Compounds suitable for cardiovascular disease treatment

Abstract

The present disclosure relates to compositions and methods, including prodrugs of (S)-3-(3-(((3,4- dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H- benzo[d]azepin-2-one that find use in the treatment of diseases and disorders, such as therapies for cardiovascular disease, including cardiac arrhythmias, including, without limitations, sinus tach (e.g. inappropriate sinus tachycardia (IST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e.g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g. angina pectoris), myocardial infarct, rhythm disturbances (e.g. supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, and left ventricular dysfunction (LVD).

Description

[0001] Compounds suitable for cardiovascular disease treatment

[0002] FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to, inter alia, prodrugs of (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7- yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one that find use in the treatment of disease, such as therapies for cardiovascular disease.

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS

[0005] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 723,333, filed November 21 , 2024, which is incorporated by reference herein in its entirety.

[0006] BACKGROUND

[0007] Cardiovascular disease is a group of diseases affecting heart and blood vessels. Cardiac arrhythmia, or an irregular heartbeat, is a medical condition characterized by an abnormal heart rate or rhythm: beating too fast, too slow, or in an irregular pattern. Inappropriate Sinus Tachycardia (1ST) is a clinical syndrome characterized by a sinus heart rate inexplicably higher than one hundred beats per minute at rest that is associated with symptoms like palpitations, dyspnea or dizziness in the absence of primary causes of tachycardia. Inappropriate sinus tachycardia (1ST) is a clinical syndrome that generally affects young patients and is associated with distressing symptoms. Although the most common symptom is palpitations, it can be accompanied by a myriad of symptoms, including anxiety, dizziness, presyncope, and syncope. Management presents a clinical challenge. The overall efficacy of lifestyle modifications and medical therapy may be limited.

[0008] Current therapeutics for treating cardiovascular disease have significant side-effects and safety issues, including longterm toxicity to the liver, lung, and thyroid, a very long half-life, and negative inotropic effects. There is a need for safe and efficacious drug for treating cardiovascular disease including 1ST.

[0009] SUMMARY

[0010] Accordingly, the present disclosure provides, in part, prodrugs of (S)-3-(3-(((3,4-dimethoxybicycio[4.2.0]octa-1,3,5- trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one and compositions thereof useful for treating a cardiovascular disease or disorder, including, without limitation, sinus tach (e.g. inappropriate sinus tachycardia (1ST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e.g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g. angina pectoris), myocardial infarct, rhythm disturbances (e.g. supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, and left ventricular dysfunction (LVD). Also provided are methods for treating cardiovascular diseases or

[0011] DBl / 163167834.4 1 disorders including inappropriate sinus tachycardia (1ST)). In embodiments, prodrugs of (S)-3-(3-(((3,4- dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H- benzo[d]azepin-2-one disclosed herein can favorably alter the pharmacokinetics (PK) profile of(S)-3-(3-(((3,4- dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H- benzo[d]azepin-2-one, provide for increased gastrointestinal absorption by improved permeability as these prodrugs provide pH independent solubility to prolong absorption through the upper Gl tract resulting in improved bioavailability and therapeutic window.

[0012] In one aspect, the present disclosure provides a compound of formula (XI), or a stereoisomer thereof: formula (XI) or a stereoisomer thereof, wherein in formula (XI):

[0013] X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;

[0014] Z is selected from I), ii), and iii): i) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0015] II) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0016] DBl / 163167834.4 2 iii) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0017] In embodiments, the compound is a compound of formula (XI) wherein Rais hydrogen or C-i-Ce alkyl. In embodiments, the compound is a compound of formula (XI) wherein Rais hydrogen. In embodiments, the compound is a compound of formula (XI) wherein Rais independently at each occurrence alkyl, optionally wherein the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl. In embodiments, the compound is a compound of formula (XI) wherein Rais selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl.

[0018] In embodiments, the compound is a compound of formula (XI) wherein Rais unbranched Ci-Ce alkyl. In embodiments, the compound is a compound of formula (XI) wherein Rais a branched Ci-Ce alkyl.

[0019] In embodiments, the compound is a compound of formula (XI) wherein Rbis hydrogen or Ci-Ce alkyl. In embodiments, the compound is a compound of formula (XI) wherein Rbis hydrogen. In embodiments, the compound is a compound of formula (XI) wherein Rbis independently at each occurrence alkyl, optionally wherein the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl. In embodiments, the compound is a compound of formula (XI) wherein Rbis selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl.

[0020] In embodiments, the compound is a compound of formula (XI) wherein Rbis unbranched Ci-Ce alkyl. In embodiments, the compound is a compound of formula (XI) wherein Rbis a branched Ci-Ce alkyl.

[0021] In embodiments, the compound is a compound of formula (XI) wherein Raand Rbare joined to form a 3-6 membered carbocyclic ring, optionally wherein the 3-6 membered carbocyclic ring is selected from cyclohexane, cyclohexene, cyclopropane, cyclobutane; cyclopentane, cyclopropene, cyclobutene, cyclopentene and cyclopentadiene.

[0022] In embodiments, the compound is a compound of formula (XI), wherein Z is -OR1.

[0023] In embodiments, the compound is a compound of formula (XI), wherein R1is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0024] In embodiments, the compound is a compound of formula (XI) wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.

[0025] In embodiments, the compound is a compound of formula (XI), wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, hexyl, and octyl.

[0026] In embodiments, the compound is a compound of formula (XI) wherein R1is phenyl or benzyl.

[0027] DBl / 163167834.4 3 In embodiments, the compound is a compound of formula (XI) wherein R1is phenyl. In embodiments, the compound is a compound of formula (XI) wherein R1is benzyl.

[0028] In embodiments, the compound is a compound of formula (XI), wherein R1is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl, optionally -OMe or phenyl.

[0029] In embodiments, the compound is a compound of formula (XI) wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0030] In embodiments, the compound is a compound of formula (XI), wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0031] In embodiments, the compound is a compound of formula (XI), wherein Z is R2.

[0032] In embodiments, the compound is a compound of formula (XI), wherein R2is Ci-Ca alkyl.

[0033] In embodiments, the compound is a compound of formula (XI), wherein R2is Ci-Cs alkyl, straight or branched chain, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl.

[0034] In embodiments, the compound is a compound of formula (XI), wherein Ci-Cs alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0035] In embodiments, the compound is a compound of formula (XI), wherein Ci-Ca alkyl is selected from methyl and n-propyl. , ,

[0036] In embodiments, the compound is a compound of formula (XI), wherein R1is phenyl. In embodiments, the compound is a compound of formula (XI), wherein R1is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0037] In embodiments, the compound is a compound of formula (XI), wherein R2is phenyl. In embodiments, the compound is a compound of formula (XI), wherein R2is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0038] In embodiments, the compound is a compound of formula (XI), wherein R1is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (XI), wherein R1is a 5- or 6-membered heteroaryl, and the 5-

[0039] DBl / 163167834.4 4 or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0040] In embodiments, the compound is a compound of formula (XI), wherein R2is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (XI), wherein R2is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0041] In embodiments, the compound is a compound of formula (XI), wherein R3is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (XI), wherein R3is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0042] In embodiments, the compound is a compound of formula (XI), wherein Z is -N(R3)2. In embodiments, the compound is a compound of formula (XI), wherein Z is -NHR3. In embodiments, R3is independently at each occurrence selected from alkyl. In embodiments, the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0043] In embodiments, the compound is a compound of formula (XI), wherein each R3is methyl.

[0044] In embodiments, the compound is a compound of formula (XI), wherein one or both R3are each independently substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe,

[0045] -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl.

[0046] In embodiments, the compound is a compound of formula (XI), wherein -N(R3)2is -N(CH3)2.

[0047] In embodiments, the compound of formula (XI) is a compound of formula (Xia), or a stereoisomer thereof: formula (Xia).

[0048] In embodiments, the compound of formula (XI) is a compound of formula (Xlb), or a stereoisomer thereof:

[0049] DB1 / 163167834.4 5 formula (Xlb).

[0050] In one aspect, the present disclosure provides a compound of formula (I), or a stereoisomer thereof: formula (I) or a stereoisomer thereof, wherein in formula (I):

[0051] X is a pharmaceutically acceptable anion;

[0052] Z is selected from I), II), and ill): i) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0053] II) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to

[0054] DBl / 163167834.4 6 form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0055] In embodiments, the compound is a compound of formula (I), wherein Z is -OR1.

[0056] In embodiments, the compound is a compound of formula (I), wherein R1is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0057] In embodiments, the compound is a compound of formula (I), wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, hexyl, and octyl

[0058] In embodiments, the compound is a compound of formula (I), wherein R1is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / '-Pr, -CF3, -CHF2, -CI-hF, -OCF3, - OCHF2, -OCH2F, and phenyl, optionally -OMe or phenyl.

[0059] In embodiments, the compound is a compound of formula (I), wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0060] In embodiments, the compound is a compound of formula (I), wherein Z is R2.

[0061] In embodiments, the compound is a compound of formula (I), wherein R2is Ci-Cs alkyl.

[0062] In embodiments, the compound is a compound of formula (I), wherein Ci-Cs alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0063] In embodiments, the compound is a compound of formula (I), wherein Ci-Cs alkyl is selected from methyl and n-propyl. In embodiments, the compound is a compound of formula (I), wherein Ci-Cs alkyl is substituted with 1 to 3 substituents selected from Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3,

[0064] In embodiments, the compound is a compound of formula (I), wherein

[0065] In embodiments, the compound is a compound of formula (I), wherein the compound of formula (I) has a formula of

[0066] DBl / 163167834.4 7

[0067]

[0068] In embodiments, the compound of formula (I) is a compound of formula (la), or a stereoisomer thereof: formula (la) In embodiments, the compound is a compound of formula (la), wherein the compound of formula (la) has a formula of

[0069] DBl / 163167834.4 8

[0070] in embodiments, the compound of formula (i) is a compound of formula (lb), or a stereoisomer thereof: formula (lb).

[0071] In embodiments, the compound is a compound of formula (lb), wherein the compound of formula (lb) has a formula of any one of formula 1021-1026:

[0072] In embodiments, the compound is a compound of formu a (I), wherein X is selected from chloride, bromide, iodide, hydroxide, sulfate (SO4-2HSO^2), nitrate, phosphate (e.g. PO4-3, HPO4-2, H2PO4-), acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.

[0073] DBl / 163167834.4 9 In embodiments, the compound is a compound of formula (I), wherein X is selected from chloride, bromide, iodide, acetate, HSC , SO42, p-toluenesulfonate, PO43, HPCh'2, F PC , and tartrate.

[0074] In embodiments, the compound is a compound of formula (I), wherein X is chloride.

[0075] In embodiments, the compound is a compound of formula (I), wherein X is iodide. In embodiments, the compound is a compound of formula (I), wherein the compound of formula (I) has a formula of any one of formula 2001-2006:

[0076] In embodiments, the compound is a compound of formula (la), wherein X is selected from chloride, bromide, iodide, hydroxide, sulfate (SO42, HSCh’2), nitrate, phosphate (e.g. PCX3, HPCx2, H2PO4'), acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.

[0077] In embodiments, the compound is a compound of formula (la), wherein X is selected from chloride, bromide, iodide, acetate, HSOr, SO42, p-toluenesulfonate, PCX3, HPCx2, H2PC , and tartrate.

[0078] In embodiments, the compound is a compound of formula (la), wherein X is chloride.

[0079] In embodiments, the compound is a compound of formula (la), wherein X is iodide. In embodiments, the compound is a compound of formula (la), wherein the compound of formula (la) has a formula of any one of formula 2011-2016:

[0080] DBl / 163167834.4 10

[0081]

[0082] In embodiments, the compound is a compound of formula (lb), wherein X is selected from chloride, bromide, iodide, hydroxide, sulfate (SCu-2, HSO2), nitrate, phosphate (e.g. PO43, HPO2, H2PO4'), acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.

[0083] In embodiments, the compound is a compound of formula (lb), wherein X is selected from chloride, bromide, iodide, acetate, HSOr, SO42, p-toluenesulfonate, PCh'3, HPO42, F PCh', and tartrate.

[0084] In embodiments, the compound is a compound of formula (lb), wherein X is chloride.

[0085] In embodiments, the compound is a compound of formula (lb), wherein X is iodide.

[0086] In embodiments, the compound is a compound of formula (lb), wherein the compound of formula (lb) has a formula of any one of formula 2021-2026:

[0087] DBl / 163167834.4 11

[0088]

[0089] In embodiments, the compound is a compound of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026, wherein the compound of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011- 1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026, exhibits improved gastrointestinal absorption (e.g. improved permeability and / or solubility) compared to (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien-7- yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0090] In embodiments, the compound is a compound of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026, wherein the compound of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011- 1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026, exhibits at least about 1 fold, at least about 2 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 6 fold, at least about 7 fold, at least about 8 fold, at least about 9 fold, at least about 10 fold, at least about 50 fold, at least about 100 fold, at least about 500 fold, or at least about 1000 fold improved gastrointestinal absorption (e.g. improved permeability and / or solubility) compared to (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0091] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (XI), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient:

[0092] DBl / 163167834.4 12 formula (XI)

[0093] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (Xia), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (Xia).

[0094] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (Xlb), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (Xlb). In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (I).

[0095] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (la), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (la).

[0096] DBl / 163167834.4 13 In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (lb), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (lb).

[0097] In embodiments, the compound of formula (XI) or formula (I) is a compound of any one of formula 1001-1006, 1011- 1016, or 1021-1026, or formula 2001-2006, 2011-2016, or 2021-2026.

[0098] In embodiments, the pharmaceutical composition is formulated for oral or parenteral administration. In embodiments, the pharmaceutical composition is formulated for topical, dermal, intradermal, intramuscular, intraperitoneal, intraarticular, intravenous, subcutaneous, intraarterial or transdermal administration. In embodiments, the pharmaceutical composition is formulated for topical administration.

[0099] In another aspect, the present disclosure provides a method of treating a disease or disorder, the method comprising administering to a subject in need thereof a compound of any one of the embodiments disclosed herein or a pharmaceutical composition comprising a compound of any one of the embodiments disclosed herein to the subject.

[0100] In embodiments, the disease or disorder is a cardiovascular disease or disorder.

[0101] In embodiments, the cardiovascular disease or disorder is selected from sinus tach (e.g. inappropriate sinus tachycardia (1ST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g. angina pectoris), myocardial infarct, rhythm disturbances (e.g. supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, and left ventricular dysfunction (LVD).

[0102] In embodiments, the cardiovascular disease or disorder is inappropriate sinus tachycardia (1ST)).

[0103] In embodiments, the cardiovascular disease or disorder is angina pectoris (e.g. chronic stable angina pectoris).

[0104] In embodiments, the disease or disorder is caused by a genetic disorder.

[0105] In embodiments, the method of treating the disease or disorder further includes inhibition of a hyperpolarization- activated cyclic nucleotide-gated (HCN) channel (e.g. hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4)) and / or inhibition of a funny current (If) channel.

[0106] In embodiments, the method of treating the disease or disorder further includes reduction of the subject’s heart rate compared to a pre-treated or untreated state.

[0107] DBl / 163167834.4 14 In embodiments, the subject has normal sinus rhythm, and optionally cannot take beta blockers, and / or has undergone coronary artery bypass grafting (CABG)

[0108] In one aspect, the present disclosure relates to method for treating a subject diagnosed with a cardiovascular disease or disorder, the method comprising: a) administering a first dose of a compound of any one of the embodiments disclosed herein or a pharmaceutical composition comprising a compound of any one of the embodiments disclosed herein to the subject while employing a wearable device or another monitor to monitor heart rhythm data of the subject; b) monitoring the subject for efficacy of the administered first dose to assess whether the first dose is efficacious for the subject during a comparison period of 1 or more days; c) if the administered first dose is efficacious for the subject, continuing to monitor the subject's heart rhythm data to ensure that the administered first dose remains efficacious.

[0109] In embodiments, assessing the efficacy of the first dose is delayed for at least 7 or 14 days after administering the first dose.

[0110] In embodiments, assessing the efficacy of the first dose is based on symptoms and / or an average heart rate measured by the wearable device or another monitor.

[0111] In embodiments, if the administered first dose is assessed as not efficacious for the subject by an end of the comparison period, adjust the amount of the first dose one or more times as necessary to achieve an efficacious result to provide an adjusted dose, wherein the efficacy of the adjusted dose is assessed during at least the comparison period and / or delay period.

[0112] In embodiments, if the administered first dose or adjusted dose is no longer efficacious, step c) is repeated with the administered first dose or adjusted dose as the first dose.

[0113] In embodiments, monitoring in step b) is conducted in a continuous manner.

[0114] In embodiments, monitoring in step b) comprises detecting a slow diastolic depolarization phase.

[0115] In embodiments, detecting comprises use of a photoplethysmography (PPG) algorithm and / or ParamAP. ParamAP is a computational tool useful for identifying and parameterizing action potentials (APs). See, e.g., Rickert and Proenza, Biophysical Journal 113:765-769 (2017), which is incorporated by reference herein in its entirety.

[0116] In embodiments, the efficacy at an administered first dose or an adjusted dose is evaluated by comparing baseline levels of the slow diastolic depolarization phase against corresponding levels of the slow diastolic depolarization phase in the comparison period.

[0117] In embodiments, the comparison period is one or more of about a day, about a week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or up to about 6 months.

[0118] In embodiments, the cardiovascular disease or disorder is selected from sinus tach (e.g. inappropriate sinus tachycardia (1ST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e.g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g. angina pectoris), myocardial infarct, rhythm disturbances (e.g.

[0119] DBl / 163167834.4 15 supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, left ventricular dysfunction (LVD).

[0120] In embodiments, the cardiovascular disease or disorder is inappropriate sinus tachycardia (1ST)).

[0121] In embodiments, the cardiovascular disease or disorder is angina pectoris (e.g. chronic stable angina pectoris).

