Method of treating neurodegenerative and ocular neovascular diseases

Abstract

The invention provides a method for treating neurodegenerative and ocular neovascular diseases comprising: administering to the subject a therapeutically effective amount of 3‑((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-1H,6H-pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one.

Description

METHOD OF TREATING NEURODEGENERATIVE AND OCULAR NEO VASCULAR DISEASESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 633,115, filed April 12, 2024, the disclosure of which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Lipoprotein-associated phospholipase A2 (Lp-PLA?) previously known as plateletactivating factor acetylhydrolase (PAF-AH), is a phospholipase A2 enzyme involved in hydrolysis of lipoprotein lipids or phospholipids. Lp-PLA2 travels with low-density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules derived from the oxidation of LDL. See, for example, Zalewski et al., Arterioscler. Thromb. Vase. Biol.. 25(5): 923-931 (2005). Lp-PLA2 hydrolyzes the sn-2 ester of the oxidized phosphatidylcholines to provide lipid mediators, lyso-phosphatidylcholine (lysoPC) and oxidized nonesterified fatty acids (NEFAs). It has been observed that lysoPC and NEFAs elicit inflammatory responses. See, for example, Zalewski et al. (2005).

[0003] A number of Lp-PLA2 inhibitors and / or uses thereof have been previously described. See, for example, U.S. Patent 9,783,546. The disclosed uses include treating disease that may be associated with the increased involvement of monocytes, macrophages, or lymphocytes, with the formation of lysophosphatidylcholine and oxidized free fatty acids, with lipid oxidation in conjunction with Lp-PLA2 activity, or with endothelial dysfunction. Examples of such diseases include neurodegeneration disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and vascular dementia), atherosclerosis, stroke, metabolic bone disorder (e.g., bone marrow abnormalities), dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, diabetic ocular disorder (e.g., macular edema, diabetic retinopathy, and posterior uveitis), macular edema, wound healing, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), psoriasis, and multiple sclerosis.

[0004] In view of the number of pathological responses that are mediated by Lp-PLA2, attempts have been made to prepare compounds that inhibit its activity. Though a number of such compounds have been disclosed in the art, attempts at treating such diseases have notbeen sufficiently successful. As such, there remains a need to develop methods of treating neurodegenerative and ocular neovascular diseases. The invention disclosed herein provides such methods of treating disease. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.BRIEF SUMMARY OF THE INVENTION

[0005] In one aspect, the invention provides a method for treating a neurodegenerative disease in a human subject in need thereof, comprising administering to the human subject a dosage of 1 mg to 180 mg of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7, 8,8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' : 3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 - one, or a pharmaceutically acceptable salt thereof, wherein the dosage can be administered once daily, twice daily, or three times daily.

[0006] In another aspect, the invention provides a method for treating an ocular neovascular disease in a human subject in need thereof, comprising administering to the human subject a dosage of 1 mg to 180 mg of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin- 4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H-pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin- 1-one, or a pharmaceutically acceptable salt thereof, wherein the dosage can be administered once daily, twice daily, or three times daily.

[0007] Further and alternative aspects and features of the disclosed principles will be appreciated from the following detailed description. As will be appreciated, the methods disclosed herein are capable of being carried out and used in other and different embodiments, and capable of being modified in various respects. Accordingly, it is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and do not restrict the scope of the appended claims.DETAILED DESCRIPTION OF THE INVENTION

[0008] The invention provides a method of treating a neurodegenerative or ocular neovascular disease in a human subject in need thereof, comprising administering to the human subject a dosage of 1 mg to 180 mg of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin- 4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H-pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin- l-one, or a pharmaceutically acceptable salt thereof, wherein the dosage can be administeredonce daily, twice daily, or three times daily. Thus, the total amount of the compound administered to a human subject can be within the range of 1 mg to 540 mg per day.

[0009] The invention also relates to methods of treating or preventing a disease associated with the activity of Lp-PLA2, which comprises administering to a subject in need thereof with a therapeutically effective amount of 3-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[T,2':3,4]imidazo[l,2-c]pyrimidin-l-one or a pharmaceutically acceptable salt thereof. The disease may be associated with the increased involvement of monocytes, macrophages, or lymphocytes, with the formation of lysophosphatidylcholine and oxidized free fatty acids, with lipid oxidation in conjunction with Lp-PLA2 activity, or with endothelial dysfunction.

