Therapeutic methods and compositions for treating movement disorders

Abstract

The present disclosure provides: a) solid state forms of a compound having Structure (I) and Structure (II); b) crystalline forms of compounds having Structure (II); c) compounds having a Formula (III); d) compounds having a Formula (VI); e) deuterated analogs; f) pharmaceutical compositions comprising one or more of the solid state forms, crystalline forms, compounds, or deuterated analogs disclosed herein, and optionally, a pharmaceutically acceptable carrier or diluent; g) formulations comprising one or more of the solid state forms, crystalline forms, compounds, or deuterated analogs disclosed herein; h) extended release compositions comprising one or more of the solid state forms, crystalline forms, compounds, or deuterated analogs disclosed herein; i) methods of treating movement disorders by administering one or more of the solid state forms, crystalline forms, compounds, deuterated analogs, formulations, or compositions disclosed herein to a subject in need thereof; and j) methods for the preparation of one or more of the solid state forms, crystalline forms, compounds, deuterated analogs, formulations, or compositions disclosed herein.

Description

THERAPEUTIC METHODS AND COMPOSITIONS FOR TREATING MOVEMENT DISORDERS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the priority benefit of U. S. Provisional Application No. 63 / 802,953, filed May 9, 2025, and U. S. Provisional Application No. 63 / 715,080, filed November 1, 2024, which are hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates to therapeutic methods, pharmaceutical compositions, and formulations for treating movement disorders, such as using a muscarinic acetylcholine receptor inhibitor, and pharmaceutically acceptable salts, solid state forms, and derivatives thereof, in combination with a muscarinic acetylcholine receptor activator, and pharmaceutically acceptable salts, solid state forms, and derivatives thereof, to treat movement disorders. The present disclosure also relates to methods for preparing and characterizing the pharmaceutically acceptable salts, solid state forms, and derivatives of the muscarinic acetylcholine receptor inhibitor and the muscarinic acetylcholine receptor activator.BACKGROUND

[0003] Movement disorders impact a substantial number of patients. One such movement disorder, dystonia, is a neurological movement disorder characterized by involuntary (unintended) muscle contractions that cause slow repetitive movements or abnormal postures that can sometimes be painful. The condition can affect one part of the body (focal dystonia), two or more adjacent parts (segmental dystonia), or multiple parts of the body (general dystonia) including the trunk. The muscle spasms can range from mild to severe. Dystonia can be described as primary or secondary. Primary dystonia is when the dystonia is the sole neurological condition experienced by a subject. Secondary dystonia is when the dystonia is caused by outside factors and can be attributed to a specific cause such as exposure to certain medications, toxins, infections, stroke, spinal cord injury, head injury, or peripheral injury. Dystonia is reported to be associated with overactivity of cholinergic interneurons (Chis) thatprovide acetylcholine (Ach) to medium spiny neurons (MSNs). Overactivity of cholinergic interneurons produces more acetylcholine for signaling to medium spiny neurons and other neuronal populations leading to dystonia. Treatment options currently available for patients with dystonia do not provide adequate therapeutic benefit for all patients and / or have significant adverse side effects.

[0004] Trihexyphenidyl ("THP"), a phenyl propylamine, is an anticholinergic agent that was first approved by the FDA in 1949. THP as a hydrochloride salt ("THP HQ") is a synthetic antispasmodic drug that is a muscarinic acetylcholine receptor inhibitor and is widely used in the treatment of patients with parkinsonism, including primary or idiopathic Parkinson’s disease, secondary symptomatic parkinsonism (postencephalitic, arteriosclerotic, infection-induced, tumor-induced, trauma-induced, and drug-induced), and involuntary movements due to side effects of certain psychiatric drugs. See, for example, Cheung et al. in “Pharmacokinetic evaluation of a sustained release formulation of trihexyphenidyl in healthy volunteers” J. Pharm. Sci. (1988) 77(9):748-50. THP HC1 is approved by the FDA as an adjunct in the treatment of parkinsonism and for the control of extrapy rami dal disorders caused by central nervous system drugs such as dibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones. THP HC1 is widely used off-label for treating certain types of dystonia. However, there are major problems associated with using THP HC1 to treat dystonia and Parkinsonism, including that it causes significant adverse side effects at the dosage typically used to treat dystonia and current reports describe frequent administration of THP HC1; each of the foregoing contribute to poor patient compliance with THP HC1 therapy and concomitant poor therapeutic outcomes.

[0005] Bethanechol ("BTC") as a chloride salt is a muscarinic acetylcholine receptor activator and a parasympathomimetic agent that is FDA-approved for the treatment of postoperative urinary retention, postpartum urinary retention, and overflow incontinence caused by neurogenic atony of the bladder. In some aspects of the present disclosure, a muscarinic acetylcholine receptor activator, like BTC, can be used in an amount effective to reduce the frequency and / or magnitude of at least one side effect of a muscarinic acetylcholine receptor inhibitor, like THP.

[0006] However, not all compounds that are muscarinic acetylcholine receptor inhibitors or activators, like THP and BTC, respectively, have characteristics affording the best potential to become useful therapeutics. Some of these characteristics include high affinity atthe receptor site, duration of receptor inhibition or activation, oral bioavailability, solubility, and stability (e.g., ability to formulate, ability to crystallize, or shelflife). Favorable characteristics can lead to improved safety, tolerability, efficacy, therapeutic index, patient compliance, cost efficiency, manufacturing ease, etc.

[0007] In addition, the isolation and commercial-scale preparation of pharmaceutically acceptable salts, solid state forms, crystalline forms, and derivatives of muscarinic acetylcholine receptor inhibitors and activators, like THP and BTC, and corresponding pharmaceutical formulations having acceptable solid state properties (including chemical stability, thermal stability, solubility, hygroscopicity, and / or particle size), compound manufacturability (including yield, impurity rejection during crystallization, filtration properties, drying properties, and milling properties), and formulation feasibility (including stability with respect to pressure or compression forces during tableting) present a number of challenges.

[0008] Accordingly, the need exists for new therapeutic methods and pharmaceutical composition for treating movement disorders, including dystonia. The present disclosure addresses the foregoing needs and provides other related advantages.

[0009] Accordingly, there is a current need for one or more pharmaceutically acceptable salts, solid state forms, crystalline forms, and derivatives of THP and / or BTC, as well as pharmaceutical compositions and formulations thereof, that have an acceptable balance of these properties and can be used in the preparation of pharmaceutically acceptable dosage forms.BRIEF SUMMARY OF THE INVENTION

[0010] Additional aspects and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The aspects and advantages of the disclosure will be realized and attained by means of the elements and combinations disclosed herein.

[0011] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.

[0012] In one aspect, the present disclosure provides a solid state form of (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof.

[0013] In another aspect, the present disclosure provides a pharmaceutically acceptable salt of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II).

[0014] In another aspect, the present disclosure provides a solid state form of bethanechol (BTC) chloride having Structure (VII):or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof.

[0015] In another aspect, the present disclosure provides a pharmaceutically acceptable salt of bethanechol (BTC) chloride having Structure (VII).

[0016] In another aspect, the present disclosure provides a crystalline form of (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof.

[0017] In some aspects, the crystalline form of (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol having Structure (II) is a free base. In some aspects, the crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II) is a pharmaceutically acceptable salt. In some aspects, the crystalline form of (R)-l-cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II) is an anhydrate.

[0018] In some aspects, the crystalline form of (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol having Structure (II) is characterized using methods disclosed herein, for example, by using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).

[0019] In another aspect, the present disclosure provides a crystalline form of (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II), wherein the crystallineform has a high level of purity (e.g., 98-100%) after a specified duration of storage at particular temperatures and relative humidity levels as disclosed herein.

[0020] In another aspect, the present disclosure provides a compound of Formula (III):or a pharmaceutically acceptable salt or solvate thereof,wherein X', R1, and R2are defined as disclosed herein.

[0021] In another aspect, the present disclosure provides a compound of Formula (VI):or a pharmaceutically acceptable salt or solvate thereof,wherein X', R9, and R10are defined as disclosed herein.

[0022] In another aspect, the present disclosure provides a compound as disclosed herein wherein one or more hydrogen atoms are replaced by a deuterium atom.

[0023] In another aspect, the present disclosure provides a compound of (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof;wherein one or more hydrogen atoms are replaced by a deuterium atom as shown in the compound of Formula (VIII):wherein w is 0-4, x is 0-11, y is 0-10, z is 0-5, and the sum of w + x + y + z is at least one.

[0024] In another aspect, the present disclosure provides a compound of bethanechol (BTC) chloride having Structure (VII):or a pharmaceutically acceptable salt thereof;wherein one or more hydrogen atoms are replaced by a deuterium atom.

[0025] In another aspect, the present disclosure provides pharmaceutical compositions and dosage forms comprising one or more of the solid state forms, crystalline forms, mixtures, or compounds (including deuteratued compounds) disclosed herein.

[0026] In another aspect, the present disclosure provides a formulation comprising: (a) (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having a Structure (II):or a pharmaceutically acceptable salt thereof, and (b) a modifying release agent.

[0027] In another aspect, the present disclosure provides a formulation comprising: (a) bethanechol having a Structure (VII):or a pharmaceutically acceptable salt thereof, and (b) a modifying release agent.

[0028] In another aspect, the present disclosure provides an extended release composition comprising (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having a Structure (II):or a pharmaceutically acceptable salt thereof, and a modifying release agent, wherein the formulation is formulated for oral administration to a human subject.

[0029] In another aspect, the present disclosure provides an extended release composition comprising bethanechol having a Structure (VII):HY ro1 1(VII),or a pharmaceutically acceptable salt thereof, and a modifying release agent, wherein the formulation is formulated for oral administration to a human subject.

[0030] In another aspect, the present disclosure provides a method of treating a movement disorder in a patient in need thereof, comprising administering to the patient one or more of the solid state forms, crystalline forms, mixtures, compounds, pharmaceutical compositions, solid dosage forms, formulations, or compositions disclosed herein.

[0031] In another aspect, the present disclosure provides a method of treating a movement disorder in a patient in need thereof, comprising administering to the patient one or more of THP HC1 or the THP-derived solid state forms, crystalline forms, mixtures, compounds, pharmaceutical compositions, solid dosage forms, formulations, or compositions disclosed herein and one or more of BTC or the BTC-derived solid state forms, crystalline forms, mixtures, compounds, pharmaceutical compositions, solid dosage forms, formulations, or compositions disclosed herein.BRIEF DESCRIPTION OF THE FIGURES

[0032] FIG. l is a powder X-ray diffraction pattern (“XRPD”) corresponding to crystalline Free Base Form I.

[0033] FIG.2 is a differential scanning calorimety thermogram (“DSC”) and a thermogravimetric analysis thermogram (“TGA”) corresponding to crystalline Free Base Form I.

[0034] FIG.3 is an XRPD pattern corresponding to crystalline Sulfate Form I.

[0035] FIG.4 is a DSC and TGA thermogram corresponding to crystalline Sulfate Form I.

[0036] FIG.5 is an XRPD pattern corresponding to crystalline Tosylate Form I overlaid with Free Base Form I.

[0037] FIG.6 is a DSC and TGA thermogram corresponding to crystalline Tosylate Form I.

[0038] FIG.7 is an XRPD pattern corresponding to crystalline Mesylate Form I overlaid with Free Base Form I.

[0039] FIG.8 is a DSC and TGA thermogram corresponding to crystalline Mesylate Form I.

[0040] FIG.9 is an XRPD pattern corresponding to crystalline Phosphate Form I overlaid with Free Base Form I.

[0041] FIG. 10 is a DSC and TGA thermogram corresponding to crystalline Phosphate Form I.

[0042] FIG. 11 is an XRPD pattern corresponding to crystalline Maleate Form I and crystalline Maleate Form II overlaid with Free Base Form I.

[0043] FIG. 12 is a DSC and TGA thermogram corresponding to crystalline Maleate Form I.

[0044] FIG. 13 is a DSC and TGA thermogram corresponding to crystalline Maleate Form II.

[0045] FIG. 14 is an XRPD pattern corresponding to crystalline Fumarate Form I overlaid with Free Base Form I.

[0046] FIG. 15 is a DSC and TGA thermogram corresponding to crystalline Fumarate Form I.

[0047] FIG. 16 is an XRPD pattern corresponding to crystalline Hemi-Malate Form I and crystalline Hemi-Malate Form II overlaid with Free Base Form I.

[0048] FIG. 17 is a DSC and TGA thermogram corresponding to crystalline Hemi-Malate Form I.

[0049] FIG. 18 is a DSC and TGA thermogram corresponding to crystalline Hemi-Malate Form II.

[0050] FIG. 19 is an XRPD pattern corresponding to crystalline Hemi-Succinate Form I overlaid with Free Base Form I.

[0051] FIG. 20 is a DSC and TGA thermogram corresponding to crystalline Hemi- Succinate Form I.

[0052] FIG. 21 is an XRPD pattern corresponding to crystalline Benzoate Form I overlaid with Free Base Form I.

[0053] FIG. 22 is a DSC and TGA thermogram corresponding to crystalline Benzoate Form I.

[0054] FIG. 23 is an XRPD pattern corresponding to crystalline Hemi-Tartrate Form I and Hemi-Tartrate Pattern 2 overlaid with Free Base Form I.

[0055] FIG. 24 is a DSC and TGA thermogram corresponding to crystalline Hemi- Tartrate Form I.

[0056] FIG. 25 is a DSC and TGA thermogram corresponding to crystalline HemiTartrate Pattern 2.

[0057] FIG. 26 is an XRPD pattern corresponding to crystalline HC1 Salt Form I overlaid with Free Base Form I.

[0058] FIG. 27 is a DSC and TGA thermogram corresponding to crystalline HC1 Salt Form I.

[0059] FIG. 28 is an XRPD pattern corresponding to crystalline HC1 Salt Form I using alternate detection conditions

[0060] FIG. 29 is in vitro dissolution profiles of THP tablet formulations in water.

[0061] FIG. 30 is in vitro dissolution profiles of THP tablet formulations undergoing a pH shift.

[0062] FIG. 31 is in vitro dissolution profiles of THP tablet formulations undergoing a pH shift.

[0063] FIG. 32 is in vitro dissolution profiles of sustained release (SR) tablets comprising THP.

[0064] FIG. 33 is in vitro dissolution profiles of BTC tablet formulations in water.

[0065] FIG. 34 is in vitro dissolution profiles of BTC tablet formulations undergoing a pH shift.

[0066] FIG. 35 is in vitro dissolution profiles of BTC immediate release (IR) commercial product and BTC extended release (ER) tablet formulations undergoing a pH shift.

[0067] FIG. 36 is in vitro dissolution profiles of BTC tablet formulations in 50 mM phosphate (pH 6.8).

[0068] FIG. 37 is an XRPD pattern corresponding to crystalline Free Base Form II.

[0069] FIG. 38 is a DSC and TGA thermogram corresponding to crystalline Free Base Form II.

[0070] FIG. 39 is an XRPD pattern corresponding to crystalline Free Base Form III.

[0071] FIG. 40 is a DSC and TGA thermogram corresponding to crystalline Free Base Form III.

[0072] FIG. 41 is an XRPD pattern corresponding to crystalline Free Base Pattern 4.

[0073] FIG. 42 is a DSC and TGA thermogram corresponding to crystalline Free Base Pattern 4.

[0074] FIG. 43 is an XRPD pattern corresponding to crystalline Free Base Pattern 5.

[0075] FIG. 44 is a DSC and TGA thermogram corresponding to crystalline Free Base Pattern 5.

[0076] FIG. 45 is an XRPD pattern corresponding to crystalline Free Base Pattern 6.

[0077] FIG. 46 is a DSC and TGA thermogram corresponding to crystalline Free Base Pattern 6.

[0078] FIG. 47 is an XRPD pattern corresponding to crystalline Free Base Pattern 7.

[0079] FIG. 48 is a DSC and TGA thermogram corresponding to crystalline Free Base Pattern 7.

[0080] FIG. 49 is an XRPD pattern corresponding to crystalline BTC Form II.

[0081] FIG. 50 is a DSC and TGA thermogram corresponding to crystalline BTC Form II.

[0082] FIG. 51 is an XRPD pattern corresponding to crystalline BTC Form III.

[0083] FIG. 52 is a DSC and TGA thermogram corresponding to crystalline BTC Form III.

[0084] FIG. 53 is an XRPD pattern corresponding to crystalline BTC Form IV.

[0085] FIG. 54 is a DSC and TGA thermogram corresponding to crystalline BTC Form IV.

[0086] FIG. 55 is an XRPD pattern corresponding to crystalline BTC Form V.

[0087] FIG. 56 DSC and TGA thermogram corresponding to crystalline BTC Form V.DETAILED DESCRIPTION OF THE INVENTIONI. Definitions

[0088] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0089] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0090] The present disclosure provides: a) solid state forms of a compound having Structure (I) and Structure (II); b) crystalline forms of compounds having Structure (II); c) compounds having a Formula (III); d) compounds having a Formula (VI); e) compoundshaving a Formula (V); f) compounds having a Formula (VI); g) compounds having a Structure (VII); h) compounds having a Formula (VIII); i) compounds having a Formula (IX); j) compounds having a Formula (X); k) deuterated analogs; and any salts, hydrates, anhydrates, and solvates thereof (collectively referred to as "Compounds of the Disclosure" or individually as a "Compound of the Disclosure"). The present disclosure also encompasses: 1) pharmaceutical compositions comprising one or more of the Compounds of the Disclosure disclosed herein, and optionally, a pharmaceutically acceptable carrier or diluent; m) formulations comprising one or more of the Compounds of the Disclosure disclosed herein; and n) extended release compositions comprising one or more of the Compounds of the Disclosure disclosed herein (collectively referred to as "Compositions of the Disclosure" or individually as a "Composition of the Disclosure").

[0091] The present disclosure encompasses any of the Compounds of the Disclosure which may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.

[0092] The characterizing data for XRPD, DSC, and TGA that is referenced throughout the application and claims are determined using the instruments and conditions specified at the beginning of the Examples section under the subheading "Instrumental Conditions."

[0093] The terms "trihexyphenidyl" and "THP" as used herein can be used interchangeably and refer a compound having the structure:and any pharmaceutically acceptable salt, solvate, hydrate, anhydrate, stereoisomer, solid state form, deuterated form, or crystalline form thereof. The term "THP HQ" as used herein refers to the hydrochloride salt of THP. Use of the term "THP" or "trihexyphenidyl" herein does not exclude the hydrochloride salt, or any salt, of THP. Likewise, use of the term"THP" or "trihexyphenidyl" herein does not exclude any stereoisomer of THP, such as (R)- THP and (S)-THP. As such, the terms "THP" and "trihexyphenidyl" as used herein includes all free base forms, salt forms, solvate forms, hydrate forms, anhydrate forms, stereoisomer forms, solid state forms, deuterated forms, and crystalline forms of THP.

[0094] The terms "bethanechol" and "BTC" as used herein can be used interchangeably and refer a compound having the structure:X"H2NY o °1r1- and any pharmaceutically acceptable salt, solvate, hydrate, anhydrate, stereoisomer, solid state form, or crystalline form thereof. BTC can include any pharmaceutically acceptable anion as X', including, but not limited to, a chloride anion. The term "BTC chloride" as used herein refers to the chloride salt of BTC. Use of the term "BTC" or "bethanechol" herein does not exclude the chloride anion, or any anion, of BTC. Likewise, use of the term "BTC" or " bethanechol " herein does not exclude any stereoisomer of BTC, such as (R)-BTC and (S)-BTC. As such, the terms "BTC" and "bethanechol" as used herein includes all free base forms, salt forms, solvate forms, hydrate forms, anhydrate forms, stereoisomer forms, solid state forms, deuterated forms, and crystalline forms of BTC.

[0095] The term "THP-derived compounds" as used herein refers to any compounds, salts, solid state forms, or crystalline forms of THP disclosed herein, or any compounds, salts, solid state forms, or crystalline forms of compounds derived from THP. Compounds derived from THP include any compound whose structure is derivable from THP, including, for example, a deuterated form of THP, or any salt, solid state form, or crystalline form thereof, or a prodrug of THP, or any salt, solid state form, or crystalline form thereof (e.g., a compound of Formula (III)).

[0096] The term "BTC-derived compounds" as used herein refers to any compounds, salts, solid state forms, or crystalline forms of BTC disclosed herein, or any compounds, salts, solid state forms, or crystalline forms of compounds derived from BTC. Compounds derived from BTC include any compound whose structure is derivable from BTC, including, for example, a deuterated form of BTC, or any salt, solid state form, or crystalline form thereof, or a prodrug of BTC, or any salt, solid state form, or crystalline form thereof (e.g., a compound of Formula (VI)).

[0097] The term "prodrug(s)" as used herein refers to bioreversible derivatives of drug molecules that undergo an enzymatic and / or chemical transformation in vivo to release the parent drug. Prodrugs are used, for example, to overcome challenges with drug delivery, toxicity, and formulation. They can be designed to increase permeability, improve solubility, improve bioavailability, provide site-specific targeting, decrease toxicity, and / or overcome rapid drug metabolism of the parent drug.

[0098] The term "Pro-Moiety" as used herein refers to the chemical group bonded to a compound or drug, typically to a functional group, e.g., -OH, -NH2, or -NH-, to form a prodrug. Pro-Moi eties are described, for example, in Dhokchawle B. V., et al., Indian Journal of Pharmaceutical Education and Research 48:35-40 (2014); Stella, J P harm Sci 109:3514-3523 (2020); Najjar et al., Molecules 25:884 (2020), doi:10.3390 / molecules25040884, Fernandes et al., Viruses 15(11):2234; (2023), https: / / doi.org / 10.3390 / vl5112234; Huttunen et al., Pharmacol Rev 63:750-771 (2011); and Markovic et al., Pharmaceutics 12:1031 (2020), doi:10.3390 / pharmaceuticsl2111031.OJ 3 Examples of "Pro-Moieties" include, but are not limited to the group consisting of R,O,,, phosphoryl, phosphate, phosphoramidate, optionally substituted Ci-Cs alkyl phosphate, sulfonate, sulfonyl, alkyl sulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; and cholesterol, wherein R3, R4, R5, R6, R7, and R8are as defined in connection with a compound of Formula (III) and a compound of Formula (VI) as disclosed herein.

[0099] In this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more," and "at least one" can be used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple." Use of the term "or" herein is not meant to imply that alternatives are mutually exclusive.

[0100] Furthermore, "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as"A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0101] In this application, the use of "or" means "and / or" unless expressly stated or understood by one skilled in the art. In the context of a multiple dependent claim, the use of "or" refers back to more than one preceding independent or dependent claim.

[0102] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.

[0103] The terms "treat," "treating," and "treatment" are meant to include approaches for obtaining beneficial or desired clinical results. "Treatment" as used herein, covers any administration or application of a therapeutic for disease in a mammal, including a human. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread (for example, metastasis) of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total). Also encompassed by "treatment" is a reduction of pathological consequence of a proliferative disease. The methods provided herein contemplate any one or more of these aspects of treatment. In-line with the above, the term treatment does not require one-hundred percent removal of all aspects of the disorder.

[0104] In the context of movement disorders, the terms "treat," "treating," and "treatment" include, but are not limited to, any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0105] The term "disease" or "condition" or "disorder" as used herein refers to a condition where treatment is needed and / or desired and denotes disturbances and / or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and / or malfunctions. As demonstrated below, the solid state forms, crystalline forms, mixtures, compounds,pharmaceutical compositions, solid dosage forms, formulations, and compositions disclosed herein can be used in treating diseases and conditions such as movement disorders.

[0106] A "therapeutically effective amount" of a substance can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the substance are outweighed by the therapeutically beneficial effects. A therapeutically effective amount can be delivered in one or more administrations. A therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic effect.

[0107] The terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of the therapeutic agent to the desired site of biological action. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergam on; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0108] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations may be sterile.

[0109] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation employed. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0110] The term "about," as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11. As is understood by one skilled in the art, reference to "about" a value or parameter herein includes (and describes) instances that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X."

[0111] The terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of any of the solid state forms, crystalline forms, or compounds disclosed herein.

[0112] The terms "drug" or "therapeutic agent," refer to a solid state form, crystalline form, mixture, compound, pharmaceutical composition, solid dosage form, formulation, or composition as disclosed herein, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.

[0113] The term "solvate" refers to a compound, solid state form, or crystalline from provided herein or a salt thereof, which further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. Where the solvent includes ethanol, the compound can be an ethanol solvate.

[0114] The terms "polymorph" and "crystalline form" are used interchangeably herein and refer to a form of a compound or a salt, hydrate, anhydrate, or solvate thereof, in a particular crystal packing arrangement. All polymorphs or crystalline forms have the same elemental composition. The term "crystalline," as used herein, refers to a solid state form which consists of orderly arrangement of structural units. Different crystalline forms of the same compound, or a salt, co-crystal, hydrate, or solvate thereof, arise from different packing of the molecules in the solid state, which results in different crystal symmetries and / or unitcell parameter. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. See, e.g., Remington's Pharmaceutical Sciences, 18thed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23rded., 1843- 1844 (1995) (incorporated herein by reference).

[0115] Crystalline forms may be characterized by X-ray powder diffraction (XRPD). An XRPD pattern of reflections (peaks, typically expressed in degrees 2-theta) is commonly considered a fingerprint of a particular crystalline form. The relative intensities of the XRPD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, filters, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type of instrument or the settings. In some instances, any particular peak in an XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type of instrument or the settings, the sensitivity of the instrument, measuring conditions, and / or purity of the crystalline form. In some instances, any particular peak in an XRPD may appear in a symmetric shape or in an asymmetric shape, e.g., having a shoulder. A skilled artisan understanding these variations is capable of discriminating or ascertaining the defining features or characteristics of a particular crystal form using XRPD, as well as using other known physicochemical techniques.

[0116] The term "amorphous" as applied to a compound or solid state form as disclosed herein refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid.Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ("glass transition").

[0117] The term "polymorphic purity" as applied to a Compound of the Disclosure as disclosed herein refers to the purity of the Compound of the Disclosure relative to other polymorphic and amorphous forms of the same compound having the same structure.

[0118] The term "anhydrate" as applied to a compound, solid state form, or crystalline form as disclosed herein refers to a solid state wherein the compound contains no structural water within the crystal lattice.

[0119] The present disclosure encompasses any of the compounds, salts, solid state forms, and crystalline forms that may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds, salts, solid state forms, and crystalline forms described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.

[0120] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0121] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0122] The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

[0123] The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.

[0124] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0125] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in z / re & AppL Chem 65:2193 (1996), unless otherwise indicated.

[0126] The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as | R - S | * 100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as([oc]obs / [oc]max)* 100, where [oc]obs is the optical rotation of the mixture of enantiomers and [oc]max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.

[0127] The terms "enantiomerically pure" or "enantiopure" refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.

[0128] The terms "enantiomerically enriched" or "enantioenriched" refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50. Enantiomerically enriched compounds may be enantiomerically pure.

[0129] Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicant intends each of those words to be so interpreted in construing this patent, including the claims below.

[0130] It is understood that aspects of the invention described herein include "consisting" and / or "consisting essentially of' aspects.

[0131] As used herein, the term "pharmaceutically acceptable anion" refers to any anion that is compatible with a compound, solid state form, salt or crystalline form disclosed herein, as well as with any other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Non-limiting pharmaceutically acceptable anions include fluoride, chloride, bromide, iodide, cyanide, cyanate, thiocyanate, hydroxide, amide, acetate, formate, hydrogen carbonate, bicarbonate, nitrate, nitrite, perchlorate, chlorate, chlorite, hypochlorite, iodate, bromate, hypobromite, permanganate, dihydrogen phosphate, hydrogen phosphate, and hydrogen sulfate. See, e.g., Haynes et al., J. Pharm. Set. (2005) 94(10):2111 - 20.

[0132] For the purpose of the present disclosure, the term "optional substituents" as used by itself or part of another group can include substituents selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy,carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercapto-alkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (haloalkoxy)alkyl, and (heteroaryl)alkyl.

[0133] For the purpose of the present disclosure, the term "alkyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (z.e., C1-12 alkyl) or the number of carbon atoms designated (i.e., a Ci alkyl such as methyl, a C2 alkyl such as ethyl, a C3 alkyl such as propyl or isopropyl, etc.). The alkyl group can be suitably chosen from a straight chain C1-10 alkyl group, a straight chain C1-8 alkyl group, a branched chain C3-10 alkyl group, a straight chain C1-6 alkyl group, a branched chain C3-6 alkyl group, a straight chain Ci-4 alkyl group, a branched chain C3-4 alkyl group, a straight or branched chain C3-4 alkyl group. The alkyl group can be partially or completely deuterated, z.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms. Non-limiting exemplary C1-10 alkyl groups include methyl (including - CD3), ethyl, propyl, isopropyl, butyl, ec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary Ci-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

[0134] For the purpose of the present disclosure, the term "optionally substituted alkyl" as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from the list of "optional substituents" listed above, or from hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carb oxami do)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (haloalkoxy)alkyl, (heteroaryl)alkyl, cycloalkyl, alkenyl, alkynyl, aryl, optionally substituted heteroaryl, and optionally substituted heterocycle. The alkyl can be an optionally substituted Ci-4 alkyl. The optionally substituted alkyl can be substituted with two substituents, or one substituent. Non-limiting exemplary optionally substituted alkyl groups include -CH2CH2NO2, -CH2CH2CO2H, -CH2CH2SO2CH3, -CH2CH2COPI1, and -CH2C6H11.

[0135] For the purpose of the present disclosure, the term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. The alkylene group may also be a Ci-Ce alkylene or a C1-C4 alkylene. Non-limiting exemplary alkylene groups include, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-,-CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

[0136] For the purpose of the present disclosure, the term "alkenyl" as used by itself or as part of another group refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds. The alkenyl group can be chosen from a C2-8 alkenyl group, a C2-6 alkenyl group, and a C2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, ec-butenyl, pentenyl, and hexenyl. In some aspects, the alkenyl group has at least one double bond in the E (or trans) configuration. In some aspects, the alkenyl group has at least one double bond in the Z (or cis) configuration. In some aspects, the alkenyl group has at least one double bond in the E (or trans) configuration and at least one double bond in the Z (or cis) configuration. In some aspects, the alkenyl group has one double bond. In some aspects, the alkenyl group has more than one double bond.

[0137] For the purpose of the present disclosure, the term "optionally substituted alkenyl" as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from the list of "optional substituents" listed above, or from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle.

[0138] For the purpose of the present disclosure, the term "alkynyl" as used by itself or as part of another group refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. The alkynyl can have one carbon-to-carbon triple bond. In some aspects, the alkynyl group has more than one triple bond. The alkynyl group can be chosen from a C2-6 alkynyl group and a C2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0139] For the purpose of the present disclosure, the term "optionally substituted alkynyl" as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from the list of "optional substituents" listed above, or from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo.