[0122] In embodiments, the subject has normal sinus rhythm, and optionally cannot take beta blockers, and / or has undergone coronary artery bypass grafting (CABG).

[0123] In embodiments, the wearable device is one or more of a patch, a watch, a wristband, a strap, a ring, a glass, a shirt, a finger, a bracelet, a SGPS / GPRS baby / control, a belt, a pants, a sock, a shoe, a Bluetooth key tracker, a holter, an implantable, or a device that adheres to a body when fitted.

[0124] In embodiments, the subject is selected for therapy based on a history of inappropriate sinus tachycardia (1ST) and / or an inappropriate sinus tachycardia (1ST) genetic risk score (GRS) indicating high risk of inappropriate sinus tachycardia (1ST) recurrence over time.

[0125] In embodiments, the subject is selected for therapy based on a positive result from a wearable FDA cleared device, a history of inappropriate sinus tachycardia (1ST) and / or an inappropriate sinus tachycardia (1ST) genetic risk score (GRS) indicating high risk of inappropriate sinus tachycardia (1ST) recurrence over time.

[0126] In embodiments, the wearable FDA cleared device is used to monitor the subject on therapy and dosing is adjusted over time based on the rate of the slow diastolic depolarization phase.

[0127] In embodiments, the risk factor comprises age, ethnicity, or a history of cardiovascular disease, cardiac amyloidosis, illicit drug use, or diabetes.

[0128] BRIEF DESCRIPTION OF THE FIGURES

[0129] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0130] FIGS. 1 A and 1 B show exemplary mass spectra of compound 2001 .

[0131] FIGS. 2A and 2B show exemplary mass spectra of compound 2002.

[0132] FIGS. 3A and 3B show exemplary mass spectra of compound 2003.

[0133] FIGS. 4A and 4B show exemplary mass spectra of compound 2004.

[0134] FIGS. 5A and 5B show exemplary mass spectra of compound 2005.

[0135] FIGS. 6A and 6B show exemplary mass spectra of compound 2006.

[0136] FIG. 7A and 7B show the AUC / dose of compound 2004 for dose linearity in rats at dosing concentrations of 3 mg / kg, 10 mg / kg and 30.

[0137] FIG. 8 shows concentration-time profiles of compound 1000 and compound 2004 in fasted and fed states.

[0138] DBl / 163167834.4 16 DETAILED DESCRIPTION

[0139] Disclosed herein are prodrugs of (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7- yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one that are useful, inter alia, for the treatment of disease, such as therapies for cardiovascular disease or disorders including sinus tach (e.g. inappropriate sinus tachycardia (1ST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e.g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g. angina pectoris), myocardial infarct, rhythm disturbances (e.g. supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, and left ventricular dysfunction (LVD). (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1 ,3,4,5- tetrahydro-2H-benzo[d]azepin-2-one (Compound 1000) is an drug used to treat certain adults with heart failure (condition in which the heart is unable to pump enough blood to the other parts of the body) to decrease the risk that their condition will worsen with adverse side effects that include liver, lung, and thyroid toxicity as well as multiple drug interactions.

[0140] (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1,3,4,5- tetrahydro-2H-benzo[d]azepin-2-one (Compound 1000)

[0141] The term "prodrug” includes compounds which, under physiological conditions, are converted into pharmaceutical agents, i.e., a compound of the present disclosure. In embodiments, one method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiological conditions to reveal the desired molecule.

[0142] As used herein, the term "alkyl” denotes branched or unbranched hydrocarbon chains, having about 1 to 10 carbons, such as, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, 2-methylpentyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl pentyl, octyl, 2,2,4-trimethylpentyl, and the like. "Substituted alkyl” includes an alkyl group unsubstituted or substituted with one or more functional groups which are attached commonly to such chains, such as, hydroxy, halogen, mercapto or thio, cyano, alkylthio, carboxy, nitro, alkoxy, or unsubstituted or substituted, alkyl, amino, alkenyl, carboxamide, carbalkoxy, alkynyl, heterocyclyl, aryl, heteroaryl, and the like to form alkyl groups such as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl, phenethyl, benzyl, and the like.

[0143] The term "halogen” or “halo” as used herein alone or as part of another group refers to chloro, bromo, fluoro, or iodo.

[0144] DB1 / 163167834.4 17 The term “alkoxy” refers to alkyl-O-, in which alkyl is as defined above.

[0145] The term “alkylthio” refers to alkyl-S-, in which alkyl is as defined above.

[0146] The term “alkylamino” refers to -NR'R”, in which R' and R” each may independently represent H, alkyl, or aryl, all as defined herein.

[0147] The term “alkylcarbonyl” refers to — C(=O)-alkyl, in which alkyl is as defined above.

[0148] The term “carboxy” refers to the moiety -C(=O)OH.

[0149] The term “carbalkoxy” refers to the moiety — C(=O)-O-alkyl, in which alkyl is as defined above.

[0150] The term “carboxamido” refers to the moiety -C(=0)-NR’R”, in which R’ and R”, each may independently represent H, alkyl, or aryl, all as defined herein.

[0151] The term “alkylsulfonyl” refers to the moiety — S(=0)2-alkyl, in which alkyl is as defined above.

[0152] The term “arylsulfonyl” refers to the moiety — S(=0)2-aryl, in which aryl is as defined herein. For example, arylsulfonyl may be -S(=O)2-phenyl.

[0153] The term “ary Isulfonyloxy” refers to the moiety - 0S(=0)2-alkyl, wherein alkyl is as defined above.

[0154] The term “amino(monoalkylamino-, dialkylamino-)sulfinyl” refers to the moiety -S(=0)NR’R”, in which R’ and R” each may independently represent H, alkyl, or aryl, all as defined herein.

[0155] The term “amino(monoalkylamino-, dial ky I amino-)sulfony I” refers to the moiety -S^O^NR’R”, in which R' and R” each may independently represent H, alkyl, or aryl, all as defined herein.

[0156] The term “alkylsulfonylamino" refers to the moiety — NHS(=O)2-alkyl , in which alkyl is as previously defined.

[0157] The term “hydroxysulfonyloxy” refers to the moiety -OS(=O)2OH.

[0158] The term “alkoxysulfonyloxy” refers to the moiety — 0S(=0)20-alkyl, in which alkyl is as defined above.

[0159] The term “alkylsulfonyloxy” refers to the moiety — 0S(=0)2-alkyl, in which alkyl is as previously defined.

[0160] The term “hydroxysulfonyl” refers to the moiety -S(=O)2OH.

[0161] The term “alkoxysulfonyl” refers to the moiety — S(=0)20-alkyl, wherein alkyl is as previously defined.

[0162] The term “alkylsulfonylalkyl” refers to the moiety -alkyl-S(=0)2-alkyl, wherein each alkyl may be as previously defined. The term “amino(monoalkylamino-, dialkylamino-)sulfonylakyl” refers to the moiety — alkyl-S(=O)2-NR’R”, wherein alkyl is as previously defined, and R’ and R” each may independently represent H, alkyl, or aryl, all as defined herein.

[0163] The term “amino(monoalkylamino-, dialkylamino-)sulfinylalkyl” refer to the moieties - alkyl-S(=O)-NR’R”, wherein alkyl is as previously defined, and R’ and R” each may independently represent H, alkyl, or aryl, all as defined herein.

[0164] Unless otherwise indicated, the term “cycloalkyl” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or more double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and cyclohexenyl. “Substituted cycloalkyl” includes a cycloalkyl group optionally substituted with 1 or more substituents

[0165] DBl / 163167834.4 18 such as halogen, alkyl, substituted alkyl, alkoxy, hydroxy, aryl, substituted aryl, aryloxy, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and / or alkylthio and / or any of the substituents included in the definition of "substituted alkyl.”

[0166] Unless otherwise indicated, the term “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain, which include one or more double bonds in the normal chain, such as vinyl, 2-propeny 1, 3-buteny 1 , 2-buteny 1 , 4-penteny I , 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4- dodecenyl, 4,8, 12-tetradecatrienyl, and the like. “Substituted alkenyl” includes an alkenyl group optionally substituted with one or more substituents, such as the substituents included above in the definition of “substituted alkyl" and “substituted cycloalkyl. "

[0167] Unless otherwise indicated, the term “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one or more triple bonds in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3- pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4- dodecynyl and the like. “Substituted alkynyl” includes an alkynyl group optionally substituted with one or more substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyl Unless otherwise indicated, the term “aryl” or “Ar” as employed herein alone or as part of another group refers to monocyclic, bicyclic, and / or polycyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1 -naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring, such as aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl rings or substituted forms thereof.

[0168] “Substituted aryl” includes an aryl group optionally substituted with one or more functional groups, such as halo, alkyl, haloalkyl (e.g., trifluoromethyl), alkoxy, haloalkoxy (e.g., difluoromethoxy), alkenyl, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are optionally substituted alkyl, aryl or any of the other substituents recited herein), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylaminocarbonyl, arylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinyl alkyl, arylsulfonylamino, or arylsulfonaminocarbonyl and / or any of the alkyl substituents recited herein.

[0169] The term “arylalkyl” refers to — alkyl-aryl, in which alkyl and aryl are as defined above.

[0170] The term “haloalkyl” refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include -CF3, -C2F5, -CHF2, -CH2F, -CCI3, -CHCI2, -C2CI5, and the like. An alkyl group in which all of the hydrogen atoms are replaced with halogen atoms can be referred to as “perhaloalkyl.”

[0171] DBl / 163167834.4 19 The term “haloalkoxy” refers to an alkoxy group having one or more halogen substituents. Example haloalkoxy groups include -OCF3, -OC2F5, -OCHF2, -OCH2F, -OCCI3, -OCHCI2, -OC2CI5, and the like. An alkyl group in which all of the hydrogen atoms are replaced with halogen atoms can be referred to as “perhaloalkyl.”

[0172] Unless otherwise indicated, the term “heteroaryl” as used herein alone or as part of another group refers to a 5- to 7- membered aromatic ring which includes 1 , 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur and such rings fused to an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring (e.g. benzothiophene, indole, quinoline, thiazole, isooxazole, benzothiazole, benzimidizole, isoquinoline, pyridine, pyrimidine, benzopyrone, oxazole, thiazole, pyrazine), and includes possible N-oxides. “Substituted heteroaryl” includes a heteroaryl group optionally substituted with 1 to 4 substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyl.” Substituted heteroaryl also includes fused heteroaryl groups which include, for example, quinoline, isoquinoline, indole, isoindole, carbazole, acridine, benzopyrene, benzopyrone, benzimidazole, benzofuran, isobenzofuran, phenanthroline, purine, and the like.

[0173] Moreover, the terms “heterocyclo,” “heterocycle,” “heterocyclyl,” or “heterocyclic ring,” as used herein, refer to an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from N, 0 or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, benzothiophene, chromone, benzopyrene, benzopyrone, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, and oxadiazolyl.

[0174] The term “heteroarylalkyl” refers to — alkyl-heteroaryl, in which alkyl and heteroaryl are as defined above.

[0175] As used herein, the terms “optionally substituted” or “substituted” may indicate that a chemical moiety referred to, for example, alkyl, aryl, and heteroaryl, may be unsubstituted or substituted with one or more groups including, without limitation, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, hydroxyl, amino, substituted amino, alkoxy, substituted alkoxy, halogen, carboxy, nitro, carbalkoxy, substituted carbalkoxy, carboxamido, substituted carboxamido, alkylamino, substituted alkyl amino, monoalkylaminosulfinyl, substituted, monoalkylaminosulfinyl, dialkylaminosulfinyl, substituted dialkylaminosulfinyl, monoalkylaminosulfonyl, substituted monoalkylaminosulfonyl, dialkylaminosulfonyl, substituted dialkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, substituted alkoxysulfonyloxy, alkylsulfonyloxy, substituted alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, substituted

[0176] DBl / 163167834.4 20 alkoxysulfonyl, alkylsulfonylalkyl, substituted alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, substituted monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, substituted dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, substituted monoalkylaminosulfinylalkyl, dialkylaminosulfinylalkyl, substituted dialkylaminosulfinylalkyl, and the like. The chemical moieties of formula (I), formula 1001-1011, formula 2001-2011 , or a pharmaceutically acceptable salt thereof, above, that may be optionally substituted include alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, aryl, heterocycle, and heteroaryl, as described herein. For example, optionally substituted alkyl may include both propyl and 2-chloro-propyl. Additionally, “optionally substituted” is also inclusive of embodiments where the named substituent or substituents have multiple substituents rather than simply a single substituent. For example, optionally substituted aryl may include both phenyl and 3-ethyl-5-methyl-6-bromo-phenyl.

[0177] “Pharmaceutically acceptable” includes approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans.

[0178] The compounds of the disclosure may be administered as salts, which are also within the scope of this disclosure. Pharmaceutically acceptable (i.e., non-toxic, physiologically compatible) salts are preferred. A "pharmaceutically acceptable salt" includes a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. The term "pharmaceutically acceptable anion" includes the anion of such acid addition salts. If the compounds of the disclosure have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkane carboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methyl- or paratoluene-sulfonic acid Corresponding acid addition salts can also be formed having plural basic centers, if desired. In embodiments, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1 -carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid,

[0179] DBl / 163167834.4 21 gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. In embodiments, salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.

[0180] In embodiments, the pharmaceutically acceptable anion is selected from the deprotonated form of valproic acid, maleic acid, tartaric acid, oxalic acid, pamoic acid, phosphonic acid, benzoic acid, citric acid, salicylic acid, succinic acid, methanesulfonic acid, malic acid, and p-toluenesulfonic acid. In embodiments, the pharmaceutically acceptable salt is selected from valproic acid, maleic acid, tartaric acid, oxalic acid, and pamoic acid.

[0181] The compounds of the disclosure having at least one acid group (e.g., carboxylic acid) can also form salts with suitable bases. Representative examples of such salts include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or trihydroxy lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine. Corresponding internal salts may also be formed.

[0182] For example, certain salts of the compounds described herein which contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate. Moreover, certain salts of the compounds described herein which contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.

[0183] All stereoisomers of the compounds of the disclosure, either in a mixture or in pure or substantially pure form, are considered to be within the scope of this disclosure. The compounds of the disclosure may have asymmetric centers at any of the carbon atoms including any one of the substituents. Consequently, compounds of the disclosure may exist in enantiomeric or diastereomeric forms or in mixtures thereof. Furthermore, where a stereocenter existing in a compound of the disclosure is represented as a racemate, it is understood that the stereocenter may encompass the racemic mixture of R and S isomers, the S isomers, and the R isomers. The processes for preparation of such compounds can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods including, chromatographic, chiral HPLC, fractional crystallization, or distillation. In embodiments, compounds of the present disclosure have groups including alkenyls, iminyls, and the like, which may exist as entgegen (E) or zusammen (Z) conformations, in which case all geometric forms thereof, both E and Z, cis and trans, and mixtures thereof, are within the scope of the present disclosure. Accordingly, when such geometric isomeric products are prepared, they can be separated by conventional methods for example, chromatographic, HPLC, distillation or crystallization.

[0184] DBl / 163167834.4 22 Accordingly, in one aspect, the present disclosure provides a compound of formula (XI), or a stereoisomer thereof: formula (XI) or a stereoisomer thereof, wherein in formula (XI):

[0185] X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;

[0186] Z is selected from i), ii), and iii): iv) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy, v) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, vi) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0187] DBl / 163167834.4 23 In embodiments, the compound is a compound of formula (XI) wherein Rais hydrogen or Ci-Ce alkyl. In embodiments, the compound is a compound of formula (XI) wherein Rais hydrogen. In embodiments, the compound is a compound of formula (XI) wherein Rais independently at each occurrence alkyl, optionally wherein the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl. In embodiments, the compound is a compound of formula (XI) wherein Rais selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl.

[0188] In embodiments, the compound is a compound of formula (XI) wherein Rais unbranched Ci-Ce alkyl. In embodiments, the compound is a compound of formula (XI) wherein Rais a branched Ci-Ce alkyl.

[0189] In embodiments, the compound is a compound of formula (XI) wherein Rbis hydrogen or Ci-Ce alkyl. In embodiments, the compound is a compound of formula (XI) wherein Rbis hydrogen. In embodiments, the compound is a compound of formula (XI) wherein Rbis independently at each occurrence alkyl, optionally wherein the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl. In embodiments, the compound is a compound of formula (XI) wherein Rbis selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl.

[0190] In embodiments, the compound is a compound of formula (XI) wherein Rbis unbranched Ci-Ce alkyl. In embodiments, the compound is a compound of formula (XI) wherein Rbis a branched Ci-Ce alkyl.

[0191] In embodiments, the compound is a compound of formula (XI) wherein Raand Rbare joined to form a 3-6 membered carbocyclic ring, optionally wherein the 3-6 membered carbocyclic ring is selected from cyclohexane, cyclohexene, cyclopropane, cyclobutane; cyclopentane, cyclopropene, cyclobutene, cyclopentene and cyclopentadiene.

[0192] In embodiments, the compound is a compound of formula (XI), wherein Z is -OR1.

[0193] In embodiments, the compound is a compound of formula (XI), wherein R1is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0194] In embodiments, the compound is a compound of formula (XI) wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.

[0195] In embodiments, the compound is a compound of formula (XI), wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, hexyl, and octyl.

[0196] In embodiments, the compound is a compound of formula (XI) wherein R1is phenyl or benzyl.

[0197] In embodiments, the compound is a compound of formula (XI) wherein R1is phenyl. In embodiments, the compound is a compound of formula (XI) wherein R1is benzyl.

[0198] In embodiments, the compound is a compound of formula (XI), wherein R1is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl, optionally -OMe or phenyl.

