Neurosteroid compounds and uses of the same

Abstract

Disclosed herein are compounds and pharmaceutical compositions useful for treating, preventing, reducing, or ameliorating diseases or conditions associated with neurodegenerative disorders. Without being bound by theory, the disclosed compounds and compositions are believed to selectively target tropomyosin receptor kinase A (TrkA) receptor-mediated pro-survival signaling pathways or the nerve growth factor (NGF) or the neurosteroid dehydroepiandrosterone (DHEA) and may prevent, treat, reduce, or ameliorate neurodegeneration.

Description

NEUROSTEROID COMPOUNDS AND USES OF THE SAMEBACKGROUND

[0001] Neurodegenerative diseases and conditions, for example, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, represent a significant and growing public health concern. These diseases and disorders, marked by progressive loss of structure or function of neurons, often lead to severe cognitive, motor, and functional impairments in affected individuals. Common pathological processes underlying these conditions include neuronal apoptosis, or programmed cell death, and neuronal injury, which collectively contribute to the gradual decline in neural network function. Preventing or mitigating such degeneration is essential to preserving neural function and enhancing quality of life for individuals affected by these disorders.

[0002] Neuronal apoptosis and injury are central mechanisms in neurodegenerative diseases. In Alzheimer’s disease, neuronal loss, particularly in regions critical for memory and cognition, is closely associated with the accumulation of neurotoxic proteins, such as amyloidbeta and tau. These proteins trigger pathways that lead to apoptosis and inflammation, contributing to progressive cognitive decline. Parkinson’s disease, on the other hand, is characterized by the loss of dopaminergic neurons in the substantia nigra, impairing motor control and resulting in the characteristic tremors and rigidity associated with the disease. Similarly, Huntington’s disease involves neuronal apoptosis within the basal ganglia due to abnormal huntingtin protein, leading to movement disorders, cognitive decline, and behavioral changes.

[0003] To date, there is a need to develop compounds, compositions and therapies to treat, prevent, or reduce neurodegenerative diseases and conditions.SUMMARY OF THE DISCLOSURE

[0004] Some embodiments relate to a pharmaceutically acceptable carrier and at least one compound represented by Formula (I),wherein,R1is selected from the group consisting of optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted organic acid, optionally substituted alcohol, optionally substituted ester, optionally substituted C1to C10alkoxy, optionally substituted C1to C6alkyl, optionally substituted C2to C6alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3to C8cycloalkyl, optionally substituted C6to C10aryl, optionally substituted C3to C8heterocyclyl, optionally substituted C3to C10heteroaryl, optionally substituted O- aryl, or optionally substituted O-heteroaryl;R2is =0, or -OH;X is CH2, or O; andthe dashed bond is present or absent.

[0005] Some embodiments disclosed herein relate to a composition including a pharmaceutically accept carrier and at least one compound represented by Formula (II),wherein,R1is selected from the group consisting of optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted organic acid, optionally substituted alcohol, optionally substituted ester, optionally substituted C1to C10alkoxy, optionally substituted C1to C6alkyl, optionally substituted C2to C6alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3to C8cycloalkyl, optionally substituted C6to C10aryl, optionally substituted C3to C8heterocyclyl, optionally substituted C3to C10heteroaryl, optionally substituted O- aryl, or optionally substituted O-heteroaryl; andR2is =0, or -OH.

[0006] Some embodiments disclosed herein relate to a composition including a pharmaceutically acceptable earner and at least one compound represented by Formula (III),wherein,R2is =0, or -OH.

[0007] Some embodiments disclosed herein relate to a composition including a pharmaceutically acceptable earner and at least one compound represented by Formula (IV),wherein,R1is selected from the group consisting of optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted organic acid, optionally substituted alcohol, optionally substituted ester, optionally substituted C1to C10alkoxy, optionally substituted C1to C6alkyl, optionally substituted C2to C6alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3to C8cycloalkyl, optionally substituted C6to C10aryl, optionally substituted C3to C8heterocyclyl, optionally substituted C3to C10heteroaryl, optionally substituted O- aryl, or optionally substituted O-heteroaryl; andR2is =0, or -OH.

[0008] Some embodiments relate to a composition including a pharmaceutically acceptable carrier and at least one compound selected from:

[0009] Some embodiments relate to a method to treat, prevent, reduce, or ameliorate a neurodegenerative disease or condition. In some embodiments, the method includes administering to a patient in need thereof a compound or composition as disclosed herein. In some embodiments, the neurodegenerative condition is related to a neuronal apoptosis or neuronal injury. In some embodiments, the neurodegenerative condition is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), retinal degeneration, retinal detachment, peripheral neuropathy caused by genetic abnormalities, diabetes, polio, herpes, AIDS, brain trauma, ischemia and stroke. In some embodiments, the neurodegenerative disease is Alzheimer’s disease or Parkinson’s disease. In some embodiments, the method further comprises administering at least one additional medicament to the patient. In some embodiments, the additional medicament comprises at least one dopamine agonist. In some embodiments, the additional medicament comprises at least one dopamine precursor. In some embodiments, the additional medicament comprises L-DOPA. In some embodiments, the additional medicament is administered at a delay time after a first administration of the composition. In some embodiments, the delay time is equal to or greater than 2 years. In some embodiments, at least one motor symptom and / or at least one motor complication develops in the patient. In some embodiments, the at least one motor symptom is selected from tremor and / or shaking in the extremities, slowed movement (bradykinesia), muscle stiffness, rigidity,immobility (freezing), muscle cramps, impaired posture and / or balance, falls, dizziness, loss of automatic movements such as blinking or smiling, changes in speech and / or writing, motor fluctuations, dystonia, and any combination of the foregoing. In some embodiments, the motor complication is selected from wearing off, dose failure, beginning of dose worsening, end-of-dose rebound, unpredictable off-periods, freezing of gait, on-period failure, acute akinesia, dyskinesia, and any combination of the foregoing. In some embodiments, the motor symptom and / or the motor complication develops at a time equal to or greater than 2 years after the additional medicament is administered. In some embodiments, the patient is a human or mammal.

[0010] Some embodiments relate to a method for preventing, treating, reducing, or ameliorating a disease or condition in a subject previously infected with a virus includes administering to the subject a compound or a composition as disclosed herein. In some embodiments, the virus is COVID-19 In some embodiments, the subject meets the Diagnosis of Chronic Fatigue Syndrome (CFS), In some embodiments, the subject has concurrent occurrence of at least one or more of Long COVID symptoms which persisted or recurred during 3 or more consecutive months of illness. In some embodiments, the Long COVID symptoms are not known to be preceded by the infection of COVID-19. In some embodiments, the Long COVID symptoms include, but are not limited to, fatigue, post-exertional malaise, headache, sleep disturbance, memory problems, problems with concentration, brain fog, fever, chills, cough, shortness of breath, difficulty breathing, loss of taste, loss of smell, and chest pain. In some embodiments, the method may further include diagnosing the subject for the presence of COVID-19 or a COVID-19 antibody.

[0011] Some embodiments relate to a pharmaceutical composition comprising at least one compound or a composition as disclosed herein and at least one pharmaceutically acceptable excipient for use in treating a neurodegenerative condition. Some embodiments relate to the use of a pharmaceutical composition as described herein. In some embodiments, pharmaceutical composition is used to treat, prevent, reduce, or ameliorate a neurodegenerative condition. In some embodiments, the neurodegenerative condition is Alzheimer’s Disease or Parkinson’s Disease. Some embodiments relate to the manufacture of a medicament for treating a neurodegenerative condition. In some embodiments, the medicament comprises at least one pharmaceutically acceptable excipient. In some embodiments, the neurodegenerativecondition is Alzheimer’s disease or Parkinson’s disease. In some embodiments, the composition, or the use, comprises at least one additional medicament. In some embodiments, the additional medicament comprises L-DOPA. In some embodiments, the additional medicament is used at a delay time after use of the pharmaceutical composition begins. In some embodiments, the delay time is equal to or greater than 2 years. In some embodiments, development of at least one motor symptom and / or at least one motor complication occurs. In some embodiments, the motor symptom is selected from tremor and / or shaking in the extremities, slowed movement (bradykinesia), muscle stiffness, rigidity, immobility (freezing), muscle cramps, impaired posture and / or balance, falls, dizziness, loss of automatic movements such as blinking or smiling, changes in speech and / or writing, motor fluctuations, dystonia, and any combination of the foregoing. In some embodiments, the motor complication is selected from wearing off, dose failure, beginning of dose worsening, end-of-dose rebound, unpredictable off-periods, freezing of gait, on-period failure, acute akinesia, dyskinesia and any combination of the foregoing. In some embodiments, the motor symptom and / or the motor complication develops at a time equal to or greater than 2 years after the use of the pharmaceutical composition begins. In some embodiments, the motor symptom and / or the motor complication develops at a time equal to or greater than 2 years after the use of the additional medicament begins.DETAILED DESCRIPTION

[0012] The following description provides context and examples, but should not be interpreted to limit the scope of the disclosure covered by the claims that follow in this specification or in any other application that claims priority to this specification. No single component or collection of components is essential or indispensable. Any feature, structure, component, material, step, or method that is described and / or illustrated m any embodiment in this specification can be used with or instead of any feature, structure, component, material, step, or method that is described and / or illustrated in any other embodiment in this specification.Definitions

[0013] As used herein and unless otherwise stated or implied by context, terms that are used herein have the meanings that are defined here. The descriptions of embodiments and examples that are described illustrate the disclosure and they are not intended to limit it in any way. Unless otherwise contraindicated or implied, e.g., by including mutually exclusive elements or options, in these definitions and throughout this specification, the terms “a” and “an” mean one or more and the term “or” means and / or.

[0014] As used herein, “amide,” refers to a chemical moiety with formula -(R)n-C(O)NHRPRor -(R)n-NHC(O)RPR, where R and RPRare independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1. An amide may be an amino acid or a peptide molecule attached to a molecule of the present disclosure, thereby forming a prodrug.

[0015] As used herein, “alkyl” means linked normal, secondary, tertiary or cyclic carbon atoms, i.e., linear, branched or cyclic. The number of carbon atoms in an alkyl group or moiety is 1 to about 20, unless otherwise specified, e.g., C1-8alkyl means an alkyl moiety containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Examples include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (i-propyl, —CH(CH3)2), 1 -butyl (n-butyl), 2-methyl-1-propyl (i-butyl, —CH2CH(CH3)2), 2-butyl (s-butyl, —CH(CH3)CH2CH3), 2-methyl-2-propyl (t-butyl, —C(CH3)3), 1-pentyl (n-pentyl), 2-pentyl (—CH(CH3)CH2CH2CH3), 3-pentyl ( ---CH(CH2CH3)2), 2-methyl-2-butyl (— C(CH3)2CH2CH3), 3-methyl-2-butyl (— CH(CH3)CH(CH3)2), 3-methyl-l -butyl (— CH2CH2CH(CH3)2), 2-methyl-l -butyl (— CH2CH(CH3)CH2CH3), 1 -hexyl, 2-hexyl (— CH(CH3)CH2CH2CH2CH3), 3 -hexyl (— CH(CH2CH3)(CH2CH2CH3)2), 2-methyl-2-pentyl (— C(CH3)2CH2CH2CH3), 3 -methyl-2-pentyl (— CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (— CH(CH3)CH2CH(CH3)2), 3-methyl-3 -pentyl ( — C(CH3)(CH2CH3)?.), 2-methyl-3 -pentyl ( — CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (— C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (— CH(CH3)C(CH3)3), cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0016] As used herein, “alkenyl” means linked normal, secondary, tertiary or cyclic carbon atoms where one or more double bonds (e.g., — CH=CH — ) are present, typically 1, 2 or 3, usually 1 or 2. The number of carbon atoms in an alkenyl group or moiety is 2 to about20, unless otherwise specified, e.g., C2-8alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0017] As used herein, “alkynyl” means linked normal, secondary, tertiary or cyclic carbon atoms where one or more triple bonds ( — C=C — ) are present, typically 1, 2 or 3, usually 1. The number of carbon atoms in an alkynyl group or moiety is 2 to about 20, unless otherwise specified, e.g., C 2-8 alkynyl means an alkynyl moiety’ containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0018] As used herein, “aromatic,” refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. The term “carbocyclic” refers to a compound which contains one or more covalently closed ring structures, and that the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon. The term “hetero aromatic” refers to an aromatic group which contains at least one heterocyclic ring.