[0140] For the purpose of the present disclosure, the term "cycloalkyl" as used by itself or as part of another group refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms ( / .<., C3-14 cycloalkyl) or the number of carbons designated. The cycloalkyl group can have two rings, or one ring. The cycloalkyl group can be chosen from a C3-8 cycloalkyl group and a C3-6 cycloalkyl group. The cycloalkyl group can contain one or more carbon-to-carbon double bonds or one carbon-to-carbon double bond. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

[0141] For the purpose of the present disclosure, the term "optionally substituted cycloalkyl" as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from the list of "optional substituents" listed above, or from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkyl sulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. The optionally substituted cycloalkyl can be substituted with two substituents or one substituent.

[0142] For the purpose of the present disclosure, the term "heterocycle" or "heterocyclo" as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members ( / .<., a 3- to 14-membered heterocyclo) and at least oneheteroatom. The heterocyclo group can be chosen from a C3-14 heterocyclo group and a C3-8 heterocyclo group. Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and / or nitrogen atoms, which can be quatemized. The term "heterocyclo" is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as P-lactam, y-lactam, 6-lactam and s-lactam, and cyclic carbamate groups such as oxazolidinyl-2-one. The term "heterocyclo" is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl, indolinyl-2-one, benzo[d]oxazolyl-2(3H)-one. The term "heterocyclo" is also meant to include groups having fused optionally substituted heteroaryl groups, e.g., 5, 6,7,8- tetrahydroimidazo[l,5-a]pyrazine. The heterocyclo group can be chosen from a 4-, 5-, 6-, 7- or 8-membered cyclic group containing one ring and one or two oxygen and / or nitrogen atoms, a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms, an 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocycle can be optionally linked to the rest of the molecule through a carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, azetidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6- azaspiro[3.4]octane, indolinyl, indolinyl-2-one, l,3-dihydro-2H-benzo[d]imidazol-2-one. In some aspects, the heterocyclo group contains 1 or more heteroatoms. In some aspects, the heterocyclo group contains 1 to 4 heteroatoms. In some aspects, the heterocyclo group contains 1 heteroatom. In some aspects, the heterocyclo group contains 2 heteroatoms. In some aspects, the heterocyclo group contains 3 heteroatoms. In some aspects, the heterocyclo group contains 4 heteroatoms. In some aspects, the heteroatoms are selected from nitrogen ("N"), sulfur ("S"), and oxygen ("O"). In some aspects, the heterocyclo group contains at least one N. In some aspects, the heterocyclo group contains at least one S. In some aspects, the heterocyclo group contains at least one O. In some aspects, the heterocyclo group contains only one or more N heteroatoms. In some aspects, the heterocyclo group contains at least one N and at least one S heteroatoms. In some aspects, the heterocyclo group contains at least one N and at least one O heteroatoms. In some aspects, the heterocyclo group contains at least one O and at least one S heteroatoms.

[0143] For the purpose of the present disclosure, the term "optionally substituted heterocyclo" as used herein by itself or part of another group means the heterocyclo asdefined above is either unsubstituted or substituted with one to four substituents independently selected from the list of "optional substituents" listed above, or from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. Substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle.

[0144] For the purpose of the present disclosure, the term "aryl" as used by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms ( / .<., Ce-14 aryl). The aryl group can be chosen from a Ce-14 aryl group, a C4-10 aryl group, and a Ce-io aryl group. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. The aryl group can be chosen from phenyl or naphthyl. The aryl group can be phenyl.

[0145] For the purpose of the present disclosure, the term "optionally substituted aryl" as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from the list of "optional substituents" listed above, or from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carb oxami do)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl,(Ci-4haloalkoxy)alkyl, (heteroaryl)alkyl. The optionally substituted aryl can be an optionally substituted phenyl. The optionally substituted phenyl can have four substituents, three substituents, two substituents, or one substituent. The optionally substituted phenyl can have one amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl substituent. Non-limiting exemplary substituted aryl groups include2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3 -methylphenyl, 3 -methoxyphenyl, 3 -fluorophenyl, 3 -chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6- di-chlorophenyl, 2-methyl, 3 -methoxyphenyl, 2-ethyl, 3 -methoxyphenyl, 3,4-di- methoxyphenyl, 3, 5 -di -fluorophenyl 3,5-di-methylphenyl, 3, 5 -dimethoxy, 4-methylphenyl, 2- fluoro-3 -chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:

[0146] For the purpose of the present disclosure, the term "heteroaryl" or "heteroaromatic" refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms ( / .<?., C5-14 heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen or sulfur. The heteroaryl group can be chosen from a C5-14 heteroaryl group and a C3-6 heteroaryl group. The heteroaryl can have three heteroatoms, two heteroatoms, or one heteroatom. The heteroaryl can be a Cs heteroaryl, or a Ce heteroaryl. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2 / / -pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3J / -indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4a7 / -carbazolyl, carbazolyl, P-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, triazolyl, tetrazolyl, and phenoxazinyl. The heteroaryl can be chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3 -furyl), pyrrolyl (e.g., lH-pyrrol-2-yl and lH-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., lH-pyrazol-3-yl, lH-pyrazol-4-yl, and lH-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5- yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), triazolyl (e.g., 1,2,4-triazolyl and 1,2,3-triazolyl). The term "heteroaryl" is also meant to include possible N-oxides. Exemplary N-oxides include pyridyl N-oxide. Insome aspects, the heteroaryl group contains 1 or more heteroatoms. In some aspects, the heteroaryl group contains 1 to 4 heteroatoms. In some aspects, the heteroaryl group contains 1 heteroatom. In some aspects, the heteroaryl group contains 2 heteroatoms. In some aspects, the heteroaryl group contains 3 heteroatoms. In some aspects, the heteroaryl group contains 4 heteroatoms. In some aspects, the heteroatoms are selected from nitrogen ("N"), sulfur ("S"), and oxygen ("O"). In some aspects, the heteroaryl group contains at least one N. In some aspects, the heteroaryl group contains at least one S. In some aspects, the heteroaryl group contains at least one O. In some aspects, the heteroaryl group contains only one or more N heteroatoms. In some aspects, the heteroaryl group contains at least one N and at least one S heteroatoms. In some aspects, the heteroaryl group contains at least one N and at least one O heteroatoms. In some aspects, the heteroaryl group contains at least one O and at least one S heteroatoms.

[0147] For the purpose of the present disclosure, the term "optionally substituted heteroaryl" as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from the list of "optional substituents" listed above, or from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carb oxami do)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R33)(R34), or -N(H)C(=O)-R35, wherein R33is hydrogen or Ci-4 alkyl; R34is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R35is alkyl, optionally substituted aryl, or optionally substituted heteroaryl. The optionally substituted heteroaryl can have one substituent. The substituent can be amino, alkylamino, dialkylamino, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, -N(R33)(R34), or -N(H)C(=O)-R35. The optionally substituted heteroaryl can be an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted.

[0148] For the purpose of the present disclosure, the term "phosphoryl" as used by itself or as part of another group refers to any group comprising a phosphorus atom and at least one oxygen atom. Non-limiting examples of phosphoryl groups include -P(=O)R2, -P(=O)(OR)(R), and -P(=O)(OR)2., wherein "R" represents a hydrogen or non-hydrogen group, or a negative charge.

[0149] For the purpose of the present disclosure, the term "phosphate" as used by itself or as part of another group refers to a group comprising a phosphorus atom and four oxygen atoms. A non-limiting example of a phosphate group is -OP(=O)(OR)2, wherein "R" represents a hydrogen or non-hydrogen group, or a negative charge.

[0150] For the purpose of the present disclosure, the term "alkyl phosphate" as used by itself or as part of another group refers to a group comprising an alkyl group attached to a phosphate group. A non-limiting example of an alkyl phosphate group is -RAOP(=O)(OR)2, wherein "RA" represents an alkyl group, and "R" represents a hydrogen or non-hydrogen group, or a negative charge.

[0151] For the purpose of the present disclosure, the term "phosphoramidate" as used by itself or as part of another group refers to a group comprising a phosphorus atom, three oxygen atoms, and an amine. Phosphoramidates are similar to phosphates, but with an oxygen substituted for an amine. Non-limiting examples of phosphoramidate groups are -NRP(=O)(OR)2 and -OP(=O)(OR)(NR2), wherein "R" represents a hydrogen or nonhydrogen group, or a negative charge.

[0152] For the purpose of the present disclosure, the term "sulfonate" as used by itself or as part of another group refers to a group comprising a sulfur atom and three oxygen atoms. A non-limiting example of a sulfonate group is -SC>2(OR), wherein "R" represents a hydrogen or non-hydrogen group, or a negative charge.

[0153] For the purpose of the present disclosure, the term "sulfonyl" as used by itself or as part of another group refers to a group comprising a sulfur atom and two oxygen atoms. A non-limiting example of a sulfonyl group is -SO2-. The term alkylsulfonyl as used by itself or as part of another group refers to a sulfonyl group attached to an alkyl group.

[0154] For the purpose of the present disclosure, the term "sulfate" as used by itself or as part of another group refers to a group comprising a sulfur atom and four oxygen atoms. A non-limiting example of a sulfonate group is -OSC>2(OR), wherein "R" represents a hydrogen or non-hydrogen group, or a negative charge.

[0155] For the purpose of the present disclosure, the term "lipid" refers the general usage of the term in the art, and can refer to organic compounds that are fats, fatty acids, or their derivatives, and that can be insoluble in water and soluble in organic solvents. Non-limiting examples of lipids include oils, waxes, steroids, sterols, fat-soluble vitamins, monoglycerides, diglycerides, hormones, and the like. One example of a lipid is "cholesterol" which has the formula:or any salt, solvate, stereoisomer, or diastereomer thereof.

[0156] For the purpose of the present disclosure, the term "phospholipid" refers to a lipid having an attached phosphate group.

[0157] The term "amino acid" is known in the art and refers to a compound or group containing both an amine group and a carboxy group.

[0158] The term "peptide" is known in the art and refers to a compound or group containing two or more amino acids connected through a covalent bond. The terms "polypeptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full- length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present disclosure, a "polypeptide" refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0159] For the purpose of the present disclosure, the term "amino" as used by itself or as part of another group refers to -NH2.

[0160] For the purpose of the present disclosure, the term "carboxy" as used by itself or as part of another group refers to a radical of the formula -COOH.

[0161] The term "carbohydrate" is known in the art and refers to a compound or group containing carbon, hydrogen, and oxygen with the general formula Cx(H2O)y.

[0162] For the purpose of the present disclosure, the term "halo" as used by itself or as part of another group refers to a halogen atom. Non-limiting exemplary halo groups include fluoro, chloro, bromo, and iodo.

[0163] For the purpose of the present disclosure, the term "nitro" as used by itself or as part of another group refers to an -NO2 group.

[0164] For the purpose of the present disclosure, the term "cyano" as used by itself or as part of another group refers to an -CN group.

[0165] For the purpose of the present disclosure, the term "alkylamino" as used by itself or as part of another group refers to-NHR36, wherein R36is C1-6 alkyl. R36can be Ci-4 alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0166] For the purpose of the present disclosure, the term "dialkylamino" as used by itself or as part of another group refers to -NR37aR37b, wherein R37aand R37bare each independently C1-6 alkyl. R37aand R37bcan each independently be Ci-4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0167] For the purpose of the present disclosure, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and / or iodine atoms. The alkyl group can be substituted by one, two, or three fluorine and / or chlorine atoms. The haloalkyl group can be chosen from a C1-6 haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluorom ethyl, pentafluoroethyl, 1,1 -difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and tri chloromethyl groups.

[0168] For the purpose of the present disclosure, the term "hydroxy alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups. The hydroxyalkyl group can be chosen from a monohydroxy alkyl group, i.e., substituted with one hydroxy group, a dihydroxy alkyl group, i.e., substituted with two hydroxy groups, and a C1-6 hydroxyalkyl group. Non-limitingexemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1 -hydroxy ethyl, 2 -hydroxy ethyl, 1,2-dihydroxy ethyl,2-hydroxypropyl, 3 -hydroxypropyl, 3 -hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-l- methylpropyl, and l,3-dihydroxyprop-2-yl.

[0169] For the purpose of the present disclosure, the term "alkoxy" as used by itself or as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom. The alkoxy group can be chosen from a Ci-6 alkoxy group and a Ci-6 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, and / c / V-butoxy.

[0170] For the purpose of the present disclosure, the term "haloalkoxy" as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom.Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0171] For the purpose of the present disclosure, the term "aryloxy" as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.

[0172] For the purpose of the present disclosure, the term "heteroaryloxy" as used by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.

[0173] For the purpose of the present disclosure, the term "aralkyl" or "arylalkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. The aralkyl group can be a Ci-6 alkyl substituted with one optionally substituted aryl group. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh2, -CH2(4-OH-Ph), and -CH(4-F-Ph)2.

[0174] For the purpose of the present disclosure, the term "aralkyloxy" or "arylalkyloxy" as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH2O-.

[0175] For the purpose of the present disclosure, the term "alkylthio" as used by itself or as part of another group refers to a sulfur atom substituted by an optionally substituted alkyl group. The alkylthio group can be chosen from a Ci-6 alkylthio group. Non-limiting exemplary alkylthio groups include -SCH3 (z.e., methylthio), and -SCFbCFF.

[0176] For the purpose of the present disclosure, the term "carboxamido" as used by itself or as part of another group refers to a radical of formula -C(=O)NR41aR41b, wherein R41aand R41bare each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R41aand R41btaken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. R41aand R41bcan each independently be hydrogen or optionally substituted alkyl. Non-limiting exemplary carboxamido groups include -CONH2, -CON(H)CH3, -CON(CH3)2, and -CON(H)Ph.

[0177] For the purpose of the present disclosure, the term "sulfonamido" as used by itself or as part of another group refers to a radical of the formula -SC>2NR42aR42b, wherein R42aand R42bare each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R42aand R42btaken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. Non-limiting exemplary sulfonamido groupsinclude -SO2NH2, -SO2N(H)CH3, and -SO2N(H)Ph.

[0178] For the purpose of the present disclosure, the term "alkylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, / .<?., -C(=O)-, substituted by an alkyl group. A non-limiting exemplary alkylcarbonyl group is -COCH3.

[0179] For the purpose of the present disclosure, the term "aryl carbonyl" as used by itself or as part of another group refers to a carbonyl group, / .<?., -C(=O)-, substituted by an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is -COPh.

[0180] For the purpose of the present disclosure, the term "alkyl sulfonyl" as used by itself or as part of another group refers to a sulfonyl group, / .<?., -SO2-, substituted by any of the above-mentioned optionally substituted alkyl groups. Non-limiting exemplary alkylsulfonyl groups are -SO2CH3 (i.e., methyl sulfonyl) and -SO2CH2CH3 (i.e., ethyl sulfonyl).

[0181] For the purpose of the present disclosure, the term "aryl sulfonyl" as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO2-, substituted by any of the above-mentioned optionally substituted aryl groups. A non-limiting exemplary arylsulfonyl group is -SChPh.

[0182] For the purpose of the present disclosure, the term "carboxyalkyl" as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a -COOH. A non-limiting exemplary carboxyalkyl group is -CH2CO2H.

[0183] For the purpose of the present disclosure, the term "alkoxyalkyl" as used by itself or as part of another group refers to an alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

[0184] For the purpose of the present disclosure, the term "(amino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with an amino group. The alkyl can be a Ci-6 alkyl. Non-limiting exemplary (amino)alkyl groupsinclude -CH2NH2, -C(NH2)(H)CH3, -CH2CH2NH2, -CH2C(NH2)(H)CH3, -CH2CH2CH2NH2, - CH2CH2CH2CH2NH2, and -CH2C(CH3)2CH2NH2.

[0185] For the purpose of the present disclosure, the term "hydroxyalkylamino" as used by itself or as part of another group refers to -NHR38, wherein R38is hydroxyalkyl.

[0186] For the purpose of the present disclosure, the term "(alkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with an alkylamino group. The alkyl can be a C1-6 alkyl. A non-limiting exemplary (alkylamino)alkyl group is -CH2CH2N(H)CH3.

[0187] For the purpose of the present disclosure, the term "(dialkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted by a dialkylamino group. The alkyl can be a C1-6 alkyl. Non-limiting exemplary (dialkylamino)alkyl groups are -CH2CH2N(CH3)2.

[0188] For the purpose of the present disclosure, the term "(cyano)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one or more cyano, e.g., - CN, groups. The alkyl can be a C1-6 alkyl. Non-limiting exemplary (cyano)alkyl groups include -CH2CH2CN, -CH2CH2CH2CN, and -CH2CH2CH2CH2CN.

[0189] For the purpose of the present disclosure, the term "(carboxamido)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with a carboxamido group. Non-limiting exemplary (carboxamido)alkyl groups include -CH2CONH2, C(H)CH3-CONH2, and -CH2CON(H)CH3.

[0190] For the purpose of the present disclosure, the term "mercaptoalkyl" as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a -SH group.

[0191] For the purpose of the present disclosure, the term "(heterocyclo)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or threeoptionally substituted heterocyclo groups. The (heterocyclo)alkyl can be a Ci-6 alkyl substituted with one optionally substituted heterocyclo group. The heterocycle can be linked to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include:

[0192] For the purpose of the present disclosure, the term "(cycloalkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted by a cycloalkylamino group. The alkyl can be a Ci-6 alkyl. Non-limiting exemplary (cycloalkylamino)alkyl groups include -CH2N(H)cyclopropyl, -CH2N(H)cyclobutyl, and -CH2N(H)cyclohexyl.

[0193] For the purpose of the present disclosure, the term "heteroaralkyl" or "(heteroaryl)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups. The (heteroaryl)alkyl group can be a Ci-4 alkyl substituted with one optionally substituted heteroaryl group. Non-limiting exemplary (heteroaryl)alkyl groups include:

[0194] The present disclosure encompasses any of the compounds, solid state forms, salts, or crystalline forms as disclosed herein being isotopically-labelled ( / .<., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H (or deuterium (D)),3H,nC,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively, e.g.,3H,nC, and14C. The present disclosure also provides a compositionwherein substantially all of the atoms at a position within the compound, solid state form, salt, or crystalline form as disclosed herein are replaced by an atom having a different atomic mass or mass number. The present disclosure also provides a composition wherein a portion of the atoms at a position within the compound, solid state form, salt, or crystalline form as disclosed herein are replaced, / .<., the compound, solid state form, salt, or crystalline form is enriched at a position with an atom having a different atomic mass or mass number. In one embodiment, the present disclosure provides a composition wherein a compound, solid state form, salt, or crystalline form as disclosed herein has from 1 to 8 hydrogens replaced with deuterium. Isotopically-labelled compound, solid state form, salt, or crystalline form as disclosed herein can be prepared by methods known in the art.

[0195] The terms "reduction" or "reduce" or "inhibition" or "inhibit" refer to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To "reduce" or "inhibit" is to decrease, reduce or arrest an activity, function, and / or amount as compared to a reference. In some embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 20% or greater. In some embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 50% or greater. In some embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater. In some embodiments, the amount noted above is inhibited or decreased over a period of time, relative to a control over the same period of time.II. Salts and Solvates

[0196] The present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, as defined and disclosed herein, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate (or sulfate) and the like; organic acid salts such as citrate, lactate, tartrate, maleate, malate, succinate, fumarate, mandelate, acetate, benzoate, di chloroacetate, trifluoroacetate, oxalate,formate and the like; sulfonates such as methanesulfonate (mesylate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate) and the like; and amino acid salts such as arginate, asparginate, glutamate and the like. The term "pharmaceutically acceptable salt" as used herein, refers to any salt, e.g., obtained by reaction with an acid or a base, of a Compound of the Disclosure that is physiologically tolerated in the target patient (e.g., a mammal, e.g., a human).

[0197] Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, di chloroacetic acid, or the like. Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.

[0198] In some aspects, the salt is selected from the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, a maleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt. In some aspects, the salt is selected from the group consisting of a maleate salt, a succinate salt, and a hydrochloride salt. In some aspects, the salt is a hydrochloride salt. In some aspects, the salt is a maleate salt. In some aspects, the salt is a succinate salt.

[0199] The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1: 1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvatedand unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(7): Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604 (2001). Atypical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.III. Solid State Forms

[0200] The present disclosure provides solid state forms of the the Compounds of the Disclosure, as defined and disclosed herein.Compounds Having Structure (I) and Structure (II)

[0201] In one aspect, the present disclosure provides solid state forms of the compound 1- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (I) and the compound (R)- l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II). Analogous solid state forms of the compound (S)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol are also an aspect of and are encompassed within this disclosure.

[0202] As with all pharmaceutical compounds and compositions, the chemical and physical properties of the compound of Structure (I) and Structure (II) are important in their commercial development. These properties include, but are not limited to: (1) packing properties such as molar volume, bulk density and hygroscopicity, (2) thermodynamic properties such as melting temperature, vapor pressure and solubility, (3) kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape, (5) mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and (6) filtration properties. Theseproperties can affect, for example, the processing and storage of the compounds and pharmaceutical compositions comprising the compounds.

[0203] Solid state forms of the Compounds of the Disclosure, including the compounds of Structure (I) and Structure (II) that improve upon one or more of these properties relative to other solid state forms of the compounds are desirable. Isolating pharmaceutically acceptable solid state forms of the compounds that can be manufactured on a commercialscale has been a challenge.

[0204] In one aspect, the present disclosure provides a solid state form of 1 -cyclohexyl- 1- phenyl-3-(l-piperidyl)propan-l-ol having Structure (I):or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof.

[0205] In another aspect, the solid state form of l-cyclohexyl-l-phenyl-3-(l- piperidyl)propan-l-ol having Structure (I) is a free base. In another aspect, the solid state form of l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (I) is a pharmaceutically acceptable salt.

[0206] In another aspect, the present disclosure provides a solid state form of (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof.

[0207] In another aspect, the solid state form of (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol having Structure (II) is a free base. In another aspect, the solid state form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II) is a pharmaceutically acceptable salt.

[0208] In some aspects, the pharmaceutically acceptable salt of a compound having Structure (I) or Structure (II) is selected from the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, a maleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt. In some aspects,the pharmaceutically acceptable salt is selected from the group consisting of a maleate salt, a succinate salt, and a hydrochloride salt. In some aspects, the pharmaceutically acceptable salt is a sulfate salt. In some aspects, the pharmaceutically acceptable salt is a tosylate salt. In some aspects, the pharmaceutically acceptable salt is a mesylate salt. In some aspects, the pharmaceutically acceptable salt is a phosphate salt. In some aspects, the pharmaceutically acceptable salt is a maleate salt. In some aspects, the pharmaceutically acceptable salt is a fumarate salt. In some aspects, the pharmaceutically acceptable salt is a malate salt. In some aspects, the pharmaceutically acceptable salt is a succinate salt. In some aspects, the pharmaceutically acceptable salt is a benzoate salt. In some aspects, the pharmaceutically acceptable salt is a tartrate salt. In some aspects, the pharmaceutically acceptable salt is a hydrochloride salt.

[0209] In some aspects, the solid state form is an amorphous form, a co-crystal form, or a crystalline form of the compound having Structure (I) or Structure (II).

[0210] In some aspects, the solid state form is an amorphous form of the compound having Structure (I) or Structure (II). In some aspects, the amorphous form is a hydrate, anhydrate, or solvate thereof. In some aspects, the amorphous form of the compound is substantially free of other polymorphic or physical forms. In some aspects, the amorphous form has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, at least 99%, or 100%.

[0211] In some aspects, the solid state form is a co-crystal form of the compound having Structure (I) or Structure (II).

[0212] In some aspects, the solid state form is a crystalline form of the compound having Structure (I) or Structure (II). In some aspects, the crystalline form is a hydrate, anhydrate, or solvate of the compound having Structure (I) or Structure (II). In some aspects, the crystalline form is a hydrate. In some aspects, the crystalline form is a anhydrate. In some aspects, the crystalline form is a solvate.

[0213] In some aspects, the crystalline form of the compound having Structure (I) or Structure (II) is substantially free of other polymorphic or physical forms. In some aspects, the crystalline form of a compound having Structure (I) or Structure (II) has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or atleast 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, at least 99%, or 100%. In some aspects, the crystalline form of a compound having Structure (I) or Structure (II) is characterized as comprising no XRPD-detectable amount of any other polymorphic or amorphous forms of compounds having Structure (I) or Structure (II).

[0214] In one aspect, the present disclosure provides a crystalline form of the compound having Structure (I):or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof.

[0215] In another apect, the crystalline form of the compound having Structure (I) is a free base. In another aspect, the crystalline form of a compound having Structure (I) is a pharmaceutically acceptable salt. In some aspects, the pharmaceutically acceptable salt is formed between l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (I) and a pharmaceutically acceptable acid, as disclosed herein.

[0216] In one aspect, the present disclosure provides a crystalline form of the compound having Structure (II):or a pharmaceutically acceptable salt thereof.

[0217] In another apect, the crystalline form of the compound having Structure (II) is a free base.

[0218] In another aspect, the crystalline form of (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol having Structure (II) is a pharmaceutically acceptable salt. In some aspects, the crystalline form is a pharmaceutically acceptable salt of (R)-l -cyclohexyl- 1- phenyl-3-(l-piperidyl)propan-l-ol having Structure (II). In some aspects, the pharmaceutically acceptable salt is selected from the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, a maleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt. In someaspects, the pharmaceutically acceptable salt is selected from the group consisting of a maleate salt, a succinate salt, and a hydrochloride salt. In some aspects, the pharmaceutically acceptable salt is a sulfate salt. In some aspects, the pharmaceutically acceptable salt is a tosylate salt. In some aspects, the pharmaceutically acceptable salt is a mesylate salt. In some aspects, the pharmaceutically acceptable salt is a phosphate salt. In some aspects, the pharmaceutically acceptable salt is a maleate salt. In some aspects, the pharmaceutically acceptable salt is a fumarate salt. In some aspects, the pharmaceutically acceptable salt is a malate salt. In some aspects, the pharmaceutically acceptable salt is a succinate salt. In some aspects, the pharmaceutically acceptable salt is a benzoate salt. In some aspects, the pharmaceutically acceptable salt is a tartrate salt. In some aspects, the pharmaceutically acceptable salt is a hydrochloride salt. In some aspects, the pharmaceutically acceptable salt is formed between (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II) and a pharmaceutically acceptable acid.

[0219] In some aspects, the pharmaceutically acceptable acid is selected from 1 -hydroxy - 2-naphthoic acid, 4-aminosalicylic acid, ascorbic acid, adipic acid, L-aspartic acid, benzene sulfonic acid, benzoic acid, trans-cinnamic acid, citric acid, ethanedisulfonic acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, malonic acid, R-mandelic acid, methanesulfonic acid, mucic acid, naphthalene sulfonic acid, nicotinic acid, oxalic acid, palmitic acid, p-toluene sulfonic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, vanillic acid, vanillin, ethyl maltol, gallic acid, gallic acid ethyl ester, 4-hydroxybenzoic acid, 4-hydroxybenzoic acid methyl ester, 3,4,5- trihydroxybenzoic acid, nicotinamide, L-proline, and D-sorbitol. In some aspects, the pharmaceutically acceptable acid is selected from sulfuric acid, p-toluene sulfonic acid, methanesulfonic acid, phosphoric acid, maleic acid, fumaric acid, malic acid, succinic acid, benzoic acid, tartric acid, and hydrochloric acid. In some aspects, the pharmaceutically acceptable acid is sulfuric acid. In some aspects, the pharmaceutically acceptable acid is p-toluenesulfonic acid. In some aspects, the pharmaceutically acceptable acid is methanesulfonic acid. In some aspects, the pharmaceutically acceptable acid is phosphoric acid. In some aspects, the pharmaceutically acceptable acid is maleic acid. In some aspects, the pharmaceutically acceptable acid is fumaric acid. In some aspects, the pharmaceutically acceptable acid is malic acid. In someaspects, the pharmaceutically acceptable acid is succinic acid. In some aspects, the pharmaceutically acceptable acid is benzoic acid. In some aspects, the pharmaceutically acceptable acid is tartric acid. In some aspects, the pharmaceutically acceptable acid is hydrochloric acid

[0220] In some aspects, the crystalline form of the compound having Structure (I) or Structure (II) is a hydrate, anhydrate, or solvate of the compound having Structure (I) or Structure (II). In some aspects, the crystalline form is a hydrate of the compound having Structure (I) or Structure (II). In some aspects, the crystalline form is an anhydrate of the compound having Structure (I) or Structure (II). In some aspects, the crystalline form is a solvate of the compound having Structure (I) or Structure (II). In some aspects, the crystalline form of the compound having Structure (I) or Structure (II) is substantially free of other polymorphic or physical forms. In some aspects, the crystalline form having Structure (I) or Structure (II) has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, at least 99%, or 100%.

[0221] The sections below disclose crystalline forms of the pharmaceutical salts of a compound having Structure (II) that have been prepared and selected properties of those crystalline forms.Compounds Having Structure (VII)

[0222] In one aspect, the present disclosure provides solid state forms of the compound bethanechol (BTC) chloride having Structure (VII). Analogous solid state forms of one or more stereoisomers (e.g., (R)-bethanechol chloride or (S)-bethanechol chloride) are also an aspect of and are encompassed within this disclosure.

[0223] As with all pharmaceutical compounds and compositions, the chemical and physical properties of the compound of Structure (VII) are important in their commercial development. These properties include, but are not limited to: (1) packing properties such as molar volume, bulk density and hygroscopicity, (2) thermodynamic properties such as melting temperature, vapor pressure and solubility, (3) kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape, (5) mechanical properties such as hardness, tensile strength, compactibility,handling, flow and blend; and (6) filtration properties. These properties can affect, for example, the processing and storage of the compounds and pharmaceutical compositions comprising the compounds.

[0224] Solid state forms of the Compounds of the Disclosure, including the compounds of Structure (VII), that improve upon one or more of these properties relative to other solid state forms of the compounds are desirable. Isolating pharmaceutically acceptable solid state forms of the compounds that can be manufactured on a commercial-scale has been a challenge.

[0225] In one aspect, the present disclosure provides a solid state form of bethanechol chloride having Structure (VII):or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof.

[0226] In some aspects, the solid state form of bethanechol chloride having Structure (VII) is Form I, as disclosed in Armel Le Bail, Powder Diffraction, 25(3), 229-234 (2010).

[0227] In some aspects, the pharmaceutically acceptable salt of a compound having Structure (VII) is selected from the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, a maleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt. In some aspects, the pharmaceutically acceptable salt is selected from the group consisting of a maleate salt, a succinate salt, and a hydrochloride salt. In some aspects, the pharmaceutically acceptable salt is a sulfate salt. In some aspects, the pharmaceutically acceptable salt is a tosylate salt. In some aspects, the pharmaceutically acceptable salt is a mesylate salt. In some aspects, the pharmaceutically acceptable salt is a phosphate salt. In some aspects, the pharmaceutically acceptable salt is a maleate salt. In some aspects, the pharmaceutically acceptable salt is a fumarate salt. In some aspects, the pharmaceutically acceptable salt is a malate salt. In some aspects, the pharmaceutically acceptable salt is a succinate salt. In some aspects, the pharmaceutically acceptable salt is a benzoate salt. In some aspects, the pharmaceutically acceptable salt is a tartrate salt. In some aspects, the pharmaceutically acceptable salt is a hydrochloride salt.

