmaceutically-acceptable salt thereof.

[0210] In some embodiments, a compound of the present disclosure is represented by the following structure:whereinR' and R" are each independently acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylthiol, heteroarylthio, arylamino, or heteroarylamino, each of which is independently substituted or substituted; or halogen, H, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, -S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R2is alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, -SO2R7, - P(=O)R8R9, or -(CH2)m-R10; and n is 0, 1, or 2; or a pharmaceutically-acceptable salt thereof.

[0211] In some embodiments, a compound of the present disclosure is represented by the following structure:WSGR Docket No. 59915-715.601wherein n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3; and each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X; or a pharmaceutically-acceptable salt thereof.

[0212] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein n is 0, 1, or 2;R' and R" are each independently acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylthiol, heteroarylthio, arylamino, or heteroarylamino, each of which is independently substituted or substituted; or halogen, H, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, -S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3; AND each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X, or a pharmaceutically-acceptable salt thereof.

[0213] In some embodiments, a compound of the present disclosure is represented by the following structure:WSGR Docket No. 59915-715.601wherein n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3; each R5is acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or-NR15R16, -NHNR15R16, -NHOH, -OR15, -C(=O)NHNR15R16, -CO2R15, - C(=O)NR15R16, -CH2X, or alkyl substituted by at least one labeling group, selected from a fluorescent group, a bioluminescent group, a chemiluminescent group, a colorimetric group, and a radioactive labeling group, or a pharmaceutically-acceptable salt thereof.

[0214] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein n is 0, 1, or 2;R' and R" are each independently acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylthiol, heteroarylthio, arylamino, or heteroarylamino, each of which is independently substituted or substituted; or halogen, H, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, -S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3; and each R5is acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or- NR15R16, -NHNR15R16, -NHOH, -OR15, -C(=O)NHNR15R16, -CO2R15, - C(=O)NR15R16, -CH2X, or alkyl substituted by at least one labeling group, selected from aWSGR Docket No. 59915-715.601 fluorescent group, a bioluminescent group, a chemiluminescent group, a colorimetric group, and a radioactive labeling group, or a pharmaceutically-acceptable salt thereof.

[0215] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein- n is 0, 1, or 2;- q is 0, 1, 2, 3, or 4;- W is S or O;- each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3; and- each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the N to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted, or a pharmaceutically-acceptable salt thereof.

[0216] In some embodiments, calcium channel stabilizer comprises the following structure:wherein n is 0, 1, or 2;W is S or O; andR' and R" are each independently acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylthiol, heteroarylthio, arylamino, or heteroarylamino, each of which is independently substituted or substituted; or halogen, H, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, -S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3,WSGR Docket No. 59915-715.601 or a pharmaceutically-acceptable salt thereof.

[0217] In some embodiments, the compound is of formula wherein R' and R" are each independently H, halogen, -OH, OMe, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -S(=O)2Ci-C4alkyl, -S(=O)Ci-C4alkyl, -S-Ci- C4alkyl, -OS(=O)2CF3, Ph, -NHCH2Ph, -C(=O)Me, -OC(=O)Me, morpholinyl, or propenyl; and n is 0, 1 or 2. In some embodiments, R' is H or OMe, and R" is H.

[0218] In some embodiments, a compound of the present disclosure is represented by the following structure:whereinR17is alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -NR15R16, -NHNR15R16, -NHOH, - OR15, or -CH2X; n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; and each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3, or a pharmaceutically-acceptable salt thereof.

[0219] In some embodiments, a compound of the present disclosure is represented by the following structure:whereinR' and R" are each independently acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylthiol, heteroarylthio, arylamino, or heteroarylamino, each of which is independently substituted or substituted; or halogen, H, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, -S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;WSGR Docket No. 59915-715.601R17is -NR15R16, -NHOH, -OR15, -CH2X, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein each alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted or unsubstituted; AND n is 0, 1, or 2, or a pharmaceutically-acceptable salt thereof.

[0220] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R' and R" are each independently acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylthiol, heteroarylthio, arylamino, or heteroarylamino, each of which is independently substituted or substituted; or halogen, H, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, -S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R18is alkyl, aryl, cycloalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or -NR15R16, -C(=O)NR15R16, -(C=O)OR15, or -OR15; q is 0, 1, 2, 3, or 4; p is 1, 2, 3, 4, 5, 6, 7, 8 9, or 10; and n is 0, 1, or 2, or a pharmaceutically-acceptable salt thereof.

[0221] In some embodiments, a compound of the present disclosure is represented by the following structure:whereinWSGR Docket No. 59915-715.601R' and R" are each independently acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylthiol, heteroarylthio, arylamino, or heteroarylamino, each of which is independently substituted or substituted; or halogen, H, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, -S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R18is alkyl, aryl, cycloalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or -NR15R16, -C(=O)NR15R16, -(C=O)OR15, or -OR15; p is 1, 2, 3, 4, 5, 6, 7, 8 9, or 10; and n is 0, 1, or 2, or a pharmaceutically-acceptable salt thereof.

[0222] In some embodiments of formula I-k-1, R’ and R” are independently selected from the group consisting of H, halogen, -OH, OMe, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -S(=O)2Ci-C4alkyl, -S(=O)Ci- C4alkyl, -S-Ci-C4alkyl, -OS(=O)2CF3, Ph, -NHCH2Ph, -C(=O)Me, -OC(=O)Me, morpholinyl and propenyl; and n is 0, 1 or 3. In some cases, R’ is H or OMe, and R” is H.

[0223] In other embodiments, R18is selected from the group consisting of — NR15R16, -(C=O)OR \ - OR15, alkyl that is substituted or unsubstituted, or aryl that is substituted or unsubstituted. In some embodiments, m is 1, and R18is Ph, -C(=O)OMe, -C(=O)OH, aminoalkyl, NH2, NHOH, or NHCbz. In other embodiments, m is 0, and R18is C1-C4 alkyl. In other embodiments, R18is Me, Et, propyl, and butyl. In some embodiments, m is 2, and R18is pyrrolidine, piperidine, piperazine, or morpholine. In some embodiments, m is 3, 4, 5, 5, 7, or 8, and R18is a fluorescent labeling group selected from bodipy, dansyl, fluorescein, rhodamine, Texas red, cyanine dyes, pyrene, coumarins, Cascade Blue™, Pacific Blue, Marina Blue, Oregon Green, 4',6-Diamidino-2-phenylindole (DAPI), indopyra dyes, lucifer yellow, propidium iodide, porphyrins, arginine, and variants and derivatives thereof.

[0224] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R' and R" are each independently acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylthiol, heteroarylthio,WSGR Docket No. 59915-715.601 arylamino, or heteroarylamino, each of which is independently substituted or substituted; or halogen, H, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, -S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, - NHNR15R16, -NHOH, -NR15R16, or -CH2X; q is 0, 1, 2, 3, or 4; and n is 0, 1, or 2, or a pharmaceutically-acceptable salt thereof.

[0225] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein n is 0, 1, or 2; q is 0, 1, 2, 3, or 4;R' and R" are each independently acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylthiol, heteroarylthio, arylamino, or heteroarylamino, each of which is independently substituted or substituted; or halogen, H, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, -S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3; andR8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH, or a pharmaceutically-acceptable salt thereof.

[0226] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein:Rdis CH2, or NRa; andWSGR Docket No. 59915-715.601Rais H, alkoxy, -(Ci-Ce alkyl)-aryl, wherein the aryl is a disubstituted phenyl or a benzo[l,3]dioxo-5-yl group, or a Boe group. or a pharmaceutically-acceptable salt thereof.

[0227] In some embodiments, Rais H.

[0228] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein:Reis -(Ci-Ce alkyl)-phenyl, -(Ci-Ce alkyl)-C(O)Rb, or substituted or unsubstituted -Ci-Ce alkyl; andRbis -OH or -O-(Ci -Ce alkyl), wherein the phenyl or the substituted alkyl is substituted with one or more of halogen, hydroxyl, -Ci-Ce alkyl, -O-(Ci-Ce alkyl), -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, cyano, or dioxolane, or a pharmaceutically-acceptable salt thereof.

[0229] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein:Reis -(Ci-Ce alkyl)-NH2, -(Ci-Ce alkyl)-ORf, wherein Rfis H or -C(O)-(Ci-Ce)alkyl, or -(Ci-Ce alkyl)-NHR8, wherein R8is carboxybenzyl.

[0230] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein: n is 0, 1, or 2; q is 0, 1, 2, 3, or 4;WSGR Docket No. 59915-715.601 each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3; each R2and R2ais independently alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, -SO2R7, -P(=O)R8R9, or -(CH2)m-R10; each R5is acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -NR15R16, -NHNR15R16, -NHOH, -OR15, -C(=O)NHNR15R16, -CO2R15, - C(=O)NR15R16, -CH2X, or alkyl substituted by at least one labeling group, selected from a fluorescent group, a bioluminescent group, a chemiluminescent group, a colorimetric group, and a radioactive labeling group; each R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NHNR15R16, -NHOH, -NR15R16, or -CH2X; each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X; each R8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH;- each R10is -NR15R16, OH, -SO2R11, -NHSO2R11, -C(=O)R12, -NH(C=O)R12, -O(C=O)R12, or -P(=O)R13R14; m is 0, 1, 2, 3, or 4; each R11, R12, R13, and R14is independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or H, OH, NH2, -NHNH2, or -NHOH;- each X is halogen, -CN, -CO2R15, -C(=O)NR15R16, -NR15R16, -OR15, -SO2R7, or -P(=O)R8R9; and each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the nitrogen atom to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted; or a pharmaceutically-acceptable salt thereof.WSGR Docket No. 59915-715.601

[0231] In some embodiments, a compound of the present disclosure is represented by the following structure:or a pharmaceutically-acceptable salt thereof, wherein each Rla, Rlb, Rlc, and Rldis independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, -CN, -NO2, -Ns, -NR3R4, -OR5, -SOsH, -SO2R6, -OSO2R6, -S(O)R6, or -SR7, each of which is independently substituted or unsubstituted, or hydrogen or halogen,R2is alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, -C(O)NR3R4, -C(O)C(O)NR3R4, -C(O)R8, -C(O)OR8, or -C(O)C(O)OR8, each of which is independently substituted or unsubstituted, each R3and R4is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; or R3and R4together with the nitrogen atom to which R3and R4are attached form a heterocyclic or heteroaromatic ring, which is unsubstituted or substituted, and each R5, R6, R7, and R8is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen.

[0232] In some embodiments, R2is -C(O)NR3R4, and the calcium channel modulator is represented by the following structure:(Il-a)WSGR Docket No. 59915-715.601 wherein each Rla, Rlb, Rlc, and Rldis independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, -CN, -NO2, -Ns, -NR3R4, -OR5, -SO3H, -SO2R6, -OSO2R6, -S(O)R6, or -SR7, each of which is independently substituted or unsubstituted, or hydrogen or halogen; each R3and R4is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; or R3and R4together with the nitrogen atom to which R3and R4are attached form a heterocyclic or heteroaromatic ring, which is unsubstituted or substituted; and each R5, R6, and R7is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; or a pharmaceutically-acceptable salt thereof.

[0233] In some embodiments, the calcium channel modulator is represented by the following structure:wherein each Rla, Rlb, Rlc, and Rldis independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, -CN, -NO2, -Ns, -NR3R4, -OR5, -SOsH, -SO2R6, -OSO2R6, -S(O)R6, or -SR7, each of which is independently substituted or unsubstituted, or hydrogen or halogen; each R3and R4is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; or R3and R4together with the nitrogen atom to which R3and R4are attached form a heterocyclic or heteroaromatic ring, which is unsubstituted or substituted; each R5, R6, and R7is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen;R9is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heterocyclyl, heteroaryl, _C(O)NR3R4, - C(O)R8, or -C(O)OR8, each of which is independently substituted or unsubstituted, or hydrogen; each R10is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heterocyclyl, heteroaryl, -NR3R4, -OR5, or -SR7, each of which is unsubstituted or substituted; andWSGR Docket No. 59915-715.601 m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; or a pharmaceutically- acceptable salt thereof.

[0234] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein each Rla, Rlb, Rlc, and Rldis independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, heterocyclyl, -CN, -NO2, -Ns, -NR3R4, -OR5, -SOsH, -SO2R6, -OSO2R6, -S(O)R6, or -SR7, each of which is independently substituted or unsubstituted, or hydrogen or halogen; each R3and R4is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; or R3and R4together with the nitrogen atom to which R3and R4are attached form a heterocyclic or heteroaromatic ring, which is unsubstituted or substituted; and each R5, R6, and R7is independently alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; or a pharmaceutically-acceptable salt thereof.

[0235] In some embodiments, a compound of the present disclosure is represented by the following structure:wherein each R1is independently halogen, haloalkyl, haloalkyloxy; and n is 1, 2, 3, or 4;WSGR Docket No. 59915-715.601 or a pharmaceutically-acceptable salt thereof.

[0236] In some embodiments, n is 1 and R1is at position 6 of the benzothiazepine ring, and the calcium channel modulator is represented by the following structure:or a pharmaceutically-acceptable salt thereof.

[0237] In some embodiments, n is 1 and R1is at position 7 of the benzothiazepine ring, and the calcium channel modulator is represented by the following structure:or a pharmaceutically-acceptable salt thereof.

[0238] In some embodiments, n is 1, and R1is at position 8 of the benzothiazepine ring, and the calcium channel modulator is represented by the following structure:

[0239] In some embodiments, n is 1, R1is at position 9 of the benzothiazepine ring, and the calcium channel modulator is represented by the following structure:WSGR Docket No. 59915-715.601or a pharmaceutically-acceptable salt thereof.

[0240] In some embodiments, n is 2, two instances of R1occur independently at positions 7 and 8 of the benzothiazepine ring, and compound represented by the following structure:or a pharmaceutically-acceptable salt thereof.

[0241] In some embodiments, compound represented by the following structure below that is piperazin- l-yl(8-(trifIuoromethyl)-2,3-dihydrobenzo[f][l,4]thiazepin-4(5H)-yl)methanone), or a pharmaceutically- acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.

[0242] In some embodiments, the compound is represented by the following structure below that is piperazin-l-yl(7-(trifluoromethyl)-2,3-dihydrobenzo[f][l,4]thiazepin-4(5H)-yl) methanone), or a pharmaceutically-acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.WSGR Docket No. 59915-715.601

[0243] In some embodiments, the compound is represented by the following structure below that is piperazin- 1 -yl(9-(trifluoromethyl)-2,3-dihydrobenzo[f] [ 1 ,4]thiazepin-4(5H)-yl)methanone), or a pharmaceutically-acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.

[0244] In some embodiments, the compound is represented by the following structure below that is piperazin-l-yl(7-(trifluoromethoxy)-2,3-dihydrobenzo[f][l,4]thiazepin-4(5H)-yl)methanone), or a pharmaceutically-acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.

[0245] In some embodiments, the compound is represented by the following structure below that is piperazin- 1 -yl(6-(trifluoromethyl)-2,3-dihydrobenzo[f] [ 1 ,4]thiazepin-4(5H)-yl)methanone), or a pharmaceutically-acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.WSGR Docket No. 59915-715.601

[0246] In some embodiments, the compound is represented by the following structure below that is (7,8- difluoro-2,3-dihydrobenzo[f][l,4]thiazepin-4(5H)-yl)(piperazin-l-yl)methanone), or a pharmaceutically- acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.

[0247] In some embodiments, compound is represented by the following structure below that is (6- chloro-2, 3 -dihydrobenzo [f][l,4]thiazepin-4(5H)-yl)(piperazin-l-yl)methanone), or a pharmaceutically- acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.

[0248] In some embodiments, the compound is represented by the following structure below that is piperazin-l-yl(6-(trifluoromethoxy)-2,3-dihydrobenzo[f][l,4]thiazepin-4(5H)-yl)methanone), or a pharmaceutically-acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.WSGR Docket No. 59915-715.601

[0249] In some embodiments, the compound is represented by the following structure below that is (6- bromo-2, 3 -dihydrobenzo [f] [ 1 ,4] 37hiazepine-4(5H)-yl)(piperazin- 1 -yl)methanone), or a pharmaceutically-acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.

[0250] In some embodiments, the compound is represented by the following structure below that is (6- iodo-2,3-dihydrobenzo[f][l,4]thiazepin-4(5H)-yl)(piperazin-l-yl)methanone), or a pharmaceutically- acceptable salt thereof. In some embodiments, the pharmaceutically-acceptable salt is a hydrochloride salt.WSGR Docket No. 59915-715.601WSGR Docket No. 59915-715.601WSGR Docket No. 59915-715.601WSGR Docket No. 59915-715.601JS59 $67WSGR Docket No. 59915-715.601WSGR Docket No. 59915-715.601WSGR Docket No. 59915-715.601WSGR Docket No. 59915-715.601or a pharmaceutically-acceptable salt of any of the foregoing.

[0252] In some embodiments, a compound of the present disclosure is represented by formula (V):wherein ringA 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(0)Rb, C(0)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.

[0253] 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-Ce)alkyl.

[0254] 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 alkylWSGR Docket No. 59915-715.601 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.

[0255] 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-C6)alkylamino. 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.

[0256] In some embodiments, R4is (Ci-Ce)alkyl.

[0257] In some embodiments, Rais (Ci-Ce)alkyl. In some embodiments, Rcis (Ci-Ce)alkyl.

[0258] In some embodiments, Rbis (Ci-Ce)alkyl.

[0259] 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-Ce)haloalkyl), haloalkyloxy (e.g., (Ci-Ce)haloalkoxy, or trifluoromethoxy), or halogen, wherein Rdand Reare independently hydrogen or alkyl.

[0260] In some embodiments, one or more carbon-bourne hydrogen atoms on the preceding possible substituents are isotopically enriched in deuterium.

[0261] In some embodiments, the compounds disclosed herein comprise their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

[0262] In some embodiments, X is sulphur.

[0263] In some embodiments, Y is C(O).

[0264] In some embodiments, A is a 6-membered aryl or heteroaryl, each of which is unsubstituted or substituted.

[0265] In some embodiments, a compound of the present disclosure is represented by formula (Va):wherein R1, R2, R3, R4, R', R", X, Y, Z, and n are as defined in formula (V).WSGR Docket No. 59915-715.601

[0266] In some embodiments, Z is hydrogen.

