Inhibitors of trimethylamine and trimethylamine-n-oxide production and uses thereof

Abstract

Described herein are compounds that reduce the production of trimethylamine-N-oxide (TMAO) in a subject, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of a kidney disease or a cardiovascular disease.

Description

INHIBITORS OF TRIMETHYLAMINE AND TRIMETHYLAMINE-N-OXIDE PRODUCTION AND USES THEREOFCROSS REFERENCE

[0001] This application claims the benefit of U.S. Application No. 63 / 677,891 filed July 31, 2024, which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Trimethylamine (TMA) and its derivative tri methyl amine N-oxide (TMAO) are metabolites linked to disorders such as kidney disease, diabetes mellitus, obesity, trimethylaminuria, and cardiovascular disease (CVD). TMA is produced in the gut by bacteria which are capable of converting substrates including but not limited to choline, to TMA. There is an unmet need for compounds which inhibit the production of TMA and TMAO by bacteria. Prevention and management of conditions associated with TMA and TMAO, including CVD, diabetes and kidney disease, is a major public health concern.SUMMARY OF THE INVENTION

[0003] In one aspect, described herein is a compound of Formula (I):Formula (I) wherein:Z is -C=CR5or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independnetly -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; or R2and R3together with the N atom to which they are attached combine together to form a 5 membered heterocycloalkyl; each R4is independently deuterium, -F, -OH, or -CH3; p is 1, 2, 3, 4, or 5;each R5is independently hydrogen, deuterium, -F, -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; andX' is a counterion; provided that the compound is not

[0004] In some embodiments, the compound is of Formula (la) or Formula (lb):Formula (lb) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; each R4is independently -F, -OH, or -CH3; p is 1, 2, 3, 4, or 5; andX' is a counterion; provided that the compound is not

[0005] In some embodiments, the compound of Formula (I) has the structure of Formula(Ila), (lIb), (lIe), or (lId):

[0006] In some embodiments, the compound is of Formula (III):wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R4is -F, or -CH3; andX" is a counterion.

[0007] In some embodiments, the compound is of Formula (IV): wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; each R4is independently -F, or -CH3;R5a, R5b, andR5care each indepenendently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; p is 1, 2, 3, 4, or 5; andX' is a counterion.

[0008] In some embodiments, the compound of Formula (IV) is of Formula (IVa), (IVb), (IVc), or (IVd):

[0009] In another aspect, provided herein is a compound of Formula (V):Formula (V) wherein:Z is -OCR5or -CR5=C(R5)2;Rlais hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3;Rlbis -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-Ce cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3; each R4is independently -F, or -CH3; each R5is independnelty hydrogen or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

[0010] In some embodiments, the compound is of Formula (V) is of Formula (Va):Formula (Va).

[0011] In some embodiments, the compound of Formula (V) is of Formula (Vb):Formula (Vb).

[0012] In another aspect, provided herein is a compound of Formula (VI):Formula (VI) wherein:Z is -C=CH or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen or deuterium;R2and R3are each independently -CH3 or -CD3; each R5is independnetly hydrogen or deuterium;Ra, Rb, Rc, Rd, and Reare each independently hydrogen or deuterium; wherein one of Rla, Rlb, Ra, Rb, Rc, Rd, Reor R5is deuterium or one of R2or R3is -CD3; andX' is a counterion.

[0013] In some embodiments, the compound of Formula (VI) is of Formula (Via):Formula (Via)

[0014] In some embodiments, the compound of Formula (VI) is of Formula (VIb):Formula (VIb).

[0015] In another aspect, provided herein is a compound of Formula (VII’):RtaR1 bFormula (VII’) wherein:Z is -OCR5or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3. each R5is independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, -CN, C1-C3 alkyl, -OH, -S(O)2CH3, or - S(O)2°-; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX' is a counterion;

[0016] In another aspect, provided herein is a compound of Formula (VIF):Formula (VIF) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3. each R5is independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, -CN, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(0)2°-; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to5-membered heterocycloalkyl; and X' is a counterion; provided that the compound is not

[0017] In some embodiments, the compound is of Formula (Vila’):Formula (Vila’) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -OH, -S(O)2CH3, or - S(O)2O’; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX' is a counterion.

[0018] In some embodiments, the compound is of Formula (Vila’):Formula (Vila’) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3 Ce cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3; hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -OH, -S(O)2CH3, or -S(O)2O’; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to5-membered heterocycloalkyl; andX' is a counterion;© x provided that the compound is not

[0019] In some embodiments the compound is of Formula (Vllb’):wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -OH, -S(O)2CH3, or -S(O)2O’; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX' is a counterion; provided that the compound is not

[0020] In some embodiments of Formula (VIF), (Vila’), or (Vllb’), R6is. wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or - S(O)2O’; or two R7combine together with the atoms to which they are attached to form a C3-C6 cycloalkyl; or two R7combine together with the atoms to which they are attached to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; and q is 1, 2, 3, 4, or 5.

[0021] In some embodiments of Formula (VII’), (Vila’), or (Vllb’), R6iswherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or - S(O)2O-;or two R7combine together with the atoms to which they are attached to form a C3-C6 cycloalkyl; or two R7combine together with the atoms to which they are attached to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; and q is 1, 2, 3, 4, or 5.

[0022] In some embodiments, the compound is of Formula (Vile’):Formula (Vile’) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0023] In some embodiments, the compound is of Formula (Vlld’):Formula (Vlld’)wherein:W is -NR7a-, -0-, -S-, -S(0)-, -S(0)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0024] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl;q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0025] In some embodiments, the compound is of Formula (Vllf):Formula (Vllf) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen, -OH, or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0026] In another aspect, provided herein is a compound of Formula (VIII):Formula (VIII) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3;each R5aR5band R5c, are independently hydrogen, deuterium, -F, -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; and X' is a counterion;

[0027] In another aspect, provided herein is a compound of Formula (IX):Formula (IX) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; each R4is independently deuterium, -F, or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

[0028] In another aspect, provided herein is a compound of Formula (X):Formula (X) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R3is -CH3, -CH2F, -CHF2, or -CF3; each R4is independently deuterium, -F, or -CH3; p is 0, 1, 2, 3, 4, or 5; and X' is a counterion.

[0029] In another aspect, provided herein is a compound of Formula (XI):Formula (XI) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-Ce cycloalkyl;R3is -CH3, -CH2F, -CHF2, or -CF3; each R4is independently deuterium, -F, or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

[0030] In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vile), (Vlld), (VII), (Vila), (Vllb), (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X~ is a counterion selected from chloride, bromide, iodide, sulfate, phosphate, tartrate, citrate, acetate, fumarate, succinate, mesylate, lactate, and stearate.

[0031] In another aspect, described herein is a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vile), (Vlld), (VII), (Vila), (Vllb), (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), and at least one pharmaceutically acceptable excipient.

[0032] In another aspect, described herein is a method of treating a chronic kidney disease, a cardiovascular disease, obesity, diabetes, a metabolic disorder, a hepatic disorder, hypertension, resistant hypertension, frailty, or sarcopenia in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb),(lIe), (nd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vile), (Vlld), (VII), (Vila), (Vllb), (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII).

[0033] In another aspect, described herein is a method of treating a kidney disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vile), (Vlld), (VII), (Vila), (Vllb), (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII). In some embodiments, described herein is a method of treating a kidney disease in a subject in need thereof, comprising administering to the subject a compound of Formula ((I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vile), (Vlld), (VII), (Vila), (Vllb), (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein the kidney disease is selected from reduced or impaired kidney function, chronic kidney disease, end-stage renal disease, and renal impairment associated with diabetes mellitus.

[0034] In another aspect, described herein is a method of treating a cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vile), (Vlld), (VII), (Vila), (Vllb), (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII). In some embodiments, described herein is a method of treating a cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vile), (Vlld), (VII), (Vila), (Vllb), (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein the cardiovascular disease is selected from atherosclerosis, coronary heart disease, cerebrovascular disease, heart, failure, cardiomyopathy, atherothrombotic disease, aorto-iliac disease, and peripheral vascular disease.

[0035] In another aspect, described herein is a method of reducing the production of trimethylamine (TMA) or trimethylamine-N-oxide (TMAO) in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vile), (Vlld), (VII), (Vila), (Vllb), (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII).

[0036] In another aspect, described herein is a method of inhibiting the conversion of choline to trimethylamine (TMA) and reducing trimethylamine-N-oxide (TMAO) level in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (Vile), (Vlld), (VII), (Vila), (Vllb), (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII).DETAILED DESCRIPTION OF THE INVENTION

[0037] TMA synthesized by bacteria resident in the gut of mammals is oxidized in die liver to trimethylamine N-oxide (TMAO). Exemplary precursors of ’TMA include choline, betaine, phosphatidylcholine, phosphocholine, glycerophosphocholine, carnitine, L-carnitine, TMAO, sphingomyelin, and lecithin, mans'- of which are derived from dietary' sources such as, for example, whole eggs and beef liver. These sources may act as substrates for bacteria that can metabolize them to TMA. Without wishing to be bound to a particular mechanism or biochemical pathway, the anaerobic conversion of choline to TMA is facilitated by a glycyl radical enzyme homologue, choline triraethylamine-lyase (CutC). The reduction of choline conversion to TM A by bacteria in the gut of an individual leads to a reduction in TMA absorption from the gut, leading to a subsequent reduction in plasma TMAO following oxidation of TMA to TMAO by the flavin monooxygenase 3 (FMO3) enzyme in the liver. Lower plasma TMAO levels are related to a lower incidence of major cardiovascular events in humans.

[0038] The compounds of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), and (XIII), described herein interfere with choline metabolism by gut microbiota resulting in reduction in the formation of TMA and TMAO. Also described herein are compositions and methods that inhibit the conversion of choline to TMA in vitro and in vivo, improve or maintain cardiovascular and kidney health, and improve or prevent a condition associated with increased TMA and TMAO.Compounds

[0039] The compounds of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), and(XIII), described herein reduce the production of trimethyl amine (TMA) and trimethylamine N-oxide (TMAO) in a subject.

[0040] In an aspect, provided herein is a compound of Formula (I):Formula (I) wherein:Z is -OCR5or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independnetly -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; or R2and R3together with the N atom to which they are attached combine together to form a 5 membered heterocycloalkyl; each R4is independently deuterium, -F, -OH, or -CH3; p is 1, 2, 3, 4, or 5; each R5is independently hydrogen, deuterium, -F, -CH3, -CD3, -CH2D, -CHD2, -CH2F, - CHF2, or -CF3; andX' is a counterion; provided that the compound is not

[0041] In an aspect, provided herein is a compound of Formula (I):wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3;or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independnetly -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -CH2F, -CHF2, or -CF3; or R2and R3together with the N atom to which they are attached combine together to form a 5 membered heterocycloalkyl; each R4is independently -F, -OH, or -CH3; p is 1, 2, 3, 4, or 5; each R5is independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; and X' is a counterion;. provided that the compound is not.

[0042] In some embodiments of Formula (I), R2and R3are each independnetly -CH3, - CH2CH3, -(CH2)2CH3, -CH(CH3)2. In some embodiments of Formula (I), R2and R3are each - CH3. In some embodiments of Formula (I), R2and R3are each -CH2CH3. In some embodiments of Formula (I), R2and R3are each independnetly -(CH2)2CH3 or -CH(CH3)2. In some embodiments of Formula (I), R2and R3are each independnetly -CH2F, -CHF2, or -CF3. In some embodiments of Formula (I), R2and R3are each -CH2F. In some embodiments of Formula (I), R2and R3are each -CHF2. In some embodiments of Formula (I), R2and R3are each -CF3. In some embodiments of Formula (I), R2and R3are each independnetly -CD3, - CH2D or -CHD2. In some embodiments of Formula (I), R2and R3are each independnetly - CD3.

[0043] In some embodiment of Formula (I), Z is -C=CR5. In some embodiments of Formula (I), Z is -CR5=C(R5)2.

[0044] In some embodiments of Formula (I), each R5is independently hydrogen, -F, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments of Formula (I), each R5is independently hydrogen, -F, or -CH3. In some embodiments of Formula (I), each R5is -F. In some embodiments of Formula (I), each R5is -OH.

[0045] In some embodiments, the compound is of Formula (la):Formula (la) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; each R4is independently -F, -OH, or -CH3; p is 1, 2, 3, 4, or 5; andX' is a counterion; provided that the compound is not

[0046] In some embodiments, the compound is of Formula (lb):Formula (lb) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; each R4is independently -F, -OH, or -CH3; p is 1, 2, 3, 4, or 5; andX' is a counterion; provided that the compound is not

[0047] In some embodiments of Formula (I), (la), or (lb), each R4is independently -F. In some embodiments of Formula (I), (la), or (lb), each R4is independently -CH3.

[0048] In some embodiments of Formula (I), (la), or (lb), p is 1, 2, 3, or 4. In some embodiments of Formula (I), (la), or (lb), p is 1, 2, or 3. In some embodiments of Formula(I), (la), or (lb), p is 1 or 2. In some embodiments of Formula (I), (la), or (lb), p is 1. In some embodiments of Formula (I), (la), or (lb), p is 2.

[0049] In some embodiments of Formula (I), (la), or (lb), Rlaand Rlbare each hydrogen; p is 1; and R4is -F.

[0050] In some embodiments, the compound of Formula (I) has the structure of Formula(Ila):Formula (Ila).

[0051] In some embodiments, the compound of Formula (I) has the structure of Formula (lIb):Formula (lIb).

[0052] In some embodiments, the compound of Formula (I) has the structure of Formula (lIc):Formula (lIe).

[0053] In some embodiments, the compound of Formula (I) has the structure of Formula (lId):Formula (lId).

[0054] In some embodiments, the compound is of Formula (III):Formula (III) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R4is -F, or -CH3; andX' is a counterion.

[0055] In some embodiments of Formula (Ila), (lIb), (lIe), (lId), or (III), R4is -F. In some embodiments of Formula (Ila), (lIb), (lIe), (lId), or (III), R4is -CH3.

[0056] In some embodiments, the compound is of Formula (IV):Formula (IV) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; each R4is independently -F, or -CH3;R5a, R5b, andR5care each indepenendently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; p is 1, 2, 3, 4, or 5; andX' is a counterion.

[0057] In some embodiments of Formula (IV), each R4is -F. In some embodiments of Formula (IV), each R4is -CH3.

[0058] In some embodiments, the compound of Formula (IV) is of Formula (IVa):Formula (IVa).

[0059] In some embodiments, the compound of Formula (IV) is of Formula (IVb):Formula (IVb).

[0060] In some embodiments, the compound of Formula (IV) is of Formula (IVc):Formula (IVc).

[0061] In some embodiments, the compound of Formula (IV) is of Formula (IVd):Formula (IVd).

[0062] In some embodiments of Formula (IVa), (IVb), (IVc), or (IVd), R4is -F. In some embodiments of Formula (IVa), (IVb), (IVc), or (IVd), R4is -CH3.

[0063] In some embodiment of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5ais hydrogen, deuterium, -F, or -CH3. In some embodiments of Formula (IV) (IVa), (IVb), (IVc), or (IVd), R5ais hydrogen. In some embodiments of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5ais -F. In some embodiments of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5ais - CH3.

[0064] In some embodiments of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5bis hydrogen, deuterium, -F, or -CH3. In some embodiments of Formula (IV), (IVa), (IVb),(IVc), or (IVd), R5bis hydrogen. In some embodiments of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5bis -F. In some embodiments of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5bis -CH3.

[0065] In some embodiment of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5cis hydrogen, deuterium, -F, or -CH3. In some embodiments of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5Cis hydrogen. In some embodiments of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5Cis -F. In some embodiments of Formula (IV), (IVa), (IVb), (IVc), or (IVd), R5cis -CH3.

[0066] In some embodiments of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), or (IVa), Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3. In some embodiments of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), or (IVa), Rlaand Rlbare each independently hydrogen, -F, -CH2F, -CHF, or -CF3. In some embodiments of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), or (IVa), Rlaand Rlbare independently hydrogen or -CH3. In some embodiments of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), or (IVd), Rlaand Rlbare each hydrogen.

[0067] In some embodiments of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), or (IVd), Rlaand Rlbtogether with the atom to which they are attached from a C3-Ce cycloalkyl. In some embodiments of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), or (IVd), Rlaand Rlbtogether with the atom to which they are attached form a cyclopropyl.

[0068] In another aspect, provided herein is a compound of Formula (V):Formula (V) wherein:Z is -C=CR5or -CR5=C(R5)2;Rlais hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3;Rlbis -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-Ce cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3; each R4is independently -F, or -CH3;each R5is independnelty hydrogen or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

[0069] In some embodiments of Formula (V), Z is -C=CR5. In some embodiments of Formula (V), Z is - CR5=C(R5)2;

[0070] In some embodiments, the compound of Formula (Va):wherein:Rlais hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3;Rlbis -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-Ce cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3; each R4is independently -F, or -CH3;R5is hydrogen or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion..

[0071] In some embodiment of Formula (Va), R5is hydrogen. In some embodiment of Formula (Va), R5is -CH3.

[0072] In some embodiments, the compound is of Formula (Vb):Formula (Vb) wherein:Rlais hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3;Rlbis -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-Ce cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;each R4is independently -F, or -CH3; each R5is independnelty hydrogen or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

[0073] In some embodiments of Formula (Vb), each R5is hydrogen. In some embodiments of Formula (Vb), each R5is independnelty -CH3.

[0074] In some embodiments of Formula (V), (Va), or (Vb), each each R4is independently -F. In some embodiments of Formula (V), (Va), or (Vb), each R4is independently -CH3.

[0075] In some embodiments of Formula (V), (Va), or (Vb), p is 0, 1, 2, or 3. In some embodiments of Formula (V), (Va), or (Vb), p is 0, 1, or 2. In some embodiments of Formula (V), (Va), or (Vb), p is 1 or 2. In some embodiments of Formula (V), (Va), or (Vb), p is 0. In some embodiments of Formula (V), (Va), or (Vb), p is 1. In some embodiments of Formula (V), (Va), or (Vb), p is 2.

[0076] In some embodiments of Formula (V), (Va), or (Vb), R2and R3are each independnetly -CH2F, -CHF2, or -CF3. In some embodiments of Formula (V), (Va), or (Vb), R2and R3are each -CH2F. In some embodiments of Formula (V), (Va), or (Vb), R2and R3are each -CHF2. In some embodiments of Formula (V), (Va), or (Vb), R2and R3are each - CF3. In some embodiments of Formula (V), (Va), or (Vb), R2and R3are each -CH3.

[0077] In some embodiments of Formula (V), (Va), or (Vb), Rlais hydrogen, -CH3, -CH2F, -CHF, or -CF3. In some embodiments of Formula (V), (Va), or (Vb), Rlais hydrogen or - CH3. In some embodiments of Formula (V), (Va), or (Vb), Rlais -CH3.

[0078] In some embodiments of Formula (V), (Va), or (Vb), Rlbis -CH3, -CH2F, -CHF, or - CF3. In some embodiments of Formula (V), (Va), or (Vb), Rlbis -CH2F. In some embodiments of Formula (V), (Va), or (Vb), Rlbis -CHF. In some embodiments of Formula (V), (Va), or (Vb), Rlbis -CF3. In some embodiments of Formula (V), (Va), or (Vb), Rlbis - CH3.

[0079] In some embodiments of Formula (V), (Va), or (Vb), Rlaand Rlbare are each -F. In some embodiments of Formula (V), (Va), or (Vb), Rlaand Rlbare are each -CF3. In some embodiments of Formula (V), (Va), or (Vb), Rlaand Rlbare are each -CH3.

[0080] In some embodiments of Formula (V), (Va), or (Vb), Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl. In some embodiments of Formula (V), (Va), or (Vb), Rlaand Rlbtogether with the atom to which they are attached from a cyclopropyl.

[0081] In another aspect, provided herein is a compound of Formula (VI):Formula (VI) wherein:Z is -C=CH or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen or deuterium;R2and R3are each independently -CH or -CD3; each R5is independnetly hydrogen or deuterium;Ra, Rb, Rc, Rd, and Reare each independently hydrogen or deuterium; wherein one of Rla, Rlb, Ra, Rb, Rc, Rd, Reor R5is deuterium or one of R2or R3is -CD3; andX' is a counterion.

[0082] In some embodiments of Formula (VI), Z is -C=CH. In some embodiments of Formula (VI), Z is -CR5=C(R5)2.

[0083] In some embodiments, the compound is of Formula (Via):Formula (Via) wherein:Rlaand Rlbare each independently hydrogen or deuterium;R2and R3are each independently -CH3 or -CD3;Ra, Rb, Rc, Rd, and Reare each independently hydrogen or deuterium; wherein one of Rla, Rlb, Ra, Rb, Rc, Rdor Reis deuterium or one of R2or R3is -CD3; and X' is a counterion.

[0084] In some embodiments, the compound is of Formula (VIb):Formula (VIb) wherein:Rlaand Rlbare each independently hydrogen or deuterium;R2and R3are each independently -CH3 or -CD3; each R5is independently hydrogen or deuterium;Ra, Rb, Rc, Rd, and Reare each independently hydrogen or deuterium; wherein one of Rla, Rlb, Ra, Rb, Rc, Rd, Reor R5is deuterium or one of R2or R3is -CD3; andX' is a counterion

[0085] In some embodiments of Formula (VI) or (VIb), each R5is halogen. In some embodiments of Formula (VI) or (VIb), each R5is deuterium.

[0086] In some embodiments of Formula (VI), (Via), or (Via), Rlaand Rlbare both hydrogen or Rlaand Rlbare both deuterium. In some embodiments of Formula (VI), (Via), or (Via), Rlaand Rlbare both hydrogen. In some embodiments of Formula (VI), (Via), or (VIb), Rlaand Rlbare both deuterium.

[0087] In some embodiments of Formula (VI), (Via), or (VIb), R2and R3are both -CH3. In some embodiments of Formula (VI), (Via), or (VIb), R2and R3are both -CD3.

[0088] In some embodiments of Formula (VI), (Via), or (VIb), at least one of Ra, Rb, Rc, Rd, and Reis deuterium. In some embodiments of Formula (VI), (Via), or (VIb), at least two of Ra, Rb, Rc, Rd, and Reare deuterium. In some embodiments of Formula (VI), (Via), or (VIb), at least three of Ra, Rb, Rc, Rd, and Reare deuterium. In some embodiments of Formula (VI), (Via), or (VIb), at least four of Ra, Rb, Rc, Rd, and Reare deuterium.

[0089] In some embodiments of Formula (VI), (Via), or (VIb), each of Ra, Rb, Rc, Rd, and Reis deuterium.

[0090] In some embodimnets of Formula (VI), (Via), or (VIb), each of Ra, Rb, Rc, Rd, and Reis hydrogen

[0091] In some embodiments of Formula (VI), (Via), or (VIb), one of Rlaor Rlbis deuterium. In some embodiments of Formula (VI), (Via), or (VIb), Ra, Rb, Rc, Rd’ or Reis deuterium. In some embodiments of Formula (VI), (Via), or (VIb), one of R2or R3is -CD3.

[0092] In another aspect, provided herein is a compound of Formula (VII):Formula (VII) wherein:Z is -OCR5or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3. each R5is independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or - S(O)2O-; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX" is a counterion; provided the compound is not

[0093] In another aspect, provided herein is a compound of Formula (VIF):Formula (VIF) wherein:Z is -OCR5or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3.each R5is independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or -S(O)2‘ or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to5-membered heterocycloalkyl; and X' is a counterion; provided that the compound is not

[0094] In another aspect, provided herein is a compound of Formula (VIF):Formula (VII’) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3. each R5is independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or - S(O)2°-; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo;or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX' is a counterion; provided that the compound is not

[0095] In some embodiment of Formula (VII) or (VH’), Z is -C=CR5. In some embodiments of Formula (VII) or (VIF), Z is -CR5=C(R5)2.

[0096] In some embodiments, the compound is of Formula (VIF):Formula (VIF) wherein: Z is -C=CR5;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3; each R5is independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl or 4 to 5-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or - S(O)2°-; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX' is a counterion;provided that the compound is not

[0097] In some embodiments, the compound is of Formula (VIF):Formula (VII’) wherein: Z is -C=CR5;Rlaand Rlbare each hydrogen;R2and R3are each -CH3;R5is hydrogen;X' is a counterion.

[0098] In some embodiments, the compound is of Formula (VIF):Formula (VII’) wherein: Z is -C=CR5;Rlaand Rlbare each hydrogen;R2and R3are each -CH3;R5is hydrogen;X' is a counterion.

[0099] In some embodiments, the compound is of Formula (VIF):Formula (VIF) wherein: Z is -C=CR5;Rlaand Rlbare each hydrogen;R2and R3are each -CH3;R5is hydrogen;X' is a counterion.