[0228] In some aspects, the solid state form is an amorphous form, a co-crystal form, or a crystalline form of the compound having Structure (VII).

[0229] In some aspects, the solid state form is an amorphous form of the compound having Structure (VII). In some aspects, the amorphous form is a hydrate, anhydrate, or solvate thereof. In some aspects, the amorphous form of the compound is substantially free of other polymorphic or physical forms. In some aspects, the amorphous form has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, at least 99%, or 100%.

[0230] In some aspects, the solid state form is a co-crystal form of the compound having Structure (VII).

[0231] In some aspects, the solid state form is a crystalline form of the compound having Structure (VII). In some aspects, the crystalline form is a hydrate, anhydrate, or solvate of the compound having Structure (VII). In some aspects, the crystalline form is a hydrate. In some aspects, the crystalline form is a anhydrate. In some aspects, the crystalline form is a solvate.

[0232] In some aspects, the crystalline form of the compound having Structure (VII) is substantially free of other polymorphic or physical forms. In some aspects, the crystalline form of a compound having Structure (VII) has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, at least 99%, or 100%. In some aspects, the crystalline form of a compound having Structure (VII) is characterized as comprising no XRPD-detectable amount of any other polymorphic or amorphous forms of compounds having Structure (VII).

[0233] In some aspects, the pharmaceutically acceptable salt of a compound having Structure (VII) is formed between a compound having Structure (VII) and a pharmaceutically acceptable acid. In some aspects, the pharmaceutically acceptable acid is selected from 1- hydroxy-2-naphthoic acid, 4-aminosalicylic acid, ascorbic acid, adipic acid, L-aspartic acid, benzene sulfonic acid, benzoic acid, trans-cinnamic acid, citric acid, ethanedisulfonic acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, malonic acid, R-mandelic acid, methanesulfonicacid, mucic acid, naphthalene sulfonic acid, nicotinic acid, oxalic acid, palmitic acid, p- toluene sulfonic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, vanillic acid, vanillin, ethyl maltol, gallic acid, gallic acid ethyl ester, 4-hydroxybenzoic acid, 4-hydroxybenzoic acid methyl ester, 3,4,5- trihydroxybenzoic acid, nicotinamide, L-proline, and D-sorbitol. In some aspects, the pharmaceutically acceptable acid is selected from sulfuric acid, p-toluene sulfonic acid, methanesulfonic acid, phosphoric acid, maleic acid, fumaric acid, malic acid, succinic acid, benzoic acid, tartric acid, and hydrochloric acid. In some aspects, the pharmaceutically acceptable acid is sulfuric acid. In some aspects, the pharmaceutically acceptable acid is p- toluenesulfonic acid. In some aspects, the pharmaceutically acceptable acid is methanesulfonic acid. In some aspects, the pharmaceutically acceptable acid is phosphoric acid. In some aspects, the pharmaceutically acceptable acid is maleic acid. In some aspects, the pharmaceutically acceptable acid is fumaric acid. In some aspects, the pharmaceutically acceptable acid is malic acid. In some aspects, the pharmaceutically acceptable acid is succinic acid. In some aspects, the pharmaceutically acceptable acid is benzoic acid. In some aspects, the pharmaceutically acceptable acid is tartric acid. In some aspects, the pharmaceutically acceptable acid is hydrochloric acid.

[0234] The sections below disclose crystalline forms of the pharmaceutical salts of a compound having Structure (VII) that have been prepared and selected properties of those crystalline forms.IV. Crystalline FormsCompounds Having Structure (II)

[0235] In one aspect, the present disclosure provides a crystalline form of (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II).or a pharmaceutically acceptable salt thereof.

[0236] In some aspects, the pharmaceutically acceptable salt is selected from the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, amaleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt.

[0237] In some aspects, the (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol is a free base.

[0238] In some aspects, the (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol is an anhydrate. In some aspects, the (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol is a hydrate. In some aspects, the (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol is a solvate.

[0239] The sections below disclose crystalline forms of the free base and pharmaceutical salts of a compound having Structure (II) that have been prepared and selected properties of those crystalline forms.Al. Free Base Form I

[0240] In one aspect, the present disclosure provides a free base crystalline form of (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Free Base Form I.

[0241] In some aspects, the crystalline Free Base Form I is an anhydrate.

[0242] In some aspects, the melting point of crystalline Free Base Form I is about 118 °C.

[0243] In another aspect, the crystalline Free Base Form I is characterized by an XRPD pattern having a peak at 18.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Free Base Form I is characterized by an XRPD pattern having peaks at 13.0, 16.8, and 18.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Free Base Form I is characterized by an XRPD pattern having peaks at 8.0, 13.0, 16.8, 17.6, and 18.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0244] In some aspects, the crystalline Free Base Form I is characterized by an XRPD pattern as shown in FIG. 1.

[0245] In some aspects, the crystalline Free Base Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 1 A in the Examples.

[0246] In some aspects, the crystalline Free Base Form I is characterized by an endothermic peak at from about 115 °C to about 121 °C, as determined by DSC. In some aspects, the crystalline Free Base Form I is characterized by an endothermic peak at from about 116 °C to about 120 °C, as determined by DSC. In some aspects, the crystalline Free Base Form I is characterized by an endothermic peak at from about 117 °C to about 119 °C, as determined by DSC. In some aspects, the crystalline Free Base Form I is characterized by an endothermic peak at about 118 °C, as determined by DSC. In some aspects, the crystalline Free Base Form I is characterized by an endothermic peak at about 118.54 °C, as determined by DSC.

[0247] In another aspect, the crystalline Free Base Form I is characterized by a DSC profile as shown in FIG. 2.

[0248] In another aspect, the crystalline Free Base Form I is characterized by from an about 0.88 wt% to about 0.98 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the crystalline crystalline Free Base Form I is characterized by from an about 0.90 wt% to about 0.96 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the crystalline form crystalline Free Base Form I is characterized by an about 0.93 wt% loss between room temperature and about 100 °C, as determined by TGA.

[0249] In another aspect, the crystalline Free Base Form I is characterized by a TGA profile as shown in FIG. 2.

[0250] In another aspect, the crystalline Free Base Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 1; a DSC profile as shown in FIG. 2; or a TGA profile as shown in FIG. 2.

[0251] In some aspects, the crystalline form Free Base Form I is substantially free of other polymorphic or physical forms. In another aspect, the crystalline Free Base Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%,or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Free Base Form I has a polymorphic purity of at least 80%.

[0252] In another aspect, the present disclosure provides a mixture comprising crystalline Free Base Form I and a second solid state form or crystalline form of a compound having Structure (II). In another aspect, the present disclosure provides a mixture comprising crystalline Free Base Form I and one or more solid state forms or crystalline forms of a compound having Structure (II).A2. Free Base Form II

[0253] In one aspect, the present disclosure provides a free base crystalline form of (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof, wherein the crystalline form is Free Base Form II.

[0254] In some aspects, the crystalline Free Base Form II is an anhydrate. In some aspects, the crystalline Free Base Form II is a hydrate.

[0255] In some aspects, the melting point of crystalline Free Base Form II is about 118 °C.

[0256] In another aspect, the crystalline Free Base Form II is characterized by an XRPD pattern having a peak at 8.9 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Free Base Form II is characterized by an XRPD pattern having peaks at 8.9, 17.1, and 17.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Free Base Form II is characterized by an XRPD pattern having peaks at 8.9, 10.2, 17.1, 17.3, and 22.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0257] In some aspects, the crystalline Free Base Form II is characterized by an XRPD pattern as shown in FIG. 37.

[0258] In some aspects, the crystalline Free Base Form II is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table IB in the Examples.

[0259] In some aspects, the crystalline Free Base Form II is characterized by an endothermic peak at from about 115 °C to about 121 °C, as determined by DSC. In some aspects, the crystalline Free Base Form II is characterized by an endothermic peak at from about 116 °C to about 120 °C, as determined by DSC. In some aspects, the crystalline Free Base Form II is characterized by an endothermic peak at from about 117 °C to about 119 °C, as determined by DSC. In some aspects, the crystalline Free Base Form II is characterized by an endothermic peak at about 117 °C, as determined by DSC. In some aspects, the crystalline Free Base Form II is characterized by an endothermic peak at about 118 °C, as determined by DSC. In some aspects, the crystalline Free Base Form II is characterized by an endothermic peak at about 117.72 °C, as determined by DSC.

[0260] In another aspect, the crystalline Free Base Form II is characterized by a DSC profile as shown in FIG. 38.

[0261] In another aspect, the crystalline Free Base Form II is characterized by from an about 1.40 wt% to about 1.60 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the crystalline crystalline Free Base Form II is characterized by from an about 1.50 wt% to about 1.60 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the crystalline form crystalline Free Base Form II is characterized by an about 1.54 wt% loss between room temperature and about 100 °C, as determined by TGA.

[0262] In another aspect, the crystalline Free Base Form II is characterized by a TGA profile as shown in FIG. 38.

[0263] In another aspect, the crystalline Free Base Form II is characterized by at least one of the following: an XRPD pattern as shown in FIG. 37; a DSC profile as shown in FIG. 38; or a TGA profile as shown in FIG. 38.

[0264] In some aspects, the crystalline form Free Base Form II is substantially free of other polymorphic or physical forms. In another aspect, the crystalline Free Base Form II has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%,or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Free Base Form II has a polymorphic purity of at least 80%.

[0265] In another aspect, the present disclosure provides a mixture comprising crystalline Free Base Form II and a second solid state form or crystalline form of a compound having Structure (II). In another aspect, the present disclosure provides a mixture comprising crystalline Free Base Form II and one or more solid state forms or crystalline forms of a compound having Structure (II).A3. FreeBase F orm III

[0266] In one aspect, the present disclosure provides a free base crystalline form of (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof, wherein the crystalline form is Free Base Form III.

[0267] In some aspects, the crystalline Free Base Form III is an anhydrate. In some aspects, the crystalline Free Base Form III is a hydrate.

[0268] In some aspects, the melting point of crystalline Free Base Form III is about 119 °C.

[0269] In another aspect, the crystalline Free Base Form III is characterized by an XRPD pattern having a peak at 17.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Free Base Form III is characterized by an XRPD pattern having peaks at 8.4, 8.6, and 17.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Free Base Form III is characterized by an XRPD pattern having peaks at 8.4, 8.6, 12.3, 16.8, and 17.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0270] In some aspects, the crystalline Free Base Form III is characterized by an XRPD pattern as shown in FIG. 39.

[0271] In some aspects, the crystalline Free Base Form III is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 1C in the Examples.

[0272] In some aspects, the crystalline Free Base Form III is characterized by an endothermic peak at from about 116 °C to about 122 °C, as determined by DSC. In some aspects, the crystalline Free Base Form III is characterized by an endothermic peak at from about 117 °C to about 121 °C, as determined by DSC. In some aspects, the crystalline Free Base Form III is characterized by an endothermic peak at from about 118 °C to about 120 °C, as determined by DSC. In some aspects, the crystalline Free Base Form III is characterized by an endothermic peak at about 119 °C, as determined by DSC. In some aspects, the crystalline Free Base Form III is characterized by an endothermic peak at about 119.11 °C, as determined by DSC. In some aspects, the crystalline Free Base Form III is characterized by an endothermic peak at about 119.41 °C, as determined by DSC.

[0273] In another aspect, the crystalline Free Base Form III is characterized by a DSC profile as shown in FIG. 40.

[0274] In another aspect, the crystalline Free Base Form III is characterized by from an about 1.8 wt% to about 1.9 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the crystalline crystalline Free Base Form III is characterized by from an about 1.84 wt% to about 1.90 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the crystalline form crystalline Free Base Form III is characterized by an about 1.87 wt% loss between room temperature and about 100 °C, as determined by TGA.

[0275] In another aspect, the crystalline Free Base Form III is characterized by a TGA profile as shown in FIG. 40.

[0276] In another aspect, the crystalline Free Base Form III is characterized by at least one of the following: an XRPD pattern as shown in FIG. 39; a DSC profile as shown in FIG.40; or a TGA profile as shown in FIG. 40.

[0277] In some aspects, the crystalline form Free Base Form III is substantially free of other polymorphic or physical forms. In another aspect, the crystalline Free Base Form III has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Free Base Form III has a polymorphic purity of at least 80%.

[0278] In another aspect, the present disclosure provides a mixture comprising crystalline Free Base Form III and a second solid state form or crystalline form of a compound having Structure (II). In another aspect, the present disclosure provides a mixture comprising crystalline Free Base Form III and one or more solid state forms or crystalline forms of a compound having Structure (II).A4. Free Base Pattern 4

[0279] In one aspect, the present disclosure provides a mixture of free base crystalline forms of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or pharmaceutically acceptable salts thereof. In some aspects, the mixture of crystalline forms is represented by Free Base Pattern 4. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is a mixture of Free Base Form II and Free Base Form III.

[0280] In some aspects, the melting point of the mixture of crystalline forms represented by Free Base Pattern 4 is about 119 °C.

[0281] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an XRPD pattern having a peak at 17.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an XRPD pattern having peaks at 8.3, 16.8, and 17.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an XRPD pattern having peaks at 8.3, 8.5, 16.8, 17.2, and 26.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0282] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an XRPD pattern as shown in FIG. 41.

[0283] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table ID in the Examples.

[0284] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an endothermic peak at from about 116 °C to about 122 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an endothermic peak at from about 117 °C to about 121 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an endothermic peak at from about 118 °C to about 120 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an endothermic peak at about 119 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an endothermic peak at about 119.08 °C, as determined by DSC.

[0285] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by a DSC profile as shown in FIG. 42.

[0286] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by from an about 1.77 wt% to about 1.87 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by from an about 1.79 wt% to about 1.85 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by an about 1.83 wt% loss between room temperature and about 100 °C, as determined by TGA.

[0287] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by a TGA profile as shown in FIG. 42.

[0288] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 4 is characterized by at least one of the following: an XRPD pattern as shown in FIG.41; a DSC profile as shown in FIG. 42; or a TGA profile as shown in FIG. 42.

[0289] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 4 is substantially free of other polymorphic or physical forms.

[0290] In another aspect, the present disclosure provides a mixture comprising the mixture of crystalline forms represented by Free Base Pattern 4 and one or more solid state forms or crystalline forms of a compound having Structure (II).A5. Free Base Pattern 5

[0291] In one aspect, the present disclosure provides a mixture of free base crystalline forms of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or pharmaceutically acceptable salts thereof. In some aspects, the mixture of crystalline forms is represented by Free Base Pattern 5. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is a mixture of Free Base Form I, Free Base Form II, and Free Base Form III.

[0292] In some aspects, the melting point of the mixture of crystalline forms represented by Free Base Pattern 5 is about 119 °C.

[0293] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an XRPD pattern having a peak at 16.8 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an XRPD pattern having peaks at 8.3, 16.8, and 17.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an XRPD pattern having peaks at 8.3, 8.6, 16.8, 17.2, and 26.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0294] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an XRPD pattern as shown in FIG. 43.

[0295] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table IE in the Examples.

[0296] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an endothermic peak at from about 116 °C to about 122 °C, asdetermined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an endothermic peak at from about 117 °C to about 121 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an endothermic peak at from about 118 °C to about 120 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an endothermic peak at about 119 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an endothermic peak at about 118.91 °C, as determined by DSC.

[0297] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by a DSC profile as shown in FIG. 44.

[0298] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by from an about 4.1 wt% to about 5.1 wt% loss between room temperature and about 110 °C, as determined by TGA. In another aspect, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by from an about 4.3 wt% to about 4.9 wt% loss between room temperature and about 110 °C, as determined by TGA. In another aspect, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by an about 4.62 wt% loss between room temperature and about 110 °C, as determined by TGA.

[0299] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by a TGA profile as shown in FIG. 44.

[0300] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 5 is characterized by at least one of the following: an XRPD pattern as shown in FIG.43; a DSC profile as shown in FIG. 44; or a TGA profile as shown in FIG. 44.

[0301] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 5 is substantially free of other polymorphic or physical forms.

[0302] In another aspect, the present disclosure provides a mixture comprising the mixture of crystalline forms represented by Free Base Pattern 5 and one or more solid state forms or crystalline forms of a compound having Structure (II).A6. Free Base Pattern 6

[0303] In one aspect, the present disclosure provides a mixture of free base crystalline forms of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or pharmaceutically acceptable salts thereof. In some aspects, the mixture of crystalline forms is represented by Free Base Pattern 6. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is a mixture of Free Base Form I and Free Base Form III.

[0304] In some aspects, the melting point of the mixture of crystalline forms represented by Free Base Pattern 6 is about 119 °C.

[0305] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by an XRPD pattern having a peak at 17.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by an XRPD pattern having peaks at 8.3, 16.8, and 17.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by an XRPD pattern having peaks at 8.3, 8.5, 16.8, 17.2, and 26.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0306] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by an XRPD pattern as shown in FIG. 45.

[0307] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table IF in the Examples.

[0308] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by an endothermic peak at from about 116 °C to about 122 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by an endothermic peak at from about 117 °C to about 121 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by an endothermic peak at from about 118 °C to about 120 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by an endothermic peak at about 119 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by FreeBase Pattern 6 is characterized by an endothermic peak at about 119.13 °C, as determined by DSC.

[0309] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by a DSC profile as shown in FIG. 46.

[0310] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by from an about 1.14 wt% to about 1.24 wt% loss between room temperature and about 110 °C, as determined by TGA. In another aspect, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by from an about 1.16 wt% to about 1.22 wt% loss between room temperature and about 110 °C, as determined by TGA. In another aspect, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by an about 1.19 wt% loss between room temperature and about 110 °C, as determined by TGA.

[0311] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by a TGA profile as shown in FIG. 46.

[0312] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 6 is characterized by at least one of the following: an XRPD pattern as shown in FIG.45; a DSC profile as shown in FIG. 46; or a TGA profile as shown in FIG. 46.

[0313] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 6 is substantially free of other polymorphic or physical forms.

[0314] In another aspect, the present disclosure provides a mixture comprising the mixture of crystalline forms represented by Free Base Pattern 6 and one or more solid state forms or crystalline forms of a compound having Structure (II).A7. Free Base Pattern 7

[0315] In one aspect, the present disclosure provides a mixture of free base crystalline forms of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or pharmaceutically acceptable salts thereof. In some aspects, the mixture of crystalline forms is represented by Free Base Pattern 7. In some aspects, the mixture of crystallineforms represented by Free Base Pattern 7 is a mixture of Free Base Form I and Free Base Form III.

[0316] In some aspects, the melting point of the mixture of crystalline forms represented by Free Base Pattern 7 is about 119 °C.

[0317] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an XRPD pattern having a peak at 8.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an XRPD pattern having peaks at 8.0, 13.0, and 17.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an XRPD pattern having peaks at 6.5, 8.0, 13.0, 16.8, and 17.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0318] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an XRPD pattern as shown in FIG. 47.

[0319] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 1G in the Examples.

[0320] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an endothermic peak at from about 116 °C to about 122 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an endothermic peak at from about 117 °C to about 121 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an endothermic peak at from about 118 °C to about 120 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an endothermic peak at about 119 °C, as determined by DSC. In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an endothermic peak at about 119.23 °C, as determined by DSC.

[0321] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by a DSC profile as shown in FIG. 48.

[0322] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by from an about 2.22 wt% to about 2.32 wt% loss between room temperature and about 110 °C, as determined by TGA. In another aspect, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by from an about 2.24 wt% to about 2.30 wt% loss between room temperature and about 110 °C, as determined by TGA. In another aspect, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by an about 2.27 wt% loss between room temperature and about 110 °C, as determined by TGA.

[0323] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by a TGA profile as shown in FIG. 48.

[0324] In another aspect, the mixture of crystalline forms represented by Free Base Pattern 7 is characterized by at least one of the following: an XRPD pattern as shown in FIG.47; a DSC profile as shown in FIG. 48; or a TGA profile as shown in FIG. 48.

[0325] In some aspects, the mixture of crystalline forms represented by Free Base Pattern 7 is substantially free of other polymorphic or physical forms.

[0326] In another aspect, the present disclosure provides a mixture comprising the mixture of crystalline forms represented by Free Base Pattern 7 and one or more solid state forms or crystalline forms of a compound having Structure (II).B. Sulfate Form I

[0327] In one aspect, the present disclosure provides a sulfate salt crystalline form of (R)- l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Sulfate Form I.

[0328] In some aspects, the crystalline Sulfate Form I is an anhydrate.

[0329] In some aspects, the melting point of crystalline Sulfate Form I is about 160 °C.

[0330] In another aspect, the crystalline Sulfate Form I is characterized by an XRPD pattern having a peak at 6.6 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Sulfate Form I ischaracterized by an XRPD pattern having peaks at 6.6, 16.3, and 20.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Sulfate Form I is characterized by an XRPD pattern having peaks at 6.6, 16.3, 20.2, 21.4, and 24.4 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0331] In some aspects, the crystalline Sulfate Form I is characterized by an XRPD pattern as shown in FIG. 3.

[0332] In some aspects, the crystalline Sulfate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 2 in the Examples.

[0333] In another aspect, the crystalline Sulfate Form I is characterized by an endothermic peak at from about 157 °C to about 163 °C, as determined by DSC. In another aspect, the crystalline Sulfate Form I is characterized by an endothermic peak at from about 158 °C to about 162 °C, as determined by DSC. In another aspect, the crystalline Sulfate Form I is characterized by an endothermic peak at from about 159 °C to about 161 °C, as determined by DSC. In another aspect, the crystalline Sulfate Form I is characterized by an endothermic peak at about 160 °C, as determined by DSC. In another aspect, the crystalline Sulfate Form I is characterized by an endothermic peak at about 160.58 °C, as determined by DSC.

[0334] In another aspect, the crystalline Sulfate Form I is characterized by a DSC profile as shown in FIG. 4.

[0335] In another aspect, the crystalline Sulfate Form I is characterized by from an about 2.15 wt% to about 2.25 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Sulfate Form I is characterized by from an about 2.17 wt% to about 2.23 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Sulfate Form I is characterized by an about 2.20% loss between room temperature and about 150.0 °C, as determined by TGA.

[0336] In another aspect, the crystalline Sulfate Form I is characterized by a TGA profile as shown in FIG. 4.

[0337] In another aspect, the crystalline Sulfate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 3; a DSC profile as shown in FIG. 4; or a TGA profile as shown in FIG. 4.

[0338] In some aspects, the crystalline Sulfate Form I is substantially free of other polymorphic or physical forms. In another aspect, the crystalline Sulfate Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Sulfate Form I has a polymorphic purity of at least 80%.

[0339] In another aspect, the present disclosure provides a mixture comprising the crystalline Sulfate Form I and a second solid state form or crystalline form of a compound having Structure (II).C. Tosylate Form I

[0340] In one aspect, the present disclosure provides a tosylate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Tosylate Form I.

[0341] In some aspects, the crystalline Tosylate Form I is an anhydrate.

[0342] In some aspects, the melting point of crystalline Tosylate Form I is about 180 °C.

[0343] In another aspect, the crystalline Tosylate Form I is characterized by an XRPD pattern having peaks at 8.6 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Tosylate Form I is characterized by an XRPD pattern having peaks at 5.2, 8.6, and 22.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Tosylate Form I is characterized by an XRPD pattern having peaks at 5.2, 8.6, 19.0, 21.1. and 22.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0344] In some aspects, the crystalline Tosylate Form I is characterized by an XRPD pattern as shown in FIG. 5.

[0345] In some aspects, the crystalline Tosylate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 3 in the Examples.

[0346] In another aspect, the crystalline Tosylate Form I is characterized by an endothermic peak at from about 177 °C to about 183 °C, as determined by DSC. In another aspect, the crystalline Tosylate Form I is characterized by an endothermic peak at from about 178 °C to about 182 °C, as determined by DSC. In another aspect, the crystalline Tosylate Form I is characterized by an endothermic peak at from about 179 °C to about 181 °C, as determined by DSC. In another aspect, the crystalline Tosylate Form I is characterized by an endothermic peak at about 180 °C, as determined by DSC. In another aspect, the crystalline Tosylate Form I is characterized by an endothermic peak at about 180.44 °C, as determined by DSC.

[0347] In another aspect, the crystalline Tosylate Form I is characterized by a DSC profile as shown in FIG. 6.

[0348] In another aspect, the crystalline Tosylate Form I is characterized by from an about 2.97 wt% to about 3.07 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Tosylate Form I is characterized by from an about 2.99 wt% to about 3.05 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Tosylate Form I is characterized by an about 3.02% loss between room temperature and about 150.0 °C, as determined by TGA.

[0349] In another aspect, the crystalline Tosylate Form I is characterized by a TGA profile as shown in FIG. 6.

[0350] In another aspect, the crystalline Tosylate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 5; a DSC profile as shown in FIG. 6; or a TGA profile as shown in FIG. 6.

[0351] In some aspects, the crystalline Tosylate Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Tosylate Form I aspects has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Tosylate Form I has a polymorphic purity of at least 80%.

[0352] In another aspect, the present disclosure provides a mixture comprising the crystalline Tosylate Form I and a second solid state form or crystalline form of a compound having Structure (II).D. Mesylate Form I

[0353] In one aspect, the present disclosure provides a mesylate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Mesylate Form I.

[0354] In some aspects, the crystalline Mesylate Form I is an anhydrate.

[0355] In some aspects, the melting point of crystalline Mesylate Form I is about 183 °C.

[0356] In another aspect, the crystalline Mesylate Form I is characterized by an XRPD pattern having a peak at 5.5 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Mesylate Form I is characterized by an XRPD pattern having peaks at 5.5, 9.2, and 13.4 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Mesylate Form I is characterized by an XRPD pattern having peaks at 5.5, 9.2, 13.4, 18.5, and 23.7 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0357] In some aspects, the crystalline Mesylate Form I is characterized by an XRPD pattern as shown in FIG. 7.

[0358] In some aspects, the crystalline Mesylate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 4 in the Examples.

[0359] In another aspect, the crystalline Mesylate Form I is characterized by an endothermic peak at from about 180 °C to about 186 °C, as determined by DSC. In another aspect, the crystalline Mesylate Form I is characterized by an endothermic peak at from about 181 °C to about 185 °C, as determined by DSC. In another aspect, the crystalline Mesylate Form I is characterized by an endothermic peak at from about 182 °C to about 185 °C, as determined by DSC. In another aspect, the crystalline Mesylate Form I is characterized by anendothermic peak at about 183 °C, as determined by DSC. In another aspect, the crystalline Mesylate Form I is characterized by an endothermic peak at about 183.60 °C, as determined by DSC.

[0360] In another aspect, the crystalline Mesylate Form I is characterized by a DSC profile as shown in FIG. 8.

[0361] In another aspect, the crystalline Mesylate Form I is characterized by from an about 0.91 wt% to about 1.01 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Mesylate Form I is characterized by from an about 0.93 wt% to about 0.99 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Mesylate Form I is characterized by an about 0.96% loss between room temperature and about 150.0 °C, as determined by TGA.

[0362] In another aspect, the crystalline Mesylate Form I is characterized by a TGA profile as shown in FIG. 8.

[0363] In another aspect, the crystalline Mesylate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 7; a DSC profile as shown in FIG. 8; or a TGA profile as shown in FIG. 8.

[0364] In some aspects, the crystalline Mesylate Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Mesylate Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Mesylate Form I has a polymorphic purity of at least 80%.

[0365] In another aspect, the present disclosure provides a mixture comprising the crystalline Mesylate Form I and a second solid state form or crystalline form of a compound having Structure (II).E. Phosphate Form I

[0366] In one aspect, the present disclosure provides a phosphate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Phosphate Form I.

[0367] In some aspects, the crystalline Phosphate Form I is an anhydrate.

[0368] In some aspects, the melting point of crystalline Phosphate Form I is about 232 °C.

[0369] In another aspect, the crystalline Phosphate Form I is characterized by an XRPD pattern having a peak at 4.4 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Phosphate Form I is characterized by an XRPD pattern having peaks at 4.4, 10.1, and 20.5 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Phosphate Form I is characterized by an XRPD pattern having peaks at 4.4, 10.1, 10.9, 18.0, and 20.5 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0370] In some aspect, the crystalline Phosphate Form I is characterized by an XRPD pattern as shown in FIG. 9.

[0371] In some aspects, the crystalline Phosphate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 5 in the Examples.

[0372] In another aspect, the crystalline Phosphate Form I is characterized by an endothermic peak at from about 228 °C to about 234 °C, as determined by DSC. In another aspect, the crystalline Phosphate Form I is characterized by an endothermic peak at from about 229 °C to about 233 °C, as determined by DSC. In another aspect, the crystalline Phosphate Form I is characterized by an endothermic peak at from about 230 °C to about 232 °C, as determined by DSC. In another aspect, the crystalline Phosphate Form I is characterized by an endothermic peak at about 231 °C, as determined by DSC. In another aspect, the crystalline Phosphate Form I is characterized by an endothermic peak at about 231.80 °C, as determined by DSC. In another aspect, the crystalline Phosphate Form I is characterized by an endothermic peak at about 232 °C, as determined by DSC.

[0373] In another aspect, the crystalline Phosphate Form I is characterized by a DSC profile as shown in FIG. 10.

[0374] In another aspect, the crystalline Phosphate Form I is characterized by from an about 0.07 wt% to about 0.17 wt% loss between room temperature and about 200.0 °C, as determined by TGA. In another aspect, the crystalline Phosphate Form I is characterized by from an about 0.09 wt% to about 0.15 wt% loss between room temperature and about 200.0 °C, as determined by TGA. In another aspect, the crystalline Phosphate Form I is characterized by an about 0.12 wt% loss between room temperature and about 200.0 °C, as determined by TGA.

[0375] In another aspect, the crystalline Phosphate Form I is characterized by a TGA profile as shown in FIG 10.

[0376] In another aspect, the crystalline Phosphate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 9; a DSC profile as shown in FIG. 10; or a TGA profile as shown in FIG. 10.

[0377] In some aspects, the crystalline Phosphate Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Phosphate Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Phosphate Form I has a polymorphic purity of at least 80%.

[0378] In another aspect, the present disclosure provides a mixture comprising the crystalline Phosphate Form I and a second solid state form or crystalline form of a compound having Structure (II).F. Maleate Form I

[0379] In one aspect, the present disclosure provides a maleate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Maleate Form I.

[0380] In some aspects, the crystalline Maleate Form I is an anhydrate.

[0381] In some aspects, the melting point of crystalline Maleate Form I is about 173 °C.

[0382] In another aspect, the crystalline Maleate Form I is characterized by an XRPD pattern having a peak at 16.8 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Maleate Form I is characterized by an XRPD pattern having peaks at 12.7, 16.8, and 21.9 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Maleate Form I is characterized by an XRPD pattern having peaks at 9.4, 9.8, 12.7, 16.8, and 21.9 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0383] In some aspect, the crystalline Maleate Form I is characterized by an XRPD pattern as shown in FIG. 11.

[0384] In some aspects, the crystalline Maleate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 6a in the Examples.

