PRODRUGS OF DIMETHYLTRYPTAMINE AND DERIVATIVES THEREOF

Abstract

Provided herein are compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B), pharmaceutically acceptable salts thereof, and compositions thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, A, B, E, W, X, and n are defined herein. The disclosed compounds are useful for treating various diseases, including depression and associated conditions.

##STR00001##

Claims

1. A compound of Formula (I-A): ##STR00117## or a pharmaceutically acceptable salt thereof, wherein: A is N or CVR.sub.16; B is N or CYR.sub.4; E is N or CZR.sub.5, wherein no more than two of A, B, and E are N; W is O, S, or NR.sub.6; V, X, Y, and Z are each independently absent, O, S, or NH; R.sub.1 and R.sub.2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R.sub.3, R.sub.4, R.sub.5, and R.sub.16 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or P(O)(OH).sub.2; R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene- optionally substituted cycloalkyl, or optionally substituted heteroalkyl; R.sub.7 and R.sub.8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring; R.sub.9 and R.sub.10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo; R.sub.11 and R.sub.12 are each independently alkyl, deuterated alkyl, O.sup.?, OH, OD, O-alkyl, O cycloalkyl, O-alkylene-cycloalkyl, O-aryl, or OM, wherein M is a pharmaceutically acceptable cation, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a heterocyclyl, and the alkyl, cycloalkyl, aryl and heterocyclyl are each optionally substituted; R.sub.13 is H, D, halogen, deuterated alkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, C(O)-(alkylene- optionally substituted aryl), or OC(O)NHR.sub.15, or R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted heterocyclic ring comprising 4-7 carbon atoms; R.sub.14 is H, D, halogen, haloalkyl, OH, an optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; and R.sub.5 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

2. The compound of claim 1, wherein A is CVR.sub.16.

3. The compound of claim 1, wherein V is absent.

4. The compound of claim 2, wherein R.sub.16 is H.

5. The compound of claim 1, wherein B in CYR.sub.4.

6. The compound of claim 5, wherein Y is absent.

7. The compound of claim 5, wherein Y is G.

8. The compound of claim 5, wherein R.sub.4 is H, optionally substituted C.sub.1-5alkyl, or P(O)(OH).sub.2.

9. The compound of claim 5, wherein R.sub.4 is methyl.

10. The compound of claim 1, wherein E is CZR.sub.5.

11. The compound of claim 10, wherein Z is absent.

12. The compound of claim 10, wherein R.sub.5 is H.

13. The compound of claim 1, wherein X is absent.

14. The compound of claim 1, wherein X is O.

15. The compound of claim 1, wherein R.sub.3 is H, optionally substituted C.sub.1-5alkyl, or P(O)(OH).sub.2.

16. The compound of claim 1, wherein W is NR.sub.6.

17. The compound of claim 16, wherein R.sub.6 is H or optionally substituted C.sub.1-5alkyl.

18. The compound of claim 16, wherein R.sub.6 is H.

19. The compound of claim 1, wherein R.sub.1 and R.sub.2 are each independently H or optionally substituted C.sub.1-5alkyl.

20. The compound of claim 1, wherein R.sub.1 and R.sub.2 are each optionally substituted C.sub.1-5alkyl.

21. The compound of claim 20, wherein R.sub.1 and R.sub.2 are methyl.

22. The compound of claim 1, wherein R.sub.7 and R.sub.8 are each independently H, F, or optionally substituted C.sub.1-5alkyl.

23. The compound of claim 1, wherein R.sub.7 and R.sub.8 are each H.

24. The compound of claim 1, wherein R.sub.9 and R.sub.10 are each independently H, F, or optionally substituted C.sub.1-5alkyl.

25. The compound of claim 1, wherein R.sub.9 and R.sub.10 are each H.

26. The compound of claim 1, wherein R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo.

27. The compound of claim 1, wherein R.sub.11 and R.sub.12 are each independently O, OH, OC.sub.1-5alkyl, or -OM.

28. The compound of claim 1, wherein R.sub.11 is O.sup.? and R.sub.12 is OH, OC.sub.1-5alkyl, or -OM.

29. The compound of claim 1, wherein R.sub.11 and R.sub.12 are each OC.sub.1-5alkyl.

30. The compound of claim 27, wherein R.sub.11 and R.sub.12 are each independently OMe, OEt, OiPr, or -OtBu.

31. The compound of claim 27, wherein R.sub.11 and R.sub.12 are each independently OC.sub.1-5haloalkyl.

32. The compound of claim 27, wherein R.sub.11 and R.sub.12 are OCH.sub.2CF.sub.3.

33. The compound of claim 1, wherein M is Na.sup.+, K.sup.+, or NH.sub.4.sup.+.

34. The compound of claim 1, wherein R.sub.11 and R.sub.12 are each OH.

35. The compound of claim 1, wherein R.sub.11 and R.sub.12 taken together with the atoms to which they are attached form an optionally substituted heterocyclyl.

36. The compound of claim 1, wherein R.sub.11 and R.sub.12 taken together with the atoms to which they are attached form an optionally substituted 5- to 12-membered heterocyclyl.

37. The compound of claim 35, wherein the optionally substituted heterocyclyl is: ##STR00118##

38. The compound of claim 1, wherein R.sub.11 and R.sub.12 are each deuterated alkyl.

39. The compound of claim 1, wherein R.sub.11 and R.sub.12 are each deuterated methyl.

40. The compound of claim 1, wherein R.sub.13 is H or optionally substituted C.sub.1-5alkyl.

41. The compound of 40, wherein R.sub.13 is methyl, ethyl, or isopropyl.

42. The compound of claim 1, wherein R.sub.14 is H, F, Cl, Br, or C.sub.1-5alkyl.

43. The compound of claim 1, wherein R.sub.14 is H.

44. The compound of claim 1, wherein R.sub.14 is haloalkyl.

45. The compound of claim 1, wherein R.sub.14 is CF.sub.3.

46. The compound of claim 1, having the structure: ##STR00119## ##STR00120## or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1, having the structure: ##STR00121## ##STR00122## or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1, having the structure: ##STR00123## or a pharmaceutically acceptable salt thereof.

49. The compound of claim 1, having the structure: ##STR00124## or a pharmaceutically acceptable salt thereof.

50-77. (canceled)

78. The compound of claim 1, having the structure: ##STR00125## or a pharmaceutically acceptable salt thereof.

79. The compound of claim 1, having the structure: ##STR00126## or a pharmaceutically acceptable salt thereof.

80. A composition comprising (i) a compound of claim 1 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient.

81. An oral dosage form comprising the pharmaceutical composition of claim 80.

82. A method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering a pharmaceutical composition of 80 to the subject.

83. A method of treating depression in a subject in need thereof, comprising administering a pharmaceutical composition of claim 80 to the subject.

84. The method of claim 83, wherein the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).

85. A method of treating an anxiety disorder in a subject in need thereof, comprising a pharmaceutical composition of claim 80 to the subject.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0067] FIGS. 1A-1C show PK studies of N-phosphonooxymethyl prodrug Compound 1 (VLS-02-23-0; 6-1-2) and metabolite (VLS-02-023-10) following intravenous (1 mg/kg) and oral administration (30 mg/kg) to male CD1 mice (in plasma).

[0068] FIGS. 2A-2B show PK studies of N-phosphonooxymethyl prodrug Compound 1 (VLS-02-23-0; 6-1-2) and metabolite (VLS-02-023-10) following intravenous (1 mg/kg) and oral administration (30 mg/kg) to male CD1 mice (in the brain).

DETAILED DESCRIPTION

[0069] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

Definitions

[0070] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0071] The terms administer, administering or administration as used herein refer to administering a compound or pharmaceutically acceptable salt of the compound or a composition or formulation comprising the compound or pharmaceutically acceptable salt of the compound to a patient.

[0072] The term pharmaceutically acceptable salts includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, acetate, tartrate, oleate, fumarate, formate, benzoate, glutamate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate salts. Base addition salts include but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g., lysine and arginine dicyclohexylamine and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0073] The term treating as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. In embodiments, treating can be improving, or at least partially ameliorating a disorder or one or more symptoms of a disorder.

[0074] The term preventing as used herein with regard to a patient or subject, refers to preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject or a patient that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.

[0075] The term therapeutically effective applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.

[0076] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, C.sub.1-C.sub.6 alkyl is intended to encompass C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5, C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4, C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3_4, C.sub.4-6, C.sub.4-5, and C.sub.5-6 alkyl.

[0077] Alkyl or alkyl group refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C.sub.1-C.sub.12 alkyl, an alkyl comprising up to 10 carbon atoms is a C.sub.1-C.sub.10 alkyl, an alkyl comprising up to 6 carbon atoms is a C.sub.1-C.sub.6 alkyl and an alkyl comprising up to 5 carbon atoms is a C.sub.1-C.sub.5 alkyl. A C.sub.1-C.sub.5 alkyl includes C.sub.5 alkyls, C.sub.4 alkyls, C.sub.3 alkyls, C.sub.2 alkyls and C.sub.1 alkyl (i.e., methyl). A C.sub.1-C.sub.6 alkyl includes all moieties described above for C.sub.1-C.sub.5 alkyls but also includes C.sub.6 alkyls. A C.sub.1-C.sub.10 alkyl includes all moieties described above for C.sub.1-C.sub.5 alkyls and C.sub.1-C.sub.6 alkyls, but also includes C.sub.7, C.sub.8, C.sub.9 and C.sub.10 alkyls. Similarly, a C.sub.1-C.sub.12 alkyl includes all the foregoing moieties, but also includes C.sub.11 and C.sub.12 alkyls. Non-limiting examples of C.sub.1-C.sub.12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0078] Aryl refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, and which is attached to the rest of the molecule by a single bond. For purposes of this disclosure, the aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryls include, but are not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the aryl can be optionally substituted.

[0079] Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spirocyclic ring systems, having from three to twenty carbon atoms (e.g., having from three to ten carbon atoms) and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0080] Heterocyclyl, heterocyclic ring or heterocycle refers to a stable saturated, unsaturated, or aromatic 3- to 20-membered ring which consists of two to nineteen carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is attached to the rest of the molecule by a single bond. Heterocyclyl or heterocyclic rings include heteroaryls, heterocyclylalkyls, heterocyclylalkenyls, and hetercyclylalkynyls. Unless stated otherwise specifically in the specification, the heterocyclyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spirocyclic ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. Examples of such heterocyclyl include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0081] Heteroaryl refers to a 5- to 20-membered ring system comprising hydrogen atoms, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, at least one aromatic ring, and which is attached to the rest of the molecule by a single bond. For purposes of this disclosure, the heteroaryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0082] The term substituted used herein means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclyl, and/or heteroaryl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, substituted includes any of the above groups in which one or more hydrogen atoms are replaced with NR.sub.gR.sub.h, NR.sub.gC(?O)R.sub.h, NR.sub.gC(?O)NR.sub.gR.sub.h, NR.sub.gC(?O)OR.sub.h, NR.sub.gSO.sub.2R.sub.h, OC(?O)NR.sub.gR.sub.h, OR.sub.g, SR.sub.g, SOR.sub.g, SO.sub.2R.sub.g, OSO.sub.2R.sub.g, SO.sub.2OR.sub.g, ?NSO.sub.2R.sub.g, and SO.sub.2NR.sub.gR.sub.h. Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with C(?O)R.sub.g, C(?O)OR.sub.g, C(?O)NR.sub.gR.sub.h, CH.sub.2SO.sub.2R.sub.g, CH.sub.2SO.sub.2NR.sub.gR.sub.h. In the foregoing, R.sub.g and R.sub.h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. Substituted further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

Compounds

[0083] The present disclosure provides compounds that are prodrugs of tryptamines and related scaffolds, for example N,N-dimethyltryptamine (DMT) as well as pharmaceutical compositions thereof.