[0100] In some embodiments, the compound is of Formula (VIF):Formula (VIF) wherein: Z is -C=CR5;Rlaand Rlbare each hydrogen;R2and R3are each -CH3;R5is hydrogen;X' is a counterion.

[0101] In some embodiments, the compound is of Formula (Vila’): wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3.R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or - S(O)2O’; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX' is a counterion.

[0102] In some embodiments, the compound is of Formula (Vila):Formula (Vila) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3.R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, or C1-C3 alkyl; or two R7combine together to form a C3-C6 cycloalkyl; and X' is a counterion.

[0103] In some embodiments, the compound is of Formula (Vllb’):Formula (Vllb’) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tertbutyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or - S(O)2O’; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl ;andX' is a counterion; provided that the compound is not

[0104]

[0105] In some embodiments, the compound is of Formula (Vllb’):Formula (Vllb’) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tertbutyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or - S(O)2O-; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl ;andX' is a counterion; provided that the compound is not

[0106] In some embodiments, the compound is of Formula (Vllb):Formula (Vllb) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3;or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to5-membered heterocycloalkyl ;andX' is a counterion; provided that the compound is not

[0107] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), R6is a 5-membered heteroaryl. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), R6is a 4-membered heterocycloalkyl. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), the 5-membered heterocycloalkyl is azetidine, oxetane, thietane oxide, thietane dioxide, oxetane-2-one, or azetidine-2-one.

[0108] In some embodiments of Formula (VIF), (Vila’), or (Vllb’), R6is, wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or -S(O)2O’; or two R7combine together with the atoms to which they are attached to form a C3-C6 cycloalkyl; or two R7combine together with the atoms to which they are attached to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O-;R7bis hydrogen or C1-C3 alkyl; and q is 1, 2, 3, 4, or 5.

[0109] In some embodiments of Formula (VIF), (Vila’), or (Vllb’), R6isorwherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or - S(O)2O’; or two R7combine together with the atoms to which they are attached to form a C3-C6 cycloalkyl; or two R7combine together with the atoms to which they are attached to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; and q is 1, 2, 3, 4, or 5.

[0110] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’),wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, or -CR7R7-; each R7is independently hydrogen, halogen, or C1-C3 alkyl; or two R7combine together with the atoms to which they are attached to form a C3-C6 cycloalkyl;R7ais hydrogen or C1-C3 alkyl; and q is 1, 2, 3, 4, or 5.

[0111] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’),

[0112] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’),

[0113] In some embodiments, the compound is of Formula (Vile’):Formula (Vile’) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0114] In some embodiments, the compound is of Formula (Vile’):Formula (Vile’) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen;R2and R3are each independently -CH3;R5is hydrogen; each R7is independently hydrogen, halogen, C1-C3 alkyl,;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl;q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0115] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W is -O- or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, or C1-C3 alkyl; or two R7combine together to form a C3-C6 cycloalkyl; q is 1, 2, 3, 4, or 5; and X' is a counterion.

[0116] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W is -O- or -CR7R7-;Rlaand Rlbare each independently hydrogen;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, or C1-C3 alkyl; or two R7combine together to form a C3-C6 cycloalkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0117] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W is -O- or -CR7R7-;Rlaand Rlbare each independently hydrogen;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen; each R7is independently hydrogen, halogen, or C1-C3 alkyl; or two R7combine together to form a C3-C6 cycloalkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0118] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W is -O- or -CR7R7-;Rlaand Rlbare each hydrogen;R2and R3are each -CH ;R5is hydrogen; each R7is independently hydrogen, halogen, or C1-C3 alkyl; or two R7combine together to form a C3-C6 cycloalkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0119] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W is -O-;Rlaand Rlbare each hydrogen;R2and R3are each -CH3;R5is hydrogen; each R7is independently hydrogen, halogen, or C1-C3 alkyl; or two R7combine together to form a C3-C6 cycloalkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0120] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W is -O-;Rlaand Rlbare each independently hydrogen;R2and R3are each independently -CH3;R5is hydrogen; each R7is independently hydrogen; q is 5; andX' is a counterion.

[0121] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W -CR7R7-;Rlaand Rlbare each independently hydrogen;R2and R3are each independently -CH ;R5is hydrogen; each R7is independently hydrogen, halogen, or C1-C3 alkyl; or two R7combine together to form a C3-C6 cycloalkyl; q is 1, 2, 3, 4, or 5; and X' is a counterion.

[0122] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W -CR7R7-;Rlaand Rlbare each independently hydrogen;R2and R3are each independently -CH ;R5is hydrogen; each R7is independently hydrogen or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0123] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W -CH2-;Rlaand Rlbare each independently hydrogen;R2and R3are each independently -CH3;R5is hydrogen; each R7is independently hydrogen or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0124] In some embodiments, the compound is of Formula (Vlld’):Formula (Vlld’) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, S+-O', -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0125] In some embodiments, the compound is of Formula (Vlld):Formula (Vlld) wherein:W is -O- or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently halogen, or C1-C3 alkyl; or two R7combine together to form a C3-C6 cycloalkyl; and q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0126] In some embodiments, the compound is of Formula (Vile):Formula (Vile) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl;or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; and X' is a counterion.

[0127] In some embodiments, the compound is of Formula (Vllf):Formula (Vllf) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen, -OH, or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

[0128] In some embodiments of Formula (Vila), (Vila’), (Vile), (Vile’), or (Vile), R5is hydrogen or -CH3. In some embodiments of Formula (Vila), (Vila’), (Vile), (Vile’), or (Vile), R5is hydrogen. In some embodiments of Formula (Vila), (Vila’), (Vile), or (Vile’), R5is -CH3.

[0129] In some embodiments of Formula (Vllb), (VHb’), (Vlld), (Vlld’), or (Vllf), R5a, R5b, and R5care each independently hydrogen, -F, -CH3, -CH2F, -CHF2, or -CF3. In someembodiments of Formula (Vllb), (Vllb’), (Vlld), (Vlld’), or (Vllf), R5a, R5b, and R5care each independently hydrogen, -F, -CH2F, -CHF2, or -CF3. R5a, R5b, and R5care each independently hydrogen or -CH3. In some embodiments of Formula (Vllb), (Vllb’), (Vlld), (Vlld’), or (Vllf), R5a, R5b, and R5care each hydrogen.

[0130] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vile’), (Vile), (Vlld), (Vlld’), (Vile), or (Vllf), R2and R3are each independnetly -CH2F, -CHF2, or -CF3. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), R2and R3are each -CH2F. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), R2and R3are each -CHF2. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), R2and R3are each - CF3. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), R2and R3are each -CH3.

[0131] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), Rlaand Rlbare each independently hydrogen, -CH3, -CH2F, -CHF, or -CF3. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), Rlaand Rlbare each independently -F, -CH2F, -CHF, or -CF3. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), Rlaand Rlbare each independently hydrogen or -CH3. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), Rlaand Rlbare each -CH3. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), Rlaand Rlbeach hydrogen.

[0132] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), Rlaand Rlbtogether with the atom to which they are attached from a cyclopropyl.

[0133] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), W is -O- or -CR7R7-. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), W is -O-. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), W is -CR7R7-. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’),(Vlld), (Vlld’), (Vile), (Vllf), W is -CF2-. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), W is -CH2-. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), W is -NR7a-. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), W is -S-, - S(O)-, or -S(O)2-. In some embodiments of Formula (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), W is -S-, -S(O)-, -S(O)2-, or -S(O)(=NR7b)-. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), or (Vllb’), W is -S-. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), W is -S(O)-. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), W is -S(O)2-. In some embodiments of Formula (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), W is -S(O)(=NR7b)-.

[0134] In some embodiments of Formula (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), (Vllf), each R7is independently -S(O)2CH3 or -S(O)2O'. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), each R7is independently hydrogen or halogen. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), each R7is independently halogen. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), each R7is independently -F. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), each R7is independently hydrogen.

[0135] In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vile), two R7combine together with the atoms to which they are attached to form a C3-C6 cycloalkyl. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), two R7combine together with the atoms to which they are attached to form a C4-C5 cycloalkyl. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), two R7combine together with the atoms to which they are attached to form a cyclobutyl or cyclopentyl. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), two R7combine together with the atoms to which they are attached to form a cyclobutyl. In some embodiments of Formula (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), two R7combine together with the atoms to which they are attached to form a cyclopentyl.

[0136] In some embodiments of Formula (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), two R7combine together with the atoms to which they are attached to form an oxo.

[0137] In some embodiments of Formula (VH’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), two R7combine together with the atoms to which they are attached to form an alkylene bridge. In some embodiments of Formula (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), two R7combine together to form a C1-C3 alkylene bridge. In some embodiments of Formula (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), two R7combine together to form a C1-C2 alkylene bridge. In some embodiments of Formula (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), two R7combine together to form a Ci alkylene bridge. In some embodiments of Formula (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), two R7combine together to form a Ci bridge across a cyclobutene to form bicyclopentane.

[0138] In some embodiments of Formula (VH’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), R7ais C1-C3 alkyl. In some embodiments of Formula (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), R7ais methyl. In some embodiments of Formula (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), R7ais -OH, -S(O)2CH3, or -S(O)2O’. In some embodiments of Formula (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), R7ais -S(O)2CH3or -S(O)2O'. In some embodiments of Formula (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), R7ais -OH. In some embodiments of Formula (VIF), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), R7ais hydrogen.

[0139] In some embodiments of Formula (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), R7bis C1-C3 alkyl. In some embodiments of Formula (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), or (Vllf), R7bis methyl. In some embodiments of Formula (VII’), (Vila’), (Vllb’), (Vile’), (Vlld’), (Vile), of (Vllf), R7bis hydrogen.

[0140] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), q is 1, 2, or 3. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), q is 1 or 2. In some embodiment of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), q is 1. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), q is 2. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), q is 3. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), or (Vllf), q is 4.

[0141] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’),embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), R6isIn a preferred embodiment, when R6is, the non-hydrogen. , , , , , ’),, , , . , IF),(Vila), (Vila’), (Vllb), or (Vllb’), R6is[n SOme embodiments of Formula(VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), R6is<° . in some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), R6is. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), R6isIn some embodiments of Formula (VII), (Vila), (Vila’), (Vllb), or (Vllb’), R6is< S

[0142] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), R6is a 6-membered heteroaryl. In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), the 6-membered heteroaryl is tetrahydrofuran, pyrrolidine, tetrahydrothiophene oxide, or tetrahydrothiophene dioxide.

[0143] In some embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’),embodiments of Formula (VII), (VIF), (Vila), (Vila’), (Vllb), or (Vllb’), R6is(, ,(VII), (VIF), (Vila), (Vila’), (Vllb),

[0144] In another aspect, provided herein is a compound of Formula (VIII):Formula (VIII) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3;or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; each R5aR5band R5care independently hydrogen, deuterium, -F, -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; andX' is a counterion;

[0145] In some embodiments of Formula (VIII), Rlaand Rlbare not each hydrogen.

[0146] In some embodiments of Formula (VIII), Rlaand Rlbare each independently hydrogen, -CH3, or -CF3. In some embodiments of Formula (VIII), Rlaand Rlbare each independently hydrogen or -CH3. In some embodiments of Formula (VIII), Rlaand Rlbare each hydrogen.

[0147] In some embodiments of Formula (VIII), R2and R3are each independently -CH3, - CH2F, -CHF2, or -CF3. In some embodiments of Formula (VIII), R2and R3are each independently -CH2F, -CHF2, or -CF3. In some embodiments of Formula (VIII), R2and R3are each independently -CH3 or -CF3. In some embodiments of Formula (VIII), R2and R3are each -CF3. In some embodiments of Formula (VIII), R2and R3are each -CH3.

[0148] In some embodiments of Formula (VIII), R5ais hydrogen, deuterium, -F, or -CH3. In some embodiments of Formula (VIII), R5ais hydrogen. In some embodiments of Formula of Formula (VIII), R5ais -F. In some embodiments of Formula (VIII), R5ais -CH3.

[0149] In some embodiments of Formula (VIII), R5bis hydrogen, deuterium, -F, or -CH3.In some embodiments of Formula (VIII), R5bis hydrogen. In some embodiments of Formula (VIII), R5bis -F. In some embodiments of Formula (VIII), R5bis -CH3.

[0150] In some embodiments of Formula (VIII), R5cis hydrogen, deuterium, -F, or -CH3. In some embodiments of Formula (VIII), R5cis hydrogen. In some embodiments of Formula (VIII), R5Cis -F. In some embodiments of Formula (VIII), R5cis -CH3.

[0151] In another aspect, provided herein is a compound of Formula (IX):Formula (IX) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; R2and R3are each independently -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; each R4is independently deuterium, -F, or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

[0152] In some embodiments of Formula (IX), R2and R3are each independently -CH3, - CH2F, -CHF2, or -CF3. In some embodiments of Formula (IX), R2and R3are each independently -CH2F, -CHF2, or -CF3. In some embodiments of Formula (IX), R2and R3are each independently -CH3 or -CF3. In some embodiments of Formula (IX), R2and R3are each -CF3. In some embodiments of Formula (IX), R2and R3are each -CH3.

[0153] In some embodiments of Formula (IX), Rlaand Rlbare each independently hydrogen, -CH3, or -CF3. In some embodiments of Formula (IX), Rlaand Rlbare each independently hydrogen or -CH3. In some embodiments of Formula (IX), Rlaand Rlbare each hydrogen.

[0154] In some embodiments of Formula (IX), Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl. In some embodiments of Formula (IX), Rlaand Rlbtogether with the atom to which they are attached from a cyclopropyl.

[0155] In some embodiments of Formula (IX), p is 0, 1, 2, 3, or 4. In some embodiment of Formula (IX), p is 0, 1, 2, or 3. In some embodiments of Formula (IX), p is 2. In some embodiments of Formula (IX), p is 1. In some embodiments of Formula (IX), p is 0.

[0156] In another aspect, provided herein is a compound of Formula (X):Formula (X) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R3is -CH3, -CH2F, -CHF2, or -CF3; each R4is independently deuterium, -F, or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

[0157] In some embodiments of Formula (X), Rlaand Rlbare each independently hydrogen, -CH3, or -CF3. In some embodiments of Formula (X), Rlaand Rlbare each independently hydrogen or -CH3. In some embodiments of Formula (X), Rlaand Rlbare each hydrogen.

[0158] In some embodiments of Formula (X), R3is -CH3 or -CH2F. In some embodiments of Formula (X), R3is -CH3. In some embodiments of Formula (X), R3is -CH2F.

[0159] In some embodiments of Formula (X), p is 0, 1, 2, 3, or 4. In some embodiment of Formula (X), p is 0, 1, 2, or 3. In some embodiments of Formula (X), p is 2. In some embodiments of Formula (X), p is 1. In some embodiments of Formula (X), p is 0.

[0160] In another aspect, provided herein is a compound of Formula (XI):Formula (XI) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R3is -CH3, -CH2F, -CHF2, or -CF3;each R4is independently deuterium, -F, or -CH3; p is 0, 1, 2, 3, 4, or 5; and X' is a counterion.

[0161] In some embodiments of Formula (XI), Rlaand Rlbare each independently hydrogen, -CH3, or -CF3. In some embodiments of Formula (XI), Rlaand Rlbare each independently hydrogen or -CH3. In some embodiments of Formula (XI), Rlaand Rlbare each hydrogen.

[0162] In some embodiments of Formula (XI), R3is -CH3 or -CH2F. In some embodiments of Formula (XI), R3is -CH3. In some embodiments of Formula (XI), R3is -CH2F.

[0163] In some embodiments of Formula (XI), p is 0, 1, 2, 3, or 4. In some embodiment of Formula (XI), p is 0, 1, 2, or 3. In some embodiments of Formula (XI), p is 2. In some embodiments of Formula (XI), p is 1. In some embodiments of Formula (XI), p is 0.

[0164] In another aspect, provided herein is a compound of Formula (XII):Formula (XII) wherein:W is -S-, -S(O)2- or -S(O)-; each R7is independently halogen, C1-C3 alkyl, or -OH;R8is C1-C3 alkyl, C1-C3 haloalkyl, or cyclopropyl; q is 0, 1, 2, 3, 4, or 5; and X' is a counterion.

[0165] In some embodiments of Formula (XII), W is -S(O)2- or -S(O)-. In some embodiments of Formula (XII), W is -S(O)2-. In some embodiments of Formula (XII), W is - S(O)-.

[0166] In some embodiments of Formula (XII), each R7is independently halogen or C1-C3 alkyl. In some embodiments of Formula (XII), each R7is independently halogen. In some embodiments of Formula (XII), each R7is independently C1-C3 alkyl.

[0167] In some emboidment of Formula (XII), q is 0, 1, or 2. In some embedments of Formula (XII), q is 0. In some embobodiments of Formula (XII), q is 1. In some embodiments of Formula (XII), q is 2.

[0168] In some embodiments of Formula (XII), R8is C1-C3 alkyl, C1-C3 haloalkyl. In some embodiments of Formula (XII), R8is C1-C3 alkyl. In some embodiments of Formula (XII), R8is C1-C3 haloalkyl. In some embodiments of Formula (XII), R8is -CH3, -CH2F, -CHF2, -CF3 - CH2CH3, -CH(CH3)2, -CH2CH2F, or cyclopropyl.

[0169] In another aspect, provided herein is a compound of Formula (XIII):Formula (XIII) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; R2is -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, -F, -CH3, -CH2F, -CHF2, or -CF3; each R9is independently halogen, C1-C3 alkyl, or -OH; or two R9together with the atoms to which they are attached form a 4 to 5 membered heterocycoalkyl; q is 1, 2, 3, 4, or 5; and X' is a counterion.

[0170] In some embodiments of Formula (XIII), Rlaand Rlbare each independently hydrogen, -F, or -CH3. In some embodiments of Formula (XIII), Rlaand Rlbare each independently hydrogen or -CH3. In some embodiments of Formula (XIII), Rlaand Rlbare each hydrogen. In some embodiments of Formula (XIII), Rlaand Rlbare each -CH3.

[0171] In some embodiments of Formula (XIII), Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl.

[0172] In some embodiments of Formula (XIII), R2is -CH3 or -CHF2. In some embodiments of Formula (XIII), R2is -CH3.

[0173] In some embodiments of Formula (XIII), R5is hydrogen.

[0174] In some embodiments of Formula (XIII), two R9together with the atoms to which they are attached form a 4 to 5 membered heterocycoalkyl. In some embodiments of Formula (XIII), two R9together with the atoms to which they are attached form a 4 membered heterocycoalkyl wherein the heteroatoms are selected from O, N, S, S(O)2, and S(O).

[0175] In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’),(Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX),(X), (XI), (XII), and (XIII) selected from:

[0176] In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX),(X), (XI), (XII), or (XIII), wherein X is a counterion selected from chloride, bromide, iodide, sulfate, sulfonate, trifluromethanesulfonate, phosphate, tartrate, citrate, acetate, fumarate, succinate, mesylate, lactate, and stearate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb),(VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X' is chloride.Preferably, X is chloride. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is bromide. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is iodide. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb),(VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf),(VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is sulfate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII),wherein X is sulfonate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is triflurom ethanesulfonate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is phosphate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X' is tartrate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is citrate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X' is acetate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is fumarate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is succinate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is mesylate. In some embodiments is a compound of Formula (I), (la),(lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X' is lactate. In some embodiments is a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein X is stearate. Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0177] In another aspect, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0178] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0179] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0180] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36C1. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In someembodiments, one or more hydrogen atoms of the compounds described herein is replaced with deuterium.

[0181] In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0182] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0183] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. The prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, ortherapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0184] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113- 191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.

[0185] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound. In some embodiments, a prodrug of the compound disclosed herein permits targeted delivery of the compound to a particular region of the gastrointestinal tract. Formation of a pharmacologically active metabolite by the colonic metabolism of drugs is a commonly used “prodrug” approach for the colon-specific drug delivery systems.

[0186] In some embodiments, a prodrug is formed by the formation of a covalent linkage between drug and a carrier in such a manner that upon oral administration the moiety remains intact in the stomach and small intestine. This approach involves the formation of a prodrug, which is a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in the biological environment to release the active drug. Formation of prodrugs has improved delivery properties over the parent drug molecule.The problem of stability of certain drugs from the adverse environment of the upper gastrointestinal tract can be eliminated by prodrug formation, which is converted into the parent drug molecule once it reaches the colon. Site specific drug delivery through site specific prodrug activation may be accomplished by the utilization of some specific property at the target site, such as altered pH or high activity of certain enzymes relative to the nontarget tissues for the prodrug-drug conversion.

[0187] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0188] A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

[0189] In additional or further embodiments, the compounds are rapidly metabolized in plasma. In additional or further embodiments, the compounds are rapidly metabolized by the intestines. In additional or further embodiments, the compounds are rapidly metabolized by the liver.Synthesis of Compounds

[0190] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0191] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0192] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wileyand Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared.

[0193] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley- VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0194] In some embodiments, compounds are prepared as described in the Examples.Certain Terminology

[0195] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0196] As used herein, Ci-Cxincludes C1-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso- propyl, / / -butyl, Ao-butyl, .scc-butyl, and / -butyl.

[0197] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a Ci-Cioalkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g. , “ 1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a Ci-Cealkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0198] An “alkylene” group refers to a divalent alkyl group. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a Ci-Cealkylene. In other embodiments, an alkylene is a Ci-C4alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C2 alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C4 alkylene). Typical alkylene groups include, but are not limited to, -CH2-, - CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, - CH2CH2CH2CH2-, and the like.

[0199] “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.

[0200] The term “alkenyl” refers to a type of alkyl group in which at least one carboncarbon double bond is present. In one embodiment, an alkenyl group has the formula - C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (z.e., vinyl), propenyl (z.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, - C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0201] The term “alkynyl” refers to a type of alkyl group in which at least one carboncarbon triple bond is present. In one embodiment, an alkenyl group has the formula -C=C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C=CH, - C=CCH3-C=CCH2CH3, -CH2C=CH.

[0202] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0203] The term “alkylamine” refers to the -N(alkyl)xHygroup, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[0204] The term “aromatic” refers to a planar ring having a delocalized 7i-electron system containing 4n+2 % electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (z.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.

[0205] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.

[0206] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a Ce-Cioaryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0207] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic group, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Insome embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fully saturated. In some embodiments, cycloalkyls are partially unsaturated. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[l. l.l]pentyl. In some embodiments, a cycloalkyl is a Cs-Cecycloalkyl. In some embodiments, a cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (z.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0208] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0209] The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, a fluoroalkyl is a Ci-Cefluoroalkyl.

[0210] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a Ci-Cefluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0211] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci- Ceheteroalkyl.

[0212] The term “heteroalkylene” refers to a divalent heteroalkyl group.

[0213] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) includerings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-l-onyl, isoindoline- 1, 3-dionyl, 3,4-dihydroisoquinolin-l(2H)-onyl, 3,4- dihydroquinolin-2(lH)-onyl, isoindoline-1, 3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or TV-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-l-yl (TV-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0214] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole,benzotriazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a Ci-Cgheteroaryl. In some embodiments, monocyclic heteroaryl is a Ci-Csheteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a Ce-Cgheteroaryl.

[0215] A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyls are spirocyclic or bridged compounds. In some embodiments, heterocycloalkyls are fully saturated. In some embodiments, heterocycloalkyls are partially unsaturated. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrroli di nonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2- onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4- Cioheterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0216] " Counterion" refers to an ion that accompanies an ionic species in order to maintain electrical neutrality. In certain embodiments disclosed herein, the counterion is an anion having a I" or 2’ charge. In certain embodiments disclosed herein, the counterion is an anion selected from, but not limited to, chloride, bromide, iodide, sulfate, phosphate, tartrate, citrate, acetate, fumarate, succinate, mesylate, lactate, and stearate.

[0217] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moi eties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0218] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0219] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). In some other embodiments, optional substituents are individually and independently selected from D, halogen, -CN, - NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), - C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -CH2CO2H, - CH2CO2alkyl, -CH2C(=O)NH2, -CH2C(=O)NH(alkyl), -CH2C(=O)N(alkyl)2, - CH2S(=O)2NH2, - CH2S(=O)2NH(alkyl), - CH2S(=O)2N(alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, - C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, - CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), -C(=O)NH2, - C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), - S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-Cecycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci- C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci-C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, - NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[0220] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0221] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, toenhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0222] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.

[0223] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0224] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0225] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0226] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancingeffective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0227] The terms “kit” and “article of manufacture” are used as synonyms.

[0228] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0229] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.Pharmaceutical compositions

[0230] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0231] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.

[0232] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0233] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0234] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unitdose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0235] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0236] Pharmaceutical compositions may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0237] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0238] Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0239] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0240] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w, for instance from 1% to 2% by weight of the formulation.

[0241] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0242] In some embodiments, a compound disclosed herein is formulated to provide a controlled release of the compound. Controlled release refers to the release of the compound described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period oftime and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.