[0199] DBl / 163167834.4 24 In embodiments, the compound is a compound of formula (XI) wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0200] In embodiments, the compound is a compound of formula (XI), wherein -OR1is selected from -OMe, -OEt, -O-Pr, -0-

[0201] In embodiments, the compound is a compound of formula (XI), wherein Z is R2.

[0202] In embodiments, the compound is a compound of formula (XI), wherein R2is Ci-Cs alkyl.

[0203] In embodiments, the compound is a compound of formula (XI), wherein R2is Ci-Cs alkyl, straight or branched chain, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl.

[0204] In embodiments, the compound is a compound of formula (XI), wherein Ci-Cs alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0205] In embodiments, the compound is a compound of formula (XI), wherein Ci-Cs alkyl is selected from methyl and n-propyl. In embodiments, the compound is a compound of formula (XI), wherein Ci-Cs alkyl is substituted with 1 to 3 substituents selected from Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCH

[0206] In embodiments, the compound is a compound of formula (XI), wherein -R2

[0207] In embodiments, the compound is a compound of formula (XI), wherein R1is phenyl. In embodiments, the compound is a compound of formula (XI), wherein R1is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCFs, -OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0208] In embodiments, the compound is a compound of formula (XI), wherein R2is phenyl. In embodiments, the compound is a compound of formula (XI), wherein R2is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0209] In embodiments, the compound is a compound of formula (XI), wherein R1is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (XI), wherein R1is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0210] In embodiments, the compound is a compound of formula (XI), wherein R2is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (XI), wherein R2is a 5- or 6-membered heteroaryl, and the 5-

[0211] DBl / 163167834.4 25 or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0212] In embodiments, the compound is a compound of formula (XI), wherein R3is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (XI), wherein R3is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0213] In embodiments, the compound is a compound of formula (XI), wherein Z is -N(R3)2. In embodiments, the compound is a compound of formula (XI), wherein Z is -NHR3. In embodiments, R3is independently at each occurrence selected from alkyl. In embodiments, the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0214] In embodiments, the compound is a compound of formula (XI), wherein each R3is methyl.

[0215] In embodiments, the compound is a compound of formula (XI), wherein one or both R3are each independently substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl.

[0216] In embodiments, the compound is a compound of formula (XI), wherein -N(R3)2is -N(CH3)2.

[0217] In one aspect, the present disclosure provides a compound of formula (Xia), or a stereoisomer thereof: formula (Xia) or a stereoisomer thereof, wherein in formula (Xia):

[0218] X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;

[0219] Z is selected from i), ii), and iii): i) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0220] II) R2, wherein R2is selected from a), b), and c):

[0221] DBl / 163167834.4 26 a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0222] In embodiments, the compound is a compound of formula (Xia) wherein Rais hydrogen or Ci-Ce alkyl. In embodiments, the compound is a compound of formula (Xia) wherein Rais hydrogen. In embodiments, the compound is a compound of formula (Xia) wherein Rais independently at each occurrence alkyl, optionally wherein the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl. In embodiments, the compound is a compound of formula (Xia) wherein Rais selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl.

[0223] In embodiments, the compound is a compound of formula (Xia) wherein Rais unbranched Ci-Ce alkyl. In embodiments, the compound is a compound of formula (Xia) wherein Rais a branched Ci-Ce alkyl.

[0224] In embodiments, the compound is a compound of formula (Xia) wherein Rbis hydrogen or Ci-Ce alkyl. In embodiments, the compound is a compound of formula (Xia) wherein Rbis hydrogen. In embodiments, the compound is a compound of formula (Xia) wherein Rbis independently at each occurrence alkyl, optionally wherein the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl. In embodiments, the compound is a compound of formula (Xia) wherein Rbis selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl.

[0225] In embodiments, the compound is a compound of formula (Xia) wherein Rbis unbranched Ci-Ce alkyl. In embodiments, the compound is a compound of formula (Xia) wherein Rbis a branched Ci-Ce alkyl.

[0226] In embodiments, the compound is a compound of formula (Xia) wherein Raand Rbare joined to form a 3-6 membered carbocyclic ring, optionally wherein the 3-6 membered carbocyclic ring is selected from cyclohexane, cyclohexene, cyclopropane, cyclobutane; cyclopentane, cyclopropene, cyclobutene, cyclopentene and cyclopentadiene.

[0227] DBl / 163167834.4 27 In embodiments, the compound is a compound of formula (Xia), wherein Z is -OR1.

[0228] In embodiments, the compound is a compound of formula (Xia), wherein R1is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0229] In embodiments, the compound is a compound of formula (Xia) wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.

[0230] In embodiments, the compound is a compound of formula (Xia), wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, hexyl, and octyl.

[0231] In embodiments, the compound is a compound of formula (Xia) wherein R1is phenyl or benzyl.

[0232] In embodiments, the compound is a compound of formula (Xia) wherein R1is phenyl. In embodiments, the compound is a compound of formula (Xia) wherein R1is benzyl.

[0233] In embodiments, the compound is a compound of formula (Xia), wherein R1is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl, optionally -OMe or phenyl.

[0234] In embodiments, the compound is a compound of formula (Xia) wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -

[0235] In embodiments, the compound is a compound of formula (Xia), wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -

[0236] In embodiments, the compound is a compound of formula (Xia), wherein Z is R2.

[0237] In embodiments, the compound is a compound of formula (Xia), wherein R2is Ci-Cs alkyl.

[0238] In embodiments, the compound is a compound of formula (Xia), wherein R2is Ci-Cs alkyl, straight or branched chain, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl.

[0239] In embodiments, the compound is a compound of formula (Xia), wherein Ci-Cs alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0240] In embodiments, the compound is a compound of formula (Xia), wherein Ci-Cs alkyl is selected from methyl and n- propyl.

[0241] In embodiments, the compound is a compound of formula (Xia), wherein Ci-Cs alkyl is substituted with 1 to 3 substituents selected from Cl, Br, I, -OMe, -OEt, -O / '-Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl, optionally phenyl.

[0242] In embodiments, the compound is a compound of formula (Xia), wherein -R2is

[0243] DBl / 163167834.4 28 In embodiments, the compound is a compound of formula (Xia), wherein R1is phenyl. In embodiments, the compound is a compound of formula (Xia), wherein R1is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, - OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0244] In embodiments, the compound is a compound of formula (Xia), wherein R2is phenyl. In embodiments, the compound is a compound of formula (Xia), wherein R2is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / '-Pr, -CF3, -CHF2, -CH2F, -OCF3, - OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0245] In embodiments, the compound is a compound of formula (Xia), wherein R1is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (Xia), wherein R1is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0246] In embodiments, the compound is a compound of formula (Xia), wherein R2is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (Xia), wherein R2is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0247] In embodiments, the compound is a compound of formula (Xia), wherein R3is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (Xia), wherein R3is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0248] In embodiments, the compound is a compound of formula (Xia), wherein Z is -N(R3)2. In embodiments, the compound is a compound of formula (Xia), wherein Z is -NHR3. In embodiments, R3is independently at each occurrence selected from alkyl. In embodiments, the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0249] In embodiments, the compound is a compound of formula (Xia), wherein each R3is methyl.

[0250] In embodiments, the compound is a compound of formula (Xia), wherein one or both R3are each independently substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / '-Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl.

[0251] In embodiments, the compound is a compound of formula (Xia), wherein -N(R3)2is -N(CH3)2.

[0252] In one aspect, the present disclosure provides a compound of formula (Xlb), or a stereoisomer thereof:

[0253] DBl / 163167834.4 29 formula (XI b) or a stereoisomer thereof, wherein in formula (Xlb):

[0254] X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;

[0255] Z is selected from i), ii), and iii): i) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0256] II) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, iii) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0257] In embodiments, the compound is a compound of formula (Xlb) wherein Rais hydrogen or Ci-Ce alkyl. In embodiments, the compound is a compound of formula (Xlb) wherein Rais hydrogen. In embodiments, the compound is a compound

[0258] DBl / 163167834.4 30 of formula (Xlb) wherein Rais independently at each occurrence alkyl, optionally wherein the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl. In embodiments, the compound is a compound of formula (Xlb) wherein Rais selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl.

[0259] In embodiments, the compound is a compound of formula (Xlb) wherein Rais unbranched Ci-Ce alkyl. In embodiments, the compound is a compound of formula (Xlb) wherein Rais a branched Ci-Ce alkyl.

[0260] In embodiments, the compound is a compound of formula (Xlb) wherein Rbis hydrogen or Ci-Ce alkyl. In embodiments, the compound is a compound of formula (Xlb) wherein Rbis hydrogen. In embodiments, the compound is a compound of formula (Xlb) wherein Rbis independently at each occurrence alkyl, optionally wherein the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl. In embodiments, the compound is a compound of formula (Xlb) wherein Rbis selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl.

[0261] In embodiments, the compound is a compound of formula (Xlb) wherein Rbis unbranched Ci-Ce alkyl. In embodiments, the compound is a compound of formula (Xlb) wherein Rbis a branched Ci-Ce alkyl.

[0262] In embodiments, the compound is a compound of formula (Xlb) wherein Raand Rbare joined to form a 3-6 membered carbocyclic ring, optionally wherein the 3-6 membered carbocyclic ring is selected from cyclohexane, cyclohexene, cyclopropane, cyclobutane; cyclopentane, cyclopropene, cyclobutene, cyclopentene and cyclopentadiene.

[0263] In embodiments, the compound is a compound of formula (Xlb), wherein Z is -OR1.

[0264] In embodiments, the compound is a compound of formula (Xlb), wherein R1is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0265] In embodiments, the compound is a compound of formula (Xlb) wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.

[0266] In embodiments, the compound is a compound of formula (Xlb), wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, hexyl, and octyl.

[0267] In embodiments, the compound is a compound of formula (Xlb) wherein R1is phenyl or benzyl.

[0268] In embodiments, the compound is a compound of formula (Xlb) wherein R1is phenyl. In embodiments, the compound is a compound of formula (Xlb) wherein R1is benzyl.

[0269] In embodiments, the compound is a compound of formula (Xlb), wherein R1is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / '-Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl, optionally -OMe or phenyl.

[0270] In embodiments, the compound is a compound of formula (Xlb) wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -

[0271] DBl / 163167834.4 31 In embodiments, the compound is a compound of formula (Xlb), wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -

[0272] In embodiments, the compound is a compound of formula (Xlb), wherein Z is R2.

[0273] In embodiments, the compound is a compound of formula (Xlb), wherein R2is Ci-Cs alkyl.

[0274] In embodiments, the compound is a compound of formula (Xlb), wherein R2is Ci-Cs alkyl, straight or branched chain, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl.

[0275] In embodiments, the compound is a compound of formula (Xlb), wherein Ci-Cs alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0276] In embodiments, the compound is a compound of formula (Xlb), wherein Ci-Cs alkyl is selected from methyl and n- propyl.

[0277] In embodiments, the compound is a compound of formula (Xlb), wherein Ci-Cs alkyl is substituted with 1 to 3 substituents selected from Cl, Br, I, -OMe, -OEt, -O / '-Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl, optionally phenyl.

[0278] In embodiments, the compound is a compound of formula (Xlb), wherein -R2is

[0279] In embodiments, the compound is a compound of formula (Xlb), wherein R1is phenyl. In embodiments, the compound is a compound of formula (Xlb), wherein R1is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -

[0280] OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0281] In embodiments, the compound is a compound of formula (Xlb), wherein R2is phenyl. In embodiments, the compound is a compound of formula (Xlb), wherein R2is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -OZ-Pr, -CF3, -CHF2, -CH2F, -OCF3, - OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0282] In embodiments, the compound is a compound of formula (Xlb), wherein R1is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (Xlb), wherein R1is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0283] In embodiments, the compound is a compound of formula (Xlb), wherein R2is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (Xlb), wherein R2is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole,

[0284] DBl / 163167834.4 32 isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0285] In embodiments, the compound is a compound of formula (Xlb), wherein R3is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (Xlb), wherein R3is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0286] In embodiments, the compound is a compound of formula (Xlb), wherein Z is -N(R3)2. In embodiments, the compound is a compound of formula (Xlb), wherein Z is -NHR3. In embodiments, R3is independently at each occurrence selected from alkyl. In embodiments, the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0287] In embodiments, the compound is a compound of formula (Xlb), wherein each R3is methyl.

[0288] In embodiments, the compound is a compound of formula (Xlb), wherein one or both R3are each independently substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl.

[0289] In embodiments, the compound is a compound of formula (Xlb), wherein -N(R3)2is -N(CHs)2.

[0290] In one aspect, the present disclosure provides a compound of formula (I), or a stereoisomer thereof: formula (I) or a stereoisomer thereof, wherein in formula (I):

[0291] X is a pharmaceutically acceptable anion;

[0292] Z is selected from I), II), and ill):

[0293] I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0294] II) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl;

[0295] DBl / 163167834.4 33 b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0296] In embodiments, the compound is a compound of formula (I), wherein Z is -OR1.

[0297] In embodiments, the compound is a compound of formula (I), wherein R1is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0298] In embodiments, the compound is a compound of formula (I) wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.

[0299] In embodiments, the compound is a compound of formula (I), wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, hexyl, and octyl.

[0300] In embodiments, the compound is a compound of formula (I) wherein R1is phenyl or benzyl.

[0301] In embodiments, the compound is a compound of formula (I) wherein R1is phenyl. In embodiments, the compound is a compound of formula (I) wherein R1is benzyl.

[0302] In embodiments, the compound is a compound of formula (I), wherein R1is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, - OCHF2, -OCH2F, and phenyl, optionally -OMe or phenyl.

[0303] In embodiments, the compound is a compound of formula (I) wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0304] In embodiments, the compound is a compound of formula (I), wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0305] In embodiments, the compound is a compound of formula (I), wherein Z is R2.

[0306] In embodiments, the compound is a compound of formula (I), wherein R2is Ci-Cs alkyl.

[0307] DBl / 163167834.4 In embodiments, the compound is a compound of formula (I), wherein R2is Ci-Cs alkyl, straight or branched chain, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl.

[0308] In embodiments, the compound is a compound of formula (I), wherein Ci-Cs alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0309] In embodiments, the compound is a compound of formula (I), wherein Ci-Cs alkyl is selected from methyl and n-propyl. In embodiments, the compound is a compound of formula (I), wherein Ci-Cs alkyl is substituted with 1 to 3 substituents selected from Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3,

[0310] In embodiments, the compound is a compound of formula (I), wherein

[0311] In embodiments, the compound is a compound of formula (I), wherein R1is phenyl. In embodiments, the compound is a compound of formula (I), wherein R1is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0312] In embodiments, the compound is a compound of formula (I), wherein R2is phenyl. In embodiments, the compound is a compound of formula (I), wherein R2is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0313] In embodiments, the compound is a compound of formula (I), wherein R1is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (I), wherein R1is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0314] In embodiments, the compound is a compound of formula (I), wherein R2is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (I), wherein R2is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0315] In embodiments, the compound is a compound of formula (I), wherein R3is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (I), wherein R3is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0316] DBl / 163167834.4 35 In embodiments, the compound is a compound of formula (I), wherein Z is -N(R3)2. In embodiments, the compound is a compound of formula (I), wherein Z is -NHR3. In embodiments, R3is independently at each occurrence selected from alkyl. In embodiments, the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0317] In embodiments, the compound is a compound of formula (I), wherein each R3is methyl. In embodiments, the compound is a compound of formula (I), wherein one or both R3are each independently substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl.

[0318] In embodiments, the compound is a compound of formula (I), wherein -N(R3)2is -N(CH3)2.

[0319] In embodiments, the compound is a compound of formula (I), wherein the compound of formula (I) has a formula of any one of formula 1001-1006:

[0320] In one aspect, the present disclosure provides a compound of formula (la), or a stereoisomer thereof: formula (la)

[0321] DBl / 163167834.4 36 or a stereoisomer thereof, wherein in formula (la):

[0322] X is a pharmaceutically acceptable anion;

[0323] Z is selected from i), ii), and iii): i) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0324] II) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, iii) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0325] In embodiments, the compound is a compound of formula (la), wherein Z is -OR1.

[0326] In embodiments, the compound is a compound of formula (la), wherein R1is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0327] In embodiments, the compound is a compound of formula (la) wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.

[0328] In embodiments, the compound is a compound of formula (la), wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, hexyl, and octyl.

[0329] In embodiments, the compound is a compound of formula (la) wherein R1is phenyl or benzyl.

[0330] In embodiments, the compound is a compound of formula (la) wherein R1is phenyl. In embodiments, the compound is a compound of formula (la) wherein R1is benzyl.

[0331] DBl / 163167834.4 37 In embodiments, the compound is a compound of formula (la), wherein R1is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, - OCHF2, -OCH2F, and phenyl, optionally -OMe or phenyl.

[0332] In embodiments, the compound is a compound of formula (la) wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0333] In embodiments, the compound is a compound of formula (la), wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0334] In embodiments, the compound is a compound of formula (la), wherein Z is R2.

[0335] In embodiments, the compound is a compound of formula (la), wherein R2is Ci-Cs alkyl.

[0336] In embodiments, the compound is a compound of formula (la), wherein R2is Ci-Cs alkyl, straight or branched chain, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl.

[0337] In embodiments, the compound is a compound of formula (la), wherein Ci-Cs alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0338] In embodiments, the compound is a compound of formula (la), wherein Ci-Cs alkyl is selected from methyl and n-propyl. In embodiments, the compound is a compound of formula (la), wherein Ci-Cs alkyl is substituted with 1 to 3 substituents selected from Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl, optionally phenyl.