[0019] As used herein, “aryl” refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanate, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and disubstituted ammo groups, and the protected derivatives thereof. When substituted, substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0020] As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term “heteroalkyi” where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyi having 1 to 4 carbon atoms. The heteroalkyi group of the compounds may be designated as “CM heteroalkyi” or similar designations. The heteroalkyi group may contain one or more heteroatoms. By way of example only, “CM heteroalkyi” indicates that there are one to four carbon atoms in the heteroalkyi chain and additionally one or more heteroatoms in the backbone of the chain,

[0021] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine. A heteroaryl group may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and disubstituted ammo groups, and the protected derivatives thereof. When substituted, substituents on a heteroayl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0022] As used herein, “heterocyclyl” refers to three-, four-, five-, six-, seven-, and eight- or more membered rings wherein carbon atoms together with from 1 to 3 heteroatomsconstitute said ring. A heterocyclyl can optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic pi-electron system does not arise. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen. A heterocyclyl can further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo- systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like.

[0023] As used herein, “cycloalkyl” refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro- connected fashion. Cycloalkyl groups may range from C3to C10, in other embodiments it may range from C3to C20. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated. When substituted, substituents on a cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including an aryl and a heteroaryl.

[0024] As used herein, “O-carboxy” refers to a “RC(=O)O-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An 0- carboxy may be substituted or unsubstituted.

[0025] As used herein, “optionally substituted amino”, optionally substituted C-amido”, “optionally substituted N-amido”, optionally substituted organic acid”, “optionally substituted alcohol”, “optionally substituted ester”, “optionally substituted alkoxy”, “optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl” “optionally substituted cycloalkyl”, “optionally substituted aryl”, “optionally substituted heterocyclyl”, “optionally substituted C3 to Cio heteroaryl”, “optionally substituted O-aryl” and “optionally substituted O-heteroaryl” mean an amino, C-amido, N-amido, organic acid, alcohol, ester, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, O-aryl, or O-heteroaryl respectively, that comprises 1, 2, 3 or more independently selected substituents bonded to a carbon atom or 1, 2, 3 or more independently selected substituents that replace or interrupt any carbon atom chain or ring. Substituents include ethers ( — O — ),ketones ( — C(O) — ), — ORPR(including — OH), — C(O)ORPR(including — C(O)OH), —OC(O)NRPR— — OC(O)NHRPR, — NRPRC(O)NRPR—, — NRPRC(O)NHRPR, — NRPRCH2—, — NRPRCH2CH2— — S—, — SRPR, — S(O)—, — S(O)(O)—, — S(O)ORPR, — S(O)H, — CN, — NO2, —O—CH2—O—C(O)—ORPR(including — O— CH2— O— C(O)— OH), —O— CH2—O—C(O)—SRPR(including — O— CH2— O— C(O)— SH), — O— CH2— C(O)— NHRPR(including — O— CH2— C(O)—NH2), —O—CH2—C(O)—RPR(including — O— CH2— C(O)— OH), —O—CH2—C(O)—-SRPR(including — O— CH2— C(O)— SH), — O— CH2— ORPR(including — O— CH2— OH), — O— CH2— CH2—ORPR(including — O— CH2— CH2—OH), —O—CH2—CH2—O—CH2—CH2—ORPR(including — O— CH2—CH2— OCH2 — CH2 — OH), halogen, and combinations of these moieties where RPRindependently is hydrogen, a protecting group or both RPRtogether are a protecting group. In some embodiments, alkenyl, alkynyl, aryl-alkenyl and aryl-alkynyl groups comprise one, two, three or more substituents, and such substituents are optionally bonded to a carbon atom that is one or more methylene moiety removed from the double bond, i.e., the substituent is separated at least by 1, 2, 3 or more CH2 moieties from a double bond.

[0026] As used herein, “heterocycle” or “heterocyclic” includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 1960, 82:5566. Examples of heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrohnyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thienyl, thiantlirenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, IH-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, [3-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of isoindole or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or P-carbohne. Typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetidyl, 1 -pyrrolyl, 1 -imidazolyl, 1-pyrazolyl, and 1 -piperidinyl.

[0027] As used herein, “heteroaryl” or “heteroaromatic” means an aromatic ring or two or more fused rings that contain one or more aromatic rings where the ring or fused rings comprise 1, 2, 3 or more heteroatoms, usually oxygen ( — O — ), nitrogen ( — NRPR— ) or sulfur ( — S — ) where RPRis — H, a protecting group, optionally substituted C1-8alkyl, optionally substituted C2-8alkenyl or optionally substituted C2-8alkynyl, usually — H. Examples are as described for heterocycle or heterocyclic and heteroaryl or heteroaromatic groups and comprise a subset of heterocycles.

[0028] As used herein, “alcohol” means an alcohol that comprises a C1-20 alkyl moiety substituted at one, two or more hydrogen atoms with one, two or more hydroxyl groups. Alcohols include ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol, 11-pentanol, i-pentanol, 11-hexanol, cyclohexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, ethylene glycol and glycerol. The arrangement of carbon atoms in alcohols can be straight, branched or cyclic. Alcohol includes any subset of the foregoing, e.g., C1-6alcohols (alcohols having 1, 2, 3, 4, 5 or 6 carbon atoms).

[0029] As used herein, “halogen” means fluorine, chlorine, bromine or iodine,

[0030] As used herein, “protecting group” or “RPR”, means a moiety that prevents the atom to which it is linked from participating in unwanted reactions, or it limits such reactions. For example, for — ORPR, RPRmay be hydrogen or a protecting group for the oxygen atom found in a hydroxyl. For — C(O) — ORPR, RPRmay be hydrogen or a carboxyl protecting group, for — SRPR, RPRmay be hydrogen or a protecting group for sulfur in thiols for instance, and for — NHRPRor — N(RPR)2 —, RPRmay be hydrogen or a nitrogen atom protecting group for primary or secondary amines. One or more hydroxyl, thiol, amine or other reactive groups may be found in the Formula compounds as described herein. These groups may require protection against reactions taking place elsewhere in the molecule. The protecting groups for oxygen, sulfur or nitrogen atoms, or for reactive groups containing heteroatoms, are used, for example, to prevent unwanted reactions with electrophilic compounds, such as acylating compounds used, e.g., in steroid chemistry. “Protecting groups” also include noncyclic or cyclic protecting groups, which have been extensively described, e.g., in “Protective Groups in Organic Chemistry”, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (hereafter “Greene”) and will not be detailed here. The corresponding cleavage reactions have also been described, e.g., in Greene. In the context of the present disclosure, these protecting groups are groups that can be removed from the molecule of the disclosure without irreversibly changing the covalent bond structure or oxidation / reduction state of the remainder of the molecule. For example, when — RPRis a removable protecting group that is bonded to a — O — or — NH — group, it is removed to form — OH or — NH2, respectively, without affecting other covalent bonds in the molecule. In some embodiments, the protecting group will not be removable without affecting other covalent bonds in the molecule. More than one protecting group can be removed at a time, or they can be removedsequentially. The Formula compounds as described herein may contain one or more than one protecting group, which may be the same or different.

[0031] As used herein, “ester” means a moiety that comprises a — C(O) — O — structure. Typically, esters as used here, comprise an organic moiety containing about 1-50 carbon atoms, usually about 2-18 carbon atoms, and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si, F, Cl, Br, or I), usually about 1-6 heteroatoms, linked to an IUPAC formula 1 or formula 2 steroid nucleus described in “IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN): The nomenclature of steroids,” Eur J, Biochem. 186, 429-458 (1989) and “International Union of Pure and Applied Chemistry and International Union of Biochemistry; Joint Commission on Biochemical Nomenclature, Nomenclature of Steroids,” Pure& Appl. Chem., Vol. 61, No, 10, pp. 1783-1822,1989, at 1, 2, 3, 4, or more of C1-C28through the — C(O) — O — structure, e.g., organic moiety-C(O) — O-steroid or organic moiety-0 — C(O)-steroid, When more than one ester is present, e.g., 2, 3, or 4 esters, each ester moiety is independently selected. The organic moiety usually comprises one or more of any of the organic groups described above, e.g., C1-20 alkyl moieties, C2-20 alkenyl moieties, C2-20alkynyl moieties, aryl moieties, C2-9 heterocycles, an ester moiety or substituted derivatives of any of these. Typical substitutions for these organic groups include 1, 2, 3, 4, or more, usually 1 or 2 independently selected, of —O—, —S—, —NRPR—, —C(O)—, —N(RPR)2, —C(O)ORPR, —OC(O)RPR, —ORPR, —SRPR, —NO2, =O, =S, —CN, —NHC(O)—, —C(O)NH—, —OC(O)—, —C(O)O—, — O-A8, — -S-A8, — C(O)-A8, — OC(O)-A8, — C(O)O-A8, =N —, — N=, — OPO3(RPR), — OSO3H2, or halogen moieties or atoms, where each RPRindependently is — H or a protecting group, or two RPRgroups together are a protecting group, and A8 is C1-8alkyl, Ci-8 alkenyl, C1-8alkynyl, C1-6alkyl- C2-9 aryl (e.g., benzyl), aryl (e.g. phenyl), or Co-6 alkyl-Ci -7 heterocycle. Substitutions are independently chosen. The organic moieties exclude obviously unstable moieties, e.g., — O — O — (in peroxides, peracids, and peresters), except where such unstable moieties are transient species that one can use to make a compound with sufficient chemical stability for the one or more of the uses described herein. The substitutions listed above are typically substituents that one can use to replace one or more carbon atoms, e.g., — O — or — C(O) —, or one or more hydrogen atom, e.g., halogen, — NH2, or — OH. In some embodiments, the ester is unsubstituted, i.e., H — C(O) — O-steroid.

[0032] As used herein, “amide” means an organic moiety as described for ester that comprises 1, 2, 3, 4, or more — C(O)NRPR— moieties, usually 1 or 2, where RPRis — H or a protecting group, RPRis usually H. In some embodiments, the — C(O)NRPR— group is linked to the steroid nucleus at 1, 2, 3, 4 or more of C1-C28through the — NRPR— moiety, e.g., organic moiety-C(O) — NRPR-steroid or steroid-C(O) — NRPR-orgamc moiety. The organic moiety is as described above for esters. In some embodiments, the amide is unsubstituted, i.e., H2N — C(O)-steroid or HC(O) — NH-steroid.

[0033] As used herein, “ether” means an organic moiety as described for ester that comprises 1, 2, 3, 4, or more — O — moieties, usually 1 or 2. In some embodiments, the — O — group is linked to the steroid nucleus at 1, 2, 3, 4, or more of C1-C28through the — O-moiety, e.g., organic moiety-O-steroid, The organic moiety is as described above for esters.