[0267] In some embodiments, a compound of the present disclosure is represented by formula (Vb):(Vb), wherein R1, R2, R3, R4, R', R", and n are as defined in formula (V).

[0268] In some embodiments, n is i.

[0269] In some embodiments, R' and R" each are hydrogen.

[0270] In some embodiments, R1and R2each are hydrogen.

[0271] In some embodiments, R1is hydrogen.

[0272] In some embodiments, R2is hydrogen.

[0273] In some embodiments, R1is hydrogen or methyl.

[0274] In some embodiments, R2is hydrogen, alkyl, or C(O)Ra, wherein Rais as defined in formula (I).

[0275] 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.

[0276] 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 -CC>2RX, wherein each Rxis independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.

[0277] 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 groupWSGR Docket No. 59915-715.601 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-Ce)haloalkyl, (Ci-Ce)haloalkyloxy (e.g., trifluoromethoxy), and halogen atom, wherein Rdand Reare independently hydrogen or (Ci-Ce)alkyl.

[0278] 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-Ce)haloalkyl, (Ci-Ce)haloalkyloxy (e.g., trifluoromethoxy), and halogen, wherein Rdand Reare independently hydrogen or (Ci-Ce)alkyl.

[0279] 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, lH-pyrazol-3-yl, 2-methyl-lH-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-pyridin-3-yl, 2-chloro-pyridin-3-yl, pyridin-4-yl, 3 -phenyl- lH-pyrazol-5-yl, lH-imidazol-4-yl, lH-imidazol-2-yl, 1 -methyl- lH-imidazol-4-yl, 1 -methyl- IH-imidazol -2 -yl, thiazol-2-yl, thiazol-4-yl, 4- methyl- 1 ,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-l-yl, 5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl, or piperazin- 1-yl.

[0280] In some embodiments, R2is C(O)Ra, wherein Rais pyridin-2-yl.

[0281] In some embodiments, R2is C(O)Ra, wherein Rais 6-chloro-pyridin-2-yl.

[0282] In some embodiments, R2is C(O)Ra, wherein Rais 5-chloro-pyridin-2-yl.

[0283] In some embodiments, R2is C(O)Ra, wherein Rais 6-hydroxy-pyridin-2-yl.

[0284] In some embodiments, R2is C(O)Ra, wherein Rais pyridin-3-yl.

[0285] In some embodiments, R2is C(O)Ra, wherein Rais 6-amino-pyridin-3-yl.

[0286] In some embodiments, R2is C(O)Ra, wherein Rais 2-chloro-pyridin-3-yl.

[0287] In some embodiments, R2is C(O)Ra, wherein Rais pyridin-4-yl.

[0288] In some embodiments, R2is C(O)Ra, wherein Rais pyrimidin-2-yl.

[0289] In some embodiments, R2is C(O)Ra, wherein Rais pyrimidin-5-yl.

[0290] In some embodiments, R2is C(O)Ra, wherein Rais 5-amino-pyrimidin-2-yl.

[0291] In some embodiments, R2is C(O)Ra, wherein Rais 5-methoxy-pyrimidin-2-yl.

[0292] In some embodiments, R2is C(O)Ra, wherein Rais lH-pyrazol-3-yl.

[0293] In some embodiments, R2is C(O)Ra, wherein Rais 2-methyl-lH-pyrazole-3-yl.

[0294] 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-hydroxy cyclohexyl, pyrimidin-2-yl, pyrimidin-2-ylmethyl, pyrimidin-3- ylmethyl, pyrimidin-4-ylmethyl, oxalyl, 2-methoxyethyl, benzyl, 4-carboxybenzyl, 4-WSGR Docket No. 59915-715.601 carboxymethylbenzyl, tetrahydro-2H-pyran-4-yl, oxetan-3-yl, l,2,4-thiadiazol-5-yl, 4-aminomethyl-1.2.3-triazol-l-ylmethyl, 4-methyl-l,2,3-thiadiazolyl-5-ylmethyl, benzo [d]thiazol-2-yl, 4-carboxylethyl-1.2.3-thiadiazolyl-5-ylmethyl, 4-carboxy- l,2,3-thiadiazolyl-5-ylmethyl, isoindoline- 1, 3-dion-2-yl, or acetyl.

[0295] 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, benzotriazolyl, morpholinyl, pyrrolidinyl, or piperidinyl.

[0296] 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 lH-l,2,3-triazol- I-yl, l / / -bcnzo|d|| 1.2.31 triazol- 1 -y I. morpholinyl, 3,3-difluoropyrrolidin-l-yl, 4,4-difluoropiperidin-l-yl, pyrazolidin-4-one, and 4-benzylpiperidin-l-yl.

[0297] 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.

[0298] 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-Ce)haloalkyl, (Ci-Ce)haloalkyloxy (e.g., trifluoromethoxy), or halogen, wherein Rdand Reare independently hydrogen or (Ci-Ce)alkyl.

[0299] 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-Ce)haloalkyl, (Ci-Ce)haloalkyloxy (e.g., trifluoromethoxy), or halogen, wherein Rdand Reare independently hydrogen or (Ci-Ce)alkyl.

[0300] In some embodiments, R3is phenyloxy, which is unsubstituted. 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.

[0301] 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-C6)haloalkyloxy (e.g., trifluoromethoxy), and halogen, wherein Rdand Reare independently hydrogen or (Ci-Ce)alkyl.WSGR Docket No. 59915-715.601

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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-Ce)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.

[0306] 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, (Cs-C^heteroaryl, (Ci-C9)heterocyclyl, or naphthalenyl, each of which is substituted or unsubstituted, or halogen.

[0307] In some embodiments, R3is independently at each occurrence halogen, (Ci-Cio)alkyl, (Ci- Cio)haloalkyl, 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, (Cs-C^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.

[0308] In some embodiments, R3is independently at each occurrence methyl, ethyl, propyl, w-butyl. secbutyl, / -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-1- yl)methoxy, (adamantan-2-yl)methoxy, (adamantan-l-yl)oxy, (adamantan-2-yl)oxy, cyclopentyloxy,WSGR Docket No. 59915-715.601 cyclohexyloxy, fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethoxy, trifluoroethoxy, phenyl, 2-chlorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3- bromophenyl, 4-bromophenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 4-bromophenyl, 2- methoxyphenyl, 3 -methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3 -methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3 -trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-cyanophenyl, 3- cyanophenyl, 4-cyanophenyl, 3-amino-4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,3- dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3, 5 -dimethoxyphenyl, 3-iodo-4- chlorophenyl, benzo[d][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- (trifluoromethoxy)phenoxy, 2-chlorophenoxy, 3 -chlorophenoxy, 4-chlorophenoxy, 2-fluorophenoxy, 3- fluorophenoxy, 4-fluorophenoxy, 2,4-dichlorophenoxy, 3, 5 -difluorophenoxy, 2-cyanophenoxy, 3- cyanophenoxy, 4-cyanophenoxy, 2-acetylphenoxy, 3 -acetylphenoxy, 4-acetylphenoxy, 3-chloro-5- cyanophenoxy, 2-chloro-4-cyanophenoxy, IH-indol-l-yl, 4-methylsulfonylphenoxy, -C(O)-NHPh, -NH- C(O)Ph, -C(O)-NHcyclohexyl, -NH-C(O)cyclohexyl, 2-(acetamido)phenyl, 2-carboxyphenyl, 3- carboxyphenyl, 4-carboxyphenyl, 2-carboxamidophenyl, 3-carboxamidophenyl, 4-carboxamidophenyl, 2-hydroxyphenyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, 2-(2 -oxyacetic acid phenyl), 3 -(2 -oxyacetic acid phenyl), 4-(2 -oxyacetic acid phenyl), 2-oxopyrrolidin-l-yl, 3-(trifluoromethyl)-lH-pyrazol-4-yl, pyridyl, naphthalene- 1-yl, naphthalene-2-yl, -S(O)2Ph, 2-oxopyridin-l(2H)-yl, indolyl, phenylsulfonyl, 2- hydroxymethylpyrrolidiny-l-yl, or hydroxypiperidine- 1-yl.

[0309] 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.

[0310] In some embodiments, R3is 2-(trifluoromethyl)phenoxy. In some embodiments, R3is 3- (trifluoromethyl)phenoxy. In some embodiments, R3is 4-(trifluoromethyl)phenoxy. In some embodiments, R3is 2-(trifluoromethoxy)phenoxy. In some embodiments, R3is 3- (trifluoromethoxy)phenoxy. In some embodiments, R3is 4-(trifluoromethoxy)phenoxy. In some embodiments, R3is 2-chlorophenoxy.

[0311] In some embodiments, R3is phenoxy.

[0312] In some embodiments, R3is 3 -chlorophenoxy.

[0313] In some embodiments, R3is 4-chlorophenoxy.

[0314] In some embodiments, R3is 2-fluorophenoxy.

[0315] In some embodiments, R3is 3 -fluorophenoxy.

[0316] In some embodiments, R3is 4-fluorophenoxy.

[0317] In some embodiments, R3is 2,4-dichlorophenoxy.

[0318] In some embodiments, R3is 3, 5 -difluorophenoxy.

[0319] 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.WSGR Docket No. 59915-715.601

[0320] In some embodiments, R4is methyl.

[0321] In some embodiments, R4is hydrogen.

[0322] 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.

[0323] Non-limiting examples of compounds of formula (V) are: (2R,5S)-5-(aminomethyl)-2-[4-(3,5- difluorophenoxy)phenyl] - 1 ,4-thiazepan-3 -one; (2R,5 S)-5 -(aminomethyl)-2-(4-bromophenyl)- 1,4- 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)- 1 ,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)- 1 ,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)- 1 ,4-thiazepan-3 -one ; (2R,5 S)-5 - (aminomethyl)-2-(2-phenoxyphenyl)-l,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)-2-(4- methoxyphenyl)- 1 ,4-thiazepan-3 -one ; (2R,5 S)-5 -(aminomethyl)-2-[4-(trifluoromethyl)phenyl] -1,4- thiazepan-3 -one ; (2R,5 S)-5 -(aminomethyl)-2-(4-benzyloxyphenyl)- 1 ,4-thiazepan-3 -one ; (2R,5 S)-5 - (aminomethyl) -2- [3 -(trifluoromethyl)phenyl] - 1 ,4-thiazepan-3 -one ; (2R, 5 S) -5 -(aminomethyl) -2-(3 - phenylphenyl)- 1 ,4-thiazepan-3-one; (2R,5 S)-5-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl] - 1 ,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) - 1 ,4-thiazepan-3 -one ; (2R,5 R) -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,5S)-5-(aminomethyl)-2-[3-[3-(trifluoromethyl)-lH- pyrazol-4-yl]phenyl] - 1 ,4-thiazepan-3 -one ; (2R,5 S)-5 -(aminomethyl)-2-(3 -iodophenyl)- 1 ,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-I,4-thiazepan-2-yl]phenyl]benzonitrile; 3-[3-WSGR Docket No. 59915-715.601[(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]-1.4-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,5 S)-5 -(aminomethyl)-2-[3 -(4-methoxyphenyl)phenyl] - 1 ,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- ( 1 ,3 -benzodioxol-5 -yl)phenyl] - 1 ,4-thiazepan-3 -one; (2R,5 S)-5 -(aminomethyl)-2- [3 -( 1 ,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,5 S)-5 -(aminomethyl)-2-[3 -(2,6-dichlorophenyl)phenyl] - 1 ,4-thiazepan-3 -one;(2R,5 S)-5 -(aminomethyl)-2-(2-bromo-5 -phenoxy-phenyl)- 1 ,4-thiazepan-3 -one; (2R,5 S)-5 - (aminomethyl)-2-(2-naphthyl)- 1 ,4-thiazepan-3 -one; (2R,5 S)-5 -(aminomethyl)-2-( 1 -naphthyl)- 1,4- 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] - 1 ,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] - 1 ,4-thiazepan-3 -one; (2 S,5 S)-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,5 S)-5 -(aminomethyl)-2-[3 -(4-chloro-3 -iodo-phenyl)phenyl] - 1 ,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] - 1 ,4-thiazepan-3 -one; (2R,5 S)-5 -(aminomethyl)-2-(3 -cyclohexylphenyl)- 1 ,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] - 1 ,4-thiazepan-3 -one; (2R,5 S)-2-[3 -(4-chlorophenyl)phenyl] -5 -(morpholinomethyl)-l,4-thiazepan-3-one; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-(morpholinomethyl)-1.4-thiazepan-3 -one ; (2R,5 S)-2-[3 -(4-chlorophenyl)phenyl] -5 - [(3 ,3 -difluoropyrrolidin- 1 -yl)methyl] -1,4- thiazepan-3 -one ; (2S,5 S)-2- [3 -(4-chlorophenyl)phenyl] -5 -[(3 ,3 -difluoropyrrolidin- 1 -yl)methyl] -1,4- thiazepan-3 -one ; (2R,5 S ) -2 - [3 -(2-chlorophenyl)phenyl] -5 -[(3 ,3 -difluoropyrrolidin- 1 -yl)methyl] -1,4- thiazepan-3-one; N-[2-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]phenyl]acetamide;WSGR Docket No. 59915-715.601(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-1.4-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,5S)-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,5S)-5-(aminomethyl)-2-[3-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]phenyl]-l,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]-1.4-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,5S)-5-(aminomethyl)-2-(4- phenoxy-3 -propyl -phenyl)- 1 ,4-thiazepan-3 -one ; (2R,5 S)-5 -(aminomethyl)-2-(3 -chloro-4-phenoxy- phenyl)- 1 ,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] - 1 ,4-thiazepan-3-one; 4-[4-[(2R,5 S)-5-(aminomethyl)-3-oxo- 1 ,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] - 1 ,4-thiazepan-3 -one ; (2R,5 S)-5 -(aminomethyl)-2-(2 -methyl -4-phenoxy-phenyl)-1.4-thiazepan-3 -one ; (2R,5 S)-5 -(aminomethyl)-2-dibenzofuran-2-yl- 1 ,4-thiazepan-3 -one; (2R,5 S)-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,5 S)-2-[4-(4-acetylphenoxy)phenyl] -5 -(aminomethyl)- 1 ,4- thiazepan-3 -one ; (2R,5 S)-5 -(aminomethyl)-2-[4-( 1 ,3 -benzodioxol-5 -yloxy)phenyl] - 1 ,4-thiazepan-3 -one ;3 -[4- [(2R,5 S)-5 -(aminomethyl)-3 -oxo- 1 ,4-thiazepan-2-yl]phenoxy] -5 -chloro-benzonitrile; (2R,5 S)-5 -WSGR Docket No. 59915-715.601(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)- 1 ,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,5 S)-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]- 1 ,4-thiazepan-3 -one ; (2R,5 S)-2-[3 -(4-chlorophenyl)phenyl] -5 -[(pyrimidin-2-ylamino)methyl] -1,4- thiazepan-3-one; (2R,5S)-5-[(pyrimidin-2-ylamino)methyl]-2-[3-[4-(trifluoromethyl)phenoxy]phenyl]- 1 ,4-thiazepan-3 -one ;(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-5-[(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one; (2R,5 S)-5 -[( 1 ,3 -benzothiazol-2-ylamino)methyl] -2-(4-phenoxyphenyl)- 1 ,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;WSGR Docket No. 59915-715.601N-[[(2R,5S)-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-carboxamide; l-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-carboxamide 6-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; 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,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-WSGR Docket No. 59915-715.601 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]urea N-[[(2R,5S)-2-[4-(4- chlorophenoxy)phenyl] -3 -oxo- 1 ,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, 5 S)-2-[3-(4-fluorophenoxy)phenyl] -3-oxo- 1 ,4-thiazepan-5-yl]methyl] - 1 -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- [( 1 ,2,4-thiadiazol-5 -ylamino)methyl] - 1 ,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 ;WSGR Docket No. 59915-715.601N-[[(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,5 S)-3 -oxo-2-(3 -phenoxyphenyl)- 1 ,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)- 1 ,4-thiazepan-3 -one ; (2R,5 S)-5 -(((( 1 r,3 S)-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] - 1 ,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,5S)- 5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one; (2R,5S)-5-(aminomethyl)- 2-[3 -(4-chlorophenyl)phenyl] -1,1 -dioxo- 1 ,4-thiazepan-3 -one ; (2R,5 S)-5 -(aminomethyl)- 1 , 1 -dioxo-2-(3 - phenoxyphenyl)- 1 ,4-thiazepan-3 -one ; (2R,5 S)- 1 , 1 -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; (2S,5S)-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; (2S,5S)-WSGR Docket No. 59915-715.6015-(aminomethyl)-2-[3-(2-chlorophenyl)phenyl]-l,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-(3- phenoxyphenyl)- 1 ,4-oxazepan-3 -one ; (2 S ,5 S)-5 -(aminomethyl)-2-[3 -(4-methoxyphenyl)phenyl] -1,4- oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(p-tolyl)phenyl]-l,4-oxazepan-3-one; (2S,5S)-5- (aminomethyl)-2-[4-(4-methoxyphenyl)phenyl]-l,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(4- chlorophenyl)phenyl]-l,4-oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[4-(2-chlorophenyl)phenyl]-l,4- oxazepan-3-one; (2S,5S)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-l,4-oxazepan-3-one; (2S,5S)-2-[3-(4- chlorophenyl)phenyl]-5-(methylaminomethyl)-l,4-oxazepan-3-one; (2S,5S)-2-[3-(4- chlorophenyl)phenyl] -5 -(dimethylaminomethyl) - 1 ,4-oxazepan-3 -one ; (2 S, 5 S) -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] - 1 ,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,5S)-5- (benzotriazol-l-ylmethyl)-2-(4-phenoxyphenyl)-l,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.

[0324] 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; (2S,5S)-5-(aminomethyl)-2-[3-(4-WSGR Docket No. 59915-715.601 chlorophenyl)phenyl]-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof; (2S,5S)-5- (aminomethyl)-2-(3-phenoxyphenyl)-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof; (2S,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2,2,2-trifhioroethylamino)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] -1,4 -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, 5 S ) -2 - [4 -( 3 ,5 -difluorophenoxy )phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - 1 -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,5S)-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,5S)-2-(4- phenoxyphenyl)-5-(piperazine-l-carbonyl)-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof; (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin-2-yhnethylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof; (2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-5-[(2,2,2- trifhioroethylamino)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- 1 -yl)methoxy)phenyl)-5-(aminomethyl)- 1 ,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof; (2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-2- methyl-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.

