N-[4-fluor-5-[[(2s, 4 r)-4-[(6-methoxy-4-pyrimidinyl)OXY]- 2-methyl-1-pyrrolidinyl] methyl ]-2-thiazolyl]acetamid for use in the treatment of alzheimer disease

Abstract

The present disclosure provides methods of treating Alzheimer's Disease (AD) using Compound (I) as represented by the structure below: [Formula should be inserted here] or a free base or pharmaceutically acceptable salt thereof.

Description

[0001] N-[4-FLUOR-5-[[(2S, 4 R)-4-[(6-METHOXY-4-PYRIMIDINYL)OXY]-

[0002] 2-METHYL-1-PYRR0LIDINYL] METHYL ]-2-THIAZ0LYL]ACETAMID FOR USE IN THE TREATMENT OF ALZHEIMER DISEASE

[0003] RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application No. 63 / 560,540, filed on March 1, 2024. The entire contents of the foregoing application are expressly incorporated herein by reference.

[0005] BACKGROUND

[0006] Alzheimer’s disease (AD) is a progressive brain disorder typically beginning with memory loss and which can lead to severe memory loss, critical thinking, and ability to carry out conversations or respond to one’s environment. AD is the most common type of dementia, however, there is no known cure. In the United States alone, approximately 6 million individuals have AD, which is expected to triple to approximately 14 million people by 2060 (Matthews KA et al. Alzheimers Dement. 2019 Jan;15(l): 17-24).

[0007] It is well established that AD and a number of related tauopathies including Progressive Supranuclear Palsy (PSP) and some forms of frontotemporal dementia (FTD) are characterized, in part, by the development of neurofibrillary tangles (NFTs). These NFTs are aggregates of paired helical filaments (PHFs) and are composed of an abnormal form of tau. It has been shown that O-linked P-A-acetylglucosam ine (O-GlcN Ac) modified tau has increased solubility and reduced aggregation in comparison to wild type tau (Balana AT et al. Biochem J. 2021 Jul 30;478(14):2733-2758).

[0008] As humans age, there is a decreased glucose availability in brain, potentially caused by the gradual impairment of glucose transport and metabolism, which leads to decreased O- GlcNAc, and thus decreased O-GlcNAc modified tau (and other proteins). The protein residues which typically have O-GlcNAc modifications are thus free and susceptible to hyperphosphorylation. In AD patients, when tau becomes hyperphosphorylated, this disrupts its normal function, forming PHFs and ultimately aggregating to form NFTs.

[0009] Six isoforms of tau are found in the human brain. In AD patients, all six isoforms of tau are found in NFTs, and all are markedly hyperphosphorylated. Tau in healthy brain tissue bears only 2 or 3 phosphate groups, whereas those found in the brains of AD patients bear, on average, 8 phosphate groups. It has recently emerged that decreased brain- and tau-O-GIcN Ac levels correlate with AD. Accordingly, the inhibition of O-GlcNAcase, which prevents the removal of O-GlcN Ac from tau, should compensate for the impact of impaired glucose metabolism and its impact on tau aggregation within the brains of patients suffering from AD or related neurodegenerative diseases.

[0010] However, a major challenge in developing inhibitors for blocking the function of mammalian glycosidases, including O-GIcN Acasc, is the large number of functionally related enzymes present in tissues of higher eukaryotes. Accordingly, the use of non-selective inhibitors in studying the cellular and organismal physiological role of one particular enzyme is complicated because complex phenotypes arise from the concomitant inhibition of such functionally related enzymes. In the case of P-N-acetylglucosaminidases, many existing compounds that act to block O-GIcN Acasc function are non-specific and act potently to inhibit the lysosomal [l-hcxosaminidascs.

[0011] International Application Publication No. WO 2020 / 061150, the entire teachings of which are incorporated herein by reference, discloses N-(4-Fluoro-5-(((25',47?)-4-((6- methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-l- yl)methyl)thiazol-2-yl)acetamide, shown below, which is a potent and selective inhibitor of O-GlcNAcase:

[0012] Further, international Application Publication No. WO 2022 / 031701, the entire teachings of which are incorporated herein by reference, discloses salt forms of N-(4-Fluoro- 5-(((2S,47?)-4-((6-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-l- yl)methyl)thiazol-2- yl)acetamide. One such salt is the L-tartrate salt, i.e. N-[4-fhioro-5-[[(2S,4R)-4-[(6-methoxy- 4-pyrimidinyl)oxy]-2-methyl-l-pyrrolidinyl]methyl]-2-thiazolyl]acetamide, L-(+)-tartrate salt (1:1) (shown below, and also referred herein as “Compound (I)”): (Compound (I)).

[0013] Although there are approved disease-modifying drugs and standard of care for AD, there is an urgent need to develop novel therapeutic interventions that attenuate the progression of AD (such as cognitive decline), preserve a patient’s current disease and cognitive state, or improve the disease and cognitive state of the patient.

[0014] SUMMARY OF THE INVENTION

[0015] In a first aspect, the present disclosure provides methods of treating a human subject with Alzheimer’s disease (AD), the method comprising administering to the subject orally a total daily dose of 0.5 to 50 mg of N-[4-fhioro-5-[[(2S,4R)-4-[(6-methoxy-4- pyrimidinyljoxy] -2-methyl- 1 -pyrrolidinyl]methyl] -2-thiazolyl] acetamide, L-(+)-tartrate salt (1:1) (referred herein as “Compound (I)”: or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 50 mg of Compound (I).

[0016] In a second aspect, the present disclosure provides Compound (I), or a free base or pharmaceutically acceptable salt thereof, for use in the treatment of a human subject with AD, wherein Compound (I) is administered to the subject orally in a total daily dose of 0.5 to 50 mg (e.g., any of total daily doses described herein), or wherein a free base or pharmaceutically acceptable salt of Compound (I) is administered to the subject orally in a an amount equivalent to a total daily dose of 0.5 mg to 50 mg (e.g., any of total daily doses described herein) of Compound (I).

[0017] In a third aspect, the present disclosure provides the use of Compound (I), or a free base or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a human subject with AD, wherein the medicament comprises Compound (I) in a total daily dose of 0.5 to 50 mg (e.g., any of total daily doses described herein), or a free base or pharmaceutically acceptable salt of Compound (I) in a an amount equivalent to a total daily dose of 0.5 mg to 50 mg (e.g., any of total daily doses described herein) of Compound (I).

[0018] In a fourth aspect, the present disclosure provides a kit comprising a pharmaceutical composition comprising 0.5 mg to 50 mg (e.g., any of total daily doses described herein) of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 50 mg (e.g., any of total daily doses described herein) of Compound C -

[0019] BRIEF DESCRIPTION OF THE FIGURES

[0020] FIG. 1 shows the mean plasma concentration of Compound (I) over time in the SAD cohorts.