[0339] In embodiments, the compound is a compound of formula (la), wherein -R2is

[0340] In embodiments, the compound is a compound of formula (la), wherein R1is phenyl. In embodiments, the compound is a compound of formula (la), wherein R1is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2,

[0341] -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0342] In embodiments, the compound is a compound of formula (la), wherein R2is phenyl. In embodiments, the compound is a compound of formula (la), wherein R2is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0343] In embodiments, the compound is a compound of formula (la), wherein R1is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (la), wherein R1is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole,

[0344] DBl / 163167834.4 38 isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0345] In embodiments, the compound is a compound of formula (la), wherein R2is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (la), wherein R2is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0346] In embodiments, the compound is a compound of formula (la), wherein R3is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (la), wherein R3is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0347] In embodiments, the compound is a compound of formula (la), wherein Z is -N(R3)2. In embodiments, the compound is a compound of formula (la), wherein Z is -NHR3. In embodiments, R3is independently at each occurrence selected from alkyl. In embodiments, the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0348] In embodiments, the compound is a compound of formula (la), wherein each R3is methyl.

[0349] In embodiments, the compound is a compound of formula (la), wherein one or both R3are each independently substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl.

[0350] In embodiments, the compound is a compound of formula (la), wherein -N(R3)2is -N(CH3)2.

[0351] In embodiments, the compound is a compound of formula (la), wherein the compound of formula (la) has a formula of any one of formula 1011-1016:

[0352] DBl / 163167834.4 39

[0353]

[0354] In one aspect, the present disclosure provides a compound of formula (lb), or a stereoisomer thereof: formula (lb) or a stereoisomer thereof, wherein in formula (lb):

[0355] X is a pharmaceutically acceptable anion;

[0356] Z is selected from i), ii), and iii): i) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ii) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, iii) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally

[0357] DBl / 163167834.4 40 substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0358] In embodiments, the compound is a compound of formula (lb), wherein Z is -OR1.

[0359] In embodiments, the compound is a compound of formula (lb), wherein R1is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0360] In embodiments, the compound is a compound of formula (lb) wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.

[0361] In embodiments, the compound is a compound of formula (lb), wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, hexyl, and octyl.

[0362] In embodiments, the compound is a compound of formula (lb) wherein R1is phenyl or benzyl.

[0363] In embodiments, the compound is a compound of formula (lb) wherein R1is phenyl. In embodiments, the compound is a compound of formula (lb) wherein R1is benzyl.

[0364] In embodiments, the compound is a compound of formula (lb), wherein R1is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, - OCHF2, -OCH2F, and phenyl, optionally -OMe or phenyl.

[0365] In embodiments, the compound is a compound of formula (lb) wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0366] In embodiments, the compound is a compound of formula (lb), wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -0-

[0367] In embodiments, the compound is a compound of formula (lb), wherein Z is R2.

[0368] In embodiments, the compound is a compound of formula (lb), wherein R2is Ci-Os alkyl.

[0369] In embodiments, the compound is a compound of formula (lb), wherein R2is Ci-Cs alkyl, straight or branched chain, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl.

[0370] In embodiments, the compound is a compound of formula (lb), wherein Ci-Cs alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0371] In embodiments, the compound is a compound of formula (lb), wherein Ci-Cs alkyl is selected from methyl and n-propyl. In embodiments, the compound is a compound of formula (lb), wherein Ci-Cs alkyl is substituted with 1 to 3 substituents selected from Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -O

[0372] In embodiments, the compound is a compound of formula (lb), wherein -

[0373] DBl / 163167834.4 41 In embodiments, the compound is a compound of formula (lb), wherein R1is phenyl. In embodiments, the compound is a compound of formula (lb), wherein R1is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0374] In embodiments, the compound is a compound of formula (lb), wherein R2is phenyl. In embodiments, the compound is a compound of formula (lb), wherein R2is phenyl and the phenyl is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl. In embodiments, phenyl is substituted with phenyl.

[0375] In embodiments, the compound is a compound of formula (lb), wherein R1is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (lb), wherein R1is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0376] In embodiments, the compound is a compound of formula (lb), wherein R2is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (lb), wherein R2is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0377] In embodiments, the compound is a compound of formula (lb), wherein R3is a 5- or 6-membered heteroaryl. In embodiments, the compound is a compound of formula (lb), wherein R3is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from pyridinyl, furyl, pyrrolidinyl, oxazole, isoxazole, pyrrazole, thiazole, isothiazole, and pyrimidine. In embodiments, the 5- or 6-membered heteroaryl is pyridinyl. In embodiments, the 5- or 6-membered heteroaryl is 3-pyridinyl. In embodiments, R2is 3-pyridinyl.

[0378] In embodiments, the compound is a compound of formula (lb), wherein Z is -N(R3)2. In embodiments, the compound is a compound of formula (lb), wherein Z is -NHR3. In embodiments, R3is independently at each occurrence selected from alkyl. In embodiments, the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0379] In embodiments, the compound is a compound of formula (lb), wherein each R3is methyl.

[0380] In embodiments, the compound is a compound of formula (lb), wherein one or both R3are each independently substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / '-Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl.

[0381] In embodiments, the compound is a compound of formula (lb), wherein -N(R3)2 is -N(CH3)2.

[0382] In embodiments, the compound is a compound of formula (lb), wherein the compound of formula (lb) has a formula of any one of formula 1021-1026:

[0383] DBl / 163167834.4 42

[0384]

[0385] In embodiments, the compound is a compound of formu a (I), wherein X is selected from chloride, bromide, iodide, hydroxide, sulfate (SCu-2, HSO2), nitrate, phosphate (e.g. PO43, HPO2, H2PO4'), acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.

[0386] In embodiments, the compound is a compound of formula (I), wherein X is selected from chloride, bromide, iodide, acetate, HSOr, SO42, p-toluenesulfonate, PCh'3, HPO42, F PCh', and tartrate.

[0387] In embodiments, the compound is a compound of formula (I), wherein X is chloride.

[0388] In embodiments, the compound is a compound of formula (I), wherein X is iodide.

[0389] In embodiments, the compound is a compound of formula (I), wherein the compound of formula (I) has a formula of any one of formula 2001-2006:

[0390] DBl / 163167834.4 43

[0391] In embodiments, the compound is a compound of formula (la), wherein X is selected from chloride, bromide, iodide, hydroxide, sulfate (SO42, HSO2), nitrate, phosphate (e.g. PO43, HPCk2, I^PC r), acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate. In embodiments, the compound is a compound of formula (la), wherein X is selected from chloride, bromide, iodide, acetate, HSOr, SO42, p-toluenesulfonate, PO43, HPO42, H2PO4 , and tartrate.

[0392] In embodiments, the compound is a compound of formula (la), wherein X is chloride.

[0393] In embodiments, the compound is a compound of formula (la), wherein X is iodide.

[0394] In embodiments, the compound is a compound of formula (la), wherein the compound of formula (la) has a formula of any one of formula 2011-2016:

[0395] DBl / 163167834.4 44

[0396]

[0397] In embodiments, the compound is a compound of formula (lb), wherein X is selected from chloride, bromide, iodide, hydroxide, sulfate (SCu-2, HSO2), nitrate, phosphate (e.g. PO43, HPO2, H2PO4'), acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.

[0398] In embodiments, the compound is a compound of formula (lb), wherein X is selected from chloride, bromide, iodide, acetate, HSOr, SO42, p-toluenesulfonate, PCh'3, HPO42, F PCU', and tartrate.

[0399] In embodiments, the compound is a compound of formula (lb), wherein X is chloride.

[0400] In embodiments, the compound is a compound of formula (lb), wherein X is iodide.

[0401] In embodiments, the compound is a compound of formula (lb), wherein the compound of formula (lb) has a formula of formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026, wherein the compound of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011- 1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026, exhibits improved gastrointestinal absorption (e.g.

[0402] DBl / 163167834.4 45 improved permeability and / or solubility) compared to (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien-7- yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0403] In embodiments, the compound is a compound of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026, wherein the compound of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011- 1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026, exhibits at least about 1 fold, at least about 2 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 6 fold, at least about 7 fold, at least about 8 fold, at least about 9 fold, at least about 10 fold, at least about 50 fold, at least about 100 fold, at least about 500 fold, or at least about 1000 fold improved gastrointestinal absorption (e.g. improved permeability and / or solubility) compared to (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien-7-yi)methyl)(methyl)amino)propyl)-7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0404] Pharmaceutical compositions

[0405] Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (XI), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (XI) or a stereoisomer thereof, wherein in formula (XI):

[0406] X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;

[0407] Z is selected from i), ii), and iii): i) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0408] II) R2, wherein R2is selected from a), b), and c):

[0409] DBl / 163167834.4 46 a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0410] Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (Xia), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (Xia) or a stereoisomer thereof, wherein in formula (Xia):

[0411] X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;

[0412] Z is selected from I), II), and ill):

[0413] I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ii) R2, wherein R2is selected from a), b), and c):

[0414] DBl / 163167834.4 47 a) Ci-C8alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b) benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c) 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, iii) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0415] Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (Xlb), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (Xlb) or a stereoisomer thereof, wherein in formula (Xlb):

[0416] X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;

[0417] Z is selected from I), ii), and iii): i) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ii) R2, wherein R2is selected from a), b), and c):

[0418] DBl / 163167834.4 48 a) Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b) benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c) 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Cs alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Cs alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0419] Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (I) wherein in formula (I):

[0420] X is a pharmaceutically acceptable anion;

[0421] Z is selected from I), II), and ill): i) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0422] II) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl;

[0423] DBl / 163167834.4 49 b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0424] Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (la), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (la) wherein in formula (la):

[0425] X is a pharmaceutically acceptable anion;

[0426] Z is selected from I), II), and ill):

[0427] I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0428] II) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy;

[0429] DBl / 163167834.4 50 c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0430] Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (lb), or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: formula (lb) wherein in formula (lb):

[0431] X is a pharmaceutically acceptable anion;

[0432] Z is selected from i), ii), and Hi):

[0433] I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0434] II) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy,

[0435] DBl / 163167834.4 51 iii) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

[0436] In embodiments, the compound of formula (XI) or formula (I) is a compound of any one of formula 1001-1006, 1011- 1016, or 1021-1026. In embodiments, the compound of formula (XI) or formula (I) is a compound of any one of formula 2001-2006, 2011-2016, or 2021-2026.

[0437] In embodiments, the pharmaceutical composition is formulated for oral or parenteral administration. In embodiments, the pharmaceutical composition is formulated for topical, dermal, intradermal, intramuscular, intraperitoneal, intraarticular, intravenous, subcutaneous, intraarterial or transdermal administration. In embodiments, the pharmaceutical composition is formulated for topical administration.

[0438] In embodiments, any of the compounds of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 disclosed herein (and / or additional agents) are included in various formulations. Any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011- 2016, or 2021-2026 (and / or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.

[0439] In embodiments, the compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 disclosed herein can possess a sufficiently basic functional group, which can react with an inorganic or organic acid, or a carboxyl group, which can react with an inorganic or organic base, to form a pharmaceutically acceptable salt. A pharmaceutically acceptable acid addition salt is formed from a pharmaceutically acceptable acid, as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in, for example, Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated by reference in their entirety.

[0440] In embodiments, the compositions disclosed herein are in the form of a pharmaceutically acceptable salt.

[0441] Further, any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001 - 1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 disclosed herein can be administered

[0442] DBl / 163167834.4 52 to a subject as a component of a pharmaceutical composition, that comprises a pharmaceutically acceptable carrier or vehicle. Such pharmaceutical compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration. Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In embodiments, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent disclosed herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any agent disclosed herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0443] In aspects, the present disclosure includes the disclosed compounds of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 in various formulations of a pharmaceutical composition. Any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 disclosed herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.

[0444] Where necessary, the pharmaceutical compositions comprising a compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011- 2016, or 2021-2026 can also include a solubilizing agent. Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art. Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device. Pharmaceutical compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.

[0445] The pharmaceutical compositions comprising a compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 of the present disclosure may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the pharmaceutical compositions are prepared by uniformly and intimately bringing therapeutic agent into association with a liquid carrier,

[0446] DBl / 163167834.4 53 a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation {e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art).

[0447] In embodiments, any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 disclosed herein is formulated in accordance with routine procedures as a pharmaceutical composition adapted for a mode of administration disclosed herein.

[0448] Administration, Dosing, and Treatment Regimens

[0449] In embodiments, any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents) described herein is formulated in accordance with routine procedures as a composition adapted for a mode of administration described herein.

[0450] Routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin In embodiments, the administering is effected orally or by parenteral injection. In most instances, administration results in the release of any agent described herein into the bloodstream.

[0451] Any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents) described herein can be administered orally. Such compounds or formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents) can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings {e.g., oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer.

[0452] Dosage forms suitable for parenteral administration {e.g., intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions {e.g., lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.

[0453] The dosage of any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents)

[0454] DBl / 163167834.4 54 described herein as well as the schedule can depend on various parameters, including, but not limited to, the disease being treated, the subject's general health, and the administering physician's discretion Any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 described herein, can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of an additional agent, to a subject in need thereof. In various embodiments the compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 and additional agent described herein are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, 1 day apart, 2 days apart, 3 days apart, 4 days apart, 5 days apart, 6 days apart, 1 week apart, 2 weeks apart, 3 weeks apart, or 4 weeks apart.

[0455] The dosage of any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents) described herein can depend on several factors including the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the subject to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected.

[0456] In embodiments, delivery can be in a vesicle, in particular a liposome (see Langer, 1990, Science 249:1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989).

[0457] Any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents) described herein can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591 ,767; 5, 120,548; 5,073,543; 5,639,476;

[0458] DBl / 163167834.4 55 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[0459] In embodiments, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 ; see also Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351 ; Howard et al., 1989, J. Neurosurg. 71 : 105).

[0460] In embodiments, a controlled-release system can be placed in proximity of the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, 1990, Science 249: 1527- 1533) may be used.

[0461] Administration of any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents) described herein can, independently, be one to four times daily or one to four times per month or one to six times per year or once every two, three, four or five years. Administration can be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the subject.

[0462] The dosage regimen utilizing any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents) described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; the pharmacogenomic makeup of the individual; and the specific compound of the disclosure employed. Any compound of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents) described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, any compound of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001 - 2006, 2011-2016, or 2021-2026 (and / or additional agents) described herein can be administered continuously rather than intermittently throughout the dosage regimen.

[0463] DBl / 163167834.4 56 Diseases; Methods of Treatment, and Patient Selections

[0464] In one aspect, the present disclosure provides a method of treating a disease or disorder, the method comprising administering to a subject in need thereof a compound of any one of the embodiments disclosed herein or a pharmaceutical composition comprising a compound of any one of the embodiments disclosed herein to the subject.

[0465] In embodiments, the disease or disorder is a cardiovascular disease or disorder.

[0466] In embodiments, the cardiovascular disease or disorder is selected from sinus tach (e.g. inappropriate sinus tachycardia (1ST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e.g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g angina pectoris), myocardial infarct, rhythm disturbances (e.g. supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, and left ventricular dysfunction (LVD).

[0467] In embodiments, the cardiovascular disease or disorder is inappropriate sinus tachycardia (1ST)).

[0468] In embodiments, the cardiovascular disease or disorder is angina pectoris (e.g. chronic stable angina pectoris).

[0469] In embodiments, the disease or disorder is caused by a genetic disorder.

[0470] In embodiments, the genetic disorder is caused by a gain-of-function mutation in the cardiac pacemaker HCN4 channel or in other mutations associated with sinus tachycardia due to mutations in other genes.

[0471] In embodiments, the method of treating the disease or disorder further includes inhibition of a hyperpolarization- activated cyclic nucleotide-gated (HCN) channel (e.g. hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4)) and / or inhibition of a funny current (If) channel.

[0472] In embodiments, the method of treating the disease or disorder further includes reduction of the subject's heart rate compared to a pre-treated or untreated state.

[0473] In embodiments, the subject has normal sinus rhythm, and optionally cannot take beta blockers, and / or has undergone coronary artery bypass grafting (CABG).

[0474] In embodiments the disclosure relates to a method of treating a subject diagnosed with congestive heart failure, LV dysfunction, and tachycardia, wherein the subject has one, two or more of (a)-(f):

[0475] (a) Symptomatic LV Dysfunction despite outpatient medical therapy;

[0476] (b) Intolerance or substantial intolerance to beta blocker therapies and I or other non-approved therapies for rate control;

[0477] (c) Tachycardia based on ambulatory FDA authorized wearable monitoring assessment >100 BPM or other threshold based on established evidence and / or guidelines;

[0478] (d) History of noncompliance with rate control therapy;

[0479] (e) Asymptomatic LV Dysfunction with tachycardia >100 or other threshold and evidence of coronary ischemia and dysfunction with exertion or at rest on any validated measure including but not limited to stress

[0480] DBl / 163167834.4 57 electrocardiogram (ekg), stress echocardiography, nuclear imaging technique, angiography results, or other non-invasive and imaging studies;

[0481] (f) Any of (a)-(e) and in relation to a genetic disease, including but not limited to Hypertrophic Cardiomyopathy (HCM), and / or a genetic disease which directly or indirectly lead to tachycardia.

[0482] In embodiments, the disclosure relates to a method of treating a subject diagnosed with congestive heart failure, and LV dysfunction in relation to Hypertrophic Cardiomyopathy (HCM), wherein the patient has one, two or more of (a)-(g):

[0483] (a) Symptomatic LV Dysfunction despite outpatient medical therapy;

[0484] (b) Intolerance or substantial intolerance to beta blocker therapies and or other non-approved therapies for rate control;

[0485] (c) Tachycardia based on ambulatory FDA authorized wearable monitoring assessment >100 BPM or other threshold based on established evidence and or guidelines;

[0486] (d) History of noncompliance with rate control therapy;

[0487] (e) Asymptomatic LV Dysfunction with tachycardia >100 or other threshold and evidence of coronary ischemia and dysfunction with exertion or at rest on any validated measure including but not limited to stress electrocardiogram (ekg), stress echocardiography, nuclear imaging technique, angiography results, or other non-invasive and imaging studies;

[0488] (f) Evidence of diastolic dysfunction and inadequate filling on echocardiography or other imaging approach;

[0489] (g) Prior or current use of a cardiac myosin inhibitor as treatment of obstructive or non-obstructive HCM.