[0325] In some embodiments, the compound of formula (V) is (2R,5S)-5-(aminomethyl)-2-[4-(3,5- difluorophenoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

[0326] In some embodiments, the compound of formula (V) is (2R,5S)-5-(aminomethyl)-2-[3-(4- chlorophenyl)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

[0327] In some embodiments, the compound of formula (V) is (2R,5S)-5-(aminomethyl)-2-[4-(2,2- dimethylpropoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

[0328] In some embodiments, the compound of formula (V) is (2S,5S)-5-(aminomethyl)-2-[3-(4- chlorophenyl)phenyl]-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof.WSGR Docket No. 59915-715.601

[0329] In some embodiments, the compound of formula (V) is (2R,5S)-2-(4-phenoxyphenyl)-5- [(pyrimidin-2-ylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

[0330] In some embodiments, the compound of formula (V) 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.

[0331] In some embodiments, the compound of formula (V) is (2R,5S)-5-(aminomethyl)-2-(4- phenoxyphenyl)-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

[0332] 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.

[0333] 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, C>, C10, C11, C12, C13, C14, C15, Cie, 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.

[0334] 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.

[0335] 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, sec-butyl, and t- butyl. Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1 -chloroethyl, 2-hydroxyethyl, 1 ,2-difluoroethyl, and 3 -carboxypropyl.

[0336] 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- 1 -yl, 4-hydroxycyclohex- 1 -yl, 3 ,3 ,5 -trimethylcyclohex- 1 -yl, octahydropentalenyl, octahydro- IH-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-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,WSGR Docket No. 59915-715.601 bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. In some embodiments, each cycloalkyl is independently (C3-C 1 o)cycloalkyl .

[0337] 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, Ce, C7, Cs, C >, 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 .

[0338] 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, 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. 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- 1 -yl .

[0339] 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.

[0340] 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.

[0341] 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. ForWSGR Docket No. 59915-715.601 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.

[0342] 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. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl. Nonlimiting examples of substituted aryl groups include 3,4-dimethylphenyl, 4-tert-buty 1 phenyl, 4- cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-(difluoromethoxy)-phenyl, 4- (trifluoromethoxy)phenyl, 3 -chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 2- chlorophenyl, 2-iodophenyl, 3 -iodophenyl, 4-iodophenyl, 2-methylphenyl, 3 -fluorophenyl, 3- methylphenyl, 3 -methoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,3 -difluorophenyl,3.4-difluorophenyl, 3, 5 -difluorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3, 5 -dichlorophenyl, 2- hydroxyphenyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3 -methoxyphenyl, 4- methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,4-difluorophenyl,2.5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6- trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6- dichlorophenyl, 3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl,2.4.5 -trichlorophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3 -dimethylphenyl, 2,4- dimethylphenyl, 2,5 -dimethylphenyl, 2,6-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl,2.3.6-trimethylphenyl, 2,4,5 -trimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 3 -ethylphenyl, 4- ethylphenyl, 2,3 -diethylphenyl, 2,4-diethylphenyl, 2,5 -diethylphenyl, 2,6-diethylphenyl, 3,4- diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5 -triethylphenyl, 2,4,6- triethylphenyl, 2-isopropylphenyl, 3 -isopropylphenyl, and 4-isopropylphenyl. In some embodiments, each aryl is independently phenyl, naphthyl, or biphenyl. In some embodiments, each aryl is independently (C4-Cio)aryl.

[0343] 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 (Ci-C9)heterocycloalkyl.

[0344] Non-limiting examples of substituted aryl groups include 2-aminophenyl, 2-(N- methylamino)phenyl, 2-(A'A'-dimcthylamino)phcnyl. 2-(A'-cthylamino)phcnyl. 2-(N,N- diethylamino)phenyl, 3 -aminophenyl, 3-(A'-mcthylamino)phcnyl. 3-(A'.A'-dimcthylamino)phcnyl. 3-(N- ethylamino)phenyl, 3-(A'.A'-dicthylamino)phcnyl. 4-aminophenyl, 4-(A'-mcthylamino)phcnyl. 4-(N,N- dimethylamino)phenyl, 4-(A'-cthylamino)phcnyl. and 4-(A'.A'-dicthylamino)phcnyl.WSGR Docket No. 59915-715.601

[0345] 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 -O-(C4- Cio)aryl.

[0346] 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 (Cs-C^heterocyclyl. In some embodiments, each heterocyclyl is independently (CAO,) heterocyclyl.

[0347] 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- 1H- azepinyl, 2,3-dihydro-lH-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- 1H- pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-l / / -benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-l / / -indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro- l / / -cycloocta[b]pyrrolyl.

[0348] Non-limiting examples of heteroaryl include: i) heteroaryl rings containing a single ring, nonlimiting examples of which include, 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, triazinyl, thiazolyl, I / / -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, non-limiting examples of which include: 727-purinyl, 927-purinyl, 6-amino-9 / / -purinyl. 5 / / -py rrolo 13.2 / | pyrimidinyl. 7 / / -pyrrolo|2.3- d'lpyrimidinyl. pyrido|2.3-t / |pyrimidinyl. 4,5,6,7-tetrahydro-l- / / -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 (Cs-C^heteroaryl. In some embodiments, each heteroaryl is a 5- or 6-membered heteroaryl.

[0349] 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.WSGR Docket No. 59915-715.601

[0350] 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.

[0351] 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, at least 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.

[0352] 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.

[0353] 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. TheWSGR Docket No. 59915-715.601 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

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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, JV-methyhnorpholine, piperidine, N- methylpiperidine, A'-cthylpipcridinc. dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.

[0358] 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 '-mcthylmorpholinc salt, a piperidine salt, an A'-mcthylpipcridinc salt, an '-cthylpipcridinc 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.

[0359] 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, methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.WSGR Docket No. 59915-715.601

[0360] 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 methane sulfonate salt, an ethane sulfonate salt, a benzene sulfonate salt, a p -toluene sulfonate salt, a citrate salt, an oxalate salt, or a maleate salt.

[0361] 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

[0362] In some embodiments, the present disclosure provides a compound that treats conditions, disorders, and diseases associated with Ryanodine Receptors (Ry Rs).

[0363] 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 RyR 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, compounds 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).

[0364] In some embodiments, the present disclosure provides a method of treating skeletal muscle dysfunction (e.g., fatigue or weakness) in a heart failure patient by administering to a subject in need thereof a therapeutically -effective amount of a compound disclosed herein, e.g., a compound of formula (I), (II), (III), (IV) or (V) as described herein, or any compound encompassed by such formula, 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.

[0365] In some embodiments, the present disclosure provides a compound, e.g., a compound of formula (I), (II), (III), (IV) or (V) as described herein, or any compound encompassed by such formula, or a pharmaceutically-acceptable salt thereof, for use in a method of treating or reducing a likelihood of occurrence of a condition.WSGR Docket No. 59915-715.601

[0366] In some embodiments, the present disclosure provides a compound, e.g., a compound of formula (I), (II), (III), (IV) or (V) as described herein, or any compound encompassed by such formula, or a pharmaceutically-acceptable salt thereof, for use in the manufacture of a medicament.

[0367] In some embodiments, the present disclosure provides a method of treating skeletal muscle dysfunction (e.g., fatigue or weakness) in a heart failure patient by administering to a subject in need thereof a therapeutically-effective amount of a Compound of formula (I) or a pharmaceutically- acceptable salt thereof (e.g., the hemi-fumarate salt). 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.

[0368] In some embodiments, the present disclosure provides a compound, e.g., a compound of formula (I) or a pharmaceutically-acceptable salt thereof(e.g., the hemi-fumarate salt), for use in a method of treating or reducing a likelihood of occurrence of a condition.

[0369] In some embodiments, the present disclosure provides a compound, e.g., a compound of formula (I) or a pharmaceutically-acceptable salt thereof (e.g., the hemi-fumarate salt), for use in the manufacture of a medicament.

[0370] 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.

[0371] 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 a heart failure patient. For example, a compound of the present disclosure can be used to improve both cardiac and skeletal muscle function in a heart failure patient.

[0372] 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.

[0373] In some embodiments, compounds of the present disclosure can preferentially bind to leaky RyR channels as compared with non-leaky channels. For example, where a subject has a condition or disease characterized by leaky RyRl, the compounds of the present disclosure can preferentially bind to and repair the leak in RyRl compared with (non-leaky) RyR2. Where a subject has a condition or disease characterized by leaky RyR2, the compounds of the present disclosure can preferentially bind to and repair the leak in RyR2 compared with (non-leaky) RyRl. Where a subject has a condition or disease characterized by leaky RyRl and RyR2 (e.g., a heart failure patient having skeletal muscle weakness), the compounds of the present disclosure can bind to and repair the leak in both RyRl and RyR2.Ryanodine Receptors: Excitation-contraction coupling (ECC) process.WSGR Docket No. 59915-715.601

[0374] The sarcoplasmic reticulum (SR) is a structure in cells that functions, among other things, as a specialized intracellular calcium (Ca2+) store. Ryanodine receptors (Ry Rs) are channels in the SR, which 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.

[0375] The RyR is the major Ca2+release channel on the SR responsible for excitation-contraction 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.

[0376] 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.

[0377] 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.

[0378] 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 the heart (diastole), thereby preventing diastolic calcium leak from the SR, and functionally couples groups of RyR2 channels to allow synchronous opening during excitation-contraction couplingWSGR Docket No. 59915-715.601

[0379] 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 calcium-dependent activation. The increased sensitivity leads to increased open probability and increased calcium release from the SR into the intracellular cytoplasm.Ryanodine Receptor 1 and Musculoskeletal Diseases.

[0380] 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.

[0381] 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.

[0382] Moreover, regulation of RyRl by posttranslational modifications other than phosphorylation, such as by nitrosylation of free sulfhydryl groups on cysteine residues (.S'-nitrosylation). and channel oxidation, can increase RyRl channel activity. .S'-nitrosylation and oxidation of RyRl each can reduce Calstabinl binding to RyRl .Heart Failure.

[0383] 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 RyRWSGR Docket No. 59915-715.601 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.

[0384] 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.

[0385] 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.

[0386] 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.

[0387] 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).

[0388] In some embodiments, the cardiac disorder or disease comprises cardiac ischemia / reperfusion (I / R) 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).

[0389] In some embodiments, the heart failure is characterized by an irregular heartbeat or an arrhythmia. In some embodiments, the heart failure is characterized by an atrial arrhythmia. In some embodiments, the heart failure is characterized by a ventricular arrhythmia. In some embodiments, the heart failure is characterized by atrial fibrillation. In some embodiments, the heart failure is characterized by ventricular fibrillation. In some embodiments, the heart failure is characterized by atrial tachyarrhythmia. In some embodiments, the heart failure is characterized by ventricular tachyarrhythmia. In some embodiments,WSGR Docket No. 59915-715.601 the heart failure is characterized by atrial tachycardia. In some embodiments, the heart failure is characterized by ventricular tachycardia. In some embodiments, the heart failure is characterized by a premature contraction (PC). In some embodiments, the heart failure is characterized by a premature ventricular contraction (PVC). In some embodiments, the heart failure is characterized by bigeminy. In some embodiments, the heart failure is characterized by sinus syndrome. In some embodiments, the heart failure is characterized by premature ventricular contraction couplet.PVCs in Heart Failure.

[0390] 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).

[0391] In some embodiments, ryanodine receptor channel modulators as described herein can be effective at treating heart failure that is characterized by PVCs. In some embodiments, compounds of the disclosure can reduce the number of PVCs in a heart failure patient. In some embodiments, compounds of the disclosure can reduce the PVC burden in a heart failure patient. In some embodiments, reduction of PVCs in a heart failure patient is indicative of target engagement, i.e., RyR2 engagement.

[0392] 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 the percentage of PVCs relative to the total number of heartbeats in a given time period .

[0393] In some embodiments, the PVC burden is at least about 0.1% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 0.2% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 0.3% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 0.4% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 0.5% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 0.6% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 0.7% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 0.8% of all heartbeats within a time period. In some embodiments, the PVC burden is at least about 0.9% of all heartbeats within a time period. 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.

[0394] 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 1WSGR Docket No. 59915-715.601 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.

[0395] 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.

[0396] 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.Skeletal Muscle Weakness in Heart Failure.

[0397] A 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 due to circulating inflammatory mediators, and this may play a role in the characteristic exercise intolerance and limitation in activities seen in heart failure patients.

[0398] 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.

[0399] Exercise capacity, measured by the peak oxygen consumption (VO2), is a prognostic marker in heart failure. The peak VO2 is affected by the ability to increase cardiac output and to extract 02 in peripheral tissues. The latter may be more important, as demonstrated by the failure of inotropic agents and vasodilators to improve exercise capacity, and the fact that fatigue remains following heart transplantation even if peak cardiac output is restored. Since fatigue and exercise intolerance in heart failure is independent of limb perfusion, these symptoms have been attributed to intrinsic skeletal muscle dysfunction. The mechanistic basis for this can be related to dysfunctional Ca2+handling.

[0400] Contraction of skeletal myocytes is dependent on triggered release into the cytoplasm of Ca2+. During muscle contraction, action potential-mediated activation of voltage gated L-type Ca2+ channels leads to increased cytoplasmic [Ca2+] mainly via opening of the ryanodine receptor (RyRl in skeletal muscle; RyR2 in cardiac muscle). Ca2+then binds to troponin C at the myofilaments and thereby enables actin-myosin cross-bridge formation. FKBP12 (Calstabinl) functions to stabilize the RyR in the closed state, thereby preventing spontaneous and pathological Ca2+leak from the sarcoplasmic reticulum, which otherwise could lead to contractile defects in the skeletal muscle. Post-translational modification of RyRlWSGR Docket No. 59915-715.601 driven by circulating inflammatory mediators involves excessive phosphorylation, S-nitrosylation and oxidation, which can negatively affect RyR-function. These modifications are linked to depletion of FKBP12 from the RyRl, perturbed Ca2+signaling and impaired muscle function.

[0401] Heart failure is associated with chronically elevated catecholamine levels and prolonged adrenergic stress leading to excessive phosphorylation of RyRl . In some embodiments, heart failure is associated with maladaptive remodeling of the skeletal muscle RyRl complex and that this may play a role in the characteristic exercise intolerance and limitation in activities of daily living seen in heart failure. In some embodiments, heart failure, skeletal muscle RyRl display excessive posttranslational modifications and FKBP12 depletion.

[0402] 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 improve both skeletal and cardiac muscle function 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.

[0403] 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), (II), (III), (IV) or (V) as described herein, or any compound encompassed by such formulae, or a pharmaceutically-acceptable salt thereof. In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) fixes calcium leak in RyRl and / or RyR2 channel of the subject.

[0404] 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 (e.g., the hemi-fumarate salt). In some embodiments, the compound of formula (I) fixes calcium leak in RyRl and / or RyR2 channel of the subject.

[0405] Skeletal muscle function can be assessed by exercise tolerance, strength and endurance. Exercise tolerance can be measured using VO2 max. Strength can be measured by grip and pinch strength. The six-minute walk test is used to measure both strength and endurance. Timed tests such as sit-to-stand measurements and four stair climb are also used to measure skeletal muscle function.

[0406] The following measurements can be used to assess muscle strength and functionality: Grip strength (kg), pinch strength (kg), quantitative muscle strength assessment (kg), time taken to complete each of the following (seconds): walk 10-meters, supine to stand, ascend 4 stairs, and descend 4 stairs, MFM-32 score for domains 1, 2, 3, and total (% of maximum score), PROMIS-fatigue subscale score (t- score), Muscle Assessment (QMA), Manual Muscle Testing (MMT), and Hand-Held Dynamometry (HHD) 10 Meter Walk Test (10-MWT), 1-Minute Sit-to-Stand Test, and 4 Stair Climb Test (4SCT).

[0407] Pulmonary Function tests, specifically Forced Vital Capacity (FVC) can be used to measure diaphragm strength.WSGR Docket No. 59915-715.601

[0408] In some embodiments, treatment with a compound of the disclosure reduces skeletal muscle weakness in the subject. In some embodiments, treatment with a compound of the disclosure improves skeletal muscle function in the subject. In some embodiments, treatment with a compound of the disclosure improves skeletal muscle strength in the subject. In some embodiments, treatment with a compound of the disclosure improves grip strength in the subject. In some embodiments, treatment with a compound of the disclosure improves pinch strength in the subject. In some embodiments, treatment with a compound of the disclosure improves pulmonary function in the subject. In some embodiments, treatment with a compound of the disclosure improves forced vital capacity in the subject. In some embodiments, treatment with a compound of the disclosure improves maximum oxygen consumption (VO2 max) in the subject. In some embodiments, treatment with a compound of the disclosure improves endurance in the subject, improves exercise capacity in the subject. In some embodiments, treatment with a compound of the disclosure improves exercise tolerance in the subject.

[0409] In some embodiments, treatment with a compound of the disclosure improves muscle weakness in a proximal muscle of the subject. In some embodiments, the proximal muscle is a deltoid muscle. In some embodiments, the proximal muscle is a shoulder muscle. In some embodiments, the proximal muscle is an upper arm muscle. In some embodiments, the proximal muscle is a hip muscle. In some embodiments, the proximal muscle is a thigh muscle. In some embodiments, the proximal muscle is a quadricep muscle. In some embodiments, the proximal muscle is a core muscle.

[0410] In some embodiments, treatment with a compound of the disclosure improves muscle weakness in a distal muscle of the subject. In some embodiments, the distal muscle is a hand muscle. In some embodiments, the distal muscle is a lower arm muscle. In some embodiments, the distal muscle is a lower leg muscle. In some embodiments, the distal muscle is a foot muscle.Combination Therapy.

[0411] In some embodiments, a compound of the disclosure (e.g., a compound of (I), (II), (III), (IV) or (V)) is administered to a subject before, after, or simultaneously to administration of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from a beta-blocker and a renin-angiotensin system inhibitor.

[0412] In some embodiments, the additional therapeutic agent is a beta-blocker. In some embodiments, the compound is administered in combination with a beta-blocker. In some embodiments, the beta blocker is administered in an amount sufficient to treat heart failure. In some embodiment, the beta blocker is administered in a dose according to recommended guidelines for treating heart failure. In some embodiments, the compound is administered in combination with a beta-blocker, wherein the beta blocker is administered in a reduced amount, wherein the reduced amount is about less than an amount used to treat heart failure in the subject in absence of the compound.