[0243] Approaches to deliver the intact therapeutic compound to the particular regions of the gastrointestinal tract (e.g., such as the colon), include:

[0244] (i) Coating with polymers: The intact molecule can be delivered to the colon without absorbing at the upper part of the intestine by coating of the drug molecule with the suitable polymers, which degrade only in the colon.

[0245] (ii) Coating with pH-sensitive polymers: The majority of enteric and colon targeted delivery systems are based on the coating of tablets or pellets, which are filled into conventional hard gelatin capsules. Most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, more specifically Eudragit®L and Eudragit® S. Eudragit® LI 00 and S 100 are copolymers of methacrylic acid and methyl methacrylate. Additional pH-dependent coating polymers include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP) and cellulose acetate trimelliate.

[0246] (iii) Coating with biodegradable polymers;

[0247] (iv) Embedding in matrices;

[0248] (v) Embedding in biodegradable matrices and hydrogels;

[0249] (vi) Embedding in pH-sensitive matrices;

[0250] (vii) Timed release systems;

[0251] (viii) Redox-sensitive polymers;

[0252] Bioadhesive systems;

[0253] Coating with microparticles;

[0254] Osmotic controlled drug delivery.

[0255] Another approach towards colon-targeted drug delivery or controlled-release systems includes embedding the drug in polymer matrices to trap it and release it in the colon. These matrices can be pH-sensitive or biodegradable. Matrix-Based Systems, such as multi-matrix (MMX)-based delayed-release tablets, ensure the drug release in the colon.

[0256] Additional pharmaceutical approaches to targeted delivery of therapeutics to particular regions of the gastrointestinal tract are known. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Sci. 2003 Jan- Apr; 6(l):33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems Crit Rev Ther Drug Carrier Syst. 2007; 24(2): 147-202. Kumar P, Mishra B. Colon targeted drug delivery systems-an overview. Curr Drug Deliv. 2008 Jul; 5(3): 186-98. Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv. 2006 Jan; 3(1): 111-25. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech. 2015 Aug; 16(4): 731-741.

[0257] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.Methods of Dosing and Treatment Regimens

[0258] In some embodiments, described herein is a method of treating a chronic kidney disease, a cardiovascular disease, obesity, diabetes, a metabolic disorder, a hepatic disorder, hypertension, resistant hypertension, frailty, or sarcopenia in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII).

[0259] In some embodiments, described herein is a method of treating a kidney disease or a cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII).

[0260] In some embodiments, described herein is a method of treating a kidney disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII). In some embodiments, described herein is a method of treating a kidney disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein the kidney disease is selected from, but is not limited to, reduced or impaired kidney function, chronic kidney disease, end-stage renal disease, and renal impairment associated with diabetes mellitus. In some embodiments, described herein is amethod of treating a kidney disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein the kidney disease is selected from reduced or impaired kidney function, chronic kidney disease, end-stage renal disease, and renal impairment associated with diabetes mellitus.

[0261] In some embodiments, described herein is a method of treating a cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII). In some embodiments, described herein is a method of treating a cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein the cardiovascular disease is selected from atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure, cardiomyopathy, atherothrombotic disease, aorto-iliac disease, and peripheral vascular disease. In some embodiments, complications associated with cardiovascular disease include, but are not limited to, myocardial infarction, stroke, angina pectoris, acute coronary syndrome, transient ischemic attacks, congestive heart failure, aortic aneurysm, atrial fibrillation or flutter, ventricular arrhythmias, cardiac conduction abnormalities, need for revascularization and death. In some embodiments, revascularization includes but is not limited to angioplasty, stenting, coronary artery bypass grafting, repair or replacement of vascular shunt or access such as an arteriovenous fistula. In some embodiments, complications associated with atherothrombotic disease include, but are not limited to, myocardial infarction, stroke, pulmonary embolism, deep venous thrombosis.

[0262] In some embodiments, described herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein the disease is associated with elevated levels of trimethylamine (TMA) or trimethylamine N-oxide (TMAO). In someembodiments, described herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile) (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein the disease is associated with elevated levels of trimethylamine (TMA). In some embodiments, described herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein the disease is associated with elevated levels of trimethylamine N-oxide (TMAO).

[0263] In some embodiments, described herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII), wherein the disease is associated with a decreased conversion of trimethylamine (TMA) or trimethylamine N-oxide (TMAO).

[0264] In some embodiments, described herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (VIII), (Vile), (Vllf), (IX), (X), (XI), (XII), or (XIII), wherein the disease is associated with a high ratio of trimethylamine (TMA) or trimethylamine N-oxide (TMAO).

[0265] In some embodiments, described herein is a method of reducing the production of trimethylamine (TMA) or trimethylamine-N-oxide (TMAO) in a subject in need thereof, comprising administering to the mammal a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (Hd), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII). In some embodiments, described herein is a method of reducing the production of trimethylamine (TMA) in a subject in need thereof, comprising administering to the mammal a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VIF), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII). In some embodiments, described herein is a method of reducing theproduction of trimethylamine-N-oxide (TMAO) in a subject in need thereof, comprising administering to the mammal a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII).

[0266] In some embodiments, described herein is a method of inhibiting the conversion of choline to trimethylamine (TMA) and reducing trimethylamine-N-oxide (TMAO) level in a subject in need thereof, comprising administering to the mammal a compound of Formula (I), (la), (lb), (Ila), (lIb), (lIe), (lId), (III), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (VII’), (Vila), (Vila’), (Vllb), (Vllb’), (Vile), (Vile’), (Vlld), (Vlld’), (Vile), (Vllf), (VIII), (IX), (X), (XI), (XII), or (XIII).

[0267] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0268] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein in order to prevent a return of the symptoms of the disease or condition.

[0269] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion, the compounds are administered chronically, that is, for an extendedperiod of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0270] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (z.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0271] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder, or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0272] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0273] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0274] In one embodiment, the daily dosages appropriate for the compound described herein are from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individualsubject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0275] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[0276] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non-systemically or locally to the mammal.

[0277] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.

[0278] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose;(ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended, or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0279] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors(e.g., the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[0280] The compounds described herein as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.EXAMPLES

[0281] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0282] All chemicals, reagents and solvents are obtained from common commercial vendors, such as Sigma-Aldrich, Fisher Scientific, and Enamine. Indicated reaction temperatures refer to those of the reaction bath, while room temperature (rt) is noted as 25°C. Analytical thin layer chromatography (TLC) is performed with glass backed silica plates (20x 20 cm, pH = 5, MF254). Visualization is accomplished using a 254 nm UV lamp. 'H spectra are recorded on a spectrometers using solutions of samples in DMSO-d6 or other commercially available deuterated solvents, as noted. Chemical shifts are reported in ppm, often with tetramethyl silane as standard. Data are reported as follows: chemical shift, number of protons, multiplicity (s = singlet, d = doublet, dd = doublet of doublet, t = triplet, q = quartet, b = broad, m = multiplet). All novel compounds are characterized by1H-NMR and mass spectroscopy (MS).

[0283] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:ACN or MeCN acetonitrile aq. aqueousDMSO dimethyl sulfoxideDCM di chloromethane eq. equivalent(s)THF tetrahydrofuran h hour(s) min minute(s)HPLC high performance liquid chromatographyDMF dimethylformamideEtOH ethanolMeOH methanolSynthesis of Compounds

[0284] The compounds described herein are generally made via alkylation of a tertiary amine to make a quaternary amine, most commonly with an alkyl halide (although other alkylating agents will be acceptable).

[0285] If not commercially available, the tertiary amine is made from a primary amine via two alkylation steps, either by alkylation with alkyl halides (or other suitable alkylating agents) or by reductive alkylation of the amine with an aldehyde.Example 1: Synthesis of 3,3-difluoro-N,N-dimethyl-N-(prop-2-yn-l-yl)cyclobutan-l- aminium chloride

[0286] To a solution of compound 3,3-difluorocyclobutan-l-amine (2.0 g, 18.7 mmol, 1.0 eq) in methanol (100 mL) were added 37% HCHO in water (8.5 g, 74.8 mmol, 4.0 eq.) and acetic acid (112 mg, 1.8 mmol, 0.1 eq.). The mixture was stirred at r.t. for 30 mins. The mixture was added NaBHsCN (8.3 g, 131.0 mmol, 7.0 eq.) and stirred at rt overnight. The reaction was concentrated under reduced pressure. The residue was purified with column chromatography on silica gel (DCM / MeOH = 1 / 0 to 80 / 1) to afford compound 3,3-difluoro- N,N-dimethylcyclobutan-l -amine (1.6 g, 64%) as yellow oil. LCMS: 136.1 [M+l]+.

[0287] To a solution of compound 3,3-difluoro-N,N-dimethylcyclobutan-l-amine (1.6 g, 11.8 mmol, 1.0 eq.) in acetone (20 mL) was added propargyl chloride (2.7 g, 35.4 mmol, 3.0 eq.). The mixture was stirred at r.t. for 7 days. The reaction was concentrated under reduced pressure. The residue was poured into acetone (10 mL) and hexane was added (5 mL). The resulting suspension was then stored at 4 °C for 24 hrs. The solid product was collected byExample 2: Synthesis of N-(tert-butyl)-N,N-dimethylprop-2-yn-l-aminium chloride

[0288] To a solution of N-( / cv7- / w / j7)-N,N-dimethylamine (500 mg, 4.9 mmol, 1.0 eq) inExample 3: Synthesis of N,N-dimethyl-N-(prop-2-yn-l-yl)oxetan-3-aminium chloride

[0289] A mixture of formaldehyde solution (22.18 g, 273.61 mmol, 5.0 eq, 37%) and HCOOH (15.11 g, 328.34 mmol, 6.0 eq.) was stirred at 55 °C for Ih. To the above mixture was added oxetan-3 -amine (4.00 g, 54.72 mmol, 1.0 eq.) dropwise over 0.5h at 55 °C. The resulting mixture was stirred at 55 °C for an additional 17 h. The resulting mixture was poured into ice water (100 mL). The mixture was basified to pH 14 with sat. NaOH (aq.) (50 mL). The aqueous layer was extracted with DCM (2 x 100 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was used in the next step directly without further purification LC / MS: mass cal cd. For C5H11NO: 101.08, found: 102.05 [M+H]+.

[0290] To a stirred solution of N,N-dimethyloxetan-3-amine (2.80 g crude, 27.68 mmol, 1.0 eq.) in MeCN (30.00 mL) was added propargyl chloride (4.13 g, 55.36 mmol, 2.0 eq) at 25 °C. The resulting mixture was stirred at 55 °C for 2 h. After cooling to r.t., the precipitated solids were collected by filtration and washed with MeCN (10 mL) and then dried under vacuum to afford N,N-dimethyl-N-(prop-2-yn-l-yl)oxetan-3-aminium chloride (43.5% yield)Example 4: Synthesis of N,N-dimethyl-N-(prop-2-yn-l-yl)bicyclo[l.l.l]pentan-l- aminium chloride

[0291] To a solution of bicyclo[ 1.1.1 ]pentan-l -amine (1.0 g, 12 mmol, 1.0 eq) in formic acid (10 mL) was added 37% formaldehyde solution (10 mL) at 0 °C. The mixture was stirred at 110 °C for 16 h. HC1 solution (2 M, 20 mL) was added at 0 °C and stirred for 2 h. The residue was concentrated under reduced pressure to afford N,N- dimethylbicyclo[l.l. l]pentan-l -amine HC1 salt (1.3 g, 73%) as a white solid.

[0292] To a solution of N,N-dimethylbicy clo[ 1.1.1 ]pentan-l -amine HC1 (1.3 g, 11.69 mmol, 1.0 eq.) in acetone (20 mL) was added NaHCCL (3.2 g, 38 mmol, 3.0 eq.). The mixture was stirred at r.t. for 16 h. The mixture was filtered. To the filtrate was added propargyl chloride (3.2 g, 35.08 mmol, 3.0 eq). The reaction mixture was stirred at r.t. for 72 h. The mixture was filtered, washed with acetone and dried to afford N,N-dimethyl-N-(prop-2-yn-l-yl)bicyclo[l.l. l]pentan-l-aminium chloride (1.3 g, 59%) as a white solid. 'H NMR (400 MHz, DMSO-tL) d 4.37 (d, J= 2.6 Hz, 2H), 4.06 (t, J= 2.5 Hz, 1H), 3.02 (s, 6H), 2.78 (s, 1H), 2.15 (s, 6H).Example 5: Synthesis of N,N-bis(methyl-d3)-N-(prop-2-yn-l-yl)cyclopropanaminium chloride,

[0293] To a solution of tert-butyl cyclopropylcarbamate (5.0 g, 31.8 mmol, 1.0 eq) in THF (100 mL) at 0 °C was added NaH (60%, 3.2 g, 79.5 mmol, 2.5 eq.). The mixture was stirred at r.t. for 30 min. To the mixture was added propargyl bromide (5.7 g, 47.7 mmol, 1.5 eq.). The mixture was stirred at r.t. overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 * 300 mL) and solvents removed under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH = 1 / 0 to 90 / 1) to afford tert-butyl cyclopropyl(prop-2-yn-l-yl)carbamate (3.0 g, 48%) as a yellow oil.

[0294] To a solution of tert-butyl cyclopropyl(prop-2-yn-l-yl)carbamate (620 mg, 3.1 mmol, 1.0 eq.) in methanol (5 mL) was added 4 M HC1 in dioxane (10 mL). The mixture was stirred at r.t. for 1 hr. The reaction was concentrated under reduced pressure to afford N- (prop-2-yn-l-yl)cyclopropanamine (305 mg, crude) as a white solid.

[0295] To a solution of N-(prop-2-yn-l-yl)cyclopropanamine (305 mg, 3.2 mmol, 1.0 eq) in acetonitrile (10 mL) were added potassium carbonate (1.3 g, 9.6 mmol, 3.0 eq.) and CD3I (1.4 g, 9.6 mmol, 3.0 eq.). The mixture was stirred at 50 °C in a sealed tube overnight. The reaction was filtered and the filtrate was concentrated under reduced pressure. The solid wasExample 6: Synthesis of N-(but-2-yn-l-yl)-N,N-dimethylcyclopropanaminium bromider.t.,

[0296] To a solution of N,N-dimethyl cyclohexylamine (1.0 g, 8.2 mmol, 1.0 eq) in acetone (10 mL) was added NaHCCh (2.1 g, 24.6 mmol, 3.0 eq). The mixture was stirred at r.t. for 16 h. The mixture was filtered. To the filtrate was added l-bromobut-2-yne (2.2 g, 16.5 mmol, 2.0 eq.). The mixture was stirred at r.t. for 16 h. The mixture was concentrated and theExample 7: Synthesis of N,N-dimethyl-N-(prop-2-yn-l-yl)cyclobutanaminium chloride

[0297] A mixture of formaldehyde solution (2.28 g, 28.12 mmol, 5.00 eq., 37%) and HCOOH (1.55 g, 33.74 mmol, 6.00 eq.) was stirred at 55 °C for 1.0 h. To the above mixture was added cyclobutylamine (400.0 mg, 5.62 mmol, 1.0 eq.) dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for an additional 17 h. The reaction was quenched by the addition of PhMe (10 mL) at 0 °C. The mixture was basified to pH 14 with sat. NaOH

[0298] To a stirred solution of N,N-dimethylcyclobutanamine (400.0 mg crude, 4.03 mmol, 1.00 eq., in 20.00 mL PhMe) in MeCN (5.00 mL) was added propargyl chloride (601.0 mg, 8.07 mmol, 2.0 eq) at 25 °C. The resulting mixture was stirred at 55 °C for 2 h. After cooling to r.t. and standing for 0.5 h, the reaction system was separated into solvent phase and oil phase. The oil phase was separated and dried under vacuum. N,N-dimethyl-N-(prop-2-yn-l- yl)cyclobutanaminium chloride (18%yield) was obtained as a yellow semi-solid. LC / MS:mass calcd. For C9HI6N: 138.13, found: 138.10 [M]+.JH NMR (400 MHz, DMSO-tL) 8: 4.40 (s, 1H), 4.17 - 4.28 (m, 1H), 4.08 (s, 1H), 3.03 (s, 6H), 2.34 - 2.47 (m, 2H), 2.02 - 2.14 (m, 2H), 1.67 - 1.77 (m, 1H), 1.54 - 1.65 (m, 1H).Example 8: Synthesis of (lR,2S)-2-fluoro-N,N-dimethyl-N-(prop-2-yn-l- yl)cyclopropan-l-aminium trifluoromethanesulfonate

[0299] To a solution of (lR,2S)-2-fluorocyclopropan-l-amine (1.3 g, 17.31 mmol, 1.0 eq.) in DCM (20 mL) were added BOC2O (3.74 g, 17.2 mmol, 1.0 eq.) and TEA(5.24 g, 51.9 mmol, 3.0 eq) at r.t. The reaction mixture was stirred at r.t. for 4 h under N2. The reaction solution was quenched with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (PEZEA = 3 / 1) to afford tert-butyl ((lR,2S)-2-fluorocyclopropyl)carbamate (1.75 g, 59%) as a white solid.

[0300] To a solution of tert-butyl ((lR,2S)-2-fluorocyclopropyl)carbamate (500 mg, 2.85 mmol, 1.0 eq.) in acetonitrile (10 mL) were added propargyl bromide (509 mg, 4.28 mmol, 1.5 eq) and CS2CO3 (2.79 g, 8.56 mmol, 3.0 eq.) at r.t. The reaction mixture was stirred at 50 °C for 2 h under N2. The reaction solution was quenched with water (20 mL) and filtered directly. The filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (PEZEA = 4 / 1) to afford tert-butyl ((lR,2S)-2-fluorocyclopropyl)(prop-2-yn-l-yl)carbamate (190 mg, 31%) as yellow solid. LC-MS: 158.1 [M-55]+.

[0301] To a solution of tert-butyl ((lR,2S)-2-fluorocyclopropyl)(prop-2-yn-l-yl)carbamate (190 mg, 0.89 mmol, 1.0 eq.) in HCI / dioxane (4 N, 5 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure, triturated with ethyl acetate and dried toafford (lR,2S)-2-fluoro-N-(prop-2-yn-l-yl)cyclopropan-l-amine (96 mg, crude) as a yellow solid. LC-MS: 114.1 [M+l]+.

[0302] To a solution of (lR,2S)-2-fluoro-N-(prop-2-yn-l-yl)cyclopropan-l-amine (96 mg, crude) in DCM (5 mL) were added methyl tritiate (418 mg, 2.55 mmol, 3.0 eq) and NaHCCL (285 mg, 3.39 mmol, 4.0 eq) at r.t. The reaction mixture was stirred for 2 h under N2 at r.t.The reaction solution was concentrated under reduced pressure and purified by flash column chromatography (DCM / MeOH = 10 / 1) to afford (lR,2S)-2-fluoro-N,N-dimethyl-N-(prop-2- yn-l-yl)cyclopropan-l-aminium trifluoromethanesulfonate (62 mg, 24% for two steps) as a yellow oil. LC-MS: 142.1 [M+l]+.1H NMR (400 MHz, methanol-d4) 3 5.06 - 5.01 (m, 1H), 4.89 (d, J= 4.0 Hz, 1H), 4.56 (t, J= 2.4 Hz, 2H), 3.62 (t, J= 2.4 Hz, 1H), 3.33 - 3.31 (m, 7H), 3.24 (dd, J= 6.0, 2.9 Hz, 1H), 2.08 (dq, J= 26.0, 3.5 Hz, 1H), 1.58 - 1.44 (m, 1H).19F NMR (376 MHz, methanol-d4) 3 -80.1, -227.3.Example 9: Synthesis of (lR,2R)-2-fluoro-N,N-dimethyl-N-(prop-2-yn-l- yl)cyclopropan-l-aminium trifluoromethanesulfonate

[0303] To a solution of (lS,2R)-2-fluorocyclopropan-l -amine (1.2 g, 15.99 mmol, 1.0 eq.) in DCM (20 mL) were added BOC2O (3.45 g, 15.83 mmol, 1.0 eq.) and TEA(4.84 g, 47.92 mmol, 3.0 eq.) at r.t. The reaction mixture was stirred at r.t. for 4 h under N2. The reaction solution was quenched with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (PEZEA = 3 / 1) to afford tert-butyl ((lS,2R)-2-fluorocyclopropyl)carbamate (1.7 g, 61%) as a white solid.

[0304] To a solution of tert-butyl ((lS,2R)-2-fluorocyclopropyl)carbamate (500 mg, 2.85 mmol, 1.0 eq.) in acetonitrile (10 mL) were added propargyl bromide (509 mg, 4.28 mmol,1.5 eq.) and CS2CO3 (2.79 g, 8.56 mmol, 3.0 eq.) at r.t.. The reaction mixture was stirred for 2 h under N2 at 50 °C. The reaction was detected by LC-MS. The reaction solution was quenched with water (20 mL) and filtered directly. The filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (PEZEA = 4 / 1) to afford tert-butyl ((lS,2R)-2- fluorocyclopropyl)(prop-2-yn-l-yl)carbamate (180 mg, 30%) as a yellow solid. LC-MS: 158.1 [M-55]+.

[0305] To a solution of tert-butyl ((lS,2R)-2-fluorocyclopropyl)(prop-2-yn-l-yl)carbamate (180 mg, 0.84 mmol, 1.0 eq.) in HC1 in dioxane (4 N, 5 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure, triturated with ethyl acetate and dried to afford (lS,2R)-2-fluoro-N-(prop-2-yn-l-yl)cyclopropan-l -amine (104 mg, crude) as a yellow solid. LC-MS: 114.1 [M+l]+.

[0306] To a solution of (lS,2R)-2-fluoro-N-(prop-2-yn-l-yl)cy cl opropan-1 -amine (104 mg, crude) in DCM (5 mL) were added methyl tritiate (452 mg, 2.75 mmol) and NaHCCL (309 mg, 3.68 mmol) at r.t. The reaction mixture was stirred for 2 h under N2 at r.t. The reaction was monitored by LC-MS. The reaction solution was concentrated under reduced pressure and purified by flash column chromatography (DCM / MeOH = 10 / 1) to afford (lR,2R)-2-Example 10: Synthesis of l-cyclopropyl-l-(prop-2-yn-l-yl)pyrrolidin-l-ium chloride

[0307] To a stirred solution of aminocyclopropane (500 mg, 8.8 mmol, 1.0 eq.) in acetonitrile (40 mL) was added 1,4-dibromobutane (2.27 g, 10.5 mmol, 1.2 eq.) and K2CO3 (3.63 g, 26.3 mmol, 3.0 eq.) in portions at 25 °C. The resulting mixture was stirred at 70 °C for 4 h. The resulting mixture was filtered and the filtrate was distilled under 45 °C. 1-Cyclopropylpyrrolidine in CH3CN (18 mL) was obtained. LC / MS: mass calcd. For C7H13N: 111.10, found: 112.05 [M+H]+. The solution was used in the next step directly.

[0308] To the above solution of 1 -cyclopropylpyrrolidine in acetonitrile (15 mL) was added propargyl chloride (2.7 g, 36.5 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at 55 °C for 2 h. The resulting mixture was concentrated under vacuum. 1-Example 11: Synthesis of N,N-dimethyl-N-(prop-2-yn-l-yl)thietan-3-aminium 1,1- dioxide chloride

[0309] A mixture of formaldehyde solution (1.0 g, 12.4 mmol, 5.0 eq., 37%) and HCOOH (683.8 mg, 14.9 mmol, 6.0 eq.) was stirred at 55 °C for 1.0 h. To the above mixture was added 3-amino-l-lambda-6-thietane-l,l-dione (300.0 mg, 2.5 mmol, 1.0 eq.) dropwise over 0.5 h at 55 °C. The resulting mixture was stirred at 55 °C for additional 17 h. The resulting mixture was poured into ice water (10 mL). The mixture was basified to pH 14 with sat. NaOH (5 mL). The aqueous layer was extracted with DCM (2x10 mL). The organic layers were combined, dried over anhydrous Na2SO4. The solid was filtered out and the filtrate was concentrated. 3-(dimethylamino)thietane 1,1 -dioxide (300 mg, crude) was obtained as a yellow oil. The crude product was used in the next step directly without further purification. LC / MS: mass calcd. For C5HIINO2S: 149.05, found: 149.95 [M+H]+.