[0034] As used herein, “ether” means an organic moiety as described for ester that comprises 1, 2, 3, 4 or more — O — moieties, usually 1 or 2, In some embodiments, the — O — group is linked to the steroid nucleus at 1, 2, 3, 4 or more of R1-R28through the — O-moiety, e.g., organic moiety-O-steroid. The organic moiety is as described above for esters.

[0035] The term “pharmaceutically acceptable salt,” as used herein, refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.

[0036] As used herein, “pharmaceutical composition,” refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0235] The term “carrier,” as used herein, refers to a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

[0037] As used herein “diluent,” refers to chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low’ concentrations, a buffered diluent rarely modifies the biological activity of a compound.

[0038] As used herein, “physiologically acceptable,” refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0039] The term “dopamine precursor,” as used herein, is a substance or medicament that is converted into dopamine within the body. These substances can enter the brain and restore depleted levels of dopamine.

[0040] A “formulation” or the like means a composition that one can administer to a subject, e.g., human or animal. Formulations are suitable for human or veterinary applications and would typically have expected characteristics for the formulation, e.g., parenteral formulations for human use would usually be sterile solutions or suspensions.

[0041] An “excipient”, “carrier”, “pharmaceutically acceptable carrier” or similar terms mean one or more component(s) or ingredient(s) that is acceptable in the sense of being compatible with the other ingredients in the disclosed compositions or formulations and not overly deleterious to the patient, animal, tissues or cells to which the formulation is to be administered.

[0042] The term “mammal,” as used herein, is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes many other mammlian species.

[0043] As used herein, “subject,” “host,” “patient,” and “individual” are used interchangeably and shall be given their ordinary meaning in the art and shall also refer to an organism that has cancer and / or leukemia. This includes mammals, e.g., a human, a non-human primate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals.

[0044] The terms “therapeutically effective amount” and “effective amount” refer to the amount of an active pharmaceutical ingredient necessary to provide the desiredpharmacologic result. In practice, the therapeutically effective amount will vary widely depending on the severity of the disease condition, age of the subject, and the desired therapeutic effect.

[0045] The terms “treatment,” “treating,” “treat,” and the like shall be given their ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease. The terms “treatment,” as used herein shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, e.g., arresting its development; and / or (c) relieving the disease symptom, e.g,, causing regression of the disease or symptom.

[0046] As used herein, “about,” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. When a value is preceded by the term about, the component is not intended to be limited strictly to that value, but it is intended to include amounts that vary from the value.

[0047] All literature and similar materials cited in this application, including but not limited to, patents, patent applications, articles, books, treatises, and internet web pages are expressly incorporated by reference in their entirety for any purpose. When definitions of terms in incorporated references appear to differ from the definitions provided in the present teachings, the definition provided in the present teachings shall control. It will be appreciated that there is an implied “about” prior to the temperatures, concentrations, times, etc. discussed in the present teachings, such that slight and insubstantial deviations are within the scope of the present teachings herein. In this application, the use of the singular includes the plural unless specifically stated otherwise. Also, the use of “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” are not intended to be limiting. It is to be understood that both the general description and the following detaileddescription are exemplary and explanatory only and are not restrictive. The term “and / or” denotes that the provided possibilities can be used together or be used in the alternative. Thus, the term “and / or” denotes that both options exist for that set of possibilities.

[0048] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term “including” should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like “preferably,” “preferred,” “desired,” or “desirable,” and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the disclosure, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the disclosure. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction “and” should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as “and / or” unless expressly stated otherwise. Similarly, a group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, but rather should be read as “and / or” unless expressly stated otherwise.

[0049] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinitearticle “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs m the claims should not be construed as limiting the scope.Composition

[0050] In aspects, a composition is provided herein. In some embodiments, the composition may include a compound of Formula (I):

[0051] In some embodiments, Formula (I) may be represented by Formula (II), Formula (III), or Formula (IV):(IV)

[0052] In some embodiments of the compounds of Formula (I), (II), or (IV), R1is selected from the group consisting of optionally substituted amino, optionally substituted acrylate, optionally substituted C-amido, optionally substituted N-amido, optionally substituted organic acid, optionally substituted alcohol, optionally substituted ester, optionally substituted C1to C10alkoxy, optionally substituted C1to C6alkyl, optionally substituted C2to C6alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3to C8cycloalkyl, optionally substituted C6to C10aryl, optionally substituted C3to C8heterocyclyl, optionally substituted C3to C10heteroaryl, optionally substituted O-aryl, optionally substituted O-heteroaryl, optionally substituted C1to C10thioalkyl, optionally substituted thioaryl, optionally substituted sulfonamide, optionally substituted carbamate, halogen (F, Cl, Br, I), nitro (NO2), cyano (CN), optionally substituted urea, or optionally substituted phosphonate. In some embodiments of the compounds of Formula (I), (II), or (IV), R1is an optionally substituted alcohol. In some embodiments of the compounds of Formula (I), (II), or (IV), R1is an optionally substituted Ci to Cio alkyl. In some embodiments of the compounds of Formula (I), (II), or (IV), R1is an optionally substituted C2to C6alkenyl. In some embodiments of the compounds of Formula (I), (II), or (IV), R1is an optionally substituted ester. In some embodiments of the compounds of Formula (I), (II), or (IV), R1is an optionally substituted acrylate.

[0053] In some embodiments of the compounds of Formula (I), (II), (III), or (IV), R2is hydrogen, halogen (F, Cl, Br, I), optionally substituted ester, =0, optionally substituted O-C1to C6alkyl, -OH. In some embodiments of the compounds of Formula (I), (II), (III), or (IV), R2is =0, or -OH. In some embodiments of the compounds of Formula (I), (II), (III), or (IV), R2is =0. In some embodiments of the compounds of Formula (I), (II), (III), or (IV), R2is -OH.

[0054] In some embodiments of the compounds of Formula (I), X is CH2, NH, S, or O. In some embodiments of the compounds of Formula (I), X is CH2 or O. In some embodiments of the compounds of Formula (I), X is CH2. In some embodiments of the compounds of Formula (I), X is O.

[0055] In some embodiments of the compounds of Formula (I), the dashed bond represented by — is present or absent. When the dashed bond is present, a double bondis formed. In some embodiments of the compounds of Formula (I), one dashed bond represented by =^=^=-= is present. In some embodiments of the compounds of Formula (I), no dashed bond is present.

[0056] In some embodiments of the compounds of Formula (I), (II), (III), or (IV), R1, R2, R3, R4, R5, and R6may form one or more isomers. In some embodiments, the bond to R1, and R2may be represented by > AAr in some embodiments, > nAr represents one or more potential stereochemistry configurations. For example, each - T may be replaced by a *— or a -- > i. In some embodiments, the compounds of Formula (I), (II), (III), or (IV), may form one or more optical isomers, such as enantiomers. In some embodiments of the compounds of Formula (I), (II), (III), or (IV), form one or more diastereomers. In some embodiments of the compounds of Formula (I), (II), (III), or (IV), form one or more stereoisomers. In some embodiments, the compounds of Formula (I), (II), (III), or (IV), may form one or more conformational isomers.

[0057] In some embodiments, the composition may include at least one compound from Table 1. In some embodiments of the compounds of Formula (I), (II), (III), or (IV) are selected from the compounds of Table 1, and pharmaceutically acceptable salts thereof. Table 1

[0058] In some embodiments, the composition excludes 17a,20R-epoxypregn-5-ene-3P,21-diol. In some embodiments, the compound of Formula (I) excludes 17a, 2QR-epoxypregn-5-ene-3P,21-diol. In some embodiments, the compound of Formula (II) excludes 17a,207?-epoxypregn-5-ene-3,21-diol. In some embodiments, the compound of Formula (III) excludes 17a,20R-epoxypregn-5-ene-3P,21-diol. In some embodiments, the compound of Formula (IV) excludes 17a,20R-epoxypregn-5-ene-3,21-diol. In some embodiments, the composition excludes (20R,3S,17S)-20-(2-bromovinyl)-5-androstene-17,10-cyclopropan-3-ol. In some embodiments, the compound of Formula (I) excludes (20R,3S,17S)-20-(2-bromovinyl)-5-androstene-17,10-cyclopropan-3-ol. In some embodiments, the compound of Formula (II) excludes (20R,3S,17S)-20-(2-bromovinyl)-5-androstene-17,10-cyclopropan-3-ol. In some embodiments, the compound of Formula (III) excludes (20R,3S,17S)-20-(2-bromovinyl)-5-androstene-17,10-cyclopropan-3-ol. In some embodiments, the compound of Formula (IV) excludes (20R,3S,l 7S)-20-(2-bromovinyl)-5-androstene-l 7,10-cyclopropan-3-ol. In some embodiments, the composition excludes (17S,20S)-3-hydroxy-l 7,20-methan-5,21 -pregna-dien-22-ethyl ester. In some embodiments, the compound of Formula (I) excludes (17S,20S)-3-hydroxy-17,20-methan-5,21-pregna-dien-22-ethyl ester. In some embodiments, the compound of Formula (II) excludes (17S,20S)-3-hydroxy-17,20-methan-5,21-pregna-dien-22-ethyl ester. In some embodiments, the compound of Formula (III) excludes (17S,20S)-3-hydroxy-I7,20-methan-5,21-pregna-dien-22-ethyl ester. In some embodiments, thecompound of Formula (IV) excludes ( 17S,20S)-3 -hydroxy- 17, 20-methan-5, 21 -pregna-dien-22-ethyl ester.Syntheses and Methods of Preparation

[0059] Compounds of Formula (I), (II), (III), (IV), or pharmaceutically acceptable salts, esters, or prodrugs thereof, described herein may be prepared in various ways, including those known to those skilled in the art. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., and will be obvious to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973); and Greene & Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known froin the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety.

[0060] Where the processes for the preparation of the compounds disclosed herein give rise to mixtures of stereoisomers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by stereoselective synthesis or by stereoselective resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base.The compounds may also be resolved using a chiral auxiliary by formation of diastereomeric derivatives such as esters, amides or ketals followed by chromatographic separation and removal of the chiral auxiliary.Pharmaceutical Compositions

[0061] In another aspect, pharmaceutical compositions are disclosed that comprise a physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof; and a compound disclosed herein. Acceptable earners or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil, and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, and soya oil may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methylacetatemethacrylate copolymer as a derivative of polyvinyl may be used as suspension agents; and plasticizers such as ester phthalates and the like may be used as suspension agents.

[0062] For each of the compounds described herein, and for each genus or sub genus of compounds described herein, also described are pharmaceutical compositions comprising the compound, alone or in a mixture with other compounds of the genus or sub genus, or with alternative compounds described herein, or with one or more alternative pharmaceutically active compounds, and one or more pharmaceutically acceptable carrier, diluent, excipient or combination thereof. The pharmaceutical compositions described hereincan be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0063] The pharmaceutical compositions disclosed herein may be manufactured in any manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0064] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in “Remington’s Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0065] Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electro transport) patches, and the like, for prolonged and / or timed, pulsed administration at a predetermined rate.

[0066] Pharmaceutical compositions for use in accordance with the present disclosure may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington’s Pharmaceutical Sciences, above.

[0067] In several embodiments, the pharmaceutical compositions include at least one pharmaceutically acceptable excipient. Non-limiting examples of pharmaceutically acceptable excipients suitable for use in the compositions include fillers, diluents, disintegrants, binders, glidants, and / or lubricants. Other pharmaceutically acceptable excipients suitable for use in the compositions include absorption enhancing agents, acidifying agents, agents for modified release, alkalizing agents, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying agents, flavoring agents, humectants, humidity-adjusting agents, pH-adjusting agents, preservatives, solubilizing agents, stabilizers, surface-active agents, suspending agents, sweetening agents, taste-masking agents, and wetting agents.