[0084] DMT is metabolically unstable and is readily converted by monoamine oxidases (MAO's) to indoleacetic acid and N-oxidation metabolites resulting in poor oral bioavailability. In embodiments, the compounds of the present disclosure allow for the controlled release of DMT. Advantages of compounds of the present disclosure may include increased metabolic stability, increased absorption, decreased maximal plasma concentrations of parent drug DMT over time, and less frequent dosing. In embodiments, compounds of the present disclosure prevent or inhibit N-oxidation to promote oral bioavailability and increased exposure.

[0085] In embodiments, the DMT compounds of the present disclosure comprise a phosphate moiety, a phosphonate moiety, or a derivate thereof. Without being bound by theory such compounds may for example, increase bioavailability by virtue of active transport of the prodrug in the small intestine by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). The DMT prodrugs disclosed herein may also reduce abuse potential by preventing absorption by snorting or insufflation.

Compounds of Formulas (I-A) and (II-A)

[0086] In embodiments, the present disclosure provides a compound of Formula (I-A):

##STR00006##

or a pharmaceutically acceptable salt thereof,
wherein:

A is N or CVR.SUB.16.;

B is N or CYR.SUB.4.;

[0087] E is N or CZR.sub.5, wherein no more than two of A, B, and E are N;

W is O, S, or NR.SUB.6.;

[0088] V, X, Y, and Z are each independently absent, O, S, or NH;
R.sub.1 and R.sub.2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl;
R.sub.3, R.sub.4, R.sub.5, and R.sub.16 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or P(O)(OH).sub.2;
R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene- optionally substituted cycloalkyl, or optionally substituted heteroalkyl;
R.sub.7 and R.sub.8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring;
R.sub.9 and R.sub.10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo;
R.sub.11 and R.sub.12 are each independently alkyl, deuterated alkyl, O.sup.?, OH, OD, O-alkyl, O cycloalkyl, O-alkylene-cycloalkyl, O-aryl, or OM, wherein M is a pharmaceutically acceptable cation, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a heterocyclyl, and the alkyl, cycloalkyl, aryl and heterocyclyl are each optionally substituted;
R.sub.13 is H, D, halogen, deuterated alkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, C(O)-(alkylene- optionally substituted aryl), or -G-C(O)NHR.sub.15, or R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted heterocyclic ring comprising 4-7 carbon atoms;
R.sub.14 is H, D, halogen, haloalkyl, OH, an optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; and
R.sub.15 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0089] In embodiments, the present disclosure provides a compound of Formula (II-A):

##STR00007##

or a pharmaceutically acceptable salt thereof,
wherein:

A is N or CVR.SUB.16.;

B is N or CYR.SUB.4.;

[0090] E is N or CZR.sub.5, wherein no more than two of A, B, and E are N;

W is O, S, or NR.SUB.6.;

[0091] V, X, Y, and Z are each independently absent, O, S, or NH;
R.sub.1 and R.sub.2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl;
R.sub.3, R.sub.4, R.sub.5, and R.sub.15 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or P(O)(OH).sub.2;
R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, or optionally substituted heteroalkyl;
R.sub.7 and R.sub.8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring;
R.sub.9 and R.sub.10 are each independently H, D, halogen, OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo;
R.sub.12 is O.sup.?, OH, OD, O-alkyl, O-cycloalkyl, O-alkylene-cycloalkyl, O-aryl, or OM, wherein M is a pharmaceutically acceptable cation, and the alkyl, cycloalkyl, and aryl are optionally substituted;
R.sub.14 is H, D, halogen, OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; and
n is 0, 1, or 2.

[0092] In embodiments, A is N. In embodiments, A is CVR.sub.16.

[0093] In embodiments, B is N. In embodiments, B is CYR.sub.4.

[0094] In embodiments, E is N. In embodiments, E is CZR.sub.5.

[0095] In embodiments, W is NR.sub.6 or O. In embodiments, W is NR.sub.6 or S. In embodiments, W is O or S. In embodiments, W is NR.sub.6. In embodiments, W is O. In embodiments, W is S.

[0096] In embodiments, V, X, Y, and Z are each independently absent, O, S, or N(C.sub.1-5)alkyl. In embodiments, V, X, Y, and Z are each independently absent or O. In embodiments, V, X, Y, and Z are each independently absent or NH. In embodiments, V, X, Y, and Z are each independently absent or S. In embodiments, V, X, Y, and Z are each absent.

[0097] In embodiments, X is O, and V, Y and Z are absent. In embodiments, Y is G, and V, X and Z are absent. In embodiments, Z is O, and V, X and Y are absent. In embodiments, V is G, and X, Y, and Z are absent. In embodiments, X is S, and V, Y and Z are absent. In embodiments, Y is S, and V, X and Z are absent. In embodiments, Z is S, and V, X and Y are absent. In embodiments, V is S, and X, Y, and Z are absent. In embodiments, X is NH, and V, Y and Z are absent. In embodiments, Y is NH, and V, X and Z are absent. In embodiments, Z is NH, and V, X and Y are absent. In embodiments, V is NH, and X, Y, and Z are absent. In embodiments, X is N(C.sub.1-5)alkyl, and V, Y and Z are absent. In embodiments, Y is N(C.sub.1-5)alkyl, and V, X and Z are absent. In embodiments, Z is N(C.sub.1-5)alkyl, and V, X and Y are absent. In embodiments, V is N(C.sub.1-5)alkyl, and X, Y, and Z are absent.

[0098] In embodiments, R.sub.1 and R.sub.2 are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl. In embodiments, R.sub.1 and R.sub.2 are each independently H, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or optionally substituted C.sub.1-5cycloalkyl heteroalkyl. In some embodiments, R.sub.1 and R.sub.2 are each independently H or alkyl. In some embodiments, R.sub.1 and R.sub.2 are each independently alkyl or deuterated alkyl. In some embodiments, R.sub.1 and R.sub.2 are each independently H or deuterated alkyl. In embodiments, R.sub.1 and R.sub.2 are each independently H or C.sub.1-5alkyl. In embodiments, R.sub.1 and R.sub.2 are each independently H or deuterated C.sub.1-5alkyl. In embodiments, R.sub.1 and R.sub.2 are each independently alkyl or deuterated C.sub.1-5alkyl. In embodiments, R.sub.1 and R.sub.2 are each alkyl. In embodiments, R.sub.1 and R.sub.2 are each deuterated alkyl. In embodiments, R.sub.1 and R.sub.2 are each C.sub.1-5alkyl. In embodiments, R.sub.1 and R.sub.2 are each deuterated C.sub.1-5alkyl. In embodiments, R.sub.1 and R.sub.2 are each independently methyl, ethyl, or isopropyl. In embodiments, R.sub.1 and R.sub.2 are each independently deuterated methyl, deuterated ethyl, or deuterated isopropyl. In embodiments, R.sub.1 and R.sub.2 are each methyl. In embodiments, R.sub.1 and R.sub.2 are each deuterated methyl. In embodiments, R.sub.1 and R.sub.2 taken together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, e.g., azetidine, pyrrolidine, or piperidine.

[0099] In embodiments, R.sub.3, R.sub.4, R.sub.5, and R.sub.16 are each independently H, D, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, optionally substituted C.sub.1-5heteroalkyl, P(O)(OC.sub.1-5alkyl).sub.2, P(O)(OPh).sub.2, or P(O)(OH).sub.2. In embodiments, R.sub.3, R.sub.4, R.sub.5, and R.sub.16 are each independently H, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, optionally substituted C.sub.1-5heteroalkyl, P(O)(OC.sub.1-5alkyl).sub.2, P(O)(OPh).sub.2, or P(O)(OH).sub.2. In embodiments, R.sub.3, R.sub.4, R.sub.5, and R.sub.16 are each independently H, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, P(O)(OC.sub.1-5alkyl).sub.2, P(O)(OPh).sub.2, or P(O)(OH).sub.2. In embodiments, R.sub.3, R.sub.4, R.sub.5, and R.sub.16 are each independently H, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or P(O)(OH).sub.2. In embodiments, R.sub.3, R.sub.4, R.sub.5, and R.sub.16 are each independently H, optionally substituted C.sub.1-5alkyl, or P(O)(OH).sub.2. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl. In embodiments, R.sub.3, R.sub.4, R.sub.5, and R.sub.16 are each H.

[0100] In embodiments, R.sub.3 is optionally substituted C.sub.1-5alkyl or P(O)(OH).sub.2, and R.sub.4, R.sub.5, and R.sub.16 are each H. In embodiments, R.sub.4 is optionally substituted C.sub.1-5alkyl or P(O)(OH).sub.2, and R.sub.3, R.sub.5, and R.sub.16 are each H. In embodiments, R.sub.5 is optionally substituted C.sub.1-5alkyl or P(O)(OH).sub.2, and R.sub.3, R.sub.4, and R.sub.16 are each H. In embodiments, R.sub.16 is optionally substituted C.sub.1-5alkyl or P(O)(OH).sub.2, and R.sub.3, R.sub.4, and R.sub.5 are each H. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl.

[0101] In embodiments, X is absent, and R.sub.3 is H, halogen, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or P(O)(OH).sub.2. In embodiments, Y is absent, and R.sub.4 is H, halogen, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or P(O)(OH).sub.2. In embodiments, Z is absent, and R.sub.3 is H, halogen, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or P(O)(OH).sub.2. In embodiments, V is absent, and R.sub.16 is H, halogen, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or P(O)(OH).sub.2. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl. In embodiments, the halogen is F, Cl, or Br.

[0102] In embodiments, R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocyclyl, or optionally substituted alkylene-aryl. In embodiments, R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkylene-cycloalkyl. In embodiments, the optionally substituted alkyl is an optionally substituted C.sub.1-5alkyl. In embodiments, the optionally substituted cycloalkyl is an optionally substituted C.sub.3-6cycloalkyl. In embodiments, the optionally substituted aryl is an optionally substituted phenyl. In embodiments, the optionally substituted heterocyclyl is an optionally substituted 4- to 6-membered heterocyclyl, e.g., an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, each of which is optionally substituted. In embodiments, the optionally substituted alkylene is an optionally substituted C.sub.1-3alkylene. In embodiments, the optionally substituted alkylene is an optionally substituted methylene. In embodiments, R.sub.6 is H, C.sub.1-5alkyl, C.sub.3-6cycloalkyl or C(?O)(C.sub.1-5 alkyl). In embodiments, R.sub.6 is H, C.sub.1-5alkyl, or C.sub.3-8 cycloalkyl. In embodiments, R.sub.6 is H or C.sub.1-5alkyl. In embodiments, R.sub.6 is H. In embodiments, R.sub.6 is C.sub.1-5alkyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, the optionally substituted C.sub.1-5alkyl is C(O)C.sub.1-4alkyl, C(O)N(H)(C.sub.1-4alkyl), or C(O)OC.sub.1-4alkyl.

[0103] In embodiments, R.sub.7 and R.sub.8 are each independently H, halogen, optionally substituted alkyl, OH, optionally substituted O-alkyl or optionally substituted O cycloalkyl. In embodiments, R.sub.7 and R.sub.8 are each independently H, halogen, optionally substituted C.sub.1-5alkyl, OH, optionally substituted OC.sub.1-5alkyl, or optionally substituted OC.sub.3-6cycloalkyl. In embodiments, R.sub.7 and R.sub.8 are each independently H or optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.7 and R.sub.8 are each H. In embodiments, R.sub.7 and R.sub.8 are each optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.7 and R.sub.8 are each halogen. In embodiments, the halogen is F. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl. In embodiments, the C.sub.1-5alkyl is methyl. In embodiments, the C.sub.1-5alkyl is ethyl.