[0413] In some embodiments, the additional therapeutic agent is a renin-angiotensin system inhibitor. In some embodiments, the compound is administered in combination with a renin-angiotensin system inhibitor. In some embodiments, the renin-angiotensin system inhibitor is administered in an amount sufficient to treat heart failure. In some embodiment, the renin-angiotensin system inhibitor isWSGR Docket No. 59915-715.601 administered in a dose according to recommended guidelines for treating heart failure. In some embodiments, the compound is administered in combination with a renin-angiotensin system inhibitor, wherein the renin-angiotensin system inhibitor is administered in a reduced amount, wherein the reduced amount is about less than an amount used to treat heart failure in the subject in absence of the compound.

[0414] In some embodiments, the renin-angiotensin system inhibitor is an angiotensin receptor neprilysin inhibitor (ARNi). In some embodiments, the renin-angiotensin system inhibitor is an angiotensinconverting enzyme (ACE) inhibitor. In some embodiments, the renin-angiotensin system inhibitor is an angiotensin II receptor blocker (ARB).

[0415] In some embodiments, the additional therapeutic agent is an angiotensin receptor neprilysin inhibitor (ARNi). In some embodiments, the compound is administered in combination with an angiotensin receptor neprilysin inhibitor (ARNi). In some embodiments, the ARNi is administered in an amount sufficient to treat heart failure. In some embodiment, the ARNi is administered in a dose according to recommended guidelines for treating heart failure. In some embodiments, the compound is administered in combination with a an ARNi, wherein the ARNi is administered in a reduced amount, wherein the reduced amount is about less than an amount used to treat heart failure in the subject in absence of the compound.

[0416] In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme (ACE) inhibitor. In some embodiments, the compound is administered in combination with an angiotensin-converting enzyme (ACE) inhibitor. In some embodiments, the ACE inhibitor is administered in an amount sufficient to treat heart failure. In some embodiment, the ACE inhibitor is administered in a dose according to recommended guidelines for treating heart failure. In some embodiments, the compound is administered in combination with a Angiotensin-converting enzyme (ACE) inhibitor, wherein the ACE inhibitor is administered in a reduced amount, wherein the reduced amount is about less than an amount used to treat heart failure in the subject in absence of the compound.

[0417] In some embodiments, the additional therapeutic agent is an angiotensin II receptor blocker (ARB). In some embodiments, the compound is administered in combination with an angiotensin II receptor blocker (ARB). In some embodiments, the ARB is administered in an amount sufficient to treat heart failure. In some embodiment, the ARB is administered in a dose according to recommended guidelines for treating heart failure. In some embodiments, the compound is administered in combination with an angiotensin II receptor blocker (ARB), wherein the ARB is administered in a reduced amount, wherein the reduced amount is about less than an amount used to treat heart failure in the subject in absence of the compound.

[0418] In some embodiments, the additional therapeutic agent is a mineralocorticoid receptor antagonist (MRA). In some embodiments, the compound is administered in combination with a mineralocorticoid receptor antagonist (MRA). In some embodiments, the MRA is administered in an amount sufficient to treat heart failure. In some embodiment, the MRA is administered in a dose according to recommended guidelines for treating heart failure. In some embodiments, the compound is administered in combination with a mineralocorticoid receptor antagonist (MRA), wherein the MRA is administered in a reducedWSGR Docket No. 59915-715.601 amount, wherein the reduced amount is about less than an amount used to treat heart failure in the subject in absence of the compound.

[0419] In some embodiments, the additional therapeutic agent is a sodium-glucose cotransporter-2 (SGLT2) inhibitor. In some embodiments, the compound is administered in combination with a sodiumglucose cotransporter-2 (SGLT2) inhibitor. In some embodiments, the SGLT2 inhibitor is administered in an amount sufficient to treat heart failure. In some embodiment, the SGLT2 inhibitor is administered in a dose according to recommended guidelines for treating heart failure. In some embodiments, the compound is administered in combination with a sodium-glucose cotransporter-2 (SGLT2) inhibitor, wherein the SGLT2 inhibitor is administered in a reduced amount, wherein the reduced amount is about less than an amount used to treat heart failure in the subject in absence of the compound.

[0420] In some embodiments, the additional therapeutic agent is a glucagon-like peptide 1 (GLP-1) agonist. In some embodiments, the compound is administered in combination with a glucagon-like peptide 1 (GLP-1) agonist. In some embodiments, the GLP-1 agonist is administered in an amount sufficient to treat heart failure. In some embodiment, the GLP-1 agonist is administered in a dose according to recommended guidelines for treating heart failure. In some embodiments, the compound is administered in combination with glucagon-like peptide 1 (GLP-1) agonist wherein the GLP agonist is administered in a reduced amount, wherein the reduced amount is about less than an amount used to treat heart failure in the subject in absence of the compound.Subjects.

[0421] 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, preadolescents, children, toddlers, infants, neonates, and non-human animals. In some embodiments, a subject is a patient.

[0422] In some embodiments, the subject is a heart failure patient. In some embodiments, the subject has heart failure classified according to the New York Heart Association (NYHA) functional classification system. The NYHA (New York Heart Association) functional classification is a system used to categorize heart failure patients based on the severity of their symptoms and physical limitations during daily activity. In some embodiments, the subject has heart failure classified as NYHA Functional Classification I. In some embodiments, the subject has heart failure classified as NYHA Functional Classification II. In some embodiments, the subject has heart failure classified as NYHA Functional Classification III. In some embodiments, the subject has heart failure classified as NYHA Functional Classification IV.

[0423] In some embodiments, the subject is age 50 years and above. In some embodiments, the subject is an age of about 50 years to about 75 years. In some embodiments, the subject is an age of about 75 years to about 100 years. In some embodiments, the subject is at least 25 years, at least 30 years, at least 35 years, at least 40 years, at least 45 years, at least 50 years, at least 55 years, at least 60 years, at least 65WSGR Docket No. 59915-715.601 years, at least 70 years, at least 75 years, at least 80 years, at least 85 years, at least 90 years, at least 95 years, or at least 100 years.Pharmaceutical Compositions

[0424] 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.

[0425] 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 fdlers, 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.

[0426] 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 intraventricular 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.

[0427] 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,WSGR Docket No. 59915-715.601 sucrose, or lactose; glycerin, gum arabic, magnesium stearate, sodium stearyl fumarate, saline, sodium alginate, starch, talc and water, among others.

[0428] 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, intrastemal, intravascular, intravenous, parenchymatous, subcutaneous, or sublingual or by way of catheter into the subject's heart.

[0429] 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.

[0430] 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, N- methylpyrrolidone and the like, which increase the permeability of the skin 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.

[0431] 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 fdlers, 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.

[0432] 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%,WSGR Docket No. 59915-715.601 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.

[0433] 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%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, 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.

[0434] 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.

[0435] 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.

[0436] 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 profde, 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.

[0437] 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 inWSGR Docket No. 59915-715.601 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.

[0438] 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.

[0439] 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.

[0440] 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.

[0441] 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.

[0442] 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 orWSGR Docket No. 59915-715.601 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.

[0443] 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.

[0444] 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 gastric fluid. 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.

[0445] 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.WSGR Docket No. 59915-715.601

[0446] 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.

[0447] 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, delayed-release formulations release at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% at 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.

[0448] 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.

[0449] 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.

[0450] 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.

[0451] 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.

[0452] 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. InWSGR Docket No. 59915-715.601 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).

[0453] In some embodiments, the gastro-resistant formulation (e.g., tablet) 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.

[0454] In some embodiments, the gastro-resistant formulation (e.g., tablet) is administered to the study subject in daily doses. In some embodiments, the gastro-resistant formulation is administered to the study subject one time per day. In some embodiments, the gastro-resistant formulation is administered to the study subject two times per day. In some embodiments, the gastro-resistant formulation is administered to the study subject three times per day.

[0455] In some embodiments, the gastro-resistant formulation (e.g., tablet) is administered to the study subject on an at least daily basis for 14 days. In some embodiments, the gastro-resistant formulation is administered to the study subject on an at least daily basis for about 28 days. In some embodiments, the gastro-resistant formulation is administered to the study subject on an at least daily basis for about a month. In some embodiments, the gastro-resistant formulation is administered to the study subject on an at least daily basis for about 2 months, 3 months, 4 months, five months, six months, seven months, eight months, nine months, ten months, eleven months twelve months ( 1 year), 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years or longer. In some embodiments, the gastro-resistant formulation is administered to the study subject daily for the life of the subject.

[0456] In some embodiments, the pharmaceutical composition in unit dosage form comprises 4-[(7- methoxy-2, 3 -dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0457] In some embodiments, the gastro-resistant formulation (e.g., tablet) comprises an amount of 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate that is equivalent to about 20 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the gastro-resistant formulation (e.g., tablet) comprises an amount of 4-[(7-methoxy-2,3- dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate that is equivalent to about 50 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the gastro-resistant formulation (e.g., tablet) comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4- benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate that is equivalent to about 100 mg of 4-[(7- methoxy-2, 3 -dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the gastro-resistant formulation (e.g., tablet) comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-WSGR Docket No. 59915-715.601 benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate that is equivalent to about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 240 mg, or about 400 mg of 4-[(7-methoxy-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0458] 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.

[0459] 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.

[0460] Non-limiting examples of pharmaceutically-acceptable binders include microcrystalline cellulose, gum tragacanth, gum arabic, gelatin, polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose, and starch.

[0461] Non-limiting examples of pharmaceutically-acceptable disintegrants include roscarmellose sodium, sodium carboxymethyl starch, and crospovidone.

[0462] 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.

[0463] 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.

[0464] Non-limiting examples of pharmaceutically-acceptable plasticizers include triethyl citrate.

[0465] Non-limiting examples of pharmaceutically-acceptable surfactants include sodium laurylsulfate or polysorbates, polyvinyl alcohol (PVA), polyethylene glycols, polyoxyethylene- polyoxypropylene block copolymers known as “poloxamer”, polyglycerin fatty acid esters such as decaglyceryl monolaurate andWSGR Docket No. 59915-715.601 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.

[0466] 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.

[0467] Non-limiting examples of pharmaceutically-acceptable pigments or colorants include alumina (dried aluminum hydroxide), annatto extract, calcium carbonate, canthaxanthin, caramel, [3-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.

[0468] 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.

[0469] 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.

[0470] Non-limiting examples of wetting agents include glycerin, cetyl alcohol, and glycerol monostearate.

[0471] 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.

[0472] Non-limiting examples of antioxidants include sorbic acid, ascorbic acid, ascorbate, glycine, a- tocopherol, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

[0473] 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.WSGR Docket No. 59915-715.601

[0474] 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).

[0475] 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).

[0476] 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 -hydroxyethyl- 1 -piperazineethanesulfonic acid buffer (HEPES), 3-(N- morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC). Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremaphor, and potassium phosphate buffer.

[0477] 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.

[0478] In some embodiments, the gastro-resistant tablet comprises a core, a sub-coating layer substantially covering the core, and a coating layer substantially covering the sub-coating layer, wherein the core comprises 4-[(7-methoxy-2,3-dihydro-I,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, maltodextrin, colloidal anhydrous silica, and sodium stearyl fumarate; the sub-coating layer comprises hypromellose, microcrystalline cellulose, and stearic acid; and the coating layer comprises hypromellose acetate succinate, triethyl citrate, sodium lauryl sulfate, and talc.WSGR Docket No. 59915-715.601Dosing and Dosing Regimens

[0479] 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.

[0480] 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.

[0481] 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 50 to about 500 mg per day, for example about 50 mg per day, about 75 mg per day, about 100 mg per day, about 110 mg per day, about 120 mg per day, about 130 mg per day, about 140 mg per day, about 150 mg per day, about 160 mg per day, about 170 mg per day, about 180 mg per day, about 190 mg per day, about 200 mg per day, about 210 mg per day, about 220 mg per day, about 230 mg per day, about 240 mg per day, about 250 mg per day, about 260 mg per day, about 270 mg per day, about 280 mg per day, about 290 mg per day, about 300 mg per day, about 310 mg per day, about 320 mg per day, about 330 mg per day, about 340 mg per day, about 350 mg per day, about 360 mg per day, about 370 mg per day, about 380 mg per day, about 390 mg per day, about 400 mg per day, about 410 mg per day, about 420 mg per day, about 430 mg per day, about 440 mg per day, about 450 mg per day, about 460 mg per day, about 470 mg per day, about 480 mg per day, about 450 mg per day, or about 500 mg per day.

[0482] 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, fromWSGR Docket No. 59915-715.601 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.

[0483] A compound described herein can be present in a composition in an amount of about, or example, 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.

[0484] A compound described herein can be present in a composition in an amount of about, or example, 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.

[0485] In some embodiments, a suitable amount of the compounds (e.g., 4-[(7-methoxy-2,3-dihydro-l,4- benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof) 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 25 mg per day to about 500 mg per day. In some embodiments, the amount is about 50 mg per day to about 500 mg per day, about 100 mg per day to about 500 mg per day, about 150 mg per day to about 500 mg per day, about 200 mg per day to about 500 mg per day, about 250 mg per day to about 500 mg per day, about 300 mg per day to about 500 mg per day, 350 mg per day to about 500 mg per day, about 400 mg per day to about 500 mg perWSGR Docket No. 59915-715.601 day, about 450 mg per day to about 500 mg per day, about 25 mg per day to about 400 mg per day, about 50 mg per day to about 400 mg per day, about 75 mg per day to about 400 mg per day, about 100 mg per day to about 400 mg per day, about 125 mg per day to about 400 mg per day, about 150 mg per day to about 400 mg per day, about 175 mg per day to about 400 mg per day, about 200 mg per day to about 400 mg per day, about 225 mg per day to about 400 mg per day, about 250 mg per day to about 400 mg per day, about 15 mg per day to about 400 mg per day, about 300 mg per day to about 400 mg per day, about 325 mg per day to about 400 mg per day, about 350 mg per day to about 400 mg per day, about 375 mg per day to about 400 mg per day, about 25 mg per day to about 300 mg per day, about 50 mg per day to about 300 mg per day, about 75 mg per day to about 300 mg per day, about 100 mg per day to about 300 mg per day, about 125 mg per day to about 300 mg per day, about 150 mg per day to about 300 mg per day, about 175 mg per day to about 300 mg per day, about 200 mg per day to about 300 mg per day, about 225 mg per day to about 300 mg per day, about 250 mg per day to about 300 mg per day, about 275 mg per day to about 300 mg per day, about 25 mg per day to about 200 mg per day, about 50 mg per day to about 200 mg per day, about 75 mg per day to about 200 mg per day, about 100 mg per day to about 200 mg per day, about 125 mg per day to about 200 mg per day, about 150 mg per day to about 200 mg per day, or about 175 mg per day to about 200 mg per day. In some embodiments, the therapeutically effective amount is about 25 mg per day, about 50 mg per day, about 75 mg per day, about 100 mg per day, about 125 mg per day, about 150 mg per day, about 175 mg per day, about 200 mg per day, about 225 mg per day, about 250 mg per day, about 15 mg per day, about 300 mg per day, about 325 mg per day, about 350 mg per day, about 375 mg per day, about 400 mg per day, about 425 mg per day, about 450 mg per day, about 475 mg per day, or about 500 mg per day.

[0486] In some embodiments, a daily dose of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid hemifumarate is an amount that is equivalent to 200 mg of 4-[(7-methoxy- 2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, a daily dose of 4- [(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate is an amount that is equivalent to 200 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, a daily dose of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid hemifumarate is an amount that is equivalent to 300 mg of 4-[(7-methoxy- 2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, a daily dose of 4- [(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate is an amount that is equivalent to 400 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, a daily dose of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid hemifumarate is 470 mg.

[0487] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to 20 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the present disclosure provides a pharmaceutical composition comprising in unitWSGR Docket No. 59915-715.601 dosage form 23.5 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0488] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to 50 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the present disclosure provides a pharmaceutical composition comprising in unit dosage form 58.75 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0489] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to 100 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the present disclosure provides a pharmaceutical composition comprising in unit dosage form 117.5 mg of 4-[(7-methoxy-2, 3 -dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0490] In some embodiments, a therapeutically-effective amount of a pharmaceutical composition is administered to a subject, the pharmaceutical composition comprising in a unit dosage form a compound that is 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable excipient, wherein the administering is once daily, and the unit dosage form comprises about 20 mg to about 250 mg of 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate. In some embodiments, the unit dosage form comprises about 23.5 mg to about 250 mg, about 25 mg to about 250 mg, about 27.5 mg to about 250 mg, about 30 mg to about 250 mg, about 20 mg to about 235 mg, about 23.5 mg to about 235 mg, about 25 mg to about 235 mg, about 27.5 mg to about 235 mg, or about 30 mg to about 235 mg. In some embodiments, the unit dosage is about 20 mg, about 23.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 40 mg, about 50 mg, about 52.5 mg, about 55 mg, about 58.75 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 112.5 mg, about 115 mg, about 117.5 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid hemifumarate.

[0491] In some embodiments, a therapeutically-effective amount of a pharmaceutical composition is administered to a subject, the pharmaceutical composition comprising in a unit dosage form a compound that is 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable excipient, wherein the administering is once daily, the unit dosage form comprising an amount of 4-[(7-methoxy-2,3-dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 mg to about 250 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid. In some embodiments, the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-WSGR Docket No. 59915-715.601 benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 23.5 mg to about 250 mg, about 25 mg to about 250 mg, about 27.5 mg to about 250 mg, about 30 mg to about 250 mg, about 20 mg to about 200 mg, about 23.5 mg to about 200 mg, about 25 mg to about 200 mg, about 27.5 mg to about 200 mg, or about 30 mg to about 200 mg 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid In some embodiments, the unit dosage form comprises an amount of 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 mg, about 23.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 40 mg, about 50 mg, about 52.5 mg, about 55 mg, about 58.75 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 112.5 mg, about 115 mg, about 117.5 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg 4-[(7-methoxy-2,3-dihydro-l,4- benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0492] 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 5 mg / kg to about 50 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.

[0493] 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 / kg to about 10 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 50 mg / kg, about 10 mg / kg to about 20 mg / kg, about 250 mg / kg to about 2000 mg / kg, about 10 mg / kg to about 800 mg / kg, about 50 mg / kg to about 400 mg / kg, about 100 mg / kg to about 300 mg / kg, or about 150 mg / kg to about 200 mg / kg. In some embodiments, 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.