[0310] To a stirred solution of 3-(dimethylamino)thietane 1,1-dioxide (300 mg, 2 mmol, 1 eq) in MeCN (3.0 mL) was added propargyl chloride (299.6 mg, 4.0 mmol, 2.0 eq.) at 25 °C. The resulting mixture was stirred at 55 °C for 2 h. After cooling to r.t., the precipitated solids were collected by filtration and washed with MeCN (2 mL), dried under vacuum to afford N,N-dimethyl-N-(prop-2-yn- l-yl)thi etan-3 -aminium 1,1-dioxide chloride (34.1 mg, 7.6% yield) as a white solid. LCMS: mass calcd. For CsHuNCLSL 188.07, found: 188.00 [M]+. 'HNMR (300 MHz, DMSO-tL) 8: 5.19 - 5.30 (m, 2H), 4.81 - 4.89 (m, 1H), 4.67 - 4.75 (m, 2H), 4.62 (d, J= 2.4 Hz, 2H), 4.19 (t, J = 2.7 Hz, 1H), 3.24 (s, 6H).Example 12: Synthesis of (lR,2R)-N,N,2-trimethyl-N-(prop-2-yn-l-yl)cyclopropan-l- aminium chloride

[0311] A mixture of formaldehyde solution (565 mg, 7.0 mmol, 5.0 eq., 37% in water) and HCOOH (477 pL, 8.4 mmol, 6.0 eq) was stirred at 55 °C for 1 h. In another flask, (lR,2R)-2-methylcyclopropan-l-amine hydrochloride (150.0 mg, 1.4 mmol, 1.0 eq) was dissolved in H2O (0.5 mL), then it was neutralized with NaOH aq. (0.69 mL, 2 M). The obtained solution was added to the first solution dropwise at 55 °C. The resulting mixture was stirred at 55 °C for additional 17 h. Toluene (2.0 mL) was added at 0 °C. The mixture was basified to pH 14 with NaOH aq. (2 M). The resulting mixture was extracted with toluene (3 x 2 mL). The combined organic phases were dried over anhydrous Na2SO4. The solid was filtered out and the filtrate (10 mL) was used for the next step directly without further purification. LC / MS: mass calcd. For GH1 N: 99.10, found: 100.20 [M+H]+.

[0312] To the above solution in toluene (10 mL) and MeCN (5 mL) was added propargyl chloride (1.03 g, 13.9 mmol, 10.0 eq.) at 25 °C. The resulting mixture was stirred at 55 °C for 17 h. After cooling to r.t, the resulting mixture was concentrated under vacuum. The semi -oil was washed with Et2O (2x2 mL). The semi -oil was dried under vacuum. This resulted in (lR,2R)-N,N,2-trimethyl-N-(prop-2-yn-l-yl)cyclopropan-l-aminium chloride (31.0 mg,Example 13: Synthesis of (lS,2S)-N,N,2-trimethyl-N-(prop-2-yn-l-yl)cyclopropan-l- aminium chloride

[0313] A mixture of formaldehyde solution (905.0 mg, 11.2 mmol, 6.0 eq., 37% in water) and HCOOH (427.8 mg, 9.3 mmol, 5.0 eq.) was stirred at 55 °C for 1 h. In another flask was added (lS,2S)-2-methylcyclopropan-l-amine hydrochloride (200.0 mg, 1.9 mmol, 1.0 eq.) and H2O (0.5 mL). The mixture was neutralized with NaOH aq. (0.92 mL, 2 M), and then it was added to the first solution dropwise at 55 °C. The resulting mixture was stirred at 55 °C for an additional 17 h. Toluene (2 mL) was added to the reaction mixture at 0 °C. The mixture was basified to pH = 14 with 2M NaOH aq. The resulting mixture was extracted with toluene (3 x 2 mL) and then the combined organic phases were dried over anhydrous Na2SO4.

[0314] To the above resulting mixture (10.0 mL) was added acetonitrile (10 mL) and propargyl chloride (1.50 g, 20.2 mmol, 10.9 eq.) dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 17 h. The resulting mixture was concentrated under vacuum. The residue was washed with 3x2 mL of Et2O, 2 x 2 mL of a 1 : 1 toluene-acetonitrile solution, and PhMe (2x2 mL), and then dried under vacuum. This resulted in (lS,2S)-N,N,2-trimethyl-N- (prop-2-yn-l-yl)cyclopropan-l-aminium chloride (43.9 mg, 24.4% yield) as a light yellow oil. LCMS: mass calcd. For C9HI6N: 138.13, found: 138.15[M]+.1H NMR (400 MHz, DMSO-tL) 8: 4.55 (d, J= 2.0 Hz, 2H), 4.08 (s, 1H), 3.05 - 3.09 (m, 1H), 3.03 (s, 3H), 2.98 (s, 3H), 1.60 - 1.71 (m, 1H), 1.42 - 1.50 (m, 1H), 1.03 (d, J= 6.0 Hz, 3H), 0.59 - 0.69 (m, 1H).Example 14: Synthesis of (21?*, 35*)-N,N,2-trimethyl-N-(prop-2-yn-l-yl)oxetan-3- aminium chloride

[0315] To a solution of ethyl 2-(dibenzylamino)acetate (10.0 g, 35.3 mmol, 1.0 eq.) in THF (75 mL) was added LDA (2.0 M in THF) (26 mL, 52.0 mmol, 1.5 eq) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 30 min and then acetaldehyde (3.9 mL, 69.9 mmol, 2.0 eq.) was added to this reaction. The reaction was stirred at -78 °C for additional 90 mins. The reaction was quenched with sat. NH4CI aq. and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (5 / 1) to afford two isomers.

[0316] Ethyl dibenzyl-D-allothreoninate (cis-) (7.2 g, 62% yield) as light yellow oil. LC / MS: mass calcd. For C20H25NO3: 327.18, found: 328.25 [M+H]+.1H NMR (400 MHz, CDCI3) 3 7.20 - 7.35 (m, 10H), 4.18 - 4.36 (m, 2H), 3.99 - 4.10 (m, 3H), 3.37 - 3.45 (m, 2H), 3.00 - 3.10 (m, 1H), 1.39 (t, J= 7.0 Hz, 3H), 1.09 (d, J= 6.0 Hz, 3H). Ethyl dibenzyl-D- threoninate (trans-) (3.0 g, 26%) as a light yellow oil. LC / MS: mass calcd. For C20H25NO3: 327.18, found: 328.25 [M+H]+.1H NMR (400 MHz, CDCI3) 7.19 - 7.40 (m, 10H), 4.20 - 4.40 (m, 2H), 4.11 - 4.19 (m, 1H), 3.89 (d, J= 13.6 Hz, 2H), 3.47 (d, J= 13.6 Hz, 2H), 3.11 (d, J= 8.8 Hz, 1H), 2.33 - 2.40 (m, 1H), 1.42 (t, J= 7.0 Hz, 3H), 1.09 (d, J= 6.4 Hz, 3H).

[0317] To a solution of ethyl dibenzyl-D-allothreoninate (trans-) (7.0 g, 21.4 mmol, 1.0 eq) in THF (50 mL) was added LAH (IM in THF) (32 mL, 32.0 mmol, 1.5 eq.) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 1 h and then quenched with sat. NH4CI aq. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combinedorganic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (1 / 1) to afford trans-2-(dibenzylamino)butane- 1 ,3-diol (4.99 g, 81.8% yield) as a light yellow solid. LC / MS: mass calcd. For CisEfeNCE: 285.17, found: 286.25 [M+H]+.1H NMR (400 MHz, DMSO-tL) 7.24 - 7.32 (m, 8H), 7.14 - 7.24 (m, 2H), 4.45 (t, J= 5.0 Hz, 1H), 4.24 (d, J= 2.4 Hz, 1H), 3.93 (d, J= 13.6 Hz, 2H), 3.71 - 3.84 (m, 2H), 3.61 - 3.70 (m, 3H), 2.34 (q, J= 6.1 Hz, 1H), 1.01 (d, J= 6.0 Hz, 3H).

[0318] To a solution of trans-2-(dibenzylamino)butane-l,3-diol (4.0 g, 14.0 mmol, 1.0 eq.) in THF (50 mL) was added t-BuOK (3.14 g, 28.0 mmol, 2.0 eq.) and TsCl (2.67 g, 14.0 mmol, 1.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with water and then extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PEZEA (2 / 1) to afford trans-N,N-dibenzyl-2-

[0319] Trans-N,N-dibenzyl-2-methyloxetan-3-amine (3.0 g, 11.2 mmol) was purified by Prep-Chiral-SFC with the following conditions (Column: CHIRALPAK AS-H, 5*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IP A; Flow rate: 180 mL / min; Gradient (B%): isocratic 30% B; Wave Length: 220 nm; RTl(min): 2.85; RT2(min): 4.2; Sample Solvent: MEOH; Injection Volume: 2 mL) to afford two enantiomers. The first peak (RT=2.85 min): (2A*,35*)-N,N-dibenzyl-2-methyloxetan-3-amine (randomly assigned, 1.38 g, 46.0% yield) as a light yellow solid. LC / MS: mass calcd. For C18H21NO: 267.16, found: 268.10 [M+H]+. ‘H NMR (300 MHz, DMSO ) 7.19 - 7.42 (m, 10H), 4.65 - 4.80 (m, 1H), 4.15 - 4.32 (m, 2H), 3.74 - 3.84 (m, 1H), 3.49 (d, J = 14.1 Hz, 2H), 3.27 (d, J = 14.1 Hz, 2H), 1.39 (d, J= 6.3 Hz, 3H).The second peak (RT=4.2 min): (25*,3A*)-N,N-dibenzyl-2-methyloxetan-3-amine (randomly assigned, 1.30 g, 43.3% yield) as a light yellow solid. LC / MS: mass calcd. For C18H21NO: 267.16, found: 268.10 [M+H]+. ‘H NMR (300 MHz, DMSO ) 8: 7.18 - 7.44 (m, 10H), 4.64 - 4.81 (m, 1H), 4.16 - 4.35 (m, 2H), 3.72 - 3.86 (m, 1H), 3.49 (d, J= 14.1 Hz, 2H), 3.27 (d, J = 14.1 Hz, 2H), 1.39 (d, J= 6.3 Hz, 3H).

[0320] To a stirred solution of (2A*,35*)-N,N-dibenzyl-2-methyloxetan-3-amine (600.0 mg, 2.2 mmol, 1.0 eq.) in MeOH (10 mL) was added Pd / C (120.0 mg, 20% w / w)and formaldehyde solution (1.45 g, 17.9 mmol, 8.0 eq., 37% in water) at room temperature. The resulting mixture was stirred at room temperature for 24 h under hydrogen atmosphere (1 atm). The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL). The resulting mixture was concentrated under vacuum until the solvent was left to about( g, ) , [ ]

[0321] To the above resulting mixture (0.10 g, 0.9 mmol, 1.0 eq) was added acetonitrile (0.4 mL), toluene (2 mL) and propargyl chloride (0.82 g, 11.0 mmol, 12.7 eq) dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 96 h. The resulting mixture was concentrated under vacuum. The residue was washed with 3 x 2 mL of 10: 1 solution ofExample 15: Synthesis of (21?*,31?*)-N,N,2-trimethyl-N-(prop-2-yn-l-yl)oxetan-3- aminium chloride

[0322] To a solution of ethyl cis-2-(dibenzylamino)-3-hydroxybutanoate (10.0 g, 30.5 mmol, 1.0 eq.) in THF (90 mL) was added LAH (IM in THF) (46.0 mL, 46 mmol, 1.5 eq.) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h and then quenched with sat. NH4CI aq. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, and then dried over anhydrousNa2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford cis-2- (dibenzylamino)butane-l,3-diol (5.6 g, 64.2% yield) as a light yellow solid. LC / MS: mass calcd. For C18H23NO2: 285.17, found: 286.20 [M+H]+.1H NMR (400 MHz, DMSO-tL) 7.17 - 7.38 (m, 10 H), 4.46 (d, J= 5.2 Hz, 1H), 4.27 - 4.32 (m, 1H), 3.75 - 3.90 (m, 3 H), 3.73 (s, 4H), 2.32 - 2.39 (m, 1H), 1.10 (d, J= 6.0 Hz, 6H).

[0323] To a solution of cis-2-(dibenzylamino)butane-l,3-diol (5.6 g, 19.6 mmol, 1.0 eq.) in THF (60 mL) was added t-BuOK (4.4 g, 39.2 mmol, 2.0 eq) and TsCl (3.74 g, 19.6 mmol, 1.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with water and then extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography, eluted with PEZEA (2 / 1) to afford cis-N,N-dibenzyl-2-methyloxetan-3-amine (732.0 mg, 14% yield) as a light yellow oil. LC / MS: mass calcd. For C18H21NO: 267.16, found: 268.20 [M+H]+1H. NMR (400 MHz, DMSO ) <5 7.19 - 7.37 (m, 10 H), 4.59 - 4.66 (m, 1H), 4.17 - 4.23 (m, 1H), 4.11 - 4.16 (m, 1H), 3.38 - 3.54 (m, 4H), 3.32 - 3.39 (m, 1H), 1.17 (d, J= 6.0 Hz, 3H).

[0324] Cis-N,N-dibenzyl-2-methyloxetan-3-amine (2.0 g, 11.2 mmol) was purified by Prep-SFC with the following conditions (Column: CHIRALPAK IG, 5*25 cm, 10 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 140 mL / min; Gradient (B%): isocratic 25% B; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 5.17; RT2(min): 6.78; Sample Solvent: EtOH; Injection Volume: 1 mL) to afford two single cis

[0325] To a solution of (2R*,3R*)-N,N-dibenzyl-2-methyloxetan-3-amine (250.0 mg, 0.9 mmol, 1.0 eq) in MeOH (5 mL) was added Pd / C (200 mg, 80% w / w). The mixture was stirred for 17 h at room temperature under hydrogen atmosphere (1 atm). The resultingmixture was used for next step directly. LC / MS: mass calcd. For C4H9NO: 87.07, found: 88.35 [M+H]+.

[0326] To the above mixture was added formaldehyde solution (380 mg, 4.7 mmol, 5.0 eq., 37% in water). The mixture was stirred for 17 h at room temperature under hydrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with MeOH. The MeOH was removed under vacuum until the solution was about 0.5 mL. The residue (0.5 mL) was diluted with water (2 mL), then the mixture was extracted with toluene (3 x 3 mL), the combined organic phases was dried over anhydrous Na2SO4. The solid was filtered out and the filtrate was used for next step directly without further purification. LCMS: mass calcd. For C6HI3NO: 115.10, found: 116.25[M+H]+.

[0327] To the above solution was added MeCN (5 mL) and propargyl chloride (692.0 mg, 9.4 mmol, 10.0 eq.) at 25 °C. The resulting mixture was stirred at 55 °C for 17 h. Additional propargyl chloride (692.0 mg, 9.4 mmol, 10.0 eq.) was added and then stirred for additional 2 days. The resulting mixture was concentrated under vacuum. The semi -oil was washed 3 x 2 mL with 10: 1 solution of PhMe-ACN, 3x1 mL of 1 : 1 Tol-ACN, and then concentrated under

[0328] To a stirred solution of (2*5,3A*)-N,N-dibenzyl-2-methyloxetan-3-amine (200 mg, 0.8 mmol, 1.0 eq.) in MeOH (5 mL) was added Pd / C (160 mg, 80% w / w) and formaldehyde solution (486.5 mg, 6 mmol, 8 eq., 37%) at room temperature. The resulting mixture was stirred at room temperature for 24 h under a hydrogen atmosphere (1 atm). The resulting mixture was filtered, the filter cake was washed with MeOH (5 mL). The resulting mixture was concentrated under vacuum until the solvent was approx. 0.5 mL. The residue wasdiluted with water (5 mL) and then extracted with CH2CI2 (3 x 10 mL). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure until the solution was approximately 1 mL. LC / MS: mass calcd. For C6HI3NO: 115.10, found: 116.15 [M+H]+.

[0329] To the above resulting mixture was added toluene (1 mL) and acetonitrile (0.2 mL). Propargyl chloride (0.6 mL, 8.3 mmol, 11.9 eq.) was added dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 120 h. The resulting mixture was concentrated under vacuum. The residue was washed with 3 x 2 mL of 1 : 1 solution of PhMe-ACN, dried under vacuum. This resulted in (25*, 3A*)-N,N,2-trimethyl-N-(prop-2-yn-l-yl)oxetan-3-aminium

[0330] To a stirred solution of (25*, 35*)-N,N-dibenzyl-2-methyloxetan-3-amine (200 mg, 0.8 mmol, 1 eq.) in MeOH (5 mL) was added (160.0 mg, 80% w / w) and formaldehyde solution (486.5 mg, 6.0 mmol, 8.0 eq., 37%) at room temperature. The resulting mixture was stirred at room temperature for 24 h under hydrogen atmosphere (1 atm). The resulting mixture was filtered, the filter cake was washed with MeOH (5 mL). The resulting mixture was concentrated under vacuum until the volume was approximately 0.5 mL. The residue was diluted with water (5 mL) and then extracted with CH2CI2 (3 x 10 mL). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure until the solution was approximately 1 mL. LC / MS: mass calcd. For C6HI3NO: 115.10, found: 116.15 [M+H]+.

[0331] To the above resulting mixture was added toluene (1 mL) and acetonitrile (0.2 mL). Propargyl chloride (0.6 mL, 8.3 mmol, 11.9 eq.) was added dropwise at 55 °C. The resultingmixture was stirred at 55 °C for 96 h. The resulting mixture was concentrated under vacuum. The residue was washed with 3 x 2 mL of 1 : 1 solution of PhMe-ACN, dried under vacuum.A ,

[0332] To a stirred solution of 2-methylcy cl obutane-1 -carboxylic acid (1.0 g, 8.8 mmol, 1.0 eq) and trimethylamine (1.1 g, 10.5 mmol, 1.2 eq.) in toluene (25.0 mL) at 80 °C was added DPPA (2.4 g, 8.8 mmol, 1.0 eq.) dropwise. The reaction mixture was stirred for 10 min until gas evolution ceased and to this was added BnOH (1.2 g, 10.5 mmol, 1.2 eq.). The resulting solution was stirred at this temperature for an additional 16 h. The reaction mixture was quenched with saturated NaHCOs solution at 0 °C and then extracted with EtOAc 3 times. The organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on Cl 8 gel (5-50% acetonitrile in water (contained 0.05% NH4HCO3)) to afford benzyl (2- methylcyclobutyl)carbamate (1.2 g, 62.5%) as a white solid. LC / MS: mass calcd. For C13H17NO2: 219.13, found: 220.13 [M+H]+.

[0333] Benzyl (2-methylcyclobutyl)carbamate (5.0 g, 22.8 mmol) was purified by Prep- Chiral-HPLC with the following conditions (Column: CHIRALPAK IE-3, 3*25 cm, 3 pm; Mobile Phase A: Hexane (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH (0.1% 7M NH3- MeOH); Flow rate: 100 mL / min; Gradient (B%): isocratic 3% B; Wave Length: 220 nm; RTl(min): 11.72; RT2(min): 12.78; Sample Solvent: EtOH : Hexane=l : l; Injection Volume: 3 mL) to afford two isomers. The first peak obtained was (RT=11.72 min): / ra / z.s-benzyl (2- methylcyclobutyl)carbamate (2.1 g, 42.0% yield), isolated as a white solid. LC / MS: mass calcd.For CI3HI7NO2: 219.13, found: 220.13 [M+H]+. The second peak (RT=12.78 min), cisbenzyl (2-methylcyclobutyl)carbamate (0.9 g, 18.0% yield), was isolated as a white solid. LC / MS: mass calcd. For CI3HI7NO2: 219.13, found: 220.13 [M+H]+.

[0334] Trans-benzyl (2-methylcyclobutyl)carbamate (2.1 g, 9.6 mmol) was further separated by Prep Chiral SFC with the following conditions (Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: ACN:IPA=1 : 1(1% NH3-IPA); Flow rate: 90 mL / min; Gradient (B%): isocratic 10% B; Wave Length: 220 nm; RTl(min): 6.27; RT2(min): 7.30; Sample Solvent: DCM (0.5% 2M NH3-MeOH); Injection Volume: 0.5 mL) to afford two isomers. The first peak (RT=6.27 min): benzyl ((lR*,2R*)-2- methylcyclobutyl)carbamate (randomly assigned; 570.0 mg, 27.1% yield) was obtained as a white solid. LC / MS: mass calcd. For Ci3Hi7NO2: 219.13, found: 220.13 [M+H]+. ‘H NMR (300 MHz, CDC13) 5: 7.30 - 7.43 (m, 5H), 5.10 (s, 2H), 4.86 (s, 1H), 3.67 - 3.78 (m, 1H), 2.07 - 2.29 (m, 2H), 1.82 - 1.91 (m, 1H), 1.56 - 1.69 (m, 1H), 1.19 - 1.32 (m, 1H), 1.13 (d, J = 6.6 Hz, 3H); The second peak (RT=7.30 min): benzyl ((lS*,2S*)-2- methylcyclobutyl)carbamate (randomly assigned, 650.0 mg, 30.9% yield) was obtained as a white solid. LC / MS: mass calcd. For Ci3Hi7NO2: 219.13, found: 220.13 [M+H]+. ‘H NMR (300 MHz, CDC13) 5: 7.30 - 7.43 (m, 5H), 5.10 (s, 2H), 4.86 (s, 1H), 3.67 - 3.78 (m, 1H), 2.07 - 2.29 (m, 2H), 1.82 - 1.91 (m, 1H), 1.56 - 1.69 (m, 1H), 1.19 - 1.32 (m, 1H), 1.13 (d, J = 6.6 Hz, 3H).

[0335] CA-benzyl (2-methylcyclobutyl)carbamate (0.9 g, 4.1 mmol) was further separated by Prep-Chiral HPLC with the following conditions (Column: CHIRALPAK IH, 2*25 cm, 5 pm; Mobile Phase A: Hexane (0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient (B%): isocratic 5% B; Wave Length: 220 nm; RTl(min): 7.64; RT2(min): 7.8714; Sample Solvent: EtOH; Injection Volume: 0.5 mL) to afford two isomers. The first peak (RT=7.64 min): benzyl ((lR*,2S*)-2-methylcyclobutyl)carbamate (randomly assigned, 310.0 mg, 34.4% yield) was isolated as a white solid. LC / MS: mass calcd. ForC13H17NO2: 219.13, found: 220.13 [M+H]+. ‘H NMR (300 MHz, CDCI3) 6: 7.31 - 7.45 (m, 5H), 5.11 (s, 2H), 4.92 (s, 1H), 4.28 - 4.36 (m, 1H), 2.60 - 2.67 (m, 1H), 2.28 - 2.37 (m, 1H), 1.86 - 2.00 (m, 2H), 1.28 - 1.38 (m, 1H), 1.06 (d, J= 7.2 Hz, 3H). The second peak (RT=7.8714 min): benzyl ((lS*,2R*)-2-methylcyclobutyl)carbamate (randomly assigned, 440.0 mg, 48.9% yield) was isolated as a white solid, LC / MS: mass calcd. For C13H17NO2: 219.13, found: 220.13 [M+H]+. ‘H NMR (300 MHz, CDCI3) 6: 7.31 - 7.45 (m, 5H), 5.11 (s, 2H), 4.92 (s, 1H), 4.28 - 4.36 (m, 1H), 2.60 - 2.67 (m, 1H), 2.28 - 2.37 (m, 1H), 1.86 - 2.00 (m, 2H), 1.28 - 1.38 (m, 1H), 1.06 (d, J= 7.2 Hz, 3H).

[0336] To a stirred solution of benzyl N-[(lR*,2R*)-2-methylcyclobutyl]carbamate (250.0 mg, 0.9 mmol, 1.0 eq) and palladium hydroxide on carbon (50.0 mg, contained -50% water, 20% w / w) in methanol (10.0 mL) was added HC1 (4 N in 1,4-dioxane, 0.2 mL). The resulting solution was stirred at ambient temperature for 16 h under a hydrogen atmosphere (1.0 atm). The resulting mixture was filtered through a pad of celite. The filtrate was concentrated under vacuum. This resulted in (lR*,2R*)-2-methylcyclobutan-l-aminium chloride (180.0 mg, crude) as a light yellow semi-solid, which was used for the next step without further purification. LC / MS: mass calcd. For C5H11N: 85.09, found: 86.09 [M+H]+.

[0337] A mixture of formaldehyde solution (3.6 g, 44.6 mmol, 30.0 eq., 37% in water) and HCOOH (1.4 g, 29.7 mmol, 20.0 eq.) was stirred at 55 °C for 1 h. In another flask was added (lR*,2R*)-2-methylcyclobutan-l-aminium chloride (180.0 mg, 1.5 mmol, 1.0 eq.) and H2O (0.5 mL). This mixture was neutralized with NaHCCf aq. (0.8 mL, 2 M), and then it was added to the first solution dropwise at 55 °C. The resulting mixture was stirred at 55°C for 4 days. Toluene (10 mL) was added to the reaction mixture at 0 °C. The mixture was basified to pH = 14 with 2M NaOH aq. The resulting mixture was extracted with toluene (2 x 5 mL) and then the combined organic phases were dried over anhydrous Na2SO4. The solid was filtered out and the filtrate (20 mL) was used for the next step directly without further purification. LC / MS: mass calcd. For C7H15N: 113.12, found: 114.12 [M+H]+.