[0021] FIG. 2 shows the effect food has on the mean plasma concentration of Compound (I) in the SAD cohorts.

[0022] FIG. 3 shows the mean plasma concentration of Compound (I) over time in the MAD cohorts.

[0023] FIG. 4 shows the mean plasma concentration of Compound (I) over time for different age groups in the MAD cohorts.

[0024] FIG. 5 shows the target occupancy of Compound (I) in the brain over time in the SAD cohorts.

[0025] FIG. 6 shows the target occupancy of Compound (I) in the brain over time in the MAD cohorts.

[0026] FIG. 7 shows the target occupancy versus plasma concentration of Compound (I).

[0027] FIG. 8 shows elevation of O-GlcNAc protein in brain tissue of tau transgenic rTg4510 mice treated with Compound (I).

[0028] FIG. 9 shows elevation of OGA receptor occupancy in brain tissue of tau transgenic rTg4510 mice treated with Compound (I).

[0029] FIG. 10 shows inhibition of OGA enzymatic activity in tau transgenic rTg4510 mice treated with Compound (I).

[0030] FIG. 11 shows reduction of Tau aggregation in tau transgenic rTg4510 mice treated with Compound (I).

[0031] FIG. 12 shows the increase in O-GlcNAc tau protein that is O-GlcNAcylated at serine 400.

[0032] DETAILED DESCRIPTION OF THE INVENTION

[0033] Definitions

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, which is the field of medicine, and of brain medicine in particular. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0035] As used herein, the term “free base” refers to a chemical compound substantially free from any salts, i.e. the neutral form of the compound. For example, the free base of Compound (I) is N-(4-Fluoro-5-(((25',47?)-4-((6-methoxypyrimidin-4-yl)oxy)-2- methylpyrrolidin-1- yl)methyl)thiazol-2-yl)acetamide, without the presence of the L-tartrate or other salt.

[0036] As used herein, the term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0037] As used herein, the word “a” before a noun represents one or more of the particular noun. As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0038] As used herein, the terms “subject” and “patient” are used interchangeably. A subject or a patient is a human patient or human subject.

[0039] For the terms “for example” and “such as,” and grammatical equivalences thereof, the phrase “without limitation” or “and without limitation” is understood to follow unless explicitly stated otherwise.

[0040] As used herein the term “Alzheimer’s disease” comprises the disease as commonly defined in the art.

[0041] The terms “administer”, “administering” or “administration” in reference to a compound or pharmaceutical agent, mean introducing the compound into the body of the patient in need of treatment.

[0042] “Treat”, “treating” or “treatment” with regard to a disorder, disease, condition, symptom or syndrome, refers to both therapeutic treatment and prophylactic treatment. “Therapeutic treatment” refers to abrogating or improving the cause and / or the effects (i.e., the symptoms, physiological, physical, psychological, emotional or functional manifestations, or any of the clinical parameters or observations) associated with the disorder, disease, condition or syndrome. “Prophylactic treatment” refers to the delay or amelioration or slowing down or prevention of the progression (i.e., the known or expected progression of the disease), severity, and / or duration of the disease or delay or amelioration or slowing down or prevention of the progression of one or more clinical parameters associated with the disease (i.e., “managing” without “curing” the condition), resulting from the administration of one or more therapies.

[0043] Treating AD according to the invention may involve improving memory, functional capacity, cognition or cognitive function as determined by tools used in the field. It may also involve total or partial reversal of cognitive dysfunction, memory loss, or a loss in functional capacity. It may also involve attenuation or stopping the progression of cognitive impairment, memory loss, or a decline in functional capacity.

[0044] “Functional capacity” refers to a person’s capability or ability to perform tasks and activities that people find necessary or desirable in their lives in different circumstances or situations. Functional capacity is most appropriately examined with reference to particular life-cycle tasks that an individual may need to perform. For instance, for adults, functional abilities in the labor force are important, as well as activities related to rearing and interacting with their children.

[0045] “Cognitive function” refers to one or more higher brain functions that generally involve aspects of thinking and information processing (i.e., cognition). Cognitive function may include attention, focus, reaction time, executive function, conceptual reasoning, memory, processing speed, and psychomotor ability.

[0046] O-GlcNAcase Inhibitors

[0047] A wide range of cellular proteins, both nuclear and cytoplasmic, are post- translationally modified by the addition of the monosaccharide 2-acetamido-2-deoxy-P-D- glucopyranoside (P -A-acetyl glucosamine) which is attached via an O-glycosidic linkage. This monosaccharide is generally referred to as O-linked A-acetylglucosamine or O-GlcN Ac. The enzyme responsible for post-translationally linking P-A-acctylglucosaminc (GlcNAc) to specific serine and threonine residues of numerous nucleocytoplasmic proteins is O-GlcNAc transferase (OGT). A second enzyme, known as O-glycoprotein-2-acetamido-2-deoxy-3-D- glucopyranosidase or O-GlcNAcase or OGA, removes this post-translational modification to liberate proteins, making the O-GlcNAc-modification a dynamic cycle occurring several times during the lifetime of a protein. However, mammalian glycosidases, including O-GlcNAcase, comprises a large number of functionally related enzymes present in tissues of higher eukaryotes. In the case of P-N-acetylglucosaminidases, many existing compounds that act to block O-GlcNAcase function are non-specific and act potently to inhibit the lysosomal [l-hcxosaminidascs.

[0048] In some embodiments, the ( -GlcN Acasc inhibitor is a selective O-GlcN Acase inhibitor.

[0049] In some embodiment, the O-GlcNAcase inhibitor is N-(4-Fhioro-5-(((2S,47?)-4-((6- methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-l- yl)methyl)thiazol-2-yl)acetamide, L-(+)- tartrate salt (1:1) (also referred herein as “Compound (I)”), or a free base pharmaceutically acceptable salt thereof. Compound (I) is represented by the following structural formula: Compound (I).

[0050] Methods of Treatment

[0051] The present disclosure provides methods of treating a human patient with Alzheimer’s disease (AD) by administering Compound (I) to the subject.

[0052] The present disclosure provides a method of treating a human subjected with AD, the method comprising administering to the subject orally a total daily dose of 0.5 to 50 mg of N- [4-fhioro-5-[[(2S,4R)-4-[(6-methoxy-4-pyrimidinyl)oxy]-2-methyl-l-pyrrolidinyl]methyl]-2- thiazolyl] acetamide, L-(+)-tartrate salt (1:1) (Compound (I)): or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 50 mg of Compound (I). Compound (I) disclosed herein can be used in the form of a free base or as a salt (preferably, a pharmaceutically acceptable salt). As Compound (I) is 1:1 L-(+)-tartrate salt of N-[4-fhioro-5-[[(2S,4R)-4-[(6-methoxy-4-pyrimidinyl)oxy]-2-methyl-l-pyrrolidinyl]methyl]- 2-thiazolyl] acetamide (free base), a salt of Compound (I) is a salt of the free base compound that is not the 1 : 1 L-(+)-tartrate salt. In some embodiments, the salt of Compound (I) is nontartrate salt of the free base. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0053] In some embodiments, in the methods of treatment disclosed herein, Compound (I) is administered as the free base. In some embodiments, in the methods of treatment disclosed herein, a pharmaceutically acceptable salt of Compound (I) is administered.