[0494] 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 0.01WSGR Docket No. 59915-715.601 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.

[0495] 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

[0496] Embodiment 1. A method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I):wherein,WSGR Docket No. 59915-715.601 n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R1is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R2is arylalkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, -SO2R7, - P(=O)R8R9, or -(CH2)m-R10;R3is acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or substituted; or H, -CO2Y, or -C(=O)NHY ;Y is alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R4is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H; each R5is acyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or - NR15R16, -(CH2)tNR15R16, -NHNR15R16, -NHOH, -OR15, -C(=O)NHNR15R16, -CO2R15, - C(=O)NR15R16, or -CH2X; each R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NHNR15R16, -NHOH, -NR15R16, or -CH2X; each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X; each R8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH;- each R10is -NR15R16, OH, -SO2R11, -NHSO2R11, -C(=O)(R12), -NHC=O(R12), -OC=O(R12), or -P(=O)R13R14; each R11, R12, R13, and R14is independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or H, OH, NH2, -NHNH2, or -NHOH; each X is independently halogen, -CN, -CO2R15, -C(=O)NR15R16, -NR15R16, -OR15, -SO2R7, or -P(=O)R8R9;WSGR Docket No. 59915-715.601 each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the N to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted; t is 1, 2, 3, 4, 5, or 6; and m is 1, 2, 3, or 4; or a pharmaceutically-acceptable salt thereof.

[0497] Embodiment 2. The method of embodiment 1, wherein the compound is:wherein R is COOH, or a pharmaceutically-acceptable salt thereof.

[0498] Embodiment 3. The method of embodiment 1, wherein the compound is:or a pharmaceutically-acceptable salt thereof.

[0499] Embodiment 4. The method of any one of embodiments 1-3, wherein the compound is the pharmaceutically-acceptable salt.

[0500] Embodiment 5. The method of embodiment 4, wherein the pharmaceutically-acceptable salt is a hemifumarate salt.

[0501] Embodiment 6. The method of any one of embodiments 1-5, wherein the treating decreases skeletal muscle weakness in the subject.

[0502] Embodiment 7. The method of any one of embodiments 1-6, wherein the treating improves skeletal muscle function in the subject.

[0503] Embodiment 8. The method of any one of embodiments 1-7, wherein the treating improves skeletal muscle strength in the subject.

[0504] Embodiment 9. The method of any one of embodiments 1-8, wherein the treating improves grip strength in the subject.WSGR Docket No. 59915-715.601

[0505] Embodiment 10. The method of any one of embodiments 1-9, wherein the treating improves pinch strength in the subject.

[0506] Embodiment 11. The method of any one of embodiments 1-10, wherein the skeletal muscle weakness comprises weakness in a proximal muscle of the subject.

[0507] Embodiment 12. The method of embodiment 11, wherein the proximal muscle is a deltoid muscle.

[0508] Embodiment 13. The method of embodiment 11, wherein the proximal muscle is a shoulder muscle.

[0509] Embodiment 14. The method of embodiment 11, wherein the proximal muscle is an upper arm muscle.

[0510] Embodiment 15. The method of embodiment 11, wherein the proximal muscle is a hip muscle.

[0511] Embodiment 16. The method of embodiment 11, wherein the proximal muscle is a thigh muscle.

[0512] Embodiment 17. The method of embodiment 11, wherein the proximal muscle is a quadricep muscle.

[0513] Embodiment 18. The method of embodiment 11, wherein the proximal muscle is a core muscle.

[0514] Embodiment 19. The method of any one of embodiments 1-10, wherein the skeletal muscle weakness comprises weakness in a distal muscle of the subject.

[0515] Embodiment 20. The method of embodiment 19, wherein the distal muscle is a hand muscle.

[0516] Embodiment 21. The method of embodiment 19, wherein the distal muscle is a lower arm muscle.

[0517] Embodiment 22. The method of embodiment 19, wherein the distal muscle is a lower leg muscle.

[0518] Embodiment 23. The method of embodiment 19, wherein the distal muscle is foot muscle.

[0519] Embodiment 24. The method of any one of embodiments 1-23, wherein the treating improves pulmonary function in the subject.

[0520] Embodiment 25. The method of any one of embodiments 1-24, wherein the treating improves forced vital capacity in the subject.

[0521] Embodiment 26. The method of any one of embodiments 1-25, wherein the treating improves maximum oxygen consumption (VO2 max) in the subject.

[0522] Embodiment 27. The method of any one of embodiments 1-26, wherein the treating improves endurance in the subject.

[0523] Embodiment 28. The method of any one of embodiments 1-27, wherein the treating improves exercise capacity in the subject.

[0524] Embodiment 29. The method of any one of embodiments 1-28, wherein the treating improves exercise tolerance in the subject.

[0525] Embodiment 30. The method of any one of embodiments 1-29, wherein the heart failure is congestive heart failure.

[0526] Embodiment 31. The method of any one of embodiments 1-30, wherein the heart failure is chronic heart failure.WSGR Docket No. 59915-715.601

[0527] Embodiment 32. The method of any one of embodiments 1-31, wherein the heart failure is heart failure with reduced ejection fraction.

[0528] Embodiment 33. The method of any one of embodiments 1-31, wherein the heart failure is heart failure with preserved ejection fraction.

[0529] Embodiment 34. The method of any one of embodiments 1-33, wherein the subject is a heart failure patient having an implantable cardioverter-defibrillator, wherein the implantable cardioverterdefibrillator is implanted in the patient.

[0530] Embodiment 35. The method of any one of embodiments 1-34, wherein the heart failure is acute heart failure.

[0531] Embodiment 36. The method of any one of embodiments 1-35, wherein the heart failure is right heart failure.

[0532] Embodiment 37. The method of any one of embodiments 1-36, wherein the heart failure is left heart failure.

[0533] Embodiment 38. The method of any one of embodiments 1-37, wherein the heart failure comprises myocardial infarction.

[0534] Embodiment 39. The method of any one of embodiments 1-38, wherein the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

[0535] Embodiment 40. The method of any one of embodiments 1-39, wherein the heart failure comprises cardiac ischemia / reperfiision injury.

[0536] Embodiment 41. The method of any one of embodiments 1-40, wherein the treating decreases calcium leak from a RyRl channel in the subject.

[0537] Embodiment 42. The method of any one of embodiments 1-41, wherein the treating decreases calcium leak from a RyR2 channel in the subject.

[0538] Embodiment 43. The method of any one of embodiments 1-42, wherein the treating decreases open probability (Po) of RyRl protein in the subject.

[0539] Embodiment 44. The method of any one of embodiments 1-43, wherein the treating decreases open probability (Po) of RyR2 protein in the subject.

[0540] Embodiment 45. The method of any one of embodiments 1-44, wherein the administering is oral.

[0541] Embodiment 46. The method of any one of embodiments 1-45, wherein the administering is once per day.

[0542] Embodiment 47. The method of any one of embodiments 1-45, wherein the administering is twice per day.

[0543] Embodiment 48. The method of any one of embodiments 1-47, wherein the compound is 4-[(7- methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof.

[0544] Embodiment 49. The method of embodiment 48, wherein the compound is provided in a solid dosage form.WSGR Docket No. 59915-715.601

[0545] Embodiment 50. The method of embodiment 49, wherein the solid dosage form is suitable for oral administration.

[0546] Embodiment 51. The method of embodiment 49 or 50, wherein the solid dosage form comprises a pharmaceutically-acceptable excipient.

[0547] Embodiment 52. The method of any one of embodiments 48-51, wherein the therapeutically- effective amount is about 50 mg to about 400 mg per day.

[0548] Embodiment 53. The method of any one of embodiments 48-51, wherein the therapeutically- effective amount is about 200 mg per day.

[0549] Embodiment 54. The method of embodiment 53, wherein the about 200 mg is administered once daily.

[0550] Embodiment 55. The method of embodiment 53, wherein the about 200 mg is administered in two daily doses of 100 mg.

[0551] Embodiment 56. The method of any one of embodiments 48-51, wherein the therapeutically- effective amount is about 300 mg.

[0552] Embodiment 57. The method of embodiment 56, wherein the about 300 mg is administered once daily.

[0553] Embodiment 58. The method of embodiment 56, wherein the about 300 mg is administered in two daily doses of 150 mg.

[0554] Embodiment 59. The method of any one of embodiments 48-51, wherein the therapeutically- effective amount is about 400 mg.

[0555] Embodiment 60. The method of embodiment 59, wherein the about 400 mg is administered once daily.

[0556] Embodiment 61. The method of embodiment 59, wherein the about 400 mg is administered in two daily doses of 200 mg.

[0557] Embodiment 62. The method of any one of embodiments 48-61, wherein the subject is an adult.

[0558] Embodiment 63. The method of embodiment 62, wherein the subject is 50 years or older.

[0559] Embodiment 64. The method of embodiment 62, wherein the subject is 60 years or older.

[0560] Embodiment 65. The method of embodiment 62, wherein the subject is 70 years or older.

[0561] Embodiment 66. The method of embodiment 62, wherein the subject is 80 years or older.

[0562] Embodiment 67. The method of any one of embodiments 48-61, wherein the subject is a child.

[0563] Embodiment 68. The method of any one of embodiments 48-67, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject as a pharmaceutical composition in unit dosage form, wherein the unit dosage form further comprises a pharmaceutically acceptable excipient.

[0564] Embodiment 69. The method of embodiment 68, wherein the unit dosage form is a tablet.

[0565] Embodiment 70. The method of embodiment 68 or 69, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarateWSGR Docket No. 59915-715.601 equivalent to about 20 to about 200 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid.

[0566] Embodiment 71. The method of any one of embodiments 68-70, wherein the unit dosage form comprises about 23.5 to about 235 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid hemifumarate.

[0567] Embodiment 72. The method of any one of embodiments 68-70, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid.

[0568] Embodiment 73. The method of any one of embodiments 68-70, wherein the unit dosage form comprises 23.5 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0569] Embodiment 74. The method of any one of embodiments 68-70, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 50 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid.

[0570] Embodiment 75. The method of any one of embodiments 68-70, wherein the unit dosage form comprises about 58.75 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0571] Embodiment 76. The method of any one of embodiments 68-70, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 100 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid.

[0572] Embodiment 77. The method of any one of embodiments 68-70, wherein the unit dosage form comprises about 117.5 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0573] Embodiment 78. A method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a solid dosage form comprising a therapeutically-effective amount of a compound of Formula (I):wherein, n is 0, 1, or 2;WSGR Docket No. 59915-715.601 q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R1is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R2is alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, - SO2R7, -P(=O)R8R9, or -(CH2)m-R10;R3is acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or substituted; or H, -CO2Y, or -C(=O)NHY ;Y is alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R4is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H; each R5is acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -NR15R16, -(CH2)tNR15R16, -NHNR15R16, -NHOH, -OR15, - C(=O)NHNR15R16, -CO2R15, -C(=O)NR15R16, or -CH2X; each R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NHNR15R16, -NHOH, -NR15R16, or -CH2X; each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X; each R8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH;- each R10is -NR15R16, OH, -SO2R11, -NHSO2R11, -C(=O)(R12), -NHC=O(R12), -OC=O(R12), or -P(=O)R13R14; each R11, R12, R13, and R14is independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or H, OH, NH2, -NHNH2, or -NHOH; each X is independently halogen, -CN, -CO2R15, -C(=O)NR15R16, -NR15R16, -OR15, -SO2R7, or -P(=O)R8R9;WSGR Docket No. 59915-715.601 each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the N to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted; t is 1, 2, 3, 4, 5, or 6; and m is 1, 2, 3, or 4; or a pharmaceutically-acceptable salt thereof.

[0574] Embodiment 79. The method of embodiment 78, wherein the compound is the pharmaceutically- acceptable salt.

[0575] Embodiment 80. The method of embodiment 79, wherein the pharmaceutically-acceptable salt is a hemifumarate salt.

[0576] Embodiment 81. The method of any one of embodiments 78-80, wherein the treating decreases skeletal muscle weakness in the subject.

[0577] Embodiment 82. The method of any one of embodiments 78-81, wherein the treating improves skeletal muscle function in the subject.

[0578] Embodiment 83. The method of any one of embodiments 78-82, wherein the treating improves skeletal muscle strength in the subject.

[0579] Embodiment 84. The method of any one of embodiments 78-83, wherein the treating improves grip strength in the subject.

[0580] Embodiment 85. The method of any one of embodiments 78-84, wherein the treating improves pinch strength in the subject.

[0581] Embodiment 86. The method of any one of embodiments 78-85, wherein the skeletal muscle weakness comprises weakness in a proximal muscle of the subject.

[0582] Embodiment 87. The method of embodiment 86, wherein the proximal muscle is a deltoid muscle.

[0583] Embodiment 88. The method of embodiment 86, wherein the proximal muscle is a shoulder muscle.

[0584] Embodiment 89. The method of embodiment 86, wherein the proximal muscle is an upper arm muscle.

[0585] Embodiment 90. The method of embodiment 86, wherein the proximal muscle is a hip muscle.

[0586] Embodiment 91. The method of embodiment 86, wherein the proximal muscle is a thigh muscle .

[0587] Embodiment 92. The method of embodiment 86, wherein the proximal muscle is a quadricep muscle.

[0588] Embodiment 93. The method of embodiment 86, wherein the proximal muscle is a core muscle.

[0589] Embodiment 94. The method of any one of embodiments 78-85, wherein the skeletal muscle weakness comprises weakness in a distal muscle of the subject.

[0590] Embodiment 95. The method of embodiment 94, wherein the distal muscle is a hand muscle.

[0591] Embodiment 96. The method of embodiment 94, wherein the distal muscle is a lower arm muscle.WSGR Docket No. 59915-715.601

[0592] Embodiment 97. The method of embodiment 94, wherein the distal muscle is a lower leg muscle.

[0593] Embodiment 98. The method of embodiment 94, wherein the distal muscle is a foot muscle.

[0594] Embodiment 99. The method of any one of embodiments 78-98, wherein the treating improves pulmonary function in the subject.

[0595] Embodiment 100. The method of any one of embodiments 78-99, wherein the treating improves forced vital capacity in the subject.

[0596] Embodiment 101. The method of any one of embodiments 78-100, wherein the treating improves maximum oxygen consumption (VO2 max) in the subject.

[0597] Embodiment 102. The method of any one of embodiments 78-101, wherein the treating improves endurance in the subject.

[0598] Embodiment 103. The method of any one of embodiments 78-102, wherein the treating improves exercise capacity in the subject.

[0599] Embodiment 104. The method of any one of embodiments 78-103, wherein the treating improves exercise tolerance in the subject.

[0600] Embodiment 105. The method of any one of embodiments 78-104, wherein the heart failure is congestive heart failure.

[0601] Embodiment 106. The method of any one of embodiments 78-105, wherein the heart failure is chronic heart failure.

[0602] Embodiment 107. The method of any one of embodiments 78-106, wherein the heart failure is heart failure with reduced ejection fraction.

[0603] Embodiment 108. The method of any one of embodiments 78-107, wherein the heart failure is heart failure with preserved ejection fraction.

[0604] Embodiment 109. The method of any one of embodiments 78-108, wherein the subject is a heart failure patient having an implantable cardioverter-defibrillator, wherein the implantable cardioverterdefibrillator is implanted in the patient.

[0605] Embodiment 110. The method of any one of embodiments 78-109, wherein the wherein the heart failure is acute heart failure.

[0606] Embodiment 111. The method of any one of embodiments 78-110, wherein the heart failure is right heart failure.

[0607] Embodiment 112. The method of any one of embodiments 78-111, wherein the heart failure is left heart failure.

[0608] Embodiment 113. The method of any one of embodiments 78-112, wherein the heart failure comprises myocardial infarction.

[0609] Embodiment 114. The method of any one of embodiments 78-113, wherein the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

[0610] Embodiment 115. The method of any one of embodiments 78-114, wherein the heart failure comprises cardiac ischemia / reperfusion injury.WSGR Docket No. 59915-715.601

[0611] Embodiment 116. The method of any one of embodiments 78-115, wherein the treating decreases calcium leak from a RyRl channel in the subject.

[0612] Embodiment 117. The method of any one of embodiments 78-116, wherein the treating decreases calcium leak from a RyR2 channel in the subject.

[0613] Embodiment 118. The method of any one of embodiments 78-117, wherein the treating decreases open probability (Po) of RyRl protein in the subject.

[0614] Embodiment 119. The method of any one of embodiments 78-118, wherein the treating decreases open probability (Po) of RyR2 protein in the subject.

[0615] Embodiment 120. The method of any one of embodiments 78-119, wherein the administering is oral.

[0616] Embodiment 121. The method of any one of embodiments 78-120, wherein the administering is once per day.

[0617] Embodiment 122. The method of any one of embodiments 78-120, wherein the administering is twice per day.

[0618] Embodiment 123. The method of any one of embodiments 78-122, wherein the compound is 4- [(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharmaceutically- acceptable salt thereof.

[0619] Embodiment 124. The method of embodiment 123, wherein the compound is provided in the solid dosage form.

[0620] Embodiment 125. The method of embodiment 124, wherein the solid dosage form is suitable for oral administration.

[0621] Embodiment 126. The method of embodiment 124 or 125, wherein the solid dosage form comprises a pharmaceutically-acceptable excipient.

[0622] Embodiment 127. The method of any one of embodiments 123-126, wherein the therapeutically- effective amount is about 50 mg to about 400 mg per day.

[0623] Embodiment 128. The method of any one of embodiments 123-127, wherein the therapeutically- effective amount is about 200 mg per day.

[0624] Embodiment 129. The method of embodiment 128, wherein the about 200 mg is administered once daily.

[0625] Embodiment 130. The method of embodiment 128, wherein the about 200 mg is administered in two daily doses of 100 mg.

[0626] Embodiment 131. The method of any one of embodiments 123-127, wherein the therapeutically- effective amount is about 300 mg per day.

[0627] Embodiment 132. The method of embodiment 131, wherein the about 300 mg is administered once daily.

[0628] Embodiment 133. The method of embodiment 131, wherein the about 300 mg is administered in two daily doses of 150 mg.WSGR Docket No. 59915-715.601

[0629] Embodiment 134. The method of any one of embodiments 123-127, wherein the therapeutically- effective amount is about 400 mg per day.