[0338] To the above resulting mixture (20 mL) was added acetonitrile (10 mL) and propargyl chloride (550.1 mg, 7.4 mmol, 5.0 eq.) dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 4 days. The resulting mixture was concentrated under vacuum. The residue was washed with 3 x 10.0 mL of Et2O, 2 x 16.5 mL of a 1 : 10 ACN-Et2O solution, and then dried under vacuum. This resulted in (lR*,2R*)-N,N,2-trimethyl-N-(prop-2-yn-l- yl)cyclobutan-l-aminium chloride (92.8 mg, 33.3% yield) as a light yellow semi-solid. LC / MS: mass calcd. For CioHisN: 152.14, found: 152.14 [M]+. ‘H NMR (300 MHz, DMSO) 5: 4.33 (d, J= 2.4 Hz, 2H), 4.08 (t, J= 2.4 Hz, 1H), 3.73 - 3.85 (m, 1H), 3.02 (d, J = 5.1 Hz,6H), 2.69 - 2.87 (m, 1H), 2.14 - 2.28 (m, 1H), 1.87 - 2.07 (m, 2H), 1.17 - 1.30 (m, 1H), 1.13 (d, .7= 6.6 Hz, 3H).

[0339] To a stirred solution of benzyl N-[(lR*,2S*)-2-methylcyclobutyl]carbamate (250.0 mg, 0.9 mmol, 1.0 eq.) and palladium hydroxide on carbon (50.0 mg, contained -50% water, 20% w / w) in methanol (10.0 mL) was added HCI (4 N in 1,4-dioxane, 0.2 mL). The resulting solution was stirred at ambient temperature for 16 h under hydrogen atmosphere (1.0 atm). The resulting mixture was filtered through a pad of celite. The filtrate was concentrated under vacuum. This resulted in (lR*,2S*)-2-methylcyclobutan-l-aminium chloride (180.0 mg, crude) as a light yellow semi-solid, which was used for the next step without further purification. LC / MS: mass calcd. For C5H11N: 85.09, found: 86.09 [M+H]+.

[0340] A mixture of formaldehyde solution (3.6 g, 44.6 mmol, 30.0 eq., 37% in water) and HCOOH (1.4 g, 29.7 mmol, 20.0 eq.) was stirred at 55 °C for 1 h. In another flask was added (lR*,2S*)-2-methylcyclobutan-l-aminium chloride (180.0 mg, 1.5 mmol, 1.0 eq) and H2O (0.5 mL). The mixture was neutralized with NaHCCf aq. (0.8 mL, 2 M), and then it was added to the first solution dropwise at 55°C. The resulting mixture was stirred at 55 °C for 4 days. Toluene (10 mL) was added to the reaction mixture at 0 °C. The mixture was basified to pH = 14 with 2 M NaOH aq. The resulting mixture was extracted with toluene (2 x 5 mL) and then the combined organic phases were dried over anhydrous Na2SO4. The solid was filtered out and the filtrate (20 mL) was used for the next step directly without further purification. LC / MS: mass calcd. For C7H15N: 113.12, found: 114.12 [M+H]+.

[0341] To the above resulting mixture (20 mL) was added acetonitrile (10 mL) and propargyl chloride (550.1 mg, 7.4 mmol, 5.0 eq) dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 5 days. The resulting mixture was concentrated under vacuum. The residue was washed with 3 x 10 mL of Et2O, 2 x 16.5 mL of a 1 : 10 ACN-Et2O solution and then dried under vacuum. This resulted in (lR*,2S*)-N,N,2-trimethyl-N-(prop-2-yn-l-yl)cyclobutan-l-aminium chloride (32.6 mg, 11.7% yield) as a brown oil. LC / MS: mass calcd. For CioHisN: 152.14, found: 152.14 [M]+. ‘H NMR (300 MHz, DMSO) 5: 4.29 - 4.30 (m, 2H), 4.01 - 4.16 (m, 2H), 3.03 (d, J= 9.0 Hz, 6H), 2.73 - 2.81 (m, 1H), 2.56 - 2.70 (m, 1H), 2.04 - 2.21 (m, 1H), 1.75 - 1.87 (m, 1H), 1.27 - 1.40 (m, 4H).

[0342] To a stirred solution of benzyl N-[(lS*,2S*)-2-methylcyclobutyl]carbamate (200.0 mg, 0.9 mmol, 1.0 eq.) and palladium hydroxide on carbon (40.0 mg, contained -50% water, 20% w / w) in methanol (8.0 mL) was added HCI (4 N in 1,4-dioxane, 0.2 mL). The resulting solution was stirred at ambient temperature for 16 h under hydrogen atmosphere (1.0 atm). The resulting mixture was filtered through a pad of celite. The filtrate was concentrated under vacuum. This resulted in (lS*,2S*)-2-methylcyclobutan-l-aminium chloride (180.0 mg, crude) as a light yellow semi-solid, which was used for the next step without further purification. LC / MS: mass calcd. For C5H11N: 85.09, found: 86.09 [M+H]+.

[0343] A mixture of formaldehyde solution (3.6 g, 44.6 mmol, 30.0 eq., 37% in water) and HCOOH (1.4 g, 29.7 mmol, 20.0 eq.) was stirred at 55 °C for 1 h. In another flask was added (lS*,2S*)-2-methylcyclobutan-l-aminium chloride (180.0 mg, 1.5 mmol, 1.0 eq.) and H2O (0.5 mL). The mixture was neutralized with NaHCCf aq. (0.8 mL, 2 M), and then it was added to the first solution dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 5 days. Toluene (10 mL) was added to the reaction mixture at 0 °C. The mixture was basified to pH = 14 with 2 M NaOH aq. The resulting mixture was extracted with toluene (2 x 5 mL) and then the combined organic phases were dried over anhydrous Na2SO4. The solid was filtered out and the filtrate (20 mL) was used for the next step directly without further purification. LC / MS: mass calcd. For C7H15N: 113.12, found: 114.12 [M+H]+.

[0344] To the above resulting mixture (20 mL) was added acetonitrile (10 mL) and propargyl chloride (550.1 mg, 7.4 mmol, 5.0 eq.) dropwise at 55 °C. The resulting mixturewas stirred at 55 °C for 4 days. The resulting mixture was concentrated under vacuum. The residue was washed with 3 x 10 mL of Et2O, 2 x 16.5 mL of a 1 : 10 ACN-Et2O solution and then dried under vacuum. This resulted in (lS*,2S*)-N,N,2-trimethyl-N-(prop-2-yn-l- yl)cyclobutan-l-aminium chloride (49.1 mg, 16.0% yield) as a brown oil. LC / MS: mass calcd. For CI0HI8N: 152.14, found: 152.14 [M]+. ‘H NMR (500 MHz, DMSO) 5: 4.29 (d, J= 2.5 Hz, 2H), 4.06 (t, J= 2.5 Hz, 1H), 3.75 - 3.82 (m, 1H), 3.01 (d, J= 7.5 Hz, 6H), 2.72 - 2.79 (m, 1H), 2.16 - 2.25 (m, 1H), 1.98 - 2.09 (m, 1H), 1.88 - 1.98 (m, 1H), 1.21 - 1.28 (m, 1H), 1.14 (d, J= 6.5 Hz, 3H).

[0345] To a stirred solution of benzyl N-[(lS*,2R*)-2-methylcyclobutyl]carbamate (250.0 mg, 1.1 mmol, 1.0 eq.) and palladium hydroxide on carbon (50.0 mg, contained -50% water, 20% w / w) in methanol (10.0 mL) was added HCI (4 N in 1,4-dioxane, 0.2 mL). The resulting solution was stirred at ambient temperature for 16 h under hydrogen atmosphere (1.0 atm). The resulting mixture was filtered through a pad of celite. The filtrate was concentrated under vacuum. This resulted in (lS*,2R*)-2-methylcyclobutan-l-aminium chloride (210.0 mg, crude) as a light yellow semi-solid, which was used for the next step without further purification. LC / MS: mass calcd. For C5H11N: 85.09 found: 86.09 [M+H]+.

[0346] A mixture of formaldehyde solution (4.2 g, 52.0 mmol, 30.0 eq., 37% in water) and HCOOH (1.6 g, 34.7 mmol, 20.0 eq) was stirred at 55 °C for 1 h. In another flask was added (lS*,2R*)-2-methylcyclobutan-l-aminium chloride (210.0 mg, 1.7 mmol, 1.0 eq.) and H2O (0.5 mL). The mixture was neutralized with NaHCCf aq. (0.9 mL, 2 M), and then it was added to the first solution dropwise at 55 °C. The resulting mixture was stirred at 55 °C for an additional 4 days. Toluene (10 mL) was added to the reaction mixture at 0 °C. The mixture was basified to pH = 14 with 2M NaOH aq. The resulting mixture was extracted with toluene (2 x 5 mL) and then the combined organic phases were dried over anhydrous Na2SO4. Thesolid was filtered out and the filtrate (20 mL) was used for the next step directly without further purification. LC / MS: mass calcd. For C7H15N: 113.12, found: 114.12 [M+H]+.

[0347] To the above resulting mixture (20 mL) was added acetonitrile (10 mL) and propargyl chloride (641.7 mg, 8.7 mmol, 5.0 eq.) dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 4 days. The resulting mixture was concentrated under vacuum. The residue was washed with 3 x 10 mL of Et2O, 2 x 16.5 mL of a 1 : 10 ACN-Et2O solution and then dried under vacuum. This resulted in (lS*,2R*)-N,N,2-trimethyl-N-(prop-2-yn-l- yl)cyclobutan-l-aminium chloride (51.9 mg, 16.0% yield) as a light brown oil. LC / MS: mass calcd. For CioHisN: 152.14, found: 152.14 [M]+.1H NMR (400 MHz, DMSO) 5: 4.30 - 4.31 (m, 2H), 4.04 - 4.13 (m, 2H), 3.03 (d, J= 12.0 Hz, 6H), 2.73 - 2.82 (m, 1H), 2.58 - 2.68 (m, 1H), 2.09 - 2.16 (m, 1H), 1.76 - 1.85 (m, 1H), 1.28 - 1.38 (m, 4H).

[0348] To a stirred solution of 3 -oxabicyclo [3.2.0] heptane-2, 4-dione (50.0 g, 396.5 mmol, 1.0 eq.) in BnOH (50.0 mL) at ambient temperature was added DMAP (4.9 g, 39.7 mmol, 0.1 mmol). The resulting mixture was stirred at ambient temperature for 16 h. The resultingmixture was concentrated under vacuum to afford cis-2-[(benzyloxy) carbonyl] cyclobutane- 1 -carboxylic acid (crude, 92.0 g) as a white solid, which was used for the next step without further purification. LC / MS: mass calcd. For C12H14FNO2: 223.25, found: 224.25 [M+H]+.

[0349] To a stirred solution of cis-2-[(benzyloxy) carbonyl] cyclobutane- 1 -carboxylic acid (92.0 g, 392.7 mmol, 1.0 eq.) in a 7:7: 1 mixture of n-Hexane-water-acetone solution (1.2 L) at ambient temperature was added AgNCh (27.4 g, 161.0 mmol, 0.4 eq.) and SelectFluor (208.7 g, 589.1 mmol, 1.5 eq). The resulting mixture was stirred at 60 °C for 3 h under nitrogen atmosphere. The resulting mixture was extracted with DCM (3 x 1000 mL). The combined organic layers were dried over Na2SO4. The solid was filtered out and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0~8% EtOAc in petroleum ether) to afford benzyl 2-fluorocyclobutane-l -carboxylate (50.0 g, 61.0% yield) as a light yellow oil.1H NMR (300 MHz, CDCI3) 8: 7.37 - 7.67 (m, 5H), 5.20 - 5.30 (m, 1H), 4.94 - 5.19 (m, 2H), 3.13 - 3.55 (m, 1H), 1.78 - 2.63 (m, 4H).

[0350] A mixture of benzyl 2-fluorocyclobutane-l-carboxylate (50.0 g, 240.1 mmol, 1.0 eq.) and palladium hydroxide on carbon (10.0 g, contained -50% water, 20% w / w) in methanol (500.0 mL) was stirred at ambient temperature for 16 h under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under vacuum to afford 2-fluorocyclobutane-l -carboxylic acid (27.4 g, crude) as a light yellow oil, which was used for the next step without further purification.1H NMR (300 MHz, CDCI3) 6: 8.82 (s, 1H), 4.93 - 5.37 (m, 1H), 3.07 - 3.58 (m, 1H), 1.60 - 2.67 (m, 4H).

[0351] To a stirred solution of 2-fluorocyclobutane-l -carboxylic acid (26.5 g, 224.4 mmol, 1.0 eq) and EtsN (27.3 g, 269.3 mmol, 1.2 eq) in toluene (500.0 mL) at 80 °C was added dropwise DPPA (67.9 g, 246.8 mmol, 1.1 eq) under nitrogen atmosphere. When the gas evolution ceased, benzyl alcohol (29.1 g, 269.3 mmol, 1.2 eq) was added, and the resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with 500 mL saturated aq. NaHCCL and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried over Na2SO4. The solid was filtered out and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-19% EtOAc in petroleum ether) and reverse phase flash chromatography on Cl 8 gel (5-20% acetonitrile in water (contained 0.05% NH4HCO3)) to afford benzyl N-(2- fluorocyclobutyl) carbamate (30.0 g, 59% yield) as a white solid. LC / MS: mass calcd. For C12H14FNO2: 223.10, found: 224.10 [M+H]+.

[0352] Benzyl N-(2-fluorocyclobutyl) carbamate (10.0 g, 44.8 mmol) was separated by Prep-Achiral SFC (Prep-Achiral SFC with the following conditions (Column: DAICEL DCpak P4VP 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA(1% 2M NH3- MEOH); Flow rate: 60 mL / min; Gradient (B%): isocratic 16% B; Wave Length: 220 nm; RTl(min): 3.15; RT2(min): 5.45; Sample Solvent: MeOH; Injection Volume: 2 mL) to afford cis-benzyl N-(2 -fluorocyclobutyl) carbamate (4.4 g, 44.0% yield) and trans-benzyl N-(2- fluorocyclobutyl) carbamate (4.0 g, 40.0% yield) isomers respectively.

[0353] The trans-benzyl N-(2-fluorocyclobutyl) carbamate (2.4 g, 10.8 mmol) was further separated by Prep-Chiral SFC with the following conditions (Column: Lux 5 pm Cellulose-4 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 80 ml / min; Gradient (B%): isocratic 10% B; Wave Length: 220 nm; RTl(min): 5.1; RT2(min): 6.03; Sample Solvent: MeOH; Injection Volume: 0.8 mL) to afford two single stereoisomers. The first peak (RT=5.1 min): benzyl N-[(lR*,2R*)-2-fluorocyclobutyl] carbamate (randomly assigned, 380 mg, 16% yield) was obtained as a white solid. LC / MS: mass calcd. For C12H14FNO2: 223.10, found: 224.10 [M+H]+. ‘H NMR (300 MHz, DMSO) 5: 7.78 (d, J= 8.4 Hz, 1H), 7.26 - 7.41 (m, 5H), 5.02 (s, 2H), 4.59 - 4.88 (m, 1H), 3.89 - 4.16 (m, 1H), 1.88 - 2.12 (m, 2H), 1.54 - 1.80 (m, 1H), 1.18 - 1.37 (m, 1H).19F NMR (282 MHz, DMSO) 5: - 163.67; The second peak (RT=6.03 min): benzyl N-[(lS*,2S*)-2-fluorocyclobutyl] carbamate (randomly assigned, 800 mg, 33% yield) was obtained as a white solid. LC / MS: mass calcd. For C12H14FNO2: 223.10, found: 224.10 [M+H .'H NMR (300 MHz, DMSO) 5: 7.77 (d, J= 8.4 Hz, 1H), 7.25 - 7.42 (m, 5H), 5.02 (s, 2H), 4.58 - 4.89 (m, 1H), 3.89 - 4.13 (m, 1H), 1.88 - 2.10 (m, 2H), 1.54 - 1.80 (m, 1H), 1.18 - 1.37 (m, 1H).19F NMR (282 MHz, DMSO) 5: -163.67.

[0354] The cis-benzyl N-(2-fluorocyclobutyl) carbamate (2.4 g, 10.8 mmol) was further separated by Prep-Chiral SFC with the following conditions (Column: CHIRALPAK IH 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA (0.1% 7M NH3-MeOH); Flow rate: 100 ml / min; Gradient (B%): isocratic 3.65% B; Wave Length: 220 nm; RTl(min): 3.65; RT2(min): 4.38; Sample Solvent: MeOH; Injection Volume: 1 mL) to afford two single stereoisomers. The first peak (RT=3.65 min): benzyl N-[(lR*,2S*)-2-fluorocyclobutyl] carbamate (randomly assigned, 600.0 mg, 25.0% yield) was obtained as a white solid. LC / MS: mass calcd. For C12H14FNO2: 223.10, found: 224.10 [M+H]+. NMR (400 M1HHz, DMSO) 5: 7.71 (d, J= 8.0 Hz, IH), 7.26 - 7.41 (m, 5H), 4.92 -5.12 (m, 3H), 4.09 - 4.23 (m, IH), 1.92 - 2.18 (m, 4H).19F NMR (377 MHz, DMSO) 5: -191.66; The second peak (RT=4.38 min): benzyl N-[(lS*,2R*)-2-fluorocyclobutyl] carbamate (randomly assigned,750.0 mg, 31.0% yield) was isolated as a white solid. LC / MS: mass calcd. For C12H14FNO2: 223.10, found: 224.10 [M+H]+.1H NMR (400 MHz, DMSO) 5: 7.72 (d, J= 8.0 Hz, 1H), 7.26 - 7.41 (m, 5H), 4.91 - 5.13 (m, 3H), 4.12 - 4.24 (m, 1H), 1.92 - 2.19 (m, 4H).19F NMR (377 MHz, DMSO) 5: -191.67.

[0355] A mixture of benzyl N-[(lR*,2R*)-2-fluorocyclobutyl]carbamate (250.0 mg, 1.1 mmol, 1.0 eq.), palladium hydroxide on carbon (50.0 mg, contained -50% water, , 20% w / w) and HC1 (4.0 M in 1,4-dioxane, 0.5 mL) in methanol (3.0 mL) was stirred at ambient temperature for 16 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under vacuum to afford (lR*,2R*)-2-fluorocyclobutan-l-amine hydrochloride (crude, 160.0 mg) as a white solid, which was used for the next step without further purification. LC / MS: mass calcd. For C4H8FN: 89.06 found: 90.06 [M+H]+.

[0356] A mixture of formaldehyde solution (2.2 g, 35% in water, 25.6 mmol, 20.0 eq.) and HCOOH (353.3 mg, 7.7 mmol, 6.0 eq.) was stirred at 55 °C for 1 h. To this was added dropwise a solution of (lR*,2R*)-2-fluorocyclobutan-l-amine hydrochloride (160.0 mg, 1.3 mmol, 1.0 eq.) in NaHCCh solution (215.0 mg, 2.6 mmol, 2.0 eq.). The resulting mixture was stirred at ambient temperature for 5 days. The reaction was cooled to 0 °C and then diluted with toluene (10.0 mL). The mixture was basified to pH 14 with NaOH (4 M) and extracted with toluene (10.0 mL). The organic layer was washed with brine and dried over Na2SO4to afford (lR*,2R*)-2-fluoro-N, N-dimethylcyclobutan-1 -amine as a crude solution in toluene. To above solution was added acetonitrile (5.0 mL) and propargyl chloride (2.0 g, 27.3 mmol, 20.0 eq.) at ambient temperature. The resulting solution was stirred at 55 °C for 5 days and then concentrated under vacuum. The residue was purified by trituration with a 1 : 10 acetonitrile-diethyl ether solution 3 times, the solid was dried under vacuum to afford (lR*,2R*)-2-fluoro-N, N-dimethyl -N-(prop-2-yn-l-yl) cyclobutan-l-aminium chloride (53.2 mg, 20% yield for 2 step) as a light brown oil. LC / MS: mass calcd. For C9H15FNA 156.12, found: 156.12 [M]+. ‘H NMR (300 MHz, DMSO) 5: 5.35 - 5.63 (m, 1H), 4.50 (d, J= 2.7 Hz, 2H), 4.29 - 4.46 (m, 1H), 4.11 (t, J = 2.4 Hz, 1H), 3.13 (d, J = 4.8 Hz, 6H), 2.15 - 2.33 (m, 1H), 1.98 - 2.13 (m, 1H), 1.67 - 1.97 (m, 2H).19F NMR (282 MHz, DMSO) 5: -164.42.Example 23: Synthesis of (lR*,2S*)-2-fluoro-N, N-dimethyl -N-(prop-2-yn-l-yl) cyclobutan-l-aminium chloride

[0357] A mixture of benzyl N-[(l*R,2S*)-2-fluorocyclobutyl] carbamate (300 mg, 1.3 mmol, 1 eq), palladium hydroxide on carbon (60 mg, contained -50% water, 20% w / w) and HCI (4.0 M in 1,4-dioxane, 0.6 mL) in methanol (5.0 mL) was stirred at ambient temperature for 16 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under vacuum to afford (lR*,2S*)-2- fluorocyclobutan-1 -amine hydrochloride (crude, 200 mg) as a light yellow semi-solid, which was used for the next step without further purification. LC / MS: mass calcd. For C4H8FN: 89.06, found: 90.06 [M+H]+.

[0358] A mixture of formaldehyde solution (2.7 g, 35% in water, 31.9 mmol, 20 eq.) and HCOOH (439.8 mg, 9.6 mmol, 6 eq) was stirred at 55 °C for 1 h. To this was added dropwise a solution of (lR*,2S*)-2-fhiorocyclobutan-l-amine hydrochloride (200.0 mg, 1.6 mmol, 1 eq) in NaHCCh solution (267.6 mg, 3.2 mmol, 2 eq.). The resulting mixture was stirred at ambient temperature for 5 days. The reaction was cooled to 0 °C and then diluted with toluene (10 mL). The mixture was basified to pH 14 with NaOH (4 M) and extracted with toluene (10 mL). The organic layer was washed with brine and dried over Na2SO4 to afford (lR*,2S*)-2-fluoro-N, N-dimethylcyclobutan-1 -amine as a crude solution in toluene. To the above solution was added acetonitrile (5.0 mL) and propargyl chloride (2.5 g, 34.1 mmol, 20.0 eq.) at ambient temperature. The resulting solution was stirred at 55 °C for 5 days and then concentrated under vacuum. The residue was purified by trituration with a 1 : 10 acetonitrile-diethyl ether solution 3 times, the solid was dried under vacuum to afford (lR*,2S*)-2-fluoro-N, N-dimethyl -N-(prop-2-yn-l-yl) cyclobutan-l-aminium chloride (56.3 mg, 17% yield for 2 step) as a brown oil. LC / MS: mass calcd. For C9H15FNL 156.12, found: 156.12 [M]+. ‘H NMR (300 MHz, DMSO) 5: 5.40 - 5.66 (m, 1H), 4.47 - 4.56 (m, 2H), 4.29 - 4.45 (m, 1H), 4.14 (t, J = 2.4 Hz, 1H), 3.17 (d, J= 11.1 Hz, 6H), 2.77 - 2.98 (m, 1H), 1.95 - 2.37 (m, 3H).19F NMR (282 MHz, DMSO) 5: -197.91.

[0359] A mixture of benzyl N-[(lS*,2S*)-2-fluorocyclobutyl] carbamate (300.0 mg, 1.3 mmol, 1.0 eq.), palladium hydroxide on carbon (60 mg, contained -50% water, 20% w / w) and HCI (4.0 M in 1,4-dioxane, 0.6 mL) in methanol (5.0 mL) was stirred at ambient temperature for 16 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under vacuum to afford (lS*,2S*)-2-fhiorocyclobutan-l-amine hydrochloride (crude, 170.0 mg) as a white solid, which was used for the next step without further purification. LC / MS: mass calcd. For C4H8FN: 89.06 found: 90.06 [M+H]+.