[0068] Non-limiting examples of fillers suitable for use in the compositions include lactose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, and collagen.

[0069] Non-limiting examples of diluents suitable for use in the compositions include e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, and sugar.

[0070] Non-limiting examples of disintegrants suitable for use in the compositions include alginic acid or alginates, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, and carboxymethyl starch.

[0071] Non-limiting examples of binders suitable for use in the compositions include acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, polyethylene oxides, povidone, and pregelatinized starch.

[0072] Non-limiting examples of glidants and / or lubricants suitable for use in the compositions include stearic acid, magnesium stearate, calcium stearate or other metallic stearates, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, and sodium acetate.

[0073] Non-limiting examples of antioxidants suitable for use in the compositions include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, and derivatives of tocopherol.

[0074] In several embodiments, the pharmaceutically acceptable excipient is selected from sodium dodecyl sulfate, microcrystalline cellulose, magnesium stearate, and any combination of the foregoing. In several embodiments, the pharmaceutically acceptable excipient is sodium dodecyl sulfate.

[0075] In several embodiments, the pharmaceutical compositions are formulated into oral dosage forms. In several embodiments, the dosage forms can include capsules and tablets. In some embodiments, the dosage forms can include one or more different types of delayed release layers selected from sealant and / or enteric layers. For example, delayed release layers having different release rate characteristics can provide the dosage form with different overall drug release characteristics. In some such embodiments, the pharmaceutically acceptable excipient is a surface active agent. In several embodiments, the surface active agent is present in an amount sufficient to provide 90% dissolution of the pharmaceutical composition in water at ambient temperature after 30 min. In several embodiments, the surface active agent is sodium lauryl sulfate. In several embodiments, the pharmaceutical composition is a capsule or a tablet.

[0076] Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. Physiologicallycompatible buffers include, but are not limited to, Hanks’s solution, Ringer’s solution, or physiological saline buffer. If desired, absorption enhancing preparations (for example, liposomes), may be utilized.

[0077] For transmucosal administration, penetrants appropriate to the barrier to be permeated may be used in the formulation.

[0078] Pharmaceutical formulations for parenteral administration, e.g., by bolus injection or continuous infusion, include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit or almond oils, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.

[0079] For subcutaneous implantation, the compounds can be formulated for long-acting, sustained release via subcutaneous implantation. Such formulations may be in the form of a solid, semi-solid, or viscous depot preparation, such as a compressed pellet, rod, or microparticle matrix. The implant may consist of the active compound in a crystalline or amorphous form, or the active compound may be dispersed within a biocompatible, and optionally biodegradable or bioresorbable, matrix. Suitable matrix materials include, but are not limited to, biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA), polylactides, polyglycolides, polycaprolactone, or polyanhydrides. Release of the active compound from the implant may be controlled by diffusion from the matrix, by erosion of the matrix, or by a combination of diffusion and erosion over a period of weeks or months.

[0080] The compounds can be formulated for intraperitoneal administration, a route often employed in preclinical or animal model studies for acute or repeated dosing. For such applications, the active compound is prepared as a sterile injectable solution or suspension. The vehicle may be an aqueous, physiologically compatible buffer, such as sterile physiological saline, phosphate-buffered saline (PBS), or Ringer's solution. For androgen analogs with poor aqueous solubility,, the formulation may utilize co-solvents (e.g., dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), ethanol), or surfactant-based vehicles (e.g., containing Tween 80 or Cremophor EL) to achieve a suitable solution or fine-particle suspension for injection.

[0081] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0082] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0083] For oral lipid-based delivery, the compounds may be formulated to enhance the oral bioavailability of the androgen analogs, particularly by facilitating lymphatic uptake and bypassing hepatic first-pass metabolism. In such embodiments, the active compound is formulated as a lipid-based delivery system, such as a self-emulsifying drug delivery system (SEDDS) or a self-microemulsifying drug delivery system (SMEDDS). These formulations typically comprise the active compound dissolved or suspended in a mixture of oils (e.g,, sesame oil, castor oil, medium-chain triglycerides), non-ionic surfactants (e.g., polysorbates, polyoxyl castor oil derivatives, lauroyl polyoxylglycerides), and / or co-solvents (e.g,, diethylene glycol monoethyl ether (Transcutol®), ethanol, propylene glycol). These lipid-based formulations are preferably encapsulated in a soft gelatin or hard gelatin capsule for oral administration. Upon contact with gastrointestinal fluids, the formulation spontaneously forms a fine-particle emulsion or microemulsion, facilitating drug dissolution and absorption.Method and Uses

[0084] Aspects of the present disclosure relate to methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject in need thereof. In some embodiments, the method includes administering to the subject a compound or a composition as described herein. In some embodiments, the disease or condition is a neurodegenerative disease or condition. In some embodiments, the methods include administering to a subject in need thereof an effective amount of one or more compounds or a composition as described herein.

[0085] Some embodiments relate to a method to prevent, treat, reduce, or ameliorate a neurological condition. In some embodiments, the method includes administering to a subject in need thereof an effective amount of one or more compound or a composition as described herein. In some embodiments, the neurological condition includes neurodegeneration. In some embodiments, neurodegeneration includes impaired function and loss of neurons. In some embodiments, the neurological condition includes neuroinflammation. In some embodiments, neuroinflammation includes the inflammatoryactivation of glial cells, microglia, astrocytes, or a combination thereof. In some embodiments, neuroinflammation may include destructive consequences for the neural system. In some embodiments, the neurodegenerative condition includes Alzheimer’s disease, Parkinson’s disease or Amyotrophic Lateral Sclerosis. In several embodiments, the neurodegenerative condition is Parkinson’s disease, parkinsonisms, a parkinsonian syndrome, or any combination of the foregoing. In several embodiments, the neurodegenerative condition includes idiopathic Parkinson’s disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and vascular parkinsonism, or any combination of the foregoing. In several embodiments, the neurodegenerative condition is Parkinson’s disease.

[0086] In some embodiments, a method is provided to treat, reduce, prevent, or ameliorate a disease or condition in a subject. In some embodiments, the disease or condition is associated with amyloid beta (Aβ) peptides. In some embodiments, the method to prevent a disease or condition in the subject may be by administration of a compound as described herein, or a pharmaceutical form thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the method to prevent a disease or condition in the subject may be by administration of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutical form thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about10 mg / kg every two weeks. In some embodiments, the compound or composition described herein is provided at about 200 mg / kg. In some embodiments, the compound or composition described herein may be provided at about 20 mg twice a day (BID) (40 mg daily). In some embodiments, the method reduces amyloid-beta load, restores cholinergic function, promotes synaptogenesis, decreases neuroinflammation, or improves cognitive performance in the subject. In some embodiments, the compound or composition may be administered orally, such as in a capsule or tablet. In other embodiments,the compound or composition may be administered via subcutaneous implantation of a biodegradable pellet system for sustained release.

[0087] Some embodiments relate to a method to treat, prevent, reduce, or ameliorate Alzheimer’s Disease or a condition associated with Alzheimer’s Disease in a subject. In some embodiments, the method includes administering to the subject at least one compound or a composition as disclosed herein. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about10 mg / kg every two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the compound or composition described herein may be provided at about 20 mg BID (40 mg daily). In some embodiments, the method reduces amyloid-beta load, restores cholinergic function, promotes synaptogenesis, decreases neuroinflammation, or improves cognitive performance in the subject. In some embodiments, the compound or composition may be administered orally, such as in a capsule or tablet. In other embodiments, the compound or composition may be administered via subcutaneous implantation of a biodegradable pellet system for sustained release.

[0088] Some embodiments relate to a method to treat, prevent, reduce, or ameliorate Parkinson’s Disease or a condition associated with Parkinson’s Disease. In some embodiments, the method includes administering to the subject at least one compound or a composition as disclosed herein. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be providedat about! 0 mg / kg every’ two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the compound or composition described herein may be provided at about 20 mg BID (40 mg daily).

[0089] Some embodiments relate to a method to treat, prevent, reduce, or ameliorate spinal cord injury (SCI) in a subject in need thereof. In some embodiments, the method includes administering to the subject an effective amount of a compound or a composition as described herein. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about10 mg / kg every two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method reduces astrogliosis and increases the density of neurons and neural stem cells following spinal cord injury. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0090] Some embodiments relate to a method to treat, prevent, reduce, or ameliorate schizophrenia or symptoms associated with schizophrenia in a subject. In some embodiments, the method includes administering to the subject an effective amount of a compound or a composition as described herein. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at aboutlO mg / kg every' two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, themethod counteracts behavioral deficits including cognitive impairments and social withdrawal associated with schizophrenia. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0091] Some embodiments relate to a method to treat, prevent, reduce, or ameliorate retinal diseases including diabetic retinopathy and retinal detachment in a subject. In some embodiments, the method includes administering to the subject an effective amount of a compound or a composition as described herein. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about10 mg / kg every two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method protects retinal cells from dying and provides neuroprotective effects. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0092] Some embodiments relate to a method to treat, prevent, reduce, or ameliorate pain and inflammation in a subject. In some embodiments, the method includes administering to the subject an effective amount of a compound or a composition as described herein. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at aboutlO mg / kg every’ two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method includesadministering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient. In some embodiments, the method provides an analgesic or anti-inflammatory effect. In some embodiments, the method includes reversing hyperalgesia in the subject.