[0054] When the stereochemical configuration at a chiral center in Compound (I) is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0055] Pharmaceutical Compositions

[0056] Pharmaceutical compositions of the disclosure (also referred to herein as the “disclosed pharmaceutical compositions”) comprise one or more pharmaceutically acceptable carrier(s) or diluent(s) and Compound (I), or a free base or pharmaceutically acceptable salt thereof.

[0057] “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Nonlimiting examples of pharmaceutically acceptable carriers and / or diluents include NaCl, lactated Ringer’s, normal sucrose, normal glucose, binders, fdlers, disintegrants, lubricants, coatings, sweeteners, flavors, alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, hydroxymethycellulose, fatty acid esters, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds or pharmaceutically acceptable salts thereof.

[0058] The pharmaceutical compositions of the disclosure optionally include one or more pharmaceutically acceptable carriers and / or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5thEd., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19) published in 1999. The carriers, diluents and / or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0059] Methods of Administration and Dosage Forms

[0060] In some embodiments, the subject is administered a total daily dose of 0.5 mg to 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 50 mg of Compound (I).

[0061] In some embodiments, the subject is administered a total daily dose of 0.5 mg to 25 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 25 mg of Compound (I).

[0062] In some embodiments, the subject is administered a total daily dose of 0.5 mg to 20 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 20 mg of Compound (I). In some embodiments, the subject is administered a total daily dose of 0.5 mg to 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 15 mg of Compound (I).

[0063] In some embodiments, the subject is administered a total daily dose of 0.5 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 10 mg of Compound (I).

[0064] In some embodiment, the subject is administered a total daily dose of 0.5 mg to 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 7.5 mg of Compound (I).

[0065] In some embodiment, the subject is administered a total daily dose of 0.5 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 5 mg of Compound (I).

[0066] In some embodiment, the subject is administered a total daily dose of 1 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg to 10 mg of Compound (I).

[0067] In some embodiment, the subject is administered a total daily dose of 1 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg to 5 mg of Compound (I).

[0068] In some embodiment, the subject is administered a total daily dose of 0.5 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 3 mg of Compound (I).

[0069] In some embodiment, the subject is administered a total daily dose of 1 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg to 3 mg of Compound (I).

[0070] In some embodiment, the subject is administered a total daily dose of 0.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg of Compound (I).

[0071] In some embodiment, the subject is administered a total daily dose of 1 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg of Compound (I).

[0072] In some embodiment, the subject is administered a total daily dose of 1.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1.5 mg of Compound (I). In some embodiment, the subject is administered a total daily dose of 2 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2 mg of Compound (I).

[0073] In some embodiment, the subject is administered a total daily dose of 2.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2.5 mg of Compound (I).

[0074] In some embodiment, the subject is administered a total daily dose of 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3 mg of Compound (I).

[0075] In some embodiment, the subject is administered a total daily dose of 3.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3.5 mg of Compound (I).

[0076] In some embodiment, the subject is administered a total daily dose of 4 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4 mg of Compound (I).

[0077] In some embodiment, the subject is administered a total daily dose of 4.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4.5 mg of Compound (I).

[0078] In some embodiment, the subject is administered a total daily dose of 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 5 mg of Compound (I).

[0079] In some embodiment, the subject is administered a total daily dose of 5.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 5.5 mg of Compound (I).

[0080] In some embodiment, the subject is administered a total daily dose of 6 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 6 mg of Compound (I).

[0081] In some embodiment, the subject is administered a total daily dose of 6.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 6.5 mg of Compound (I).

[0082] In some embodiment, the subject is administered a total daily dose of 7 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 7 mg of Compound (I). In some embodiment, the subject is administered a total daily dose of 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 7.5 mg of Compound (I).

[0083] In some embodiment, the subject is administered a total daily dose of 8 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 8 mg of Compound (I).

[0084] In some embodiment, the subject is administered a total daily dose of 8.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 8.5 mg of Compound (I).

[0085] In some embodiment, the subject is administered a total daily dose of 9 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9 mg of Compound (I).

[0086] In some embodiment, the subject is administered a total daily dose of 9.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9.5 mg of Compound (I).

[0087] In some embodiment, the subject is administered a total daily dose of 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 10 mg of Compound (I).

[0088] In some embodiment, the subject is administered a total daily dose of 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 15 mg of Compound (I).

[0089] In some embodiment, the subject is administered a total daily dose of 30 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 30 mg of Compound (I).

[0090] In some embodiment, the subject is administered a total daily dose of 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 50 mg of Compound (I).

[0091] In some embodiments, Compound (I), or a free base or pharmaceutically acceptable salt thereof, is administered to the subject once daily. In some embodiments, Compound (I), or a free base or pharmaceutically acceptable salt thereof, is administered to the subject twice daily (BID).

[0092] In some embodiments, the subject is administered a once daily dose of 0.5 mg to 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 50 mg of Compound (I). In some embodiments, the subject is administered a once daily dose of 0.5 mg to 25 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 25 mg of Compound (I).

[0093] In some embodiments, the subject is administered a once daily dose of 0.5 mg to 20 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 20 mg of Compound (I).

[0094] In some embodiments, the subject is administered a once daily dose of 0.5 mg to 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 15 mg of Compound (I).

[0095] In some embodiments, the subject is administered a once daily dose of 0.5 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 10 mg of Compound (I).

[0096] In some embodiment, the subject is administered a once daily dose of 0.5 mg to 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 7.5 mg of Compound (I).

[0097] In some embodiment, the subject is administered a once daily dose of 0.5 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 5 mg of Compound (I).

[0098] In some embodiment, the subject is administered a once daily dose of 1 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1 mg to 10 mg of Compound (I).

[0099] In some embodiment, the subject is administered a once daily dose of 1 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1 mg to 5 mg of Compound (I).

[0100] In some embodiment, the subject is administered a once daily dose of 0.5 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 3 mg of Compound (I).

[0101] In some embodiment, the subject is administered a once daily dose of 1 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1 mg to 3 mg of Compound (I).

[0102] In some embodiment, the subject is administered a once daily dose of 0.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg of Compound (I). In some embodiment, the subject is administered a once daily dose of 1 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1 mg of Compound (I).