[0385] In another aspect, the crystalline Maleate Form I is characterized by an endothermic peak at from about 170 °C to about 176 °C, as determined by DSC. In another aspect, the crystalline Maleate Form I is characterized by an endothermic peak at from about 171 °C to about 175 °C, as determined by DSC. In another aspect, the crystalline Maleate Form I is characterized by an endothermic peak at from about 172 °C to about 174 °C, as determined by DSC. In another aspect, the crystalline Maleate Form I is characterized by an endothermic peak at about 173 °C, as determined by DSC. In another aspect, the crystalline Maleate Form I is characterized by an endothermic peak at about 173.23 °C, as determined by DSC.

[0386] In another aspect, the crystalline Maleate Form I is characterized by a DSC profile as shown in FIG. 12.

[0387] In another aspect, the crystalline Maleate Form I is characterized by from an about 0.17 wt% to about 0.27 wt% loss between room temperature and about 150 °C, as determined by TGA. In another aspect, the crystalline Maleate Form I is characterized by from an about 0.19 wt% to about 0.25 wt% loss between room temperature and about 150 °C, as determined by TGA. In another aspect, the crystalline Maleate Form I is characterized by an about 0.22 wt% loss between room temperature and about 150 °C, as determined by TGA.

[0388] In another aspect, the crystalline Maleate Form I is characterized by a TGA profile as shown in FIG. 12.

[0389] In another aspect, the crystalline Maleate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 11; a DSC profile as shown in FIG. 12; or a TGA profile as shown in FIG. 12.

[0390] In some aspects, the crystalline Maleate Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Maleate Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Maleate Form I has a polymorphic purity of at least 80%.

[0391] In another aspect, the present disclosure provides a mixture comprising the crystalline Maleate Form I and a second solid state form or crystalline form of a compound having Structure (II).G. Maleate Form II

[0392] In one aspect, the present disclosure provides a maleate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Maleate Form II.

[0393] In some aspects, the crystalline Maleate Form II is an anhydrate.

[0394] In another aspect, the crystalline Maleate Form II is characterized by an XRPD pattern having a peak at 8.8 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Maleate Form II is characterized by an XRPD pattern having peaks at 8.8, 19.9, and 24.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Maleate Form II is characterized by an XRPD pattern having peaks at 8.8, 17.7, 18.1, 19.9, and 24.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0395] In some aspects, the crystalline Maleate Form II is characterized by an XRPD pattern as shown in FIG. 11.

[0396] In some aspects, the crystalline Maleate Form II is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 6b in the Examples.

[0397] In another aspect, the crystalline Maleate Form II is characterized by an endothermic peak at from about 165 °C to about 171 °C and at from about 170 °C to about 176 °C, as determined by DSC. In another aspect, the crystalline Maleate Form II is characterized by an endothermic peak at from about 166 °C to about 170 °C and at from about 171 °C to about 175 °C, as determined by DSC. In another aspect, the crystalline Maleate Form II is characterized by an endothermic peak at from about 167 °C to about 169 °C and at from about 172 °C to about 174 °C, as determined by DSC. In another aspect, the crystalline Maleate Form II is characterized by an endothermic peak at about 168 °C and at about 173 °C, as determined by DSC. In another aspect, the crystalline Maleate Form II is characterized by an endothermic peak at about 168.29 °C and at about 173.00 °C, as determined by DSC.

[0398] In another aspect, the crystalline Maleate Form II is characterized by a DSC profile as shown in FIG. 13.

[0399] In another aspect, the crystalline Maleate Form II is characterized by from an about 0.87 wt% to about 0.97 wt% loss between room temperature and about 150 °C, as determined by TGA. In another aspect, the crystalline Maleate Form II is characterized by from an about 0.89 wt% to about 0.95 wt% loss between room temperature and about 150 °C, as determined by TGA. In another aspect, the crystalline Maleate Form II is characterized by an about 0.92 wt% loss between room temperature and about 150 °C, as determined by TGA.

[0400] In another aspect, the crystalline Maleate Form II is characterized by a TGA profile as shown in FIG. 13.

[0401] In another aspect, the Maleate Form II is characterized by at least one of the following: an XRPD pattern as shown in FIG. 11; a DSC profile as shown in FIG. 13; or a TGA profile as shown in FIG. 13.

[0402] In some aspects, the crystalline Maleate Form II is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Maleate Form II has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, orat least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% or 100%. In some aspects, the crystalline Maleate Form II has a polymorphic purity of at least 80%.

[0403] In another aspect, the present disclosure provides a mixture comprising the crystalline Maleate Form II and a second solid state form or crystalline form of a compound having Structure (II).H. Fumarate Form I

[0404] In one aspect, the present disclosure provides the fumarate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Fumerate Form I.

[0405] In some aspects, the crystalline Fumarate Form I is an anhydrate.

[0406] In some aspects, the melting point of crystalline Fumarate Form I is about 239 °C.

[0407] In another aspect, the crystalline Fumarate Form I is characterized by an XRPD pattern having a peak at 19.5 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Fumarate Form I is characterized by an XRPD pattern having peaks at 8.8, 19.5, and 20.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Fumarate Form I is characterized by an XRPD pattern having peaks at 8.8, 18.9, 19.5, 20.1, and 24.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0408] In some aspect, the crystalline Fumarate Form I is characterized by an XRPD pattern as shown in FIG. 14.

[0409] In some aspects, the crystalline Fumarate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 7 in the Examples.

[0410] In another aspect, the crystalline Fumarate Form I is characterized by an endothermic peak at from about 235 °C to about 241 °C, as determined by DSC. In anotheraspect, the crystalline Fumarate Form I is characterized by an endothermic peak at from about 236 °C to about 240 °C, as determined by DSC. In another aspect, the crystalline Fumarate Form I is characterized by an endothermic peak at from about 237 °C to about 239 °C, as determined by DSC. In another aspect, the crystalline Fumarate Form I is characterized by an endothermic peak at about 239 °C, as determined by DSC. In another aspect, the crystalline Fumarate Form I is characterized by an endothermic peak at about 238.91 °C, as determined by DSC.

[0411] In another aspect, the crystalline Fumarate Form I is characterized by a DSC profile as shown in FIG. 15.

[0412] In another aspect, the crystalline Fumarate Form I is characterized by from an about 1.13 wt% to about 1.23 wt% loss between room temperature and about 200.0 °C, as determined by TGA. In another aspect, the crystalline Fumarate Form I is characterized by from an about 1.15 wt% to about 1.21 wt% loss between room temperature and about 200.0 °C, as determined by TGA. In another aspect, the crystalline Fumarate Form I is characterized by an about 1.18 wt% loss between room temperature and about 200.0 °C, as determined by TGA.

[0413] In another aspect, the crystalline Fumarate Form I is characterized by a TGA profile as shown in FIG. 15.

[0414] In another aspect, the crystalline Fumarate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 14; a DSC profile as shown in FIG. 15; or a TGA profile as shown in FIG. 15.

[0415] In some aspects, the crystalline Fumarate Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Fumarate Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Fumarate Form I has a polymorphic purity of at least 80%.

[0416] In another aspect, the present disclosure provides a mixture comprising the crystalline Fumarate Form I and a second solid state form or crystalline form of a compound having Structure (II).I. Hemi-Malate Form I

[0417] In one aspect, the present disclosure provides the malate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof.

[0418] In some aspects, the (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and the malate are present in a molar ratio of 1: 1 or 1:0.5. In another aspect, the (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and the malate are present in a molar ratio of 1:0.5.

[0419] In some aspects, the crystalline form is Hemi-Malate Form I.

[0420] In another aspect, the crystalline Hemi-Malate Form I is formed between (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and racemic malic acid, L-malic acid, or D- malic acid. In another aspect, the crystalline Hemi-Malate Form I is formed between (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and racemic malic acid. In another aspect, the crystalline Hemi-Malate Form I is formed between (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol and L-malic acid. In another aspect, the crystalline Hemi-Malate Form I is formed between (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and D-malic acid.

[0421] In some aspects, the crystalline Hemi-Malate Form I is an anhydrate.

[0422] In some aspects, the melting point of crystalline Hemi-Malate Form I is about 164 °C.

[0423] In another aspect, the crystalline Hemi-Malate Form I is characterized by an XRPD pattern having a peak at 16.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Hemi-Malate Form I is characterized by an XRPD pattern having peaks at 9.4, 16.1, and 16.9 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Hemi-Malate Form I is characterized by an XRPD pattern having peaks at 9.4, 16.1, 16.9, 20.2, and 21.9 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0424] In some aspects, the crystalline Hemi-Malate Form I is characterized by an XRPD pattern as shown in FIG. 16.

[0425] In some aspects, the crystalline Hemi-Malate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 8a in the Examples.

[0426] In another aspect, the crystalline Hemi-Malate Form I is characterized by an endothermic peak at from about 160 °C to about 166 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form I is characterized by an endothermic peak at from about 161 °C to about 165 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form I is characterized by an endothermic peak at from about 162 °C to about 164 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form I is characterized by an endothermic peak at about 163 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form I is characterized by an endothermic peak at about 164 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form I is characterized by an endothermic peak at about 163.69 °C, as determined by DSC.

[0427] In another aspect, the crystalline Hemi-Malate Form I is characterized by a DSC profile as shown in FIG. 17.

[0428] In another aspect, the crystalline Hemi-Malate Form I is characterized by from an about 0.04 wt% to about 0.14 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Hemi-Malate Form I is characterized by from an about 0.06 wt% to about 0.12 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Hemi-Malate Form I is characterized by an about 0.09 wt% loss between room temperature and about 150.0 °C, as determined by TGA.

[0429] In another aspect, the crystalline Hemi-Malate Form I is characterized by a TGA profile as shown in FIG. 17.

[0430] In another aspect, the crystalline Hemi-Malate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 16; a DSC profile as shown in FIG.17; or a TGA profile as shown in FIG. 17.

[0431] In some aspects, the crystalline Hemi-Malate Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Hemi-Malate Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or atleast 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Hemi-Malate Form I has a polymorphic purity of at least 80%.

[0432] In another aspect, the present disclosure provides a mixture comprising the crystalline Hemi-Malate Form I and a second solid state form or crystalline form of a compound having Structure (II).J. Hemi-Malate Form II

[0433] In one aspect, the present disclosure provides a second malate salt crystalline form of (R)-l -cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Hemi- Malate Form II.

[0434] In another aspect, the (R)-l -cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol and the malate are present in a molar ratio of 1: 1 or 1:0.5. In another aspect, the (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and the malate are present in a molar ratio of 1:0.5.

[0435] In another aspect, the crystalline Hemi-Malate Form II is formed between (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and racemic malic acid, L-malic acid, or D- malic acid. In another aspect, the crystalline Hemi-Malate Form II is formed between (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and racemic malic acid. In another aspect, the crystalline Hemi-Malate Form II is formed between (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol and L-malic acid. In another aspect, the crystalline Hemi-Malate Form II is formed between (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and D-malic acid.

[0436] In some aspects, the crystalline Hemi-Malate Form II is an anhydrate.

[0437] In some aspects, the melting point of crystalline Hemi-Malate Form II is about 137 °C. In some aspects, the melting point of crystalline Hemi-Malate Form II is about 138 °C.

[0438] In another aspect, the crystalline Hemi-Malate Form II is characterized by an XRPD pattern having a peak at 8.7 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Hemi-Malate Form II is characterized by an XRPD pattern having peaks at 8.7, 17.5, and 19.6 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Hemi-Malate Form II is characterized by an XRPD pattern having peaks at 8.7, 9.7, 17.5, 17.9, and 19.6 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0439] In some aspects, the crystalline Hemi-Malate Form II is characterized by an XRPD pattern as shown in FIG. 16.

[0440] In some aspects, the crystalline Hemi-Malate Form II is characterized by three or more, four or more, five or more, or six or more XRPD peaks liste in Table 8b in the Examples.

[0441] In another aspect, the crystalline Hemi-Malate Form II is characterized by an endothermic peak at from about 134 °C to about 140 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form II is characterized by an endothermic peak at from about 135 °C to about 139 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form II is characterized by an endothermic peak at from about 136 °C to about 138 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form II is characterized by an endothermic peak at about 137 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form II is characterized by an endothermic peak at about 138 °C, as determined by DSC. In another aspect, the crystalline Hemi-Malate Form II is characterized by an endothermic peak at about 137.64 °C, as determined by DSC.

[0442] In another aspect, the crystalline Hemi-Malate Form II is characterized by a DSC profile as shown in FIG. 18.

[0443] In another aspect, the crystalline Hemi-Malate Form II is characterized by from an about 0.01 wt% to about 0.05 wt% loss between room temperature and about 120.0 °C, as determined by TGA. In another aspect, the crystalline Hemi-Malate Form II is characterized by an about 0.03 wt% loss between room temperature and about 120.0 °C, as determined by TGA.

[0444] In another aspect, the crystalline Hemi-Malate Form II is characterized by a TGA profile as shown in FIG. 18.

[0445] In another aspect, the crystalline Hemi-Malate Form II is characterized by at least one of the following: an XRPD pattern as shown in FIG. 16; a DSC profile as shown in FIG.18; or a TGA profile as shown in FIG. 18.

[0446] In some aspects, the crystalline Hemi-Malate Form II is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Hemi-Malate Form II has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Hemi-Malate Form II has a polymorphic purity of at least 80%.

[0447] In another aspect, the present disclosure provides a mixture comprising the crystalline Hemi-Malate Form I and a second solid state form or crystalline form of a compound having Structure (II).K. Hemi-Succinate Form I

[0448] In one aspect, the present disclosure provides the succinate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Hemi- Succinate Form I.

[0449] In another aspect, the (R)-l -cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol and the succinate are present in a molar ratio of 1: 1 or 1:0.5. In another aspect, the (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and the succinate are present in a molar ratio of 1:0.5.

[0450] In some aspects, the crystalline Hemi-Succinate Form I is an anhydrate.

[0451] In some aspects, the melting point of crystalline Hemi-Succinate Form I is about 187 °C.

[0452] In another aspect, the crystalline Hemi-Succinate Form I is characterized by an XRPD pattern having a peak at 17.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Hemi-SuccinateForm I is characterized by an XRPD pattern having peaks at 9.5, 16.4, and 17.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Hemi-Succinate Form I is characterized by an XRPD pattern having peaks at 9.5, 12.7, 16.4, 17.1, and 22.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0453] In some aspects, the crystalline Hemi-Succinate Form I is characterized by an XRPD pattern as shown in FIG. 19.

[0454] In some aspects, the crystalline Hemi-Succinate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 9 in the Examples.

[0455] In another aspect, the crystalline Hemi-Succinate Form I is characterized by an endothermic peak at from about 184 °C to about 190 °C, as determined by DSC. In another aspect, the crystalline Hemi-Succinate Form I is characterized by an endothermic peak at from about 185 °C to about 189 °C, as determined by DSC. In another aspect, the crystalline Hemi-Succinate Form I is characterized by an endothermic peak at from about 186 °C to about 188 °C, as determined by DSC. In another aspect, the crystalline Hemi-Succinate Form I is characterized by an endothermic peak at about 187 °C, as determined by DSC. In another aspect, the crystalline Hemi-Succinate Form I is characterized by an endothermic peak at about 187.12 °C, as determined by DSC.

[0456] In another aspect, the crystalline Hemi-Succinate Form I is characterized by a DSC profile as shown in FIG. 20.

[0457] In another aspect, the crystalline Hemi-Succinate Form I is characterized by from an about 1.78 wt% to about 1.88 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Hemi-Succinate Form I is characterized by from an about 1.80 wt% to about 1.86 wt% loss between room temperature and about 150.0 °C, as determined by TGA. In another aspect, the crystalline Hemi- Succinate Form I is characterized by an about 1.83 wt% loss between room temperature and about 150.0 °C, as determined by TGA.

[0458] In another aspect, the crystalline Hemi-Succinate Form I is characterized by a TGA profile as shown in FIG. 20.

[0459] In another aspect, the crystalline Hemi-Succinate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 19; a DSC profile as shown in FIG. 20; or a TGA profile as shown in FIG. 20.

[0460] In some aspects, the crystalline Hemi-Succinate Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Hemi-Succinate Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Hemi- Succinate Form I has a polymorphic purity of at least 80%.

[0461] In another aspect, the present disclosure provides a mixture comprising the crystalline Hemi-Succinate Form I and a second solid state form or crystalline form of a compound having Structure (II).L. Benzoate Form I

[0462] In one aspect, the present disclosure provides a benzoate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is Benzoate Form I.

[0463] In some aspects, the crystalline Benzoate Form I is an anhydrate.

[0464] In some aspects, the melting point of crystalline Benzoate Form I is about 104 °C.

[0465] In another aspect, the crystalline Benzoate Form I is characterized by an XRPD pattern having a peak at 9.5 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Benzoate Form I is characterized by an XRPD pattern having peaks at 8.4, 9.5, and 21.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Benzoate Form I is characterized by an XRPD pattern having peaks at 8.4, 9.5, 19.1, 21.1, and 22.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0466] In some aspects, the crystalline Benzoate Form I is characterized by an XRPD pattern as shown in FIG. 21.

[0467] In some aspects, the crystalline Benzoate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 10 in the Examples.

[0468] In another aspect, the crystalline Benzoate Form I is characterized by an endothermic peak at from about 100 °C to about 106 °C, as determined by DSC. In another aspect, the crystalline Benzoate Form I is characterized by an endothermic peak at from about 101 °C to about 105 °C, as determined by DSC. In another aspect, the crystalline Benzoate Form I is characterized by an endothermic peak at from about 102 °C to about 104 °C, as determined by DSC. In another aspect, the crystalline Benzoate Form I is characterized by an endothermic peak at about 104 °C, as determined by DSC. In another aspect, the crystalline Benzoate Form I is characterized by an endothermic peak at about 103.92 °C, as determined by DSC.

[0469] In another aspect, the crystalline Benzoate Form I is characterized by a DSC profile as shown in FIG. 22.

[0470] In another aspect, the crystalline Benzoate Form I is characterized by from an about 1.00 wt% to about 1.10 wt% loss between room temperature and about 90.0 °C, as determined by TGA. In another aspect, the crystalline Benzoate Form I is characterized by from an about 1.02 wt% to about 1.08 wt% loss between room temperature and about 90.0 °C, as determined by TGA. In another aspect, the crystalline Benzoate Form I is characterized by an about 1.05 wt% loss between room temperature and about 90.0 °C, as determined by TGA.

[0471] In another aspect, the crystalline Benzoate Form I is characterized by a TGA profile as shown in FIG. 22.

[0472] In another aspect, the crystalline Benzoate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 21; a DSC profile as shown in FIG. 22; or a TGA profile as shown in FIG. 22.

[0473] In some aspects, the crystalline Benzoate Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Benzoate Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%,or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Benzoate Form I has a polymorphic purity of at least 80%.

[0474] In another aspect, the present disclosure provides a mixture comprising the crystalline Benzoate Form I and a second solid state form or crystalline form of a compound having Structure (II).M. Hemi-Tartrate Form I

[0475] In one aspect, the present disclosure provides a tartrate salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is HemiTartrate Form I.

[0476] In another aspect, the (R)-l -cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol and the tartrate are present in a molar ratio of 1: 1 or 1:0.5. In another aspect, the (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and the tartrate are present in a molar ratio of 1:0.5.

[0477] In another aspect, the Hemi-Tartrate Form I is formed between (R)-l-cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol and racemic tartaric acid, R, R-tartaric acid, S, S-tartaric acid, or meso-tartaric acid. In another aspect, the Hemi-Tartrate Form I is formed between (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and racemic tartaric acid. In another aspect, the crystalline Hemi-Tartrate Form I is formed between (R)-l -cyclohexyl- l-phenyl-3- (l-piperidyl)propan-l-ol and R, R-tartaric acid. In another aspect, the Hemi-Tartrate Form I is formed between (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol and S, S-tartaric acid. In another aspect, the Hemi-Tartrate Form I is formed between (R)-l -cyclohexyl- 1- phenyl-3-(l-piperidyl)propan-l-ol and meso-tartaric acid.

[0478] In some aspects, the crystalline Hemi-Tartrate Form I is an anhydrate.

[0479] In some aspects, the melting point of crystalline Hemi-Tartrate Form I is about 139 °C.

[0480] In another aspect, the crystalline Hemi-Tartrate Form I is characterized by an XRPD pattern having a peak at 8.4 degrees two theta using Cu Ka radiation, wherein the twotheta values are ± 0.2 degrees two theta. In some aspects, the crystalline Hemi-Tartrate Form I is characterized by an XRPD pattern having peaks at 8.4, 16.9, and 21.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Hemi-Tartrate Form I is characterized by an XRPD pattern having peaks at 8.4, 16.9, 17.2, 18.4, and 21.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0481] In some aspects, the crystalline Hemi-Tartrate Form I is characterized by an XRPD pattern as shown in FIG. 23.

[0482] In some aspects, the crystalline Hemi-Tartrate Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 11 in the Examples.

[0483] In another aspect, the crystalline Hemi-Tartrate Form I is characterized by an endothermic peak at from about 135 °C to about 141 °C, as determined by DSC. In another aspect, the crystalline Hemi-Tartrate Form I is characterized by an endothermic peak at from about 136 °C to about 140 °C, as determined by DSC. In another aspect, the crystalline Hemi-Tartrate Form I is characterized by an endothermic peak at from about 137 °C to about 139 °C, as determined by DSC. In another aspect, the crystalline Hemi-Tartrate Form I is characterized by an endothermic peak at about 138 °C, as determined by DSC. In another aspect, the crystalline Hemi-Tartrate Form I is characterized by an endothermic peak at about 139 °C, as determined by DSC. In another aspect, the crystalline Hemi-Tartrate Form I is characterized by an endothermic peak at about 138.71 °C, as determined by DSC.

[0484] In another aspect, the crystalline Hemi-Tartrate Form I is characterized by a DSC profile as shown in FIG. 24.

[0485] In another aspect, the crystalline Hemi-Tartrate Form I is characterized by from an about 0.97 wt% to about 1.07 wt% loss between room temperature and about 100.0 °C, as determined by TGA. In another aspect, the crystalline Hemi-Tartrate Form I is characterized by from an about 0.99 wt% to about 1.05 wt% loss between room temperature and about 100.0 °C, as determined by TGA. In another aspect, the crystalline Hemi-Tartrate Form I is characterized by an about 1.02 wt% loss between room temperature and about 100.0 °C, as determined by TGA.

[0486] In another aspect, the crystalline Hemi-Tartrate Form I is characterized by a TGA profile as shown in FIG. 24.

[0487] In another aspect, the crystalline Hemi-Tartrate Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 23; a DSC profile as shown in FIG.24; or a TGA profile as shown in FIG. 24.

[0488] In some aspects, the crystalline Hemi-Tartrate Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline Hemi-Tartrate Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Hemi-Tartrate Form I has a polymorphic purity of at least 80%.

[0489] In another aspect, the present disclosure provides a mixture comprising the crystalline Hemi-Tartrate Form I and a second solid state form or crystalline form of a compound having Structure (II).N. Mixture of Hemi -Tartrate Form I and an Unknown Form

[0490] In one aspect, the present disclosure provides a mixture of two tartrate salt crystalline forms of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or pharmaceutically acceptable salts thereof.

[0491] In some aspects, both crystalline forms are anhydrates.

[0492] In another aspect, the mixture of Hemi -Tartrate Form II and another crystalline form of a tartrate salt of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol is characterized by an XRPD pattern as shown in FIG. 23.

[0493] In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol is characterized by endothermic peaks at from about 127 °C to about 133 °C and at from about 135 °C to about 141 °C, as determined by DSC. In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l -cyclohexyl- 1- phenyl-3-(l-piperidyl)propan-l-ol characterized by endothermic peaks at from about 128 °Cto about 132 °C and at from about 136 °C to about 140 °C, as determined by DSC. In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol characterized by endothermic peaks at from about 129 °C to about 131 °C and at from about 137 °C to about 139 °C, as determined by DSC. In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l-cyclohexyl-l-phenyl-3-(l- piperidyl)propan-l-ol characterized by endothermic peaks at about 130.80 and at about 138.55 °C, as determined by DSC.

[0494] In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol is characterized by a DSC profile as shown in FIG. 25.

[0495] In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol is characterized by from an about 0.61 wt% to about 0.71 wt% loss between room temperature and about 100.0 °C, as determined by TGA. In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l -cyclohexyl- 1- phenyl-3-(l-piperidyl)propan-l-ol characterized by from an about 0.63 wt% to about 0.69 wt% loss between room temperature and about 100.0 °C, as determined by TGA. In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l -cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol characterized by an about 0.66 wt% loss between room temperature and about 100.0 °C, as determined by TGA.

[0496] In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol characterized by a TGA profile as shown in FIG. 25.

[0497] In another aspect, the mixture of crystalline Hemi-Tartrate Form II and another crystalline form of a tartrate salt of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol characterized by at least one of the following: an XRPD pattern as shown in FIG. 23; a DSC profile as shown in FIG. 25; or a TGA profile as shown in FIG. 25.O. HC1 Salt Form I

[0498] In one aspect, the present disclosure provides a hydrochloride (HC1) salt crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt thereof. In some aspects, the crystalline form is HC1 Salt Form I.

[0499] In some aspects, the crystalline HC1 Salt Form I is an anhydrate.

[0500] In some aspects, the melting point of crystalline HC1 Salt Form I is about 283 °C.

[0501] In another aspect, the crystalline HC1 Salt Form I is characterized by an XRPD pattern having a peak at 5.8 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline HC1 Salt Form I is characterized by an XRPD pattern having peaks at 5.8, 17.7, and 19.4 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline HC1 Salt Form I is characterized by an XRPD pattern having peaks at 5.8, 17.7, 19.4, 23.7, and 30.8 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0502] In some aspects, the crystalline HC1 Salt Form I is characterized by an XRPD pattern as shown in FIG. 26.

[0503] In some aspects, the crystalline HC1 Salt Form I is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 12 in the Examples.

[0504] In another aspect, the crystalline HC1 Salt Form I is characterized by an endothermic peak at from about 279 °C to about 285 °C, as determined by DSC. In another aspect, the crystalline HC1 Salt Form I is characterized by an endothermic peak at from about 280 °C to about 284 °C, as determined by DSC. In another aspect, the crystalline HC1 Salt Form I is characterized by an endothermic peak at from about 281 °C to about 283 °C, as determined by DSC. In another aspect, the crystalline HC1 Salt Form I is characterized by an endothermic peak at about 283 °C, as determined by DSC. In another aspect, the crystalline HC1 Salt Form I is characterized by an endothermic peak at about 282.92 °C, as determined by DSC.

[0505] In another aspect, the crystalline HC1 Salt Form I is characterized by a DSC profile as shown in FIG. 27.

[0506] In another aspect, the crystalline HC1 Salt Form I is characterized by from an about 0.54 wt% to about 0.64 wt% loss between room temperature and about 100.0 °C, asdetermined by TGA. In another aspect, the crystalline HC1 Salt Form I is characterized by from an about 0.56 wt% to about 0.62 wt% loss between room temperature and about 100.0 °C, as determined by TGA. In another aspect, the crystalline HC1 Salt Form I is characterized by an about 0.59 wt% loss between room temperature and about 100.0 °C, as determined by TGA.

[0507] In another aspect, the crystalline HC1 Salt Form I is characterized by a TGA profile as shown in FIG. 27.

[0508] In another aspect, the crystalline HC1 Salt Form I is characterized by at least one of the following: an XRPD pattern as shown in FIG. 26; a DSC profile as shown in FIG. 27; or a TGA profile as shown in FIG. 27.

[0509] In some aspects, the crystalline HC1 Salt Form I is substantially free of other polymorphic or physical forms. In some aspects, the crystalline HC1 Salt Form I has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline HC1 Salt Form I has a polymorphic purity of at least 80%.

[0510] In another aspect, the present disclosure provides a mixture comprising the crystalline HC1 Salt Form I and a second solid state form or crystalline form of a compound having Structure (II).

[0511] In another aspect, the present disclosure provides stable crystalline forms. In one aspect, the present disclosure provides a crystalline form, wherein the crystalline form’s purity level does not change within the limits of XRPD detection after about 1 day of storage at 25 °C and 60% relative humidity. In one aspect, the present disclosure provides a crystalline form, wherein the crystalline form’s purity level does not change within the limits of XRPD detection after about 3 days of storage at 25 °C and 60% relative humidity. In one aspect, the present disclosure provides a crystalline form, wherein the crystalline form’s purity level does not change within the limits of XRPD detection after about 7 days of storage at 25 °C and 60% relative humidity.

[0512] In one aspect, the present disclosure provides a crystalline form, wherein the crystalline form’s purity level does not change within the limits of XRPD detection after about 1 day of storage at 40 °C and 75% relative humidity. In one aspect, the presentdisclosure provides a crystalline form, wherein the crystalline form’s purity level does not change within the limits of XRPD detection after about 3 days of storage at 40 °C and 75% relative humidity. In one aspect, the present disclosure provides a crystalline form, wherein the crystalline form’s purity level does not change within the limits of XRPD detection after about 7 days of storage at 40 °C and 75% relative humidity.

[0513] In one aspect, the present disclosure provides a crystalline form, wherein the crystalline form’s purity level decreases by less than about 0.15 % based on XRPD detection after about 1 day of storage at 40 °C and 75% relative humidity. In one aspect, the present disclosure provides a crystalline form, wherein the crystalline form’s purity level decreases by less than about 0.15 % based on XRPD detection after about 3 days of storage at 40 °C and 75% relative humidity. In one aspect, the present disclosure provides a crystalline form, wherein the crystalline form’s purity level decreases by less than about 0.15 % based on XRPD detection after about 7 days of storage at 40 °C and 75% relative humidity.

[0514] In one aspect, the present disclosure provides a crystalline form wherein the crystalline form has a purity level of about 100% after about 1, 3, and 7 days of storage at 25 °C and 60 % relative humidity. In another aspect, the crystalline form has a purity level of about 100% after about 1 day of storage at 25 °C and 60 % relative humidity. In another aspect, the crystalline form has a purity level of about 100% after about 3 days of storage at 25 °C and 60 % relative humidity. In another aspect, the crystalline form has a purity level of about 100% after about 7 days of storage at 25 °C and 60 % relative humidity.

[0515] In one aspect, the present disclosure provides a crystalline form wherein the crystalline form has a purity level of about 100% after about 1, 3, and 7 days of storage at 40 °C and 75 % relative humidity and wherein impurities, if any, are detected at an amount of less than about 0.15 %. In another aspect, the crystalline form has a purity level of about 100% after about 1 day of storage at 40 °C and 75 % relative humidity and wherein impurities, if any, are detected at an amount of less than about 0.15 %. In another aspect, the crystalline form has a purity level of about 100% after about 3 days of storage at 40 °C and 75 % relative humidity and wherein impurities, if any, are detected at an amount of less than about 0.15 %. In another aspect, the crystalline form has a purity level of about 100% after about 7 days of storage at 40 °C and 75 % relative humidity and wherein impurities, if any, are detected at an amount of less than about 0.15 %.

[0516] In one aspect, the present disclosure provides a crystalline form wherein the crystalline form has a purity level of about 100% after about 1, 3, and 7 days of storage at 60 °C and ambient % relative humidity. In another aspect, the crystalline form has a purity level of about 100% after about 1 day of storage at 60 °C and ambient % relative humidity. In another aspect, the crystalline form has a purity level of about 100% after about 3 days of storage at 60 °C and ambient % relative humidity. In another aspect, the crystalline form has a purity level of about 100% after about 7 days of storage at 60 °C and ambient % relative humidity.