[0093] Some embodiments relate to a method to treat, prevent, reduce, or ameliorate multiple sclerosis (MS) in a subject. In some embodiments, the method includes administering to the subject an effective amount of a compound or a composition as described herein. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about10 mg / kg every two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method protects mature oligodendrocytes and reduces amyloid-beta plaques, protects neurons, improves cognitive function, and acts as an analgesic and anti-inflammatory agent. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0094] Some embodiments relate to a method to treat, prevent, reduce, or ameliorate Amyotrophic Lateral Sclerosis (ALS) or a condition associated with ALS. In some embodiments, the method includes administering to the subject a compound or a composition as disclosed herein. In some embodiments, the method protects motor neurons from degradation or reduces oxidative stress in the subject. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may beprovided at aboutlO mg / kg every two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0095] In several embodiments, a compound of Formula (I), (II), (III), or (IV) administered to the subject is a synthetic molecule that mimics the effects of nerve growth factor (NGF). In some embodiments, the compound activates one or both of the NGF receptors, TrkA and p75NTR, In some embodiments, the compound may be capable of crossing the blood-brain barrier. In some embodiments, the compound may be capable of crossing the blood-retinal barrier. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about10 mg / kg every two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0096] In some embodiments, a method for preventing, treating, reducing, or ameliorating a disease or condition in a subject previously infected with a virus includes administering to the subject a compound of Formula (I), (II), (III), or (IV), or a pharmaceutical form thereof. In some embodiments, the virus is COVID-19. In some embodiments, the subject meets the Diagnosis of Chronic Fatigue Syndrome (CFS). In some embodiments, the subject has concurrent occurrence of at least one or more of Long CO VID symptoms which persisted or recurred during 3 or more consecutive months of illness. In some embodiments, the Long COVID symptoms are not known to be preceded by the infection of COVID-19. In some embodiments, the Long COVID symptoms include, but are not limited to, fatigue, post-exertional malaise, headache, sleep disturbance, memory problems, problems with concentration, brain fog, fever, chills, cough, shortness of breath, difficulty breathing, loss oftaste, loss of smell, and chest pain. In some embodiments, the method may further include diagnosing the subject for the presence of COVID-19 or a COVID-19 antibody. In some embodiments, the method includes administering a combination of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutical form thereof, and an anti-inflammatory agent to reduce systemic inflammation associated with Long COVID. In some embodiments, the method incorporates a regimen of physical therapy designed to gradually improve exercise tolerance and manage post-exertional malaise in subjects meeting the Diagnosis of Chronic Fatigue Syndrome (CFS). In some embodiments, the method involves psychological or cognitive behavioral therapy to address memory problems, concentration difficulties, and brain fog in subjects with Long COVID symptoms. In some embodiments, the treatment includes supplemental oxygen therapy or respiratory exercises for subjects experiencing persistent shortness of breath or difficulty breathing. In some embodiments, the method includes administering a course of vitamins and nutriti onal supplements aimed at boosting the immune system and alleviating fatigue and weakness. In some embodiments, the method involves the use of telemedicine for ongoing monitoring and management of Long COVID symptoms, especially for subjects with limited mobility or access to healthcare facilities. In some embodiments, the method includes a holistic approach, integrating lifestyle modifications such as diet changes, stress management techniques, and sleep hygiene practices to improve overall well-being and mitigate symptoms like sleep disturbance and fatigue. In some embodiments, the method further includes administering neuroprotective agents to treat neurological symptoms such as loss of taste, loss of smell, and neuropathic pain. In some embodiments, the method further includes the use of antiviral medications in combination with a compound of Formula (I), (II), (III), or (IV), or a pharmaceutical form thereof, to target any residual viral activity that may be contributing to ongoing symptoms. In some embodiments, the method further includes periodic screening for secondary infections or complications that could exacerbate Long COVID symptoms, ensuring comprehensive care of the subject. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 nig / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or compositiondescribed herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about10 mg / kg every two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0097] In some embodiments, a method for preventing, treating, reducing, or ameliorating a disease or condition in a subject afflicted with a post-viral illness includes administering to the subject a compound of Formula (I), (II), (III), or (IV), or a pharmaceutical form thereof, wherein the post-viral illness is caused by or associated with the viral disease or infection in the subject. In some embodiments, the post-viral illness is caused by the viral disease in the subject. In some embodiments, a compound of Formula (I), (II), (III), or (IV), or a pharmaceutical form thereof, treats symptoms associated with recovery from the viral disease in the subject. In some embodiments, the symptoms include fatigue, post-exertional malaise (PEM), problems with memory or concentration, sore throat, headache, muscle or joint pain, dizziness, brain fog, shortness of breath, and / or unrefreshing sleep. In some embodiments, the post-viral illness is Long COVID In some embodiments, the method further includes administering a compound of Formula (I), (II), (III), or (IV), or a pharmaceutical form thereof, in conjunction with an anticoagulant or blood thinner to treat or prevent blood clotting issues commonly seen in post-viral illnesses like Long CO VID. In some embodiments, the method includes the use of supplemental oxygen or respiratory support devices for subjects experiencing persistent respiratory difficulties as a result of the post-viral illness. In some embodiments, the method includes cognitive rehabilitation therapies to specifically address and ameliorate problems with memory and concentration associated with brain fog in Long COVID patients. In some embodiments, the method involves administering a tailored regimen of gentle physical exercises and physiotherapy to help subjects manage muscle or joint pain and gradually improve their physical function. In some embodiments, the method incorporates psychological counseling or therapy to help subjects cope with the mental health impacts, such as anxiety or depression, that often accompany prolonged illnesses like Long COVID In some embodiments, the method includes the use of nutritional supplements or dietary' adjustments to support overall health and mitigate symptoms like fatigue and unrefreshing sleep. In someembodiments, the method includes the administration of immune modulators or supplements to balance the immune response and reduce systemic inflammation characteristic of post-viral syndromes. In some embodiments, the method includes regular monitoring and assessment of cardiovascular health, given the increased risk of heart-related issues in post-viral illness scenarios. In some embodiments, the method includes using hydration therapy, either orally or intravenously, to alleviate symptoms of dizziness and improve overall energy levels in subjects. In some embodiments, the method further includes the use of non-phamiacological interventions such as acupuncture or massage therapy to provide relief from symptoms like muscle pain and headache. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about10 mg / kg every two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0098] In some embodiments, the subject may experience prevention or reduction in one or more symptoms associated with a previous viral infection after administration of a compound or composition as described herein. In some embodiments, the subject may experience prevention or reduction in one or more symptoms associated with Long COVID after administration of a compound or composition as described herein. In some embodiments, the prevention or reduction in symptoms related to Long CO VID may be reduced by an amount equal to or greater than approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 99%, 100%, or within ranges including and / or spanning the aforementioned values after administration of the compound or composition as described herein. For example, subjects may experience prevention or reduction in one or more symptoms of Long CO VID from approximately 5% to 100% after administration of thecompound or composition as described herein and at least one pharmaceutically acceptable excipient.

[0099] In some embodiments, the subject may experience an improvement or amelioration in one or more symptoms associated with a previous viral infection after administration of a compound or composition as described herein. In some embodiments, the subject may experience an improvement or amelioration m one or more symptoms associated with Long COVID after administration of a compound or composition as described herein. In some embodiments, the prevention or reduction in symptoms related to Long COVID may be reduced by an amount equal to or greater than approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 99%, 100%, or within ranges including and / or spanning the aforementioned values after administration of the compound or composition as described herein. For example, subjects may experience improvement or amelioration m one or more symptoms of Long COVID from approximately 5% to 100% after administration of the compound or composition as described herein and at least one pharmaceutically acceptable excipient. In some embodiments, the compound or composition as described herein may be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about10 mg / kg every two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0100] In several embodiments, the methods include administering at least one additional medicament to the subject. In some embodiments, the additional medicament comprises at least one dopamine agonist, which may include an ergoline dopamine agonist, a non-ergoline dopamine agonist, or any combination thereof. Non-limiting examples of suitable dopamine agonists include bromocriptine, cabergoline, apomorphine, pramipexole, ropinirole, rotigotine, APOKYN, KYNMOBI, MIRAPEX, NEUPRO, PARLODEL, and REQUIP. Insome embodiments, the additional medicament comprises at least one dopamine precursor. Non-limiting examples of suitable dopamine precursors include carbidopa, L-DOPA (i.e., levodopa), entacapone, COMTAN, DUOP A, INBRIJA, RYTARY, SINEMET, SINEMET CR, and STALEVO. In some embodiments, the additional medicament comprises L-DOPA.

[0101] In several embodiments, the additional medicament is administered at a delay time after a first administration of the composition. In several embodiments, the first administration may occur using a dosage schedule that is daily, weekly, monthly, or any combination of the foregoing. In several embodiments, the dosage schedule of the first administration may include one, two, three, or more daily dosages of the composition. In several embodiments, the dosage schedule of the first administration may include one, two, three, or more weekly dosages of the composition. In several embodiments, the dosage schedule of the first administration may include one, two, three, or more monthly dosages of the composition. In several embodiments, the delay time is equal to or greater than about: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or is within ranges including and / or spanning the aforementioned values. In several embodiments, the delay time may be equal to or greater than 2 years. In some embodiments, the delay time may be zero and the additional medicament may be administered concurrently with the first administration of the composition. In several embodiments, the additional medicament may be administered using a dosage schedule that is daily, weekly, monthly, or any combination of the foregoing. In several embodiments, the dosage schedule of the additional medicament may include one, two, three, or more daily dosages of the composition. In several embodiments, the dosage schedule of the additional medicament may include one, two, three, or more weekly dosages of the composition. In several embodiments, the dosage schedule of the additional medicament may include one, two, three or more monthly dosages of the composition.

[0102] In some embodiments, the subject is administered the compound or composition as described herein upon observation of at least one motor symptom associated with a neurological disease or condition. In some embodiments, the compound or composition is administered at the onset of or following diagnosis of a motor symptom such as tremor, bradykinesia, rigidity, or gait disturbance. In some embodiments, the compound or composition is administered to the subject prior to the development of disabling motor symptoms, including prior to the loss of postural balance, freezing of gait, or recurrent falls. Insome embodiments, the compound or composition is administered during early, moderate, or advanced disease stages, as determined by a healthcare provider. In some embodiments, the compound or composition is administered to the subject upon initial clinical identification of motor fluctuations, including transitions between “on-periods” and “off-periods.” In some embodiments, the compound or composition is administered in response to worsening frequency, duration, or severity of “off-periods.” In some embodiments, the compound or composition is administered to reduce, prevent, or delay the development of dyskinesia, dystonia, or other motor complications associated with disease progression or treatment. In some embodiments, the compound or composition is administered in conjunction with one or more additional medications used to treat motor symptoms, including but not limited to dopaminergic agents, MAO-B inhibitors, COMT inhibitors, or amantadine. In some embodiments, the compound or composition is administered according to a continuous, intermittent, titrated, or as-needed dosing regimen, which may be adjusted based on clinical evaluation. In some embodiments, the compound or composition is administered as part of a maintenance therapy to stabilize motor function and reduce motor symptom fluctuations. In some embodiments, the compound or composition is administered to a subject identified as being at increased risk of developing motor complications, based on clinical assessment, genetic markers, neuroimaging results, or disease course.

[0103] In several embodiments, at least one motor symptom develops in the patient. The term “motor symptom,” as used herein, is one or more of tremor and / or shaking in the extremities, slowed movement (bradykmesia), muscle stiffness, rigidity, immobility (freezing), muscle cramps, impaired posture and / or balance, falls, dizziness, loss of automatic movements such as blinking or smiling, changes in speech and / or writing, motor fluctuations, and dystonia. The term “dystonia,” as used herein, is a state of abnormal muscle tone resulting in muscular spasm and abnormal posture. In several embodiments, at least one motor complication develops in the patient. The term “motor complication,” as used herein, can be a cycling between on-periods and off-periods. The term “on-period,” as used herein, is a state of positive response to the composition, the additional medicament, or a combination thereof. The on-period is characterized by the absence of, or a decrease in, symptoms related to Parkinson’s disease, parkinsonisms, a parkinsonian syndrome, or any combination of the foregoing. The term “off-period,” as used herein, is a state of no response to the composition, the additionalmedicament, or a combination thereof. The off-period is characterized by the presence of symptoms related to Parkinson’s disease, parkinsonisms, a parkinsonian syndrome, or any combination of the foregoing. In several embodiments, the symptoms related to Parkinson’s disease parkinsonisms, and / or a parkinsonian syndrome may include at least one motor symptom, as described elsewhere herein.