[0103] In some embodiment, the subject is administered a once daily dose of 1.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1.5 mg of Compound (I).

[0104] In some embodiment, the subject is administered a once daily dose of 2 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 2 mg of Compound (I).

[0105] In some embodiment, the subject is administered a once daily dose of 2.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 2.5 mg of Compound (I).

[0106] In some embodiment, the subject is administered a once daily dose of 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 3 mg of Compound (I).

[0107] In some embodiment, the subject is administered a total daily dose of 3.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3.5 mg of Compound (I).

[0108] In some embodiment, the subject is administered a once daily dose of 4 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 4 mg of Compound (I).

[0109] In some embodiment, the subject is administered a once daily dose of 4.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 4.5 mg of Compound (I).

[0110] In some embodiment, the subject is administered a once daily dose of 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 5 mg of Compound (I).

[0111] In some embodiment, the subject is administered a once daily dose of 5.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 5.5 mg of Compound (I).

[0112] In some embodiment, the subject is administered a once daily dose of 6 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 6 mg of Compound (I). In some embodiment, the subject is administered a once daily dose of 6.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 6.5 mg of Compound (I).

[0113] In some embodiment, the subject is administered a once daily dose of 7 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 7 mg of Compound (I).

[0114] In some embodiment, the subject is administered a once daily dose of 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 7.5 mg of Compound (I).

[0115] In some embodiment, the subject is administered a once daily dose of 8 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 8 mg of Compound (I).

[0116] In some embodiment, the subject is administered a once daily dose of 8.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 8.5 mg of Compound (I).

[0117] In some embodiment, the subject is administered a once daily dose of 9 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 9 mg of Compound (I).

[0118] In some embodiment, the subject is administered a once daily dose of 9.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9.5 mg of Compound (I).

[0119] In some embodiment, the subject is administered a total daily dose of 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 10 mg of Compound (I).

[0120] In some embodiment, the subject is administered a once daily dose of 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 15 mg of Compound (I).

[0121] In some embodiment, the subject is administered a once daily dose of 30 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 30 mg of Compound (I).

[0122] In some embodiment, the subject is administered a once daily dose of 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 50 mg of Compound (I). In some embodiments, the subject is administered a dose of 0.25 mg to 25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 25 mg of Compound (I) twice a day.

[0123] In some embodiments, the subject is administered a dose of 0.25 mg to 12.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 12.5 mg of Compound (I) twice a day.

[0124] In some embodiments, the subject is administered a dose of 0.25 mg to 10 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 10 mg of Compound (I) twice a day.

[0125] In some embodiments, the subject is administered a dose of 0.25 mg to 7.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 7.5 mg of Compound (I) twice a day.

[0126] In some embodiments, the subject is administered a dose of 0.25 mg to 5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 5 mg of Compound (I) twice a day'.

[0127] In some embodiment, the subject is administered a dose of 0.25 mg to 3.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 3.75 mg of Compound (I) twice a day.

[0128] In some embodiment, the subject is administered a dose of 0.25 mg to 2.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 2.5 mg of Compound (I) twice a day.

[0129] In some embodiment, the subject is administered a dose of 0.5 mg to 5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.5 mg to 5 mg of Compound (I) twice a day.

[0130] In some embodiment, the subject is administered a dose of 0.5 mg to 2.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.5 mg to 2.5 mg of Compound (I) twice a day.

[0131] In some embodiment, the subject is administered a dose of 0.25 mg to 1.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 1.5 mg of Compound (I) twice a day.

[0132] In some embodiment, the subject is administered a dose of 0.5 mg to 1.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.5 mg to 1.5 mg of Compound (I) twice a day. In some embodiment, the subject is administered a dose of 0.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg of Compound (I) twice a day.

[0133] In some embodiment, the subject is administered a dose of 0.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.5 mg of Compound (I) twice a day.

[0134] In some embodiment, the subject is administered a dose of 0.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.75 mg of Compound (I) twice a day.

[0135] In some embodiment, the subject is administered a dose of 1.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 1.0 mg of Compound (I) twice a day.

[0136] In some embodiment, the subject is administered a dose of 1.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 1.25 mg of Compound (I) twice a day.

[0137] In some embodiment, the subject is administered a dose of 1.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 1.5 mg of Compound (I) twice a day.

[0138] In some embodiment, the subject is administered a dose of 1.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 1.75 mg of Compound (I) twice a day.

[0139] In some embodiment, the subject is administered a dose of 2.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 2.0 mg of Compound (I) twice a day.

[0140] In some embodiment, the subject is administered a dose of 2.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 2.25 mg of Compound (I) twice a day.

[0141] In some embodiment, the subject is administered a dose of 2.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 2.5 mg of Compound (I) twice a day.

[0142] In some embodiment, the subject is administered a dose of 2.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 2.75 mg of Compound (I) twice a day. In some embodiment, the subject is administered a dose of 3.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 3.0 mg of Compound (I) twice a day.

[0143] In some embodiment, the subject is administered a dose of 3.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 3.25 mg of Compound (I) twice a day.

[0144] In some embodiment, the subject is administered a dose of 3.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 3.5 mg of Compound (I) twice a day.

[0145] In some embodiment, the subject is administered a dose of 3.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 3.75 mg of Compound (I) twice a day.

[0146] In some embodiment, the subject is administered a dose of 4.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 4.0 mg of Compound (I) twice a day.

[0147] In some embodiment, the subject is administered a dose of 4.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 4.25 mg of Compound (I) twice a day.

[0148] In some embodiment, the subject is administered a dose of 4.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 4.5 mg of Compound (I) twice a day.

[0149] In some embodiment, the subject is administered a dose of 4.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 4.75 mg of Compound (I) twice a day.

[0150] In some embodiment, the subject is administered a dose of 5.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 5.0 mg of Compound (I) twice a day.

[0151] In some embodiment, the subject is administered a dose of 7.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 7.5 mg of Compound (I) twice a day.

[0152] In some embodiment, the subject is administered a dose of 15 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 15 mg of Compound (I) twice a day. In some embodiment, the subject is administered a dose of 25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 25 mg of Compound (I) twice a day.

[0153] In some embodiments, Compound (I), or a free base or pharmaceutically acceptable salt thereof, is administered to the subject after fasting.

[0154] In some embodiments, Compound (I), or a free base or pharmaceutically acceptable salt thereof, is administered to the subject after fasting for at least 8 hours.

[0155] In some embodiments, Compound (I), or a free base or pharmaceutically acceptable salt thereof, is administered to the subject after or while eating.

[0156] Kits

[0157] This disclosure also features kits for treating AD, comprising Compound (I), or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the kit comprises a pharmaceutical composition comprising 0.5 mg to 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 50 mg of Compound (I).

[0159] In some embodiments, the kit comprises a pharmaceutical composition comprising 0.5 mg to 25 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 25 mg of Compound (I).