[0104] In embodiments, R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an oxo or an optionally substituted cycloalkyl ring. In embodiments, R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an oxo. In embodiments, R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted C.sub.3-6cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted cyclopropyl. In embodiments, R.sub.7 is H and R.sub.5 is optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.7 is H and R.sub.5 is F. In embodiments, R.sub.7 is H and R.sub.5 is OH. In embodiments, R.sub.7 is H and R.sub.5 is OCH.sub.3. In embodiments, R.sub.7 is F and R.sub.5 is F. In embodiments, R.sub.7 and R.sub.8 are each optionally substituted C.sub.1-5alkyl. In embodiments, the C.sub.1-5alkyl is methyl.

[0105] In embodiments, R.sub.9 and R.sub.10 are each independently H, halogen, optionally substituted alkyl, OH, optionally substituted O-alkyl or optionally substituted O cycloalkyl. In embodiments, R.sub.9 and R.sub.10 are each independently H, halogen, optionally substituted C.sub.1-5alkyl, OH, optionally substituted OC.sub.1-5alkyl, or optionally substituted OC.sub.3-6cycloalkyl. In embodiments, R.sub.9 and R.sub.10 are each independently H or optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.9 and R.sub.10 are each H. In embodiments, R.sub.9 and R.sub.10 are each optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.9 and R.sub.10 are each halogen. In embodiments, the halogen is F. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl. In embodiments, the C.sub.1-5alkyl is methyl. In embodiments, the C.sub.1-5alkyl is ethyl.

[0106] In embodiments, R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted C.sub.3-6cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted cyclopropyl. In embodiments, R.sub.9 is H and R.sub.10 is optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.9 is H and R.sub.10 is F. In embodiments, R.sub.9 is H and R.sub.10 is OH. In embodiments, R.sub.9 is H and R.sub.10 is OCH.sub.3. In embodiments, R.sub.9 and R.sub.10 are each F. In embodiments, R.sub.9 and R.sub.10 are each optionally substituted C.sub.1-5alkyl. In embodiments, the C.sub.1-5alkyl is methyl.

[0107] In embodiments of Formula (I-A), R.sub.11 and R.sub.12 are each independently alkyl, deuterated alkyl, O.sup.?, OH, optionally substituted O-alkyl, optionally substituted O-cycloalkyl, optionally substituted O-alkylene-cycloalkyl, optionally substituted O-aryl, or OM, wherein M is a pharmaceutically acceptable cation. In embodiments, the optionally substituted O-alkyl is an optionally substituted O-haloalkyl, a hemiaminal, an acetal, or an amino acid residue. In embodiments, R.sub.11 and R.sub.12 are each independently O.sup.?, OH, optionally substituted OC.sub.1-5alkyl, optionally substituted OC.sub.1-5haloalkyl, optionally substituted OC.sub.3-6cycloalkyl, or -OM. In embodiments, R.sub.11 and R.sub.12 are each independently O.sup.?, OH, optionally substituted OC.sub.1-5alkyl, optionally substituted OC.sub.1-5haloalkyl, or -OM. In embodiments, R.sub.11 is O.sup.? and R.sub.12 is OH, optionally substituted OC.sub.1-5alkyl, optionally substituted OC.sub.1-5haloalkyl, or -OM. In embodiments, R.sub.11 and R.sub.12 are each optionally substituted OC.sub.1-5alkyl. In embodiments, R.sub.11 and R.sub.12 are each optionally substituted OC.sub.1-3alkyl. In embodiments, R.sub.11 and R.sub.12 are each independently OMe, OEt, OiPr, or -OtBu. In embodiments, R.sub.11 and R.sub.12 are each optionally substituted OC.sub.1-5haloalkyl. In embodiments, the OC.sub.1-5haloalkyl is OCH.sub.3, OCH.sub.2F, OCHF.sub.2, or OCH.sub.2CF.sub.3. In embodiments, the OC.sub.1-5haloalkyl is a OCH.sub.2CF.sub.3. In embodiments, R.sub.11 and R.sub.12 are each independently alkyl, deuterated alkyl, O.sup.?, OH, OD, O-alkyl, or O cycloalkyl. In embodiments, R.sub.11 and R.sub.12 are each independently alkyl or deuterated alkyl. In embodiments, M is Na.sup.+, K.sup.+, NH.sub.4.sup.+, or Ca.sup.+2. In embodiments, M is Na.sup.+, K.sup.+, or NH.sub.4.sup.+.

[0108] In embodiments of Formula (I-A), R.sub.11 and R.sub.12 taken together with the atoms to which they are attached form a heterocyclyl. In embodiments, R.sub.11 and R.sub.12 taken together with the atoms to which they are attached form a 5- to 12-membered heterocyclyl. In embodiments, the heterocyclyl has the structure:

##STR00008##

[0109] In embodiments of Formula (II-A), R.sub.12 is O.sup.?, OH, optionally substituted O-alkyl, optionally substituted O-cycloalkyl, optionally substituted O-alkylene-cycloalkyl, optionally substituted O-aryl, or OM, wherein M is a pharmaceutically acceptable cation. In embodiments, the optionally substituted O-alkyl is an optionally substituted O-haloalkyl, a hemiaminal, an acetal, or an amino acid residue. In embodiments, R.sub.12 is O.sup.?, OH, O-alkyl, O-haloalkyl, O-cycloalkyl, or -OM. In embodiments, R.sub.12 is O.sup.?, OH, optionally substituted O-alkyl, optionally substituted O-haloalkyl, or -OM. In embodiments, R.sub.12 is O.sup.?, optionally substituted O-alkyl, or optionally substituted O-haloalkyl. In embodiments, R.sub.12 is optionally substituted O-alkyl. In embodiments, the optionally substituted O-alkyl is an optionally substituted OC.sub.1-5alkyl. In embodiments, the O-alkyl is OMe, OEt, OiPr, or -OtBu. In embodiments, R.sub.12 is O-haloalkyl. In embodiments, the optionally substituted O-haloalkyl is optionally substituted OC.sub.1-5haloalkyl. In some embodiments, the O-haloalkyl is OCH.sub.2CF.sub.3. In embodiments, R.sub.12 is O.sup.?, OH, OC.sub.1-5alkyl, OC.sub.1-5haloalkyl, OC.sub.3-6cycloalkyl, or -OM. In embodiments, M is Na.sup.+, K.sup.+, NH.sub.4.sup.+, or Ca.sup.+2. In embodiments, M is Na.sup.+, K.sup.+, or NH.sub.4.sup.+. In embodiments, the O-alkyl is OMe, OEt, OiPr, or -OtBu. In embodiments, the OC.sub.1-5haloalkyl is OCH.sub.3, OCH.sub.2F, OCHF.sub.2, or OCH.sub.2CF.sub.3. In embodiments, the OC.sub.1-5haloalkyl is OCH.sub.2CF.sub.3.

[0110] In embodiments, R.sub.13 is H, D, or C.sub.1-5alkyl. In embodiments, R.sub.13 is H or C.sub.1-5alkyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, propyl, isopropyl, or butyl. In embodiments, R.sub.13 is H, methyl, ethyl, or isopropyl.

[0111] In embodiments of Formula (I), R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted heterocyclic ring comprising 4-7 carbon atoms. In embodiments, R.sub.1 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted 5-to 7-membered heterocyclic ring. In embodiments, R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted 5- or 6-membered heterocyclic ring.

[0112] In embodiments, R.sub.14 is H, halogen, OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl. In embodiments, R.sub.14 is H, halogen, or optionally substituted alkyl. In embodiments, R.sub.14 is H or alkyl. In some embodiments, R.sub.14 is H. In embodiments, R.sub.14 is alkyl. In embodiments, the alkyl is a C.sub.1-C.sub.5alkyl. In embodiments, the C.sub.1-C.sub.5 alkyl is s methyl, ethyl, or isopropyl. In embodiments, R.sub.14 is halogen. In embodiments, the halogen is Cl, Br, or F. In embodiments, the cycloalkyl is a C.sub.3-C.sub.6 cycloalkyl. In embodiments, the cycloalkyl is cyclopropyl. In embodiments, the optionally substituted heteroalkyl is CH.sub.2OC.sub.1-5alkyl. In embodiments, the optionally substituted heteroalkyl is CH.sub.2N(H)(C.sub.1-5alkyl) or CH.sub.2N(C.sub.1-5alkyl).sub.2.

Compounds of Formulas (I-B) and (II-B)

[0113] In embodiments, the present disclosure provides a compound of Formula (I-B):

##STR00009##

or a pharmaceutically acceptable salt thereof,
wherein:

A is N or CH;

B is N or CYR.SUB.4.;

[0114] E is N or CZR.sub.5, wherein no more than two of A, B, and E are N;

W is O, S, or NR.SUB.6.;

[0115] X, Y, and Z are each independently absent, O, S, or NH;
R.sub.1 and R.sub.2 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl;
R.sub.3, R.sub.4, and R.sub.5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or P(O)(OH).sub.2;
R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene- optionally substituted cycloalkyl, or optionally substituted heteroalkyl;
R.sub.7 and R.sub.8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring;
R.sub.9 and R.sub.10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo;
R.sub.11 and R.sub.12 are each independently O.sup.?, OH, OD, O-alkyl, O-cycloalkyl, O-alkylene-cycloalkyl, O-aryl, or OM, wherein M is a pharmaceutically acceptable cation, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a heterocyclyl, and the alkyl, cycloalkyl, aryl and heterocyclyl are each optionally substituted;
R.sub.13 is H, D, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, C(O)-(alkylene- optionally substituted aryl), or OC(O)NHR.sub.15, or R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted heterocyclic ring comprising 4-7 carbon atoms;
R.sub.14 is H, D, halogen, OH, an optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; and
R.sub.15 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0116] In embodiments, is the present disclosure provides a compound of Formula (II-B):

##STR00010##

or a pharmaceutically acceptable salt thereof,
wherein:

A is N or CH;

B is N or CYR.SUB.4.;

[0117] E is N or CZR.sub.5, wherein no more than two of A, B, and E are N;

W is O, S, or NR.SUB.6.;

[0118] X, Y, and Z are each independently absent, O, S, or NH;
R.sub.1 and R.sub.2 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl;
R.sub.3, R.sub.4, and R.sub.5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or P(O)(OH).sub.2;
R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, or optionally substituted heteroalkyl;
R.sub.7 and R.sub.8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring;
R.sub.9 and R.sub.10 are each independently H, D, halogen, OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo;
R.sub.12 is O.sup.?, OH, OD, O-alkyl, O-cycloalkyl, O-alkylene-cycloalkyl, O-aryl, or OM, wherein M is a pharmaceutically acceptable cation, and the alkyl, cycloalkyl, and aryl are optionally substituted;
R.sub.14 is H, D, halogen, OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; and
n is 0, 1, or 2.

[0119] In embodiments, A is N. In embodiments, A is CH.

[0120] In embodiments, B is N. In embodiments, B is CYR.sub.4.

[0121] In embodiments, E is N. In embodiments, E is CZR.sub.5.

[0122] In embodiments of Formula (I), W is NR.sub.6 or O. In embodiments, W is NR.sub.6 or S. In embodiments, W is O or S. In embodiments, W is NR.sub.6. In embodiments, W is O. In embodiments, W is S.

[0123] In embodiments, X, Y, and Z are each independently absent, O, S, or N(C.sub.1-5)alkyl. In embodiments, X, Y, and Z are each independently absent or O. In embodiments, X, Y, and Z are each independently absent or NH. In embodiments, X, Y, and Z are each independently absent or S. In embodiments, X, Y, and Z are each absent.

[0124] In embodiments, X is O, and Y and Z are absent. In embodiments, Y is G, and X and Z are absent. In embodiments, Z is O, and X and Y are absent. In embodiments, X is S, and Y and Z are absent. In embodiments, Y is S, and X and Z are absent. In embodiments, Z is S, and X and Y are absent. In embodiments, X is NH, and Y and Z are absent. In embodiments, Y is NH, and X and Z are absent. In embodiments, Z is NH, and X and Y are absent. In embodiments, X is N(C.sub.1-5)alkyl, and Y and Z are absent. In embodiments, Y is N(C.sub.1-5)alkyl, and X and Z are absent. In embodiments, Z is N(C.sub.1-5)alkyl, and X and Y are absent.