[0517] In one aspect, the present disclosure provides a crystalline form wherein the crystalline form has a purity level of about 100% after about 1, 3, and 7 days of storage at 60 °C and 75 % relative humidity and wherein impurities are detected at an amount of less than about 0.15 %. In another aspect, the crystalline form has a purity level of about 100% after about 1 day of storage at 60 °C and 75 % relative humidity and wherein impurities are detected at an amount of less than about 0.15 %. In another aspect, the crystalline form has a purity level of about 100% after about 3 days of storage at 60 °C and 75 % relative humidity and wherein impurities are detected at an amount of less than about 0.15 %. In another aspect, the crystalline form has a purity level of about 100% after about 7 days of storage at 60 °C and 75 % relative humidity and wherein impurities are detected at an amount of less than about 0.15 %.

[0518] In one aspect, the present disclosure provides a crystalline form wherein the crystalline form has a purity level of about 100% after about 1, 3, and 7 days of storage at 80 °C and ambient % relative humidity. In another aspect, the crystalline form has a purity level of about 100% after about 1 day of storage at 80 °C and ambient % relative humidity. In another aspect, the crystalline form has a purity level of about 100% after about 3 days of storage at 80 °C and ambient % relative humidity. In another aspect, the crystalline form has a purity level of about 100% after about 7 days of storage at 80 °C and ambient % relative humidity.

[0519] In one aspect, the present disclosure provides a crystalline form wherein the crystalline form has a purity level of about 100% after about 1, 3, and 7 days of storage at 80 °C and 75 % relative humidity and wherein impurities are detected at an amount of less than about 0.15 %. In another aspect, the crystalline form has a purity level of about 100% after about 1 day of storage at 80 °C and 75 % relative humidity and wherein impurities aredetected at an amount of less than about 0.15 %. In another aspect, the crystalline form has a purity level of about 100% after about 3 days of storage at 80 °C and 75 % relative humidity and wherein impurities are detected at an amount of less than about 0.15 %. In another aspect, the crystalline form has a purity level of about 100% after about 7 days of storage at 80 °C and 75 % relative humidity and wherein impurities are detected at an amount of less than about 0.15 %.

[0520] In one aspect, the present disclosure provides any of the solid state forms or crystalline forms defined and disclosed herein, wherein the solid state form or crystalline form is substantially free of other polymorphic or physical forms. In another aspect, any of the solid state forms or crystalline forms defined and disclosed herein is a hydrate, anhydrate, or solvate thereof.Compound Having Structure (VII)A. Bethanechol Chloride Form II

[0521] In one aspect, the present disclosure provides a crystalline form of bethanechol chloride having Structure (VII):or a pharmaceutically acceptable salt thereof, wherein the crystalline form is Form II.

[0522] In some aspects, the crystalline Form II is a hydrate.

[0523] In some aspects, the melting point of crystalline Form II is about 230 °C.

[0524] In another aspect, the crystalline Form II is characterized by an XRPD pattern having a peak at 13.54 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Form II is characterized by an XRPD pattern having peaks at 13.54, 16.38, and 21.87 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Form II is characterized by an XRPD pattern having peaks at 13.54, 16.38, 20.74, 21.87, and 27.34 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0525] In some aspects, the crystalline Form II is characterized by an XRPD pattern as shown in FIG. 49.

[0526] In some aspects, the crystalline Form II is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 29 in the Examples.

[0527] In some aspects, the crystalline Form II is characterized by an endothermic peak at from about 227 °C to about 233 °C, as determined by DSC. In some aspects, the crystalline Form II is characterized by an endothermic peak at from about 228 °C to about 232 °C, as determined by DSC. In some aspects, the crystalline Form II is characterized by an endothermic peak at from about 229 °C to about 231 °C, as determined by DSC. In some aspects, the crystalline Form II is characterized by an endothermic peak at about 230 °C, as determined by DSC. In some aspects, the crystalline Form II is characterized by an endothermic peak at about 230.20 °C, as determined by DSC.

[0528] In another aspect, the crystalline Form II is characterized by a DSC profile as shown in FIG. 50.

[0529] In another aspect, the crystalline Form II is characterized by from an about 4.10 wt% to about 4.40 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the crystalline crystalline Form II is characterized by from an about 4.20 wt% to about 4.30 wt% loss between room temperature and about 100 °C, as determined by TGA. In another aspect, the crystalline form crystalline Form II is characterized by an about 4.23 wt% loss between room temperature and about 100 °C, as determined by TGA.

[0530] In another aspect, the crystalline Form II is characterized by a TGA profile as shown in FIG. 50.

[0531] In another aspect, the crystalline Form II is characterized by at least one of the following: an XRPD pattern as shown in FIG. 49; a DSC profile as shown in FIG. 50; or a TGA profile as shown in FIG. 50.

[0532] In some aspects, the crystalline Form II is substantially free of other polymorphic or physical forms. In another aspect, the crystalline Form II has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Form II has a polymorphic purity of at least 80%.

[0533] In another aspect, the present disclosure provides a mixture comprising crystalline Form II and a second solid state form or crystalline form of a compound having Structure(VII). In another aspect, the present disclosure provides a mixture comprising crystalline Form II and one or more solid state forms or crystalline forms of a compound having Structure (VII).B. Bethanechol Chloride Form III

[0534] In one aspect, the present disclosure provides a crystalline form of bethanechol chloride having Structure (VII):or a pharmaceutically acceptable salt thereof, wherein the crystalline form is Form III.

[0535] In some aspects, the crystalline Form III is an anhydrate.

[0536] In some aspects, the melting point of crystalline Form III is about 227 °C.

[0537] In another aspect, the crystalline Form III is characterized by an XRPD pattern having a peak at 18.66 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Form III is characterized by an XRPD pattern having peaks at 15.25, 18.66, and 22.25 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Form III is characterized by an XRPD pattern having peaks at 15.25, 16.17, 18.66, 22.25, and 22.90 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0538] In some aspects, the crystalline Form III is characterized by an XRPD pattern as shown in FIG. 51.

[0539] In some aspects, the crystalline Form III is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 30 in the Examples.

[0540] In some aspects, the crystalline Form III is characterized by an endothermic peak at from about 224 °C to about 230 °C, as determined by DSC. In some aspects, the crystalline Form III is characterized by an endothermic peak at from about 225 °C to about 229 °C, as determined by DSC. In some aspects, the crystalline Form III is characterized by an endothermic peak at from about 226 °C to about 228 °C, as determined by DSC. In some aspects, the crystalline Form III is characterized by an endothermic peak at about 227 °C, as determined by DSC. In some aspects, the crystalline Form III is characterized by an endothermic peak at about 226.56 °C, as determined by DSC.

[0541] In another aspect, the crystalline Form III is characterized by a DSC profile as shown in FIG. 52.

[0542] In another aspect, the crystalline Form III is characterized by from an about 3.2 wt% to about 3.5 wt% loss between room temperature and about 200 °C, as determined by TGA. In another aspect, the crystalline crystalline Form III is characterized by from an about 3.30 wt% to about 3.40 wt% loss between room temperature and about 200 °C, as determined by TGA. In another aspect, the crystalline form crystalline Form III is characterized by an about 3.34 wt% loss between room temperature and about 200 °C, as determined by TGA.

[0543] In another aspect, the crystalline Form III is characterized by a TGA profile as shown in FIG. 52.

[0544] In another aspect, the crystalline Form III is characterized by at least one of the following: an XRPD pattern as shown in FIG. 51; a DSC profile as shown in FIG. 52; or a TGA profile as shown in FIG. 52.

[0545] In some aspects, the crystalline Form III is substantially free of other polymorphic or physical forms. In another aspect, the crystalline Form III has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Form III has a polymorphic purity of at least 80%.

[0546] In another aspect, the present disclosure provides a mixture comprising crystalline Form III and a second solid state form or crystalline form of a compound having Structure (VII). In another aspect, the present disclosure provides a mixture comprising crystalline Form III and one or more solid state forms or crystalline forms of a compound having Structure (VII).C. Bethanechol Chloride Form IV

[0547] In one aspect, the present disclosure provides a crystalline form of bethanechol chloride having Structure (VII):or a pharmaceutically acceptable salt thereof, wherein the crystalline form is Form IV.

[0548] In some aspects, the crystalline Form IV is an anhydrate.

[0549] In some aspects, the melting point of crystalline Form IV is about 227 °C.

[0550] In another aspect, the crystalline Form IV is characterized by an XRPD pattern having a peak at 20.66 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Form IV is characterized by an XRPD pattern having peaks at 19.27, 20.66, and 26.92 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Form IV is characterized by an XRPD pattern having peaks at 15.99, 19.27, 19.97, 20.66, and 26.92 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0551] In some aspects, the crystalline Form IV is characterized by an XRPD pattern as shown in FIG. 53.

[0552] In some aspects, the crystalline Form IV is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 31 in the Examples.

[0553] In some aspects, the crystalline Form IV is characterized by an endothermic peak at from about 224 °C to about 230 °C, as determined by DSC. In some aspects, the crystalline Form IV is characterized by an endothermic peak at from about 225 °C to about 229 °C, as determined by DSC. In some aspects, the crystalline Form IV is characterized by an endothermic peak at from about 226 °C to about 228 °C, as determined by DSC. In some aspects, the crystalline Form IV is characterized by an endothermic peak at about 227 °C, as determined by DSC. In some aspects, the crystalline Form IV is characterized by an endothermic peak at about 227.21 °C, as determined by DSC.

[0554] In another aspect, the crystalline Form IV is characterized by a DSC profile as shown in FIG. 54.

[0555] In another aspect, the crystalline Form IV is characterized by from an about 2.8 wt% to about 3.1 wt% loss between room temperature and about 200 °C, as determined by TGA. In another aspect, the crystalline crystalline Form IV is characterized by from an about 2.90 wt% to about 3.00 wt% loss between room temperature and about 200 °C, as determined by TGA. In another aspect, the crystalline form crystalline Form IV is characterized by an about 2.94 wt% loss between room temperature and about 200 °C, as determined by TGA.

[0556] In another aspect, the crystalline Form IV is characterized by a TGA profile as shown in FIG. 54.

[0557] In another aspect, the crystalline Form IV is characterized by at least one of the following: an XRPD pattern as shown in FIG. 53; a DSC profile as shown in FIG. 54; or a TGA profile as shown in FIG. 54.

[0558] In some aspects, the crystalline Form IV is substantially free of other polymorphic or physical forms. In another aspect, the crystalline Form IV has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Form IV has a polymorphic purity of at least 80%.

[0559] In another aspect, the present disclosure provides a mixture comprising crystalline Form IV and a second solid state form or crystalline form of a compound having Structure (VII). In another aspect, the present disclosure provides a mixture comprising crystalline Form IV and one or more solid state forms or crystalline forms of a compound having Structure (VII).D. Bethanechol Chloride Form V

[0560] In one aspect, the present disclosure provides a crystalline form of bethanechol chloride having Structure (VII):or a pharmaceutically acceptable salt thereof, wherein the crystalline form is Form V.

[0561] In some aspects, the crystalline Form V is a hydrate.

[0562] In some aspects, the melting point of crystalline Form V is about 228 °C.

[0563] In another aspect, the crystalline Form V is characterized by an XRPD pattern having a peak at 13.03 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Form V is characterized by an XRPD pattern having peaks at 6.53, 13.03, and 13.36 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta. In some aspects, the crystalline Form V is characterized by an XRPD pattern having peaks at 6.53, 13.03, and 13.36, 14.76, and 29.88 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

[0564] In some aspects, the crystalline Form V is characterized by an XRPD pattern as shown in FIG. 55.

[0565] In some aspects, the crystalline Form V is characterized by three or more, four or more, five or more, or six or more XRPD peaks listed in Table 31 A in the Examples.

[0566] In some aspects, the crystalline Form V is characterized by an endothermic peak at from about 225 °C to about 231 °C, as determined by DSC. In some aspects, the crystalline Form V is characterized by an endothermic peak at from about 226 °C to about 230 °C, as determined by DSC. In some aspects, the crystalline Form V is characterized by an endothermic peak at from about 227 °C to about 229 °C, as determined by DSC. In some aspects, the crystalline Form V is characterized by an endothermic peak at about 228 °C, as determined by DSC. In some aspects, the crystalline Form V is characterized by an endothermic peak at about 228.40 °C, as determined by DSC.

[0567] In another aspect, the crystalline Form V is characterized by a DSC profile as shown in FIG. 56.

[0568] In another aspect, the crystalline Form V is characterized by from an about 15.0 wt% to about 17.0 wt% loss between room temperature and about 150 °C, as determined by TGA. In another aspect, the crystalline crystalline Form V is characterized by from an about 15.50 wt% to about 16.50 wt% loss between room temperature and about 150 °C, as determined by TGA. In another aspect, the crystalline crystalline Form V is characterized by from an about 15.90 wt% to about 16.10 wt% loss between room temperature and about 150 °C, as determined by TGA. In another aspect, the crystalline form crystalline Form V is characterized by an about 16.04 wt% loss between room temperature and about 150 °C, as determined by TGA.

[0569] In another aspect, the crystalline Form V is characterized by a TGA profile as shown in FIG. 56.

[0570] In another aspect, the crystalline Form V is characterized by at least one of the following: an XRPD pattern as shown in FIG. 55; a DSC profile as shown in FIG. 56; or a TGA profile as shown in FIG. 56.

[0571] In some aspects, the crystalline Form V is substantially free of other polymorphic or physical forms. In another aspect, the crystalline Form V has a polymorphic purity of at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%,or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100%. In some aspects, the crystalline Form V has a polymorphic purity of at least 80%.

[0572] In another aspect, the present disclosure provides a mixture comprising crystalline Form V and a second solid state form or crystalline form of a compound having Structure (VII). In another aspect, the present disclosure provides a mixture comprising crystalline Form V and one or more solid state forms or crystalline forms of a compound having Structure (VII).V. Prodrugs

[0573] In one aspect, the present disclosure provides a prodrug of THP. In another aspect, the THP is racemic. In another aspect, the present disclosure provides a prodrug of (R)-THP. In another aspect, the present disclosure provides a prodrug of (S)-THP.

[0574] In another aspect, the present disclosure provides a compound of Formula (III):or a pharmaceutically acceptable salt or solvate thereof, wherein:X' is either not present, or is a pharmaceutically acceptable anion;R1is selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, optionally substituted heteroaryl, and a Pro-Moiety;R2is either not present, or is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, and a Pro-Moiety;or R1and R2together with the atoms to which they are attached form an optionally substituted 3 to 14-membered heterocycle or an optionally substituted 3 to 14-membered cycloalkyl; andwherein R1is not hydrogen when R2is not present.

[0575] In some aspects, X' is a pharmaceutically acceptable anion known in the art. Nonlimiting examples of anions include hydride, fluoride, chloride, bromide, iodide, cyanide,cyanate, thiocyanate, hydroxide, amide, acetate, formate, hydrogen carbonate, bicarbonate, nitrate, nitrite, perchlorate, chlorate, chlorite, hypochlorite, iodate, bromate, hypobromite, permanganate, dihydrogen phosphate, hydrogen phosphate, and hydrogen sulfate. In some aspects, X' is selected from the group consisting of a chloride anion, a fluoride anion, a bromide anion, and an iodide anion. In some aspects, X' is a chloride anion. In some aspects, X~ is a bromide anion. In some aspects, X~ is a fluoride anion. In some aspects, X~ is an iodide anion.

[0576] In some aspects, R1is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, and a Pro-Moiety.

[0577] In some aspects, R1is optionally substituted alkyl. In some aspects, R1is optionally substituted C1-C12 alkyl. In some aspects, R1is optionally substituted Ci-Cs alkyl. In some aspects, R1is optionally substituted C1-C4 alkyl. In some aspects, R1is optionally substituted Ci alkyl. In some aspects, R1is optionally substituted C2 alkyl. In some aspects, R1is optionally substituted C3 alkyl. In some aspects, R1is optionally substituted C4 alkyl. In some aspects, R1is any alkyl group as defined and disclosed herein.

[0578] In some aspects, R1is optionally substituted alkenyl. In some aspects, R1is optionally substituted C2-C12 alkenyl. In some aspects, R1is optionally substituted C2-C8 alkenyl. In some aspects, R1is optionally substituted C2-C4 alkenyl. In some aspects, R1is optionally substituted C2 alkenyl. In some aspects, R1is optionally substituted C3 alkenyl. In some aspects, R1is optionally substituted C4 alkenyl. In some aspects, R1is optionally substituted Cs alkenyl. In some aspects, R1is optionally substituted Ce alkenyl. In some aspects, R1is any alkenyl group as defined and disclosed herein.

[0579] In some aspects, R1is optionally substituted alkynyl. In some aspects, R1is optionally substituted C2-C12 alkynyl. In some aspects, R1is optionally substituted C2-C8 alkynyl. In some aspects, R1is optionally substituted C2-C4 alkynyl. In some aspects, R1is optionally substituted C2 alkynyl. In some aspects, R1is optionally substituted C3 alkynyl. In some aspects, R1is optionally substituted C4 alkynyl. In some aspects, R1is optionally substituted Cs alkynyl. In some aspects, R1is optionally substituted Ce alkynyl. In some aspects, R1is any alkynyl group as defined and disclosed herein.

[0580] In some aspects, R1is optionally substituted cycloalkyl. In some aspects, R1is optionally substituted C3-C16 cycloalkyl. In some aspects, R1is optionally substituted C3-C12 cycloalkyl. In some aspects, R1is optionally substituted C3-C8 cycloalkyl. In some aspects, R1is optionally substituted C3-C6 cycloalkyl. In some aspects, R1is optionally substituted C3 cycloalkyl. In some aspects, R1is optionally substituted C4 cycloalkyl. In some aspects, R1is optionally substituted Cs cycloalkyl. In some aspects, R1is optionally substituted Ce cycloalkyl. In some aspects, R1is optionally substituted cyclopropyl. In some aspects, R1is optionally substituted cyclobutyl. In some aspects, R1is optionally substituted cyclopentyl. In some aspects, R1is optionally substituted cyclohexyl. In some aspects, R1is any cycloalkyl group as defined and disclosed herein.

[0581] In some aspects, R1is optionally substituted heterocycle. In some aspects, R1is optionally substituted 3- to 14-membered heterocycle. In some aspects, R1is optionally substituted 3- to 10-membered heterocycle. In some aspects, R1is optionally substituted 3- to 6-membered heterocycle. In some aspects, R1is optionally substituted 3-membered heterocycle. In some aspects, R1is optionally substituted 4-membered heterocycle. In some aspects, R1is optionally substituted 5-membered heterocycle. In some aspects, R1is optionally substituted 6-membered heterocycle. In some aspects, R1is any heterocycle group as defined and disclosed herein.

[0582] In some aspects, R1is optionally substituted aryl. In some aspects, R1is optionally substituted C4-C16 aryl. In some aspects, R1is optionally substituted C4-C12 aryl. In some aspects, R1is optionally substituted C4-C10 aryl. In some aspects, R1is optionally substituted C4-C6 aryl. In some aspects, R1is optionally substituted Ce aryl. In some aspects, R1is optionally substituted phenyl. In some aspects, R1is any aryl group as defined and disclosed herein.

[0583] In some aspects, R1is optionally substituted heteroaryl. In some aspects, R1is optionally substituted 3- to 14-membered heteroaryl. In some aspects, R1is optionally substituted 3- to 10-membered heteroaryl. In some aspects, R1is optionally substituted 3- to 6-membered heteroaryl. In some aspects, R1is optionally substituted 3-membered heteroaryl. In some aspects, R1is optionally substituted 4-membered heteroaryl. In some aspects, R1is optionally substituted 5-membered heteroaryl. In some aspects, R1is optionally substituted 6-membered heteroaryl. In some aspects, R1is any heteroaryl group as defined and disclosed herein.

[0584] In some aspects, R1is a Pro-Moiety.

[0585] In some aspects, R2is not present.

[0586] In some aspects, R2is optionally substituted alkyl. In some aspects, R2is optionally substituted C1-C12 alkyl. In some aspects, R2is optionally substituted Ci-Cs alkyl. In some aspects, R2is optionally substituted C1-C4 alkyl. In some aspects, R1is optionally substituted Ci alkyl. In some aspects, R2is optionally substituted C2 alkyl. In some aspects, R1is optionally substituted C3 alkyl. In some aspects, R2is optionally substituted C4 alkyl. In some aspects, R2is any alkyl group as defined and disclosed herein.

[0587] In some aspects, R2is optionally substituted alkenyl. In some aspects, R2is optionally substituted C2-C12 alkenyl. In some aspects, R2is optionally substituted C2-C8 alkenyl. In some aspects, R2is optionally substituted C2-C4 alkenyl. In some aspects, R2is optionally substituted C2 alkenyl. In some aspects, R2is optionally substituted C3 alkenyl. In some aspects, R2is optionally substituted C4 alkenyl. In some aspects, R2is optionally substituted Cs alkenyl. In some aspects, R2is optionally substituted Ce alkenyl. In some aspects, R2is any alkenyl group as defined and disclosed herein.

[0588] In some aspects, R2is optionally substituted alkynyl. In some aspects, R2is optionally substituted C2-C12 alkynyl. In some aspects, R2is optionally substituted C2-C8 alkynyl. In some aspects, R2is optionally substituted C2-C4 alkynyl. In some aspects, R2is optionally substituted C2 alkynyl. In some aspects, R2is optionally substituted C3 alkynyl. In some aspects, R2is optionally substituted C4 alkynyl. In some aspects, R2is optionally substituted Cs alkynyl. In some aspects, R2is optionally substituted Ce alkynyl. In some aspects, R2is any alkynyl group as defined and disclosed herein.

[0589] In some aspects, R2is a Pro-Moiety.

[0590] In some aspects, R1and R2together with the atoms to which they are attached form an optionally substituted heterocycle. In some aspects, R1and R2together with the atoms to which they are attached form an optionally substituted 3 to 14-membered heterocycle. In some aspects, R1and R2together with the atoms to which they are attached form an optionally substituted 3 to 10-membered heterocycle.

[0591] In some aspects, R1and R2together with the atoms to which they are attached form an optionally substituted cycloalkyl. In some aspects, R1and R2together with the atoms to which they are attached form an optionally substituted 3 to 14-memberedcycloalkyl. In some aspects, R1and R2together with the atoms to which they are attached form an optionally substituted 3 to 10-membered cycloalkyl.

[0592] In some aspects, R1is not hydrogen when R2is not present. In some aspects, R1is hydrogen when R2is not present.

[0593] In some aspects, both R1and R2are Pro-Moieties. In some aspects, R1is a Pro- Moiety and R2is not a Pro-Moiety. In some aspects, R1is not a Pro-Moiety and R2is a Pro- Moiety.

[0594] In some aspects, the Pro-Moiety (or Pro-Moieties) are independently selected Ofrom the group consisting of,,OR4'O R phosphoryl, phosphate, phosphoramidate, optionally substituted Ci-Cs alkyl phosphate, sulfonate, sulfonyl, alkyl sulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; and cholesterol. In some aspects, the Pro-Moiety is selected fromO3

[0595] In some aspects, the Pro-Moiety isR.

[0596] In some aspects, R3is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. R3is selected from the group consisting of optionally substituted Ci- Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl

[0597] In some aspects, R3is optionally substituted alkyl. In some aspects, R3is optionally substituted C1-C12 alkyl. In some aspects, R3is optionally substituted Ci-Cs alkyl. In some aspects, R3is optionally substituted C1-C4 alkyl. In some aspects, R3is optionally substituted Ci alkyl. In some aspects, R3is optionally substituted C2 alkyl. In some aspects,R3is optionally substituted C3 alkyl. In some aspects, R3is optionally substituted C4 alkyl. In some aspects, R3is any alkyl group as defined and disclosed herein.

[0598] In some aspects, R3is optionally substituted alkenyl. In some aspects, R3is optionally substituted C2-C12 alkenyl. In some aspects, R3is optionally substituted C2-C8 alkenyl. In some aspects, R3is optionally substituted C2-C4 alkenyl. In some aspects, R3is optionally substituted C2 alkenyl. In some aspects, R3is optionally substituted C3 alkenyl. In some aspects, R3is optionally substituted C4 alkenyl. In some aspects, R3is optionally substituted Cs alkenyl. In some aspects, R3is optionally substituted Ce alkenyl. In some aspects, R3is any alkenyl group as defined and disclosed herein.

[0599] In some aspects, R3is optionally substituted alkynyl. In some aspects, R3is optionally substituted C2-C12 alkynyl. In some aspects, R3is optionally substituted C2-C8 alkynyl. In some aspects, R3is optionally substituted C2-C4 alkynyl. In some aspects, R3is optionally substituted C2 alkynyl. In some aspects, R3is optionally substituted C3 alkynyl. In some aspects, R3is optionally substituted C4 alkynyl. In some aspects, R3is optionally substituted Cs alkynyl. In some aspects, R3is optionally substituted Ce alkynyl. In some aspects, R3is any alkynyl group as defined and disclosed herein.

[0600] In some aspects, R3is optionally substituted cycloalkyl. In some aspects, R3is optionally substituted C3-C16 cycloalkyl. In some aspects, R3is optionally substituted C3-C12 cycloalkyl. In some aspects, R3is optionally substituted C3-C8 cycloalkyl. In some aspects, R3is optionally substituted C3-C6 cycloalkyl. In some aspects, R3is optionally substituted C3 cycloalkyl. In some aspects, R3is optionally substituted C4 cycloalkyl. In some aspects, R3is optionally substituted Cs cycloalkyl. In some aspects, R3is optionally substituted Ce cycloalkyl. In some aspects, R3is optionally substituted cyclopropyl. In some aspects, R3is optionally substituted cyclobutyl. In some aspects, R3is optionally substituted cyclopentyl. In some aspects, R3is optionally substituted cyclohexyl. In some aspects, R3is any cycloalkyl group as defined and disclosed herein.

[0601] In some aspects, R3is optionally substituted heterocycle. In some aspects, R3is optionally substituted 3- to 14-membered heterocycle. In some aspects, R3is optionally substituted 3- to 10-membered heterocycle. In some aspects, R3is optionally substituted 3- to 6-membered heterocycle. In some aspects, R3is optionally substituted 3-membered heterocycle. In some aspects, R3is optionally substituted 4-membered heterocycle. In some aspects, R3is optionally substituted 5-membered heterocycle. In some aspects, R3isoptionally substituted 6-membered heterocycle. In some aspects, R3is any heterocyclo group as defined and disclosed herein.

[0602] In some aspects, R3is optionally substituted aryl. In some aspects, R3is optionally substituted C4-C16 aryl. In some aspects, R3is optionally substituted C4-C12 aryl. In some aspects, R3is optionally substituted C4-C10 aryl. In some aspects, R3is optionally substituted C4-C6 aryl. In some aspects, R3is optionally substituted Ce aryl. In some aspects, R3is optionally substituted phenyl. In some aspects, R3is any aryl group as defined and disclosed herein.

[0603] In some aspects, R3is optionally substituted heteroaryl. In some aspects, R3is optionally substituted 3- to 14-membered heteroaryl. In some aspects, R3is optionally substituted 3- to 10-membered heteroaryl. In some aspects, R3is optionally substituted 3- to 6-membered heteroaryl. In some aspects, R3is optionally substituted 3-membered heteroaryl. In some aspects, R3is optionally substituted 4-membered heteroaryl. In some aspects, R3is optionally substituted 5-membered heteroaryl. In some aspects, R3is optionally substituted 6-membered heteroaryl. In some aspects, R3is any heteroaryl group as defined and disclosed herein.O|R4AD3

[0604] In some aspects, the Pro-Moiety is O R.

[0605] In some aspects, R4is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl. R4is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl.

[0606] In some aspects, R4is optionally substituted alkyl. In some aspects, R4is optionally substituted C1-C12 alkyl. In some aspects, R4is optionally substituted Ci-Cs alkyl. In some aspects, R4is optionally substituted C1-C4 alkyl. In some aspects, R4is optionally substituted Ci alkyl. In some aspects, R4is optionally substituted C2 alkyl. In some aspects, R4is optionally substituted C3 alkyl. In some aspects, R4is optionally substituted C4 alkyl. In some aspects, R4is any alkyl group as defined and disclosed herein.

[0607] In some aspects, R4is optionally substituted alkenyl. In some aspects, R4is optionally substituted C2-C12 alkenyl. In some aspects, R4is optionally substituted C2-C8 alkenyl. In some aspects, R4is optionally substituted C2-C4 alkenyl. In some aspects, R4is optionally substituted C2 alkenyl. In some aspects, R4is optionally substituted C3 alkenyl. Insome aspects, R4is optionally substituted C4 alkenyl. In some aspects, R4is optionally substituted C5 alkenyl. In some aspects, R4is optionally substituted Ce alkenyl. In some aspects, R4is any alkenyl group as defined and disclosed herein.

[0608] In some aspects, R4is optionally substituted alkynyl. In some aspects, R4is optionally substituted C2-C12 alkynyl. In some aspects, R4is optionally substituted C2-C8 alkynyl. In some aspects, R4is optionally substituted C2-C4 alkynyl. In some aspects, R4is optionally substituted C2 alkynyl. In some aspects, R4is optionally substituted C3 alkynyl. In some aspects, R4is optionally substituted C4 alkynyl. In some aspects, R4is optionally substituted Cs alkynyl. In some aspects, R4is optionally substituted Ce alkynyl. In some aspects, R4is any alkynyl group as defined and disclosed herein.O

[0609] In some aspects, the Pro-Moiety is O O

[0610] In some aspects, R5is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. In some aspects, R5is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl.

[0611] In some aspects, R5is optionally substituted alkyl. In some aspects, R5is optionally substituted C1-C12 alkyl. In some aspects, R5is optionally substituted Ci-Cs alkyl. In some aspects, R5is optionally substituted C1-C4 alkyl. In some aspects, R5is optionally substituted Ci alkyl. In some aspects, R5is optionally substituted C2 alkyl. In some aspects, R5is optionally substituted C3 alkyl. In some aspects, R5is optionally substituted C4 alkyl. In some aspects, R5is any alkyl group as defined and disclosed herein.

[0612] In some aspects, R5is optionally substituted alkenyl. In some aspects, R5is optionally substituted C2-C12 alkenyl. In some aspects, R5is optionally substituted C2-C8 alkenyl. In some aspects, R5is optionally substituted C2-C4 alkenyl. In some aspects, R5is optionally substituted C2 alkenyl. In some aspects, R5is optionally substituted C3 alkenyl. In some aspects, R5is optionally substituted C4 alkenyl. In some aspects, R5is optionally substituted Cs alkenyl. In some aspects, R5is optionally substituted Ce alkenyl. In some aspects, R5is any alkenyl group as defined and disclosed herein.