[0160] In some embodiments, the kit comprises a pharmaceutical composition comprising 0.5 mg to 20 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 20 mg of Compound (I).

[0161] In some embodiments, the kit comprises a pharmaceutical composition comprising 0.5 mg to 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 15 mg of Compound (I).

[0162] In some embodiments, the kit comprises a pharmaceutical composition comprising 0.5 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 10 mg of Compound (I).

[0163] In some embodiments, the kit comprises a pharmaceutical composition comprising 0.5 mg to 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 7.5 mg of Compound (I).

[0164] In some embodiments, the kit comprises a pharmaceutical composition comprising 0.5 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 5 mg of Compound (I). In some embodiments, the kit comprises a pharmaceutical composition comprising 1 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 1 mg to 10 mg of Compound (I).

[0165] In some embodiments, the kit comprises a pharmaceutical composition comprising 1 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 1 mg to 5 mg of Compound (I).

[0166] In some embodiments, the kit comprises a pharmaceutical composition comprising 0.5 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 3 mg of Compound (I).

[0167] In some embodiments, the kit comprises a pharmaceutical composition comprising 1 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 1 mg to 3 mg of Compound (I).

[0168] In some embodiments, the kit comprises a pharmaceutical composition comprising 0.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg of Compound (I).

[0169] In some embodiments, the kit comprises a pharmaceutical composition comprising 1 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg of Compound (I).

[0170] In some embodiments, the kit comprises a pharmaceutical composition comprising

[0171] 1.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1.5 mg of Compound (I).

[0172] In some embodiments, the kit comprises a pharmaceutical composition comprising 2 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2 mg of Compound (I).

[0173] In some embodiments, the kit comprises a pharmaceutical composition comprising

[0174] 2.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2.5 mg of Compound (I).

[0175] In some embodiments, the kit comprises a pharmaceutical composition comprising 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3 mg of Compound (I).

[0176] In some embodiments, the kit comprises a pharmaceutical composition comprising

[0177] 3.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3.5 mg of Compound (I). In some embodiments, the kit comprises a pharmaceutical composition comprising 4 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4 mg of Compound (I).

[0178] In some embodiments, the kit comprises a pharmaceutical composition comprising

[0179] 4.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4.5 mg of Compound (I).

[0180] In some embodiments, the kit comprises a pharmaceutical composition comprising 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 5 mg of Compound (I).

[0181] In some embodiments, the kit comprises a pharmaceutical composition comprising

[0182] 5.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 5.5 mg of Compound (I).

[0183] In some embodiments, the kit comprises a pharmaceutical composition comprising 6 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 6 mg of Compound (I).

[0184] In some embodiments, the kit comprises a pharmaceutical composition comprising

[0185] 6.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 6.5 mg of Compound (I).

[0186] In some embodiments, the kit comprises a pharmaceutical composition comprising 7 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 7 mg of Compound (I).

[0187] In some embodiments, the kit comprises a pharmaceutical composition comprising

[0188] 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 7.5 mg of Compound (I).

[0189] In some embodiments, the kit comprises a pharmaceutical composition comprising 8 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 8 mg of Compound (I).

[0190] In some embodiments, the kit comprises a pharmaceutical composition comprising

[0191] 8.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 8.5 mg of Compound (I).

[0192] In some embodiments, the kit comprises a pharmaceutical composition comprising 9 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9 mg of Compound (I). In some embodiments, the kit comprises a pharmaceutical composition comprising 9.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9.5 mg of Compound (I).

[0193] In some embodiments, the kit comprises a pharmaceutical composition comprising 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 10 mg of Compound (I).

[0194] In some embodiments, the kit comprises a pharmaceutical composition comprising 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 15 mg of Compound (I).

[0195] In some embodiments, the kit comprises a pharmaceutical composition comprising 30 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 30 mg of Compound (I).

[0196] In some embodiments, the kit comprises a pharmaceutical composition comprising 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 50 mg of Compound (I).

[0197] In some embodiments, for the kits described above, the pharmaceutical composition in the kits comprises a pharmaceutically acceptable carrier in addition to Compound (I) or a free base or pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the kits described above further comprise an instruction for using the pharmaceutical composition for treating AD.

[0199] Exemplification

[0200] Abbreviations

[0201] AE = adverse event

[0202] AD = Alzheimer’s disease

[0203] AR = accumulation ratio

[0204] AUC = area under the concentration-time curve

[0205] AUCinf = area under the concentration-time curve from time zero extrapolated to infinity

[0206] AUCiast = area under the concentration-time curve from time zero to time of the last measurable concentration

[0207] AUCtau = area under the concentration-time curve within a dosing interval

[0208] Cmax = maximum observed concentration Ctrough = trough concentration

[0209] C-SSRS = Columbia Suicide Severity Rating Scale

[0210] CL / F = apparent total body clearance

[0211] Emax = maximum effect

[0212] EC50 = concentration resulting in 50% effective response

[0213] ECG = electrocardiogram

[0214] FIH = first in human

[0215] HTRF = homogeneous time resolved fluorescence

[0216] IV = intravenous

[0217] MAD = multiple ascending dose

[0218] NOAEL = no observed adverse effect level

[0219] OGA = O-GlcNAcase

[0220] PD = pharmacodynamics

[0221] PET = positron emission tomography

[0222] PK = pharmacokinetics

[0223] PT = preferred term

[0224] SAD = single ascending dose

[0225] SAE = serious adverse event

[0226] SOC = system organ class

[0227] SST = safety surveillance team ti / 2 = terminal elimination half-life

[0228] Tmax = time to maximum observed concentration

[0229] TEAE = treatment-emergent adverse event

[0230] TO = target occupancy

[0231] Example 1. Phase 1 study of Compound (I) in healthy human participants

[0232] Study Design

[0233] This was a Phase 1, randomized, blinded, placebo-controlled, single- and multipleascending dose-escalation study to evaluate the safety, tolerability and PK, with an open-label TO study, of single- and multiple-ascending doses of oral Compound (I) in healthy participants.

[0234] This FIH study comprised 3 integrated parts: Part A (SAD), Part B (MAD), and Part C (OGA-PET SAD / MAD). This study was designed to evaluate the safety, tolerability, PK, and TO of single- and multiple-ascending doses of oral Compound (I) comprising 3 integrated parts (Part A [SAD], Part B [MAD], and Part C [OGA-PET SAD / MAD]) conducted in healthy adult participants. Females and infertile / vasectomized males were selected as the FIH population. OGA protein levels in the brain are similar between healthy volunteers and patients with AD, indicating that healthy participants are a suitable population for this study. Part of this study included participants aged 65 to 75 years (Part B [MAD]: Cohort 9 / Elderly) to reflect the target population and provide a bridge to the Phase 2 development of Compound (I).