[0630] Embodiment 135. The method of embodiment 134, wherein the about 400 mg is administered once daily.

[0631] Embodiment 136. The method of embodiment 134, wherein the about 400 mg is administered in two daily doses of 200 mg.

[0632] Embodiment 137. The method of any one of embodiments 123-136, wherein the subject is an adult.

[0633] Embodiment 138. The method of embodiment 137, wherein the subject is 50 years or older.

[0634] Embodiment 139. The method of embodiment 137, wherein the subject is 60 years or older.

[0635] Embodiment 140. The method of embodiment 137, wherein the subject is 70 years or older.

[0636] Embodiment 141. The method of embodiment 137, wherein the subject is 80 years or older.

[0637] Embodiment 142. The method of any one of embodiments 123-136, wherein the subject is a child.

[0638] Embodiment 143. The method of any one of embodiments 123-142, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject as a pharmaceutical composition in unit dosage form, wherein the unit dosage form further comprises a pharmaceutically acceptable excipient.

[0639] Embodiment 144. The method of embodiment 143, wherein the unit dosage form is a tablet.

[0640] Embodiment 145. The method of embodiment 143 or 144, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 to about 200 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid.

[0641] Embodiment 146. The method of any one of embodiments 143-145, wherein the unit dosage form comprises about 23.5 to about 235 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid hemifumarate.

[0642] Embodiment 147. The method of any one of embodiments 143-145, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid.

[0643] Embodiment 148. The method of any one of embodiments 143-145, wherein the unit dosage form comprises 23.5 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0644] Embodiment 149. The method of any one of embodiments 132-145, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 50 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid.WSGR Docket No. 59915-715.601

[0645] Embodiment 150. The method of any one of embodiments 143-145, wherein the unit dosage form comprises about 58.75 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0646] Embodiment 151. The method of any one of embodiments 143-145, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 100 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid.

[0647] Embodiment 152. The embodiment of any one of embodiments 143-145, wherein the unit dosage form comprises about 117.5 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin- 4(5H)yl)methyl]benzoic acid hemifumarate.

[0648] Embodiment Bl. A method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (V):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;WSGR Docket No. 59915-715.601R4is 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.

[0649] Embodiment B2. The method of embodiment Bl, wherein X is sulphur.

[0650] Embodiment B3. The method of embodiment Bl or embodiment B2, wherein Y is C(O).

[0651] Embodiment B4. The method of embodiment Bl, wherein the compound is of formula (Va):

[0652] Embodiment B5. The method of any one of embodiments B1-B4, wherein Z is hydrogen.

[0653] Embodiment B6. The method of embodiment Bl, wherein the compound is of formula (Vb):

[0654] Embodiment B7. The method of any one of embodiments B1-B6, wherein n is 1.

[0655] Embodiment B8. The method of any one of embodiments B1-B7, wherein R' and R" are each hydrogen.

[0656] Embodiment B9. The method of any one of embodiments B1-B8, wherein R1and R2are each hydrogen.

[0657] Embodiment B10. The method of any one of embodiments B1-B8, wherein R1is hydrogen.

[0658] Embodiment Bll. The method of any one of embodiments B1-B8, wherein R1is methyl.

[0659] Embodiment B12. The method of any one of embodiments Bl-Bl 1, wherein R2is hydrogen.WSGR Docket No. 59915-715.601

[0660] Embodiment B13. The method of any one of embodiments B1-B8, BIO, and Bl 1, wherein R2is alkyl.

[0661] Embodiment B14. The method of any one of embodiments B1-B8, BIO, and Bl 1, wherein R2is C(O)Ra.

[0662] Embodiment B15. The method of any one of embodiments B1-B8, BIO, and Bl 1, wherein R2is C(O)Ra, wherein Rais ary l or heteroaryl, each of which is substituted or unsubstituted.

[0663] Embodiment B16. The method of any one of embodiments B1-B8, B10, and Bl 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.

[0664] Embodiment B17. The method of any one of embodiments B1-B8, B10, and Bl 1, wherein R2is C(O)Ra, wherein Rais pyrimidin-2-yl, pyrimidin-5-yl, 5-amino-pyrimidin-2-yl, 5-methoxy-pyrimidin-2- yl, lH-pyrazol-3-yl, 2-methyl-lH-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-pyridin-3-yl, 2-chloro-pyridin-3- yl, pyridin-4-yl, 3 -phenyl- lH-pyrazol-5-yl, lH-imidazol-4-yl, lH-imidazol-2-yl, 1 -methyl- IH-imidazol- 4-yl, 1 -methyl- IH-imidazol -2 -yl, thiazol-2-yl, thiazol-4-yl, 4-methyl-l,2,3-thiadiazol-5-yl, 5- pheny lisoxazol -3 -yl, 5 -(4-chlorophenyl)isoxazole-3 -yl, 5 -methy 1-3 -pheny lisoxazol-4-yl, 4-phenylthiazol- 2-yl, LH-tetrazol-5-yl, pyridazin-2-yl, pyridazin-3-yi,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- 1 -yl, 1 ,2,4-triazin-3 -yl, 4-methy lpyrid-2-ylamino, 3 -oxopiperazin- 1 -yl, 5 -(4-fluorophenyI)-1.3.4-oxadiazoI-2-yl, or piperazin- 1-yl.

[0665] Embodiment Bl 8. The method of any one of embodiments B1-B8, wherein R1and R2are each independently hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3 -hydroxy cyclobutyl, 3,3- difluorocyclobutyl, cyclohexyl, 2 -hydroxy cyclohexyl, 3 -hydroxy cyclohexyl, 4-hydroxy cyclohexyl, pyrimidin-2-yl, pyrimidin-2-ylmethyl, pyrimidin-3-ylmethyl, pyrimidin-4-ylmethyl, oxalyl, 2- methoxyethyl, benzyl, 4-carboxybenzyl, 4-carboxymethylbenzyl, tetrahydro-2H-pyran-4-yl, oxetan-3-yl,1.2.4-thiadiazol-5 -yl, 4-aminomethyl- 1 ,2,3 -triazol- 1 -ylmethyl, 4-methyl- 1 ,2,3 -thiadiazolyl-5 -ylmethyl, benzo[d]thiazol-2-yl, 4-carboxylethyl- 1,2, 3 -thiadiazolyl-5 -ylmethyl, 4-carboxy- 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.

[0666] Embodiment Bl 9. The method of any one of embodiments Bl -Bl 8, wherein R3is alkoxy, cycloalkyloxy, or aryloxy, each of which is substituted or unsubstituted, or halogen.

[0667] Embodiment B20. The method of any one of embodiments B1-B18, wherein R3is phenyloxy, which is substituted or unsubstituted.WSGR Docket No. 59915-715.601

[0668] Embodiment B21. The method of any one of embodiments Bl -Bl 8, 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.

[0669] Embodiment B22. The method of any one of embodiments Bl -Bl 8, wherein R3is independently at each occurrence alkyl, cyclohexyl, alkyloxy, cycloalkyloxy, 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, or naphthalenyl, each of which is substituted or unsubstituted, or halogen.

[0670] Embodiment B23. The method of any one of embodiments B1-B22, wherein R4is hydrogen.

[0671] Embodiment B24. The method of any one of embodiments B1-B23, wherein the compound is the pharmaceutically-acceptable salt.

[0672] Embodiment B25. The method of any one of embodiments B1-B24, wherein the pharmaceutically-acceptable salt is a sodium salt.

[0673] Embodiment B25. The method of embodiment Bl, wherein the compound is:(2R,5 S)-5 -(aminomethyl)-2-[4-(3 ,5 -difluorophenoxy )phenyl] - 1 ,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, 5 S)-2-(4-bromophenyl)-5 -(dimethylaminomethyl)- l,4-thiazepan-3 -one;(25.55)-5-(aminomethyl)-2-(4-bromophenyl)-l,4-thiazepan-3-one;(2R,5 S)-5 -(aminomethyl)-2-[4-(2-chlorophenyl)phenyl] - 1 ,4-thiazepan-3 -one ;(2R,5 S)-5 -(aminomethyl)-2-[4-(4-chlorophenyl)phenyl] - 1 ,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,5 S)-5 -[(4-benzyl- 1 -piperidyl)methyl] -2-(4-bromophenyl)- 1 ,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,5 S)-5 -(aminomethyl)-2-(3 -phenylphenyl)- 1 ,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;WSGR Docket No. 59915-715.601(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,5 S)-5 -(aminomethyl)-2-[3 -(4-methoxyphenoxy)phenyl] - 1 ,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,5 S)-5 -(aminomethyl)-2-[3 -(3 -chlorophenyl)phenyl] - 1 ,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,5 S)-5 -(aminomethyl)-2-[3 -(3 -pyridyl)phenyl] - 1 ,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,5 S)-5 -(aminomethyl)-2-[3 -( 1 ,3 -benzodioxol-5 -yl)phenyl] - 1 ,4-thiazepan-3 -one;(2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-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)-!, 4-thiazepan-3-one;WSGR Docket No. 59915-715.601(2R,5 S)-5 -(aminomethyl)-2-( 1 -naphthyl)- 1 ,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,5 S)-5 -(aminomethyl)-2-[3 -(o-tolyl)phenyl] - 1 ,4-thiazepan-3 -one ;(2R,5 S)-5 -(aminomethyl)-2-[3 -(p-tolyl)phenyl] - 1 ,4-thiazepan-3 -one ;(2R,5S)-5-(aminomethyl)-2-[3-(l-ethylpropyl)phenyl]-l,4-thiazepan-3-one;(2R,5S)-5-(arninomethyl)-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-(arninomethyl)-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,5 S)-5 -(aminomethyl)-3 -oxo- 1 ,4-thiazepan-2-yl]phenyl]benzamide ;N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]cyclohexanecarboxamide;(2R,5 S)-5 -(aminomethyl)-2-[3 -(4-fluorophenyl)phenyl] - 1 ,4-thiazepan-3 -one ;(2R,5 S)-5 -(aminomethyl)-2-(3 -cyclohexylphenyl)- 1 ,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,5 S ) -2 - [ 3 -(4-chlorophenyl)phenyl] -5 -[(3 ,3 -difluoropyrrolidin- 1 -yl)methyl] - 1 ,4-thiazepan-3 - one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4-thiazepan-3- one;(2R,5 S ) -2 - [ 3 -(2-chlorophenyl)phenyl] -5 -[(3 ,3 -difluoropyrrolidin- 1 -yl)methyl] - 1 ,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;WSGR Docket No. 59915-715.601(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,5 S)-5 -(aminomethyl)-2-[3 -(cyclohexoxy )phenyl] - 1 ,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,5S)-5-(aminomethyl)-2-(4-phenoxy-3-propyl-phenyl)-l,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,5 S)-5 -(aminomethyl)-2-[4-(cyclohexoxy)phenyl] - 1 ,4-thiazepan-3 -one ;(2R,5 S)-5 -(aminomethyl)-2-[4-(cyclopentoxy)phenyl] - 1 ,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,5 S)-5 -(aminomethyl)-2-[4-( 1 ,3 -benzodioxol-5 -yloxy)phenyl] - 1 ,4-thiazepan-3-one ;WSGR Docket No. 59915-715.6013-[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,5 S)-2-(3 -phenylphenyl) -5 -[(pyrimidin-2-ylamino)methyl] - 1 ,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, 5 S) -2 - [4 -(3 ,5 -difluorophenoxy )phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - 1 -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,5 S)-2-[3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[ [(2R,5 S)-2-[3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]thiazole-4- carboxamide;N-[ [(2R,5 S)-2-[3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] -4-methyl- thiadiazole-5-carboxamide;WSGR Docket No. 59915-715.601N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH-pyrazole-3- carboxamide;N-[ [(2R,5 S)-2-[3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-5 - carboxamide;6-amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-3- carboxamide;N-[ [(2R,5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,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-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- 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-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;WSGR Docket No. 59915-715.601N-[[(2R,5S)-2-[4-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[ [(2R, 5 S) -2 - [4 -(3 ,5 -difluorophenoxy )phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-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,5 S)-3 -oxo-2-[3 -[4-(trifluoromethyl)phenoxy]phenyl] - 1 ,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,5 S) -2 - [3 -(cyclohexoxy )phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;4.4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-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;WSGR Docket No. 59915-715.6012 - [ 5 -(4-chlorophenyl)isoxazol-3 -y 1] -N-[ [(2R,5 S)-3 -oxo-2-(4-phenoxyphenyl)- 1 ,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;1-(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 -morpholinoacetamide;N-[ [(2R,5 S)-2- [3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - 1 -methyl - imidazole-4-carboxamide;N-[ [(2R,5 S)-2- [3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - lH-pyrazole-3 - carboxamide;N-[ [(2R,5 S)-2-[4-(4-chlorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - 1 -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,5 S) -2 - [ 3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyridazine-3 - carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-2 -morpholinoacetamide;N-[ [(2R,5 S) -2 - [ 3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyridine-2- sulfonamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-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,5 S)-2-[4-(4-chlorophenoxy)phenyl] -5 -[( 1 ,2,4-thiadiazol-5 -ylamino)methyl] - 1 ,4-thiazepan-3 - one;WSGR Docket No. 59915-715.601N-[[(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,5 S)-2- [3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,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,5 S)-2-[4-(4-chlorophenoxy)phenyl] -3 -oxo- 1 ,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-[ [(2 S , 5 S) -2 - [4 -( 3 ,5 -difluorophenoxy )phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;N-[ [(2R,5R)-2-[4-(3 ,5 -difluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-l,4-thiazepan-5-yl]methyl]- 1 , 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-yhnethylamino)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,5 S ) -2 - [ 3 -(4-chlorophenyl)phenyl] -5 -[(cyclopropylamino)methyl] - 1 ,4-thiazepan-3 -one ;(2R,5 S)-5-[(cyclopropylamino)methyl] -2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3-one;(2R,5 S)-5-[(cyclobutylamino)methyl] -2-(4-phenoxyphenyl)- 1 ,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;WSGR Docket No. 59915-715.601(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,5 S)-5 - [[(3 ,3 -difluorocyclobutyl)amino]methyl] -2-(4-phenoxyphenyl)- 1 ,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-yhnethylamino)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,5 S)-5 -[(2,2,2-trifluoroethylamino)methyl] -2-[3 -[2-(trifluoromethyl)phenyl]phenyl] -1,4- thiazepan-3-one;(2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-l,4-thiazepan-3-one;(2R,5 S)-2-[3-(2,2-dimethylpropoxy)phenyl] -5 -[(2,2,2-trifluoroethylamino)methyl]- 1 ,4-thiazepan- 3 -one;(2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5 S)-5 -(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl] -1,1 -dioxo- 1 ,4-thiazepan-3-one ;(2R,5 S)-5-(aminomethyl)- 1 , 1 -dioxo-2-(3-phenoxyphenyl)- 1 ,4-thiazepan-3-one;(2R,5 S)- 1 , 1 -dioxo-2-(3 -phenoxyphenyl) -5 -[(2,2,2-trifluoroethylamino)methyl] - 1 ,4-thiazepan-3 - one;(2R,5 S)-5 - [(2 -oxopiperazin- 1 -yl)methyl] -2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3 -one;(2S,5 S)-5 -(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl] - 1 ,4-oxazepan-3 -one ;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(2S,5 S)-5 -(aminomethyl)-2-[3 -(2-chlorophenyl)phenyl] - 1 ,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;WSGR Docket No. 59915-715.601(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;(2S,5 S ) -2 - [3 -(4-chlorophenyl)phenyl] -5 -(methylaminomethyl)- 1 ,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-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyrimidine-2- carboxamide;6-amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-3- carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyridine-2- carboxamide;6-chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-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-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl] - 1 -methyl-imidazole- 2-carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl] - 1 -methyl-imidazole- 4-carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyridine-3 - carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyridine-4- carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyridazine-3 - carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-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-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,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,5 S)-2-(4-phenoxyphenyl)-5-(piperazine- 1 -carbonyl)- 1 ,4-thiazepan-3-one;(2R,5 S)-5 -(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl] -2 -methyl- 1 ,4-oxazepan-3 -one ;WSGR Docket No. 59915-715.601(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.

[0674] Embodiment B26. The method of embodiment Bl, wherein the compound is:(2R,5 S)-5 -(aminomethyl)-2-[4-(3 ,5 -difluorophenoxy )phenyl] - 1 ,4-thiazepan-3 -one, or a pharmaceutically-acceptable salt thereof;(2R,5 S)-5 -(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl] - 1 ,4-thiazepan-3 -one, or a pharmaceutically-acceptable salt thereof;(2R,5 S)-5 -(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl] - 1 ,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-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,5S)-2-(4-bromophenyl)-3-oxo-l,4-thiazepan-5-yl]methyl]-3-phenyl-lH-pyrazole-5- carboxamide...

Claims

1. WSGR Docket No. 59915-715.601CLAIMSWhat is claimed is:

1. A method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I):wherein, n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R1is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R2is arylalkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, -SO2R7, - P(=O)R8R9, or -(CH2)m-R10;R3is acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or substituted; or H, -CO2Y, or -C(=O)NHY ;Y is alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R4is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H; each R5is acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -NR15R16, -(CH2)tNR15R16, -NHNR15R16, -NHOH, -OR15, - C(=O)NHNR15R16, -CO2R15, -C(=O)NR15R16, or -CH2X;WSGR Docket No. 59915-715.601 each R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NHNR15R16, -NHOH, -NR15R16, or -CH2X; each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X; each R8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH;- each R10is -NR15R16, OH, -SO2Rn, -NHSO2Rn, -C(=O)(R12), -NHC=O(R12), -OC=O(R12), or -P(=O)R13R14; each R11, R12, R13, and R14is independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or H, OH, NH2, -NHNH2, or -NHOH; each X is independently halogen, -CN, -CO2R15, -C(=O)NR15R16, -NR15R16, -OR15, -SO2R7, or -P(=O)R8R9; each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the N to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted; t is 1, 2, 3, 4, 5, or 6; and m is 1, 2, 3, or 4; or a pharmaceutically-acceptable salt thereof.

2. The method of claim 1, wherein the compound is:wherein R is COOH, or a pharmaceutically-acceptable salt thereof.

3. The method of claim 1, wherein the compound is:WSGR Docket No. 59915-715.601or a pharmaceutically-acceptable salt thereof.