[0125] In embodiments, R.sub.1 and R.sub.2 are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl. In embodiments, R.sub.1 and R.sub.2 are each independently H, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6Cycloalkyl, or optionally substituted C.sub.1-5cycloalkyl heteroalkyl. In some embodiments, R.sub.1 and R.sub.2 are each independently H or alkyl. In embodiments, R.sub.1 and R.sub.2 are each independently H or C.sub.1-5alkyl. In embodiments, R.sub.1 and R.sub.2 are each alkyl. In embodiments, R.sub.1 and R.sub.2 are each C.sub.1-5alkyl. In embodiments, R.sub.1 and R.sub.2 are each independently methyl, ethyl, or isopropyl. In embodiments, R.sub.1 and R.sub.2 are each methyl. In embodiments, R.sub.1 and R.sub.2 taken together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, e.g., azetidine, pyrrolidine, or piperidine.

[0126] In embodiments, R.sub.3, R.sub.4, and R.sub.5 are each independently H, D, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, optionally substituted C.sub.1-5heteroalkyl, P(O)(OC.sub.1-5alkyl).sub.2, P(O)(OPh).sub.2, or P(O)(OH).sub.2. In embodiments, R.sub.3, R.sub.4, and R.sub.5 are each independently H, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, optionally substituted C.sub.1-5heteroalkyl, P(O)(OC.sub.1-5alkyl).sub.2, P(O)(OPh).sub.2, or P(O)(OH).sub.2. In embodiments, R.sub.3, R.sub.4, and R.sub.5 are each independently H, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, P(O)(OC.sub.1-5alkyl).sub.2, P(O)(OPh).sub.2, or P(O)(OH).sub.2. In embodiments, R.sub.3, R.sub.4, and R.sub.5 are each independently H, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or P(O)(OH).sub.2. In embodiments, R.sub.3, R.sub.4, and R.sub.5 are each independently H, optionally substituted C.sub.1-5alkyl, or P(O)(OH).sub.2. In embodiments, the C.sub.1-5 alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl. In embodiments, R.sub.3, R.sub.4, and R.sub.5 are each H.

[0127] In embodiments, R.sub.3 is optionally substituted C.sub.1-5alkyl or P(O)(OH).sub.2, and R.sub.4 and R.sub.5 are each H. In embodiments, R.sub.4 is optionally substituted C.sub.1-5alkyl or P(O)(OH).sub.2, and R.sub.3 and R.sub.5 are each H. In embodiments, R.sub.5 is optionally substituted C.sub.1-5alkyl or P(O)(OH).sub.2, and R.sub.3 and R.sub.4 are each H. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl.

[0128] In embodiments, X is absent, and R.sub.3 is H, halogen, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or P(O)(OH).sub.2. In embodiments, Y is absent, and R.sub.4 is H, halogen, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or P(O)(OH).sub.2. In embodiments, Z is absent, and R.sub.3 is H, halogen, optionally substituted C.sub.1-5alkyl, optionally substituted C.sub.3-6cycloalkyl, or P(O)(OH).sub.2. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl. In embodiments, the halogen is F, Cl, or Br.

[0129] In embodiments, R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, optionally substituted alkylene-heterocyclyl, or optionally substituted alkylene-aryl. In embodiments, R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted alkylene-cycloalkyl. In embodiments, the optionally substituted alkyl is an optionally substituted C.sub.1-5alkyl. In embodiments, the optionally substituted cycloalkyl is an optionally substituted C.sub.3-6cycloalkyl. In embodiments, the optionally substituted aryl is an optionally substituted phenyl. In embodiments, the optionally substituted heterocyclyl is an optionally substituted 4- to 6-membered heterocyclyl, e.g., an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, each of which is optionally substituted. In embodiments, the optionally substituted alkylene is an optionally substituted C.sub.1-3alkylene. In embodiments, the optionally substituted alkylene is an optionally substituted methylene. In embodiments, R.sub.6 is H, C.sub.1-5alkyl, C.sub.3-6cycloalkyl or C(?O)(C.sub.1-5 alkyl). In embodiments, R.sub.6 is H, C.sub.1-5alkyl, or C.sub.3-8 cycloalkyl. In embodiments, R.sub.6 is H or C.sub.1-5alkyl. In embodiments, R.sub.6 is H. In embodiments, R.sub.6 is C.sub.1-5alkyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl. In embodiments, the optionally substituted C.sub.1-5alkyl is C(O)C.sub.1-4alkyl, C(O)N(H)(C.sub.1-4alkyl), or C(O)OC.sub.1-4alkyl.

[0130] In embodiments, R.sub.7 and R.sub.8 are each independently H, halogen, optionally substituted alkyl, OH, optionally substituted O-alkyl or optionally substituted O cycloalkyl. In embodiments, R.sub.7 and R.sub.8 are each independently H, halogen, optionally substituted C.sub.1-5alkyl, OH, optionally substituted OC.sub.1-5alkyl, or optionally substituted OC.sub.3-6cycloalkyl. In embodiments, R.sub.7 and R.sub.8 are each independently H or optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.7 and R.sub.8 are each H. In embodiments, R.sub.7 and R.sub.8 are each optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.7 and R.sub.8 are each halogen. In embodiments, the halogen is F. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl. In embodiments, the C.sub.1-5alkyl is methyl. In embodiments, the C.sub.1-5alkyl is ethyl.

[0131] In embodiments, R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an oxo or an optionally substituted cycloalkyl ring. In embodiments, R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an oxo. In embodiments, R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted C.sub.3-6cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted cyclopropyl. In embodiments, R.sub.7 is H and R.sub.5 is optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.7 is H and R.sub.5 is F. In embodiments, R.sub.7 is H and R.sub.5 is OH. In embodiments, R.sub.7 is H and R.sub.5 is OCH.sub.3. In embodiments, R.sub.7 is F and R.sub.5 is F. In embodiments, R.sub.7 and R.sub.8 are each optionally substituted C.sub.1-5alkyl. In embodiments, the C.sub.1-5alkyl is methyl.

[0132] In embodiments, R.sub.9 and R.sub.10 are each independently H, halogen, optionally substituted alkyl, OH, optionally substituted O-alkyl or optionally substituted O cycloalkyl. In embodiments, R.sub.9 and R.sub.10 are each independently H, halogen, optionally substituted C.sub.1-5alkyl, OH, optionally substituted OC.sub.1-5alkyl, or optionally substituted OC.sub.3-6cycloalkyl. In embodiments, R.sub.9 and R.sub.10 are each independently H or optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.9 and R.sub.10 are each H. In embodiments, R.sub.9 and R.sub.10 are each optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.9 and R.sub.10 are each halogen. In embodiments, the halogen is F. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, or isopropyl. In embodiments, the C.sub.1-5alkyl is methyl. In embodiments, the C.sub.1-5alkyl is ethyl.

[0133] In embodiments, R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted C.sub.3-6cycloalkyl ring. In embodiments, the optionally substituted cycloalkyl ring is an optionally substituted cyclopropyl. In embodiments, R.sub.9 is H and R.sub.10 is optionally substituted C.sub.1-5alkyl. In embodiments, R.sub.9 is H and R.sub.10 is F. In embodiments, R.sub.9 is H and R.sub.10 is OH. In embodiments, R.sub.9 is H and R.sub.10 is OCH.sub.3. In embodiments, R.sub.9 and R.sub.10 are each F. In embodiments, R.sub.9 and R.sub.10 are each optionally substituted C.sub.1-5alkyl. In embodiments, the C.sub.1-5alkyl is methyl.

[0134] In embodiments of Formula (I), R.sub.11 and R.sub.12 are each independently O.sup.?, OH, optionally substituted O-alkyl, optionally substituted O-cycloalkyl, optionally substituted O-alkylene-cycloalkyl, optionally substituted O-aryl, or OM, wherein M is a pharmaceutically acceptable cation. In embodiments, the optionally substituted O-alkyl is an optionally substituted O-haloalkyl, a hemiaminal, an acetal, or an amino acid residue. In embodiments, R.sub.11 and R.sub.12 are each independently O.sup.?, OH, optionally substituted OC.sub.1-5alkyl, optionally substituted OC.sub.1-5haloalkyl, optionally substituted OC.sub.3-6cycloalkyl, or -OM. In embodiments, R.sub.11 and R.sub.12 are each independently O.sup.?, OH, optionally substituted OC.sub.1-5alkyl, optionally substituted OC.sub.1-5haloalkyl, or -OM. In embodiments, R.sub.11 is O.sup.? and R.sub.12 is OH, optionally substituted OC.sub.1-5alkyl, optionally substituted OC.sub.1-5haloalkyl, or -OM. In embodiments, R.sub.11 and R.sub.12 are each optionally substituted OC.sub.1-5alkyl. In embodiments, R.sub.11 and R.sub.12 are each optionally substituted OC.sub.1-3alkyl. In embodiments, R.sub.11 and R.sub.12 are each independently OMe, OEt, OiPr, or -OtBu. In embodiments, R.sub.11 and R.sub.12 are each optionally substituted OC.sub.1-5haloalkyl. In embodiments, the OC.sub.1-5haloalkyl is OCH.sub.3, OCH.sub.2F, OCHF.sub.2, or OCH.sub.2CF.sub.3. In embodiments, the OC.sub.1-5haloalkyl is a OCH.sub.2CF.sub.3. In embodiments, M is Na.sup.+, K.sup.+, NH.sub.4.sup.+, or Ca.sup.+2. In embodiments, M is Na.sup.+, K.sup.+, or NH.sub.4.sup.+.

[0135] In embodiments of Formula (I), R.sub.11 and R.sub.12 taken together with the atoms to which they are attached form a heterocyclyl. In embodiments, R.sub.11 and R.sub.12 taken together with the atoms to which they are attached form a 5- to 12-membered heterocyclyl. In embodiments, the heterocyclyl has the structure:

##STR00011##

[0136] In embodiments of Formula (II), R.sub.12 is O.sup.?, OH, optionally substituted O-alkyl, optionally substituted O-cycloalkyl, optionally substituted O-alkylene-cycloalkyl, optionally substituted O-aryl, or OM, wherein M is a pharmaceutically acceptable cation. In embodiments, the optionally substituted O-alkyl is an optionally substituted O-haloalkyl, a hemiaminal, an acetal, or an amino acid residue. In embodiments, R.sub.12 is O.sup.?, OH, O-alkyl, O-haloalkyl, O-cycloalkyl, or -OM. In embodiments, R.sub.12 is O.sup.?, OH, optionally substituted O-alkyl, optionally substituted O-haloalkyl, or -OM. In embodiments, R.sub.12 is O, optionally substituted O-alkyl, or optionally substituted O-haloalkyl. In embodiments, R.sub.12 is optionally substituted O-alkyl. In embodiments, the optionally substituted O-alkyl is an optionally substituted OC.sub.1-5alkyl. In embodiments, the O-alkyl is OMe, OEt, OiPr, or -OtBu. In embodiments, R.sub.12 is O-haloalkyl. In embodiments, the optionally substituted O-haloalkyl is optionally substituted OC.sub.1-5haloalkyl. In some embodiments, the O-haloalkyl is OCH.sub.2CF.sub.3. In embodiments, R.sub.12 is O.sup.?, OH, OC.sub.1-5alkyl, OC.sub.1-5haloalkyl, OC.sub.3-6cycloalkyl, or -OM. In embodiments, M is Na.sup.+, K.sup.+, NH.sub.4.sup.+, or Ca.sup.+2. In embodiments, M is Na.sup.+, K.sup.+, or NH.sub.4.sup.+. In embodiments, the O-alkyl is OMe, OEt, OiPr, or -OtBu. In embodiments, the OC.sub.1-5haloalkyl is OCH.sub.3, OCH.sub.2F, OCHF.sub.2, or OCH.sub.2CF.sub.3. In embodiments, the OC.sub.1-5haloalkyl is OCH.sub.2CF.sub.3.