[0613] In some aspects, R5is optionally substituted alkynyl. In some aspects, R5is optionally substituted C2-C12 alkynyl. In some aspects, R5is optionally substituted C2-C8 alkynyl. In some aspects, R5is optionally substituted C2-C4 alkynyl. In some aspects, R5is optionally substituted C2 alkynyl. In some aspects, R5is optionally substituted C3 alkynyl. In some aspects, R5is optionally substituted C4 alkynyl. In some aspects, R5is optionally substituted Cs alkynyl. In some aspects, R5is optionally substituted Ce alkynyl. In some aspects, R5is any alkynyl group as defined and disclosed herein.

[0614] In some aspects, R5is optionally substituted cycloalkyl. In some aspects, R5is optionally substituted C3-C16 cycloalkyl. In some aspects, R5is optionally substituted C3-C12 cycloalkyl. In some aspects, R5is optionally substituted C3-C8 cycloalkyl. In some aspects, R5is optionally substituted C3-C6 cycloalkyl. In some aspects, R5is optionally substituted C3 cycloalkyl. In some aspects, R5is optionally substituted C4 cycloalkyl. In some aspects, R5is optionally substituted Cs cycloalkyl. In some aspects, R5is optionally substituted Ce cycloalkyl. In some aspects, R5is optionally substituted cyclopropyl. In some aspects, R5is optionally substituted cyclobutyl. In some aspects, R5is optionally substituted cyclopentyl. In some aspects, R5is optionally substituted cyclohexyl. In some aspects, R5is any cycloalkyl group as defined and disclosed herein.

[0615] In some aspects, R3is optionally substituted heterocycle. In some aspects, R5is optionally substituted 3- to 14-membered heterocycle. In some aspects, R5is optionally substituted 3- to 10-membered heterocycle. In some aspects, R5is optionally substituted 3- to 6-membered heterocycle. In some aspects, R5is optionally substituted 3-membered heterocycle. In some aspects, R5is optionally substituted 4-membered heterocycle. In some aspects, R5is optionally substituted 5-membered heterocycle. In some aspects, R5is optionally substituted 6-membered heterocycle. In some aspects, R5is any heterocyclo group as defined and disclosed herein.

[0616] In some aspects, R5is optionally substituted aryl. In some aspects, R5is optionally substituted C4-C16 aryl. In some aspects, R5is optionally substituted C4-C12 aryl. In some aspects, R5is optionally substituted C4-C10 aryl. In some aspects, R5is optionally substituted C4-C6 aryl. In some aspects, R5is optionally substituted Ce aryl. In some aspects, R5is optionally substituted phenyl. In some aspects, R5is any aryl group as defined and disclosed herein.

[0617] In some aspects, R5is optionally substituted heteroaryl. In some aspects, R5is optionally substituted 3- to 14-membered heteroaryl. In some aspects, R5is optionally substituted 3- to 10-membered heteroaryl. In some aspects, R5is optionally substituted 3- to 6-membered heteroaryl. In some aspects, R5is optionally substituted 3-membered heteroaryl. In some aspects, R5is optionally substituted 4-membered heteroaryl. In some aspects, R5is optionally substituted 5-membered heteroaryl. In some aspects, R5is optionally substituted 6-membered heteroaryl. In some aspects, R5is any heteroaryl group as defined and disclosed herein.O

[0618] In some aspects, the Pro-Moiety is R7

[0619] In some aspects, R6and R7are each selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl. In some aspects, R6and R7are each selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, and optionally substituted C3- Cs cycloalkyl. In some aspects, R6is both hydrogen. In some aspects, R7is hydrogen. In some aspects, R6and R7are both hydrogen.

[0620] In some aspects, R6or R7, or both R6and R7, are optionally substituted alkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C1-C12 alkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted Ci-Cs alkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C1-C4 alkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted Ci alkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C2 alkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C3 alkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C4 alkyl. In some aspects, R6or R7, or both R6and R7, are any alkyl group as defined and disclosed herein.

[0621] In some aspects, R6or R7, or both R6and R7, are optionally substituted alkenyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C2-C12 alkenyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C2-C8 alkenyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C2-C4 alkenyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C2 alkenyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C3 alkenyl. In some aspects, R6or R7,or both R6and R7, are optionally substituted C4 alkenyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C5 alkenyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted Ce alkenyl. In some aspects, R6or R7, or both R6and R7, are any alkenyl group as defined and disclosed herein.

[0622] In some aspects, R6or R7, or both R6and R7, are optionally substituted alkynyl.In some aspects, R6or R7, or both R6and R7, are optionally substituted C2-C12 alkynyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C2-C8 alkynyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C2-C4 alkynyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C2 alkynyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C3 alkynyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C4 alkynyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted Cs alkynyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted Ce alkynyl. In some aspects, R6or R7, or both R6and R7, are any alkynyl group as defined and disclosed herein.

[0623] In some aspects, R6or R7, or both R6and R7, are optionally substituted cycloalkyl.In some aspects, R6or R7, or both R6and R7, are optionally substituted C3-C16 cycloalkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C3-C12 cycloalkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C3-C8 cycloalkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C3-C6 cycloalkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C3 cycloalkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted C4 cycloalkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted Cs cycloalkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted Ce cycloalkyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted cyclopropyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted cyclobutyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted cyclopentyl. In some aspects, R6or R7, or both R6and R7, are optionally substituted cyclohexyl. In some aspects, R6or R7, or both R6and R7, are any cycloalkyl group as defined and disclosed herein.

[0624] In some aspects, R6and R7are taken together with nitrogen to which they are attached to form an optionally substituted heterocycle or an optionally substituted heteroaryl. In some aspects, R6and R7are taken together with nitrogen to which they are attached to form an optionally substituted heterocycle. In some aspects, the heterocycle is an optionallysubstituted 3- to 14-membered heterocycle. In some aspects, the heterocycle is an optionally substituted 3- to 10-membered heterocycle. In some aspects, the heterocycle is an optionally substituted 3- to 6-membered heterocycle. In some aspects, the heterocycle is an optionally substituted 3-membered heterocycle. In some aspects, the heterocycle is an optionally substituted 4-membered heterocycle. In some aspects, the heterocycle is an optionally substituted 5-membered heterocycle. In some aspects, the heterocycle is an optionally substituted 6-membered heterocycle. In some aspects, the heterocycle is any heterocycle group as defined and disclosed herein.

[0625] In some aspects, R6and R7are taken together with nitrogen to which they are attached to form an optionally substituted heteroaryl. In some aspects, the heteroaryl is an optionally substituted 3- to 14-membered heteroaryl. In some aspects, the heteroaryl is an optionally substituted 3- to 10-membered heteroaryl. In some aspects, the heteroaryl is an optionally substituted 3- to 6-membered heteroaryl. In some aspects, the heteroaryl is an optionally substituted 3-membered heteroaryl. In some aspects, the heteroaryl is an optionally substituted 4-membered heteroaryl. In some aspects, the heteroaryl is an optionally substituted 5-membered heteroaryl. In some aspects, the heteroaryl is an optionally substituted 6-membered heteroaryl. In some aspects, the heteroaryl is any heteroaryl group as defined and disclosed herein.

[0626] In some aspects, the Pro-Moiety is

[0627] In some aspects, R8is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. In some aspects, R8is selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl. In some aspects, R8is hydrogen.

[0628] In some aspects, R8is optionally substituted alkyl. In some aspects, R8is optionally substituted C1-C12 alkyl. In some aspects, R8is optionally substituted Ci-Cs alkyl. In some aspects, R8is optionally substituted C1-C4 alkyl. In some aspects, R8is optionally substituted Ci alkyl. In some aspects, R8is optionally substituted C2 alkyl. In some aspects,R8is optionally substituted C3 alkyl. In some aspects, R8is optionally substituted C4 alkyl. In some aspects, R8is any alkyl group as defined and disclosed herein.

[0629] In some aspects, R8is optionally substituted alkenyl. In some aspects, R8is optionally substituted C2-C12 alkenyl. In some aspects, R8is optionally substituted C2-C8 alkenyl. In some aspects, R8is optionally substituted C2-C4 alkenyl. In some aspects, R8is optionally substituted C2 alkenyl. In some aspects, R8is optionally substituted C3 alkenyl. In some aspects, R8is optionally substituted C4 alkenyl. In some aspects, R8is optionally substituted Cs alkenyl. In some aspects, R8is optionally substituted Ce alkenyl. In some aspects, R8is any alkenyl group as defined and disclosed herein.

[0630] In some aspects, R8is optionally substituted alkynyl. In some aspects, R8is optionally substituted C2-C12 alkynyl. In some aspects, R8is optionally substituted C2-C8 alkynyl. In some aspects, R8is optionally substituted C2-C4 alkynyl. In some aspects, R8is optionally substituted C2 alkynyl. In some aspects, R8is optionally substituted C3 alkynyl. In some aspects, R8is optionally substituted C4 alkynyl. In some aspects, R8is optionally substituted Cs alkynyl. In some aspects, R8is optionally substituted Ce alkynyl. In some aspects, R8is any alkynyl group as defined and disclosed herein.

[0631] In some aspects, R8is optionally substituted cycloalkyl. In some aspects, R8is optionally substituted C3-C16 cycloalkyl. In some aspects, R8is optionally substituted C3-C12 cycloalkyl. In some aspects, R8is optionally substituted C3-C8 cycloalkyl. In some aspects, R8is optionally substituted C3-C6 cycloalkyl. In some aspects, R8is optionally substituted C3 cycloalkyl. In some aspects, R8is optionally substituted C4 cycloalkyl. In some aspects, R8is optionally substituted Cs cycloalkyl. In some aspects, R8is optionally substituted Ce cycloalkyl. In some aspects, R8is optionally substituted cyclopropyl. In some aspects, R8is optionally substituted cyclobutyl. In some aspects, R8is optionally substituted cyclopentyl. In some aspects, R8is optionally substituted cyclohexyl. In some aspects, R8is any cycloalkyl group as defined and disclosed herein.

[0632] In some aspects, R8is optionally substituted heterocycle. In some aspects, R8is optionally substituted 3- to 14-membered heterocycle. In some aspects, R8is optionally substituted 3- to 10-membered heterocycle. In some aspects, R8is optionally substituted 3- to 6-membered heterocycle. In some aspects, R8is optionally substituted 3-membered heterocycle. In some aspects, R8is optionally substituted 4-membered heterocycle. In some aspects, R8is optionally substituted 5-membered heterocycle. In some aspects, R8isoptionally substituted 6-membered heterocycle. In some aspects, R8is any heterocyclo group as defined and disclosed herein.

[0633] In some aspects, R8is optionally substituted aryl. In some aspects, R8is optionally substituted C4-C16 aryl. In some aspects, R8is optionally substituted C4-C12 aryl. In some aspects, R8is optionally substituted C4-C10 aryl. In some aspects, R8is optionally substituted C4-C6 aryl. In some aspects, R8is optionally substituted Ce aryl. In some aspects, R8is optionally substituted phenyl. In some aspects, R8is any aryl group as defined and disclosed herein.

[0634] In some aspects, R8is optionally substituted heteroaryl. In some aspects, R8is optionally substituted 3- to 14-membered heteroaryl. In some aspects, R8is optionally substituted 3- to 10-membered heteroaryl. In some aspects, R8is optionally substituted 3- to 6-membered heteroaryl. In some aspects, R8is optionally substituted 3-membered heteroaryl. In some aspects, R8is optionally substituted 4-membered heteroaryl. In some aspects, R8is optionally substituted 5-membered heteroaryl. In some aspects, R8is optionally substituted 6-membered heteroaryl. In some aspects, R8is any heteroaryl group as defined and disclosed herein.

[0635] In some aspects, the Pro-Moiety is phosphoryl, phosphate, phosphoramidate, optionally substituted Ci-Cs alkyl phosphate, sulfonate, sulfonyl, alkyl sulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; and cholesterol.

[0636] In some aspects, the Pro-Moiety is phosphoryl. In some aspects, the Pro-Moiety is any phosphoryl group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is phosphate. In some aspects, the Pro-Moiety is any phosphate group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is phosphoramidate. In some aspects, the Pro-Moiety is any phosphoramidate group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is sulfonate. In some aspects, the Pro-Moiety is any sulfonate group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is sulfonyl. In some aspects, the Pro-Moiety is any sulfonyl group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is alkyl sulfonyl. In some aspects, the Pro-Moiety is any alkylsulfonyl group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is a lipid. In some aspects, the Pro-Moiety is any lipid group as defined and disclosed herein and knownto a skilled artisan. In some aspects, the Pro-Moiety is a phospholipid. In some aspects, the Pro-Moiety is any phospholipid group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is an amino acid. In some aspects, the Pro-Moiety is any amino acid group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is a carbohydrate. In some aspects, the Pro-Moiety is any carbohydrate group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is a peptide. In some aspects, the Pro-Moiety is any peptide group as defined and disclosed herein and known to a skilled artisan. In some aspects, the Pro-Moiety is cholesterol. In some aspects, the Pro-Moiety is any cholesterol group as defined and disclosed herein and known to a skilled artisan.

[0637] In some aspects, the R1, R2, R3, R4, R5, R6, R7, and R8groups are unsubstituted.

[0638] In some aspects, one or more of the R1, R2, R3, R4, R5, R6, R7, and / or R8groups are optionally substituted. In some aspects, the optional substituents on R1, R2, R3, R4, R5, R6, R7, and / or R8are independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carb oxami do)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl,(Ci-4haloalkoxy)alkyl, and (heteroaryl)alkyl.

[0639] In some aspects, the optional substituents on R1, R2, R3, R4, R5, R6, R7, and / or R8are independently selected from the group consisting of hydroxy, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (Ci-4haloalkoxy)alkyl, and (heteroaryl)alkyl.

[0640] In some aspects, the optional substituents on one or more of R1, R2, R3, R4, R5, R6, R7, and / or R8are independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, (Ci-Ce) alkylamino, di-(Ci-Ce) alkylamino, halo (Ci-Ce) alkyl, hydroxy (Ci- Ce) alkyl, Ci-Ce alkoxy, halo (Ci-Ce) alkoxy, aryloxy, heteroaryloxy, ar-(Ci-Ce) alkyl, ar-(Ci- Ce) alkyloxy, (Ci-Ce) alkylthio, carboxamido, sulfonamido, (Ci-Ce) alkylcarbonyl, arylcarbonyl, (Ci-Ce) alkylsulfonyl, arylsulfonyl, carboxy, carboxy-(Ci-Ce) alkyl, Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, optionally substituted C4-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy-(Ci-Ce) alkyl, (amino)-(Ci-Ce) alkyl, hydroxy-(Ci-Ce) alkylamino, (alkylamino)-(Ci- Ce) alkyl, (dialkylamino)-(Ci-C6)alkyl, (cyano)-(Ci-Ce)alkyl, (carboxamido)-(Ci-Ce) alkyl, mercapto-(Ci-Ce) alkyl, (heterocyclo)-(Ci-Ce)alkyl, (cycloalkylamino)-(Ci-C6)alkyl, (Ci-4haloalkoxy)-(Ci-Ce) alkyl, and (heteroaryl)-(Ci-Ce) alkyl.

[0641] In some aspects, the optional substituents on one or more of R1, R2, R3, R4, R5, R6, R7, and / or R8are independently selected from the group consisting of hydroxy, (Ci-Ce) alkylamino, di-(Ci-Ce) alkylamino, halo (Ci-Ce) alkyl, hydroxy (Ci-Ce) alkyl, Ci-Ce alkoxy, halo (Ci-Ce) alkoxy, aryloxy, heteroaryloxy, ar-(Ci-Ce) alkyl, ar-(Ci-Ce) alkyloxy, (Ci-Ce) alkylthio, carboxamido, sulfonamido, (Ci-Ce) alkylcarbonyl, arylcarbonyl, (Ci-Ce) alkylsulfonyl, arylsulfonyl, carboxy, carboxy-(Ci-Ce) alkyl, Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, optionally substituted C4-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy-(Ci-Ce) alkyl, (amino)-(Ci-Ce) alkyl, hydroxy-(Ci-Ce) alkylamino, (alkylamino)-(Ci-Ce) alkyl, (dialkylamino)-(Ci-C6)alkyl, (cyano)-(Ci-Ce)alkyl, (carboxamido)-(Ci-Ce) alkyl, mercapto- (Ci-Ce) alkyl, (heterocyclo)-(Ci-Ce)alkyl, (cycloalkylamino)-(Ci-C6)alkyl, (Ci-4haloalkoxy)- (Ci-Ce) alkyl, and (heteroaryl)-(Ci-Ce) alkyl.

[0642] In some aspects, the optional substituents on R1, R2, R3, R4, R5, R6, R7, and / or R8are independently any of the above listed groups as defined and disclosed herein and known to a skilled artisan.o

[0643] In some aspects, R1is selected from the group consisting ofR3andO, and R2is not present. In some aspects, R1is selected from the groupconsistingpresent.

[0644] In some aspects, R3is selected from the group consisting of optionally substituted Ci-Cs alkyl and optionally substituted heteroaryl. In some aspects, R3is a heteroaryl containing one or more nitrogen atoms. In some aspects, R3is a heteroaryl containing one or more oxygen atoms. In some aspects, R3is a heteroaryl containing one or more sulfur atoms. In some aspects, R3is a 5-membered heteroaryl. In some aspects, R3is a 6-membered heteroaryl. In some aspects, R3is an imidazole. In some aspects, R3is an pyrrole. In some aspects, R3is a triazole. In some aspects, R3is a tetrazole. In some aspects, R3is a thiazole. In some aspects, R3is a thiophene. In some aspects, R3is a thiadiazole. In some aspects, R3is a furan. In some aspects, R3is an oxazole. In some aspects, R3is an oxadiazole. In some aspects, R3is a heteroaryl as defined and disclosed herein and known to a skilled artisan.

[0645] In some aspects, R3is an optionally substituted Ci-Cs alkyl. In some aspects, R3is an optionally substituted C1-C4 alkyl. In some aspects, R3is an optionally substituted C4 alkyl. In some aspects, R3is an amine substituted C4 alkyl.

[0646] In some aspects R4is an optionally substituted Ci-Cs alkyl. In some aspects R4is an optionally substituted C1-C4 alkyl. In some aspects R4is an optionally substituted Ci alkyl. In some aspects R4is an optionally substituted C2 alkyl. In some aspects R4is an optionally substituted C3 alkyl. In some aspects R4is an optionally substituted C4 alkyl. In some aspects R4is a methylene group.

[0647] In some aspects R5is an optionally substituted Ci-Cs alkyl. In some aspects R5is an optionally substituted C1-C4 alkyl. In some aspects R5is an optionally substituted Ci alkyl. In some aspects R5is an optionally substituted C2 alkyl. In some aspects R5is an optionally substituted C3 alkyl. In some aspects R5is an optionally substituted C4 alkyl. In some aspects R5is a methyl group.- Ill -

[0648] In some aspects, R1is selected from the group consisting

[0649] In some aspects, R1is selected from the group consistingO

[0650] In some aspects, R2is selected from the group consisting ofand 0,

[0651] In some aspects, R2is selected from the group consisting of phosphoryl and an optionally substituted alkyl phosphate. In some aspects, R2is a phosphoryl group. In someaspects, R2is an optionally substituted Ci-Cs alkyl phosphate. In some aspects, R2is an optionally substituted C1-C4 alkyl phosphate. In some aspects, R2is an optionally substituted C1-C2 alkyl phosphate. In some aspects, R2is an optionally substituted Ci alkyl phosphate. In some aspects, R2is an optionally substituted C2 alkyl phosphate. In some aspects, R2is an optionally substituted C3 alkyl phosphate. In some aspects, R2is an optionally substituted C4 alkyl phosphate. In some aspects, R2is methylene group. In some aspects, R2is

[0652] In some aspects, R1and R2together with the atoms to which they are attached form an optionally substituted 3 to 14-membered heterocycle. In some aspects, R1and R2together with the atoms to which they are attached form an optionally substituted 3 to 10- membered heterocycle. In some aspects, R1and R2together with the atoms to which they are attached form an optionally substituted 6 to 10-membered heterocycle. In some aspects, the heterocycle is as defined and disclosed herein and known to a skilled artisan. In some aspects, the 3 to 14-membered heterocycle is optionally substituted with one or more of the optional substitutents disclosed herein. In some aspects, the optional substituents on the 3 to 14-membered heterocycle are independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, (Ci-Ce) alkylamino, di-(Ci-Ce) alkylamino, halo (Ci-Ce) alkyl, hydroxy (Ci-Ce) alkyl, Ci-Ce alkoxy, halo (Ci-Ce) alkoxy, aryloxy, heteroaryloxy, ar- (Ci-Ce) alkyl, ar-(Ci-Ce) alkyloxy, (Ci-Ce) alkylthio, carboxamido, sulfonamido, (Ci-Ce) alkylcarbonyl, arylcarbonyl, (Ci-Ce) alkylsulfonyl, arylsulfonyl, carboxy, carboxy-(Ci-Ce) alkyl, Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, optionally substituted C4-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxy-(Ci-Ce) alkyl, (amino)-(Ci-Ce) alkyl, hydroxy-(Ci-Ce) alkylamino, (alkylamino)-(Ci-Ce) alkyl, (dialkylamino)-(Ci-C6)alkyl, (cyano)-(Ci-Ce)alkyl, (carboxamido)-(Ci-Ce) alkyl, mercapto-(Ci-Ce) alkyl, (heterocyclo)-(Ci-Ce)alkyl, (cycloalkylamino)-(Ci-C6)alkyl, (Ci-4haloalkoxy)-(Ci-Ce) alkyl, and (heteroaryl)-(Ci-Ce) alkyl. In some aspects, the optional substituent is a carbonyl group.

[0653] In some aspects, the compound of Formula (III) is a compound having Formula (IV):or a pharmaceutically acceptable salt or solvate thereof. In some aspects, X' is a pharmaceutically acceptable anion as defined and disclosed herein, and known to a skilled artisan.

[0654] In some aspects, the compound of Formula (III) is a compound having a Formula (V):or a pharmaceutically acceptable salt or solvate thereof. In some aspects, R1and R2are as defined and disclosed herein. In some aspects, X' is a pharmaceutically acceptable anion as defined and disclosed herein, and known to a skilled artisan.

[0655] In one aspect, the present disclosure provides a prodrug of BTC. In another aspect, the BTC is racemic. In another aspect, the present disclosure provides a prodrug of (R)-BTC. In another aspect, the present disclosure provides a prodrug of (S)-BTC.

[0656] In one aspect, the present disclosure provides a compound of Formula (VI):or a pharmaceutically acceptable salt or solvate thereof,whereinX' is either not present, or is a pharmaceutically acceptable anion; andR9is a Pro-Moiety;R10is selected from the group consisting of hydrogen, hydroxy, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, and a Pro-Moiety.

[0657] In some aspects, X' is not present. In some aspects, X' is a pharmaceutically acceptable anion as defined and disclosed herein and known to a skilled artisan. In some aspects, X~ is a chloride.

[0658] In some aspects, R9is a Pro-Moiety as defined and disclosed herein and known to a skilled artisan.

[0659] In some aspects, R10is a Pro-Moiety as defined and disclosed herein and known to a skilled artisan.

[0660] In some aspects, R10is selected from the group consisting of hydrogen, hydroxy, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl. In some aspects, R10is hydrogen. In some aspects, R10is hydroxy. In some aspects, R10is an optionally substituted Ci-Cs alkyl. In some aspects, R10is an optionally substituted C2-C8 alkenyl. In some aspects, R10is an optionally substituted C2-C8 alkynyl. In some aspects, the alkyl group, the alkenyl group, and the alkynyl group are alkyl, alkenyl, and alkynyl groups as defined and disclosed herein and known to a skilled artisan.

[0661] In some aspects, the Pro-Moieties are independently selected from the group Oconsisting of, , , phosphoryl, phosphate, phosphoramidate, optionally substituted Ci-Cs alkyl phosphate, sulfonate, sulfonyl, alkyl sulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; and cholesterol. In some aspects, the Pro-Moieties are independently selected from the group

[0662] In some aspects, R3is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. In some aspects, R3is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl. In some aspects, the the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclo group, the aryl group, and the heteroaryl group are alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclo, aryl, and heteroaryl groups as defined and disclosed herein and known to a skilled artisan.

[0663] In some aspects, R4is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl. In some aspects, R4is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl. In some aspects, the alkyl group, the alkenyl group, and the alkynyl group are alkyl, alkenyl, and alkynyl groups as defined and disclosed herein and known to a skilled artisan.

[0664] In some aspects, R5is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. In some aspects, R5is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl. In some aspects, the the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclo group, the aryl group, and the heteroaryl group are alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, and heteroaryl groups as defined and disclosed herein and known to a skilled artisan.

[0665] In some aspects, R6and R7are each selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted cycloalkyl. In some aspects, R6and R7are each selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, and optionally substituted C3- Cs cycloalkyl. In some aspects, R6and R7are both hydrogen. In some aspects, R6is hydrogen. In some aspects, R7is hydrogen. In some aspects, neither R6nor R7are hydrogen. In some aspects, the alkyl group, the alkenyl group, the alkynyl group, and the cycloalkyl group are alkyl, alkenyl, alkynyl, and cycloalkyl groups as defined and disclosed herein and known to a skilled artisan.

[0666] In some aspects, R6and R7are taken together with nitrogen to which they are attached to form an optionally substituted heterocycle or an optionally substituted heteroaryl.In some aspects, the heterocyclo group and the heteroaryl group are heterocyclo and heteroaryl groups as defined and disclosed herein and known to a skilled artisan.

[0667] In some aspects, R8is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. In some aspects, R8is selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl. In some aspects, R8is hydrogen. In some aspects, the the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclo group, the aryl group, and the heteroaryl group are alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, and heteroaryl groups as defined and disclosed herein and known to a skilled artisan.

[0668] In some aspects, one or more of R3, R4, R5, R8, R9, and R10are optionally substituted. In some aspects, the optional substituents on R3, R4, R5, R8, R9, and / or R10are independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkyl sulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (Ci-4haloalkoxy)alkyl, and (heteroaryl)alkyl.

[0669] In some aspects, one or more of R3, R4, R5, R8, R9, and R10are optionally substituted. In some aspects, the optional substituents on R3, R4, R5, R8, R9, and / or R10are independently selected from the group consisting of hydrogen, hydroxy, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (Ci-4haloalkoxy)alkyl, and (heteroaryl)alkyl.

[0670] In some aspects, the optional substituents on R3, R4, R5, R8, R9, and / or R10are independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, (Ci-Ce) alkylamino, di-(Ci-Ce) alkylamino, halo (Ci-Ce) alkyl, hydroxy (Ci-Ce) alkyl, Ci-Ce alkoxy, halo (Ci-Ce) alkoxy, aryloxy, heteroaryloxy, ar-(Ci-Ce) alkyl, ar-(Ci-Ce) alkyloxy, (Ci-Ce) alkylthio, carboxamido, sulfonamido, (Ci-Ce) alkylcarbonyl, arylcarbonyl, (Ci-Ce) alkyl sulfonyl, arylsulfonyl, carboxy, carboxy-(Ci-Ce) alkyl, Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, optionally substituted C4-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy-(Ci-Ce) alkyl, (amino)-(Ci-Ce) alkyl, hydroxy-(Ci-Ce) alkylamino, (alkylamino)-(Ci-Ce) alkyl, (dialkylamino)-(Ci-C6)alkyl, (cyano)-(Ci-Ce)alkyl, (carboxamido)-(Ci-Ce) alkyl, mercapto- (Ci-Ce) alkyl, (heterocyclo)-(Ci-Ce)alkyl, (cycloalkylamino)-(Ci-C6)alkyl, (Ci-4haloalkoxy)- (Ci-Ce) alkyl, and (heteroaryl)-(Ci-Ce) alkyl. In some aspects, the optional substituents on R3, R4, R5, R8, R9, and / or R10are independently any of the above listed groups as defined and disclosed herein and known to a skilled artisan.

[0671] In some aspects, the optional substituents on R3, R4, R5, R8, R9, and / or R10are independently selected from the group consisting of hydrogen, hydroxy, (Ci-Ce) alkylamino, di-(Ci-Ce) alkylamino, halo (Ci-Ce) alkyl, hydroxy (Ci-Ce) alkyl, Ci-Ce alkoxy, halo (Ci-Ce) alkoxy, aryloxy, heteroaryloxy, ar-(Ci-Ce) alkyl, ar-(Ci-Ce) alkyloxy, (Ci-Ce) alkylthio, carboxamido, sulfonamido, (Ci-Ce) alkylcarbonyl, arylcarbonyl, (Ci-Ce) alkylsulfonyl, arylsulfonyl, carboxy, carboxy-(Ci-Ce) alkyl, Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, optionally substituted C4-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy-(Ci-Ce) alkyl, (amino)-(Ci- Ce) alkyl, hydroxy-(Ci-Ce) alkylamino, (alkylamino)-(Ci-Ce) alkyl, (dialkylamino)-(Ci- Ce)alkyl, (cyano)-(Ci-Ce)alkyl, (carboxamido)-(Ci-Ce) alkyl, mercapto-(Ci-Ce) alkyl, (heterocyclo)-(Ci-Ce)alkyl, (cycloalkylamino)-(Ci-C6)alkyl, (Ci-4haloalkoxy)-(Ci-Ce) alkyl, and (heteroaryl)-(Ci-Ce) alkyl. In some aspects, the optional substituents on R3, R4, R5, R8, R9, and / or R10are independently any of the above listed groups as defined and disclosed herein and known to a skilled artisan.

[0672] In some aspects, R8is selected from the group consisting of hydrogen and optionally substituted Ci-Cs alkyl. In some aspects, R8is hydrogen. In some aspects, R8isCi-Cs alkyl. In some aspects, R8is Ci alkyl. In some aspects, R8is C2 alkyl. In some aspects, R8is C3 alkyl. In some aspects, R8is C4 alkyl.O-^-R4

[0673] In some aspects, R9is 'O O in some aspects, R4and R5are optionally substituted Ci-Cs alkyl. In some aspects, R4is an optionally substituted Ci alkyl. In some aspects, R4is an optionally substituted C2 alkyl. In some aspects, R4is an optionally substituted C3 alkyl. In some aspects, R4is an optionally substituted C4 alkyl. In some aspects, R4is a methylene group. In some aspects, R5is an optionally substituted Ci alkyl. In some aspects, R5is an optionally substituted C2 alkyl. In some aspects, R5is an optionally substituted C3 alkyl. In some aspects, R5is an optionally substituted C4 alkyl. In some aspects, R5is a methyl group.O~^~R4

[0674] In some aspects, R9is '0 R3. In some aspects, R4is an optionally substituted Ci-Cs alkyl. In some aspects, R4is an optionally substituted Ci alkyl. In some aspects, R4is an optionally substituted C2 alkyl. In some aspects, R4is an optionally substituted C3 alkyl. In some aspects, R4is an optionally substituted C4 alkyl. In some aspects, R4is a methylene group. In some aspects, R3is optionally substituted heteroaryl. In some aspects, the the heteroaryl group is a heteroaryl group as defined and disclosed herein and known to a skilled artisan.

[0675] In some aspects, R9is selected from the group consisting ofOH,O1 z"T- O O, and. In some aspects, R9is. in some aspects, R9is,

[0676] In some aspects, R10is selected from the group consisting of hydrogen, hydroxy, and phosphate. In some aspects, R10is hydrogen. In some aspects, R10is hydroxy. In some aspects, R10is phosphate.