[0104] In some embodiments, the subject is administered the compound or composition as described herein upon observation or diagnosis of at least one non-motor symptom associated with a neurological disease or condition. In some embodiments, the subject is administered the compound or composition as described herein prior to the onset of motor symptoms. In some embodiments, the compound or composition is administered during a prodromal or early stage of the neurological disease. In some embodiments, the compound or composition is administered in response to measured progression or worsening of one or more non-motor symptoms. In some embodiments, the compound or composition is administered following a physician’s clinical assessment indicating increased risk of developing a neurodegenerative condition. In some embodiments, the compound or composition is administered to a subject having a confirmed biomarker, genetic marker, neuroimaging result, or other diagnostic indicator associated with a neurological disease or condition, even in the absence of motor symptoms. In some embodiments, the compound or composition is administered to prevent or delay progression from mild cognitive impairment to dementia. In some embodiments, the compound or composition is provided to the subject as part of an ongoing therapeutic, preventive, or maintenance regimen. In some embodiments, the compound or composition is administered chronically, intermittently, as needed, or according to a dosing schedule determined by a healthcare provider. In some embodiments, the compound or composition is administered together with one or more additional therapeutic agents, behavioral interventions, neuroprotective therapies, or supportive care strategies. In some embodiments, the subject develops at least one non-motor symptom. As used herein, the term “non-motor symptom” refers to a symptom, sign, or clinical manifestation of a neurological disease or condition that does not primarily affect voluntary motor control, but may involve cognitive, behavioral, neuropsychiatric, autonomic, sleep-related, sensory’, or gastrointestinal processes. In some embodiments, the non-motor symptom is selected from the group consisting of memory impairment; mild cognitive impairment; cognitive decline;reduced attention or concentration; impaired judgment or executive dysfunction; slowed information processing (bradyphrema); difficulty with language (aphasia); difficulty with visuospatial processing or spatial disorientation; apathy; depression; anxiety; emotional lability; agitation; irritability; psychosis; hallucinations; delusions; impulse control disorders; compulsive or repetitive behaviors; decreased motivation or anhedonia; sleep disturbances including insomnia, REM sleep behavior disorder (RBD), excessive daytime sleepiness (somnolence), sleep fragmentation, or circadian rhythm disruption; autonomic dysfunction including constipation, gastroparesis, nausea, dysphagia, urinary urgency, urinary frequency, urinary incontinence, nocturia, orthostatic hypotension, dizziness, syncope, sweating abnormalities (hyperhidrosis or hypohidrosis), therm or egulatory intolerance, sexual dysfunction, or sialorrhea (excessive salivation) or xerostomia (dry mouth); sensory abnormalities including hyposmia or anosmia (reduced or lost sense of smell), altered or diminished sense of taste, pain, central pain syndromes, numbness, tingling (paresthesia), or heightened sensitivity to touch or temperature; chronic fatigue; weight loss or weight gain without explanation; vision disturbances including blurred vision or reduced contrast sensitivity; and any combination thereof.

[0105] In some embodiments, the subject develops at least one non-motor complication. As used herein, the term “non-motor complication” refers to a clinically significant worsening, progression, or consequence of one or more non-motor symptoms, including but not limited to a loss of cognitive, behavioral, psychiatric, autonomic, or functional capacity. In some embodiments, the non-motor complication is selected from the group consisting of: dementia; severe, progressive cognitive decline; loss of ability to perform activities of daily living (ADLs); loss of speech or severe impairment of communication; severe depression or treatment-resistant mood disorder; persistent psychosis; paranoia or delusional thinking leading to safety risk; profound apathy resulting in social withdrawal; severe dysphagia; recurrent aspiration or aspiration pneumonia; marked gastrointestinal immobility including severe gastroparesis or bowel obstruction; chronic malnutrition or dehydration; cardiovascular instability or recurrent syncope; injury or fractures resulting from falls associated with dizziness or autonomic dysfunction; and any combination thereof.

[0106] In several embodiments, the motor complications can include wearing off, dose failure, beginning of dose worsening, end-of-dose rebound, unpredictable off-periods,freezing of gait, on-period failure, acute akinesia, or a combination of the foregoing. The term "wearing off," as used herein, is a reemergence of symptoms related to Parkinson’s disease that occurs as metabolization of the composition, the additional medicament, or a combination thereof reaches completion. The term “unpredictable off-period” is an off-period that is not correlated with the administration the composition, the additional medicament, or a combination thereof. The term “freezing of gait,” as used herein, is a state in which forward progression halts or is markedly reduced. The term “on-period failure,” as used herein, is absence of an on-period after the administration the composition, the additional medicament, or a combination thereof. The term “acute akinesia,” as used herein, is a sudden and / or severe increase of symptoms related to Parkinson’s disease, including an akinetic state that lasts for several days and does not respond to the administration the composition, the additional medicament, or a combination thereof,

[0107] In several embodiments, the motor complications can include dyskinesia. The term “dyskinesia,” as used herein, is an abnormality or impairment of voluntary movement and / or posture. In several embodiments, the motor complications include dyskinesia selected from L-DOPA-induced dyskinesia, chorea, dystonia, ballism, myoclonus, peak-dose dyskinesia, diphasic dyskinesia, wearing-off dyskinesia, wearing-off dystonia, or a combination of the foregoing. The term “peak-dose dyskinesia,” as used herein, appears during an on-period and begins at about 30 to 90 minutes after administration of the composition, the additional medicament, or a combination thereof. The term “diphasic dyskinesia,” as used herein, includes two separate periods of involuntary movement after administration of the composition, the additional medicament, or a combination thereof. The first one occurring at the start of an on-period and the second one occurring at the start of an off-period. The term “wearing-off dyskinesia,” as used herein, is less common and is sometimes characterized by large-amplitude leg movements. The condition described by term “wearing-off dystonia,” as used herein, manifests as dystonia during an off-periods and usually involves the limbs but sometimes involving the face, neck, or trunk. In several embodiments, the dyskinesia appears at various times in relation to the administration the composition, the additional medicament, or a combination thereof.

[0108] In several embodiments, the motor symptom occurs when the composition, the additional medicament, or a combination thereof has been completely metabolized. Inseveral embodiments, the motor symptom occurs when the composition has been completely metabolized. In several embodiments, the motor symptom occurs when the additional medicament has been completely metabolized. In several embodiments, the motor symptom occurs when the dopamine agonist has been completely metabolized. In several embodiments, the motor symptom occurs when the dopamine precursor has been completely metabolized. In several embodiments, the motor symptom occurs when the L-DOPA has been completely metabolized.

[0109] In several embodiments, the motor complication occurs when the composition, the additional medicament, or a combination thereof has been completely metabolized. In several embodiments, the motor complication occurs when the composition has been completely metabolized. In several embodiments, the motor complication occurs when the additional medicament has been completely metabolized. In several embodiments, the motor complication occurs when the dopamine agonist has been completely metabolized. In several embodiments, the motor complication occurs when the dopamine precursor has been completely metabolized. In several embodiments, the motor complication occurs when the L-DOPA has been completely metabolized.

[0110] In several embodiments, the motor symptom develops at a time equal to or greater than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 years after the composition is administered. In several embodiments, the motor symptom develops at a time equal to or greater than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 years after the additional medicament is administered. In several embodiments, the motor symptom develops at a time equal to or greater than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 years after the dopamine precursor is administered. In several embodiments, the motor symptom develops at a time equal to or greater than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 years after the L-DOPA is administered.

[0111] In several embodiments, the motor complication develops at a time equal to or greater than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 years after the composition is administered. In several embodiments, the motor complication develops at a time equal to or greater than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 years after the additional medicament isadministered. In several embodiments, the motor complication develops at a time equal to or greater than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 years after the dopamine precursor is administered. In several embodiments, the motor complication develops at a time equal to or greater than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30years after the L-DOPA is administered.

[0112] Several embodiments of the present disclosure relate to pharmaceutical compositions including at least one compound as disclosed herein for use in treating a neurodegenerative condition. In several embodiments, the neurodegenerative condition is Alzheimer’s disease, Parkinson’s disease, or Amyotrophic Lateral Sclerosis. In several embodiments, the neurodegenerative condition is Parkinson’s disease, parkinsonisms, a parkinsonian syndrome, or any combination of the foregoing. In several embodiments, the neurodegenerative condition includes idiopathic Parkinson disease, progressive supranuclear palsy, multiple system atrophy, corti cobasal degeneration, and vascular parkinsonism, or any combination of the foregoing. In several embodiments, the neurodegenerative condition is Parkinson’s disease. In several embodiments, the pharmaceutical compositions include at least one pharmaceutically acceptable excipient.

[0113] In several embodiments, the pharmaceutical compositions are used with at least one additional medicament. In several embodiments, the additional medicament includes at least one dopamine agonist, as described elsewhere herein. In several embodiments, the additional medicament includes at least one dopamine precursor as described elsewhere herein. In several embodiments, the additional medicament includes L-DOPA. In several embodiments, the additional medicament is used at a delay time after use of the pharmaceutical composition begins. In several embodiments, the delay time is equal to or greater than 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or is within ranges including and / or spanning the aforementioned values. In several embodiments, the delay time is equal to or greater than 2 years.

[0114] In several embodiments, at least one motor symptom may develop while the pharmaceutical compositions are used. Such motor symptoms are described elsewhere herein. In several embodiments, the motor symptom develops at a time after the use of the pharmaceutical composition begins that is 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or is within ranges including and / or spanning the aforementionedvalues. In several embodiments, the motor symptom develops at a time equal to or greater than 2 years after the use of the pharmaceutical composition begins. In several embodiments, the motor symptom develops at a time after the use of the additional medicament begins that is 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or is within ranges including and / or spanning the aforementioned values. In several embodiments, the motor symptom develops at a time equal to or greater than 2 years after the use of the additional medicament begins.

[0115] In several embodiments, at least one motor complication may develop while the pharmaceutical compositions are used. Such motor complications are described elsewhere herein. In several embodiments, the motor complication develops at a time after the use of the pharmaceutical composition begins that is 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or is within ranges including and / or spanning the aforementioned values. In several embodiments, the motor complication develops at a time equal to or greater than 2 years after the use of the pharmaceutical composition begins. In several embodiments, the motor complication develops at a time after the use of the additional medicament begins that is 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or is within ranges including and / or spanning the aforementioned values. In several embodiments, the motor complication develops at a time equal to or greater than 2 years after the use of the additional medicament begins.

[0116] Several embodiments of the present disclosure relate to the use of pharmaceutical compositions including a compound of Formula (I), (II), (III), or (IV), or a pharmaceutical form thereof, for treating a neurodegenerative condition. In several embodiments, the neurodegenerative condition is Alzheimer’s disease, Parkinson’s disease, or Amyotrophic Lateral Sclerosis. In several embodiments, the neurodegenerative condition is Parkinson’s disease, parkinsonisms, a parkinsonian syndrome, or any combination of the foregoing. In several embodiments, the neurodegenerative condition includes idiopathic Parkinson disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and vascular parkinsonism, or any combination of the foregoing. In several embodiments, the neurodegenerative condition is Parkinson’s disease. In several embodiments, the pharmaceutical compositions include at least one pharmaceutically acceptable excipient. In some embodiments, the compound or composition as described hereinmay be provided to the subject via a pellet or orally. In some embodiments, the administration may be provided at one or more doses. In some embodiments, the compound or composition may be provided at about 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, or within ranges including and / or spanning the aforementioned values. In some embodiments, the compound or composition described herein may be provided daily for seven days. In some embodiments, the compound or composition described herein may be provided at about! 0 mg / kg every’ two weeks. In some embodiments, the compound or composition described herein may be provided at about 200 mg / kg. In some embodiments, the method includes administering the compound or composition as described herein in combination with at least one pharmaceutically acceptable excipient.

[0117] In several embodiments, the use is concurrent with at least one additional medicament. The additional medicament may include at least one dopamine agonist, at least one dopamine precursor, or L-DOPA In several embodiments, administration of the additional medicament may occur after a delay following initiation of the pharmaceutical composition. The delay time may be equal to or greater than 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or may be within ranges including and / or spanning these values. In several embodiments, the delay time may be equal to or greater than 2 years. In several embodiments, the use may result in the development of at least one motor complication, as described elsewhere herein. The motor complication may develop at a time after initiation of the pharmaceutical composition or the additional medicament, with possible onset at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or within ranges including and / or spanning these values. In several embodiments, the motor complication develops at a time equal to or greater than 2 years after initiation of the pharmaceutical composition or the additional medicament.

[0118] In several embodiments, the use may result in the development of at least one motor complication, as described elsewhere herein. The motor complication may develop at a time after initiation of the medicament or the additional medicament, with possible onset at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or within ranges including and / or spanning these values. In several embodiments, the motor complication develops at a time equal to or greater than 2 years after initiation of the medicament or the additional medicament.