[0137] In embodiments, R.sub.13 is H, D, or C.sub.1-5alkyl. In embodiments, R.sub.13 is H or C.sub.1-5alkyl. In embodiments, the C.sub.1-5alkyl is methyl, ethyl, propyl, isopropyl, or butyl. In embodiments, R.sub.13 is H, methyl, ethyl, or isopropyl.

[0138] In embodiments of Formula (I), R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted heterocyclic ring comprising 4-7 carbon atoms. In embodiments, R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted 5-to 7-membered heterocyclic ring. In embodiments, R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted 5- or 6-membered heterocyclic ring.

[0139] In embodiments, R.sub.14 is H, halogen, OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl. In embodiments, R.sub.14 is H, halogen, or optionally substituted alkyl. In embodiments, R.sub.14 is H or alkyl. In some embodiments, R.sub.14 is H. In embodiments, R.sub.14 is alkyl. In embodiments, the alkyl is a C.sub.1-C.sub.5alkyl. In embodiments, the C.sub.1-C.sub.5 alkyl is s methyl, ethyl, or isopropyl. In embodiments, R.sub.14 is halogen. In embodiments, the halogen is Cl, Br, or F. In embodiments, the cycloalkyl is a C.sub.3-C.sub.6 cycloalkyl. In embodiments, the cycloalkyl is cyclopropyl. In embodiments, the optionally substituted heteroalkyl is CH.sub.2OC.sub.1-5alkyl. In embodiments, the optionally substituted heteroalkyl is CH.sub.2N(H)(C.sub.1-5alkyl) or CH.sub.2N(C.sub.1-5alkyl).sub.2.

[0140] In embodiments of Formula (I), R.sub.15 is H, optionally substituted C.sub.1-5alkyl, or optionally substituted phenyl.

[0141] In embodiment of Formula (II), n is 0 or 1. In embodiments, n is 0. In some embodiments, n is 1. In embodiments, n is 2.

[0142] In embodiments, provided herein is one or more compounds of Formula (I-A) or (I-B) selected from Table 1 or a pharmaceutically acceptable salt thereof.

TABLE-US-00001 TABLE 1 Compounds [00012] embedded image [00013] [00014] [00015] [00016] [00017] [00018] [00019] [00020] [00021] [00022] [00023] [00024] [00025] [00026] [00027] [00028] [00029] [00030] [00031] [00032] [00033] or [00034]

[0143] In embodiments, provided herein is one or more compounds of Formula (I-A) or (I-B) selected from Table 2 or a pharmaceutically acceptable salt thereof.

TABLE-US-00002 TABLE 2 Compounds [00035] embedded image [00036] [00037] [00038] [00039] [00040] [00041] [00042] [00043] [00044] [00045] [00046] [00047] [00048] [00049] [00050] [00051] [00052] [00053] [00054] [00055] [00056] [00057] [00058] [00059] [00060]

[0144] In embodiments, provided herein is one or more compounds of Formula (II-A) or (II-B) selected from Table 3 or a pharmaceutically acceptable salt thereof.

TABLE-US-00003 TABLE 3 Compounds [00061] embedded image [00062]

[0145] In embodiments, provided herein is one or more compounds of Formula (II-A) or (II-B) selected from Table 4 or a pharmaceutically acceptable salt thereof.

TABLE-US-00004 TABLE 4 Compounds [00063] embedded image [00064]

[0146] In embodiments, provided herein is a compound of Formula (I-A), (I-B), (II-A), or (II-B) as described herein, wherein the Formulas (I-A), (I-B), (II-A), and (II-B) exclude the compounds described in International Application No. PCT/US2022/032918.

Compositions

[0147] In embodiments of the present disclosure, a pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B) or Compounds of Table 1, Table 2, Table 3, or Table 4) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0148] The pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes. In embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprise a pharmaceutically acceptable carrier. In embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent. In embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0149] For the purposes of this disclosure, the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.

Methods of Use

[0150] In one aspect, the present disclosure provides methods of treating or preventing neurological disorders in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B) or Compounds of Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.

[0151] In embodiments, the neurological disorder is a mood disorder. In embodiments, the mood disorder is clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, major depressive disorder, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior. In embodiments, the method described herein provides therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In embodiments, the mood disorder is associated with neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e.g., Parkinson's Disease), or women's health disorders or conditions. In embodiments, the mood disorder is depression. In embodiments, the mood disorder is treatment-resistant depression or major depressive disorder. In embodiments, the mood disorder is major depressive disorder. In embodiments, the mood disorder is treatment-resistant depression.

[0152] In embodiments, the present disclosure provides methods of treating or preventing PTSD, mood disorders, general anxiety disorder, addictive disorders, and/or drug dependence in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B) or Compounds of Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.

[0153] In embodiments, the present disclosure provides methods of treating or preventing PTSD in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B) or Compounds of Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.

[0154] In embodiments, the methods include treating PTSD through induction and maintenance therapy by administering a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In embodiments, the compounds of the present disclosure are used for induction and maintenance therapy to treat PTSD with an improved safety profile when compared to treatment with the entactogenic, oneirophrenic or psychedelic compound (e.g., dimethyltryptamine or related compound, psilocybin, or MDMA) alone.

[0155] In embodiments, the present disclosure provides methods of treating or preventing behavioral or mood disorders in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B) or Compounds of Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject. In embodiments, the behavioral or mood disorder includes anxiety, such as social anxiety in autistic subjects (e.g., autistic adults) and anxiety related to life-threatening illnesses. In embodiments, the behavioral or mood disorder includes stress (where moderation thereof is measured, e.g., by effects on amygdala responses). In embodiments, the anxiety disorder is panic disorder, obsessive-compulsive disorder, and/or general anxiety disorder. In embodiments, the subject suffers from a lack of motivation, attention, lack of accuracy in memory recall, speed of response, perseveration, and/or cognitive engagement. Further examples include depression (e.g., MDD or TRD), attention disorders, disorders of executive function and/or cognitive engagement, obsessive compulsive disorder, bipolar disorder, panic disorder, phobia, schizophrenia, psychopathy, antisocial personality disorder and/or neurocognitive disorders.

[0156] In embodiments, the present disclosure provides methods for treating an addictive disorder in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B) or Compounds of Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject. In embodiments, the addictive disorder is alcohol abuse, substance abuse, smoking, obesity, or mixtures thereof. In embodiments, the disorder is an eating disorder (e.g., anorexia nervosa, bulimia, nervosa, binge eating disorder, etc.) or an auditory disorder.

[0157] In embodiments, the present disclosure provides methods for treating an impulsive disorder in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B) or Compounds of Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject. In embodiments, the impulsive disorder is attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Tourette's syndrome, autism, or combinations thereof.

[0158] In embodiments, the present disclosure provides methods for treating a compulsive disorder in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B) or Compounds of Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject. In embodiments, the compulsive disorder is obsessive compulsive disorder (OCD), gambling, aberrant sexual behavior, or combinations thereof.

[0159] In embodiments, the present disclosure provides methods for treating a personality disorder in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., compounds of Formula (I-A), Formula (I-B), Formula (II-A), Formula (II-B) or Compounds of Table 1, Table 2, Table 3, or Table 4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In embodiments, the personality disorder is conduct disorder, antisocial personality, aggressive behavior, or combinations thereof to the subject.

NUMBERED EMBODIMENTS

[0160] 1. A compound of Formula (I-B)

##STR00065##

or a pharmaceutically acceptable salt thereof,
wherein: [0161] A is N or CH; [0162] B is N or CYR.sub.4; [0163] E is N or CZR.sub.5, wherein no more than two of A, B, and E are N; [0164] W is O, S, or NR.sub.6; [0165] X, Y, and Z are each independently absent, O, S, or NH; [0166] R.sub.1 and R.sub.2 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; [0167] R.sub.3, R.sub.4, and R.sub.5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or P(O)(OH).sub.2; [0168] R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene-optionally substituted cycloalkyl, or optionally substituted heteroalkyl; [0169] R.sub.7 and R.sub.8 are each independently H, D, F, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring; [0170] R.sub.9 and R.sub.10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo; [0171] R.sub.11 and R.sub.12 are each independently O.sup.?, OH, OD, O-alkyl, O-cycloalkyl, O-alkylene-cycloalkyl, O-aryl, or OM, wherein M is a pharmaceutically acceptable cation, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a heterocyclyl, and the alkyl, cycloalkyl, aryl and heterocyclyl are each optionally substituted; [0172] R.sub.13 is H, D, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, C(O)-(alkylene-optionally substituted aryl), or OC(O)NHR.sub.15, or R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted heterocyclic ring comprising 4-7 carbon atoms; [0173] R.sub.14 is H, D, halogen, OH, an optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; and [0174] R.sub.15 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
2. The compound of embodiment 1, wherein A is CH.
3. The compound of embodiment 1 or 2, wherein B in CYR.sub.4.
4. The compound of any one of embodiments 1-3, wherein Y is absent.
5. The compound of any one of embodiments 1-3, wherein Y is O.
6. The compound of any one of embodiments 1-5, wherein R.sub.4 is H, C.sub.1-5alkyl, C.sub.3-6cycloalkyl, alkylene- C.sub.3-6cycloalkyl, or P(O)(OH).sub.2.
7. The compound of any one of embodiments 1-6, wherein R.sub.4 is H, C.sub.1-5alkyl, or P(O)(OH).sub.2.
8. The compound of any one of embodiments 1-7, wherein E is CZR.sub.5.
9. The compound of any one of embodiments 1-8, wherein Z is absent.
10. The compound of any one of embodiments 1-8, wherein Z is O.
11. The compound of any one of embodiments 1-10, wherein R.sub.5 is H, C.sub.1-5alkyl, C.sub.3-6cycloalkyl, alkylene-C.sub.3-6cycloalkyl, or P(O)(OH).sub.2.
12. The compound of any one of embodiments 1-10, wherein R.sub.5 is H or C.sub.1-5alkyl.
13. The compound of any one of embodiments 1-10, wherein R.sub.5 is H.
14. The compound of any one of embodiments 1-7, wherein E is N.
15. The compound of any one of embodiments 1, 2, and 8-13, wherein B is N.
16. The compound of any one of embodiments 1-15, wherein X is absent.
17. The compound of any one of embodiments 1-15, wherein X is O.
18. The compound of any one of embodiments 1-17, wherein R.sub.3 is H, alkyl, cycloalkyl, alkylene-cycloalkyl, or P(O)(OH).sub.2.
19. The compound of any one of embodiments 1-18, wherein R.sub.3 is H, C.sub.1-5alkyl, or P(O)(OH).sub.2.
20. The compound of any one of embodiments 1-19, wherein R.sub.3 is H.
21. The compound of any one of embodiments 1-20, wherein W is NR.sub.6.
22. The compound of any one of embodiments 1-21, wherein R.sub.6 is H, C.sub.1-5alkyl, C.sub.3-6cycloalkyl, or alkylene-C.sub.3-6cycloalkyl.
23. The compound of any one of embodiments 1-22, wherein R.sub.6 is H or C.sub.1-5alkyl.
24. The compound of any one of embodiments 1-23, wherein R.sub.6 is H.
25. The compound of any one of embodiments 1-24, wherein R.sub.1 and R.sub.2 are each independently H or alkyl.
26. The compound of any one of embodiments 1-25, wherein R.sub.1 and R.sub.2 are each alkyl.
27. The compound of embodiment 25 or 26, wherein the alkyl is a C.sub.1-5alkyl.
28. The compound of embodiment 25 or 26, wherein the alkyl is methyl, ethyl, or isopropyl.
29. The compound of any one of embodiments 1-28, wherein R.sub.7 and R.sub.8 are each independently H, F, or alkyl.
30. The compound of any one of embodiments 1-29, wherein R.sub.7 and R.sub.8 are each independently H or alkyl.
31. The compound of any one of embodiments 1-29, wherein R.sub.7 and R.sub.8 are each alkyl.
32. The compound of any one of embodiments 29-31, wherein the alkyl is a C.sub.1-5alkyl.
33. The compound of any one of embodiments 29-31, wherein the alkyl is a methyl.
34. The compound of any one of embodiments 1-29, wherein R.sub.7 and R.sub.8 are each independently H or F.
35. The compound of any one of embodiments 1-29, wherein R.sub.7 and R.sub.8 are each H.
36. The compound of any one of embodiments 1-29, wherein R.sub.7 is H and R.sub.5 is F.
37. The compound of any one of embodiments 1-28, wherein R.sub.7 and R.sub.8 taken together with the atom to which they are attached form a C.sub.3-6cycloalkyl.
38. The compound of any one of embodiments 1-28, wherein R.sub.7 and R.sub.8 taken together with the atom to which they are attached form a cyclopropyl.
39. The compound of any one of embodiments 1-38, wherein R.sub.9 and R.sub.10 are each independently H, F, or C.sub.1-5alkyl.
40. The compound of any one of embodiments 1-39, wherein R.sub.9 and R.sub.10 are each independently H or C.sub.1-5alkyl.
41. The compound of any one of embodiments 1-39, wherein R.sub.9 and R.sub.10 are each C.sub.1-5alkyl.
42. The compound of any one of embodiments 1-39, wherein the R.sub.9 and R.sub.10 are each C.sub.1-3alkyl.
43. The compound of any one of embodiments 1-39, wherein the R.sub.9 and R.sub.10 are each independently H or methyl.
44. The compound of any one of embodiments 1-39, wherein R.sub.9 and R.sub.10 are each independently H or F.
45. The compound of any one of embodiments 1-39, wherein R.sub.9 and R.sub.10 are each H.
46. The compound of any one of embodiments 1-39, wherein R.sub.9 is H and R.sub.10 is F.
47. The compound of any one of embodiments 1-38, wherein R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo.
48. The compound of any one of embodiments 1-47, wherein R.sub.11 and R.sub.12 are each independently O.sup.?, OH, OC.sub.1-5alkyl, OC.sub.1-5haloalkyl, O C.sub.3-6cycloalkyl, or -OM.
49. The compound of any one of embodiments 1-48, wherein R.sub.11 and R.sub.12 are each independently O.sup.?, OH, OC.sub.1-5alkyl, OC.sub.1-5haloalkyl, or -OM.
50. The compound of any one of embodiments 1-49, wherein R.sub.11 is O.sup.? and R.sub.12 is OH, OC.sub.1-5alkyl, OC.sub.1-5haloalkyl, or -OM.
51. The compound of any one of embodiments 1-49, wherein R.sub.11 and R.sub.12 are each OC.sub.1-5alkyl.
52. The compound of any one of embodiments 1-49, wherein R.sub.11 and R.sub.12 are each OC.sub.1-3alkyl.
53. The compound of any one of embodiments 1-49, wherein R.sub.11 and R.sub.12 are each independently OMe, OEt, OiPr, or -OtBu.
54. The compound of any one of embodiments 1-49, wherein R.sub.11 and R.sub.12 are each OC.sub.1-5haloalkyl.
55. The compound of any one of embodiments 48-50 and 54, wherein the OC.sub.1-5haloalkyl is a OCH.sub.2CF.sub.3.
56. The compound of any one of embodiments 1-50, wherein M is Na.sup.+, K.sup.+, or NH.sub.4.sup.+.
57. The compound of any one of embodiments 1-47, wherein R.sub.11 and R.sub.12 taken together with the atoms to which they are attached form a heterocyclyl.
58. The compound of any one of embodiments 1-47, wherein R.sub.11 and R.sub.12 taken together with the atoms to which they are attached form a 5- to 12-membered heterocyclyl.
59. The compound of embodiment 57 or 58, wherein the heterocyclyl is:

##STR00066##

60. The compound of any one of embodiments 1-59, wherein R.sub.13 is H, D, or C.sub.1-5alkyl.
61. The compound of any one of embodiments 1-60, wherein R.sub.13 is H or C.sub.1-5alkyl.
62. The compound of any one of embodiments 1-60, wherein R.sub.13 is H, methyl, ethyl, or isopropyl.
63. The compound of any one of embodiments 1-60, wherein R.sub.14 is H, F, Cl, Br or methyl.
64. The compound of any one of embodiments 1-63, wherein R.sub.14 is H.
65. The compound of embodiment 1, having the structure:

##STR00067## ##STR00068##

[0175] or a pharmaceutically acceptable salt thereof.

66. The compound of embodiment 1, having the structure:

##STR00069##

[0176] or a pharmaceutically acceptable salt thereof,

67. A compound of Formula (II-B):

##STR00070##

or a pharmaceutically acceptable salt thereof, [0177] wherein: [0178] A is N or CH; [0179] B is N or CYR.sub.4; [0180] E is N or CZR.sub.5, wherein no more than two of A, B, and E are N; [0181] W is O, S, or NR.sub.6; [0182] X, Y, and Z are each independently absent, O, S, or NH; [0183] R.sub.1 and R.sub.2 are each independently D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; [0184] R.sub.3, R.sub.4, and R.sub.5 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or P(O)(OH).sub.2; [0185] R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylene-cycloalkyl, or optionally substituted heteroalkyl; [0186] R.sub.7 and R.sub.8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring; [0187] R.sub.9 and R.sub.10 are each independently H, D, halogen, OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo; [0188] R.sub.12 is O.sup.?, OH, OD, O-alkyl, O-cycloalkyl, O-alkylene-cycloalkyl, O-aryl, or OM, wherein M is a pharmaceutically acceptable cation, and the alkyl, cycloalkyl, aryl and heterocyclyl are each optionally substituted; [0189] R.sub.14 is H, D, halogen, OH, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; and [0190] n is 0, 1, or 2.
68. The compound of embodiment 67, wherein A is CH.
69. The compound of embodiment 67 or 68, wherein B in C-YR.sub.4.
70. The compound of any one of embodiments 67-69, wherein Y is absent.
71. The compound of any one of embodiments 67-69, wherein Y is O.
72. The compound of any one of embodiments 67-71, wherein R.sub.4 is H, C.sub.1-5alkyl, C.sub.3-6cycloalkyl, alkylene-C.sub.3-6cycloalkyl, or P(O)(OH).sub.2.
73. The compound of any one of embodiments 67-72, wherein R.sub.4 is H, C.sub.1-5alkyl, or P(O)(OH).sub.2.
74. The compound of any one of embodiments 67-73, wherein E is CZR.sub.5.
75. The compound of any one of embodiments 67-74, wherein Z is absent.
76. The compound of any one of embodiments 67-74, wherein Z is O.
77. The compound of any one of embodiments 67-76, wherein R.sub.5 is H, C.sub.1-5alkyl, C.sub.3-6cycloalkyl, alkylene-C.sub.3-6cycloalkyl, or P(O)(OH).sub.2.
78. The compound of any one of embodiments 67-76, wherein R.sub.5 is H or C.sub.1-5alkyl.
79. The compound of any one of embodiments 67-76, wherein R.sub.5 is H.
80. The compound of any one of embodiments 67-73, wherein E is N.
81. The compound of any one of embodiments 67, 68, and 74-79, wherein B is N.
82. The compound of any one of embodiments 67-81, wherein X is absent.
83. The compound of any one of embodiments 67-81, wherein X is O.
84. The compound of any one of embodiments 67-83, wherein R.sub.3 is H, C.sub.1-5alkyl, C.sub.3-6cycloalkyl, alkylene-C.sub.3-6cycloalkyl, or P(O)(OH).sub.2.
85. The compound of any one of embodiments 67-84, wherein R.sub.3 is H, C.sub.1-5alkyl, or P(O)(OH).sub.2.
86. The compound of any one of embodiments 67-85, wherein R.sub.3 is H.
87. The compound of any one of embodiments 67-86, wherein W is NR.sub.6.
88. The compound of any one of embodiments 67-87, wherein R.sub.6 is H, C.sub.1-5alkyl, C.sub.3-6cycloalkyl, or alkylene-C.sub.3-6cycloalkyl.
89. The compound of any one of embodiments 67-88, wherein R.sub.6 is H or C.sub.1-5alkyl.
90. The compound of any one of embodiments 67-89, wherein R.sub.6 is H.
91. The compound of any one of embodiments 67-90, wherein R.sub.1 and R.sub.2 are each independently H or alkyl.
92. The compound of any one of embodiments 67-91, wherein R.sub.1 and R.sub.2 are each alkyl.
93. The compound of embodiment 91 or 92, wherein the alkyl is a C.sub.1-5alkyl.
94. The compound of embodiment 91 or 92, wherein the alkyl is methyl, ethyl, or isopropyl.
95. The compound of any one of embodiments 67-94, wherein R.sub.7 and R.sub.8 are each independently H, F, or alkyl.
96. The compound of any one of embodiments 67-95, wherein R.sub.7 and R.sub.8 are each independently H or alkyl.
97. The compound of any one of embodiments 67-95, wherein R.sub.7 and R.sub.8 are each alkyl.
98. The compound of embodiment 97, wherein the alkyl is a C.sub.1-5alkyl.
99. The compound of embodiment 97 or 98, wherein the alkyl is a methyl.
100. The compound of any one of embodiments 67-95, wherein R.sub.7 and R.sub.8 are each independently H or F.
101. The compound of any one of embodiments 67-95, wherein R.sub.7 and R.sub.8 are each H.
102. The compound of any one of embodiments 67-95, wherein R.sub.7 is H and R.sub.5 is F.
103. The compound of any one of embodiments 67-94, wherein R.sub.7 and R.sub.8 taken together with the atom to which they are attached form a C.sub.3-6cycloalkyl.
104. The compound of any one of embodiments 67-94, wherein R.sub.7 and R.sub.8 taken together with the atom to which they are attached form a cyclopropyl.
105. The compound of any one of embodiments 67-104, wherein R.sub.9 and R.sub.10 are each independently H, F, or alkyl.
106. The compound of any one of embodiments 67-105, wherein R.sub.9 and R.sub.10 are each independently H or alkyl.
107. The compound of any one of embodiments 67-105, wherein R.sub.9 and R.sub.10 are each alkyl.
108. The compound of any one of embodiments 105-107, wherein the alkyl is a C.sub.1-5alkyl.
109. The compound of any one of embodiments 105-107, wherein the alkyl is a methyl.
110. The compound of any one of embodiments 67-105, wherein R.sub.9 and R.sub.10 are each independently H or F.
111. The compound of any one of embodiments 67-105, wherein R.sub.9 and R.sub.10 are each H.
112. The compound of any one of embodiments 67-105, wherein R.sub.9 is H and R.sub.10 is F.
113. The compound of any one of embodiments 67-104, wherein R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo.
114. The compound of any one of embodiments 67-113, wherein R.sub.12 is O.sup.?, OH, O-alkyl, O haloalkyl, O-cycloalkyl, or -OM.
115. The compound of any one of embodiments 67-114, wherein R.sub.12 is O.sup.?, OH, O-alkyl, O haloalkyl, or -OM.
116. The compound of any one of embodiments 67-115, wherein R.sub.12 is O, O-alkyl, O haloalkyl.
117. The compound of any one of embodiments 67-115, wherein R.sub.12 is O-alkyl.
118. The compound of any one of embodiments 113-117, wherein the O-alkyl is OC.sub.1-5alkyl.
119. The compound of any one of embodiments 113-118, wherein the O-alkyl is OMe, OEt, OiPr, or -OtBu.
120. The compound of any one of embodiments 67-115, wherein R.sub.12 is O-haloalkyl.
121. The compound of any one of embodiments 114-116 and 120, wherein the O-haloalkyl is OC.sub.1-5haloalkyl.
122. The compound of any one of embodiments 114-116 and 120, wherein the O-haloalkyl is OCH.sub.2CF.sub.3.
123. The compound of any one of embodiments 67-115, wherein M is Na.sup.+, K.sup.+, or NH.sub.4.sup.+.
124. The compound of any one of embodiments 67-123, wherein R.sub.14 is H, F, Cl, Br, or C.sub.1-5alkyl.
125. The compound of any one of embodiments 67-124, wherein R.sub.14 is H.
126. The compound of any one of embodiments 67-125, having the structure:

##STR00071##

or a pharmaceutically acceptable salt thereof.
127. The compound of any one of embodiments 1-66, wherein the compound of Formula (I) excludes the compounds described in International Application No. PCT/US2022/032918.
128. The compound of any one of embodiments 67-126, wherein the compound of Formula (II) excludes the compounds described in International Application No. PCT/US2022/032918.
129. A compound of Formula (I-A):

##STR00072##

or a pharmaceutically acceptable salt thereof,
wherein:

[0191] A is N or CVR.sub.16;

[0192] B is N or CYR.sub.4;

[0193] E is N or CZR.sub.5, wherein no more than two of A, B, and E are N;

[0194] W is O, S, or NR.sub.6;

[0195] V, X, Y, and Z are each independently absent, O, S, or NH;

[0196] R.sub.1 and R.sub.2 are each independently H, D, deuterated alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl;

[0197] R.sub.3, R.sub.4, R.sub.5, and R.sub.16 are each independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or P(O)(OH).sub.2;

[0198] R.sub.6 is H, optionally substituted alkyl, optionally substituted cycloalkyl, alkylene-optionally substituted cycloalkyl, or optionally substituted heteroalkyl;

[0199] R.sub.7 and R.sub.8 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.7 and R.sub.8 taken together with the atom to which they are attached form an optionally substituted cycloalkyl ring;

[0200] R.sub.9 and R.sub.10 are each independently H, D, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl, or R.sub.9 and R.sub.10 taken together with the atom to which they are attached form an oxo;

[0201] R.sub.11 and R.sub.12 are each independently alkyl, deuterated alkyl, O, OH, OD, O-alkyl, O-cycloalkyl, O-alkylene-cycloalkyl, O-aryl, or OM, wherein M is a pharmaceutically acceptable cation, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a heterocyclyl, and the alkyl, cycloalkyl, aryl and heterocyclyl are each optionally substituted;

[0202] R.sub.13 is H, D, halogen, deuterated alkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylene-optionally substituted aryl, C(O)-(alkylene- optionally substituted aryl), or -G-C(O)NHR.sub.15, or R.sub.11 and R.sub.13 taken together with the atoms to which they are attached form an optionally substituted heterocyclic ring comprising 4-7 carbon atoms;

[0203] R.sub.14 is H, D, halogen, haloalkyl, OH, an optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heteroalkyl; and

[0204] R.sub.15 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein the compound is not:

##STR00073##

EXAMPLES

[0205] Compounds of the present disclosure can be synthesized using the following exemplary methods or other methods that are known to those skilled in the art.

[0206] General reaction conditions are provided, and reaction products can be purified by known methods including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol and the like or preparative reverse phase high pressure liquid chromatography.

[0207] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley & Sons, 2006, as well as in Jerry March, Advanced Organic Chemistry, 4.sup.th edition, John Wiley & Sons, publisher, New York, 1992 which are incorporated herein by reference in their entirety.

Example 1. Synthesis of Compounds of the Disclosure

[0208] Compounds 1-10 of Table 5 were prepared as described by the methods below.

TABLE-US-00005 TABLE 5 Prepared Compounds 1-10 of the Disclosure. Compound ID Structure Name 1 [00074] embedded image ((2-(1H-indol-3-yl)ethyl)dimethyl-?.sup.4- azaneyl)methyl hydrogen phosphate 2 [00075] ((2-(1H-indol-3-yl)ethyl)dimethyl-?.sup.4- azaneyl)methyl diisopropyl phosphate 3 [00076] ((2-(1H-indol-3-yl)ethyl)dimethyl-?.sup.4- azaneyl)methyl diethyl phosphate 4 [00077] ((2-(1H-indol-3-yl)ethyl)dimethyl-?.sup.4- azaneyl)methyl phosphate 5 [00078] embedded image di-tert-butyl (((2-(5-hydroxy-1H-indol- 3-yl)ethyl)dimethyl-?.sup.4-azaneyl)methyl) phosphate 6 [00079] di-tert-butyl (((2-(5-methoxy-1H-indol- 3-yl)ethyl)dimethyl-?.sup.4-azaneyl)methyl) phosphate 7 [00080] monosodium mono(((2-(1H-indol-3- yl)ethyl)dimethyl-?.sup.4-azaneyl)methyl phosphate) 8 [00081] embedded image potassium ((2-(1H-indol-3- yl)ethyl)dimethylammonio)methyl phosphate 9 [00082] ((2-(1H-indol-3- yl)ethyl)dimethylammonio)methyl (?.sup.5- azaneyl) phosphate 10 [00083] calcium ((2-(1H-indol-3- yl)ethyl)dimethylammonio)methyl phosphate

[0209] Compounds 1-4 were synthesized from a commercially available intermediate tryptophan according to Scheme 1.

##STR00084##

[0210] Compounds 5 and 6 were synthesized from commercially available intermediate 5-substituted tryptophan according to Scheme 2.

##STR00085##

[0211] Salts of the disclosed compounds were synthesized in one step from compound 1 as shown in Scheme 3.

##STR00086##

Synthesis of Compound 1

[0212] ##STR00087##

[0213] Step 1. To a solution of tryptamine (200 mg, 1.25 mmol, 1.0 equiv) in 3 mL of methanol was added sodium cyanoborohydride (197 mg, 3.13 mmol, 2.5 equiv), acetic acid (0.15 mL) and formaldehyde (254 mg, 3.13 mol, 2.5 equiv, 37% aq. solution) in methanol (1.5 mL) at 0? C. The mixture solution was stirred overnight at 25? C. and then concentrated under vacuum. The resulting solution was diluted with 20 mL of saturated sodium bicarbonate and extracted with ethyl acetate (3?20 mL). The combined organic layers were washed with brine (2?20 mL) of, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was dissolved in 2 mL of acetonitrile, then di-tert-butyl (chloromethyl) phosphate (274 mg, 1.06 mmol, 2.0 equiv), Me.sub.5-piperidine (164.5 mg, 1.06 mmol, 2.0 equiv) and sodium iodide (8.0 mg, 0.05 mmol, 0.1 equiv) was added at 25? C. under nitrogen atmosphere. The mixture was stirred for 24 h at 40? C. The resulting solution was diluted with 20 mL of ethyl acetate and washed sequentially with saturated sodium bicarbonate solution (2?10 mL) and saturated sodium chloride solution (10 mL). The combined organic layers were washed with brine (2?20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (120 mg) was used in the next step directly without further purification.

[0214] Step 2. To a solution of intermediate (120 mg, 0.29 mmol, 1.0 equiv) from above Step 1 in dichloromethane (1.2 mL) under argon was added trifluoroacetic acid (0.6 mL) slowly at RT. The resulting solution was stirred for 1 h and then concentrated under reduced pressure. The crude product was purified by reverse phase-chromatography: Column, C.sub.18 silica gel; mobile layer, water, and methanol (20% to 100% methanol over 15 min and hold 100% for 5 min); Detector, 220 nm. The fractions were concentrated under reduced pressure. Compound 1 was obtained as a white solid (28 mg, 28%). MS m/z [M+H].sup.+ (ESI): 299.05. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.11 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 7.11-6.98 (m, 2H), 4.89 (d, J=8.7 Hz, 2H), 3.51-3.45 (m, 2H), 3.18-3.13 (m, 2H), 3.07 (s, 6H). .sup.31P NMR (121 MHz, DMSO-d.sub.6) ??1.88.

Synthesis of Compound 2

[0215] ##STR00088##

[0216] To a solution of Compound 1 (100 mg, 0.34 mmol, 1.00 equiv) in N,N-Dimethylformamide (1 mL) was added 2-Iodopropane (171 mg, 1.00 mmol, 3.0 equiv) and trimethylamine (101 mg, 1.00 mmol, 3.0 equiv) at 25? C. The resulting mixture was stirred overnight at 50? C. and then diluted with 20 mL of dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution (2?20 mL) and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure and purified by reverse-phase: Column, C18 silica gel; mobile phase, water (with 0.05% NH.sub.4CO.sub.3), 10% to 100% gradient in 20 min; detector, UV 254 nm. Compound 2 was obtained as a white solid (20 mg, 17%) of: MS m/z [M+H].sup.+ (ESI): 341.05. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.98 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.12-7.08 (m, 1H), 7.03-6.99 (m, 1H), 4.87 (d, J=8.8 Hz, 2H), 4.29-4.22 (m, 1H), 3.50-3.45 (m, 2H), 3.19-3.15 (m, 2H), 3.08 (s, 6H), 1.12 (d, J=6.0 Hz, 6H).

Synthesis of Compound 3

[0217] ##STR00089##

[0218] In a similar manner described for Compound 2, Compound 3 was prepared from 100 mg of Compound 1 and 156 mg of iodoethane Compound 3 was obtained as a white solid (19 mg 17%). MS m/z [M+H].sup.+ (ESI): 327.05. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.98 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.26-7.00 (m, 3H), 4.88 (d, J=8.8 Hz, 2H), 3.77-3.69 (m, 2H), 3.50-3.44 (m, 2H), 3.20-3.15 (m, 2H), 3.08 (s, 6H), 1.13-1.04 (m, 3H).

Synthesis of Compound 4

[0219] ##STR00090##

[0220] In a similar manner described for Compound 2, Compound 4 was prepared from 100 mg of Compound 1 and 156 mg of iodomethane. The reaction was purified by Preparative-HPLC: Column: YMC Triart C18 ExRS, 20*150 mm, 5 ?m; Mobile Phase A: 10 mmol NH.sub.4HCO.sub.3+0.05% NH.sub.3.Math.H.sub.2O, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 34% B in 12 min, 34% B; Wavelength: 220 nm. Compound 4 was obtained as a white solid (19 mg). MS m/z [M+H].sup.+ (ESI): 313.10. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.00 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 7.10-7.02 (m, 2H), 4.89 (d, J=8.4 Hz, 2H), 3.52 (s, 3H), 3.42-3.40 (m, 2H), 3.20-3.09 (m, 8H).

Synthesis of Compound 5

[0221] ##STR00091##

[0222] To a solution of 5-hydroxytryptamine (1 g, 5.2 mmol, 1.0 equiv) in methanol (10 mL) was added sodium cyanoborohydride (0.83 g, 13 mmol, 2.5 equiv), acetic acid (0.5 mL) and formaldehyde (1.1 mL, 13 mol, 2.5 equiv, 40% in water) at 0? C. The mixture solution was stirred overnight at 25? C. and then concentrated under vacuum. The crude product was dissolved in 2 mL of acetonitrile, then di-tert-butyl (chloromethyl) phosphate (480 mg, 1.9 mmol, 2.0 equiv), Me.sub.5-piperidine (330 mg, 1.9 mmol, 2.0 equiv) and sodium iodide (15 mg, 0.2 mmol, 0.1 equiv) was added at 25? C. under nitrogen. The mixture was stirred for 24 h at 40? C. The resulting solution was diluted with ethyl acetate (20 mL) and washed with saturated sodium bicarbonate solution (2?10 mL) and saturated sodium chloride solution (10 mL), respectively. The combined organic layers were washed with brine (2?20 mL) and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure and purified by Preparative-HPLC: Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5 ?m; Mobile Phase A: 10 mmol NH.sub.4HCO.sub.3+0.05% NH.sub.3H.sub.2O, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 8 min, 50% B; Wavelength: 254 nm. Compound 5 was obtained as a white solid (38 mg). MS m/z [M+H].sup.+ (ESI): 371.15. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 10.79 (s, 1H), 9.35 (s, 1H), 7.16-7.09 (m, 3H), 6.64-6.60 (m, 1H), 4.92 (d, J=8.1 Hz, 2H), 3.50-3.48 (m, 2H), 3.07-3.02 (m, 8H), 1.33 (s, 9H).