[0360] A mixture of formaldehyde solution (2.3 g, 35% in water, 27.1 mmol, 20.0 eq.) and HCOOH (373.9 mg, 8.1 mmol, 6.0 eq) was stirred at 55 °C for 1 h. To this was added dropwise a solution of (lS,2S)-2-fhiorocyclobutan-l-amine hydrochloride (170.0 mg, 1.4 mmol, 1.0 eq.) in NaHCCh solution (227.5 mg, 2.7 mmol, 2.0 eq). The resulting mixture was stirred at ambient temperature for 5 days. The reaction was cooled to 0 °C and then diluted with toluene (lOmL). The mixture was basified to pH 14 with NaOH (4 M) and extracted with toluene (10 mL). The organic layer was washed with brine and dried over Na2SO4. The solid was filtered out to afford (lS*,2S*)-2-fluoro-N, N-dimethylcyclobutan-1 -amine as a crude solution in toluene. To the above solution was added acetonitrile (5.0 mL) and propargyl chloride (2.2 g, 29 mmol, 20 eq.) at ambient temperature. The resulting solution was stirred at 55 °C for 5 days and then concentrated under vacuum. The residue was purified by trituration with a 1 : 10 acetonitrile-di ethyl ether solution 3 times, then the solid was dried under vacuum to afford (lS*,2S*)-2-fluoro-N, N-dimethyl -N-(prop-2-yn-l-yl) cyclobutan-l- aminium chloride (53.4 mg, 19% yield for 2 step) as a brown oil. LC / MS: mass calcd. For C9HI5FN+: 156.12, found: 156.12 [M]+. ‘H NMR (300 MHz, DMSO) 5: 5.35 - 5.65 (m, 1H), 4.54 (d, J= 2.7 Hz, 2H), 4.32 - 4.50 (m, 1H), 4.12 (t, J= 2.4 Hz, 1H), 3.14 (d, J = 4.5 Hz,6H), 2.16 - 2.30 (m, 1H), 1.98 - 2.14 (m, 1H), 1.66 - 1.97 (m, 2H).19F NMR (282 MHz, DMSO) 5: -164.40.

[0361] A mixture of benzyl N-[(lS*,2R*)-2-fluorocyclobutyl] carbamate (300.0 mg, 1.3 mmol, 1.0 eq.), palladium hydroxide on carbon (60.0 mg, -50% water, 20% w / w) and HCI (4.0 M in 1,4-dioxane, 0.6 mL) in methanol (3.0 mL) was stirred at ambient temperature for 16 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under vacuum to afford (lS*,2R*)-2- fluorocyclobutan-1 -amine hydrochloride (crude, 200.0 mg) as a white solid, which was used for the next step without further purification. LC / MS: mass calcd. For C4H8FN: 89.06 found: 90.06 [M+H]+.

[0362] A mixture of formaldehyde solution (2.6 g, 35% in water, 32.0 mmol, 20 eq.) and HCOOH (441.6 mg, 9.6 mmol, 6 eq.) was stirred at 55 °C for 1 h. To this solution was added dropwise a solution of (lS*,2R*)-2-fluorocyclobutan-l-amine hydrochloride (200.0 mg, 1.6 mmol, 1.0 eq.) in NaHCCF solution (267.6 mg, 3.2 mmol, 2.0 eq.). The resulting mixture was stirred at ambient temperature for 5 days. The reaction was cooled to 0 °C and then diluted with toluene (10 mL). The mixture was basified to pH 14 with NaOH (4 M) and extracted with toluene (10 mL). The organic layer was washed with brine and dried over IS^SCU to afford (lS*,2R*)-2-fluoro-N, N-dimethyl cyclobutan-1 -amine as a crude solution in toluene. To the above solution was added acetonitrile (5.0 mL) and 3 -chloroprop- l-yne (2.4 g, 32 mmol, 20 eq.) at ambient temperature. The resulting solution was stirred at 55 °C for 5 days and then concentrated under vacuum. The residue was purified by trituration with a 1 : 10 acetonitrile-diethyl ether solution 3 times, the solid was dried under vacuum to afford (lS*,2R*)-2-fluoro-N, N-dimethyl -N-(prop-2-yn-l-yl) cyclobutan-l-aminium chloride (50.0 mg, 15% yield for 2 step) as a light brown oil. LC / MS: mass calcd. For C9H15FNL 156.12,found: 156.12 [M]+.1H NMR (300 MHz, DMSO) 5: 5.39 - 5.66 (m, 1H), 4.49 - 4.57 (m, 2H), 4.31 - 4.48 (m, 1H), 4.13 (t, J= 2.4 Hz, 1H), 3.17 (d, J = 11.1 Hz, 6H), 2.77 - 2.98 (m, 1H), 1.93 - 2.35 (m, 3H).19F NMR (282 MHz, DMSO) 5: -197.90.

[0363] A solution of thi etan-3 -amine hydrochloride (1.0 g, 8.0 mmol, 1.0 eq.) in H2O (5.0 mL) was treated with NaHCCL (0.74 g, 8.7 mmol, 1.1 eq.) at room temperature for Ih under nitrogen atmosphere. In another 40 mL reaction flask was added HCOOH (10 mL) and formaldehyde solution (1.9 g, 23.8 mmol, 3.0 eq., 36% wt%) which was stirred at 55°C for 1 h under nitrogen atmosphere. To this was added the neutralized thi etan-3 -amine hydrochloride solution at room temperature. The resulting mixture was stirred at 55 °C for 16 h under nitrogen atmosphere. The reaction was poured into water / ice at 0 °C. The mixture was basified to pH=14 with NaOH (aq.) (10M). The resulting mixture was extracted with DCM (3x10 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford N, N-dimethylthietan-3-amine (1.0 g) as a brown oil. The crude product was used in the next step directly without further purification. LC / MS: mass calcd. For C5H11NS: 117.06, found: 118.35 [M+H]+.

[0364] A solution of N, N-dimethylthi etan-3 -amine (200.0 mg, 1.7 mmol, 1.0 eq.) and propargyl chloride (381.4 mg, 5.1 mmol, 3.0 eq.) in acetonitrile (5.0 mL) was stirred at 55 °C for 16 h under nitrogen atmosphere. The precipitated solids were collected by filtration, washed with acetonitrile (3x5 mL) and dried under vacuum. This resulted in N, N-dimethyl-Example 27: Synthesis of cZs-N,N-dimethyl-N-(prop-2-yn-l-yl)thietan-3-aminium 1- oxide chloride

[0365] To a stirred solution of thi etan-3 -amine hydrochloride (1.0 g, 8.0 mmol, 1.0 eq.) and BOC2O (2.6 g, 11.9 mmol, 1.5 eq.) in DCM (10.0 mL) and THF (10.0 mL) was added TEA (2.4 g, 23.9 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature for 16 h under air atmosphere. The resulting mixture was concentrated under reduced pressure The residue was purified by silica gel column chromatography eluted

[0366] To a stirred solution of tert-butyl N-(thi etan-3 -yl)carbamate (1.5 g, 7.9 mmol, 1.0 eq.) in DCM (15.0 mL) was added mCPBA (1.1 g, 6.3 mmol, 0.8 eq.). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with the following conditions: column, C18 column; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The fractions were combined and concentrated to afford two products: cz.s-tert-butyl (l-oxidothietan-3-yl)carbamate (380 mg,

[0367] To a stirred solution of cz.s-tert-butyl (1-oxidothi etan-3 -yl)carbamate (120.0 mg, 0.58 mmol, 1.0 eq.) in DCM (5.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford cz -3-amino-llambda4-thietan-l-one TFA salt (120 mg, crude) as a yellow oil. LC / MS: mass calcd. For C3H7NOS: 105.02, found: 106.25 [M+H]+.

[0368] A mixture of formaldehyde solution (282.1 mg, 3.4 mmol, 6.0 eq., 37% in water) and formic acid (133.0 mg, 2.8 mmol, 5.0 eq.) was stirred at 55°C for 1 h. 3-aminothietan-l- ium-l-olate TFA salt (120.0 mg crude, -0.58 mmol) in H2O (0.3 mL) was neutralized with NaOH aq. (0.3 mL, 2 M), then it was added to the above mixture dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for additional 17 h. The resulting mixture was poured into ice water (5 mL). The mixture was basified to pH 14 with NaOH (2 M) and extracted with CH2CI2 (10 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used for the next step directly without further purification. LC / MS: mass calcd. For C5H11NOS: 133.06, found: 134.00 [M+H]+.

[0369] To the above crude product was added acetonitrile (4.0 mL) and propargyl chloride propargyl chloride (223.7 mg, 3.0 mmol, 5.0 eq.). The resulting mixture was stirred at 55 °C for 4 days. After cooling to room temperature, the precipitated solids were collected by filtration and washed with MeCN (3x1 mL), dried under vacuum. This resulted in cis-N,N-dimethyl-N-(prop-2-yn- l-yl)thi etan-3 -aminium 1-oxide chloride (48.1 mg, 30.8% yield) as an off-white solid. LC / MS: mass calcd. For CsHuNOS: 172.08, found: 172.10 [M]+. ‘H NMR (300 MHz, DMSO) 54.40 (s, 2H), 4.26 - 4.38 (m, 1H), 4.03 - 4.19 (m, 3H), 3.57 - 3.74 (m, 2H), 3.13 (s, 6H).Example 28: Synthesis of trans-N,N-dimethyl-N-(prop-2-yn-l-yl)thietan-3-aminium 1- oxide chloride

[0370] To a stirred solution of / ra / z.s-tert-butyl (l-oxidothietan-3-yl)carbamate (120.0 mg,O.58 mmol, 1.0 eq.) in DCM (5.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford trans-3 -amino- llambda4-thietan-l -one TFA salt (120 mg, crude) as a yellow oil. LC / MS: mass calcd. For C3H7NOS: 105.02, found: 106.00 [M+H]+.

[0371] A mixture of formaldehyde solution (282.1 mg, 3.4 mmol, 6.0 eq., 37% in water) and formic acid (133.0 mg, 2.9 mmol, 5.0 eq.) was stirred at 55 °C for 1 h. Trans-3- aminothietan-l-ium-l-olate TFA salt (120.0 mg crude, -0.58 mmol) in H2O (0.3 mL) wasneutralized with NaOH aq. (0.3 mL, 2 M), then it was added to the above mixture dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for additional 17 h. The resulting mixture was poured into ice water (5 mL). The mixture was basified to pH 14 with NaOH (2 M) and extracted with CH2Q2 (3x10 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used for the next step directly without further purification. LC / MS: mass calcd. For C5H11NOS: 133.06, found: 134.05 [M+H]+.

[0372] To the above crude product was added acetonitrile (4.0 mL) and propargyl chloride (223.7 mg, 3.0 mmol, 5.0 eq.). The resulting mixture was stirred at 55 °C for 16 h. After cooling to room temperature, the precipitated solids were collected by filtration and washedExample 29: Synthesis of (ls,3s)-3-methanesulfonyl-N,N-dimethyl-N-(prop-2-yn-l- yl)cyclobutan-l-aminium

[0373] A solution of formic acid (138.0 mg, 3.0 mmol, 5.00 eq.) and formaldehyde (276.1 mg, 3.6 mmol, 6.0 eq., 37% in water) was stirred at 55 °C for 1 h. (ls,3s)-3- methanesulfonylcyclobutan-1 -amine hydrochloride (104.9 mg, 0.6 mmol, 1.0 eq.) in H2O (0.5 mL) was neutralized with NaOH aq. (0.3 mL, 2 M), then it was added to the above mixture dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for 17 h. The resulting mixture was poured into ice water (5 mL). The mixture was basified to pH 14 with NaOH (2 M) and extracted with CH2CI2 (10 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used for the next step directly without further purification. LCMS: mass calcd. For C7HI5NO2S: 177.08, found: 178.15 [M+H]+.

[0374] To the above crude product was added MeCN (1.0 mL) and propargyl chloride (94.2 mg, 1.3 mmol, 1.6 eq.) at room temperature. The resulting solution was stirred at 55 °C for 17 h. After cooling to room temperature, the precipitated solids were collected by filtration and washed with MeCN (3x1 mL), dried under vacuum. This resulted in (ls,3s)-3-Example 30: Synthesis of (lr,3r)-N,N-dimethyl-3-(methylsulfonyl)-N-(prop-2-yn-l yl)cyclobutan-l-aminium chloride

[0375] A solution of formaldehyde (210.8 mg, 2.6 mmol, 6.0 eq., 37% in water) and formic acid (100.0 mg, 2.17 mmol, 5.0 eq.) at 55 °C for Ih. (lr,3r)-3-methanesulfonylcyclobutan-l- amine (64.84 mg, 0.44 mmol, 1.0 eq.) in H2O (0.5 mL) was neutralized with aq. NaOH (0.22 mL, 2 M), then it was added to the above mixture dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for an additional 4 days. The resulting mixture was poured into ice water (5 mL). The residue was basified to pH=14 with NaOH (aq.). The aqueous layer was extracted with CH2Q2 (3x4 mL). The organic phases were combined and dried by anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used for the next step without any purification. LCMS: mass calcd. For C7HI5NO2S: 177.08, found: 178.20 [M+H]+.

[0376] To the above crude product was added acetonitrile (1.5 mL) and propargyl chloride (94.6 mg, 1.3 mmol, 1.5 eq.) at 55 °C. The resulting mixture was stirred at 55 °C for 16 h. After cooling to room temperature, the precipitated solids were collected by filtration and washed with acetonitrile (3x3 mL), dried under vacuum to afford (lr,3r)-3-methanesulfonyl- N,N-dimethyl-N-(prop-2-yn-l-yl)cyclobutan-l-aminium chloride (42.3 mg, 19.8% yield) as a white solid. LCMS: mass calcd. For CioHi8N02S: 216.11, found: 216.10 [M]+. 'H NMR (300 MHz, DMSO-tL) 6: 4.38 - 4.53 (m, 3H), 4.10 (s, IH), 3.85 - 3.96 (m, IH), 2.97 - 3.16 (m, 11H), 2.55 - 2.67 (m, 2H).Example 31: Synthesis of 3-methanesulfonyl-N,N-dimethyl-N-(prop-2-yn-l- yl)bicyclo[l.l.l]pentan-l-aminium chloride

[0377] A mixture of formaldehyde solution (502.7 mg, 6.2 mmol, 5.0 eq., 37% in water) and HCOOH (345.0 mg, 7.5 mmol, 6.0 eq.) was stirred at 55 °C for 1 h. To the above mixture was added 3-methanesulfonylbicyclo[l.l. l]pentan-l-amine (200.0 mg, 1.2 mmol, 1.0 eq.) over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for an additional 17 h. The resulting mixture was poured into ice water (20 mL). The mixture was basified to pH = 14 with 2M NaOH aq. The resulting mixture was extracted with DCM (2 x 10 mL) and then the combined organic phases were dried over anhydrous Na2SO4. The solid was filtered out and the filtrate was concentrated. 200 mg crude of 3-methanesulfonyl-N,N- dimethylbicyclo[l.l. l]pentan-l -amine was obtained as a white solid. The crude product was used for the next step directly without further purification. LCMS: mass calcd. For C8HI5NO2S: 189.08, found: 190.10 [M+H]+.

[0378] To the above crude product (200 mg crude, 1.1 mmol, 1.0 eq.) was added acetonitrile (1.5 mL) and propargyl chloride (162.8 mg, 2.2 mmol, 2.0 eq.) dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 17 h. After cooling to r.t., the precipitated solids were collected by filtration and washed with acetonitrile (2 mL), then dried underExample 32: Synthesis of (3R)-N,N-dimethyl-l,l-dioxo-N-(prop-2-yn-l-yl)- tetrahydrothiophen-3-aminium chloride

[0379] A mixture of formaldehyde solution (209.9 mg, 7.0 mmol, 6.0 eq., 37%) andHCOOH (268.2 mg, 5.8 mmol, 5.0 eq.) was stirred at 55 °C for 1 h. In another round-bottomflask was added (3R)-3-amino- tetrahydrothiophene- 1,1 -di one hydrochloride (200.0 mg, 1.2 mmol, 1.0 eq.) and H2O (0.5 mL). The mixture was neutralized with NaOH aq. (0.6 mL, 2 M), then it was added to the first solution dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 17 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature. To the reaction was added H2O (3 mL) at room temperature. The mixture was basified to pH=4 with NaOH (aq.) (3M). The resulting mixture was extracted with DCM (3x20 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (3R)-3 -(dimethylamino)- tetrahydrothiophen -1,1-dione (180.0 mg) as a light yellow oil. The crude product was used in the next step directly without further purification. LCMS: mass calcd. For C6Hi3NO2S: 163.07, found: 164.15 [M+H]+.

[0380] A solution of (3R)-3 -(dimethylamino)- tetrahydrothiophen- 1,1 -di one (180.0 mg, 1.1 mmol, 1.0 eq.) and propargyl chloride (821.6 mg, 11.0 mmol, 10.0 eq.) in acetonitrile (3.0 mL) was stirred at 55 °C for 17 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The resulting solid was washed with acetonitrile (3x3 mL), dried under vacuum. This resulted in (3R)-N,N-dimethyl-l,l-dioxo-N-(prop-2-yn-l-yl)-Example 33: Synthesis of (3S)-N,N-dimethyl-l,l-dioxo-N-(prop-2-yn-l-yl)- tetrahydrothiophen -3-aminium chloride

[0381] A mixture of formaldehyde solution (174.9 mg, 5.8 mmol, 5.0 eq. 37%) and HCOOH (321.8 mg, 7.0 mmol, 6.0 eq.) was stirred at 55 °C for 1 h. In another round-bottom flask was added was added (3 S)-3 -amino-tetrahydrothiophene -1,1-dione hydrochloride (200.0 mg, 1.2 mmol, 1.0 eq.) in H2O (0.5 mL). The mixture was neutralized with NaOH aq. (0.6 mL, 2 M), then it was added to the first solution dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 17 h under nitrogen atmosphere. The reaction mixture wascooled to room temperature. To the reaction was added H2O (3 mL) at room temperature. The mixture was basified to pH=14 with NaOH (aq.) (3M). The resulting mixture was extracted with DCM (3x15 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (3 S)-3 -(dimethylamino)- tetrahydrothiophene -1,1-dione (120.0 mg) as a light yellow oil. The crude product was used in the next step directly without further purification. LCMS: mass calcd. For C6H13NO2S: 163.07, found: 164.15 [M+H]+.

[0382] A solution of (3 S)-3 -(dimethylamino)- tetrahydrothiophene -1,1-dione (120.0 mg, 0.7 mmol, 1.0 eq.) and propargyl chloride (543.0 mg, 7.3 mmol, 10.0 eq.) in acetonitrile (2 mL) was stirred at 55 °C for 17 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The resulting solid was washed with acetonitrile (3x3 mL), dried under vacuum. This resulted in (3S)-N,N-dimethyl-l,l-dioxo-N-(prop-2-yn-l-yl)-Example 34: Synthesis of N,N-dimethyl-l,l-dioxo-N-(prop-2-en-l-yl)- tetrahydrothiophen-3-aminium chloride

[0383] A mixture of formaldehyde solution (668.9 mg, 8.3 mmol, 5.0 eq., 37% in water) and HCOOH (455.9 mg, 9.9 mmol, 6.0 eq.) was stirred at 55 °C for 1 h. To the above mixture was added 3 -amino-tetrahydrothiophene -1,1-dione (200.0 mg, 1.7 mmol, 1.0 eq.) dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for an additional 17h. The resulting mixture was poured into ice water (5 mL). The mixture was basified to pH=14 with 2M NaOH aq. The resulting mixture was extracted with DCM (2x5 mL) and then the combined organic phases were dried over anhydrous Na2SO4. The solid was filtered out and the filtrate was concentrated. 200.0 mg crude of 3-(dimethylamino)- tetrahydrothiophene -1,1 -di one was obtained as a yellow oil. The crude product was used for the next step directly without further purification. LC / MS: mass calcd. For C5H11NO2S: 149.05, found: 150.25 [M+H]+.

[0384] To the above crude product (200.0 mg crude, 1.3 mmol, 1.0 eq.) was added acetonitrile (2.0 mL) and then propargyl chloride (205.1 mg, 2.7 mmol, 2.0 eq.) dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 2 h. After cooling to r.t., the precipitated solids were collected by filtration and washed with MeCN (2 mL), then dried under vacuum. This resulted in N,N-dimethyl-l,l-dioxo-N-(prop-2-en-l-yl)-tetrahydrothiophene-3-aminium chloride (32.5 mg, 10.7% yield) as a white solid. LCMS: mass calcd. For CsHieNCLS:

[0385] To a stirred solution of thiolan-3 -amine (4.4 g, 42.6 mmol, 1.0 eq.) and BOC2O (13.9 g, 63.9 mmol, 1.5 eq.) in DCM (80.0 mL) was added TEA (12.9 g, 127.9 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column

[0386] To a stirred solution of tert-butyl N-(thiolan-3-yl)carbamate (5.9 g, 29.0 mmol, 1.0 eq.) in DCM (100 mL) was added mCPBA (4.0 g, 23.2 mmol, 0.8 eq.). The resulting mixturewas stirred at room temperature for 1 h. The residue was purified by silica gel column chromatography, eluted with CITCb / MeOH (20: 1) to afford tert-butyl N-(l-oxo-llambda4- thiolan-3-yl)carbamate (5.0 g, 78.5% yield) as a white solid. LCMS: mass calcd. For C9H17NO3S: 219.09, found: 220.00 [M+H]+.

[0387] Tert-butyl (1-oxidotetrahydrothi ophen-3 -yl)carbamate (6.1 g) was purified by PREP ACHIRAL SFC with the following conditions: Column: YMC-Actus Triart Diol- HILIC, 5pm, 30 mm*250 mm; Mobile Phase A: CO2, Mobile Phase B: ACN: MeOH=4: 1 (with 0.3% NH3 (7 M in MeOH)); Flow rate: 100 mL / min; Gradient (B%): isocratic 15% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 254 nm; RT1: 3.05 min; RT2: 5.4 min; Total Elution Time: 7 min; Pressure(Bar): 100; Sample Solvent: MEOH; Injection Volume: 2.5 mL; Number Of Runs: 42.0. The fractions were combined and concentrated to afford two products: The first peak (RT=3.05 min): (randomly assigned cis) tert-butyl (1-oxidotetrahydrothi ophen-3 -yl)carbamate (4.5 g, 73.7%yield). LCMS: mass calcd. For C9H17NO3S: 219.09, found: 220.00[M+H]+. 'H NMR (300 MHz, DMSO) 5: 7.09 (d, J= 7.6 Hz, 1H), 4.01 - 4.23 (m, 1H), 3.34 - 3.43 (m, 1H), 2.75 - 2.95 (m, 2H), 2.42 - 2.48 (m, 1H), 2.17 - 2.33 (m, 2H), 1.38 (s, 9H); The second peak (RT=5.4 min): (randomly assigned trans) tert-butyl (l-oxidotetrahydrothiophen-3-yl)carbamate (1.6 g, 26.2% yield) as a white solid. LC / MS: mass calcd. For C9H17NO3S: 219.09, found; 220.00[M+H]+. ‘H NMR (300 MHz, DMSO) 5 7.14 (d, J= 7.3 Hz, 1H), 4.40 - 4.58 (m, 1H), 3.03 - 3.19 (m, 1H), 2.78 -2.97 (m, 2H), 2.60 - 2.72 (m, 1H), 2.34 - 2.47 (m, 1H), 1.83 - 1.99 (m, 1H), 1.39 (s, 9H).

[0388] (randomly assigned cis) tert-butyl (l-oxidotetrahydrothiophen-3-yl)carbamate (4.5 g) was purified by Prep-SFC with the following conditions: Column: CHIRALPAK IH 3*25 cm, 5 urn; Mobile Phase A: CO2, Mobile Phase B: MEOH: MTBE=1 : l(0.1%2M NH3- MeOH); Flow rate: 100 mL / min; Gradient (B%)12% B; RTl(min): 7; RT2(min): 9; Total Elution Time(min): 11; Sample Solvent: ACN-MEOH=3: 1; Injection Volume: 0.8 mL; Number Of Runs: 70) to afford two enantiomers. The first peak (RT=7 min): (randomly assigned c / .sj-tert-butyl ((3 S*)- 1-oxidotetrahydrothi ophen-3 -yl)carbamate (1.7 g, 37.7%yield) as a white solid. LC / MS: mass calcd. For C9H17NO3S: 219.09, found: 220.00[M+H]+. 'H NMR (300 MHz, DMSO) 5: 7.09 (d, J= 7.6 Hz, IH), 4.01 - 4.23 (m, IH), 3.34 - 3.43 (m, IH), 2.75 - 2.95 (m, 2H), 2.42 - 2.48 (m, IH), 2.17 - 2.33 (m, 2H), 1.38 (s, 9H);

[0389] The second peak (RT=9 min): (randomly assigned cis) tert-butyl ((3R*)-1- oxidotetrahydrothiophen-3-yl)carbamate (1.8 g, 40.0%yield) as a white solid. LCMS: mass calcd. For C9H17NO3S: 219.09, found: 220.00[M+H]+. NMR (3010H MHz, DMSO) 5: 7.09(d, J= 7.6 Hz, 1H), 4.01 - 4.23 (m, 1H), 3.34 - 3.43 (m, 1H), 2.75 - 2.95 (m, 2H), 2.42 - 2.48 (m, 1H), 2.17 - 2.33 (m, 2H), 1.38 (s, 9H)

[0390] To a stirred solution of (randomly assigned cis )-tert-butyl ((3S*)-1- oxidotetrahydrothiophen-3-yl)carbamate (300.0 mg, 1.36 mmol, 1.0 eq.) in DCM (5.0 mL) was added TFA (1.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford (randomly assigned cis (3S*)-3-aminotetrahydrothiophene 1 -oxide TFA salt (300 mg, crude) as a yellow oil. LCMS: mass calcd. For C4H9NOS: 119.04, found: 120.25 [M+H]+.