[0119] Some embodiments relate to a use of a compound or a composition as described herein for treating Alzheimer’s Disease, wherein the compound or the composition is administered orally, such as in a capsule or tablet. In some embodiments, the oral dose is about 20 mg BID (about 40 mg daily). In another such embodiment, the oral dose is about 1 mg / kg daily or about 50 mg / kg daily.

[0120] Some embodiments relate to a use of a compound or a composition as described herein for treating Alzheimer’s Disease, wherein the compound or the composition is administered via subcutaneous implantation of a biodegradable pellet system. In one such embodiment, the pellet is formulated to provide a sustained release dose of about 1 mg / kg to about 10 mg / kg daily for a period of about 10 days to about 60 days,

[0121] Some embodiments relate to a use of a compound or a composition as described herein for treating Parkinson’s Disease, wherein the compound or the composition is administered orally. In some embodiments, the oral dose is about 20 mg BID (about 40 mg daily). In another such embodiment, the oral dose is about 1 mg / kg, administered daily for seven days.

[0122] Some embodiments relate to a use of a compound or a composition as described herein for treating Parkinson’s Disease, wherein the compound or the composition is administered via a subcutaneous biodegradable pellet system for sustained release. In one such embodiment, the pellet is formulated to provide a sustained release dose of about 1 mg / kg to about 10 mg / kg daily for a period of about 10 days to about 60 days.

[0123] Some embodiments relate to a use of a compound or a composition as described herein for treating Multiple Sclerosis, wherein the compound or the composition is administered orally at a dose of about 1 mg / kg daily. In some embodiments, the oral dose is about 20 mg BID (about 40 mg daily). In another such embodiment, the oral dose is about 1 mg / kg, administered daily for seven days.

[0124] Some embodiments relate to a use of a compound or a composition as described herein for treating Spinal Cord Injury, wherein the compound or the composition is administered via subcutaneous implantation of a biodegradable pellet system at a dose of about 1 mg / kg, and wherein the method reduces astrogliosis and increases the density of neurons. In one such embodiment, the pellet is formulated to provide a sustained release dose of about 1 mg / kg to about 10 mg / kg daily for a period of about 10 days to about 60 days.

[0125] Some embodiments relate to a use of a compound or a composition as described herein for treating symptoms associated with Long COVID, wherein the compound or the composition is administered orally as a capsule at a dose of about 20 mg BID (about 40 mg daily) to reduce symptoms of fatigue and brain fog. In another such embodiment, the oral dose is about 1 mg / kg, administered daily for seven days.

[0126] The subject matter of the present application includes features discussed in WO 2004 / 019953 Al, WO 2008 / 039566 A2, WO 2009 / 124300 A2, and WO 2022 / 245532 Al which are hereby incorporated by reference in their entirety for all purposes.EXAMPLES

[0127] To further illustrate aspects of the present disclosure, the following examples are included. The examples should not, of course, be construed as specifically limiting the disclosure. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the disclosure as described and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the disclosure without exhaustive examples.Example 1. Injectable Pharmaceutical Composition

[0128] To prepare an injectable formulation, 0.1 mg to 100 mg of a compound of Formula (I), (II), (III), or (IV) manufactured to specifications suitable for injection with regard to pyrogen and bioburden, is dissolved in sterile, pyrogen-free, aqueous concentrated beta-cylcodextrin sulfobutyl ether to achieve a final compound concentration of 0.1 to 20 mg / niL and terminally sterilized by 0.2 llm filtration into a sterile glass vial of suitable size and subsequently capped with a sterile rubber septum.Example 2, Oral Pharmaceutical Composition

[0129] To prepare a pharmaceutical composition for oral delivery, 0.1 mg to 120 mg of a compound of an embodiment as described herein is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, or 0.1 mg to 120 mg of compound is granulated with binder solution such as starch solution along withsuitable diluents such as microcrystalline cellulose or the like, disintegrants such as croscaramellose sodium, and the resultant mixture is dried, lubricant is added to the mixture, and the mixture is then compressed into tablet which is suitable for oral administration.Example 3. Human Subject Study

[0130] This is a prophetic example, the compounds of the disclosure are tested to in vivo to determine their neuroprotective and neurogenic effects and potential to treat neurodegenerative diseases and brain trauma,

[0131] A study is planned to randomize 10 participants, each receiving either 2 to 100 mg of a compound, as described in an embodiment of this disclosure, or a placebo twice daily for 30 days. Eligible subjects are male or female, aged 60 to 85 years at screening, with mild to moderate probable Alzheimer’s Disease (AD). Inclusion criteria require that participants meet the National Institute on Aging and Alzheimer’s Association (NIA-AA, 2011) criteria for all-cause dementia and probable AD. Additional criteria include:

[0132] A Clinical Dementia Rating (CDR) Global Score of 1 to 2 (indicating mild to moderate AD),

[0133] A Mini-Mental State Examination (MMSE) score between 14 and 24, inclusive, at both Screening and Baseline visits,

[0134] A score difference between Screening and Baseline of less than 3 points.

[0135] The compounds will be investigated for pharmacokinetics, blood-brain barrier permeability, and anti-inflammatory effects, with mechanisms of action targeting multiple pathways involved in Alzheimer’s disease pathology. Six cognitive and functional domains — memory, orientation, judgment, community affairs, home hobbies, and personal care — will be assessed by certified raters. These raters will conduct interviews with both participants and their informants, with higher scores indicating greater severity of disease.Example 4: In vitro Receptor Affinity and Selectivity Profile

[0136] This is a prophetic example describing a process to determine the binding affinity and functional selectivity of a compound of the disclosure for human neurotrophic receptors TrkA, TrkB, TrkC, and p75N1R.

[0137] Surface Plasmon Resonance (SPR) analysis is performed using a BIAcore instrument. Recombinant human extracellular domains of TrkA, TrkB, TrkC, and p75N1Rare individually immobilized on a sensor chip. A compound of the dislcosure is prepared in a dilution series (e.g., 0.1 nM to 10 pM) and flowed over the chip. Sensorgrams are recorded to determine the association (fc«) and dissociation (koff) rates. The equilibrium dissociation constant (KD) is calculated (koff / kon) to quantify binding affinity. PC12 cells (which endogenously express TrkA and p75TR) and primary cortical neurons (expressing a mix of receptors) are cultured. Cells are treated with a compound of the disclosure (100 nM), native human NGF (10 ng / mL, positive control), BDNF (10 ng / mL, positive control for TrkB), or vehicle for 15 minutes. Cell lysates are collected and analyzed by Western blot using antibodies specific for phosphorylated-TrkA (p-TrkA), phosphorylated-TrkB (p-TrkB), and phosphorylated-TrkC (p-TrkC).

[0138] It is expected that an active compound of the disclosure will demonstrate high-affinity binding to both TrkA (KD < 100 nM) and p75NTR(KD < 100 nM), It is also expected that a compound of the disclosure shows no significant binding to TrkB (KD > 10 pM). It is expected that a compound of the disclosure will show moderate to high affinity for TrkC. Western blot analysis will confirm that treatment with a compound of the disclosure leads to a significant increase in the phosphorylation of TrkA and TrkC, at levels comparable to or exceeding the native NGF control. No significant increase in p-TrkB will be observed, confirming that a compound of the disclosure does not activate the TrkB receptor. These results will establish a compound of the disclosure as a potent and selective NGF mimetic.Example 5: Assessment of in vivo Hormonal Activity

[0139] This is a prophetic example describing an assay to determine the lack of androgenic hormonal activity. A compound of the disclosure is prophetically tested using the Hershberger assay (OECD Test Guideline 441). Immature, castrated male rats are treated daily for 10 consecutive days with vehicle control (e.g., sesame oil), testosterone propionate (positive control, e.g., 0.4 mg / kg / day), or a compound of the disclosure (e.g., 10 mg / kg / day and 100 mg / kg / day). On day 11, five androgen-sensitive tissues (seminal vesicles, ventral prostate, glans penis, levator ani muscle, and bulbocavernosus muscle) are excised and weighed. It is expected that while the testosterone propionate group will show a statisticallysignificant increase in the weights of all five tissues, the groups treated with a compound of the disclosure at both low and high doses will show no statistically significant increase in any of the tissue weights, confirming the compound is devoid of androgenic hormonal action.Example 6: Assessment of Nociceptive Effects

[0140] A prophetic study is conducted to determine if a compound of the disclosure avoids the hyperalgesic side effects associated with native Nerve Growth Factor (NGF). Adult C57BL / 6 mice are administered vehicle control, native NGF (e.g., 1 mg / kg, positive control), or a compound of the disclosure (e.g,, 10 mg / kg and 50 mg / kg). Mechanical hyperalgesia is assessed using the von Frey test to measure the paw withdrawal threshold (PWT) at baseline and at multiple time points (e.g,, 2, 4, 8, and 24 hours) after administration. It is expected that the NGF-treated group will show a significant decrease in PWT (increased pain sensitivity), whereas the groups treated with a compound of the disclosure at both doses will show no significant change in PWT compared to the vehicle control, demonstrating a lack of nociceptive side effects.Example 7: In Vivo Efficacy in a Transgenic Mouse Model of Alzheimer's Disease

[0141] The neuroprotective, neurogenic, and cognitive-enhancing effects of a compound of the disclosure are prophetically assessed in vivo in the 5XFAD transgenic mouse model of Alzheimer's Disease. At 3 months of age, 5XFAD mice are subcutaneously implanted with a biodegradable pellet formulated to provide continuous, sustained release of a compound of the disclosure (e.g., at 1 mg / kg / day or 10 mg / kg / day) for 60 days; control 5XFAD mice receive a placebo pellet. After 60 days, cognitive function is assessed using the Y-maze and Morns Water Maze. Subsequently, brain tissue and plasma are collected. It is expected that a compound of the disclosure will be readily detected in the brain parenchyma, confirming its ability to cross the blood-brain barrier. Behaviorally, it is expected that 5XFAD mice treated with a compound of the disclosure will show statistically significant improvements in cognitive and memory tasks compared to placebo-treated controls. Immunohistochemical analysis of the brain tissue is expected to show that treatment with a compound of the disclosure significantly reduces amyloid-beta (A[3) plaque load, significantly increases the number of DCX-positiveneuroblasts in the hippocampus (indicating neurogenesis), and significantly preserves synaptophysin staining (indicating neuroprotection against synaptic loss).Example 8: Neuroprotective Effects of a Compound of the Disclosure in Neural Stem Cells

[0142] In order to evaluate the cell protective effects of a compound of the disclosure, neural stem cell (NSC) cultures are prepared from postnatal day 7 (P7) mouse hippocampi. The NSCs are plated and allowed to form neurospheres under standard culture conditions.

[0143] To induce cytotoxicity, oligomeric amyloid-[342 (A[342) peptide is added to the culture medium at a concentration sufficient to increase cell death, as measured by a realtime cell death assay (e.g,, CellTox Green Cytotoxicity Assay, Promega). NSC cultures are divided into the following groups: (1) untreated control, (2) A[342 alone, (3) A[342 plus a compound of the disclosure, (4) A[342 plus Bram-Derived Neurotrophic Factor (BDNF), and (5) A[342 plus pro-BDNF. The compound of the disclosure is added to the relevant wells at a concentration effective for neuroprotection, for example, 100 nM. Cultures are incubated for 48 hours.