[0010] This invention also provides methods of treating or preventing a disease by inhibiting Lp-PLA2 activity. Exemplary diseases include, but are not limited to, neurodegeneration disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), atherosclerosis, stroke, metabolic bone disorder (e.g., bone marrow abnormalities), dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, and hyperparathyroidism, diabetic ocular disorder (e.g., macular edema, diabetic retinopathy, and posterior uveitis), macular edema, wound healing, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), psoriasis, and multiple sclerosis. The methods comprise administering a therapeutically effective amount of a compound of this invention to a subject in need thereof. It is not intended that the invention is limited to any particular stage of the disease (e.g. early or advanced), or age of the treated subjects, or under or in combination with other treatments involving therapeutics or devices.

[0011] In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In certain embodiments, the Alzheimer’s disease is clinical, pre-clinical, or prodromal Alzheimer's disease.

[0012] In some embodiments the neurodegenerative disease is Down’s syndrome, cerebral amyloid angiopathy, vascular dementia, or dementia caused by neurodegeneration. In certain embodiments, the cerebral amyloid angiopathy is clinical or pre-clinical cerebral amyloid angiopathy.

[0013] In some embodiments, the ocular neovascular disease is diabetic retinopathy, proliferative diabetic retinopathy, retinal vein occlusion, central retinal vein occlusion, branched retinal vein occlusion, diabetic macular edema, diabetic retinal ischemia, ischemicretinopathy, or diabetic retinal edema. In certain embodiments, the ocular neovascular disease is diabetic macular edema.

[0014] As used herein, unless otherwise indicated, “disease” refers to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and / or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disease can also include a distemper, ailing, ailment, malady, disorder, sickness, illness, complaint, interdisposition, and / or affectation.

[0015] As used herein, unless otherwise indicated, “neurodegenerative disease” refers to a class of neurological disease where the neurological disease is characterized by a gradual and progressive loss of neural tissue, and / or altered neurological function, typically reduced neurological function as a result of a gradual and progressive loss of neural tissue. This gradual loss may take place in the brain or outside of the brain where nerve cells are present. In certain embodiments, the neurodegenerative diseases described herein include neurodegenerative diseases where there is a defective blood-brain barrier, for example, a permeable blood-brain barrier. In certain embodiments, the neurodegenerative diseases described herein include neurodegenerative diseases caused by the deterioration of the bloodbrain barrier. Examples of neurodegenerative diseases where there is a defective blood-brain barrier include, but are not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, vascular dementia, and the like. In some embodiments, the neurodegenerative diseases described herein include neurodegenerative diseases caused by adverse effects derived from LysoPC and NEFAs. In certain embodiments, the neurodegenerative diseases described herein include neurodegenerative diseases caused by adverse effects derived from LysoPC. In certain embodiments, the neurodegenerative diseases described herein include neurodegenerative diseases caused by adverse effects derived from NEFAs.

[0016] As used herein, unless otherwise indicated, “vascular dementia” is also referred to as “multi-infarct dementia,” which refers to a group of syndromes caused by different mechanisms, which all result in vascular lesions in the brain. The main subtypes of vascular dementia are, for example, vascular mild cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct (affecting the thalamus, the anterior cerebral artery, the parietal lobes, or the cingulated gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (including, for example, vascular dementia due to lacunar lesions and Binswanger disease), and mixed dementia.

[0017] As used herein, unless otherwise indicated, “blood-brain barrier” or “BBB” are used interchangeably herein and are used to refer to the permeable barrier that exists in blood vessels as they travel through the brain tissue that severely restricts and closely regulates what is exchanged between the blood and the brain tissue. The blood-brain barrier components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that are structural correlate of the BBB, the basement membrane of endothelial cells and the expanded foot process of nearby astrocytes which cover nearly all of the exposed outer surface of the blood vessel.

[0018] As used herein, unless otherwise indicated, “treat,” “treating,” or “treatment” in reference to a disease means (1) to ameliorate the disease or one or more of the biological manifestations of the disease, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the disease or (b) one or more of the biological manifestations of the disease, (3) to alleviate one or more of the symptoms or effects associated with the disease, (4) to slow the progression of the disease or one or more of the biological manifestations of the disease, and / or (5) to diminish the likelihood of severity of a disease or biological manifestations of the disease. In one embodiment, “treat,” “treating,” or “treatment” in reference to Alzheimer's disease means to slow the progression of cognitive function decline.

[0019] The references herein to 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7,8, 8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' :3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 -one include each of (a) the racemic mixture of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7,8, 8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' :3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 -one and (b) the A-enantiomer of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H-pyrrolo[T,2':3,4]imidazo[l,2-c]pyrimidin-l-one.