[0235] Part A (SAD)

[0236] 36 participants (healthy females and infertile / vasectomized males) 18 to 64 years of age, inclusive, were enrolled in 4 cohorts, with 9 unique participants per cohort who were randomly assigned to a single dose of study treatment in a 6:3 ratio (Compound (I):placebo). Among the planned cohorts, a cohort (cohort 3) with a 2-period arm to estimate the effect of food on Compound (I) single-dose was included. The planned dosing was a single dose of Compound (I) 0.5, 3, 15, or 50 mg orally. No dose escalation above 50 mg was implemented for Part A (SAD) based on the TO readout from Part C (OGA-PET SAD).

[0237] Part B (MAD)

[0238] 27 participants (healthy females and infertile / vasectomized males) were enrolled in 3 planned cohorts of 9 unique participants per cohort who were randomly assigned to receive multiple doses of study treatment in a 6:3 ratio (Compound (I):placebo). In 2 of the 3 planned MAD cohorts, the age range was to be from 18 to 64 years of age. An additional cohort (cohort 9) of elderly participants (65 to 75 years of age) was included in the MAD study to evaluate the PK, safety, and tolerability in an older population. The planned dosing was Compound (I) 15 or 50 mg orally once daily for 14 days. No dose escalation above 50 mg was implemented for Part B (MAD) based on the TO readout from Part C (OGA-PET SAD).

[0239] Part C (OGA-PET)

[0240] Approximately 24 participants (healthy females and infertile / vasectomized males) 20 to 64 years of age were to be enrolled in up to 4 OGA-PET SAD cohorts and up to 2 OGA- PET MAD cohorts, with approximately 4 unique participants per cohort. For the OGA-PET SAD, the planned dosing was a single dose of Compound (I) 3 mg orally. Given that a TO of > 90% was achieved at 3 mg, a lower dose of 0.5 mg was implemented. For the OGA-PET MAD, Compound (I) 0.5 mg orally once daily for 14 days was implemented to confirm the predictions of TO > 90% in a multiple-dose setting for Compound (I). The reading confirmed the TO predictions, and no dose escalation above 0.5 mg was implemented for Part C (OGA- PET MAD).

[0241] In addition, for Part C (OGA-PET SAD and OGA-PET MAD), a tracer ((S)-N-(5-((3- ((5-fhioropyridin-2-yl)(methyl)amino)piperidin-l- yl)methyl)thiazol-2-yl)[nC]acetamide) was administered at 200 ± 20 MBq / 70 kg of body weight per dose by IV injection prior to each PET scan.

[0242] Control Matching placebo was administered orally to each cohort following the same dosing regimen as Compound (I). Placebo consisted of size 2 white opaque hypromellose capsules containing 10 mg micro crystalline cellulose excipient.

[0243] Duration The duration for the different trials is listed in the table below.

[0244] Table 1. Trial duration data *ND = not determined / no set time; N / A = Not Applicable

[0245] Treatments

[0246] Participants received either Compound (I) or placebo orally either once (Part A [SAD]) or once daily for 14 days (Part B [MAD]). Additionally, participants received Compound (I) orally either once (Part C [OGA-PET SAD]) or once daily for 14 days (Part C [OGA-PET MAD]). An overview of the treatment groups and integration of study parts is provided in Table 2.

[0247] The effect of food was investigated in participants randomly assigned to Part A (SAD: Cohort 3). For Cohort 3 (fed; Period 2), after an overnight fast of at least 8 hours, study treatment (Compound (I) or placebo) was administered at the same dose as in Period 1 within 30 minutes after starting a high-fat, high-calorie breakfast. A high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 kcal) meal was provided that derived approximately 150, 250, and 500-600 kcal from protein, carbohydrate, and fat, respectively.

[0248] For Part C (OGA-PET SAD / MAD), the tracer ((S)-N-(5-((3-((5-fhioropyridin-2- yl)(methyl)amino)piperidin-l- yl)methyl)thiazol-2-yl)[nC]acetamide) was administered by IV injection prior to each PET scan.

[0249] Table 2: Overview of Treatment Groups and Integration of Study Parts a: Number of unique participants planned per cohort. b: Excluding Part A (SAD: Cohort 3 [fed; Period 2]), doses (morning for Part A

[0250] [SAD] and Part B [MAD], afternoon for Part C [OGA-PET SAD / MAD]) were preceded by a fast from food (not including water) of at least 8 hours and followed by fast from food (not including water) for at least 2 hours postdose. Participants in MAD cohorts received study treatment once daily. c: The effect of food was assessed in the same participants in Part A (SAD: Cohort 3) following a washout period of at least 2 weeks (14 days). Demographics

[0251] A summary of the demographics is shown in Table 3.

[0252] Table 3: Summary of the demographics of study participants

[0253] Results

[0254] Pharmacokinetics

[0255] Following a single oral dose in the fasted state, Compound (I) was rapidly absorbed, with median Tmaxranging between 1.0 and 1.5 hours postdose, over the dose range of 0.5 to 50 mg (FIG. 1). The geometric mean ti / 2 of Compound (I) was approximately 40 hours for the 0.5 mg dose cohort, and approximately 30 hours in the 1, 3, 15, and 50 mg dose cohorts, demonstrating that once daily dosing is appropriate for Compound (I).

[0256] Under fasted conditions, Compound (I) systemic exposure increased in an approximately dose-proportional fashion over the dose range of 0.5 to 50 mg.

[0257] Administration of Compound (I) with food did not affect the extent of absorption as evidenced by no relevant change in AUC after administration with or without food; however, the rate of absorption was reduced as evidenced by a 50% decrease in Cmaxand a 2-hour increase in Tmax(FIG. 2). The amount of Compound (I) excreted unchanged in urine was minimal, accounting for approximately 2% or less of the administered single oral dose of Compound (I) at all dose levels.

[0258] A summary of the single dose PK data is shown in Table 4. Table 4: Summary of Compound (I) Single Dose PK Data

[0259] As observed in Part A (SAD), Compound (I) was rapidly absorbed after administration of 15 and 50 mg in Part B (MAD), with median Tmaxof 1.0 hour postdose on Day 1, and between 1.0 and 1.5 hours postdose on Day 14 (FIG. 3). Compound (I) systemic exposure increased in an approximately dose-proportional fashion after single and multiple oral doses of 15 and 50 mg.

[0260] The difference between the geometric mean AUCinf after a single dose of Compound (I) and AUCtau on Day 14 was less than 20%. Additionally, there were no clinically significant differences in CL / F after a single dose and at steady-state in the Compound (I) 15 and 50 mg dose cohorts. These results demonstrate that there are no time-dependent changes in Compound (I) PK with multiple doses at both 15 and 50 mg. Geometric mean Compound (I) C trough values collected on Days 7 through 14 in Part B were similar, indicating that systemic exposure to Compound (I) reaches steady state after approximately 7 days of once daily administration.