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

5. The method of claim 4, wherein the pharmaceutically-acceptable salt is a hemifumarate salt.

6. The method of claim 1, wherein the treating decreases skeletal muscle weakness in the subject.

7. The method of claim 1, wherein the treating improves skeletal muscle function in the subject.

8. The method of claim 1, wherein the treating improves skeletal muscle strength in the subject.

9. The method of claim 1, wherein the treating improves grip strength in the subject.

10. The method of claim 1, wherein the treating improves pinch strength in the subject.

11. The method of claim 1, wherein the skeletal muscle weakness comprises weakness in a proximal muscle of the subject.

12. The method of claim 11, wherein the proximal muscle is a deltoid muscle.

13. The method of claim 11, wherein the proximal muscle is a shoulder muscle.

14. The method of claim 11, wherein the proximal muscle is an upper arm muscle.

15. The method of claim 11, wherein the proximal muscle is a hip muscle.

16. The method of claim 11, wherein the proximal muscle is a thigh muscle.

17. The method of claim 11, wherein the proximal muscle is a quadricep muscle.WSGR Docket No. 59915-715.60118. The method of claim 11, wherein the proximal muscle is a core muscle.

19. The method of claim 1, wherein the skeletal muscle weakness comprises weakness in a distal muscle of the subject.

20. The method of claim 19, wherein the distal muscle is a hand muscle.

21. The method of claim 19, wherein the distal muscle is a lower arm muscle.

22. The method of claim 19, wherein the distal muscle is a lower leg muscle.

23. The method of claim 19, wherein the distal muscle is foot muscle.

24. The method of claim 1, wherein the treating improves pulmonary function in the subject.

25. The method of claim 1, wherein the treating improves forced vital capacity in the subject.

26. The method of claim 1, wherein the treating improves maximum oxygen consumption (VO2 max) in the subject.

27. The method of claim 1, wherein the treating improves endurance in the subject.

28. The method of claim 1, wherein the treating improves exercise capacity in the subject.

29. The method of claim 1, wherein the treating improves exercise tolerance in the subject.

30. The method of claim 1, wherein the heart failure is congestive heart failure.

31. The method of claim 1, wherein the heart failure is chronic heart failure.

32. The method of claim 1, wherein the heart failure is heart failure with reduced ejection fraction.

33. The method of claim 1, wherein the heart failure is heart failure with preserved ejection fraction.

34. The method of claim 1, wherein the subject is a heart failure patient having an implantable cardioverter-defibrillator, wherein the implantable cardioverter-defibrillator is implanted in the patient.

35. The method of claim 1, wherein the heart failure is acute heart failure.WSGR Docket No. 59915-715.60136. The method of claim 1, wherein the heart failure is right heart failure.

37. The method of claim 1, wherein the heart failure is left heart failure.

38. The method of claim 1, wherein the heart failure comprises myocardial infarction.

39. The method of claim 1, wherein the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

40. The method of claim 1, wherein the heart failure comprises cardiac ischemia / reperfiision injury.

41. The method of claim 1, wherein the treating decreases calcium leak from a RyRl channel in the subject.

42. The method of claim 1, wherein the treating decreases calcium leak from a RyR2 channel in the subject.

43. The method of claim 1, wherein the treating decreases open probability (Po) of RyRl protein in the subject.

44. The method of claim 1, wherein the treating decreases open probability (Po) of RyR2 protein in the subject.

45. The method of claim 1, wherein the administering is oral.

46. The method of claim 1, wherein the administering is once per day.

47. The method of claim 1, wherein the administering is twice per day.

48. The method of claim 1, wherein the compound is 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharmaceutically-acceptable salt thereof.

49. The method of claim 48, wherein the compound is provided in a solid dosage form.

50. The method of claim 49, wherein the solid dosage form is suitable for oral administration.

51. The method of claim 49, wherein the solid dosage form comprises a pharmaceutically-acceptable excipient.

52. The method of claim 48, wherein the therapeutically-effective amount is about 50 mg to aboutWSGR Docket No. 59915-715.601400 mg per day.

53. The method of claim 48, wherein the therapeutically-effective amount is about 200 mg per day.

54. The method of claim 53, wherein the about 200 mg is administered once daily.

55. The method of claim 53, wherein the about 200 mg is administered in two daily doses of 100 mg.

56. The method of claim 48, wherein the therapeutically-effective amount is about 300 mg.

57. The method of claim 56, wherein the about 300 mg is administered once daily.

58. The method of claim 56, wherein the about 300 mg is administered in two daily doses of 150 mg.

59. The method of claim 48, wherein the therapeutically-effective amount is about 400 mg.

60. The method of claim 59, wherein the about 400 mg is administered once daily.

61. The method of claim 59, wherein the about 400 mg is administered in two daily doses of 200 mg.

62. The method of claim 48, wherein the subject is an adult.

63. The method of claim 48, wherein the subject is 50 years or older.

64. The method of claim 48, wherein the subject is 60 years or older.

65. The method of claim 48, wherein the subject is 70 years or older.

66. The method of claim 48, wherein the subject is 80 years or older.

67. The method of claim 56, wherein the subject is a child.

68. The method of claim 48, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject as a pharmaceutical composition in unit dosage form, wherein the unit dosage form further comprises a pharmaceutically acceptable excipient.

69. The method of claim 68, wherein the unit dosage form is a tablet.WSGR Docket No. 59915-715.60170. The method of claim 68, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 to about 200 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

71. The method of claim 68, wherein the unit dosage form comprises about 23.5 to about 235 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

72. The method of claim 68, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

73. The method of claim 68, wherein the unit dosage form comprises 23.5 mg of 4-[(7-methoxy-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate .

74. The method of claim 68, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 50 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

75. The method of claim 68, wherein the unit dosage form comprises about 58.75 mg of 4-[(7- methoxy-2, 3 -dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate .

76. The method of claim 68, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 100 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

77. The method of claim 68, wherein the unit dosage form comprises about 117.5 mg of 4-[(7- methoxy-2, 3 -dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate .

78. A method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a solid dosage form comprising a therapeutically- effective amount of a compound of Formula (I):WSGR Docket No. 59915-715.601 wherein, n is 0, 1, or 2; q is 0, 1, 2, 3, or 4; each R is independently acyl, -O-acyl, alkyl, alkoxyl, alkylamino, alkylarylamino, alkylthio, cycloalkyl, alkylaryl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, arylthio, arylamino, heteroarylthio, or heteroarylamino, each of which is independently substituted or unsubstituted; or halogen, -OH, -NH2, -NO2, -CN, -CF3, -OCF3, -N3, -SO3H, - S(=O)2alkyl, -S(=O)alkyl, or -OS(=O)2CF3;R1is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R2is arylalkyl, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, each of which is independently substitsuted or unsubstituted; or H, -C(=O)R5, -C(=S)R6, - SO2R7, -P(=O)R8R9, or -(CH2)m-R10;R3is acyl, -O-acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or substituted; or H, -CO2Y, or -C(=O)NHY ;Y is alkyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H;R4is alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H; each R5is acyl, alkyl, alkenyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -NR15R16, -(CH2)tNR15R16, -NHNR15R16, -NHOH, -OR15, - C(=O)NHNR15R16, -CO2R15, -C(=O)NR15R16, or -CH2X; each R6is acyl, alkenyl, alkyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NHNR15R16, -NHOH, -NR15R16, or -CH2X; each R7is alkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or -OR15, -NR15R16, -NHNR15R16, -NHOH, or -CH2X; each R8and R9are each independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or OH;- each R10is -NR15R16, OH, -SO2R11, -NHSO2R11, -C(=O)(R12), -NHC=O(R12), -OC=O(R12), or -P(=O)R13R14; each R11, R12, R13, and R14is independently acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted; or H, OH, NH2, -NHNH2, or -NHOH;WSGR Docket No. 59915-715.601 each X is independently halogen, -CN, -CO2R15, -C(=O)NR15R16, -NR15R16, -OR15, -SO2R7, or -P(=O)R8R9; each R15and R16is independently acyl, alkenyl, alkoxyl, OH, NH2, alkyl, alkylamino, aryl, alkylaryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is independently substituted or unsubstituted, or H; or R15and R16together with the N to which R15and R16are bonded form a heterocycle that is substituted or unsubstituted; t is 1, 2, 3, 4, 5, or 6; and m is 1, 2, 3, or 4; or a pharmaceutically-acceptable salt thereof.

79. The method of claim 78, wherein the compound is the pharmaceutically-acceptable salt.

80. The method of claim 79, wherein the pharmaceutically-acceptable salt is a hemifumarate salt.

81. The method of claim 78, wherein the treating decreases skeletal muscle weakness in the subject.

82. The method of claim 78, wherein the treating improves skeletal muscle function in the subject.

83. The method of claim 78, wherein the treating improves skeletal muscle strength in the subject.

84. The method of claim 78, wherein the treating improves grip strength in the subject.

85. The method of claim 78, wherein the treating improves pinch strength in the subject.

86. The method of claim 78, wherein the skeletal muscle weakness comprises weakness in a proximal muscle of the subject.

87. The method of claim 86, wherein the proximal muscle is a deltoid muscle.

88. The method of claim 86, wherein the proximal muscle is a shoulder muscle.

89. The method of claim 86, wherein the proximal muscle is an upper arm muscle.

90. The method of claim 86, wherein the proximal muscle is a hip muscle.

91. The method of claim 86, wherein the proximal muscle is a thigh muscle.

92. The method of claim 86, wherein the proximal muscle is a quadricep muscle.WSGR Docket No. 59915-715.60193. The method of claim 86, wherein the proximal muscle is a core muscle.

94. The method of claim 78, wherein the skeletal muscle weakness comprises weakness in a distal muscle of the subject.

95. The method of claim 94, wherein the distal muscle is a hand muscle.

96. The method of claim 94, wherein the distal muscle is a lower arm muscle.

97. The method of claim 94, wherein the distal muscle is a lower leg muscle.

98. The method of claim 94, wherein the distal muscle is foot muscle.

99. The method of claim 78, wherein the treating improves pulmonary function in the subject.

100. The method of claim 78, wherein the treating improves forced vital capacity in the subject.

101. The method of claim 78, wherein the treating improves maximum oxygen consumption (VO2 max) in the subject.

102. The method of claim 78, wherein the treating improves endurance in the subject.

103. The method of claim 78, wherein the treating improves exercise capacity in the subject.

104. The method of claim 78, wherein the treating improves exercise tolerance in the subject.

105. The method of claim 78, wherein the heart failure is congestive heart failure.

106. The method of claim 78, wherein the heart failure is chronic heart failure.

107. The method of claim 78, wherein the heart failure is heart failure with reduced ejection fraction.

108. The method of claim 78, wherein the heart failure is heart failure with preserved ejection fraction.

109. The method of claim 78, wherein the subject is a heart failure patient having an implantable cardioverter-defibrillator, wherein the implantable cardioverter-defibrillator is implanted in the patient.

110. The method of claim 78, wherein the wherein the heart failure is acute heart failure.WSGR Docket No. 59915-715.601111. The method of claim 78, wherein the heart failure is right heart failure.

112. The method of claim 78, wherein the heart failure is left heart failure.

113. The method of claim 78, wherein the heart failure comprises myocardial infarction.

114. The method of claim 78, wherein the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

115. The method of claim 78, wherein the heart failure comprises cardiac ischemia / reperfusion injury.

116. The method of claim 78, wherein the treating decreases calcium leak from a RyRl channel in the subject.

117. The method of claim 78, wherein the treating decreases calcium leak from a RyR2 channel in the subject.

118. The method of claim 78, wherein the treating decreases open probability (Po) of RyRl protein in the subject.

119. The method of claim 78, wherein the treating decreases open probability (Po) of RyR2 protein in the subject.

120. The method of claim 78, wherein the administering is oral.

121. The method of claim 78, wherein the administering is once per day.

122. The method of claim 78, wherein the administering is twice per day.

123. The method of claim 78, wherein the compound is 4-[(7-methoxy-2,3-dihydro-l,4- benzothiazepin-4(5H)yl)methyl]benzoic acid or a pharmaceutically -acceptable salt thereof.

124. The method of claim 123, wherein the compound is provided in the solid dosage form.

125. The method of claim 124, wherein the solid dosage form is suitable for oral administration.

126. The method of claim 124, wherein the solid dosage form comprises a pharmaceutically-acceptable excipient.

127. The method of claim 123, wherein the therapeutically-effective amount is about 50 mg to aboutWSGR Docket No. 59915-715.601400 mg.

128. The method of claim 123, wherein the therapeutically-effective amount is about 200 mg.

129. The method of claim 128, wherein the about 200 mg is administered once daily.

130. The method of claim 128, wherein the about 200 mg is administered in two daily doses of 100 mg.

131. The method of claim 123, wherein the therapeutically-effective amount is about 300 mg.

132. The method of claim 131, wherein the about 300 mg is administered once daily.

133. The method of claim 131, wherein the about 300 mg is administered in two daily doses of 150 mg.

134. The method of claim 123, wherein the therapeutically-effective amount is about 400 mg.

135. The method of claim 134, wherein the about 400 mg is administered once daily.

136. The method of claim 134, wherein the about 400 mg is administered in two daily doses of 200 mg.

137. The method of claim 123, wherein the subject is an adult.

138. The method of claim 123, wherein the subject is 50 years or older.

139. The method of claim 123, wherein the subject is 60 years or older.

140. The method of claim 123, wherein the subject is 70 years or older.

141. The method of claim 123, wherein the subject is 80 years or older.

142. The method of claim 123, wherein the subject is a child.

143. The method of claim 123, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject as a pharmaceutical composition in unit dosage form, wherein the unit dosage form further comprises a pharmaceutically acceptable excipient.WSGR Docket No. 59915-715.601144. The method of claim 143, wherein the unit dosage form is a tablet.

145. The method of claim 143, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 to about 200 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

146. The method of claim 143, wherein the unit dosage form comprises about 23.5 to about 235 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

147. The method of claim 143, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 20 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

148. The method of claim 143, wherein the unit dosage form comprises 23.5 mg of 4-[(7-methoxy-2,3- dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate .

149. The method of claim 143, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 50 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

150. The method of claim 143, wherein the unit dosage form comprises about 58.75 mg of 4-[(7- methoxy-2, 3 -dihydro- 1 ,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate .

151. The method of claim 143, wherein the unit dosage form comprises an amount of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate equivalent to about 100 mg of 4-[(7-methoxy-2,3-dihydro-l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

152. The method of claim 143, wherein the unit dosage form comprises about 117.5 mg of 4-[(7- methoxy-2, 3 -dihydro- l,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

153. A method of treating skeletal muscle weakness associated with heart failure, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (V):WSGR Docket No. 59915-715.601(V), 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.

154. The method of claim 153, wherein X is sulphur.

155. The method of claim 153, wherein Y is C(O).WSGR Docket No. 59915-715.601156. The method of claim 153, wherein the compound is of formula (Va):

158. The method of claim 153, wherein the compound is of formula (Vb):

159. The method of claim 153, wherein n is 1.

160. The method of claim 153, wherein R' and R" are each hydrogen.

161. The method of claim 153, wherein R1and R2are each hydrogen.

162. The method of claim 153, wherein R1is hydrogen.

163. The method of claim 153, wherein R1is methyl.

164. The method of claim 153, wherein R2is hydrogen.

165. The method of claim 153, wherein R2is alkyl.

166. The method of claim 153, wherein R2is C(O)Ra.

167. The method of claim 153, wherein R2is C(O)Ra, wherein Rais aryl or heteroaryl, each of which isWSGR Docket No. 59915-715.601 substituted or unsubstituted.

168. The method of claim 153, 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.

169. The method of claim 153, wherein R2is C(O)Ra, wherein Rais pyrimidin-2-yl, pyrimidin-5-yl, 5- amino-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, lH-pyrazol-3-yl, 2-methyl-lH-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-pyridin-3-yl, 2-chloro-pyridin-3-yl, pyridin-4-yl, 3 -phenyl- lH-pyrazol-5-yl, IH-imidazol-4-yl, lH-imidazol-2-yl, 1 -methyl- lH-imidazol-4-yl, 1 -methyl- IH-imidazol -2 -yl, thiazol-2-yl, thiazol-4- yl, 4-methyl- 1 ,2,3 -thiadiazol-5 -yl, 5 -phenylisoxazol-3 -yl, 5 -(4-chloropheny l)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-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.

170. The method of claim 153, wherein R1and R2are each independently hydrogen, methyl, 2,2,2- trifluoroethyl, cyclopropyl, cyclobutyl, 3 -hydroxycyclobutyl, 3, 3 -difluorocyclobutyl, cyclohexyl, 2- hydroxycyclohexyl, 3 -hydroxy cyclohexyl, 4-hydroxy cyclohexyl, pyrimidin-2-yl, pyrimidin-2-ylmethyl, pyrimidin-3-ylmethyl, pyrimidin-4-ylmethyl, oxalyl, 2-methoxyethyl, benzyl, 4-carboxybenzyl, 4- carboxymethylbenzyl, tetrahydro-2H-pyran-4-yl, oxetan-3-yl, l,2,4-thiadiazol-5-yl, 4-aminomethyl-1.2.3-triazol-l-ylmethyl, 4-methyl-l,2,3-thiadiazolyl-5-yhnethyl, benzo [d]thiazol-2-yl, 4-carboxylethyl-1.2.3-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.

171. The method of claim 153, wherein R3is alkoxy, cycloalkyloxy, or aryloxy, each of which is substituted or unsubstituted, or halogen.

172. The method of claim 153, wherein R3is phenyloxy, which is substituted or unsubstituted.

173. The method of claim 153, wherein R3is substituted by one or two substituents selected from the group consisting of hydroxy, fluorine, chlorine, bromine, iodide, CF3, CHF2, methoxy, SCFMc. cyano, and C(O)Me.

174. The method of claim 153, wherein R3is independently at each occurrence alkyl, cyclohexyl,WSGR Docket No. 59915-715.601 alkyloxy, cycloalkyloxy, 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, or naphthalenyl, each of which is substituted or unsubstituted, or halogen.