[0391] A solution of formic acid (312.8 mg, 6.8 mmol, 5.0 eq.) and formaldehyde solution (664.6 mg, 8.2 mmol, 6.0 eq., 37% in water) was stirred at 55 °C for Ih. (randomly assigned cis) (3S*)-3-aminotetrahydrothiophene 1-oxide TFA salt (300 mg crude, -1.36 mmol) in H2O (0.3 mL) was neutralized with NaOH aq. (0.6 mL, 2 M), then it was added to the above mixture dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for additional 17 h. The resulting mixture was poured into ice water (5 mL). The mixture was basified to pH=14 with NaOH (2 M) and extracted with CH2Q2 (10 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used for the next step directly without further purification. LCMS: mass calcd.[M+H]+.

[0392] To the above crude product was added acetonitrile (4.00 mL) and propargyl chloride (503.2 mg, 6.8 mmol, 5.0 eq.). The resulting mixture was stirred at 55 °C for 17 h. After cooling to room temperature, the precipitated solids were collected by filtration and washed with MeCN (3x1 mL), dried under vacuum. This resulted in (randomly assigned cis) (3S*)- N,N-dimethyl-N-(prop-2-yn- l-yl)tetrahydrothi ophen-3 -aminium 1-oxide chloride (31.9 mg, 10.6% yield) as a white solid. LCMS: mass calcd. For C9H16NOS: 186.09, found: 186.05 [M+H]+.1H NMR (400 MHz, DMSO) 54.51 - 4.65 (m, 3H), 4.17 (s, IH), 3.51-3.59 (m, IH), 3.35 - 3.39 (m, IH), 3.11-3.19 (m, 7H), 2.62 - 2.85 (m, 3H).Example 36: Synthesis of trans-(3R*)-N,N-dimethyl-N-(prop-2-yn-l- yl)tetrahydrothiophen-3-aminium 1-oxide chloriderandomly assigned transstereochemistry randomly stereochemistry randomly mixture of enantiomers assigned assignedstereochemistry randomly assigned

[0393] (Randomly assigned trans) tert-butyl (1-oxidotetrahydrothi ophen-3 -yl)carbamate (1.6 g) was purified by Prep-SFC with the following conditions (Column: CHIRALPAK IH 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.1% 7M NHs-MeOH); Flow rate: 80 mL / min; Gradient (B%): isocratic 40% B; RTl(min): 4.4; RT2(min): 5; Total Elution Time(min): 6; Sample Solvent: ACN: MEOH=4: 1; Injection Volume: 0.5 mL; Number Of Runs: 60) to afford two enantiomers. The first peak (RT=4.4 min): (randomly assigned trans) tert-butyl ((3R*)-l-oxidotetrahydrothiophen-3-yl)carbamate (510 mg, 31.88% yield). LCMS: mass calcd. For C9H17NO3S: 219.09, found: 220.00[M+H]+. ‘H NMR (300 MHz, DMSO) 5 7.14 (d, J= 13 Hz, IH), 4.40 - 4.58 (m, IH), 3.03 - 3.19 (m, IH), 2.78 -2.97 (m, 2H), 2.60 - 2.72 (m, IH), 2.34 - 2.47 (m, IH), 1.83 - 1.99 (m, IH), 1.39 (s, 9H). The second peak (RT=5 min): (Randomly assigned trans) tert-butyl ((3S*)-l-oxidotetrahydrothiophen-3-yl)carbamate (520.0 mg, 32.50% yield) as a white solid. LCMS: mass calcd. For C9H17NO3S: 219.09, found: 220.00 [M+H]+. ‘H NMR (300 MHz, DMSO) 5 7.14 (d, J= 13 Hz, IH), 4.40 - 4.58 (m, IH), 3.03 - 3.19 (m, IH), 2.78 -2.97 (m, 2H), 2.60 - 2.72 (m, IH), 2.34 - 2.46 (m, IH), 1.83 - 1.98 (m, IH), 1.39 (s, 9H).

[0394] To a stirred solution of (randomly assigned trans) tert-butyl ((3R*)-1- oxidotetrahydrothiophen-3-yl)carbamate (250 mg, 1.14 mmol, 1.0 eq.) in DCM (6.0 mL) was added TFA (1.2 mL). The resulting mixture was stirred at 55 °C for 1 h. The resulting mixture was concentrated under reduced pressure to afford (randomly assigned trans) (3R*)- 3 -aminotetrahydrothiophene 1 -oxide (250 mg, crude) as a yellow oil. LCMS: mass calcd. For C4H9NOS: 119.04, found: 120.05[M+H]+.

[0395] A solution of formic acid (262.2 mg, 5.7 mmol, 5.0 eq.) and formaldehyde solution (551.3 mg, 6.8 mmol, 6.0 eq., 37% in water) was stirred at 55 °C for 1 h. (Randomly assigned trans) (3R*)-3-aminotetrahydrothiophene 1-oxide TFA salt (250 mg crude, -1.14 mmol) inH2O (0.3 mL) was neutralized with NaOH aq. (0.6 mL, 2 M), then it was added to the above mixture dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for additional 17 h. The resulting mixture was poured into ice water (5 mL). The mixture was basified to pH=14 with NaOH (2 M) and extracted with CH2Q2 (10 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used for the next step directly without further purification. LCMS: mass cal cd. For found: 148.25[M+H]+.

[0396] To the above crude product was added acetonitrile (4.00 mL) and propargyl chloride (421.8 mg, 5.7 mmol, 5.0 eq.). The resulting mixture was stirred at 55 °C for 17 h. After cooling to room temperature, the precipitated solids were collected by filtration and washed with MeCN (3x1 mL), dried under vacuum. This resulted in (randomly assigned trans) (3R*)-N,N-dimethyl-N-(prop-2-yn-l-yl)tetrahydrothiophen-3-aminium 1-oxide chloride (34.8 mg, 13.8% yield) as a white semi-solid. LCMS: mass calcd. For C9H16NOS: 186.09, found: 186.05[M]+.1H NMR (300 MHz, DMSO) 5 4.69 - 4.83 (m, 1H), 4.52 - 4.56 (m, 2H), 4.12 - 4.18 (m, 1H), 3.36 - 3.42 (m, 1H), 3.30 - 3.35 (m, 1H), 3.20 - 3.30 (m, 1H), 3.13 - 3.19 (m, 6H), 2.80 - 2.93 (m, 1H), 2.52 - 2.69 (m, 2H).

[0397] To a stirred solution of (randomly assigned cis) tert-butyl ((3R*)-1- oxidotetrahydrothiophen-3-yl)carbamate (300.0 mg, 1.36 mmol, 1.0 eq.) in DCM (5.0 mL) was added TFA (1.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford (randomly assigned cis) (3R*)-3-aminotetrahydrothiophene 1-oxide TFA salt (300 mg, crude) as a yellow oil. LCMS: mass calcd. For C4H9NOS: 119.04, found: 120.25 [M+H]+.

[0398] A solution of formic acid (312.8 mg, 6.8 mmol, 5.0 eq.) and formaldehyde solution (664.6 mg, 8.2 mmol, 6.0 eq., 37% in water) was stirred at 55°C for 1 h. (Randomly assigned cis) (3R*)-3-aminotetrahydrothiophene 1-oxide TFA salt (300 mg crude, -1.36 mmol) inH2O (0.3 mL) was neutralized with NaOH aq. (0.6 mL, 2 M), then it was added to the above mixture dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for additional 17 h. The resulting mixture was poured into ice water (5 mL). The mixture was basified to pH=14 with NaOH (2 M) and extracted with CH2Q2 (10 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used for the next step directly without further purification. LCMS: mass cal cd. For[M+H]+.

[0399] To the above crude product was added acetonitrile (4.00 mL) and propargyl chloride (503.2 mg, 6.8 mmol, 5.0 eq.). The resulting mixture was stirred at 55 °C for 17 h. After cooling to room temperature, the precipitated solids were collected by filtration and washed with MeCN (3x1 mL), dried under vacuum. This resulted in (randomly assigned cis) (3R*)- N,N-dimethyl-N-(prop-2-yn- l-yl)tetrahydrothi ophen-3 -aminium 1-oxide chloride (36.0 mg, 112.0% yield) as a white solid. LCMS: mass calcd. For CgHieNOS: 186.09, found: 186.05 [M+H]+.1H NMR (400 MHz, DMSO) 54.51 - 4.65 (m, 3H), 4.17 (s, 1H), 3.51-3.59 (m, 1H), 3.35 - 3.39 (m, 1H), 3.11-3.19 (m, 7H), 2.62 - 2.85 (m, 3H).

[0400] To a stirred solution of (randomly assigned trans) tert-butyl ((3S*)-1- oxidotetrahydrothiophen-3-yl)carbamate (250.0 mg, 1.14 mmol, 1.00 eq.) in DCM (4.00 mL) was added TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for Ih under air atmosphere. The resulting mixture was concentrated under vacuum to afford (randomly assigned trans) (3 S*)-3 -aminotetrahydrothiophene 1-oxide (250 mg, crude) as a colorless oil. LCMS: mass calcd. For C4H9NOS: 119.04, found: 120.25 [M+H]+.

[0401] A solution of formic acid (262.2 mg, 5.7 mmol, 5.0 eq.) and formaldehyde solution (551.3 mg, 6.8 mmol, 6.0 eq., 37% in water) was stirred at 55 °C for 1 h. (Randomly assigned trans) (3S*)-3-aminotetrahydrothiophene 1-oxide TFA salt (250 mg crude, -1.14 mmol) inH2O (0.3 mL) was neutralized with NaOH aq. (0.6 mL, 2 M), then it was added to the above mixture dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for additional 17 h. The resulting mixture was poured into ice water (5 mL). The mixture was basified to pH=14 with NaOH (2 M) and extracted with CH2Q2 (10 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used for the next step directly without further purification. LCMS: mass cal cd. For found: 148.25[M+H]+.

[0402] To the above crude product was added acetonitrile (4.00 mL) and propargyl chloride (421.8 mg, 5.7 mmol, 5.0 eq.). The resulting mixture was stirred at 55 °C for 17 h. After cooling to room temperature, the precipitated solids were collected by filtration and washed with MeCN (3x1 mL), dried under vacuum. This resulted in (randomly assigned trans) (3S*)- N,N-dimethyl-N-(prop-2-yn- l-yl)tetrahydrothi ophen-3 -aminium 1-oxide chloride (33.1 mg, 13.1% yield,) as a white semi-solid. LCMS: mass calcd. For C9H16NOS: 186.29, found: 186.05 [M]+. 1H NMR (300 MHz, DMSO) 54.67 - 4.83 (m, 1H), 4.49 - 4.55 (m, 2H), 4.13 - 4.18 (m, 1H), 3.36 - 3.44 (m, 1H), 3.32 - 3.36 (m, 1H), 3.21 - 3.28 (m, 1H), 3.13 - 3.19 (m, 6H), 2.80 - 2.93 (m, 1H), 2.52 - 2.69 (m, 2H).Example 39: Synthesis of N.N.3-triniethyl-N-(prop-2-yn-l-yl)bicyclo| 1.1.1 |pentan-l- aminium chloride

[0403] A mixture of formaldehyde solution (608.1 mg, 7.5 mmol, 5.0 eq., 37% in water) and HCOOH (415.0 mg, 9.0 mmol, 6.0 eq.) was stirred at 55 °C for 1 h. To the above mixture was added 3-methylbicyclo[l.l. l]pentan-l-amine hydrochloride (200.0 mg, 1.5 mmol, 1.0 eq.). The resulting mixture was stirred at 55 °C for additional 17 h. The resulting mixture was poured into ice water (3 mL). The mixture was basified to pH=14 with sat. NaOH. The aqueous layer was extracted with toluene (2x3 mL). The organic phase was collected and dried by anhydrous Na2SO4 and used in the next step without any purification. LCMS: mass calcd. For C8HI5N: 125.12, found: 126.10 [M+H]+.

[0404] To the above resulting mixture (6.0 mL) was added propargyl chloride (1190.1 mg, 16.0 mmol, 10.0 eq.) dropwise at room temperature. The resulting mixture was stirred for 17h at 55 °C. After cooling to r.t., the precipitated solids were collected by filtration and washed with PhMe (3 mL), then dried under vacuum. N,N, 3 -trimethyl -N-(prop-2-yn-l-Example 40: Synthesis of 3-cyano-N,N-dimethyl-N-(prop-2-yn-l- yl)bicyclo[l.l.l]pentan-l-aminium chloride

[0405] A mixture of formaldehyde solution (249.2 mg, 8.3 mmol, 6.0 eq.) and HCOOH (318.3 mg, 6.9 mmol, 5.0 eq.) was stirred at 55 °C for 1 h. To the above mixture was added 3 -aminobicyclo[l. l.l]pentane-l -carbonitrile hydrochloride (200.0 mg, 1.4 mmol, 1.0 eq.) dropwise over 10 min at 55 °C. The resulting mixture was stirred at 55 °C for additional 17 h. The resulting mixture was poured into ice water (5 mL). The mixture was basified to pH=14 with sat. NaOH (2 mL). The aqueous layer was extracted with DCM (2x5 mL). The organic layers were combined, dried over anhydrous Na2SO4. The solid was filtered out and the filtrate was concentrated. 3 -(dimethylamino)bicyclo[l.l. l]pentane-l -carbonitrile (200.0 mg, crude product) was obtained as yellow oil. The crude product was used in the next step directly without further purification. LCMS: mass calcd. For C8H12N2: 136.10, found: 137.15 [M+H]+.

[0406] To the above crude product (200.0 mg, 1.5 mmol, 1.0 eq.) was added acetonitrile (2.0 mL) and propargyl chloride (0.5 mL) dropwise at 25 °C. The resulting mixture was stirred at 55 °C for 17h. After cooling to r.t., the precipitated solids were collected by filtration and washed with PhMe:MeCN (5: 1, 6 mL), and then dried under vacuum. This resulted in 3-cyano-N N-dimethyl-N-(prop-2-yn-l-yl)bicyclo[l 1 l]pentan-l-aminiumExample 41: Synthesis of 3-fluoro-N,N-dimethyl-N-(prop-2-yn-l- yl)bicyclo[l.l.l]pentan-l-aminium chloride

[0407] A mixture of formaldehyde solution (3.0 g, 36.5 mmol, 5.0 eq., 37% in water) and HCOOH (2.0 g, 43.8 mmol, 6.0 eq.) was stirred at 55 °C for 1 h. In another flask, 3- fhrorobicyclo[l.l. l]pentan-l -amine hydrochloride (1.0 g, 7.3 mmol, 1.0 eq.) was dissolved in H2O (2.0 mL), then it was neutralized with NaOH aq. (3.7 mL, 2M). The obtained solution was added to the first solution dropwise at 55 °C. The resulting mixture was stirred at 55 °C for an additional 17 h. The reaction mixture was used for the next step directly. LC / MS: mass calcd. For C7Hi2FN: 129.10, found: 130.25 [M+H]+.

[0408] To the above reaction mixture was added acetonitrile (10.0 mL) and propargyl chloride (5.0 mL, 67.1 mmol, 9.2 eq.) dropwise at 55 °C. The resulting mixture was stirred at 55 °C for 17 h. After cooling to r.t., the reaction mixture was purified by Prep-HPLC with the following conditions: Column: XBridge BEH Shield RP18 Column, 19*250 mm, 5 pm; Mobile Phase A: water / l OmM NH4HCO3, Mobile Phase B: ACN; Flow rate: 25ml / min mL / min; Gradient (B%): 30% B to 50% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.9. The fractions were combined and lyophilized directly. 47.0 mg of the product with 90% purity was obtained as a yellow oil. The product was dissolved in MeOH and CH3CN (1.0 mL). The resulting mixture was purified by Prep-HPLC for the second time with the following conditions: Column XBridge BEH Shield RP18 Column, 19*250 mm, 5 pm; Mobile Phase A: Water(0.1% HC1), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 0%B to 15%B in 7 min; Wave Length: 254 / 220 nm; RTl(min): 4. The fractions were combined and lyophilized directly. This resulted in 3-fluoro-N,N-dimethyl-N-(prop-2-yn-l- yl)bicyclo[l.l. l]pentan-l-aminium chloride (10.2 mg, 0.7% yield, 99.5% purity) as a colorless oil. LCMS: mass calcd. For CIOHI5F+: 168.12, found: 168.15 [M]+. ‘H NMR (300 MHz, DMSO-tL) 5: 4.48 (s, 2H), 4.12 (s, 1H), 3.16 (s, 6H), 2.63 (s, 6H).Table 1. Compounds of the DisclosureNote: For select compounds, exact stereochemistry is not yet known, though in many case the cis or trans diastereomers have been identified. Examples 1-42 detail the synthetic techniques and the extent to which the compounds have been characterized. Compound with an * denote that absolute stereochemistry is not yet known.Example 42: Assay for Identifying and Characterizing Compounds that Inhibit the Formation of TMA from Choline in Whole Cell Bacteria

[0409] The ability of compounds to inhibit the conversion of choline to TMA in whole cells were determined using methods as described in Wang, Z, Roberts, AB, Buffa JA, et al.(2015) Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis, Cell 163: 1585-1595. Briefly, an overnight culture of wild-type P. mirabilis was diluted 1 : 100 in LB medium and shaken at 37 °C until an ODeoo = 0.5 was reached. At this point, the cells were aliquoted (400 pL) in 13 x 100 mm threaded glass tubes with gastight mininert caps. Potential inhibitor compounds were serially diluted (10-fold) and addedto the reaction mixtures at 1 : 100 dilutions. Each inhibitor concentration was done in triplicate. The mixture was then allowed to incubate for at least 15 minutes before the addition of substrate (choline-d9) to initiate the reaction, which was carried out for 2 hours at 37 °C. The reactions were quenched with the addition of 200 pL of 1 M NaOH and 0.5 pM of the internal standard (25 pM TMA-13C315NI) and put on ice. After 15 minutes, to each reaction mixture was added 1.6 mL lysis buffer, 2 mL hexane, and 1 mL butanol. The tubes were then vortexed for 1 minute and centrifuged at 2500 x g for 10 minutes. The top, organic layer was then transferred to 12 x 75 mm PTFE capped threaded glass tube, acidified with the addition of 200 pl of 0.2 N formic acid, vortexed and the organic and aqueous layers were separated by centrifugation. After centrifugation, an aliquot of formic acid containing the d9- TMA product was transferred to a mass spectrometry vial containing a plastic insert for quantification by stable isotope dilution LC-MS / MS analysis. dg-TMA was quantified by Stable isotope dilution LC-MS / MS analysis.

[0410] The samples were injected onto a reverse phase Cl 8 HPLC column and resolved with a liner gradient using 0.2% formic acid in water and 0.2% formic acid in Methanol; the effluent was analyzed by Shimadzu 8050 triple quadrupole mass spectrometer using electrospray ionization in the positive multiple reaction monitoring (MRM) mode, The dg- TMA were quantified by measuring peak area ratio of the precursor to product ion transition of d9-TMA the internal standard [13C315NI] TMA (m / z: 64>47). Reactionswithout cells were used as blank controls. The average activity for the lowest inhibitor concentration (n=3) was set as 100% and used to normalize the activity for all concentrations tested. The data analyses were performed using GraphPad Prism (vlO). For ICso calculations, the data were fit to a nonlinear regression curve (normalized response, variable slope). Results are shown in Table 2.Note: For select compounds, exact stereochemistry is not yet known, though in many case the cis or trans diastereomers have been identified. Examples 1 -42 detail the synthetic techniques and the extent to which the compounds have been characterized. Compound with an * denote that absolute stereochemistry is not yet known.Example 43: Polymicrobial Screening Method

[0411] Human fecal polymicrobial incubation with deuterium labeled choline compound screening method, including cell viability assay. All materials are pre-reduced in an anaerobic chamber for 24 hours before using in the experiments and experimental procedures are performed under anaerobic conditions (chamber purged with 85% nitrogen, 5% hydrogen, 10% carbon dioxide).

[0412] Human fecal samples are collected from a healthy male volunteer with no chronic illnesses, blood borne diseases or active infections. The volunteer had not received antibiotics within two months prior to donation and provided written informed consent. Samples are diluted to make a 20% (w / v) fecal slurry by resuspension of the feces in a media containing 3% (w / v) tryptic soy broth, 1% (w / v) trehalose, pH 7.3. The fecal slurry is homogenized and

[0413] For the PrestoBlue cell viability assay, an aliquot of the fecal polymicrobial community assay is added to M9 media in a black, clear bottom 96 well plate. To this is added PrestoBlue reagent, covered and shaken for 1 minute at 800 rpm. The plates are incubated at 37 °C for 30 minutes and fluorescence read following the manufacturers instructions. Cell viability is calculated as % fluorescence compared to vehicle control (e.g., 1% DM SO).Example 44: Direct and Time-Dependent Inhibition of CYP Enzymes

[0414] The compounds disclosed herein feature a terminal alkyne or proparylamines, where the alkyne is terminal. A recognized risk of terminal alkynes and propargylamines is the compound reacting with proteins or forming metabolites that can react with proteins. This type of reactivity can lead to undesirable in vivo effects and toxicity issues.

[0415] Examples of compounds of the invention with terminal alkynes were tested for their ability to inhibit P450 enzymes to show time-dependent inhibition of P450 enzymes and to form adducts with glutathione in the presence of human liver S9 preps. Surprisingly, the compounds of the disclosure show a lack of activity in the presence of p450 enzymes as shown by the experiments described below.

[0416] The Master Solution was prepared according to Table 3. Substrates solutions were prepared in acetonitrile and ultra-pure H2O mixture (1 : 9, v:v) just before use, as listed in Table 4.Table 3. Preparation of Master SolutionTable 4. Substrate Information

[0417] The "Master Solution" was pre-warmed at 37 °C for 5 minutes. 169 pL of "PreIncubation solution" and 1 pL of multiple concentrations of test compounds or positive control compounds was transferred from “Compound Plate” to the “Incubation Plate”.

[0418] For the 0 min pre-incubation, 10 pL of substrate was added to the Incubation Plate, and then 20 pL of 10 mM NADPH solution was added to start the reaction at the final concentration of 1 mM, and then incubated for the appointed time listed in Tables 5, 6, and 7 The final concentrations of DMSO and acetonitrile in the incubation solutions were both 0.5% (v / v).

[0419] For the 30 min pre-incubation with NADPH, 20 pL of 10 mM NADPH solution was added to the Incubation Plate at the final concentration of 1 mM and then the plate was preincubated in the 37 °C water bath for 30 minutes. After 30 minutes incubation, 10 pL of substrate was added to start the reaction. And then incubated for the appointment time listed in Tables 5, 6, and 7. The final concentration of DMSO and acetonitrile in the incubation solutions were both 0.5% (v / v).

[0420] For the 30 min pre-incubation without NADPH, the Incubation Plate was preincubated in the 37 °C water bath for 30 minutes. After 30 minutes incubation, 10 pL of substrate were added to the Incubation Plate, 20 pL of 10 mM NADPH solution was added to start the reaction at the final concentration of 1 mM. And then incubated for the appointed time listed in Tables 5, 6, and 7. The final concentrations of DMSO and acetonitrile in the incubation solutions were both 0.5% (v / v).

[0421] The assay was performed in duplicate. At the end of the incubation reactions, each incubation mixture was added by 400 pL of cold methanol containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 pM ketoprofen) to precipitate protein and release compound. Vortexed thoroughly. Samples were centrifuged at 3,220 g for 60 minutes at 4 °C . And then 100 pL of the supernatant was transferred to each well of a new 96-well plate containing an appropriate volume of ultra-pure water (depends on the LC-MS / MS signal response and peak shape) for LC-MS / MS analysis.

[0422] All calculations were carried out using Microsoft Excel. The formation of metabolites was analyzed by using LC-MS / MS. A decrease in the formation of the metabolites in peak area ratios to vehicle control was used to calculate three ICso values (0 min pre-incubation, 30 min pre-incubation with NADPH and 30 min pre-incubation without NADPH) by using Prism 5.0 software (Graphpad). The ICso shift was calculated for evaluating the mechanism of the inhibition.Example 45: Test for Reactive Metabolites (test for Glutathione Adduct Formation)

[0423] Test compounds were incubated with human liver S9 preparations. Human liver S9 fractions (2mg / mL; purchased from Xenotech, Cat. No. H0610.S9, Lot No. 2310054) were used with cofactors NADPH (2mM) and glutathione (GSH) (5mM), at a total volume of 20 mL and test concentration of 10 mM. Test compounds were incubated for 60 minutes at 37 °C. Incubations were quenched with 3 volumes of acetonitrile followed by centrifugation for 30 min at 16,000 g. Aliquots of 70 pL of the supernatant was mixed with 140 pL of pure water and used for LC-MS / MS analysis. A Vanquish UHPLC system (Thermo FisherScientific, USA) with Orbitrap Exploris 480 (Thermo Fisher Scientific, USA) were used, with these LC conditions: Column: Waters Atlantis® T3, 100 x 4.6 mm, 3 pm; Solvents: A, water (0.1% formic acid); B, methanol; Flow rate: 800 pL / min; Program: 0-1.5 min, 5%B, 1.5-9 min, 5%-45%B, 9-12 min, 45%-100%B, 12-14min, 100%B, 14-14.3 min, 100%-5%B, 14.3-15 min, 5%B. MS conditions: Ionization mode: Positive ion mode; Spray Voltage: 3.5 kV; Aux. gas flow rate: 10; Aux. gas heater temp (°C): 350°C; Scan type: Full MS / ddMS2; Resolution: 60,000; AGC Target: standard; NCE / stepped NCE: 40, 50, 60.