[0490] In one aspect, the present disclosure relates to method for treating a subject diagnosed with a cardiovascular disease or disorder, the method comprising: a) administering a first dose of a compound of any one of the embodiments disclosed herein or a pharmaceutical composition comprising a compound of any one of the embodiments disclosed herein to the subject while employing a wearable device or another monitor to monitor heart rhythm data of the subject; b) monitoring the subject for efficacy of the administered first dose to assess whether the first dose is efficacious for the subject during a comparison period of 1 or more days; c) if the administered first dose is efficacious for the subject, continuing to monitor the subject's heart rhythm data to ensure that the administered first dose remains efficacious.

[0491] In embodiments, assessing the efficacy of the first dose is delayed for at least 7 or 14 days after administering the first dose.

[0492] In embodiments, assessing the efficacy of the first dose is based on symptoms and / or an average heart rate measured by the wearable device or another monitor. Non-limiting examples of symptoms include chest pain, pain, weakness or numb legs and / or arms, breathlessness, very fast or slow heartbeat or palpitations, dizziness, fatigue, and swollen limbs.

[0493] In embodiments, if the administered first dose is assessed as not efficacious for the subject by an end of the comparison period, adjust the amount of the first dose one or more times as necessary to achieve an efficacious result to provide

[0494] DBl / 163167834.4 58 an adjusted dose, wherein the efficacy of the adjusted dose is assessed during at least the comparison period and / or delay period.

[0495] In embodiments, if the administered first dose or adjusted dose is no longer efficacious, step c) is repeated with the administered first dose or adjusted dose as the first dose.

[0496] In embodiments, monitoring in step b) is conducted in a continuous manner.

[0497] In embodiments, monitoring in step b) comprises detecting a slow diastolic depolarization phase.

[0498] In embodiments, detecting comprises use of a photoplethysmography (PPG) algorithm and / or ParamAP. ParamAP is a computational tool useful for identifying and parameterizing action potentials (APs). See, e.g., Rickert and Proenza, Biophysical Journal 113:765-769 (2017), which is incorporated by reference herein in its entirety.

[0499] In embodiments, the efficacy at an administered first dose or an adjusted dose is evaluated by comparing baseline levels of the slow diastolic depolarization phase against corresponding levels of the slow diastolic depolarization phase in the comparison period.

[0500] In embodiments, the comparison period is one or more of about a day, about a week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or up to about 6 months.

[0501] In embodiments, the cardiovascular disease or disorder is selected from sinus tach (e.g. inappropriate sinus tachycardia (1ST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e.g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g. angina pectoris), myocardial infarct, rhythm disturbances (e.g. supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, left ventricular dysfunction (LVD).

[0502] In embodiments, the cardiovascular disease or disorder is inappropriate sinus tachycardia (1ST)).

[0503] In embodiments, the cardiovascular disease or disorder is angina pectoris (e.g. chronic stable angina pectoris).

[0504] In embodiments, the subject has normal sinus rhythm, and optionally cannot take beta blockers, and / or has undergone coronary artery bypass grafting (CABG).

[0505] In embodiments, the wearable device is one or more of a patch, a watch, a wristband, a strap, a ring, a glass, a shirt, a finger, a bracelet, a SGPS / GPRS baby / control, a belt, a pants, a sock, a shoe, a Bluetooth key tracker, a holter, an implantable, or a device that adheres to a body when fitted.

[0506] In embodiments, the subject is selected for therapy based on a history of inappropriate sinus tachycardia (1ST) and / or an inappropriate sinus tachycardia (1ST) genetic risk score (GRS) indicating high risk of inappropriate sinus tachycardia (1ST) recurrence over time.

[0507] In embodiments, the subject is selected for therapy based on a positive result from a wearable FDA cleared device, a history of inappropriate sinus tachycardia (1ST) and / or an inappropriate sinus tachycardia (1ST) genetic risk score (GRS) indicating high risk of inappropriate sinus tachycardia (1ST) recurrence over time.

[0508] DBl / 163167834.4 59 In embodiments, the wearable FDA cleared device is used to monitor the subject on therapy and dosing is adjusted over time based on the rate of the slow diastolic depolarization phase.

[0509] In embodiments, the risk factor comprises age, ethnicity, or a history of cardiovascular disease, cardiac amyloidosis, illicit drug use, or diabetes.

[0510] Wearables

[0511] Non-limiting examples of wearables and the use of wearables for monitoring 1ST are found in US 2023 / 0372284, WO 2023 / 233510, US10617302B2, US8374701 B2, US 20060058694, Electrodynamic sensors and applications thereof, to T. Clark et al.; WO 2003 / 048789, Electrodynamic sensors and applications thereof, by T. D. Clark et al.; or C. J. Harland et al., High resolution ambulatory electrocardiographic monitoring using wrist-mounted electric potential sensors, 14 Meas. Sci. Technol. 923-928 (2003). which are incorporated by reference herein in its entirety.

[0512] In one aspect, the present disclosure relates to method for treating a subject diagnosed with a cardiovascular disease or disorder. In embodiments, the method comprises a) administering a first dose of a compound of any one of the embodiments disclosed herein or a pharmaceutical composition comprising a compound of any one of the embodiments disclosed herein to the subject while employing a wearable device or another monitor to monitor heart rhythm data of the subject; b) monitoring the subject for efficacy of the administered first dose to assess whether the first dose is efficacious for the subject during a comparison period of 1 or more days; c) if the administered first dose is efficacious for the subject, continuing to monitor the subject's heart rhythm data to ensure that the administered first dose remains efficacious.

[0513] In embodiments, assessing the efficacy of the first dose is delayed for at least 7 or 14 days after administering the first dose.

[0514] In embodiments, assessing the efficacy of the first dose is based on symptoms and / or an average heart rate measured by the wearable device or another monitor. Non-limiting examples of symptoms include chest pain. pain, weakness or numb legs and / or arms, breathlessness, very fast or slow heartbeat or palpitations, dizziness, fatigue, and swollen limbs.

[0515] In embodiments, if the administered first dose is assessed as not efficacious for the subject by an end of the comparison period, adjust the amount of the first dose one or more times as necessary to achieve an efficacious result to provide an adjusted dose, wherein the efficacy of the adjusted dose is assessed during at least the comparison period and / or delay period.

[0516] In embodiments, if the administered first dose or adjusted dose is no longer efficacious, step c) is repeated with the administered first dose or adjusted dose as the first dose.

[0517] In embodiments, monitoring in step b) is conducted in a continuous manner.

[0518] In embodiments, monitoring in step b) comprises detecting a slow diastolic depolarization phase.

[0519] DBl / 163167834.4 60 In embodiments, detecting comprises use of a photoplethysmography (PPG) algorithm and / or ParamAP. ParamAP is a computational tool useful for identifying and parameterizing action potentials (APs). See, e.g., Rickert and Proenza, Biophysical Journal 113:765-769 (2017), which is incorporated by reference herein in its entirety.

[0520] In embodiments, the efficacy at an administered first dose or an adjusted dose is evaluated by comparing baseline levels of the slow diastolic depolarization phase against corresponding levels of the slow diastolic depolarization phase in the comparison period.

[0521] In embodiments, the comparison period is one or more of about a day, about a week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or up to about 6 months.

[0522] In embodiments, the cardiovascular disease or disorder is selected from sinus tach (e.g. inappropriate sinus tachycardia (1ST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e.g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g. angina pectoris), myocardial infarct, rhythm disturbances (e.g. supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, left ventricular dysfunction (LVD).

[0523] The comparison period recited above is designed to provide a temporal limit for determining the efficacy of the pharmacotherapy which, in the absence of such a limit, could be construed to be indefinitely long extending for years or decades. Hence, for the purposes herein, a comparison period is a duration of time, after the start of efficacy monitoring as described above, over which heart rhythm data acquired from the patient (e.g., via a wearable fitted to and / or employed on the patient) is analyzed to compare with previous heart rhythm or heart rate data and / or I ST / AFib data of the patient (e.g., baseline data acquired during the qualification period, and / or data acquired during previous a comparison period data). In embodiments, the comparison period is at least as long as the qualification period described herein or based on a different period of time such as daily, weekly, and at least about 2-weeks (e.g., 13, 14, or 15 days) or twice, three or four times as long (i.e., at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks). In an example, the comparison period can be a length that at least extends beyond a time at which the drug level has substantially stabilized in the patient (e.g , at least 2-3 days, 7 days, 14 days, etc. in a patient provided the compound of the disclosure (e.g. a compound of any one of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021 -1026 or formula 2001 -2006, 2011-2016, or 2021 -2026)), or can have a shorter length (e.g., continuously, or 1 day or more) if the comparison period begins after drug levels have substantially stabilized in the patient, (e.g., beginning 2 days or beginning 3 days after initiation of administering a compound of the disclosure at a given dosage). In embodiments, the comparison period is one or more of about a day, about a week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or up to about 6 months.

[0524] DBl / 163167834.4 61 The term "wearable” refers to any device that can be worn by a user, e.g., as an accessory, as clothing and / or embedded in clothing, a patch, a watch, a wristband, a strap, a ring, a glass, a shirt, a finger, a bracelet, a SGPS / GPRS baby / control, a belt, a pants, a sock, a shoe, a Bluetooth key tracker, a holter, an implantable, or a device that adheres to a body when fitted. etc., or that can be subdermally implanted in a patient.

[0525] In embodiments, a patient is “fitted with a wearable” when the wearable is being worn by, is subdermally implanted into, or is otherwise fixed to, the patient to be able to measure the heart rhythm or heart rate of the patient.

[0526] Instrumentation

[0527] The instrumentation used in the methods described herein is designed to be fitted to the patient as part of either the qualification protocol and / or the pharmacotherapy used with the patient as described herein.

[0528] Wearables that are used for diagnosis are conventional and aim to inform the clinician whether the patient either has 1ST and / or AFib or not and / or if the patient has 1ST and / or AFib, possibly information about the patient's IST / AFib burden and the number of episodes of IST / AFib. Such diagnostic analysis fails to address any pharmacotherapeutic suitability, efficacy, and / or dose, which extends beyond diagnosis. The pharmacotherapeutic methods described herein include identifying patients who qualify for drug therapy and / or monitoring the qualified patient during treatment with the pharmacotherapy to assess the drug's effectiveness (e.g., in reducing the number of episodes of long duration IST / AFib). The monitoring may allow for dose adjusting for the patient until the patient is deemed to be responsive to therapy or is disqualified from pharmacotherapy due to a failure to respond. The pharmacotherapeutic methods described herein allow for continuous monitoring of the patient to determine an efficacious dose of the drug as well as to ensure that the patient remains responsive to that dose. Accordingly, the wearables described herein are designed and / or selected to be robust for extended use, and / or comfortable and / or easy to use by the patient.

[0529] In practice, the wearable may include a cardiac monitoring component, which may be either an assisted or an unassisted component, for measuring heart rhythm in patients Many of the wearables are engageable and removable by the patient or are sub-dermally implanted. The specific cardiac monitoring component employed in the wearable is not critical, provided it can accurately measure the heart rhythm. The wearable may be capable of reporting measured heart rhythm data, such as by generating and / or transmitting data indicating the length of time of a detected period of IST / AFib, and / or by generating and / or transmitting data indicating the number of episodes of long duration IST / AFib detected (e.g., over a time period of interest, such as a week, a month, etc.). Also, or alternatively, the wearable may be configured to transmit heart rhythm data to a device configured to detect IST / AFib and / or determine the length of time of a detected period of IST / AFib and / or a number of episodes of long duration IST / AFib (e.g., over the time period

[0530] DBl / 163167834.4 62 of interest). In embodiments, the wearable is approved by one or more regulatory bodies, such as the US Food & Drug Administration (FDA).

[0531] Assisted Components

[0532] In embodiments, in the methods of the disclosure, detecting comprises use of photoplethysmography (PPG) (e.g. a PGG algorithm).

[0533] An assisted cardiac monitoring component may use photoplethysmography (PPG) to detect a patient's heart rate and rhythm. PPG is a conventional technology found in standard oximeters, measures light reflection in tissue to detect arterial pulsations and, accordingly, heart rhythm patterns. However, to continuously and / or semi-continuously measure heart rhythm, one must account for the fact that PPG signals generated during patient movement are often distorted, weak, and have a significant amount of noise relative to detected data. To account for such deficiencies, an algorithm may be used to reduce enough the distortion and / or noise to provide a reliable signal. In embodiments, both a PPG sensor and accelerometer are employed with an algorithm that allows for appropriate (e.g., sufficient signal-to- noise ratio). When so assisted, PPG may allow for reliable detection of both heart rates and heart rhythm. See, for example, Wojcikowski, et al., Photoplethysmographic time-domain heart rate measurement algorithm for resource- constrained wearable devices and its implementation, SENSORS 20, no. 6 (2020): 1783 which is incorporated herein by reference in its entirety.

[0534] In embodiments, the cardiac monitor component uses piezoelectric material and / or rhythm electroactive polymers to detect blood flow, thereby indirectly measuring heart rhythm.

[0535] In embodiments, a combination of PPG and / or piezoelectric measurements and electrocardiogram data from singleelectrode wearables (i.e., iEKG, e.g., as opposed to EKG, which refers to a conventional multiple-electrode electrocardiogram) can be combined to increase the specificity of the measurement. The iEKG (i.e., iECG) and the PPG or the piezoelectric data can originate either from two separate devices communicating by transceivers, for example, an armband and a smartwatch, or they can originate from a single device, for example, a wristband on a smartwatch (e.g., the Kardia™ Band on an i Watch). Once an arrhythmia is detected in the PPG data, the corresponding (e.g., in time) iECG data may be analyzed by an algorithm.

[0536] Unassisted Components

[0537] In embodiments, the wearable may include an unassisted cardiac monitor component, such as a portable electrocardiogram. The portable electrocardiogram component may be wearable, engageable at-will by the patient, and / or capable of transmitting data, e.g., via a built-in antenna or Bluetooth data transmitting device. The wearable comprising the unassisted cardiac monitor component can measure heart rates and heart rhythms. The wearable may be configured to detect and log IST / AFib burden and / or long duration (episode) of I ST / AFib (LEAF) over an observation period (e.g., of about 2 weeks or longer). The unassisted cardiac monitor component employs direct measurement, which means that the device is reading electrical signals generated by the heart. The direct measurement may be less affected by noise and distortion than indirect measurements, such as PPG measurements, which may enable

[0538] DBl / 163167834.4 63 transmitting measurement data to a clinician without the use of an algorithm, and / or with reduced use of any algorithm or data processing.

[0539] In embodiments, the wearable may further include a specialized accessory, such as a cardiac monitor device, that can detect the electrical activities of a heart including heart rhythm through an electrode. The specialized accessory may be capable of initiating transmission and / or may comprise and / or be connected to a transmission device.

[0540] In embodiments, the cardiac monitor device can be a component that is an integral part of a single wearable device, such as a smartwatch. By providing a single device that is wearable by a user and is capable of monitoring the electric field of the heart of the user, the electrical activities of the heart can be monitored continuously over a prolonged period, such as days or even months.

[0541] In embodiments, the cardiac monitor device may include an analog-to-digital converter capable of digitalizing measured electric field data (e.g., measured potential difference data) to transmit and / or store in memory the measured data as digitized data. The cardiac monitor device can include an output that can transmit signals carrying information about the difference of potential between the limb and the body to an external circuit. The output can take various forms. In one case, the output can be a transceiver that communicates to another transceiver / receiver in another unit, for example, a watch or a tablet. In embodiments, a central analysis center (e.g., a remote lab, such as a CORE lab and / or a remote data analysis center and / or a server) may interpret and / or summarize the IST / AFib data and / or the LEAF data. The central analysis center may also transmit a dose adjustment recommendation to the treating clinician, without a need for the patient to visit his or her physician (e.g., as part of a patient monitoring program). Also, or alternatively, an artificial intelligence algorithm may be used to determine the dose adjustment and may transmit the dose adjustment recommendation to the physician

[0542] In embodiments, the wearable may be a small consumer electronic device, for example, a watch, an armband, a ring, a strap, and / or a wristband. The wearable may include a housing that carries the cardiac monitor component and any associated circuitry, CPU, and the like. The wearable can also be worn at other locations on the user, including, but not limited to, the wrist, leg, neck, and / or body. The wearable may comprise a specialized accessory capable of communicating with another electronic device such as a tablet, a laptop computer, a desktop computer, and / or other similar devices, which, in turn, can communicate to a cloud network to transmit information from the device to the clinician. Also, or alternatively, the specialized accessory may be capable of transmitting information directly and / or via a network to the clinician.

[0543] The heart rhythm and iECG wearables may be Bluetooth, Z-Wave, Zigbee, and / or Advanced and Adaptive Network Technology (ANT)-enabled. For example, the IECG and / or the heart rhythm monitoring and / or recording device (e.g., PPG or a piezoelectric heart rhythm monitoring and / or recording device) may be paired with an application that may be configured to automatically detect IST / AFib based on data from the iECG and / or the heart rhythm monitoring and / or recording device. The iECG device and / or the rhythm monitoring and / or recording device may be configured to transmit data to the application. The data can be transmitted using one or more data transmissions methods such as Bluetooth,

[0544] DBl / 163167834.4 64 Z-Wave, Zigbee, or ANT protocols. The application may be configured to analyze the data using a proprietary software. Based on the data from the iECG and / or the heart rhythm monitoring and / or recording device, the application may be able to interpret and / or detect IST / AFib with a sensitivity of >90% and a specificity of >80%.

[0545] Combination Therapies and Conjugation

[0546] In embodiments, the disclosure provides for compounds of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 and methods that further comprise administering an additional agent to a subject. In embodiments, the disclosure pertains to co-administration and / or co-formulation. Any of the compositions described herein may be co-formulated and / or co-administered.