175. The method of claim 153, wherein R4is hydrogen.

176. The method of claim 153, wherein the compound is the pharmaceutically-acceptable salt.

177. The method of claim 176, wherein the pharmaceutically-acceptable salt is a sodium salt.

178. The method of claim 153, wherein the compound 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,5 S)-2-(4-bromophenyl)-5 -(dimethylaminomethyl)- 1 ,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,5 S)-5 -[(4-benzyl- 1 -piperidyl)methyl] -2-(4-bromophenyl)- 1 ,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,5 S)-5 -(aminomethyl)-2-[3 -(trifluoromethyl)phenyl] - 1 ,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 ;(2S,5 S)-5 -(aminomethyl)-2-(3 -phenoxyphenyl)- 1 ,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,5 S)-5-(aminomethyl)-2-[3-[4-(trifluoromethyl)phenoxy]phenyl] - 1 ,4-thiazepan-3 -one;WSGR Docket No. 59915-715.601(2R,5 S)-5 -(aminomethyl)-2-[3 -(4-methoxyphenoxy)phenyl] - 1 ,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,5 S)-5 -(aminomethyl)-2-[3 -(3 -chlorophenyl)phenyl] - 1 ,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,5 S)-5 -(aminomethyl)-2-[3 -(3 -pyridyl)phenyl] - 1 ,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,5 S)-5 -(aminomethyl)-2-[3 -( 1 ,3 -benzodioxol-5 -yl)phenyl] - 1 ,4-thiazepan-3 -one;(2S,5R)-5-(aminomethyl)-2-[3-(2,6-dichlorophenyl)phenyl]-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-( 1 -naphthyl)- 1 ,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;WSGR Docket No. 59915-715.601(2R,5 S)-5 -(aminomethyl)-2-[3 -(o-tolyl)phenyl] - 1 ,4-thiazepan-3 -one ;(2R,5 S)-5 -(aminomethyl)-2-[3 -(p-tolyl)phenyl] - 1 ,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;(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,5 S)-5 -(aminomethyl)-3 -oxo- 1 ,4-thiazepan-2-yl]phenyl]benzamide ;N-[3-[(2R,5S)-5-(aminomethyl)-3-oxo-l,4-thiazepan-2-yl]phenyl]cyclohexanecarboxamide;(2R,5 S)-5 -(aminomethyl)-2-[3 -(4-fluorophenyl)phenyl] - 1 ,4-thiazepan-3 -one ;(2R,5 S)-5 -(aminomethyl)-2-(3 -cyclohexylphenyl)- 1 ,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,5 S ) -2 - [ 3 -(4-chlorophenyl)phenyl] -5 -[(3 ,3 -difluoropyrrolidin- 1 -yl)methyl] - 1 ,4-thiazepan-3 - one;(25.55)-2-[3-(4-chlorophenyl)phenyl]-5-[(3,3-difluoropyrrolidin-l-yl)methyl]-l,4-thiazepan-3- one;(2R,5 S ) -2 - [ 3 -(2-chlorophenyl)phenyl] -5 -[(3 ,3 -difluoropyrrolidin- 1 -yl)methyl] - 1 ,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 ;WSGR Docket No. 59915-715.601(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,5 S)-5 -(aminomethyl)-2-[3 -(cyclohexoxy )phenyl] - 1 ,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,5S)-5-(aminomethyl)-2-(4-phenoxy-3-propyl-phenyl)-l,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,5 S)-5 -(aminomethyl)-2-[4-(cyclohexoxy)phenyl] - 1 ,4-thiazepan-3 -one ;(2R,5 S)-5 -(aminomethyl)-2-[4-(cyclopentoxy)phenyl] - 1 ,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,5 S)-5 -(aminomethyl)-2-[4-( 1 ,3 -benzodioxol-5 -yloxy)phenyl] - 1 ,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;WSGR Docket No. 59915-715.601(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,5 S)-2-(3 -phenylphenyl) -5 -[(pyrimidin-2-ylamino)methyl] - 1 ,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, 5 S) -2 - [4 -(3 ,5 -difluorophenoxy )phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - 1 -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,5 S)-2-[3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-2-[3-(2,2-dimethylpropoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;N-[ [(2R,5 S)-2-[3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]thiazole-4- carboxamide;N-[ [(2R,5 S)-2-[3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] -4-methyl- thiadiazole-5-carboxamide;N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-lH-pyrazole-3- carboxamide;WSGR Docket No. 59915-715.601N-[ [(2R,5 S)-2-[3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-5 - carboxamide;6-amino-N-[[(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyridine-3- carboxamide;N-[ [(2R,5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,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-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- 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-carboxamide 6-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;WSGR Docket No. 59915-715.601N-[ [(2R, 5 S) -2 - [4 -(3 ,5 -difluorophenoxy )phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-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,5 S)-3 -oxo-2-[3 -[4-(trifluoromethyl)phenoxy]phenyl] - 1 ,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,5 S) -2 - [3 -(cyclohexoxy )phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;4.4-difluoro-N-[[(2R,5S)-3-oxo-2-(4-phenoxyphenyl)-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,5 S)-3 -oxo-2-(4-phenoxyphenyl)- 1 ,4-thiazepan-5 - yl]methyl]acetamide;WSGR Docket No. 59915-715.6016-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;1-(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 -morpholinoacetamide;N-[ [(2R,5 S)-2- [3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - 1 -methyl - imidazole-4-carboxamide;N-[ [(2R,5 S)-2- [3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - lH-pyrazole-3 - carboxamide;N-[ [(2R,5 S)-2-[4-(4-chlorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - 1 -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,5 S) -2 - [ 3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyridazine-3 - carboxamide;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]-2 -morpholinoacetamide;N-[ [(2R,5 S) -2 - [ 3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyridine-2- sulfonamide;N-[[(2R,5S)-2-[4-(4-chlorophenoxy)phenyl]-3-oxo-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,5 S)-2-[4-(4-chlorophenoxy)phenyl] -5 -[( 1 ,2,4-thiadiazol-5 -ylamino)methyl] - 1 ,4-thiazepan-3 - one;N-[[(2R,5S)-2-[3-(4-fluorophenoxy)phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2- carboxamide;WSGR Docket No. 59915-715.6015-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,5 S)-2- [3 -(4-fluorophenoxy)phenyl] -3 -oxo- 1 ,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,5 S)-2-[4-(4-chlorophenoxy)phenyl] -3 -oxo- 1 ,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-[ [(2 S , 5 S) -2 - [4 -( 3 ,5 -difluorophenoxy )phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;N-[ [(2R,5R)-2-[4-(3 ,5 -difluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl]pyrimidine-2- carboxamide;5-(4-fluorophenyl)-N-[[(2R,5S)-3-oxo-2-[4-(trifluoromethyl)phenyl]-l,4-thiazepan-5-yl]methyl]- 1 , 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-yhnethylamino)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,5 S ) -2 - [ 3 -(4-chlorophenyl)phenyl] -5 -[(cyclopropylamino)methyl] - 1 ,4-thiazepan-3 -one ;(2R,5 S)-5-[(cyclopropylamino)methyl] -2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3-one;(2R,5 S)-5-[(cyclobutylamino)methyl] -2-(4-phenoxyphenyl)- 1 ,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;WSGR Docket No. 59915-715.601(2R,5S)-5-[[(4-hydroxycyclohexyl)amino]methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5 S)-5 - [[(3 ,3 -difluorocyclobutyl)amino]methyl] -2-(4-phenoxyphenyl)- 1 ,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-yhnethylamino)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,5 S)-5 -[(2,2,2-trifluoroethylamino)methyl] -2-[3 -[2-(trifluoromethyl)phenyl]phenyl] -1,4- thiazepan-3-one;(2R,5S)-2-[3-(2-methoxyphenyl)phenyl]-5-[(2,2,2-trifluoroethylamino)methyl]-l,4-thiazepan-3- one;(2R,5S)-2-[3-(4-chlorophenyl)phenyl]-5-[(2-methoxyethylamino)methyl]-l,4-thiazepan-3-one;(2R,5 S)-2-[3-(2,2-dimethylpropoxy)phenyl] -5 -[(2,2,2-trifluoroethylamino)methyl]- 1 ,4-thiazepan- 3 -one;(2R,5S)-5-[(2-methoxyethylamino)methyl]-2-(4-phenoxyphenyl)-l,4-thiazepan-3-one;(2R,5 S)-5 -(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl] -1,1 -dioxo- 1 ,4-thiazepan-3-one ;(2R,5 S)-5-(aminomethyl)- 1 , 1 -dioxo-2-(3-phenoxyphenyl)- 1 ,4-thiazepan-3-one;(2R,5 S)- 1 , 1 -dioxo-2-(3 -phenoxyphenyl) -5 -[(2,2,2-trifluoroethylamino)methyl] - 1 ,4-thiazepan-3 - one;(2R,5 S)-5 - [(2 -oxopiperazin- 1 -yl)methyl] -2-(4-phenoxyphenyl)- 1 ,4-thiazepan-3 -one;(2S,5 S)-5 -(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl] - 1 ,4-oxazepan-3 -one ;(2R,5S)-5-(aminomethyl)-2-[3-(4-chlorophenyl)phenyl]-l,4-oxazepan-3-one;(2S,5 S)-5 -(aminomethyl)-2-[3 -(2-chlorophenyl)phenyl] - 1 ,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;WSGR Docket No. 59915-715.601(25.55)-5-(aminomethyl)-2-[3-(p-tolyl)phenyl]-l,4-oxazepan-3-one;(2S,5 S ) -2 - [3 -(4-chlorophenyl)phenyl] -5 -(methylaminomethyl)- 1 ,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-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyrimidine-2- carboxamide;6-amino-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-l,4-oxazepan-5-yl]methyl]pyridine-3- carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyridine-2- carboxamide;6-chloro-N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-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-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl] - 1 -methyl-imidazole- 2-carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl] - 1 -methyl-imidazole- 4-carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyridine-3 - carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyridine-4- carboxamide;N-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,4-oxazepan-5 -yl]methyl]pyridazine-3 - carboxamide;N-[[(2S,5S)-2-[3-(4-chlorophenyl)phenyl]-3-oxo-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-[ [(2 S , 5 S) -2 - [3 -(4-chlorophenyl)phenyl] -3 -oxo- 1 ,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,5 S)-2-(4-phenoxyphenyl)-5-(piperazine- 1 -carbonyl)- 1 ,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;WSGR Docket No. 59915-715.601(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.

179. The method of claim 153, wherein the compound is:(2R,5 S)-5 -(aminomethyl)-2-[4-(3 ,5 -difluorophenoxy )phenyl] - 1 ,4-thiazepan-3 -one, or a pharmaceutically-acceptable salt thereof;(2R,5 S)-5 -(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl] - 1 ,4-thiazepan-3 -one, or a pharmaceutically-acceptable salt thereof;(2R,5 S)-5 -(aminomethyl)-2-[4-(2,2-dimethylpropoxy)phenyl] - 1 ,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-[4-(cyclopentoxy)phenyl]-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,5S)-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;WSGR Docket No. 59915-715.601(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, 1 -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,5 S)-5 -(aminomethyl)-2-[3 -(4-chlorophenyl)phenyl] -2 -methyl- 1 ,4-oxazepan-3 -one, or a pharmaceutically-acceptable salt thereof;(2R,5S)-5-(aminomethyl)-2-methyl-2-(4-phenoxyphenyl)-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.

180. The method of claim 153, wherein the compound is (2R,5S)-5-(aminomethyl)-2-[4-(3,5- difluorophenoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

181. The method of claim 153, wherein the compound is (2R,5S)-5-(aminomethyl)-2-[3-(4- chlorophenyl)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

182. The method of claim 153, wherein the compound is (2R,5S)-5-(aminomethyl)-2-(4- phenoxyphenyl)-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

183. The method of claim 153, wherein the compound is (2R,5S)-5-(aminomethyl)-2-[4-(2,2- dimethylpropoxy)phenyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

184. The method of claim 153, wherein the compound is (2S,5S)-5-(aminomethyl)-2-[3-(4- chlorophenyl)phenyl]-l,4-oxazepan-3-one, or a pharmaceutically-acceptable salt thereof.

185. The method of claim 153, wherein the compound is (2R,5S)-2-(4-phenoxyphenyl)-5-[(pyrimidin- 2-ylamino)methyl]-l,4-thiazepan-3-one, or a pharmaceutically-acceptable salt thereof.

186. The method of claim 153, wherein the compound is N-[[(2R,5S)-2-[4-(3,5-WSGR Docket No. 59915-715.601 difluorophenoxy )phenyl]-3-oxo-l,4-thiazepan-5-yl]methyl]pyrimidine-2 -carboxamide, or a pharmaceutically-acceptable salt thereof.

187. The method of claim 153, wherein the compound is N-[[(2R,5S)-2-[4-(3,5- difluorophenoxy)phenyl] -3 -oxo- 1 ,4-thiazepan-5 -yl]methyl] - 1 -methyl -imidazole -4-carboxamide, or a pharmaceutically-acceptable salt thereof.

188. The method of claim 153, wherein the compound is 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.

189. The method of claim 153, wherein the treating decreases skeletal muscle weakness in the subject.

190. The method of claim 153, wherein the treating improves skeletal muscle function in the subject.

191. The method of claim 153, wherein the treating improves skeletal muscle strength in the subject.

192. The method of claim 153, wherein the treating improves grip strength in the subject.

193. The method of claim 153, wherein the treating improves pinch strength in the subject.

194. The method of claim 153, wherein the skeletal muscle weakness comprises weakness in a proximal muscle of the subject.

195. The method of claim 194, wherein the proximal muscle is a deltoid muscle.

196. The method of claim 194, wherein the proximal muscle is a shoulder muscle.

197. The method of claim 194, wherein the proximal muscle is an upper arm muscle.

198. The method of claim 194, wherein the proximal muscle is a hip muscle.

199. The method of claim 194, wherein the proximal muscle is a thigh muscle.

200. The method of claim 194, wherein the proximal muscle is a quadricep muscle.

201. The method of claim 194, wherein the proximal muscle is a core muscle.WSGR Docket No. 59915-715.601202. The method of claim 153, wherein the skeletal muscle weakness comprises weakness in a distal muscle of the subject.

203. The method of claim 202, wherein the distal muscle is a hand muscle.

204. The method of claim 202, wherein the distal muscle is a lower arm muscle.

205. The method of claim 202, wherein the distal muscle is a lower leg muscle.

206. The method of claim 202, wherein the distal muscle is foot muscle.

207. The method of claim 153, wherein the treating improves pulmonary function in the subject.

208. The method of claim 153, wherein the treating improves forced vital capacity in the subject.

209. The method of claim 153, wherein the treating improves maximum oxygen consumption (VO2 max) in the subject.

210. The method of claim 153, wherein the treating improves endurance in the subject.

211. The method of claim 153, wherein the treating improves exercise capacity in the subject.

212. The method of claim 153, wherein the treating improves exercise tolerance in the subject.

213. The method of claim 153, wherein the heart failure is congestive heart failure.

214. The method of claim 153, wherein the heart failure is chronic heart failure.

215. The method of claim 153, wherein the heart failure is heart failure with reduced ejection fraction.

216. The method of claim 153, wherein the heart failure is heart failure with preserved ejection fraction.

217. The method of claim 153, wherein the subject is a heart failure patient having an implantable cardioverter-defibrillator, wherein the implantable cardioverter-defibrillator is implanted in the patient.

218. The method of claim 153, wherein the heart failure is acute heart failure.WSGR Docket No. 59915-715.601219. The method of claim 153, wherein the heart failure is right heart failure.

220. The method of claim 153, wherein the heart failure is left heart failure.

221. The method of claim 153, wherein the heart failure comprises myocardial infarction.

222. The method of claim 153, wherein the subject is a heart failure patient in need of preservation of cardiac function post myocardial infarction.

223. The method of claim 153, wherein the heart failure comprises cardiac ischemia / reperfusion injury.

224. The method of claim 153, wherein the treating decreases calcium leak from a RyRl channel in the subject.

225. The method of claim 153, wherein the treating decreases calcium leak from a RyR2 channel in the subject.

226. The method of claim 153, wherein the treating decreases open probability (Po) of RyRl protein in the subject.

227. The method of claim 153, wherein the treating decreases open probability (Po) of RyR2 protein in the subject.

228. The method of claim 153, wherein the administering is oral.

229. The method of claim 153, wherein the administering is once per day.

230. The method of claim 153, wherein the administering is twice per day.

231. The method of claim 153, wherein the compound is provided in a solid dosage form.

232. The method of claim 231, wherein the solid dosage form is suitable for oral administration.

233. The method of claim 231, wherein the solid dosage form comprises a pharmaceutically-acceptable excipient.

234. The method of claim 231, wherein the subject is an adult.WSGR Docket No. 59915-715.601235. The method of claim 231, wherein the subject is 50 years or older.

236. The method of claim 231, wherein the subject is 60 years or older.

237. The method of claim 231, wherein the subject is 70 years or older.

238. The method of claim 231, wherein the subject is 80 years or older.

239. The method of claim 153, wherein the subject is a child.

240. The method of claim 153, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject as a pharmaceutical composition in unit dosage form, wherein the unit dosage form further comprises a pharmaceutically acceptable excipient.

241. The method of claim 240, wherein the unit dosage form is a tablet.

242. The method of any one of claims 1-241, further comprising administering an additional therapeutic agent to the subject.

243. The method of claim 242, wherein the additional therapeutic agent is a beta-blocker.

244. The method of claim 242, wherein the additional therapeutic agent is a renin-angiotensin system inhibitor.

245. The method of claim 244, wherein the renin-angiotensin system inhibitor is an angiotensin receptor neprilysin inhibitor (ARNi).

246. The method of claim 244, wherein the renin-angiotensin system inhibitor is an angiotensinconverting enzyme (ACE) inhibitor.

247. The method of claim 244, wherein the renin-angiotensin system inhibitor is an angiotensin II receptor blocker (ARB).

248. The method of claim 242, wherein the additional therapeutic agent is a mineralocorticoid receptor antagonist (MRA).

249. The method of claim 242, wherein the additional therapeutic agent is a sodium -glucose cotransporter-2 (SGLT2) inhibitor.WSGR Docket No. 59915-715.601250. The method of claim 242, wherein the additional therapeutic agent is a glucagon-like peptide 1 (GLP-1) agonist.

251. The method of any one of claims 243-250, wherein the additional therapeutic agent is administered in an amount sufficient to treat heart failure.

252. The method of any one of claims 243-250, wherein the additional therapeutic agent is administered in a dose according to recommended guidelines for treating heart failure.

253. The method of any one of claims 243-250, wherein the additional therapeutic agent is administered in a reduced amount, wherein the reduced amount is less than an amount used to treat heart failure in the subject in absence of the compound.

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