[0424] For Compound 3 and Compound 19, No GSH adducts were detected, no evidence of reactive metabolites was observed. Parent recovery was 100%.Example 46: In-vivo TMAO inhibition assay in rats dosed through ileal-cecal catheter

[0425] Ileal -cecal catheters are surgically implanted into male Sprague-Dawley rats, aged 7-9 weeks, and the rats are allowed to recover from surgery for at least 96 h prior to use in experiments. Then, in the three days prior to dosing, as well as during the dosing and followup periods, the rats are provided with choline (1% w / w) in their drinking water. The animals are fasted overnight the day before dosing and access to food is resumed 4 h after dosing.

[0426] Test compounds are prepared as solutions in saline at concentrations to enable a dosing volume of 1 mL / kg. After dosing with either test compound solution or saline control, the ileal-cecal catheter is rinsed with 0.05 mL of saline. Plasma is collected at 0.5, 1, 2, 4, 8, 12, 24, and 48 h and analyzed for TMAO concentration using an LC / MS / MS method as described below. TMAO inhibition is reported as the percent reduction of plasma TMAO concentration observed of the test compound vs. the saline control at the timepoint with the lowest TMAO value.HPLC / MS / MS Method for Quantification of TMAO in Rat PlasmaTable 8. HPLC / MS / MS Method ConditionsTable 9. Ion TransitionsSample Preparation:

[0427] Water was used as surrogate matrix for all sample analysis.

[0428] Plasma: The desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution. 5 pL of working solutions (1, 2, 5, 10, 20, 50, 100, 500, 1000, 2000 pM) were added to 50 pL of water to achieve calibration standards of 0.1-200 pM (0.1, 0.2, 0.5, 1, 2, 5, 10, 50 ,100, 200 pM) in a total volume of 55 pL. Six quality control samples at 0.3 pM, 0.6 pM, 1.5 pM, 3 pM , 50 pM and 160 pM for plasma were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards.

[0429] 55 pL standards, 55 pL QC samples and 55 pL unknown samples (50 pL plasma with 5 pL blank solution) were added to 200 pL of acetonitrile containing internal standard (IS) mixture for precipitating protein respectively. Then the samples were vortexed for 30 s. After centrifugation at 4 °C, 4000 rpm for 15 min, the supernatant was diluted 3 times withwater. 0.5 pL of diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.Table 10. Results of TMAO Inhibition Assay in RatsExample 47: Pharmacokinetic analysis of excretion profile in rats

[0430] Male Sprague-Dawley rats, aged 7-9 weeks, were administered a single dose of a test compound via oral gavage and the urine and feces of each animal were then collected over a period of 72 h. The test compound was prepared as a solution in saline at an appropriate concentration to obtain a dosing volume of 10 mL / kg.

[0431] The urine and feces from each animal were analyzed separately by HPLC / MS / MS to quantify the concentration of test compound present in each. The analytical method is described below.HPLC / MS / MS Method for Quantification of Test Compound in Rat Urine and FecesTable 11. HPLC / MS / MS Method ConditionsSample Preparation (urine):

[0432] The desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution. 5 pL of working solutions (1, 2, 5, 10, 20, 50, 100, 500, 1000, 5000 ng / mL) were added to 50 pL of the blank SD Rat urine to achieve calibration standards of 0.1~ 500 ng / mL (0.1, 0.2, 0.5, 1, 2, 5, 10, 50, 100, 500 ng / mL) in a total volume of 55 pL. Six quality control samples at 0.3 ng / mL, 0.6 ng / mL, 1.5 ng / mL, 3 ng / mL, 50 ng / mL and 400 ng / mL for urine were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards.

[0433] 55 μL standards, 55 μL QC samples and 55 μL unknown samples (50 μL urine with 5 μL blank solution) were added to 200 μL of acetonitrile containing IS mixture for precipitating protein respectively. Then the samples were vortexed for 30 s. After centrifugation at 4 °C, 4000 rpm for 15 min, the supernatant was diluted 5 times with water.10 μL of diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.Sample Preparation (feces):

[0434] Feces samples were added with water by feces weight (g) to water volume (mL) ratio 1 :6 for homogenization.

[0435] The desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution. 5 μL of working solutions (5, 10, 20, 50, 100, 500, 1000, 5000, 10000) were added to 50 μL of the blank SD Rat feces homogenate to achieve calibration standards of 0.5 ~ 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 55 μL. Five quality control samples at 1.5 ng / mL, 3 ng / mL, 6 ng / mL, 50 ng / mL and 800 ng / mL for feces homogenate were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards.

[0436] 55 pL standards, 55 pL QC samples and 55 pL unknown samples (50 pL feces homogenate with 5 pL blank solution) were added to 200 pL of acetonitrile containing IS mixture for protein precipitation, respectively. Then the samples were vortexed for 30 s. Aftercentrifugation at 4 °C, 4000 rpm for 15 min, the supernatant was diluted 5 times with water. 10 pL of diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.Table 12. Resultsquantification at this very low dose

[0437] The results with ICC dosing show that when the test compound is delivered directly to the colon (the compartment of interest containing the bacterial enzyme target), the majority of the dose is recovered in the feces and only a small amount is recovered from the urine. This indicates that colonic dosing delivers drug efficiently to the target while also greatly minimizing unnecessary systemic exposure of the test compound.

[0438] Surprisingly, PO dosing of test compound 3 led to predominant recovery of the compound in the feces, indicating that even in the absence of a colon-targeting formulation the majority of the dose reached the compartment of interest.

Claims

1. CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (I): wherein:Z is -C=CR5or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independnetly -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -CD3, - CH2D, -CHD2, -CH2F, -CHF2, or -CF3; or R2and R3together with the N atom to which they are attached combine together to form a 5 membered heterocycloalkyl; each R4is independently deuterium, -F, -OH, or -CH3; p is 1, 2, 3, 4, or 5; each R5is independently hydrogen, deuterium, -F, -CH3, -CD3, -CH2D, -CHD2, -CH2F, - CHF2, or -CF3; andX' is a counterion; provided that when Z is C=CH, then R4is not -OH.

2. A compound of Formula (I): wherein:Z is -C=CR5or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3;or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independnetly -CH3, -CH2CH3, -(CH^CJR, -CH(CH3)2, -CD3, - CH2D, -CHD2, -CH2F, -CHF2, or -CF3; or R2and R3together with the N atom to which they are attached combine together to form a 5 membered heterocycloalkyl; each R4is independently deuterium, -F, -OH, or -CH3; p is 1, 2, 3, 4, or 5; each R5is independently hydrogen, deuterium, -F, -CH3, -CD3, -CH2D, -CHD2, -CH2F, - CHF2, or -CF3; andX' is a counterion;• 1 - provided that the compund is not.

3. The compound of claim 1 or 2, wherein R2and R3are each -CH3.

4. The compound of claim 1 or 2, wherein the compound is of Formula (la) or Formula(lb):wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; each R4is independently -F, -OH, or -CH3; p is 1, 2, 3, 4, or 5; andX~ is a counterion; provi •d 1ed1 t1hat t1he compund 1 i-s not5. The compound of any one of claims 1 to 4, wherein p is 1.

6. The compound of any one of claims 1 to 4, wherein p is 2.

7. The compound of any one of claims 1 to 6 wherein each R4is -F.

8. The compound of any one of claims 1 to 5, wherein Rlaand Rlbare each hydrogen; p is 1; and R4is -F.

9. The compound of claim 1 or 2, wherein the compound of Formula (I) has the structure of Formula (Ila), (lIb), (lIe), or (lId):, .

10. The compound of any one of claims 1 to 3, wherein the compound is of Formula (III):Formula (III) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R4is -F, or -CH3; andX' is a counterion.

11. The compound of claim 9 or 10, wherein R4is -F.

12. The compound of claim 9 or 10, wherein R4is -CH3.

13. The compound of claim 1 or 2, wherein the compound is of Formula (IV):Formula (IV) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl; each R4is independently -F, or -CH3;R5a, R5b, andR5care each indepenendently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; p is 1, 2, 3, 4, or 5; andX' is a counterion.

14. The compound of claim 13, wherein p is 1 or 2.

15. The compound of claim 13 or 14, wherein each R4is -F.

16. The compound of any one of claims 13 to 15 wherein Rlaand Rlbare each hydrogen; p is 1; and R4is -F.

17. The compound of claim 13, wherein the compound is of Formula (IV) is of Formula (IVa), (IVb), (IVc), or (IVd):

18. The com,19. The compound of any one of claims 13 to 18, wherein R5ais hydrogen, deuterium, -F, or -CH3.

20. The compound of claim 19, wherein R5ais hydrogen.

21. The compound of claim 19, wherein R5ais -F.

22. The compound of claim 19, wherein R5ais -CH3.

23. The compound of any one of claims 13 to 22, wherein R5bis hydrogen, deuterium, -F, or -CH3.

24. The compound of claim 23, wherein R5bis hydrogen.

25. The compound of claim 23, wherein R5bis -F.

26. The compound of claim 23, wherein R5bis -CH3.

27. The compound of any one of claims 13 to 26, wherein R5cis hydrogen, deuterium, -F, or -CH3.

28. The compound of claim 27, wherein R5cis hydrogen.

29. The compound of claim 27, wherein R5cis -F.

30. The compound of claim 27, wherein R5cis -CH3.

31. The compound of any one of claims 1 to 7, 9 to 15, or 17 to 30, wherein Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3.

32. The compound of claim 31, wherein Rlaand Rlbare independently hydrogen or -CH3.

33. The compound of claim 32, wherein Rlaand Rlbare each hydrogen.

34. The compound of any one of claims 1 to 7, 9 to 15, or 17 to 30, wherein Rlaand Rlbtogether with the atom to which they are attached form a cyclopropyl.

35. The compound of any one of claims 1 to 34, wherein the compound is selected from:

36. A compound of Formula (V):Formula (V) wherein:Z is -OCR5or -CR5=C(R5)2;Rlais hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3;Rlbis -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-Ce cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3; each R4is independently -F, or -CH3; each R5is independnelty hydrogen or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

37. The compound of claim 36, wherein the compound is of Formula (Va):Formula (Va) wherein:Rlais hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3;Rlbis -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-Ce cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3; each R4is independently -F, or -CH3;R5is hydrogen or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

38. The compound of claim 37, wherein R5is hydrogen.

39. The compound of claim 37, wherein R5is -CH3.

40. The compound of claim 36, wherein the compound is of Formula (Vb):Formula (Vb) wherein:Rlais hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3;Rlbis -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3; each R4is independently -F, or -CH3; each R5is independnelty hydrogen or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

41. The compound of claim 40, wherein each R5is hydrogen.

42. The compound of any one of claims 36 to 41, wherein each R4is -F.

43. The compound of any one of claims 36 to 42, wherein p is 1.

44. The compound of any one of claims 36 to 42, wherein p is 0.

45. The compound of any one of claims 36 to 44, wherein R2and R3are each -CH3.

46. The compound of any one of claims 36 to 45, wherein Rlais hydrogen or -CH3.

47. The compound of claim 46, wherein Rlais hydrogen.

48. The compound of any one of claims 36 to 47, wherien Rlbis -CH3.

49. The compound of any one of claims 36 to 45, wherein Rlaand Rlbare are each -CH3.

50. The compound of any one of claims 36 to 45, wherein Rlaand Rlbtogether with the atom to which they are attached from a cyclopropyl.

51. The compound of any one of claims 36 to 40, wherein the compound is selected from:

52. A compound of Formula (VI):Formula (VI) wherein:Z is -C=CH or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen or deuterium;R2and R3are each independently -CH3 or -CD3; each R5is independnetly hydrogen or deuterium;Ra, Rb, Rc, Rd, and Reare each independently hydrogen or deuterium; wherein at least one of Rla, Rlb, Ra, Rb, Rc, Rd, Reor R5is deuterium or at least one of R2or R3is -CD3; andX' is a counterion.

53. The compound of claim 52, wherein the compound is of Formula (Via):Formula (Via) wherein:Rlaand Rlbare each independently hydrogen or deuterium;R2and R3are each independently -CH or -CD3;Ra, Rb, Rc, Rd, and Reare each independently hydrogen or deuterium; wherein at least one of Rla, Rlb, Ra, Rb, Rc, Rd, or Reis deuterium or at least one of R2orR3is -CD3; andX' is a counterion.

54. The compound of claim 52, wherein the compound is of Formula (VIb):Formula (VIb) wherein:Rlaand Rlbare each independently hydrogen or deuterium;R2and R3are each independently -CH3 or -CD3; each R5is independently hydrogen or deuterium;Ra, Rb, Rc, Rd, and Reare each independently hydrogen or deuterium; wherein one of Rla, Rlb, Ra, Rb, Rc, Rd, Reor R5is deuterium or one of R2or R3is -CD3; andX' is a counterion.

55. The compound of claim 54, wherein each R5is deuterium.

56. The compound of claim 54, wherein each R5is hydrogen.

57. The compound of any one of claims 52 to 56, wherein Rlaand Rlbare both hydrogen or Rlaand Rlbare both deuterium.

58. The compound of claim 57, wherein Rlaand Rlbare both hydrogen.

59. The compound of claim 57, wherein Rlaand Rlbare both deuterium.

60. The compound of any one of claims 52 to 59, wherein R2and R3are both -CH3.

61. The compound of any one of claims 52 to 59, whererin R2and R3are both -CD3.

62. The compound of any one of claims 52 to 61, wherien at least one of Ra, Rb, Rc, Rd, and Reis deuterium.

63. The compound of any one of claims 52 to 61, wherein each of Ra, Rb, Rc, Rd, and Reis deuterium.

64. The compound of any one of claims 52 to 61, wherein each of Ra, Rb, Rc, Rd, and Reis hydrogen.

65. The compound of any one of claims 52 to 64, wherein the compound is selected from:

66. A compound of Formula (VIF):Formula (VII’) wherein:Z is -OCR5or -CR5=C(R5)2;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3; each R5is independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or - S(O)2°-; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX' is a counterion; provided that the compound is not67. The compound of claim 66, wherein the compound of Formula (VII’) is of Formula(Vila’):Formula (Vila’) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or - S(O)2O-; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX' is a counterion; provided that the compound is not68. The compound of claim 66, wherein the compound of Formula (VH’) is of Formula (Vllb’):Formula (Vllb’) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF2, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;R6is cyclobutyl, 4 to 5-membered heterocycloalkyl, 5-membered heteroaryl, or tert-butyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R7; each R7is independently hydrogen, halogen, C1-C3 alkyl, -OH, -CN, -S(O)2CH3, or - S(O)2O’; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge when R6is cyclobutyl or 4 to 5-membered heterocycloalkyl; andX' is a counterion; provided that the compound is not69. The compound of any one of claims 66 to 68, whereinwhereinW is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or - S(O)2O’; or two R7combine together with the atoms to which they are attached to form a C3-C6 cycloalkyl; or two R7combine together with the atoms to which they are attached to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; and q is 0, 1, 2, 3, 4, or 570. The compound of claim 67, wherein the compound of Formula (Vila’) is of Formula(Vile’):Formula (Vile’) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3;each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or - S(O)2O’; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

71. The compound of claim 68, wherein the compound of Formula (Vllb’) is of Formula (Vlld’):Formula (Vlld’) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, - CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or - S(O)2O-; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen, -OH, or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

72. The compound of claim 67, wherein the compound of Formula (Vila’) is of Formula (Vile):Formula (Vile) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

73. The compound of claim 68, wherein the compound of Formula (Vllb’) is of Formula (Vllf):Formula (Vllf) wherein:W is -NR7a-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NR7b)-, or -CR7R7-;Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CH2F, -CHF2, or -CF3;R5a, R5b, and R5care each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF2, or -CF3; each R7is independently hydrogen, halogen, C1-C3 alkyl, -CN, -S(O)2CH3, or -S(O)2O'; or two R7combine together to form a C3-C6 cycloalkyl; or two R7combine together to form an oxo; or two R7combine together to form a C1-C3 alkylene bridge;R7ais hydrogen, C1-C3 alkyl, -OH, -S(O)2CH3, or -S(O)2O’;R7bis hydrogen, -OH, or C1-C3 alkyl; q is 1, 2, 3, 4, or 5; andX' is a counterion.

74. The compound of claim 67, 70, or 72, wherein R5is hydrogen.

75. The compound of claim 68, 71, or 73, wherein R5a, R5b, and R5care each hydrogen.

76. The compound of any one of claims 66 to 75, wherein R2and R3are each -CH3.

77. The compound of any one of claims 66 to 76, wherein Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3.

78. The compound of claim 77, wherein Rlaand Rlbeach hydrogen.

79. The compound of any one of claims 66 to 76, wherein Rlaand Rlbtogether with the atom to which they are attached from a cyclopropyl.

80. The compound of any one of claims 69 to 79, wherein W is -S(O)-, -S(O)2-, or - S(O)(=NR7b)-.

81. The compound of any one of claims 69 to 79, wherein W is -O- or -CR7R7-.

82. The compound of any one of claims 69 to 79, wherein W is -O-.

83. The compound of any one of claims 69 to 79, wherein W is -CH2-.

84. The compound of any one of claims 66 to 83, wherein each R7is independently hydrogen or halogen.

85. The compound of any one of claims 66 to 83, wherein two R7combine together with the atoms to which they are attached to form a C3-C6 cycloalkyl.

86. The compound of any one of claims 66 to 83, wherein two R7combine together with the atoms to which they are attached to form an oxo.

87. The compound of any one of claims 66 to 69, wherein R6is88.

89. The compound of claim 88, wherein R6is90. The compound of claim 88, wherein R6is91. The compound of claim 88, wherein R6is92. The compound of claim 88, wherein R6is93. The compound of claim 88, wherein R6isi / \®94. The compound of claim 88, wherein R6is r \ / s— 0095. The compound of any one of claims 66 to 94, wherein the compound is selected from:

96. The compound of any claim any one of claims 66 to 94, wherein the compound is selected from97. The compound of any claim any one of claims 66 to 94, wherein the compound is selected from98. A compound of Formula (VIII):Formula (VIII) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; each R5aR5band R5care independently hydrogen, deuterium, -F, -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; andX' is a counterion;99. The compound of claim 98, wherein Rlaand Rlbare not each hydrogen.

100. The compound of claim 98, wherein Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3.

101. The compound of claim 100, wherein Rlaand Rlbare independently hydrogen or - CH3.

102. The compound of any one of claims 98 to 101, wherein R2and R3are each -CH3.

103. The compound of any one of claims 98 to 102, wherein R5ais hydrogen, deuterium, - F, or -CH3.

104. The compound of claim 103, wherein R5ais hydrogen.

105. The compound of claim 103, wherein R5ais -F.

106. The compound of claim 103, wherein R5ais -CH3.

107. The compound of any one of claims 98 to 106, wherein R5bis hydrogen, deuterium, - F, or -CH3.

108. The compound of claim 107, wherein R5bis hydrogen.

109. The compound of claim 107, wherein R5bis -F.

110. The compound of claim 107, wherein R5bis -CH3.

111. The compound of any one of claims 98 to 110, wherein R5cis hydrogen, deuterium, -F, or -CH3.

112. The compound of claim 111, wherein R5cis hydrogen.

113. The compound of claim 111, wherein R5cis -F.

114. The compound of claim 111, wherein R5cis -CH3.

115. The compound of any one of claims 98 to 114, wherein the compound iFormula (IX) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2and R3are each independently -CH3, -CD3, -CH2D, -CHD2, -CH2F, -CHF2, or -CF3; each R4is independently deuterium, -F, or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

117. The compound of claim 116, wherein R2and R3are each -CH3.

118. The compound of claim 116 or 117, wherein Rlaand Rlbare each hydrogen.

119. The compound of any one of claims 116 to 118, wherein p is 0.

120. The compound of any one of claims 116 to 119, wherein the compound is121. A compound of Formula (X):Formula (X) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R3is -CH3, -CH2F, -CHF2, or -CF3; each R4is independently deuterium, -F, or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

122. The compound of claim 121, wherein Rlaand Rlbare each hydrogen.

123. The compound of claim 121 or 122, wherein p is 0.

124. The compound of any one of claims 121 to 123, wherein R3is -CH3 or -CH2F.

125. The compound of claim 124, wherien R3is -CH3.

126. The compund of claim 124, wherein R3is -CH2F.

127. The compound of any one of claims 121 to 126, wherein the compound is128. A compound of Formula (XI):Formula (XI) wherein:Rlaand Rlbare each independently hydrogen, deuterium, -F, -CH3, -CH2F, -CHF, or - CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R3is -CH3, -CH2F, -CHF2, or -CF3; each R4is independently deuterium, -F, or -CH3; p is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

129. The compound of claim 128, wherein Rlaand Rlbare each hydrogen.

130. The compound of claim 128 or 129, wherein p is 0.

131. The compound of any one of claims 128 to 130, wherein R3is -CH3 or -CH2F.

132. The compound of claim 131, wherien R3is -CH3.

133. The compund of claim 131, wherein R3is -CH2F.

134. The compound of any one of claims 128 to 133, wherein the compound is135. A compound of Formula of Formula (XII):Formula (XII) wherein:W is -S-, -S(O)2- or -S(O)-; each R7is independently halogen, C1-C3 alkyl, or -OH;R8is C1-C3 alkyl, C1-C3 haloalkyl, or cyclopropyl; q is 0, 1, 2, 3, 4, or 5; andX' is a counterion.

136. The compound of claim 135, wherein the compoundA compound of Formula of Formula (XIII):Formula (XIII) wherein:Rlaand Rlbare each independently hydrogen, -F, -CH3, -CH2F, -CHF, or -CF3; or Rlaand Rlbtogether with the atom to which they are attached from a C3-C6 cycloalkyl;R2is -CH3, -CH2F, -CHF2, or -CF3;R5is hydrogen, -F, -CH3, -CH2F, -CHF2, or -CF3; each R9is independently halogen, C1-C3 alkyl, or -OH; or two R9together with the atoms to which they are attached form a 4 to 5 membered heterocycoalkyl; q is 1, 2, 3, 4, or 5; and X' is a counterion.

138. The compound of any one of claims 1 to 137, wherein X' is a counterion selected from chloride, bromide, iodide, sulfate, phosphate, tartrate, citrate, acetate, fumarate, succinate, mesylate, lactate, and stearate.

139. The compound of claim 138, wherein X' is a counterion selected from chloride, bromide, and iodide.

140. A compound of any of the preceding claims, wherein the compound is described in Table 1.

141. A pharmaceutical composition comprising a compound of any one of claims 1 to 140, and at least one pharmaceutically acceptable excipient.

142. A method of treating a chronic kidney disease, a cardiovascular disease, obesity, adiposity, diabetes, a metabolic disorder, a hepatic disorder, hypertension, resistant hypertension, frailty, or sarcopenia in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 140 or a pharmaceutical composition of claim 141.

143. A method of treating a kidney disease in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 140 or a pharmaceutical composition of claim 141.

144. The method of claim 142 or 143, wherein the kidney disease is selected from reduced or impaired kidney function, chronic kidney disease, acute kidney disease, diabetic kidney disease, end-stage renal disease, and renal impairment associated with diabetes mellitus.

145. A method of treating a cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 140 or a pharmaceutical composition of claim 141.

146. The method of claim 145, wherein the cardiovascular disease is selected from atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure, cardiomyopathy, atherothrombotic disease, aorto-iliac disease, peripheral vascular disease, stroke, thrombosis, acute myocardial infarction, ischemic heart failure, abdominal aortic aneurysm, ascending aortic aneurysm, and atrial fibrillation.

147. The method of claim 146, wherein the cardiovascular disease is selected from heart failure and abdominal aortic aneurysm.

148. The method of claim 147, wherein the heart failure comprises heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with mildly reduced ejection fraction (HFmrEF).

149. A method of reducing the production of trimethylamine (TMA) or trimethylamine-N- oxide (TMAO) in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 140 or a pharmaceutical composition of claim 141.

150. A method of inhibiting the conversion of choline to trimethylamine (TMA) and reducing trimethylamine-N-oxide (TMAO) level in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 140 or a pharmaceutical composition of claim 141.

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