[0547] In embodiments, the compounds of formula (IX), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), formula 1001-1006, 1011-1016, 1021-1026 or formula 2001-2006, 2011-2016, or 2021-2026 (and / or additional agents) described herein, include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the composition such that covalent attachment does not prevent the activity of the composition. For example, but not by way of limitation, derivatives include composition that have been modified by, inter alia, glycosylation, lipidation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of turicamycin, efc. Additionally, the derivative can contain one or more non-classical amino acids.

[0548] Subjects and / or Animals

[0549] In embodiments, the subject and / or animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In embodiments, the subject and / or animal is a non-mammal, such, for example, a zebrafish In embodiments, the subject and / or animal may comprise fluorescently-tagged cells (with e.g. GFP). In embodiments, the subject and / or animal is a transgenic animal comprising a fluorescent cell.

[0550] In embodiments, the subject and / or animal is a human. In embodiments, the human is a pediatric human. In embodiments, the human is an adult human. In embodiments, the human is a geriatric human. In embodiments, the human may be referred to as a patient.

[0551] In embodiments, the human has an age in a range of from about 0 months to about 6 months old, from about 6 to about 12 months old, from about 6 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about

[0552] DBl / 163167834.4 65 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old.

[0553] In embodiments, the subject is a non-human animal, and therefore disclosure pertains to veterinary use. In a specific embodiment, the non-human animal is a household pet. In another specific embodiment, the non-human animal is a livestock animal. In embodiments, the livestock animal Is selected from pigs, hogs, calves, cows, steers, horses, lambs, sheep, turkeys, ducks, and chicken.

[0554] Kits

[0555] The disclosure provides kits that can simplify the administration of any agent described herein. An illustrative kit of the disclosure comprises any composition described herein in unit dosage form. In embodiments, the unit dosage form is a container, such as a pre-filled syringe, which can be sterile, containing any agent described herein and a pharmaceutically acceptable carrier, diluent, excipient, or vehicle. The kit can further comprise a label or printed instructions instructing the use of any agent described herein. The kit may also include a lid speculum, topical anesthetic, and a cleaning agent for the administration location. The kit can also further comprise one or more additional agent described herein. In embodiments, the kit comprises a container containing an effective amount of a composition of the disclosure and an effective amount of another composition, such those described herein.

[0556] In embodiments, the kit may also contain oral medications, instructions for use, and / or wearables to use and record heart rhythms.

[0557] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0558] General Synthetic Procedures

[0559] The compounds of the disclosure may be prepared using the techniques described below. Some of the schemes and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions and techniques can be found in a number of treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods (1974 et seq.). Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, CO2 from the decarboxylation of a diacid, etc.). In addition, in some instances, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0560] Starting materials and reagents may be obtained from commercial sources or may be synthesized in analogy to or according to methods that are known in the art. In the preparation of starting materials, existing functional groups which

[0561] DBl / 163167834.4 66 do not participate in the reaction should, if necessary, be protected. Protecting groups, their introduction and their removal are described herein.

[0562] In some of the reaction schemes and examples described herein, certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0563] Generally, the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g. , -78° C. to 0° C.). Any reference in the disclosure to a stoichiometric range, a temperature range, a pH range, etc., whether or not expressly using the word “range,” also includes the indicated endpoints.

[0564] Many of the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane); aromatic hydrocarbons (e.g., benzene, toluene, xylenes); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol, 2- methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy- ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, di-isopropyl ether, dibutyl ether, 1 ,2-dimethoxyethane, 1 ,2-diethoxy-ethane, 1-methoxy-2-(2-methoxy-ethoxy)- ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1 ,4-dioxane); ketones (e g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene-1, 1, -dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric triamide).

[0565] General scheme 1 shows exemplary methods for preparing compounds of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), and formula (lb), wherein the substituents are as defined for formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), and formula (lb), except where further noted. The following general procedure outlines a synthesis of (S)-3-(3-(((3,4~dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl) amino)propyl)-7,8-

[0566] DBl / 163167834.4 67 dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one derivatives (i.e., compounds of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), or formula 1001-1006, 1011-1016, 1021-1026 or formula 2001- 2006, 2011-2016, or 2021-2026) by reacting a halogenated hydrocarbon group (e.g. a carbonate with a halogenated hydrocarbon group ) with (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl) amino)propyl)- 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one via nucleophilic substitution following standard literature- reported conditions.

[0567] General Scheme 1

[0568] General scheme 2 shows exemplary methods for preparing compounds of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), and formula (lb), wherein the substituents are as defined for formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), and formula (lb), except where further noted. The following general procedure outlines a synthesis of (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl) amino)propyl)-7,8- dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one derivatives (i.e., compounds of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), or formula 1001-1006, 1011-1016, 1021-1026 or formula 2001- 2006, 2011-2016, or 2021-2026) by reacting a halogenated hydrocarbon group (e.g. a carbonate with a halogenated hydrocarbon group ) with (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl) amino)propyl)- 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one via nucleophilic substitution following standard literature- reported conditions.

[0569] General Scheme 2

[0570] DBl / 163167834.4 68

[0571]

[0572] General scheme 3 shows exemplary methods for preparing compounds of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), and formula (lb), wherein the substituents are as defined for formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), and formula (lb), except where further noted. The following general procedure outlines a synthesis of (S)-3-(3-(((3,4~dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl) amino)propyl)-7,8- dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one derivatives (i.e., compounds of formula (XI), formula (Xia), formula (Xlb), formula (I), formula (la), formula (lb), or formula 1001-1006, 1011-1016, 1021-1026 or formula 2001- 2006, 2011-2016, or 2021-2026) by reacting a halogenated hydrocarbon group (e.g. an ester with a halogenated hydrocarbon group) with (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl) amino)propyl)- 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one via nucleophilic substitution following standard literature- reported conditions.

[0573] General Scheme 3

[0574] DBl / 163167834.4 69 While these procedures provide exemplary foundational methodology, variations in reagents, stoichiometry, reaction time, and temperature may apply depending on the specific compound, with detailed conditions reported alongside each individual example, as would be understood by one of ordinary skill in the art.

[0575] EXAMPLES

[0576] The examples herein are provided to illustrate advantages and benefits of the present disclosure and to further assist a person of ordinary skill in the art with preparing or using the (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien- 7-yi)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one prodrugs of the present disclosure. The examples herein are also presented in order to more fully illustrate the preferred aspects of the present disclosure. The examples should in no way be construed as limiting the scope of the present disclosure, as defined by the appended claims. The examples can include or incorporate any of the variations, aspects or embodiments of the present disclosure described above. The variations, aspects or embodiments described above may also further each include or incorporate the variations of any or all other variations, aspects or embodiments of the present disclosure.

[0577] Example 1: Synthesis of ( S)-3-(3-(((3, 4-dimethoxybicyclo[4.2.0]octa-1,3, 5-trien-7-yl)methyl) (methyl)amino)propyl)-7, 8- dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (Compound 1000) prodrugs

[0578] A) Synthesis of compound 2001 (chloride of compound 1001):

[0579] Step-1 : Synthesis of chloro methyl methyl carbonate (3):

[0580] To a solution of methanol, 1 (1.0 g, 31.25 mmol, 1.0 equiv ) in DCM (30 mL), pyridine (6.3 mL, 78.12 mmol, 2.5 equiv.) was added to the reaction mixture at 0°C. After 15 min of stirring at 0°C, chloromethyl chloroformate, 2 (3.6 mL, 37.5 mmol, 1.2 equiv.) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 16 hrs. After completion, reaction mixture was diluted with DCM, the mixture was washed with sat. NaHCOs solution (50 mL X

[0581] DBl / 163167834.4 70 2), 2N HCI (50 mL X 2) then with brine (50 mL X 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to yield chloromethyl methyl carbonate compound 3. (0.4 g, colorless oil).

[0582] Step-2: Synthesis of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-A / -(((S)-3,4- dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-N-(((methoxycarbonyl)oxy)methyl)-A / -methylpropan-1- aminium chloride (2001):

[0583] A sealed tube was charged with compound 4 (0.2 g, 0.43 mmol, 1.0 equiv.) and compound chloromethyl methyl carbonate, 3 (1 .05 g, 854 mmol, 20.0 equiv.) under neat condition. Reaction mixture was stirred in microwave at 100°C for 4 hrs. After completion of reaction, crude obtained was washed with diethyl ether: DCM to obtain 3-(7,8-dimethoxy- 2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)- / V-(((S)-3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)- / V-(((methoxycarbonyl)oxy)methyl)-W-methylpropan-1-aminium chloride (2001) (0.010 g, Light yellow solid).1H-NMR (300 MHz, DMSO-c / e) 5 6.91 - 6.81 (m, 3H), 6.72(d, J = 7.2 Hz, 2H), 5.40 (s, 2H), 3.86 (s, 3H), 3.78-3.75 (m, 4H), 3.71-3.61 (m, 16H), 3.40 - 3.34 (m, 6H), 3.13 (s, 3H), 3.09 - 2.79 (m, 3H), 1.98 (brs, 2H)„ ESI-MS (m / z) Calcd for C30H41N2O8- 557.2. Found 557.2 (M)+. HPLC purity: 69.90 %.

[0584] B) Synthesis of compound 2002 (chloride of compound 1002):

[0585] Step-1 : Synthesis of chloromethyl ethyl carbonate (3):

[0586] DB1 / 161977366.6 71 139106-5002-WC

[0587] To a solution of ethanol, 1 (0.91 mL, 15.6 mmol, 2.0 equiv.) in DCM (20 mL), pyridine (1.88 mL, 23.4 mmol, 3.0 equiv.) was added to the reaction mixture at 0°C. After 15 min of stirring at 0°C, chloromethyl chloroformate, 2 (0.68 mL, 7.81 mmol, 1 .0 equiv.) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 16 hrs. After completion, reaction mixture was diluted with water, the mixture was extracted with DCM (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to yield chloromethyl ethyl carbonate compound 3. (0.67 g, colorless oil).

[0588] Step-2: Synthesis of iodomethyl ethyl carbonate (4):

[0589] A two neck round bottom flask was charged with chloromethyl ethyl carbonate, 3 (1.0 g, 7.24 mmol, 1.0 equiv.) and sodium iodide (4.3 g, 28.90 mmol, 4.0 equiv.) in acetonitrile (10 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 hrs. After completion of reaction, reaction mixture was filtered, filtrate was concentrated. The resulting residue was purified by column chromatography to yield 4 (0.61 g, yellow oil).

[0590] Step-3: Synthesis of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-N-(((S)-3,4- dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-N-(((ethoxycarbonyl)oxy)methyl)-A / -methylpropan-1- aminium iodide (6):

[0591] A sealed tube was charged with compound 5 (0.2 g, 0.43 mmol, 1.0 equiv.) and compound 4 (0.19 g, 0.85 mmol, 2.0 equiv.) in ACN (10 mL) and reaction mixture was stirred at room temperature for 2 hrs. After completion of reaction, mixture was concentrated and yellow oil obtained was then washed with diethyl ether (10 mL X 2) and pentane (10 mL X 2) to obtain 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-A / -(((S)-3,4- dimethoxybicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)methyl)-W-(((ethoxycarbonyl)oxy)methyl)-W-methylpropan-1-aminium iodide 6. (0.090 g, white solid, 33.50% Yield).

[0592] Step-4: Synthesis of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-N-(((S)-3,4- dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-N-(((ethoxycarbonyl)oxy)methyl)-N-methylpropan-1- aminium chloride (2002):

[0593] A thoroughly washed column was packed with ion-exchange resin, amberlite IRA-900 chloride (20 g). The resin was washed with acetonitrile. Compound 6 (0.090 g, 0.13 mmol, 1.0 eq) was dissolved in acetonitrile (7 mL) and added over resin. Desired chloride salt was eluted with acetonitrile, and solvent was concentrated, washed with diethyl ether (10 mL X 2) to give 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-N-(((S)-3,4- dimethoxybicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)methyl)-N-(((ethoxycarbonyl)oxy)methyl)-W-methylpropan-1-aminium chloride salt (2002). (0.067 g, white solid).1H-NMR (300 MHz, DMSO-d6) 5: 6.88 - 6.85 (m, 1 H), 6.81 (s, 1 H), 6.72 - 6.67 (d, J = 7.2 Hz, 2H), 5.42 (s, 2H), 4.32 - 4.25 (q, J= 6.9 Hz, 2H), 3.87 (brs, 2H), 3.78-3.68 (m, 16H), 3.47 - 3.29

[0594] DB1 / 161977366.6 72 139106-5002-WC

[0595] (m, 6H), 3.16 (s, 3H), 2.99 - 2.93 (m, 3H), 1.99 (brs, 2H), 1.31-1.26 (t, J = 7.0 Hz, 2H), 1.11-1.06 (t, J = 6.9 Hz, 3H).

[0596] ESI-MS (m / z) Calcd for C3iH43N2O8+: 571.3. Found 571 5 [M]+HPLC purity: 98.12%.

[0597] C) Synthesis of compound 2003 (Iodide of compound 1003):

[0598] Step-1 : Synthesis of chloromethyl isopropyl carbonate (3):

[0599] To a solution of propan-2-ol, 1 (2.6 mL, 33.3 mmol, 1 .0 equiv.) in DCM (30 mL), pyridine (5.4 mL, 66.6 mmol, 2.0 equiv.) was added to the reaction mixture at 0°C. After 15 min of stirring at 0°C, chloromethyl chloroformate, 2 (3.0 mL, 33.3 mmol, 1.0 equiv.) was added dropwise to the reaction mixture. The mixture was stirred at 0°C for 30 min and then at room temperature for 30 min. After completion, reaction mixture was diluted with water, the mixture was extracted with DCM (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (silica gel: 100-200 mesh; 05:95 ethyl acetate: hexane) to yield compound 3. (1.1 g, colorless oil).

[0600] Step-2: Synthesis of iodomethyl isopropyl carbonate (4):

[0601] A two neck round bottom flask was charged with chloromethyl isopropyl carbonate, 3 (0.52 g, 3.4 mmol, 1.0 equiv.) and potassium iodide (1.7 g, 10.20 mmol, 3.0 equiv.) in acetone (10 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 hrs. After completion of reaction, reaction mixture was filtered, filtrate was concentrated. Then, reaction mixture was diluted with water, the mixture was extracted with ethyl acetate (100 mL X 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and

[0602] DB1 / 161977366.6 73 139106-5002-WC concentrated. The resulting residue was purified by column chromatography (silica gel: 100-200 mesh; 02:98 Ethyl acetate: hexane) to yield 4 (0.47 g, yellow oil).

[0603] Step-3: Synthesis of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-A / -(((S)-3,4- dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-N-(((isopropoxycarbonyl)oxy)methyl)-A / -methylpropan- 1-aminium iodide (2003):

[0604] A sealed tube was charged with compound 5 (0.07 g, 0.15 mmol, 1.0 equiv.) and compound 4 (0.18 g, 0.75 mmol, 5.0 equiv.) in DCM (10 mL) and reaction mixture was stirred at room temperature for 16 hrs. After completion of reaction, mixture was concentrated and yellow oil obtained was then washed with diethyl ether (10 mL X 2) and pentane (10 mL X 2) to obtain 2003. (0.035 g, Cream-colored solid, 32.77% Yield).1H-NMR (300 MHz, CDCI3) 5: 6.93 (s, 1 H), : 6.65 (s, 1 H), 6.60 (s, 1 H), 6.56 (s, 1 H), 5.53-5.50 (m, 2H), 4.98-4.96 (m, 1 H), 4.13-4.09 (m, 1 H), 3.94-3.92 (m, 1 H), 3.90- 3.62 (m, 17H), 3.60 - 3.43 (m, 6H), 3.34 (s, 3H), 3.12 -3.04 (m, 2H), 3.01-2.96- (m, 1 H), 1.36-1.34 (d, J= 6.4 Hz, 6H), 1.33-1.20 (m, 2H). ESI-MS (m / z) Calcd for C32H45N2O87 585.3. Found 585.3 (M)+. HPLC purity: 79.07 %.

[0605] D) Synthesis of compound 2004 (chloride of compound 1004):

[0606] Step-1 : Synthesis of butyl (chloromethyl) carbonate (3):

[0607] To a solution of butan-1-ol, 1 (4.2 mL, 46.9 mmol, 2.0 equiv.) in DCM (20 mL), pyridine (6.0 mL, 70.29 mmol, 3.0 equiv.) was added to the reaction mixture at 0°C. After 15 min of stirring at 0°C, chloromethyl chloroformate, 2 (2.14 mL, 23.4 mmol, 1.0 equiv.) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 16 hrs.

[0608] DB1 / 161977366.6 74 139106-5002-WC

[0609] After completion, reaction mixture was diluted with DCM, the mixture was washed with sat. NaHCOs solution (50 mL X 2), 1 N HCI (50 mL X 2) then with brine (50 mL X 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to yield compound 3. (2.4 g, colorless oil).

[0610] Step-2: Synthesis of butyl (iodomethyl) carbonate (4):

[0611] A two neck round bottom flask was charged with butyl (chloromethyl) carbonate, 3 (1.0 g, 6.02 mmol, 1.0 equiv.) and sodium iodide (3.6 g, 24.09 mmol, 4.0 equiv.) in acetone (10 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 hrs. After completion of reaction, reaction mixture was filtered, filtrate was concentrated to yield 4 (0.80 g, yellow oil).

[0612] Step-3: Synthesis of N-(((butoxycarbonyl)oxy)methyl)-3-(7,8-dimethoxy-2-oxo-1 ,2,4,5-tetrahydro-3H- benzo[d]azepin-3-yl)-A / -(((S)-3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-A / -methylpropan-1- aminium iodide (6):

[0613] A sealed tube was charged with compound 5 (0.3 g, 0.43 mmol, 1.0 equiv.) and compound 4 (0.23 g, 0.89 mmol, 2.1 equiv.) in ACN (10 mL) and reaction mixture was stirred at room temperature for 2 hrs. After completion of reaction, mixture was concentrated to obtain 6.