[0677] In some aspects, X" is an anion selected from the group consisting of chloride, fluoride, bromide, and iodide.

[0678] In some aspects, the compound having Formula (VI) is a racemic mixture. In some aspects, the compound having Formula (VI) is enantioenriched with respect to the (R)isomer. In some aspects, the compound having Formula (VI) has an enantiomeric excess with respect to the (R) isomer of 75% or more, 85% or more, 90% or more, or 95% or more. In some aspects, the compound having Formula (VI) is enantioenriched with respect to the (S) isomer. In some aspects, the compound having Formula (VI) has an enantiomeric excess with respect to the (S) isomer of 75% or more, 85% or more, 90% or more, or 95% or more. The present disclosure encompasses all stereoisomers of the compound having Formula (VI) and mixtures thereof (e.g., a racemic mixture, an enantiomerically enriched mixture, an enantiomerically pure mixture, etc.).

[0679] In some aspects, a Compound of the Disclosure is a compound having Formula (IX) or Formula (X):or a pharmaceutically acceptable salt or solvate thereof. In some aspects, a Compound of the Disclosure is a compound having Formula (IX). In some aspects, a Compound of the Disclosure is a compound having Formula (X).

[0680] In some aspects, the pharmaceutically acceptable salt of any of the aspects disclosed herein is selected from the group consisting of a sodium salt, a potassium salt, a cesium salt, a calcium salt, a magnesium salt, a hydrochloride salt, a hydrobromide salt, a phosphate salt, a sulphate salt, a citrate salt, a lactate salt, a tartrate salt, a maleate salt, a fumarate salt, a mandelate salt, an acetate salt, a dichloroacetate salt, a trifluoroacetate salt, an oxalate salt, a formate salt, a tosylate salt, a mesylate salt, a besylate salt, a succinate salt, a benzoate salt, a malate salt, and a gluconate salt.

[0681] In some aspects, the pharmaceutically acceptable salt of any of the aspects disclosed herein is selected from the group consisting of a gluconate salt and a malate salt.

[0682] In some aspects, the prodrugs as disclosed herein can be prepared using methods and procedures as known in the art, see, e.g., Dhokchawle B. V., et al., Indian Journal of Pharmaceutical Education and Research 48:35-40 (2014); Stella, J Pharm Sci 109:3514- 3523 (2020); Najjar et al., Molecules 25:884 (2020), doi:10.3390 / molecules25040884, Fernandes et al., Viruses 15(11):2234; (2023), https: / / doi.org / 10.3390 / vl5112234; Huttunen et al., Pharmacol Rev 63:750-771 (2011); Markovic et al., Pharmaceutics 12:1031 (2020),doi:10.3390 / pharmaceuticsl2111031; WO 2019 / 200340; WO 2022 / 266237; US 10,577,381; US 11,672,775; US 9,226,932; and 10,780,174.VI. Deuterated Compounds

[0683] In another aspect, the present disclosure provides a deuterated analog of THP, or a pharmaceutically acceptable salt thereof. In some aspects, one or more hydrogen atoms on THP are replaced by a deuterium atom. The THP can be racemic or chiral. The deuterated analog of THP can also be racemic or chiral. In some aspects, the THP is (R)-THP. In some aspects, the THP is (S)-THP. In some aspects, the THP is racemic THP. In some aspects, the THP, (R)-THP, and the (S)-THP are in the form of a hydrochloride salt.

[0684] In another aspect, the present disclosure provides a deuterated analog of BTC, or a pharmaceutically acceptable salt thereof. In some aspects, one or more hydrogen atoms on BTC are replaced by a deuterium atom. The BTC can be racemic or chiral. The deuterated analog of BTC can be racemic or chiral. In some aspects, the BTC is (R)-BTC. In some aspects, the BTC is (S)-BTC. In some aspects, the BTC is racemic BTC. In some aspects, the BTC, (R)-BTC, and the (S)-BTC are in the form of a chloride salt.

[0685] In one aspect, the present disclosure provides deuterated analogs of any of the Compounds of the Disclosure as defined and disclosed herein. In some aspects, one or more hydrogen atoms of a compound, solid state form, and crystalline form as defined and disclosed herein is replaced by a deuterium atom. In some aspects, one hydrogen atom of a compound, solid state form, and crystalline form as defined and disclosed herein is replaced by a deuterium atom. In some aspects, more than one hydrogen atom of a compound, solid state form, and crystalline form as defined and disclosed herein is replaced by a deuterium atom.

[0686] In some aspects, the one or more hydrogen atoms are replaced by a deuterium atom as shown in the compound having Formula (VIII):wherein w is 0-4, x is 0-11, y is 0-10, z is 0-5, and the sum of w + x + y + z is at least one. In some aspects, w is 1. In some aspects, w is 2. In some aspects, w is 2 or more. In someaspects, x is 1. In some aspects, x is 2. In some aspects, x is 3. In some aspects, x is 4. In some aspects, x is 4 or more. In some aspects, y is 1. In some aspects, y is 2. In some aspects, y is 3. In some aspects, y is 4. In some aspects, y is 4 or more. In some aspects, z is 1. In some aspects, z is 2. In some aspects, z is 2 or more. In some aspects, the sum of w + x + y + z is 1. In some aspects, the sum of w + x + y + z is 2. In some aspects, the sum of w + x + y + z is 3. In some aspects, the sum ofw + x + y + z is 4 or more.

[0687] In some aspects, one or more hydrogen atoms on the piperidine ring of the compound having Structure (I) or Structure (II) are replaced by a deuterium atom. In some aspects, one or more hydrogen atoms on the cyclohexyl ring of the compound having Structure (I) or Structure (II) are replaced by a deuterium atom. In some aspects, one or more hydrogen atoms on the phenyl ring of the compound having Structure (I) or Structure (II) are replaced by a deuterium atom. In some aspects, one or more hydrogen atoms on the carbon chain of the compound having Structure (I) or Structure (II) are replaced by a deuterium atom. In some aspects, the hydrogen atom on the hydroxy group of the compound having Structure (I) or Structure (II) is replaced by a deuterium atom.

[0688] In another aspect, the present disclosure provides a deuterated analog of a compound having Formula (VI). In some aspects, one or more hydrogen atoms attached to a carbon atom in a compound having Formula (VI) are replaced by a deuterium atom. In some aspect, a hydrogen atom on a nitrogen atom of a compound having Formula (VI) is replaced by a deuterium atom. In some aspect, a hydrogen atom on an oxygen atom of a compound having Formula (VI) is replaced by a deuterium atom.VII. Pharmaceutical Compositions

[0689] In one aspect, the solid state forms, crystalline forms, compounds, and salts as disclosed herein, and mixtures thereof, can be administered to a mammal in the form of a raw chemical without any other components present, or they can also be administered to a mammal as part of a pharmaceutical composition containing the solid state form, crystalline form, compound, or salt combined with a suitable pharmaceutically acceptable carrier (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Such a carrier can be selected from pharmaceutically acceptable excipients and auxiliaries. The term"pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

[0690] In one aspect, the present disclosure provides a pharmaceutical composition comprising one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein and one or more pharmaceutically acceptable carriers or diluents.

[0691] In another aspects, the present disclosure provides a solid dosage form. In some aspects, the solid dosage form comprises one or more of the solid state forms, crystalline forms, mixtures, or compounds defined and disclosed herein. In some aspects, the solid dosage form comprises one or more pharmaceutically acceptable carriers or diluents. Solid dosage forms can include, but are not limited to, tablets, capsules, pills, granules, powders, sachets, chewables, and films. In some embodiments, the solid dosage form is for use in a method of treating a movement disorder.

[0692] In some aspects, the solid state forms, crystalline forms, mixtures, or compounds as disclosed herein, and mixtures thereof, may be administered to subjects via the oral, parenteral (such as subcutaneous, intravenous, intramuscular, intrasternal and infusion techniques), rectal, intranasal, topical or transdermal (e.g., through the use of a patch) routes.

[0693] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound having Structure (I), as disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0694] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound having Structure (II), as disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0695] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound having Formula (III), as disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0696] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound having Formula (IV), as disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0697] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound having Formula (V), as disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0698] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound having Formula (VI), as disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0699] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound having Structure (VII), as disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0700] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound having Formula (VIII), as disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0701] In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound as defined and disclosed herein and BTC, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0702] In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound as defined and disclosed herein and (R)-BTC, and optionally one or more pharmaceutically acceptable carriers or diluents. In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound as defined and disclosed herein and (S)-BTC, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0703] In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound as defined and disclosed herein and a compound having Structure (VII) as defined and disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0704] In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound as defined and disclosed herein and a compound having Structure (I) as defined and disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0705] In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound as defined and disclosed herein and a compound having Structure (II) as defined and disclosed herein, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0706] In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound as defined and disclosed herein and THP, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0707] In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound as defined and disclosed herein and (R)-THP, and optionally one or more pharmaceutically acceptable carriers or diluents. In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound as defined and disclosed herein and (S)-THP, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0708] In some aspects, the present disclosure provides a pharmaceutical composition comprising one or more of a solid state form having Structure (I) or Structure (II), a crystalline form having Structure (I) or Structure (II), a compound having Formula (III), a compound having Formula (IV), a compound having Formula (V), and a compound having Formula (VIII), and one or more of a compound havintg Formula (VI) and compound having Structure (VII), and optionally one or more pharmaceutically acceptable carriers or diluents.

[0709] In some aspects, the present disclosure provides a pharmaceutical composition comprising one or more of a solid state form having Structure (I) or Structure (II), a crystalline form having Structure (I) or Structure (II), a compound having Formula (III), a compound having Formula (IV), a compound having Formula (V), and a compound having Formula (VIII), and BTC, and optionally one or more pharmaceutically acceptable carriers or diluents.

[0710] In some aspects, the present disclosure provides a pharmaceutical composition comprising THP and one or more of a compound havintg Formula (VI) and compound having Structure (VII), and optionally one or more pharmaceutically acceptable carriers or diluents.

[0711] In some aspects, the pharmaceutical composition comprises a mixture of two or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein.

[0712] In some aspects, the pharmaceutical composition is an orally acceptable dosage form comprising one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein.

[0713] In some aspects, the orally acceptable dosage form can include, but is not limited to a tablet, a pill, a soft or hard gelatin capsule, a powder, a granulate, a microsphere, a lozenge, a powder sachet, and combinations thereof. In some aspects, the orally acceptable dosage form can include, but is not limited to, capsules, tablets, aqueous suspensions, and solutions. In some aspects, the orally acceptable dosage form can include, but is not limited to a gastroresistant capsule, an enteric coated capsule, a gastroresistant tablet, and an enteric coated tablet.

[0714] For oral administration, known carriers can be included in the pharmaceutical composition. For example, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably com, potato or tapioca starch), methylcellulose, alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia, can be included in a tablet. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred materials in this connection include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and / or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

[0715] In some embodiments, the pharmaceutical composition is a parenteral formulation comprising one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein.

[0716] In some embodiments, the pharmaceutical composition is a parenteral formulation comprising one or more of the solid state forms, crystalline forms, mixtures, or compounds asdefined and disclosed herein and an amorphous form of a compound as defined and disclosed herein.

[0717] For parenteral administration, solutions containing one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein can be prepared in either sesame or peanut oil, in aqueous propylene glycol, or in sterile water or saline. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0718] In some aspects, the pharmaceutical composition may be prepared as liquid suspension or solution using a liquid, such as an oil, water, an alcohol, and combinations of these.

[0719] In some aspects, the pharmaceutical composition may be prepared as a sterile injectable, which may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art.

[0720] In some aspects, the pharmaceutical composition may be administered in the form of suppositories for rectal administration.

[0721] In some aspects, the pharmaceutical composition may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment, lotion, or cream containing the active component suspended or dissolved in one or more carriers.

[0722] In some aspects, the pharmaceutical composition may also be administered ophthalmically and formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[0723] In some aspects, the pharmaceutical composition may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0724] In some aspects, the pharmaceutical compositions to be used for in vivo administration can be sterile. This is readily accomplished by filtration through, e.g., sterile filtration membranes.

[0725] Pharmaceutical compositions within the scope of the present disclosure include all compositions where one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein is combined with one or more pharmaceutically acceptable carriers or diluents. In one embodiment, one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein is present in the composition in an amount that is effective to achieve its intended therapeutic purpose.

[0726] Pharmaceutical compositions of the present disclosure can be administered to any patient that may experience the beneficial effects of one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein. Foremost among such patients are mammals, e.g., humans and companion animals, although the disclosure is not intended to be so limited. In one embodiment, the patient is a human.

[0727] In another aspect, the present disclosure provides kits which comprise one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein packaged in a manner that facilitates their use to practice methods of the present disclosure. In one aspect, the kit includes one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure. In one aspect, the composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration. In some aspects, the present disclosure provides a kit which comprises one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the solid state forms, crystalline forms, mixtures, or compounds as defined anddisclosed herein, or a pharmaceutically acceptable salt or solvate thereof, to a patient having a movement disorder.

[0728] In some aspects, the present disclosure provides a pharmaceutical composition comprising one or more of the solid state forms, crystalline forms, mixtures, or compounds as defined and disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent, wherein the pharmaceutical composition is for use in a method for treating a movement disorder.VIII. Formulations

[0729] The present disclosure further provides pharmaceutical formulations providing modified release of an active ingredient. In some aspects, the active ingredient is THP. In some aspects, the active ingredient is BTC. In some aspects, the pharmaceutical formulation comprises both THP and BTC.A. Formulation Comprising THP

[0730] In one aspect, the present disclosure provides a formulation comprising: (a) (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof. It is understood that (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II) is also referred to herein as trihexyphenidyl, THP, and / or (R)-THP. Also, within the scope of the present disclosure is trihexyphenidyl in any physical form (crystalline, amorphous, polymorphic, solvate, enantiomer, stereoisomer, deuterated, etc.). In some aspects, the THP is in the form of a pharmaceutically acceptable salt, hydrate, anhydrate, solvate, and / or deuterated form thereof.

[0731] In one aspect, the present disclosure provides a formulation comprising: (a) (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):or a pharmaceutically acceptable salt, hydrate, anhydrate, solvate, and / or deuterated form thereof, and (b) a modifying release agent.

[0732] In some aspects, the pharmaceutically acceptable salt is selected from the group consisting of the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, a maleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt. In some aspects, the pharmaceutically acceptable salt is a hydrochloride salt.

[0733] In some aspects, the total weight of the formulation includes the weight of all ingredients and components, including a coating (e.g., tablet plus coating). In some aspects, the total weight of the formulation includes the weight of all ingredients and components but does not include the weight of a coating (e.g., tablet without coating). The percent values disclosed herein can refer to either the total weight of the formulation including the weight of a coating, or the total weight of the formulation not including the weight of a coating.

[0734] In some aspects, the formulation comprising (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol (or THP or Compounds of the Disclosure) is administered separately from formulations comprising other active ingredients (e.g., BTC, or Compounds of the Di...

Claims

1. WE CLAIM:

1. A solid state form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):

4. 6.or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof.

2. The solid state form of claim 1, which is a pharmaceutically acceptable salt of (R)- l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II).

3. The solid state form of claim 2, wherein the pharmaceutically acceptable salt is selected from the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, a maleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt.

4. The solid state form of claim 3, wherein the pharmaceutically acceptable salt is selected from the group consisting of a maleate salt, a succinate salt, and a hydrochloride salt.

5. The solid state form of claim 4, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

6. The solid state form of claim 4, wherein the pharmaceutically acceptable salt is a maleate salt.

7. The solid state form of claim 4, wherein the pharmaceutically acceptable salt is a succinate salt.

8. The solid state form of any one of claims 1-7, wherein the (R)- 1 -cyclohexyl- 1- phenyl-3-(l-piperidyl)propan-l-ol, or a pharmaceutically acceptable salt thereof, is in an amorphous form, a co-crystal form, or a crystalline form.

9. A crystalline form of (R)-l-cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol having Structure (II):

15. 17.or a pharmaceutically acceptable salt thereof.

10. The crystalline form of claim 9, wherein the pharmaceutically acceptable salt is selected from the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, a maleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt.

11. The crystalline form of claim 9, wherein the (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol is a free base.

12. The crystalline form of claim 9, wherein the (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol is an anhydrate.

13. The crystalline form of claim 12, wherein the crystalline form is Free Base Form I.

14. The crystalline form of claim 13, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 13.0, 16.8, and 18.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

15. The crystalline form of claim 13, characterized by an XRPD pattern as shown in FIG. 1.

16. The crystalline form of any one of claims 13-15, characterized by an endothermic peak at about 118.54 °C, as determined by differential scanning calorimetry (DSC).

17. The crystalline form of any one claims 13-16, characterized by a DSC profile as shown in FIG. 2.

18. The crystalline form of any one of claims 13-17, characterized by an about 0.93 wt% loss between room temperature and about 100 °C, as determined by thermogravimetric analysis (TGA).

19. The crystalline form of any one of claims 13-18, characterized by a TGA profile as shown in FIG. 2.

20. The crystalline form of claim 11, wherein the crystalline form is Free Base Form II.

21. The crystalline form of claim 20, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.9, 17.1, and 17.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

22. The crystalline form of claim 20, characterized by an XRPD pattern as shown in FIG. 37.

23. The crystalline form of any one of claims 20-22, characterized by an endothermic peak at about 117.72 °C, as determined by differential scanning calorimetry (DSC).

24. The crystalline form of any one claims 20-23, characterized by a DSC profile as shown in FIG. 38.

25. The crystalline form of any one of claims 20-24, characterized by an about 1.54 wt% loss between room temperature and about 100 °C, as determined by thermogravimetric analysis (TGA).

26. The crystalline form of any one of claims 20-25, characterized by a TGA profile as shown in FIG. 38.

27. The crystalline form of claim 11, wherein the crystalline form is Free Base Form III.

28. The crystalline form of claim 27, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 8.4, 8.6, and 17.2 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

29. The crystalline form of claim 27, characterized by an XRPD pattern as shown in FIG. 39.

30. The crystalline form of any one of claims 27-29, characterized by an endothermic peak at about 119.11 °C, as determined by differential scanning calorimetry (DSC).

31. The crystalline form of any one claims 27-30, characterized by a DSC profile as shown in FIG. 40.

32. The crystalline form of any one of claims 27-31, characterized by an about 1.87 wt% loss between room temperature and about 100 °C, as determined by thermogravimetric analysis (TGA).

33. The crystalline form of any one of claims 27-32, characterized by a TGA profile as shown in FIG. 40.

34. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a sulfate salt.

35. The crystalline form of claim 34, wherein the crystalline form is Sulfate Form I.

36. The crystalline form of claim 35, characterized by an XRPD pattern having peaks at 6.6, 20.2, and 16.3 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

37. The crystalline form of claim 35, characterized by an XRPD pattern as shown in FIG. 3.

38. The crystalline form of any one of claims 35-37, characterized by an endothermic peak at about 160.58 °C, as determined by DSC.

39. The crystalline form of any one of claims 35-38, characterized by a DSC profile as shown in FIG. 4.

40. The crystalline form of any one of claims 35-39, characterized by an about 2.20 wt% loss between room temperature and about 150.0 °C, as determined by TGA.

41. The crystalline form of any one of claims 35-40, characterized by a TGA profile as shown in FIG. 4.

42. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a tosylate salt.

43. The crystalline form of claim 42, wherein the crystalline form is Tosylate Form I.

44. The crystalline form of claim 43, characterized by an XRPD pattern having peaks at 5.2, 8.6, and 22.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

45. The crystalline form of claim 43, characterized by an XRPD pattern as shown in FIG. 5.

46. The crystalline form of any one of claims 43-45, characterized by an endothermic peak at about 180.44 °C, as determined by DSC.

47. The crystalline form of any one of claims 43-46, characterized by a DSC profile as shown in FIG. 6.

48. The crystalline form of any one of claims 43-47, characterized by an about 3.02 wt% loss between room temperature and about 150.0 °C, as determined by TGA.

49. The crystalline form of any one of claims 43-48, characterized by a TGA profile as shown in FIG. 6.

50. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a mesylate salt.

51. The crystalline form of claim 50, wherein the crystalline form is Mesylate Form I.

52. The crystalline form of claim 51, characterized by an XRPD pattern having peaks at 5.5, 9.2, and 13.4 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

53. The crystalline form of claim 52, characterized by an XRPD pattern as shown in FIG. 7.

54. The crystalline form of any one of claims 51-53, characterized by an endothermic peak at about 183.60 °C, as determined by DSC.

55. The crystalline form of any one of claims 51-54, characterized by a DSC profile as shown in FIG. 8.

56. The crystalline form of any one of claims 51-55, characterized by an about 0.96 wt% loss between room temperature and about 150.0 °C, as determined by TGA.

57. The crystalline form of any one of claims 51-56, characterized by a TGA profile as shown in FIG. 8.

58. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a phosphate salt.

59. The crystalline form of claim 58, wherein the crystalline form is Phosphate Form I.

60. The crystalline form of claim 59, characterized by an XRPD pattern having peaks at 4.4, 10.1, and 20.5 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

61. The crystalline form of claim 59, characterized by an XRPD pattern as shown in FIG. 9.

62. The crystalline form of any one of claims 59-61, characterized by an endothermic peak at about 231.80 °C, as determined by DSC.

63. The crystalline form of any one of claims 59-62, characterized by a DSC profile as shown in FIG. 10.

64. The crystalline form of any one of claims 59-63, characterized by an about 0.12 wt% loss between room temperature and about 200.0 °C, as determined by TGA.

65. The crystalline form of any one of claims 59-64, characterized by a TGA profile as shown in FIG. 10.

66. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a maleate salt.

67. The crystalline form of claim 66, wherein the crystalline form is Maleate Form I.

68. The crystalline form of claim 67, characterized by an XRPD pattern having peaks at 12.7, 16.8, and 21.9 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

69. The crystalline form of claim 67, characterized by an XRPD pattern as shown in FIG. 11.

70. The crystalline form of any one of claims 67-69, characterized by an endothermic peak at about 173.23 °C, as determined by DSC.

71. The crystalline form of any one of claims 67-70, characterized by a DSC profile as shown in FIG. 12.

72. The crystalline form of any one of claims 67-71, characterized by an about 0.22 wt% loss between room temperature and about 150 °C, as determined by TGA.

73. The crystalline form of any one of claims 67-72, characterized by a TGA profile as shown in FIG. 12.

74. The crystalline form of claim 66, wherein the crystalline form is Maleate Form II.

75. The crystalline form of claim 74, characterized by an XRPD pattern having peaks at 8.8, 19.9, and 24.0 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

76. The crystalline form of claim 74, characterized by an XRPD pattern as shown in FIG. 11.

77. The crystalline form of any one of claims 74-76, characterized by an endothermic peak at about 168.29 °C and at about 173.00 °C, as determined by DSC.

78. The crystalline form of any one of claims 74-77, characterized by a DSC profile as shown in FIG. 13.

79. The crystalline form of any one of claims 74-78, characterized by an about 0.92 wt% loss between room temperature and about 150 °C, as determined by TGA.

80. The crystalline form of any one of claims 74-79, characterized by a TGA profile as shown in FIG. 13.

81. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a fumarate salt.

82. The crystalline form of claim 81, wherein the crystalline form is Fumarate Form I.

83. The crystalline form of claim 82, characterized by an XRPD pattern having peaks at 8.8, 19.5, and 20.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

84. The crystalline form of claim 82, characterized by an XRPD pattern as shown in FIG. 14.

85. The crystalline form of any one of claims 82-84, characterized by an endothermic peak at about 238.91 °C, as determined by DSC.

86. The crystalline form of any one of claims 82-85, characterized by a DSC profile as shown in FIG. 15.

87. The crystalline form of any one of claims 82-86, characterized by an about 1.18 wt% loss between room temperature and about 200.0 °C, as determined by TGA.

88. The crystalline form of any one of claims 82-87, characterized by a TGA profile as shown in FIG. 15.

89. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a malate salt.

90. The crystalline form of claim 89, wherein the (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol and the malate are present in a molar ratio of 1: 1 or 1:0.5.

91. The crystalline form of claim 89, wherein the (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol and the malate are present in a molar ratio of 1:0.5.

92. The crystalline form of claims 89 or 91, wherein the crystalline form is Hemi- Malate Form I.

93. The crystalline form of claim 92, characterized by an XRPD pattern having peaks at 9.4, 16.1, and 16.9 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

94. The crystalline form of claim 92, characterized by an XRPD pattern as shown in FIG. 16.

95. The crystalline form of any one of claims 92-94, characterized by an endothermic peak at about 163.69 °C, as determined by DSC.

96. The crystalline form of any one of claims 92-95, characterized by a DSC profile as shown in FIG. 17.

97. The crystalline form of any one of claims 92-96, characterized by an about 0.09 wt% loss between room temperature and about 150.0 °C, as determined by TGA.

98. The crystalline form of any one of claims 92-97, characterized by a TGA profile as shown in FIG. 17.

99. The crystalline form of claims 89 or 91, wherein the crystalline form is Hemi- Malate Form II.

100. The crystalline form of claim 99, characterized by an XRPD pattern having peaks at 8.7, 17.5, and 19.6 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

101. The crystalline form of claim 99, characterized by an XRPD pattern as shown in FIG. 16.

102. The crystalline form of any one of claims 99-101, characterized by an endothermic peak at about 137.64 °C, as determined by DSC.

103. The crystalline form of any one of claims 99-102, characterized by a DSC profile as shown in FIG. 18.

104. The crystalline form of any one of claims 99-103, characterized by an about 0.03 wt% loss between room temperature and about 120.0 °C, as determined by TGA.

105. The crystalline form of any one of claims 99-104, characterized by a TGA profile as shown in FIG. 18.

106. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a succinate salt.

107. The crystalline form of claim 106, wherein the (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol and the succinate are present in a molar ratio of 1: 1 or 1:0.5.

108. The crystalline form of claim 106, wherein the (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol and the succinate are present in a molar ratio of 1:0.5.

109. The crystalline form of claims 106 or 108, wherein the crystalline form is Hemi- Succinate Form I.

110. The crystalline form of claim 109, characterized by an XRPD pattern having peaks at 9.5, 16.4, and 17.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

111. The crystalline form of claim 109, characterized by an XRPD pattern as shown in FIG. 19.

112. The crystalline form of any one of claims 109-111, characterized by an endothermic peak at about 187.12 °C, as determined by DSC.

113. The crystalline form of any one of claims 109-112, characterized by a DSC profile as shown in FIG. 20.

114. The crystalline form of any one of claims 109-113, characterized by an about 1.83 wt% loss between room temperature and about 150.0 °C, as determined by TGA.

115. The crystalline form of any one of claims 109-114, characterized by a TGA profile as shown in FIG. 20.

116. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a benzoate salt.

117. The crystalline form of claim 116, wherein the crystalline form is Benzoate Form I.

118. The crystalline form of claim 117, characterized by an XRPD pattern having peaks at 8.4, 9.5, and 21.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

119. The crystalline form of claim 117, characterized by an XRPD pattern as shown in FIG. 21.

120. The crystalline form of any one of claims 117-119, characterized by an endothermic peak at about 103.92 °C, as determined by DSC.

121. The crystalline form of any one of claims 117-120, characterized by a DSC profile as shown in FIG. 22.

122. The crystalline form of any one of claims 117-121, characterized by an about 1.05 wt% loss between room temperature and about 90.0 °C, as determined by TGA.

123. The crystalline form of any one of claims 117-122, characterized by a TGA profile as shown in FIG. 22.

124. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a tartrate salt.

125. The crystalline form of claim 124, wherein the (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol and the tartrate are present in a molar ratio of 1: 1 or 1:0.5.

126. The crystalline form of claim 124, wherein the (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol and the tartrate are present in a molar ratio of 1:0.5.

127. The crystalline form of claims 124 or 126, wherein the crystalline form is HemiTartrate Form I.

128. The crystalline form of claim 127 characterized by an XRPD pattern having peaks at 8.4, 16.9, and 21.1 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

129. The crystalline form of claim 127, characterized by an XRPD pattern as shown in FIG. 23.

130. The crystalline form of any one of claims 127-129, characterized by an endothermic peak at about 138.71 °C, as determined by DSC.

131. The crystalline form of any one of claims 127-130, characterized by a DSC profile as shown in FIG. 24.

132. The crystalline form of any one of claims 127-131, characterized by an about 1.02 wt% loss between room temperature and about 100.0 °C, as determined by TGA.

133. The crystalline form of any one of claims 127-132, characterized by a TGA profile as shown in FIG. 24.

134. A mixture comprising the crystalline form of claim 127 and another crystalline form of a tartrate salt of (R)-l -cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol.

135. The mixture of claim 134, characterized by an XRPD pattern as shown in FIG. 23.

136. The mixture of claims 134 or 135, characterized by endothermic peaks at about 130.80 and at about 138.55 °C, as determined by DSC.

137. The mixture of any one of claims 134-136, characterized by a DSC profile as shown in FIG. 25.

138. The mixture of any one of claims 134-137, characterized by an about 0.66 wt% loss between room temperature and about 100.0 °C, as determined by TGA.

139. The mixture of any one of claims 134-138, characterized by a TGA profile as shown in FIG. 25.

140. The crystalline form of any one of claims 9, 10, or 12, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

141. The crystalline form of claim 140, wherein the crystalline form is HC1 Salt Form I.

142. The crystalline form of claim 141, characterized by an XRPD pattern having peaks at 5.8, 17.7, and 19.4 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

143. The crystalline form of claim 141, characterized by an XRPD pattern as shown in FIG. 26.

144. The crystalline form of any one of claims 141-143, characterized by an endothermic peak at about 282.92 °C, as determined by DSC.

145. The crystalline form of any one of claims 141-144, characterized by a DSC profile as shown in FIG. 27.

146. The crystalline form of any one of claims 141-145, characterized by an about 0.59 wt% loss between room temperature and about 100.0 °C, as determined by TGA.

147. The crystalline form of any one of claims 141-146, characterized by a TGA profile as shown in FIG. 27.

148. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 1 day of storage at 25 °C and 60 % relative humidity.

149. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 3 days of storage at 25 °C and 60 % relative humidity.

150. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 7 days of storage at 25 °C and 60 % relative humidity.

151. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 1 day of storage at 40 °C and 75 % relative humidity, and wherein impurities are detected at an amount of less than about 0.15 %.

152. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% e after about 3 days of storage at 40 °C and 75 % relative humidity, and wherein impurities are detected at an amount of less than about 0.15 %.

153. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 7 days of storage at 40 °C and 75 % relative humidity, and wherein impurities are detected at an amount of less than about 0.15 %.

154. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 1 day of storage at 80 °C and ambient % relative humidity.

155. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 3 days of storage at 80 °C and ambient % relative humidity.

156. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 7 days of storage at 80 °C and ambient % relative humidity.

157. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 1 day of storage at 80 °C and 75% relative humidity, and wherein impurities are detected at an amount of less than about 0.15 %.