[0261] There were no clinically meaningful differences in Compound (I) PK between elderly (65 to 75 years of age) and non-elderly participants (18 to 64 years of age), after single and multiple doses of Compound (I) 15 mg once daily for 14 days (FIG. 4). There was no meaningful changes in plasma cholesterol and 4P-hydroxycholesterol levels after nonce daily administration of 15 mg or 50 mg of Compound (I) for 14 days. These results suggest that once daily administration of Compound (I) up to 50 mg does not induce CYP3.

[0262] The amount of Compound (I) excreted unchanged in urine was minimal, accounting for approximately 5% or less of the administered dose after multiple oral doses of Compound (I) 15 or 50 mg once daily.

[0263] A summary of the multiple dose PK data is shown in Table 5. Table 5: Summary of Compound (I) Single Dose PK Data

[0264] Target Occupancy

[0265] The TO of OGA by Compound (I) was assessed in Part C using an OGA-PET tracer, namely (S)-N-(5-((3-((5-fluoropyridin-2-yl)(methyl)amino)piperidin-l- yl)methyl)thiazol-2- yl)[nC]acetamide (Compound A). Each participant received a baseline PET scan (with no administration of Compound (I)) following the IV administration of 200 ± 20 MBq of Compound A in the morning. Acquisition was performed up to 120 minutes and volumes of distribution calculated. Participants then received a predetermined oral dose of Compound (I) at around lunch time; they were administered another IV dose of Compound A and scanned again after an early (between 2 and 6 hours after Compound (I) administration) and late (between 24, 48, or 72 hours after Compound (I) administration) time point. Up to 3 administrations of the PET tracer and 3 PET scans were obtained for each participant. Volumes of distribution were acquired post- treatment with Compound (I). The difference between the baseline and the postdose volumes of distribution (at 2 time points) was used to determine TO in a dose- and time-dependent manner.

[0266] The summary of TO of OGA by Compound (I) is presented in Table 6. Ten participants were dosed with Compound (I) and imaged at different time points post administration. A single oral dose of Compound (I) 3 mg maintained > 90% TO up to 48 hours post injection (FIG. 5). Multiple oral doses of Compound (I) 0.5 mg once daily for 14 days maintained > 90% TO up to 48 hours post injection (FIG. 6).

[0267] Table 6: Average Percent Target Occupancy for Compound (I) doses over time

[0268] *NT = Not Tested

[0269] Pharmacokinetic and Target Occupancy Relationship

[0270] A simple Emaxmodel described the relationship between plasma Compound (I) concentrations and TO. There is no apparent delay between appearance of Compound (I) in plasma and TO (FIG. 7). Results indicate that 0.5 mg Compound (I) once daily will achieve a mean TO >90% over the entire dosing interval. Unbound ECso in plasma is approximately 0.17 nM (0.0658 ng / mL)

[0271] Safety

[0272] Part A (SAD)

[0273] Twenty-three participants received Compound (I) ranging between 0.5 mg and 50 mg, while 12 participants received placebo. Overall, the incidence of participants who experienced at least 1 AE was slightly higher in the total Compound (I) group (11 participants [47.8%]) than the pooled placebo group (5 participants [41.7%]). All AEs were mild (8 participants [34.8%] in the total Compound (I) group and 2 participants [16.7%] in the pooled placebo group) or moderate (3 participants [13.0%] in the total Compound (I) group and 3 participants [25.0%] in the pooled placebo group) in severity. The most frequently reported (> 2 participants in either treatment group) AEs by PTs included headache (5 participants [21.7%] on Compound (I); 2 participants [16.7%] on placebo).

[0274] Part B (MAD)

[0275] Multiple oral doses of Compound (I) up to 50 mg (fasted) were well-tolerated when administered to healthy participants. Two participants experienced AEs that led to discontinuation of study treatment: 1 in the MAD Cohort 7 (Compound (I) 50 mg) group (PT: tremor) who remained in the study for follow-up and 1 in the pooled placebo group (PT : tonsillitis) who withdrew from the study. Thirteen participants (72.2%) in the total Compound (I) group and 5 participants (55.6%) in the pooled placebo group experienced at least 1 AEs. The incidence of AEs that were considered related to the study treatment by the Investigator was similar between the total Compound (I) group (11.1%) and pooled placebo group (11.1%).

[0276] The most frequently reported (>2 participants in either treatment group) AEs included headache (33.3% of participants on Compound (I), 11.1% of participants on placebo), dizziness (16.7% of participants on Compound (I), 11.1% of participants on placebo), and tremor (16.7% of participants on Compound (I), 0 participant on placebo).

[0277] All AEs were mild or moderate in severity. No severe AEs were observed. There were no deaths or SAEs. There were no clinically significant changes or trends in clinical laboratory results, vital signs, ECGs, or C-SSRS results.

[0278] Part C (OGA-PET SAD)

[0279] Single oral doses of Compound (I) up to 3 mg were well-tolerated when administered to healthy participants. Seven participants (100.0%) in the total Compound (I) group experienced at least 1 AE. There were no AEs considered related to the study treatment by the Investigator. Catheter site pain, contusion, and post procedural contusion were the most common (> 2 participants in total Compound (I) group) AEs reported by participants who received Compound (I) (28.6% of participants in each).

[0280] All AEs were mild or moderate in severity. No severe AEs were observed. There were no deaths or SAEs. There were no clinically significant changes or trends in clinical laboratory results, vital signs, ECGs, or C-SSRS results.

[0281] Part C (OGA-PET MAD)

[0282] Multiple oral doses of Compound (I) at 0.5 mg were well-tolerated when administered to healthy participants. Three participants (100.0%) experienced at least 1 AE. One participant (33.3%) experienced an AE that was considered related to the study treatment by the Investigator. Medical device site eczema was the most common AE (> 2 participants) reported by participants who received Compound (I) (100.0% of participants).

[0283] All AEs were mild in severity. No moderate or severe AEs were observed. There were no deaths or SAEs. There were no clinically significant changes or trends in clinical laboratory results, vital signs, ECGs, or C-SSRS results.

[0284] A summary of the safety results in shown in Table 7. Table 7: Safety data

[0285] Summary of Results Compound (I) was found to be safe and well tolerated at both a single 50 mg dose as well as multiple 50 mg doses. No deaths or serious adverse events were discovered, and all adverse events were mild. There was no clinically meaningful changes in other safety parameters.