Synthesis of Compound 6

[0223] ##STR00092##

[0224] To a solution of 5-Methoxytryptamine (1 g, 5.2 mmol, 1.0 equiv) in methanol (10 mL) was added sodium cyanoborohydride (0.83 g, 13 mmol, 2.5 equiv), acetic acid (0.5 mL) and formaldehyde (1.1 mL, 13 mol, 2.5 equiv, 40% in water) at 0? C. The mixture solution was stirred overnight at 25? C. and then concentrated under vacuum. The crude product was dissolved in 2 mL of acetonitrile, then di-tert-butyl (chloromethyl) phosphate (480 mg, 1.9 mmol, 2.0 equiv), Me.sub.5-piperidine (330 mg, 1.9 mmol, 2.0 equiv) and sodium iodide (15 mg, 0.2 mmol, 0.1 equiv) was added at 25? C. under nitrogen atmosphere. The mixture was stirred for 24 h at 40? C. The resulting solution was diluted with ethyl acetate (20 mL) and washed with saturated sodium bicarbonate solution (2?10 mL) and saturated sodium chloride solution (10 mL), respectively. The combined organic layers were washed with brine (2?20 mL) and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure and purified by Preparative-HPLC: Column: XBridge Prep OBD C.sub.18 Column, 30*150 mm, 5 ?m; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3+0.1% NH.sub.3H.sub.2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35% B in 9 min, 35% B; Wavelength: 220 nm. Compound 6 was obtained as a white solid (31 mg). MS m/z [M+H].sup.+ (ESI): 385.20. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.88 (s, 1H), 7.27-7.15 (m, 3H), 6.75-6.72 (m, 1H), 4.86 (d, J=8.7 Hz, 2H), 3.79 (s, 3H), 3.48-3.43 (m, 2H), 3.15-3.10 (m, 2H), 3.08 (s, 6H), 1.31 (s, 9H).

Synthesis of Compound 7

[0225] ##STR00093##

[0226] To a solution of Compound 1 (40 mg, 0.13 mmol, 1.00 equiv) in water (1 mL) were added sodium hydroxide (5.3 mg, 0.13 mmol, 1.0 equiv) at 25? C. The mixture was stirred for 15 min at 25? C. and the resulting solution was concentrated by lyophilization.) of Compound 7 was obtained as a white solid (30.0 mg, 70%). MS m/z [M+H].sup.+ (ESI): 299.05. .sup.1H NMR (400 MHz, Deuterium Oxide) ? 7.57-7.52 (m, 1H), 7.43-7.39 (m, 1H), 7.18-7.13 (m, 2H), 7.11-7.06 (m, 1H), 4.66 (d, J=6.4 Hz, 2H), 3.38-3.31 (m, 2H), 3.07-3.01 (m, 2H), 2.92 (s, 6H).

Synthesis of Compound 8

[0227] ##STR00094##

[0228] To a solution of Compound 1 (40 mg, 0.13 mmol, 1.0 equiv) in water (1 mL) were added potassium hydroxide (7 mg, 0.13 mmol, 1.0 equiv) at 25? C. The mixture was stirred for 15 min at 25? C. and the resulting solution was concentrated by lyophilization. Compound 8 was obtained as a white solid (32 mg, 71%). MS m/z [M+H].sup.+ (ESI): 299.05. .sup.1H NMR (400 MHz, Deuterium Oxide) ? 7.57-7.52 (m, 1H), 7.43-7.39 (m, 1H), 7.18-7.13 (m, 2H), 7.11-7.06 (m, 1H), 4.66 (d, J=6.4 Hz, 2H), 3.38-3.31 (m, 2H), 3.07-3.01 (m, 2H), 2.92 (s, 6H).

Synthesis of Compound 9

[0229] ##STR00095##

[0230] To a solution of Compound 1 (40 mg, 0.13 mmol, 1.00 equiv) in water (1 mL) were added ammonium hydroxide (23 mg, 0.13 mmol, 1.0 equiv) at 25? C. The mixture was stirred for 15 min at 25? C. and the resulting solution was concentrated by lyophilization. Compound 9 was obtained as a yellow solid (28 mg, 70%). MS m/z [M+H].sup.+ (ESI): 299.05. .sup.1H NMR (400 MHz, Methanol-d.sub.4) ? 7.69-7.61 (m, 1H), 7.39-7.34 (m, 1H), 7.24 (s, 1H), 7.16-7.04 (m, 2H), 4.92-4.90 (m, 2H), 3.67-3.57 (m, 2H), 3.32-3.27 (m, 2H), 3.17 (s, 6H).

Synthesis of Compound 10

[0231] ##STR00096##

[0232] To a solution of Compound 1 (40 mg, 0.13 mmol, 1.00 equiv) in water (1 mL) were added calcium hydroxide (5 mg, 0.07 mmol, 0.5 equiv) at 25? C. The mixture was stirred for 15 min at 25? C. and the resulting solution was concentrated by lyophilization. Compound 10 was obtained as a white solid (33 mg, 72%). MS m/z [M+H].sup.+ (ESI): 299.05. .sup.1H NMR (300 MHz, Deuterium Oxide) ? 7.52-7.47 (m, 1H), 7.38-7.33 (m, 1H), 7.15-7.00 (m, 3H), 4.62-4.61 (m, 2H), 3.36-3.25 (m, 2H), 3.06-2.94 (m, 2H), 2.88 (s, 6H).

TABLE-US-00006 TABLE 6 Prepared Compounds 11-28 of the Disclosure. Compound ID Structure Name 11 [00097] embedded image ((2-(1H-indol-3-yl)ethyl)dimethyl-?.sup.4- azaneyl)((bis(2,2,2- trifluoroethoxy)phosphoryl)oxy)methylium 12 [00098] ((2-(1H-indol-3- yl)ethyl)dimethylammonio)methyl tert- butyl phosphate 13 [00099] 2-(1H-indol-3-yl)-N,N-dimethyl-N-(((2- oxido-1,3,2-dioxaphospholan-2- yl)oxy)methyl)ethan-1-aminium 14 [00100] embedded image 2-(1H-indol-3-yl)-N,N-dimethyl-N-(((2- oxidobenzo[d][1,3,2]dioxaphosphol-2- yl)oxy)methyl)ethan-1-aminium 15 [00101] 2-(1H-indol-3-yl)-N,N-dimethyl-N-(((2- oxido-1,3,2-dioxaphosphinan-2- yl)oxy)methyl)ethan-1-aminium 16 [00102] N-(2-(1H-indol-3-yl)ethyl)-2-methoxy- N,N-dimethyl-1,2-oxaphosphinan-6- aminium 2-oxide 17 [00103] embedded image 6-((2-(1H-indol-3- yl)ethyl)dimethylammonio)-1,2- oxaphosphinan-2-olate 2-oxide 18 [00104] 1-((2-(1H-indol-3-yl)ethyl)dimethyl-?.sup.4- azaneyl)-1-(phosphonooxy)ethan-1-ylium 19 [00105] N-(2-(1H-indol-3-yl)ethyl)-N,N-dimethyl- 1-(phosphonooxy)propan-1-aminium 20 [00106] 1-((2-(1H-indol-3-yl)ethyl)dimethyl-?.sup.4- azaneyl)-2-methyl-1- (phosphonooxy)propan-1-ylium 21 [00107] embedded image ((2-(5-hydroxy-1H-indol-3- yl)ethyl)dimethylammonio)methyl hydrogen phosphate 22 [00108] (dimethyl(2-(5-(phosphonooxy)-1H-indol- 3-yl)ethyl)ammonio)methyl hydrogen phosphate 23 [00109] ((2-(5-methoxy-1H-indol-3- yl)ethyl)dimethylammonio)methyl hydrogen phosphate 24 [00110] (dimethyl(2-(4-(phosphonooxy)-1H-indol- 3-yl)ethyl)ammonio)methyl hydrogen phosphate 25 [00111] embedded image ((2-(4-hydroxy-1H-indol-3- yl)ethyl)dimethyl-?.sup.4- azaneyl)metheyliumyl hydrogen phosphate 26 [00112] tert-butyl (((2-(5-hydroxy-1H-indol-3- yl)ethyl)dimethylammonio)methyl) phosphate 27 [00113] tert-butyl (((2-(4-hydroxy-1H-indol-3- yl)ethyl)dimethylammonio)methyl) phosphate 28 [00114] embedded image ((2-(1H-indol-3- yl)ethyl)dimethylammonio)methyl (2,2,2- trifluoroethyl) phosphate

Example 2. Evaluation of Chemical Stability of Disclosed Compounds

[0233] ##STR00115##

Illustration of the Prodrug Strategy:

[0234] ##STR00116##

[0235] Compound 1 was synthesized as part of a novel prodrug strategy for improving the water solubility of tertiary amine-containing drugs. As shown in the above scheme, tertiary amine DMT (parent) was converted in two-step reaction to the polar Intermediate Prodrug 1.

[0236] Intermediate Prodrug 1 releases the parent DMT in vivo through a two-step bio-reversion process. The rate determining first step is via an enzymatic process, where prodrug bio-reversion involves a phosphatase-catalyzed dephosphorylation to give the resultant hydroxymethyl quaternary ammonium intermediate and inorganic phosphate. The second step involves conversion of the hydroxymethyl quaternary ammonium intermediate chemically to DMT and formaldehyde at physiological pH.

[0237] Chemical and plasma stability of prodrug Compound 1 was evaluated and the results enumerated in Table 7 and Table 8, respectively. PK studies of prodrug Compound 1 and metabolite (VLS-02-23-10) in mice were also conducted and both plasma exposure and brain exposure were analyzed as shown in FIGS. 1A-1C and FIGS. 2A-2B, respectively.

Chemical Stability of N-Phosphonooxymethyl Prodrug Compound 1

[0238]

TABLE-US-00007 TABLE 7 Stability Results of Test Compounds in PBS pH 6.5, SGF with and without Pepsin T? Remaining Percentage (%) Compound Incubation (min) 0 min 30 min 60 min 120 min 240 min Chlorambucil PBS (pH 6.5) 43.17 100.00 61.12 43.17 15.12 2.15 Erythromycin SGF with 40.26 100.00 56.55 34.88 11.22 1.60 pepsin Erythromycin SGF without 37.36 100.00 59.45 33.60 10.27 1.20 pepsin Compound 1 PBS (pH 6.5) 9999.00 100.00 104.71 106.37 107.29 117.35 Compound 1 SGF with 6227.35 100.00 96.70 106.43 102.36 96.82 pepsin Compound 1 SGF without 9999.00 100.00 98.76 107.08 101.90 108.80 pepsin

Plasma Stability of N-Phosphonooxymethyl Prodrug Compound 1

[0239]

TABLE-US-00008 TABLE 8 Stability Results of Test Compounds in Mouse Plasma T? Remaining Percentage (%) Compound Species (min) 0 min 15 min 30 min 60 min 120 min Propantheline Mouse 34.09 100.00 80.81 64.04 34.86 9.05 Compound 1 568.34 100.00 114.24 110.21 109.95 91.16

PRODRUGS OF DIMETHYLTRYPTAMINE AND DERIVATIVES THEREOF

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Cpc classification

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C07B59/004

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A61K31/675

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C07B2200/05

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C07F9/657163

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C07F9/5728

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International classification

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C07F9/572

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C07B59/00

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A61K31/675

HUMAN NECESSITIES

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C07F9/6571

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Abstract

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