158. The crystalline form of any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 3 days of storage at 80 °C and 75% relative humidity, and wherein impurities are detected at an amount of less than about 0.15 %.

159. The crystalline form of claims any one of claims 140-147, wherein the crystalline form has a purity level of about 100% after about 7 days of storage at 80 °C and 75% relative humidity, and wherein impurities are detected at an amount of less than about 0.15 %.

160. The solid state form or crystalline form of any one of the preceding claims, wherein the solid state form or crystalline form is substantially free of other polymorphic or physical forms.

161. The solid state form or crystalline form of any one of claims 1-11, wherein the solid state form or crystalline form is a hydrate, anhydrate, or solvate thereof.

162. A solid state form of bethanechol chloride having Structure (VII):

159. 161.or a pharmaceutically acceptable salt thereof.

163. The solid state form of claim 162, wherein the bethanechol chloride, or a pharmaceutically acceptable salt thereof, is in an amorphous form, a co-crystal form, or a crystalline form.

164. A crystalline form of bethanechol chloride having Structure (VII):163.H2NY O°Y1"1(VII),164.or a pharmaceutically acceptable salt thereof.

165. The crystalline form of claim 164, wherein the bethanechol chloride is an anhydrate.

166. The crystalline form of claim 164, wherein the bethanechol chloride is a hydrate.

167. The crystalline form of claim 164, wherein the crystalline form is Form II.

168. The crystalline form of claim 167, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 13.54, 16.38, and 21.87 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

169. The crystalline form of claim 167, characterized by an XRPD pattern as shown in FIG. 49.

170. The crystalline form of any one of claims 167-169, characterized by an endothermic peak at about 230.20 °C, as determined by differential scanning calorimetry (DSC).

171. The crystalline form of any one claims 167-170, characterized by a DSC profile as shown in FIG. 50.

172. The crystalline form of any one of claims 167-171, characterized by an about 4.23 wt% loss between room temperature and about 100 °C, as determined by thermogravimetric analysis (TGA).

173. The crystalline form of any one of claims 167-172, characterized by a TGA profile as shown in FIG. 50.

174. The crystalline form of claim 164, wherein the crystalline form is Form III.

175. The crystalline form of claim 174, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 15.25, 18.66, and 22.25 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

176. The crystalline form of claim 174, characterized by an XRPD pattern as shown in FIG. 51.

177. The crystalline form of any one of claims 174-176, characterized by an endothermic peak at about 226.56 °C, as determined by differential scanning calorimetry (DSC).

178. The crystalline form of any one claims 174-177, characterized by a DSC profile as shown in FIG. 52.

179. The crystalline form of any one of claims 174-178, characterized by an about 3.34 wt% loss between room temperature and about 200 °C, as determined by thermogravimetric analysis (TGA).

180. The crystalline form of any one of claims 174-179, characterized by a TGA profile as shown in FIG. 52.

181. The crystalline form of claim 164, wherein the crystalline form is Form IV.

182. The crystalline form of claim 181, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 19.27, 20.66, and 26.92 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

183. The crystalline form of claim 181, characterized by an XRPD pattern as shown in FIG. 53.

184. The crystalline form of any one of claims 181-183, characterized by an endothermic peak at about 227.21 °C, as determined by differential scanning calorimetry (DSC).

185. The crystalline form of any one claims 181-184, characterized by a DSC profile as shown in FIG. 54.

186. The crystalline form of any one of claims 181-185, characterized by an about 2.94 wt% loss between room temperature and about 200 °C, as determined by thermogravimetric analysis (TGA).

187. The crystalline form of any one of claims 181-186, characterized by a TGA profile as shown in FIG. 54.

188. The crystalline form of claim 164, wherein the crystalline form is Form V.

189. The crystalline form of claim 188, characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 6.53, 13.03, and 13.36 degrees two theta using Cu Ka radiation, wherein the two theta values are ± 0.2 degrees two theta.

190. The crystalline form of claim 188, characterized by an XRPD pattern as shown in FIG. 55.

191. The crystalline form of any one of claims 188-190, characterized by an endothermic peak at about 228.40 °C, as determined by differential scanning calorimetry (DSC).

192. The crystalline form of any one claims 188-191, characterized by a DSC profile as shown in FIG. 56.

193. The crystalline form of any one of claims 188-192, characterized by an about 16.04 wt% loss between room temperature and about 150 °C, as determined by thermogravimetric analysis (TGA).

194. The crystalline form of any one of claims 188-193, characterized by a TGA profile as shown in FIG. 56.

195. A compound of Formula (III):

194. 196.or a pharmaceutically acceptable salt or solvate thereof,197.wherein198.X' is either not present, or is a pharmaceutically acceptable anion;199.R1is selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, optionally substituted heteroaryl, and a Pro- Moiety;200.R2is either not present, or is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, and a Pro-Moiety;201.or R1and R2together with the atoms to which they are attached form an optionally substituted 3 to 14-membered heterocycle or an optionally substituted 3 to 14-membered cycloalkyl; and202.wherein R1is not hydrogen when R2is not present.

196. The compound of claim 195,204.or a pharmaceutically acceptable salt or solvate thereof, 0205.J206.wherein the Pro-Moieties are selected from the group consisting of R,211.

212. phosphoryl, phosphate, phosphoramidate, optionally substituted Ci-Cs alkyl phosphate, sulfonate, sulfonyl, alkyl sulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; and cholesterol;213.R3is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl;214.R4is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl;215.R5is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl;216.R6and R7are each selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, and optionally substituted C3-C8 cycloalkyl;217.or R6and R7are taken together with nitrogen to which they are attached to form an optionally substituted heterocycle or an optionally substituted heteroaryl; and218.R8is selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl.

197. The compound of claims 195 or 196, or a pharmaceutically acceptable salt or solvate thereof, wherein the optional substituents on R1, R2, R3, R4, R5, R6, R7, and / or R8are independently selected from the group consisting of hydrogen, hydroxy, (Ci-Ce) alkylamino, di-(Ci-Ce) alkylamino, halo (Ci-Ce) alkyl, hydroxy(Ci-Ce) alkyl, Ci-Ce alkoxy, halo (Ci-Ce) alkoxy, aryloxy, heteroaryloxy, ar-(Ci- Ce) alkyl, ar-(Ci-Ce) alkyloxy, (Ci-Ce) alkylthio, carboxamido, sulfonamido, (Ci- Ce) alkylcarbonyl, arylcarbonyl, (Ci-Ce) alkylsulfonyl, arylsulfonyl, carboxy, carboxy-(Ci-Ce) alkyl, Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, (C2- Ce) alkenyl, (C2-C6) alkynyl, optionally substituted C4-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy-(Ci-Ce) alkyl, (amino)-(Ci-Ce) alkyl, hydroxy-(Ci-Ce) alkylamino, (alkylamino)-(Ci-Ce) alkyl, (dialkylamino)-(Ci-Ce)alkyl, (cyano)-(Ci-Ce)alkyl, (carboxamido)-(Ci-Ce) alkyl, mercapto-(Ci-Ce) alkyl, (heterocyclo)-(Ci-Ce)alkyl, (cycloalkylamino)-(Ci- Ce)alkyl, (Ci-4haloalkoxy)-(Ci-Ce) alkyl, and (heteroaryl)-(Ci-Ce) alkyl.

198. The compound of any one of claims 195-197, or a pharmaceutically acceptable salt O221.3or solvate thereof, wherein R1is selected from the group consisting of222.

223. R and226.

227. not present.

199. The compound of any one of claims 195-198, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from the group consisting of optionally substituted Ci-Cs alkyl and optionally substituted heteroaryl.

200. The compound of claim 195 or 196, or a pharmaceutically acceptable salt or230.solvate thereof, wherein R1is selected from the group consisting231.

234.

235.

201. The compound of claim 195 or 196, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from the group consisting of237.

202. The compound of any one of claims 195-201, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from the group consisting of241.

203. The compound of any one of claims 194-201, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from the group consisting of phosphoryl and an optionally substituted Ci-Cs alkyl phosphate.

204. The compound of claim 203, or a pharmaceutically acceptable salt or solvate245.thereof, wherein246.

205. The compound of claim 195 or 196, or a pharmaceutically acceptable salt or solvate thereof, wherein R1and R2together with the atoms to which they are attached form an optionally substituted 3 to 14-membered heterocycle.

206. The compound of claim 205, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a compound having Formula (IV):

251.

252.

207. The compound of any one of claims 195-205, wherein the compound has a Formula (V):

254.

208. A compound of Formula (VI):

259. 261.or a pharmaceutically acceptable salt or solvate thereof,262.wherein263.X' is either not present, or is a pharmaceutically acceptable anion; and264.R9is a Pro-Moiety;265.R10is selected from the group consisting of hydrogen, hydroxy, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, and a Pro-Moiety.

209. The compound of claim 208,267.or a pharmaceutically acceptable salt or solvate thereof,268.O269.J3wherein the Pro-Moieties are selected from the group consisting of R,274.

275. phosphoryl, phosphate, phosphoramidate, optionally substituted Ci-Cs alkyl phosphate, sulfonate, sulfonyl, alkyl sulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; and cholesterol;276.R3is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl;277.R4is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl;278.R5is selected from the group consisting of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl;279.R6and R7are each selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, and optionally substituted C3-C8 cycloalkyl;280.or R6and R7are taken together with nitrogen to which they are attached to form an optionally substituted heterocycle or an optionally substituted heteroaryl; and281.R8is selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocycle, optionally substituted C4-C10 aryl, and optionally substituted heteroaryl.

210. The compound of claim 208 or 209, or a pharmaceutically acceptable salt or solvate thereof, wherein the optional substituents on R3, R4, R5, R8, R9, and / or R10are independently selected from the group consisting of hydrogen, hydroxy, (Ci- Ce) alkylamino, di-(Ci-Ce) alkylamino, halo (Ci-Ce) alkyl, hydroxy (Ci-Ce) alkyl, Ci-Ce alkoxy, halo (Ci-Ce) alkoxy, aryloxy, heteroaryloxy, ar-(Ci-Ce) alkyl, ar-(Ci- Ce) alkyloxy, (Ci-Ce) alkylthio, carboxamido, sulfonamido, (Ci-Ce) alkylcarbonyl, arylcarbonyl, (Ci-Ce) alkylsulfonyl, arylsulfonyl, carboxy, carboxy-(Ci-Ce) alkyl, Ci-Ce alkyl, optionally substituted C3-C8 cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, optionally substituted C4-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy-(Ci-Ce) alkyl, (amino)-(Ci-Ce) alkyl, hydroxy-(Ci-Ce) alkylamino, (alkylamino)-(Ci-Ce) alkyl, (dialkylamino)-(Ci- Ce)alkyl, (cyano)-(Ci-Ce)alkyl, (carboxamido)-(Ci-Ce) alkyl, mercapto-(Ci-Ce) alkyl, (heterocyclo)-(Ci-Ce)alkyl, (cycloalkylamino)-(Ci-C6)alkyl,283.(Ci-4haloalkoxy)-(Ci-Ce) alkyl, and (heteroaryl)-(Ci-Ce) alkyl.

211. The compound of any one of claims 208-210, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is selected from the group consisting of hydrogen and optionally substituted Ci-Cs alkyl.

212. The compound of any one of claims 208-210, or a pharmaceutically acceptable salt285.or solvate thereof, wherein R9is286.

287. , and wherein R4and R5are optionally substituted Ci-Cs alkyl.

213. The compound of any one of claims 208-210, or a pharmaceutically acceptable salt O289.or solvate thereof, wherein R9is290.

291. , R4is optionally substituted Ci-Cs alkyl, and R3is optionally substituted heteroaryl.

214. The compound of any one of claims 208-210, or a pharmaceutically acceptable salt or solvate thereof, wherein R9is selected from the group consisting of -^OH,295.

215. The compound of any one of claims 208-214, or a pharmaceutically acceptable salt or solvate thereof, wherein R10is hydrogen.

216. The compound of any one of claims 208-214, or a pharmaceutically acceptable salt or solvate thereof, wherein R10is hydroxy.

217. The compound of any one of claims 208-214, or a pharmaceutically acceptable salt or solvate thereof, wherein R10is a phosphate.

218. The compound of any one of claims 208-217, or a pharmaceutically acceptable salt or solvate thereof, wherein X' is an anion selected from the group consisting of chloride, fluoride, bromide, and iodide.

219. The compound of any one of claims 195-217, wherein the pharmaceutically acceptable salt is selected from the group consisting of a sodium salt, a potassium salt, a cesium salt, a calcium salt, a magnesium salt, a hydrochloride salt, a hydrobromide salt, a phosphate salt, a sulphate salt, a citrate salt, a lactate salt, a tartrate salt, a maleate salt, a fumarate salt, a mandelate salt, an acetate salt, a dichloroacetate salt, a trifluoroacetate salt, an oxalate salt, a formate salt, a tosylate salt, a mesylate salt, a besylate salt, a succinate salt, a benzoate salt, a malate salt, and a gluconate salt.

220. The compound of claim 219, wherein the pharmaceutically acceptable salt is selected from the group consisting of a gluconate salt and a malate salt.

221. The compound of any one of claims 208-219, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a Formula (IX) or a Formula (X):

304.

222. The compound claim 221, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a Formula (IX).

223. The compound claim 221, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a Formula (X).

224. The solid state form, crystalline form, mixture, or compound of any one of claims 1-219, wherein one or more hydrogen atoms is replaced by a deuterium atom.

225. The solid state form of any one of claims 1-8, wherein one or more hydrogen atoms are replaced by a deuterium atom as shown in the compound of Formula (VIII):

310. 312.wherein w is 0-4, x is 0-11, y is 0-10, z is 0-5, and the sum of w + x + y + z is at least one.

226. The solid state form, crystalline form, mixture, or compound of any one of claims 1-207, wherein one or more hydrogen atoms on the cyclohexyl ring are replaced by a deuterium atom.

227. The compound of any one of claims 208-220, wherein one or more hydrogen atoms attached to a carbon atom are replaced by a deuterium atom.

228. A pharmaceutical composition comprising one or more of the solid state forms, crystalline forms, mixtures, or compounds of any one of claims 1-227 and one or more pharmaceutically acceptable carriers or diluents.

229. A solid dosage form comprising one or more of the solid state forms, crystalline forms, mixtures, or compounds of any one of claims 1-227.

230. The pharmaceutical composition of claim 228, formulated for oral, parenteral, rectal, intranasal, topical, or transdermal administration.

231. A pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound of any one of claims 1-207, a compound of any one of claims 208-218, and optionally one or more pharmaceutically acceptable carriers or diluents.

232. A pharmaceutical composition comprising a solid state form, crystalline form, mixture, or compound of any one of claims 1-207 and a compound having Structure (VII):

320.

233. A pharmaceutical composition comprising a compound of any one of claims 208- 218 and a compound having Structure (I):

324.

234. A pharmaceutical composition comprising a compound of any one of claims 208- 218 and a compound having Structure (II):

328.

235. A formulation comprising: (a) (R)- 1 -cyclohexyl- l-phenyl-3-(l -piperidyl)propan-l- ol having a Structure (II):

332. 334.or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof, and (b) a modifying release agent.

236. The formulation of claim 235, wherein the pharmaceutically acceptable salt is selected from the group consisting of the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, a maleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt.

237. The formulation of claims 235 or 236, wherein the modifying release agent comprises one or more hydroxypropylmethylcellulose (HPMC) polymers.

238. The formulation of claim 237, wherein the one or more HPMC polymers have viscosities ranging from about 50 cP to about 50,000 cP.

239. The formulation of claim 237, wherein the one or more HPMC polymers have viscosities ranging from about 50 cP to about 20,000 cP.

240. The formulation of claim 237, comprising an HPMC polymer having a viscosity of about 100 cP and an HPMC polymer having a viscosity of about 15,000 cP.

241. The formulation of claim 235 or 236, wherein the (R)-l-cyclohexyl-l-phenyl-3-(l- piperidyl)propan-l-ol is present in an amount of about 0.5% to about 10% by weight of the total weight of the formulation.

242. The formulation of any one of claims 235-241, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of about 100 cP in an amount of from about 1% to about 50% by weight of the total weight of the formulation.

243. The formulation of claim 242, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of about 100 cP in an amount of from about 10% to about 30% by weight of the total weight of the formulation.

244. The formulation of any one of claims 235-243, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of about 15,000 cP in an amount of from about 0% to about 50% by weight of the total weight of the formulation.

245. The formulation of claim 244, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of about 15,000 cP in an amount of from about 10% to about 30% by weight of the total weight of the formulation.

246. The formulation of any one of claims 235-239, wherein the modifying release agent does not comprise an HPMC polymer having a viscosity of 15,000 cP.

247. The formulation of any one of claims 235-246, further comprising one or more additional ingredients selected from the group consisting of lubricants, fillers, glidants, pH adjusting agents, plasticizers, opacifiers, colorants, and combinations thereof.

248. The formulation of claim 247, further comprising a lubricant that is present in an amount of from about 0.1% to about 2% by weight, or from about 0.1% to about 1% by weight, or about 0.5% by weight of the total weight of the formulation.

249. The formulation of claim 248, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and combinations thereof.

250. The formulation of claim 249, wherein the lubricant is magnesium stearate.

251. The formulation of claim 247, further comprising one or more fillers that are present in a total amount of from about 30% to about 80% by weight, or from about 50% to about 70% by weight of the total weight of the formulation.

252. The formulation of claim 247, further comprising more than one filler.

253. The formulation of any one of claims 247-252, wherein the one or more fillers are selected from the group consisting of calcium carbonate, dicalcium phosphate anhydrous, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, xylitol, starch, pregelatinized starch, sucrose, alpha-lactose monohydratelactose, and combinations thereof.

254. The formulation of claim 253, wherein the one or more fillers are selected from the group consisting of microcrystalline cellulose, dicalcium phosphate anhydrous, lactose, and combinations thereof.

255. The formulation of claim 254, comprising microcrystalline cellulose in an amount of from about 5% to about 20% by weight of the total weight of the formulation, dicalcium phosphate anhydrous in an amount of from about 35% to about 55% by weight of the total weight of the formulation, and lactose in an amount of from about 1% by weight to about 5% by weight of the total weight of the formulation.

256. The formulation of claim 254, comprising microcrystalline cellulose in an amount of from about 5% to about 20% by weight of the total weight of the formulation and lactose in an amount of from about 40% by weight to about 60% by weight of the total weight of the formulation.

257. The formulation of any one of claims 235-256, wherein the formulation is a liquid, a semi-solid, or a solid.

258. The formulation of any one of claims 235-256, wherein the formulation is selected from the group consisting of a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a gel, an ointment, a foam, and combinations thereof.

259. The formulation of any one of claims 235-256, wherein the formulation is selected from the group consisting of a tablet, a pill, a soft or hard gelatin capsule, a powder, a granulate, a microsphere, a lozenge, a powder sachet, and combinations thereof.

260. The formulation of any one of claims 235-256, wherein the formulation is selected from the group consisting of a gastroresistant capsule, an enteric coated capsule, a gastroresistant tablet, and an enteric coated tablet.

261. The formulation of claim 259, wherein the formulation is a tablet, and the tablet comprises an intra-granular portion and an extra-granular portion.

262. The formulation of claim 261, wherein the intra-granular portion comprises a lubricant present in an amount of from about 0.1% to about 1% by weight of the total weight of the formulation.

263. The formulation of claim 261, wherein the extra-granular portion comprises a lubricant present in an amount of from about 0.1% to about 1% by weight of the total weight of the formulation.

264. The formulation of claim 262 or 263, wherein the lubricant is magnesium stearate.

265. The formulation of any one of claims 235-256, wherein the formulation is a tablet, and the tablet further comprises an enteric coating.

266. The formulation of any one of claims 235-265, wherein the formulation is formulated for oral, parenteral, rectal, intranasal, topical, or transdermal administration.

267. A formulation comprising: (a) bethanechol having a Structure (VII):

364. 366.or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof, and (b) a modifying release agent.

268. The formulation of claim 267, wherein the pharmaceutically acceptable salt is selected from the group consisting of a sulfate salt, a tosylate salt, a mesylate salt, a besylate salt, a phosphate salt, a maleate salt, a fumarate salt, a malate salt, a succinate salt, a benzoate salt, a tartrate salt, and a hydrochloride salt.

269. The formulation of claims 267 or 268, wherein the modifying release agent comprises one or more hydroxypropylmethylcellulose (HPMC) polymers.

270. The formulation of claim 269, wherein the one or more HPMC polymers have viscosities ranging from about 50 cP to about 50,000 cP.

271. The formulation of claim 269, wherein the one or more HPMC polymers have viscosities ranging from about 50 cP to about 20,000 cP.

272. The formulation of claim 269, comprising an HPMC polymer having a viscosity of about 100 cP and an HPMC polymer having a viscosity of about 15,000 cP.

273. The formulation of any one of claims 267-272, wherein bethanechol is present in an amount of from about 5% to about 40% by weight of the total weight of the formulation.

274. The formulation of any one of claims 267-272, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of about 100 cP in an amount of from about 1% to about 40% by weight of the total weight of the formulation.

275. The formulation of any one of claims 267-272, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of about 100 cP in an amount of from about 5% to about 15% by weight of the total weight of the formulation.

276. The formulation of any one of claims 267-272, wherein the modifying release agent further comprises one or more HPMC polymers having a viscosity of about 15,000 cP in an amount of from about 10% to about 50% by weight of the total weight of the formulation.

277. The formulation of any one of claims 267-272, wherein the modifying release agent further comprises one or more HPMC polymers having a viscosity of about 15,000 cP in an amount of from about 20% to about 40% by weight of the total weight of the formulation.

278. The formulation of any one of claims 267-272, wherein the modifying release agent comprises both an HPMC polymer having a viscosity of about 100 cP and an HPMC polymer having a viscosity of about 15,000 cP.

279. The formulation of any one of claims 267-278, further comprising one or more ingredients selected from the group consisting of lubricants, fillers, glidants, pH adjusting agents, plasticizers, opacifiers, colorants, and combinations thereof.

280. The formulation of claim 279, further comprising a lubricant that is present in an amount of from about 0.1% to about 4% by weight, or from about 0.1% to about 2% by weight, or about 1% by weight, or about 0.5% by weight of the total weight of the formulation.

281. The formulation of claim 280, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and combinations thereof.

282. The formulation of claim 281, wherein the lubricant is magnesium stearate.

283. The formulation of claim 279, further comprising one or more fillers that are present in a total amount of from about 30% to about 60% by weight, or from about 40% to about 50% by weight of the total weight of the formulation.

284. The formulation of claim 279, further comprising more than one filler.

285. The formulation of claim 284, wherein the one or more fillers are selected from the group consisting of calcium carbonate, dicalcium phosphate anhydrous, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, xylitol, starch, pregelatinized starch, sucrose, alpha-lactose monohydratelactose, and combinations thereof.

286. The formulation of claim 285, wherein the one or more fillers are selected from the group consisting of microcrystalline cellulose, dicalcium phosphate anhydrous, and lactose, and combinations thereof.

287. The formulation of claim 286, comprising microcrystalline cellulose in an amount of from about 10% to about 40% by weight of the total weight of the formulationand dicalcium phosphate anhydrous in an amount of from about 15% to about 35% by weight of the total weight of the formulation.

288. The formulation of any one of claims 267-287, wherein the formulation is a liquid, a semi-solid, or a solid.

289. The formulation of any one of claims 267-287, wherein the formulation is selected from the group consisting of a solution, a suspension, an emulsion, a microemulsion, a cream, a paste, a gel, an ointment, a foam, and combinations thereof.

290. The formulation of any one of claims 267-287, wherein the formulation is selected from the group consisting of a tablet, a pill, a soft or hard gelatin capsule, a powder, a granulate, a microsphere, a lozenge, a powder sachet, and combinations thereof.

291. The formulation of any one of claims 267-287, wherein the formulation is selected from the group consisting of a gastroresistant capsule, an enteric coated capsule, and an enteric coated modified release tablet.

292. The formulation of claim 290, wherein the formulation is a tablet, and the tablet comprises an intra-granular portion and an extra-granular portion.

293. The formulation of claim 292, wherein the intra-granular portion comprises a lubricant present in an amount of from about 0.1% to about 1% by weight of the total weight of the formulation.

294. The formulation of claim 292, wherein the extra-granular portion comprises a lubricant present in an amount of from about 0.1% to about 1% by weight of the total weight of the formulation.

295. The formulation of claim 293 or 294, wherein the lubricant is magnesium stearate.

296. The formulation of any one of claims 267-288, wherein the formulation is a tablet, and the tablet further comprises an enteric coating.

297. The formulation of any one of claims 267-296, wherein the formulation is formulated for oral, parenteral, rectal, intranasal, topical, or transdermal administration.

298. An extended release composition comprising (R)-l -cyclohexyl- l-phenyl-3-(l- piperidyl)propan-l-ol having a Structure (II):

396. 398.or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof, and a modifying release agent, wherein the formulation is formulated for oral administration to a human subject.

299. The composition of claim 298, wherein less than about 50% of the (R)-l - cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol in the composition is released within about 2 hours after administration to a human subject.

300. The composition of claim 298, wherein less than about 50% of the (R)-l - cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol in the composition is released within about 4 hours after administration to a human subject.

301. The composition of claim 298, wherein less than about 50% of the (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol in the composition is released within about 8 hours after administration to a human subject.

302. The composition of claim 298, wherein less than about 80% of the (R)-l - cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol in the composition is released within about 4 hours after administration to a human subject.

303. The composition of claim 298, wherein less than about 80% of the (R)-l- cyclohexyl-l-phenyl-3-(l-piperidyl)propan-l-ol in the composition is released within about 8 hours after administration to a human subject.

304. The composition of claim 298, wherein less than about 80% of the (R)-l - cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol in the composition is released within about 16 hours after administration to a human subject.

305. The composition of claim 298, wherein less than about 90% of the (R)-l - cyclohexyl- l-phenyl-3-(l-piperidyl)propan-l-ol in the composition is released within about 20 hours after administration to a human subject.

306. The composition of claim 298, wherein the release of the (R)- 1 -cyclohexyl- 1- phenyl-3-(l-piperidyl)propan-l-ol is extended for about 4 hours to about 20 hours.

307. The composition of any one of claims 298-306, wherein the (R)- 1 -cyclohexyl- 1- phenyl-3-(l-piperidyl)propan-l-ol is present in an amount of from about 1% to about 10% by weight of the total weight of the composition.

308. The composition of any one of claims 298-307, wherein the modifying release agent comprises one or more HPMC polymers present in an amount of about 1% to about 40% by weight of the total weight of the composition.

309. The composition of any one of claims 298-307, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of from about 50 cP to about 25,000 cP.

310. The composition of any one of claims 298-307, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of from about 50 cP to about 200 cP.

311. The composition of any one of claims 298-307, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of from about 10,000 cP to about 20,000 cP.

312. The composition of any one of claims 298-307, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of from about 50 cP to about 200 cP and one or more HPMC polymers having a viscosity of from about 10,000 cP to about 20,000 cP.

313. The composition of any one of claims 298-307, wherein the composition comprises from about 1% to about 10% by weight of the (R)-l-cyclohexyl-l-phenyl-3-(l- piperidyl)propan-l-ol, from about 5% to about 40% by weight of an HPMC polymer having a viscosity of from about 50 cP to about 200 cP, and from about 0% to about 40% by weight of an HPMC polymer having a viscosity of from about 10,000 cP to about 20,000 cP.

314. An extended release composition comprising bethanechol having a Structure (VII):413.-Y '414.o (VII),415.or a pharmaceutically acceptable salt, hydrate, anhydrate, or solvate thereof, and a modifying release agent, wherein the formulation is formulated for oral administration to a human subject.

315. The composition of claim 314, wherein less than about 90% of the bethanechol in the composition is released within about 2 hours after administration to a human subject.

316. The composition of claim 314, wherein less than about 80% of the bethanechol in the composition is released within about 2 hours after administration to a human subject.

317. The composition of claim 314, wherein less than about 70% of the bethanechol in the composition is released within about 1 hour after administration to a human subject.

318. The composition of claim 314, wherein less than about 95% of the bethanechol in the composition is released within about 4 hours after administration to a human subject.

319. The composition of claim 314, wherein the release of the bethanechol is extended for about 1 hour to about 6 hours.

320. The composition of any one of claims 314-319, wherein the bethanechol is present in an amount of from about 5% to about 30% by weight of the total weight of the composition.

321. The composition of any one of claims 314-320, wherein the modifying release agent comprises one or more HPMC polymers present in an amount of about 1% to about 40% by weight of the total weight of the composition.

322. The composition of any one of claims 314-320, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of from about 50 cP to about 25,000 cP.

323. The composition of any one of claims 314-320, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of from about 50 cP to about 200 cP.

324. The composition of any one of claims 314-320, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of from about 10,000 cP to about 20,000 cP.

325. The composition of any one of claims 314-320, wherein the modifying release agent comprises one or more HPMC polymers having a viscosity of from about 50 cP to about 200 cP and one or more HPMC polymers having a viscosity of from about 10,000 cP to about 20,000 cP.

326. The composition of any one of claims 314-320, wherein the composition comprises from about 5% to about 30% by weight of the bethanechol, from about 5% to about20% by weight of an HPMC polymer having a viscosity of from about 50 cP to about 200 cP, and from about 20% to about 40% by weight of an HPMC polymer having a viscosity of from about 10,000 cP to about 20,000 cP.

327. A method of treating a movement disorder in a patient in need thereof, comprising administering to the patient one or more of the solid state forms, crystalline forms, mixtures, compounds, pharmaceutical compositions, solid dosage form, formulations, or compositions of any one of claims 1-326.

328. The method of claim 280, wherein the patient is administered one or more of the solid state forms, crystalline forms, mixtures, or compounds of any one of claims 1-160 and one or more of the compounds of any one of claims 208-220.

329. The method of claim 280, wherein the patient is administered one or more of the formulations or compositions of any one of claims 235-266 and 298-313 and one or more of the formulations or compositions of any one of claims 267-297 and 314- 326.

330. A method of treating a movement disorder in a patient in need thereof, comprising administering to the patient one or more of the solid state forms, crystalline forms, mixtures, or compounds of any one of claims 1-207 and a compound having Structure (VII):

432.

331. A method of treating a movement disorder in a patient in need thereof, comprising administering to the patient one or more of the formulations or compositions of any one of claims 235-266 and 298-313 and a compound having Structure (VII):

437.

438.

332. A method of treating a movement disorder in a patient in need thereof, comprising administering to the patient one or more of the compounds of any one of claims 208-220 and a compound having Structure (I):

440.

333. A method of treating a movement disorder in a patient in need thereof, comprising administering to the patient one or more of the formulations or compositions of any one of claims 267-297 and 314-326 and a compound having Structure (I):

444.

334. A method of treating a movement disorder in a patient in need thereof, comprising administering to the patient one or more of the compounds of any one of claims 208-220 and a compound having Structure (II):

448.

335. A method of treating a movement disorder in a patient in need thereof, comprising administering to the patient one or more of the formulations or compositions of any one of claims 267-297 and 314-326 and a compound having Structure (II):451.

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