[0614] Step-4: Synthesis of N-(((butoxycarbonyl)oxy)methyl)-3-(7,8-dimethoxy-2-oxo-1 ,2,4,5-tetrahydro-3H- benzo[d]azepin-3-yl)-A / -(((S)-3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-A / -methylpropan-1- aminium chloride (2004):

[0615] A thoroughly washed column was packed with ion-exchange resin, amberlite IRA-900 chloride (20 g). The resin was washed with acetonitrile. Compound 6 was dissolved in acetonitrile (7 mL) and added over resin. Desired chloride salt 2004 was eluted with acetonitrile, and solvent was concentrated to give the chloride salt. The chloride salt was washed with ethyl acetate: diethyl ether (1 : 1) (10 mL X 4). (0.21 g, white solid).1H-NMR (300 MHz, DMSO-d6) 5: 6.87 - 6.84 (m, 1H), 6.81 (s, 1 H), 6.72 - 6.67 (d, J = 7.2 Hz, 2H), 5.40 (s, 2H), 4.26 - 4.22 (t, J= 6.45 Hz, 2H), 3.88 (brs, 2H), 3.86- 3.62 (m, 17H), 3.40 - 3.26 (m, 6H), 3.14 (s, 3H), 2.99 - 2.91 (m, 3H), 1.98 (brs, 2H), 1.68-1.59 (m, 2H), 1.39-1.11 (m, 5H). ESI-MS (m / z) Calcd for C33H47N2O8T 599.3. Found 599.4 [M]+. HPLC purity: 95.11 %.

[0616] E) Synthesis of compound 2005 (chloride of compound 1005):

[0617] DB1 / 161977366.6 75

[0618]

[0619] Step-1 : Synthesis of chloromethyl (2-methoxyethyl) carbonate (3):

[0620] To a solution of 2-methoxyethan-1-ol, 1 (3.7 mL, 46.9 mmol, 2.0 equiv.) in DCM (20 mL), pyridine (5.6 mL, 70.29 mmol, 3.0 equiv.) was added to the reaction mixture at 0°C. After 15 min of stirring at 0°C, chloromethyl chloroformate, 2

[0621] (2.14 mL, 23.4 mmol, 1.0 equiv.) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 2 hrs. After completion, reaction mixture was diluted with DCM, the mixture was washed with sat. NaHCOs solution (50 mL X 2), 1 N HCI (50 mL X 2) then with brine (50 mL X 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to yield compound 3. (2.4 g, colorless oil).

[0622] Step-2: Synthesis of iodomethyl (2-methoxyethyl) carbonate (4):

[0623] A two neck round bottom flask was charged with chloromethyl (2-methoxyethyl) carbonate, 3 (1.0 g, 5.95 mmol, 1.0 equiv.) and sodium iodide (3.5 g, 23.80 mmol, 4.0 equiv.) in acetone (10 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 hrs. After completion of reaction, reaction mixture was filtered, filtrate was concentrated to yield 4 (0.66 g, yellow oil).

[0624] Step-3: Synthesis of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-A / -(((S)-3,4- dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-N-((((2-methoxyethoxy)carbonyl)oxy)methyl)-N- methylpropan-1-aminium iodide (6):

[0625] DB1 / 161977366.6 76 A sealed tube was charged with compound 5 (0.2 g, 0.43 mmol, 1.0 equiv.) and compound 4 (0.23 g, 0.89 mmol, 2.1 equiv.) in ACN (10 mL) and reaction mixture was stirred at room temperature for 2 hrs. After completion of reaction, mixture was concentrated to obtain 6.

[0626] Step-4: Synthesis of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-A / -(((S)-3,4- dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-N-((((2-methoxyethoxy)carbonyl)oxy)methyl)-N- methylpropan-1-aminium chloride (2005):

[0627] A thoroughly washed column was packed with ion-exchange resin, amberlite IRA-900 chloride (20 g). The resin was washed with acetonitrile. Compound 6 was dissolved in acetonitrile (7 mL) and added over resin. Desired chloride salt 2005 was eluted with acetonitrile, and solvent was concentrated to give the chloride salt. The chloride salt was washed with ethyl acetate: diethyl ether (1 : 1) (10 mL X 4). (0.081 g, white solid).1H-NMR (300 MHz, DMSO-d6) 5: 6.87 - 6.84 (m, 1 H), 6.81 (s, 1H), 6.72 - 6.67 (d, J = 7.2 Hz, 2H), 5.42 (s, 2H), 4.36 (brs, 2H), 3.85 (brs, 2H), 3.78-3.58 (m, 18H), 3.41 - 3.26 (m, 9H), 3.14 (s, 3H), 2.99 - 2.91 (m, 3H), 1.98 (brs, 2H). ESI-MS (m / z) Calcd for C32H45N2O9T 601.3. Found 601.4 [M]+. HPLC purity: 96.72%.

[0628] F) Synthesis of compound 2006 (Iodide of compound 1006):

[0629] Step-1 : Synthesis of chloromethyl 2-phenylacetate (2):

[0630] To a solution of phenylacetic acid, 1 (3.0 g, 22.05 mmol, 1.0 equiv.) in DCM (30 mL) was added chloromethyl chlorosulfate (2.7 mL, 26.70 mmol, 1.2 equiv.) and TBAHS (0.80 g, 23.60 mmol, 0.1 equiv.) at room temperature. This was followed by the addition of water (30 mL) and sodium bicarbonate (7.1 g, 84.50 mmol, 4.0 equiv.). The reaction mixture was stirred at room temperature for 2 hrs. After completion, reaction mixture was diluted with water, the mixture

[0631] DB1 / 161977366.6 77 was extracted with DCM (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (silica gel: 100-200 mesh; 05:95 ethyl acetate: hexane) to yield compound 2. (2.30 g, 56.79% Yield).

[0632] Step-2: Synthesis of iodomethyl 2-phenylacetate (3):

[0633] A two neck round bottom flask was charged with chloromethyl 2-phenylacetate, 2 (2.0 g, 10.8 mmol, 1.0 equiv.) and sodium iodide (3.3 g, 21.60 mmol, 2.0 equiv.) in acetonitrile (20 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 hrs. After completion of reaction, reaction mixture was filtered, filtrate was concentrated. Then, reaction mixture was diluted with water, the mixture was extracted with ethyl acetate (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (silica gel: 100-200 mesh; 02:98 Ethyl acetate: hexane) to yield 3 (2.0 g, yellow oil, 67.11 % Yield).

[0634] Step-3: Synthesis of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-A / -(((S)-3,4- dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-N-methyl-N-((2-phenylacetoxy)methyl)propan-1- aminium iodide (2006):

[0635] A sealed tube was charged with compound 4 (0.1 g, 0.21 mmol, 1.0 equiv.) and compound 3 (0.18 g, 0.63 mmol, 3.0 equiv.) in DCM (5 mL) and reaction mixture was stirred at room temperature for 16 hrs. After completion of reaction, mixture was concentrated, and yellow oil obtained was then washed with diethyl ether (10 mL X 2) and pentane (10 mL X 2) to obtain 2006. (0.035 g, yellow oil, 22.01 % Yield).1H-NMR (300 MHz, CDCI3) 5 7.30-7.22 (m, 5H), 6.77 - 6.60 (m, , 3H), 6.48 (s, 1 H), 5.64 (s, 2H), 3.85-3.64 (m, 17H), 3.40 - 3.26 (m, 6H), 3.22-3.15 (m, 2H), 3.01 (s, 3H), 2.99 - 2.91 (m, 4H), 2.34-2.11 (m, 2H). ESI-MS (m / z) Calcd for C36H45N2O7+: 617.3. Found 617.4 (M)+. HPLC purity: 66.48 %.

[0636] Example 2: Ex-vivo results of plasma conversion: (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7- yl)methyl)(methyl)amino)propyl)-7, 8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (Compound 1000) and prodrugs thereof of the disclosure

[0637] (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1,3,4,5- tetrahydro-2H-benzo[d]azepin-2-one (Compound 1000)

[0638] DB1 / 161977366.6 78 139106-5002-WC

[0639] Conversion of compounds 2002, 2004, and 2005 into (S)-3-(3-(((3,4-dimethoxybicyclo[4.2,0]octa-1 ,3,5-trien-7- yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (Compound 1000) was examined in rat plasma, and all were found to convert into Compound 1000 beginning at 0 minutes, with the majority of the compound converted to Compound 1000 after 15 minutes. The conversion was completed within 1 hour. (Table 1).

[0640] Table 1. Rat plasma conversion of compounds 2002, 2004, and 2005

[0641] Preparation of the plasma conversion experiment:

[0642] Compound 2002 and 2005:

[0643] Stock solution: 10 mg / ml in DMSO

[0644] Matrix: SD Rat plasma

[0645] Blank Sample preparation: 2.5 pl of DMSO was added to 47.5 pil of blank plasma then 100 pl of 100% acetonitrile was added. Solution was vortexed for about 5 min and centrifuged for 10 min. Supernatant was analyzed by HPLC.

[0646] Control sample preparation: 100 pil ot 100% Acetonitrile was added to 47.5 pil ot blank plasma, then 2.5 pil 10 mg / ml stock solution was added. Solution was vortexed for about 5 min and centrifuged for 10 min. Supernatant was analyzed by HPLC.

[0647] Reaction Mixture: 25 pil of stock solution (10 mg / ml) in 475 pil plasma was incubated at 37°C.

[0648] From the reaction mixture, 50 pl sample was taken out and immediately the reaction was stopped with 100 pl of 100% acetonitrile (0-minute sample). 50 pl of reaction mixture was taken out at different time points (0, 5, 15, 30 min, and 1 hr) then the reaction was stopped with 100 pl of 100% acetonitrile. Solution was vortexed for about 5 min and centrifuged for 10 mins at 10,000 rpm (4°C). Supernatants were analyzed by HPLC.

[0649] DB1 / 161977366.6 79 139106-5002-WC

[0650] Compound 2004:

[0651] Calibration curve protocol: 2.5 pL of analyte was added to each standard except blank (Calibration Curve). 47.5 pL of plasma was transferred to labelled 1 .5 ml Eppendorf using a pipette. 100 pL of acetonitrile was added to each tube. All tubes were mixed on a multi-tube vortex for approximately 5 minutes. The tubes were centrifuged at 10,000 rpm for at least 10 minutes at 4°C (Biofuge). The supernatant was collected using a pipette and was transferred to labelled HPLC vials.

[0652] Stock solution: 10 mg / ml in DMSO

[0653] Matrix: SD Rat plasma / Dog Plasma / Human Plasma

[0654] Blank Sample preparation: 1.5 pl of DMSO was added to 48.5 pl of blank plasma then 100pl of 100% acetonitrile was added. Solution was vortexed for about 5 min and centrifuged for 10 min. Supernatant was analyzed by HPLC.

[0655] Control sample preparation: 10OpI of 100% Acetonitrile was added to 48.5pl of blank plasma, then 1 .5 pl 10mg / ml stock solution was added. Solution was vortexed for about 5 min and centrifuged for 10 min. Supernatant was analyzed by HPLC.

[0656] Reaction Mixture: 15 pl of stock solution (10mg / ml) in 485 pl plasma was incubated at 37°C.

[0657] From the reaction mixture, 50 pl sample was taken out and immediately the reaction was stopped with 100 pl of 100% acetonitrile (0-minute sample). 50 pl of reaction mixture was taken out at different time points (5, 15, 30 min 1 , and 2hr) then the reaction was stopped with 100 pl of 100% Acetonitrile. Solution was vortexed for about 5 min and centrifuged for 10 mins at 10,000 rpm (4°C). Supernatants were analyzed by HPLC.

[0658] Complete conversion of Compound 2004 to Compound 1000 was found to occur within 15-30 minutes in rat plasma, 1-2 hours in dog plasma, and within 30 minutes-1 hour of incubation in human plasma (Table 2).

[0659] Table 2: Rat, dog and human plasma conversion of compound 2004

[0660] DB1 / 161977366.6 80 139106-5002-WC

[0661] Example 3. Pharmacokinetic Evaluation of Compounds 1000, 2002, 2004, and 2005

[0662] The pharmacokinetic parameters of compounds 1000, 2002, 2004, and 2005 were measured in rats. Six rats per compound were evaluated, and results shown in Tables 3-7 disclose averages over all six rats.

[0663] A. Compound 1000 and Compounds 2002, 2004 and 2005 via oral administration (10 mg / kg and 20 mg / kg)

[0664] Compound 1000, compound 2002, compound 2004 and compound 2005 was administered to the animals at doses of 10 mg / kg and, in a separate experiment, 20 mg / kg following a 12-hour fast via the oral route. Blood samples were collected at predetermined time points post-administration. Plasma samples were collected after centrifugation at 10,000 rpm for 10 minutes at 4°C. Drug concentrations in plasma were determined using a validated analytical method, such as LC-MS / MS. The time points and corresponding plasma concentrations were recorded for each study subject and organized in a spreadsheet. Data was analyzed using Non-Compartmental Analysis (NCA) with extravascular input module in PK Solver software. The area under the curve (AUC) was calculated using the linear / log-linear trapezoidal method in Prism software. The following PK parameters were generated: Maximum Plasma Concentration (Cmax), Time to Reach Maximum Concentration (tmax), Area under the Curve (AUC), Elimination Half-Life (t1 / 2), Clearance {Cl), Volume of Distribution (Vd).

[0665] Table 3 discloses the pharmacokinetic parameters of Compounds 1000 and 2004 that were administered via a single 20 mg / kg oral dosage equivalent to that of Compound 1000.

[0666] Table 3. Pharmacokinetic parameters of Compounds 1000, and 2004 (20 mg / kg equivalent)

[0667] Cmax = maximum level of concentration; Tmax = time to Cmax; AUC = area under the curve; T1 / 2 = elimination half-life; Vd = volume of distribution; CL = clearance; MRT = mean residence time

[0668] Pharmacokinetic parameters of Compound 2004 were compared with those of Compound 1000 at an equivalent oral dose of 20 mg / kg (T able 3). Compound 2004 produced lower and slower plasma exposure of the active drug compared to direct Compound 1000 administration. Compound 2004 exhibited a higher volume of distribution (Vd) and higher clearance (CL), indicating broader tissue distribution and faster plasma elimination, which partly explains the lower plasma AUC / Cmax. Compound 2004 showed slower absorption, but elimination rates are comparable with that of

[0669] DB1 / 161977366.6 81 139106-5002-WC

[0670] Compound 1000. The conversion from prodrug (Compound 2004) to the parent drug (Compound 1000) appears efficient, as the overall exposure patters are similar in magnitide and time course. These results suggest that Comopund 4 may serve as an acceptable prodrug, particularly if a lower Cmax helps reduce toxicity.

[0671] Table 4 discloses the pharmacokinetic parameters of Compounds 1000, 2002, 2004, and 2005 that were administered to fasted rats via a single 10 mg / kg oral dosage equivalent to that of Compound 1000.

[0672] Table 4. Pharmacokinetic parameters of Compounds 1000, 2002, 2004 and 2005 (10 mg / kg equivalent oral)

[0673] Cmax = maximum level of concentration; Tmax = time to Cmax; AUG = area under the curve; T1 / 2 = elimination half-life; Vd = volume of distribution; CL = clearance; MRT = mean residence time

[0674] Pharmacokinetic parameters of Compounds 1000, 2002, 2004, and 2005 following a single 10 mg / kg oral administration in fasted rats were compared (Table 4). All prodrugs (Compounds 2002, 2004 and 2005) exhibited slower absorption as reflected by delayed Tmax values. Among the prodrugs, Compound 2002 demonstrated the greatest exposure, showing the highest AUC and moderate Cmax, indicative of improved overall exposure and potentially enhanced oral bioavailability. All prodrugs displayed similar T1 / 2 and MRT values, suggesting that once converted to the parent drug, their elimination kinetics are comparable.

[0675] B. Compound 1000, Compound 2004, and Compound 2005 via single IV administration (0.5 mg / kg, nonfasted):

[0676] Compound 1000, compound 2004 and compound 2005 was administered to animals at a dose of 0.5 mg / kg in nonfasted animals via intravenous route. Blood samples were collected at predetermined time points post-administration. Plasma was obtained after centrifugation at 10,000 rpm for 10 minutes at 4°C. Drug concentrations in plasma were determined using a validated analytical method, such as LC-MS / MS. The time points and corresponding plasma concentrations were recorded for each study subject and organized in a spreadsheet. Data were analyzed using NonCompartmental Analysis (NCA) with the IV bolus input module in PK Solver software. The area under the curve (AUC) was calculated using the linear / log-linear trapezoidal method in Prism software. The following PK parameters were generated: Maximum Plasma Concentration (Cmax), Time to Reach Maximum Concentration (tmax), Area under the Curve (AUC), Elimination Half-Life (t1 / 2), Clearance (Cl), volume of Distribution (Vd).

[0677] DB1 / 161977366.6 82 139106-5002-WC

[0678] Table 5 discloses the pharmacokinetic parameters of Compounds 1000, 2004 and 2005 that were administered to non-fasted rats via a single 0 5 mg / kg intravenous (IV) dosage equivalent to that of Compound 1000.

[0679] Table 5. Pharmacokinetic parameters of Compounds 1000, 2004 and 2005 (0.5 mg / kg equivalent IV)

[0680] Cmax = maximum level of concentration; Tmax = time to Cmax; AUG = area under the curve; T1 / 2 = elimination half-life; Vd = volume of distribution; CL = clearance; MRT = mean residence time

[0681] Pharmacokinetic parameters of Compound 2004 and Compound 2005 were compared with Compound 1000 at an equivalent IV dose of 0.5 mg / kg (Table 5). Compound 2004 and Compound 2005 were observed to have better plasma exposure of Compound 1000 compared to Compound 1000.