[0144] After incubation, cytotoxicity is assessed using the CellTox Green Cytotoxicity Assay according to the manufacturer’s instructions. It is expected that exposure to;\p42 will significantly increase cytotoxicity in NSC cultures compared to untreated controls. It is further expected that treatment with the compound of the disclosure will reduce A[342-induced cytotoxicity, similar to the effect observed with BDNF. Statistical analysis (e.g., ANOVA followed by post hoc tests) is performed to compare the groups. These results would demonstrate that the compound of the disclosure is effective in protecting neural stem cells from A[342-induced cytotoxicity, supporting its potential utility in the treatment or prevention of neurodegenerative conditions such as Alzheimer’s disease.Example 9: Prophetic Phase 2a Human Clinical Trial in Alzheimer’s Disease

[0145] A prophetic 12-week, multi-center, randomized, double-blind, placebo-controlled study is conducted to evaluate the safety, tolerability, and preliminary efficacy of a compound of the disclosure in approximately 90 human subjects diagnosed with mild-to-moderate Alzheimer’s Disease (AD). Subjects are randomized (2:1) to receive either acompound of the disclosure (e.g., 20 mg, oral capsule, twice daily [BID]) or a matching placebo. The primary endpoint is safety and tolerability'. Secondary and exploratory endpoints include changes from baseline in cognitive scores (e.g., ADAS-Cog11), functional scores (e.g., ADCS-ADL), and CSF biomarkers (e.g., Aβ 42 / 40 ratio, p-tau181, NfL, and GFAP). It is expected that a compound of the disclosure will be safe and well-tolerated. It is further expected that, after 12 weeks, the group treated with a compound of the disclosure will show a statistically significant slowing of cognitive decline as measured by ADAS-Cog11 and will demonstrate a statistically significant improvement in CSF biomarkers, including a reduction in the neuroinflammation marker GFAP and the neuroaxonal damage marker NfL, compared to the placebo group.

Claims

WHAT IS CLAIMED IS:

1. A composition, comprising:a pharmaceutically accepablet carrier; andat least one compound represented by Formula (I),wherein,R1is selected from the group consisting of optionally substituted ammo, optionally substituted C-amido, optionally substituted N-amido, optionally substituted organic acid, optionally substituted alcohol, optionally substituted ester, optionally substituted Ci to Cio alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted Cato Co alkenyl, optionally substituted Cato Cealkynyl, optionally substituted Cato Cs cycloalkyl, optionally substituted C6to C10aryl, optionally substituted Cato Csheterocyclyl, optionally substituted Cato Cio heteroaryl, optionally substituted O- aryl, or optionally substituted O-heteroaryl;R2is O, or -OH;X is CII2 or O; andthe dashed bond is present or absent.

2. A composition, comprising:a pharmaceutically acceptable carrier; andat least one compound represented by Formula (II),wherein,R1is selected from the group consisting of optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted organic acid, optionally substituted alcohol, optionally substituted ester, optionally substituted Ci to Cio alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to Cealkynyl, optionally substituted C?to Cs cycloalkyl, optionally substituted C6to C10aryl, optionally substituted C3to C8heterocyclyl, optionally substituted C3to C10heteroaryl, optionally substituted O-aryl, or optionally substituted O-heteroaryl; andR2is =O, or -OH.

3. A composition, comprising:a pharmaceutically acceptable carrier; andat least one compound represented by Formula (III),wherein,R2is =O, or -OH 4. A composition, comprising:a pharmaceutically acceptable carrier; andat least one compound represented by Formula (IV),wherein,R1is selected from the group consisting of optionally substituted ammo, optionally substituted C-amido, optionally substituted N-amido, optionally substituted organic acid, optionally substituted alcohol, optionally substituted ester, optionally substituted Ci to Cio alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted Cato Co alkenyl, optionally substituted Cato Cealkynyl, optionally substituted Cato Cs cycloalkyl, optionally substituted C6to C10aryl, optionally substituted Cato Csheterocyclyl, optionally substituted Cato Cio heteroaryl, optionally substituted O-aryl, or optionally substituted O-heteroaryl; andR2is O, or -OH5. A composition, comprising:a pharmaceutically acceptable carrier; andat least one compound selected from:-99-6. The composition of any one of claims 1 to 3 or 5, wherein the at least one compound7. The composition of any one of claims 1 to 3 or 5, wherein the at least one compound8. The composition of any one of claims 1 to 3 or 5, wherein the at least one compound9. A method to treat, prevent, reduce, or ameliorate a neurodegenerative disease or condition, the method comprising:administering to a patient in need thereof an effective amount of the composition of any one of claims 1 to 8.

10. The method of Claim 9, wherein the neurodegenerative condition is related to a neuronal apoptosis or neuronal injury.

11. The method of Claim 10, wherein the neurodegenerative disease or condition is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, parkinsonisms, Huntington’s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), schizophrenia, retinal degeneration, retinal detachment, peripheral neuropathy caused by genetic abnormalities, diabetes, polio, herpes, AIDS, brain trauma, ischemia and stroke.

12. The method of claim 11, wherein the neurodegenerative disease or condition is Alzheimer’s disease or Parkinson’s disease.

13. The method of any one of Claims 9 to 12, wherein the method further comprises administering at least one additional medicament to the patient.

14. The method of any one of Claims 9 to 13, wherein administration of the composition activates one or both of the TrkA and p75NTR receptors, increases neuronal NGF, TrkA, or p75NTR signaling, or reduces neuroinflammation, reduces amyloid- beta load,restores cholinergic function, promotes synaptogenesis, reduces astrogliosis, increases the density of neurons or neural stem cells, protects mature oligodendrocytes, protects motor neurons, or a combination thereof.

15. The method of Claim 13 or 14, wherein the at least one additional medicament is administered at a delay time after a first administration of the composition.

16. The method of Claim 15, wherein the delay time is equal to or greater than 2 years,17. The method of any one of Claims 9 to 16, wherein at least one non-motor symptom and / or at least one non-motor complication develops in the patient,18. The method of any one of Claims 9 to 16, wherein at least one motor symptom and / or at least one motor complication develops in the patient.

19. The method of Claim 18, wherein the at least one motor symptom is selected from the group consisting of tremor and / or shaking in the extremities, slowed movement (bradykinesia), muscle stiffness, rigidity, immobility (freezing), muscle cramps, impaired posture and / or balance, falls, dizziness, loss of automatic movements such as blinking or smiling, changes in speech and / or writing, motor fluctuations, dystonia, and any combination of the foregoing.

20. The method of Claim 18, wherein the at least one motor complication is selected from the group consisting of wearing off, dose failure, beginning of dose worsening, end-of-dose rebound, unpredictable off-periods, freezing of gait, on-period failure, acute akinesia, dyskinesia, and any combination of the foregoing.

21. The method of any one of Claims 18 to 20, wherein the at least one motor symptom and / or the motor complication develops at a time equal to or greater than 2 years after an additional medicament is administered.

22. The method of any of Claims 9 to 16, wherein the method improves motor coordination, cognitive performance, memory, attention, fatigue, or sleep stability.

23. The method of any one of Claims 9 to 22, wherein the patient is a human or mammal.

24. The method of any one of Claims 9 to 23, wherein the composition is administered to the patient by a subcutaneous sustained- release pellet or orally,25. The method of any of Claims 9 to 24, wherein the total daily dose of the composition is about 1 mg / kg, about 3 mg / kg, about 6 mg / kg, about 10 mg / kg, about 50 mg / kg, about 100 mg / kg, or about 200 mg / kg, or wherein the composition is administered at a human dose of about 20 mg BID (about 40 mg daily),26. A pharmaceutical composition comprising at least one compound of Claim 1 to 8 and at least one pharmaceutically acceptable excipient for use in treating a neurodegenerative disease or condition.

27. The pharmaceutical composition of claim 26, formulated as an oral tablet, capsule, solution, or suspension.

28. The pharmaceutical composition of Claim 26, wherein the neurodegenerative disease or condition is Parkinson’s disease.

29. The pharmaceutical composition of Claim 26, wherein the composition, or the use, comprises at least one additional medicament.

30. The pharmaceutical composition of Claim 26, wherein the additional medicament comprises L-dopa.

31. The pharmaceutical composition of Claim 26, wherein the additional medicament is used at a delay time after use of the pharmaceutical composition begins.

32. The pharmaceutical composition of Claim 26, wherein the delay time is equal to or greater than 2 years.

33. The pharmaceutical composition of Claim 26, wherein development of at least one motor symptom and / or at least one motor complication occurs.

34. The pharmaceutical composition of Claim 26, wherein the motor symptom is selected from tremor and / or shaking in the extremities, slowed movement (bradykinesia), muscle stiffness, rigidity, immobility (freezing), muscle cramps, impaired posture and / or balance, falls, dizziness, loss of automatic movements such as blinking or smiling, changes in speech and / or writing, motor fluctuations, dystonia, and any combination of the foregoing.

35. The pharmaceutical composition of Claim 26, wherein the motor complication is selected from wearing off, dose failure, beginning of dose worsening, end-of-dose rebound, unpredictable off-periods, freezing of gait, on-period failure, acute akinesia, dyskinesia and any combination of the foregoing.

36. The pharmaceutical composition of Claim 26, wherein the motor symptom and / or the motor complication develops at a time equal to or greater than 2 years after the use of the pharmaceutical composition begins.

37. The pharmaceutical composition of Claim 26, wherein the motor symptom and / or the motor complication develops at a time equal to or greater than 2 years after the use of the additional medicament begins.

38. Use of a compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, for improving neurological function in a subject having a neurodegenerative disorder or treating neurodegenerative disease or condition.

39. The use of Claim 38, wherein the neurological function, neurodegenerative disease or condition is selected from the group consisting of Parkinson’s disease, Alzheimer’s disease,amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury (SCI), schizophrenia, a retinal disease, pain, inflammation, a post- viral illness, or post-COVID-19 cognitive impairment.

40. The use of claim 39, wherein the neurological function, neurodegenerative disease or condition is Alzheimer’s Disease or Parkinson’s Disease.

41. The use of claim 40, wherein the improving the neurological function improves at least one non-motor symptom and at least one motor symptom in a subject.

42. A method to treat, prevent, reduce, or ameliorate a post- viral illness in a subject, the method comprising: administering to a patient in need thereof an effective amount of the composition of any one of Claims 1 to 8.

43. A method to treat, prevent, reduce, or ameliorate spinal cord injury (SCI) in a subject, the method comprising: administering to a patient in need thereof an effective amount of the composition of any one of Claims 1 to 8.

44. A method to treat, prevent, reduce, or ameliorate schizophrenia in a subject, the method comprising: administering to a patient in need thereof an effective amount of the composition of any one of Claims 1 to 8.

45. A method to treat, prevent, reduce, or ameliorate a retinal disease in a subject, the method comprising: administering to a patient in need thereof an effective amount of the composition of any one of Claims 1 to 8.

46. A method to treat, prevent, reduce, or ameliorate pain or inflammation in a subject, the method comprising: administering to a patient in need thereof an effective amount of the composition of any one of Claims 1 to 8.

47. A method for reducing amyloid-beta load in a subject in need thereof, the method comprising: administering to the subject an effective amount of the composition of any one of Claims 1 to 8.

48. A method for promoting synaptogenesis or restoring cholinergic function in a subject in need thereof, the method comprising: administering to the subject an effective amount of the composition of any one of Claims 1 to 8.

49. A method for protecting mature oligodendrocytes or protecting motor neurons in a subject in need thereof, the method comprising: administering to the subject an effective amount of the composition of any one of Claims 1 to 8.

50. The method of any one of claims 42 to 49, wherein the composition is administered orally at a dose of about 20 mg BID (about 40 mg daily) or wherein the composition is administered orally at a dose of about 1 mg / kg daily or about 50 mg / kg daily.

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