[0286] Following a single oral dose in the fasted state, Compound (I) was rapidly absorbed over the dose range of 0.5 to 50 mg. The geometric mean ti / 2 of Compound (I) of approximately 30 hours in the 1, 3, 15, and 50 mg dose cohorts demonstrates that once daily dosing is appropriate for Compound (I). Systemic exposure to Compound (I) reaches steady- state after approximately 7 days of once daily administration. There were no time-dependent changes in Compound (I) PK with repeated doses at 15 and 50 mg.

[0287] Under fasted conditions, Compound (I) exposure (Cmax, AUCiast, and AUCmf) increased in an approximately dose-proportional fashion over the dose range of 0.5 to 50 mg. Administration of Compound (I) with food did not affect the extent of absorption; however, the rate of oral absorption was reduced.

[0288] Renal excretion is a minor route of elimination for Compound (I).

[0289] There were no clinically meaningful differences in Compound (I) PK between elderly and non-elderly participants, after single and once daily doses of Compound (I) 15mg. There was no meaningful induction of CYP3A by Compound (I) observed at doses up to 50 mg once daily.

[0290] Results indicated that plasma Compound (I) concentrations achieved after administration of 0.5 mg once daily can maintain TO > 90% over the entire dosing interval.

[0291] Example 2. In vivo mouse model study of the effect of OGA inhibition on tau pathology It was further discovered that in mouse models, long-term inhibition of OGA resulted in reduced tau pathology development in brain. rTg4510 mice were treated daily with Compound (I) at 50 mg / kg / day via chow dosing for 16 weeks starting at age 6 weeks, shortly before tau pathology onset, and ending at age 22 weeks, where robust tau pathology can be observed in this model. Brain tissue was analyzed for elevation of O-protein and O-tau (FIGs 8 and 12), ex vivo receptor occupancy (FIG. 9), and OGA enzymatic activity (FIG. 10). Chronic treatment with Compound (I) resulted in 86% TO, as measured by ex vivo receptor occupancy and 98% inhibition of OGA enzymatic activity. This corresponded to a 5.4-fold increase in brain O-protein. OGA protein levels were increased by 2.9-fold compared to vehicle-treated animals by end of study. Tau was robustly O-GlcNAcylated at serine 400 (FIG. 12), and the tau O-GlcNAc signal was restricted to the lower molecular size bands ranging from 45 to 60 kDa, indicative of O-GlcNAcylation of only soluble tau. Tau pathology was quantified by 2 biochemical methods and 1 histological method, as follows:

[0292] 1) The abundance of tau aggregates was determined in cortex homogenate by a single-epitope anti-tau HTRF assay.

[0293] 2) Hyperphosphorylated insoluble tau as indicated by the presence of a 64 kDa band was quantified in cortex homogenate by Western blotting.

[0294] 3) The presence of NFT-like tau aggregates was established by immunohistochemistry in brain sections. Tau aggregates in the cortex were reduced by 43% (HTRF assay; FIG. 11); hyperphosphorylated, insoluble tau (64 kDa band) was reduced by 27% (Western blot); and NFT-like tau aggregates were reduced by 20% in the cortex and hippocampus (immunohistochemistry) in Compound (I)-treated animals compared to vehicle-treated animals by the end of the study.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a human subject with Alzheimer’s disease, the method comprising administering to the subject orally a total daily dose of 0.5 to 50 mg of N-[4- fhioro-5-[[(2S,4R)-4-[(6-methoxy-4-pyrimidinyl)oxy]-2-methyl-l-pyrrolidinyl]methyl]-2- thiazolyl] acetamide, L-(+)-tartrate salt (1:1) (Compound (I)):(i); or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 50 mg of Compound (I).

2. The method of claim 1, wherein the subject is administered a total daily dose of 0.5 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 10 mg of Compound (I).

3. The method of claim 1, wherein the subject is administered a total daily dose of 0.5 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 5 mg of Compound (I).

4. The method of claim 1, wherein the subject is administered a total daily dose of 1 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg to 5 mg of Compound (I).

5. The method of claim 1, wherein the subject is administered a total daily dose of 0.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg of Compound (I).

6. The method of claim 1, wherein the subject is administered a total daily dose of 1 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg of Compound (I).

7. The method of claim 1, wherein the subject is administered a total daily dose of 1.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1.5 mg of Compound (I).

8. The method of claim 1, wherein the subject is administered a total daily dose of 2 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2 mg of Compound (I).

9. The method of claim 1, wherein the subject is administered a total daily dose of 2.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2.5 mg of Compound (I).

10. The method of claim 1, wherein the subject is administered a total daily dose of 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3 mg of Compound (I).

11. The method of claim 1 , wherein the subject is administered a total daily dose of 3.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3.5 mg of Compound (I).

12. The method of claim 1, wherein the subject is administered a total daily dose of 4 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4 mg of Compound (I).

13. The method of claim 1, wherein the subject is administered a total daily dose of 4.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4.5 mg of Compound (I).

14. The method of claim 1, wherein the subject is administered a total daily dose of 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 5 mg of Compound (I).

15. The method of any one of claims 1 to 14, wherein Compound (I), or a free base or pharmaceutically acceptable salt thereof, is administered to the subject once daily.

16. A kit comprising a pharmaceutical composition comprising 0.5 mg to 50 mg of N-[4- fhioro-5-[[(2S,4R)-4-[(6-methoxy-4-pyrimidinyl)oxy]-2-methyl-l-pyrrolidinyl]methyl]-2- thiazolyl] acetamide, L-(+)-tartrate salt (1:1) (Compound (I)):or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 50 mg of Compound (I).

17. The kit of claim 16, comprising a pharmaceutical composition comprising 0.5 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 10 mg of Compound (I).

18. The kit of claim 16, comprising a pharmaceutical composition comprising 0.5 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 5 mg of Compound (I).

19. The kit of claim 16, comprising a pharmaceutical composition comprising 1 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg to 5 mg of Compound (I).

20. The kit of claim 16, comprising a pharmaceutical composition comprising 0.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg of Compound (I).

21. The kit of claim 16, comprising a pharmaceutical composition comprising 1 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg of Compound (I).

22. The kit of claim 16, comprising a pharmaceutical composition comprising 1.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1.5 mg of Compound (I).

23. The kit of claim 16, comprising a pharmaceutical composition comprising 2 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2 mg of Compound (I).

24. The kit of claim 16, comprising a pharmaceutical composition comprising 2.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2.5 mg of Compound (I).

25. The kit of claim 16, comprising a pharmaceutical composition comprising 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3 mg of Compound (I).

26. The kit of claim 16, comprising a pharmaceutical composition comprising 3.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3.5 mg of Compound (I).

27. The kit of claim 16, comprising a pharmaceutical composition comprising 4 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4 mg of Compound (I).

28. The kit of claim 16, comprising a pharmaceutical composition comprising 4.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4.5 mg of Compound (I).

29. The kit of claim 16, comprising a pharmaceutical composition comprising 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 5 mg of Compound (I).

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