[0682] C. Compound 2004 via oral administration (3 mg / kg, 10 mg / kg, and 30 mg / kg)

[0683] Compound 2004 was administered to animals at doses of 3mg / kg, 10 mg / kg and 30mg / kg in 12-hour fasted animals via the oral route. Blood samples were collected at predetermined time points post-administration. Plasma was obtained after centrifugation at 10000 rpm for 10 minutes at 4°C. Drug concentrations in plasma were determined using a validated analytical method, such as LC-MS / MS. The time points and corresponding plasma concentrations were recorded for each study subject and organized in a spreadsheet. Data were analyzed using Non-Compartmental Analysis (NCA) under the extravascular input module in PK Solver software. The area under the curve (AUC) was calculated using the linear / log-linear trapezoidal method in Prism software. The following PK parameters were generated: Maximum Plasma Concentration (Cmax), Time to Reach Maximum Concentration (tmax), Area under the Curve (AUC), Elimination Half-Life (t1 / 2), Clearance (Cl), Volume of Distribution (Vd).

[0684] Table 6 discloses the pharmacokinetic parameters of Compound 2004 that were administered to fasted rats via a single 3, 10 and 30 mg / kg oral dosage equivalent to those of Compound 1000.

[0685] Table 6. Pharmacokinetic parameters of Compound 2004 (3, 10, 30 mg / kg equivalent oral)

[0686] DB1 / 161977366.6 83 139106-5002-WC

[0687] Cmax = maximum level of concentration; Tmax = time to Cmax; AUG = area under the curve; T1 / 2 = elimination half-life; Vd = volume of distribution; CL = clearance; MRT = mean residence time

[0688] Pharmacokinetic parameters of Compound 2004 at oral doses of 3, 10, and 30 mg / kg were compared (Table 6; FIG. 7 A and FIG. 7B). Compound 2004 exhibited dose linearity across the 3, 10, and 30 mg / kg dosing concentrations. All three doses produced reasonable exposure of the parent drug, Compound 1000. No systemic exposure of Compound 2004 was observed, indicating complete conversion to the parent drug upon oral administration. A significant higher mean residence time (MRT) was observed in one rat from each group, attributed to elevated plasma level observed even at 24 hours in these animals compared to others within the same group.

[0689] D. Compound 1000 and Compound 2004 via oral administration (10 mg / kg fasted and fed)

[0690] Compound 1001 and compound 2004 was administered to the animals at a dose of 10 mg / kg under both 12-hour fasted and fed conditions via the oral route. Blood samples were collected at predetermined time points postadministration. Plasma was obtained after centrifugation at 10,000 rpm for 10 minutes at 4°C. Drug concentrations in plasma were determined using a validated analytical method, such as LC-MS / MS. The time points and corresponding plasma concentrations were recorded for each study subject and organized in a spreadsheet. Data were analyzed using Non-Compartmental Analysis (NCA) with the extravascular input module in PK Solver software. For calculation of the area under the curve (AUG), the linear / log-linear trapezoidal method was applied in Prism software. The following PK parameters were generated: Maximum Plasma Concentration (Cmax), Time to Reach Maximum Concentration (tmax), Area under the Curve (AUC), Elimination Half-Life (t112), Clearance (Cl), Volume of Distribution (Vd).

[0691] Table 7 discloses the pharmacokinetic parameters of Compound 1000 and Compound 2004 that were administered to fed and fasted rats via a single 10 mg / kg oral dosage equivalent to those of Compound 1000.

[0692] Table 7. Pharmacokinetic parameters of Compounds 1000 and 2004 (10 mg / kg equivalent oral, fed and fasted)

[0693] DB1 / 161977366.6 84 Cmax = maximum level of concentration; Tmax = time to Cmax; AUG = area under the curve; T1 / 2 = elimination half-life; MRT = mean residence time

[0694] Pharmacokinetic parameters of Compound 1000 and Compound 2004 at an equivalent oral dosage of 10 mg / kg were compared under fasted and fed conditions (Table 7, and FIG. 8). Both formulations demonstrate positive food effect, with increased systemic exposure (AUC) in the fed state, when administered with food, AUCO-t increased 35-fold for Compound 1000 and 2.5-fold for Compound 2004. Food intake delayed absorption for both formulations: Tmax for Compound 1000 increased from 0.14 to 0.8 hours, and Tmax for Compound 2004 was increased from 0.26 to 1.92 hours.

[0695] The fed state also showed higher pharmacokinetic variability (CV%) across most parameters. Under fasted conditions, Compound 1000 exposures are comparable between direct Compound 1000 administration (653 ng«h / mL) and prodrug Compound 2004 administration (532 ng«h / ml_). In the fed state, prodrug Compound 2004 resulted in 1.7-fold lower Compound 1000 exposure (1320 ng«h / mL) compared to direct Compound 1000 administration (2280 ng«h / mL).

[0696] INCORPORATION BY REFERENCE

[0697] All patents and publications referenced herein are hereby incorporated by reference in their entireties.

[0698] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure.

[0699] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections.

[0700] EQUIVALENTS

[0701] While the disclosure has been disclosed in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure as come within known or customary practice within the art to which the disclosure pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

[0702] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments disclosed specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

[0703] DB1 / 161977366.6 85

Claims

CLAIMSWhat is claimed is:1 . A compound of formula (XI):formula (XI) or a stereoisomer thereof, wherein in formula (I):X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;Z is selected from I), II), and ill):I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,II) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionallyDB1 / 161977366.6 86substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

2. The compound of claim 1 , wherein the compound of formula (XI) is a compound of formula (Xia), or a stereoisomer thereof,formula (Xia) wherein in formula (Xia):X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;Z is selected from I), II), and ill):I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ii) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionallyDB1 / 161977366.6 87substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

3. The compound of claim 1 , wherein the compound of formula (XI) is a compound of formula (Xia), or a stereoisomer thereof,formula (Xlb) wherein in formula (Xlb):X is a pharmaceutically acceptable anion; each of Raand Rbis independently hydrogen or Ci-Ce alkyl, wherein Raand Rbare optionally joined to form a 3-6 membered carbocyclic ring;Z is selected from I), II), and ill):I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ii) R2, wherein R2is selected from a), b), and c): a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2 both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionallyDB1 / 161977366.6 88substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

4. The compound of any one of claims 1-3, wherein Rais hydrogen or Ci-Ce alkyl.

5. The compound of any one of claims 1-4, wherein Rbis hydrogen or Ci-Ce alkyl.

6. The compound of any one of claims 1-5, wherein Raand Rbare joined to form a 3-6 membered carbocyclic ring.

7. The compound of any one of claims 1-5, wherein Rais hydrogen and Rbis hydrogen.

8. The compound of any one of claims 1 , 4, 5 or 7, wherein the compound of formula (XI) is a compound of formula (I):formula (I) or a stereoisomer thereof, wherein in formula (I):X is a pharmaceutically acceptable anion;Z is selected from I), II), and ill):I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,II) R2, wherein R2is selected from a), b), and c):DB1 / 161977366.6 89a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

9. The compound of any one of claims 2, 4, 5, or 7-8, wherein the compound of formula (Xia) is a compound of formula (la):formula (la) or a stereoisomer thereof, wherein in formula (la):X is a pharmaceutically acceptable anion;Z is selected from i), ii), and Hi):I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,II) R2, wherein R2is selected from a), b), and c):DB1 / 161977366.6 90a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

10. The compound of any one of claims 3-5, or 7-8, wherein the compound of formula (Xlb) is a compound of formula (lb):formula (lb) or a stereoisomer thereof, wherein in formula (lb):X is a pharmaceutically acceptable anion;Z is selected from i), ii), and Hi):I) -OR1, wherein R1is selected from alkyl, aryl, arylalkyl, alkenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, wherein the alkyl, aryl, arylalkyl, alkenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, aryl, arylalkyl, alkenyl, halogen, alkoxy, haloalkyl, and haloalkoxy,II) R2, wherein R2is selected from a), b), and c):DB1 / 161977366.6 91a. Ci-Cs alkyl, wherein the alkyl is optionally interrupted by 1 to 2 heteroatoms, and / or optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, haloalkyl, haloalkoxy, and aryl; b. benzyl or phenyl, optionally wherein the benzyl or phenyl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy; c. 5 or 6 membered heteroaryl containing 1-3 heteroatoms selected from 0, S and N, optionally wherein the heteroaryl is substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, ill) -NHR3or -N(R3)2, wherein R3is independently at each occurrence selected from alkyl, phenyl, and 5-6 membered heteroaryl containing 1-3 heteroatoms selected from 0 and N, wherein the alkyl, phenyl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy, wherein in -N(R3)2both R3can optionally be joined to form a 4-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms, and is optionally substituted with 1 to 3 substituents selected from Ci-Ce alkyl, halogen, alkoxy, haloalkyl, and haloalkoxy.

11. The compound of any one of claims 1-10, wherein Z is -OR1.

12. The compound of any one of claims 1-11 , wherein R1is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

13. The compound of any one of claims 1-12, wherein R1is selected from methyl, ethyl, n-propyl, isopropyl, secbutyl, n-butyl, hexyl, and octyl.

14. The compound of any one of claims 1-13, wherein R1is substituted with 1 to 3 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl, optionally -OMe or phenyl.

15. The compound of any one of claims 1-14, wherein -OR1is selected from -OMe, -OEt, -O- / Pr, -O-nBu, and16. The compound of any one of claims 1-10, wherein Z is R2.DB1 / 161977366.6 92139106-5002-WC17. The compound of any one of claims 1-10 or 16, wherein R2is Ci-Cs alkyl.

18. The compound of any one of claims 1-10, 16, or 17, wherein Ci-Cs alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

19. The compound of any one of claims 1-10, or 16-18, wherein Ci-Cs alkyl is selected from methyl and n-propyl.20 The compound of any one of claims 1-10 or 16-19, wherein Ci-Cs alkyl is substituted with 1 to 3 substituents selected from Cl, Br, I, -OMe, -OEt, -O / -Pr, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and phenyl, optionally phenyl.

21. The compound of any one of claims 1-10 or 16-20, wherein -R2is22. The compound of any one of claims 1-21 , wherein the compound of formula (XI) has a formula of any one ofDB1 / 161977366.6 93DB1 / 161977366.6 9423. The compound of any one of claims 1-22, wherein X is selected from chloride, bromide, iodide, hydroxide, sulfate (SO4-2, HSCh'2), nitrate, phosphate (e.g. PC3, HPCM, ^PC ), acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.

24. The compound of any one of claims 1-23, wherein X is selected from chloride, bromide, iodide, acetate, HSO SO4-2, p-toluenesulfonate, PCM, HPCM, H2PO4', and tartrate.25 The compound of any one of claims 1-24, wherein X is chloride.

26. The compound of any one of claims 1-24, wherein X is iodide.

27. The compound of claim 25 or 26, wherein the compound of formula (IX), (Xia), (Xlb), (I), (la) or (lb) has a formula of any one of formula 2001-2006, 2011-2016, or 2021-2026:DB1 / 161977366.6 9528 The compound of any one of claims 1-27, wherein the compound of formula (XI) exhibits improved gastrointestinal absorption (e.g. improved permeability and / or solubility) compared to (S)-3-(3-(((3,4- dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1l3,4,5-tetrahydro-2H- benzo[d]azepin-2-one.DB1 / 161977366.6 9629. The compound of claim 28, wherein the compound of formula (XI) exhibits at least about 1 fold, at least about 2 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 6 fold, at least about 7 fold, at least about 8 fold, at least about 9 fold, at least about 10 fold, at least about 50 fold, at least about 100 fold, at least about 500 fold, or at least about 1000 fold improved gastrointestinal absorption (e.g. improved permeability and / or solubility) compared to (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa- 1 , 3, 5-trien-7-y l)methy I) (methy I) ami no)propy I )-7, 8- dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.30 A pharmaceutical composition comprising a compound of any one of claims 1-29, and a pharmaceutically acceptable excipient.31 . A method of treating a disease or disorder, the method comprising administering to a subject in need thereof a compound of any one of claims 1-29 or a pharmaceutical composition of claim 30 to the subject.32 The method of claim 31, wherein the disease or disorder is a cardiovascular disease or disorder.

33. The method of any one of claims 31 or 32, wherein the cardiovascular disease or disorder is selected from sinus tach (e.g. inappropriate sinus tachycardia (1ST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e.g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g. angina pectoris), myocardial infarct, rhythm disturbances (e.g. supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, and left ventricular dysfunction (LVD).

34. The method of claim 33, wherein the cardiovascular disease or disorder is inappropriate sinus tachycardia (1ST)).

35. The method of claim 33, wherein the cardiovascular disease or disorder is angina pectoris (e.g. chronic stable angina pectoris).

36. The method of any one of claims 31-35, wherein the disease or disorder is caused by a genetic disorder.37 The method of any one of claims 31-36, wherein the method of treating the disease or disorder further includes inhibition of a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel (e.g. hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4)) and / or inhibition of a funny current (lf) channel.DB1 / 161977366.6 9738 The method of any one of claims 31-37, wherein the method of treating the disease or disorder further includes reduction of the subject's heart rate compared to a pre-treated or untreated state.

39. The method of any one of claims 31-38, wherein the subject has normal sinus rhythm, and optionally cannot take beta blockers, and / or has undergone coronary artery bypass grafting (CABG).40 A method for treating a subject diagnosed with a cardiovascular disease or disorder, the method comprising: a) administering a first dose of a compound of any one of claims 1-29 or a pharmaceutical composition of claim 30 to the subject while employing a wearable device or another monitor to monitor heart rhythm data of the subject; b) monitoring the subject for efficacy of the administered first dose to assess whether the first dose is efficacious for the subject during a comparison period of 1 or more days; c) if the administered first dose is efficacious for the subject, continuing to monitor the subject's heart rhythm data to ensure that the administered first dose remains efficacious.41 . The method of claim 40, wherein assessing the efficacy of the first dose is delayed for at least 7 or 14 days after administering the first dose.42 The method of claim 40 or 41 , wherein assessing the efficacy of the first dose is based on symptoms and / or an average heart rate measured by the wearable device or another monitor.

43. The method of any one of claims 40-42, wherein if the administered first dose is assessed as not efficacious for the subject by an end of the comparison period, adjust the amount of the first dose one or more times as necessary to achieve an efficacious result to provide an adjusted dose, wherein the efficacy of the adjusted dose is assessed during at least the comparison period and / or delay period.

44. The method of any one of claims 40-43, wherein if the administered first dose or adjusted dose is no longer efficacious, step c) is repeated with the administered first dose or adjusted dose as the first dose.

45. The method of any one of claims 40-44, wherein monitoring in step b) is conducted in a continuous manner.

46. The method of any one of claims 40-45, wherein monitoring in step b) comprises detecting a slow diastolic depolarization phase.DB1 / 161977366.6 9847 The method of any claim 46, wherein detecting comprises use of a photoplethysmography (PPG) algorithm and / or ParamAP.

48. The method of any one of claims 40-47, wherein the efficacy at an administered first dose or an adjusted dose is evaluated by comparing baseline levels of the slow diastolic depolarization phase against corresponding levels of the slow diastolic depolarization phase in the comparison period.

49. The method of any one of claims 40-48, wherein the comparison period is one or more of about a day, about a week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or up to about 6 months.

50. The method of any one of claims 40-49, wherein the cardiovascular disease or disorder is selected from sinus tach (e.g. inappropriate sinus tachycardia (1ST)), postural orthostatic tachycardia syndrome (POTS), coronavirus (COVID-19) (e.g. long COVID) and COVID-associated cardiovascular abnormalities, supraventricular tachycardia (SVT), tachycardia (e.g. rapid heart rate, atrial tachycardia), heart failure (e.g. congestive heart failure (CHF), systolic heart failure, pediatric heart failure, chronic heart failure), myocardial ischaemia, angina (e.g. angina pectoris), myocardial infarct, rhythm disturbances (e.g. supraventricular rhythm disturbances), chest pain, cardiomyopathy, coronary artery disease, left ventricular dysfunction (LVD).51 The method of claim 50, wherein the cardiovascular disease or disorder is inappropriate sinus tachycardia (1ST)).

52. The method of claim 50, wherein the cardiovascular disease or disorder is angina pectoris (e.g. chronic stable angina pectoris).53 The method of any one of claims 40-52, wherein the subject has normal sinus rhythm, and optionally cannot take beta blockers, and / or has undergone coronary artery bypass grafting (CABG).

54. The method of any one of claims 40-53, wherein the wearable device is one or more of a patch, a watch, a wristband, a strap, a ring, a glass, a shirt, a finger, a bracelet, a SGPS / GPRS baby / control, a belt, a pants, a sock, a shoe, a Bluetooth key tracker, a holier, an implantable, or a device that adheres to a body when fitted.DB1 / 161977366.6 9955. The method of any one of claims 40-54, wherein the subject is selected for therapy based on a history of inappropriate sinus tachycardia (1ST) and / or an inappropriate sinus tachycardia (1ST) genetic risk score (GRS) indicating high risk of inappropriate sinus tachycardia (1ST) recurrence over time.

56. The method of any one of claims 40-55, wherein the subject is selected for therapy based on a positive result from a wearable FDA cleared device, a history of inappropriate sinus tachycardia (1ST) and / or an inappropriate sinus tachycardia (1ST) genetic risk score (GRS) indicating high risk of inappropriate sinus tachycardia (1ST) recurrence over time.

57. The method of claim 56, wherein the wearable FDA cleared device is used to monitor the subject on therapy and dosing is adjusted over time based on the rate of the slow diastolic depolarization phase.

58. The method of any one of claims 55-57, wherein the risk factor comprises age, ethnicity, or a history of cardiovascular disease, cardiac amyloidosis, illicit drug use, or diabetes.DB1 / 161977366.6 100

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