[0020] The structure of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7,8, 8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' :3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 -one can be depicted as follows:

[0021] The structure of the 7?-enantiomer of 3-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[T,2':3,4]imidazo[l,2-c]pyrimidin-l-one can be depicted as follows:

[0022] In some embodiments, the compound administered is a racemic mixture of 3-((3,5- difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[T,2':3,4]imidazo[l,2-c]pyrimidin-l-one. In other embodiments, the compound administered is the pure 7?-enantiomer of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7, 8,8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' : 3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 - one. In additional embodiments, the compound administered is a pharmaceutically acceptable salt of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9- tetrahydro-lH,6H-pyrrolo[T,2':3,4]imidazo[l,2-c]pyrimidin-l-one.

[0023] In some embodiments, 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7, 8,8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' : 3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 - one, or a pharmaceutically acceptable salt thereof, can be administered as a dosage of 1 mg / day to 180 mg / day, e.g., 1 mg / day, 5 mg / day, 10 mg / day, 15 mg / day, 20 mg / day, 25mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, or 180 mg / day, or a dosage within a range defined by any two of the aforementioned values, either at a single time per day or in two or more subdoses per day to equate to the aforementioned amounts per day.

[0024] In some embodiments, 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7, 8,8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' : 3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 - one, or a pharmaceutically acceptable salt thereof, can be administered as a dosage of 1 mg to 180 mg, wherein the dosage is administered twice daily e.g., 1 mg twice daily, 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily, 25 mg twice daily, 30 mg twice daily, 35 mg twice daily, 40 mg twice daily, 45 mg twice daily, 50 mg twice daily, 55 mg twice daily, 60 mg twice daily, 65 mg twice daily, 70 mg twice daily, 75 mg twice daily, 80 mg twice daily, 85 mg twice daily, 90 mg twice daily, 95 mg twice daily, 100 mg twice daily, 105 mg twice daily, 110 mg twice daily, 115 mg twice daily, 120 mg twice daily, 125 mg twice daily, 130 mg twice daily, 135 mg twice daily, 140 mg twice daily, 145 mg twice daily, 150 mg twice daily, 155 mg twice daily, 160 mg twice daily, 165 mg twice daily, 170 mg twice daily, 175 mg twice daily, or 180 mg twice daily, or a dosage within a range defined by any two of the aforementioned values.

[0025] In some embodiments, 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7, 8,8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' : 3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 - one, or a pharmaceutically acceptable salt thereof, can be administered as a dosage of 1 mg to 180 mg, wherein the dosage is administered three times daily e.g., 1 mg three times daily, 5 mg three times daily, 10 mg three times daily, 15 mg three times daily, 20 mg three times daily, 25 mg three times daily, 30 mg three times daily, 35 mg three times daily, 40 mg three times daily, 45 mg three times daily, 50 mg three times daily, 55 mg three times daily, 60 mg three times daily, 65 mg three times daily, 70 mg three times daily, 75 mg three times daily, 80 mg three times daily, 85 mg three times daily, 90 mg three times daily, 95 mg three times daily, 100 mg three times daily, 105 mg three times daily, 110 mg three times daily, 115 mg three times daily, 120 mg three times daily, 125 mg three times daily, 130 mg three times daily, 135 mg three times daily, 140 mg three times daily, 145 mg three times daily, 150 mg three times daily, 155 mg three times daily, 160 mg three times daily, 165 mg three timesdaily, 170 mg three times daily, 175 mg three times daily, or 180 mg three times daily, or a dosage within a range defined by any two of the aforementioned values.

[0026] In some embodiments, 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7, 8,8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' : 3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 - one, or a pharmaceutically acceptable salt thereof, can be administered as a dosage of 1 to 30 mg / day, 60 to 90 mg / day, or 120 to 180 mg / day. In other embodiments, the dosage can be administered as 1 to 30 mg, 60 to 90 mg, or 120 to 180 mg twice daily. In other embodiments, the dosage can be administered as 1 to 30 mg, 60 to 90 mg, or 120 to 180 mg three times daily.

[0027] 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9- tetrahydro-lH,6H-pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof, may be formulated into a pharmaceutical composition prior to administration to a subject. The pharmaceutical composition can comprise 3-((3,5-difluoro-4- ((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0028] As used herein, “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition, carrier, or vehicle involved in providing form or consistency to the pharmaceutical composition. Each excipient may be compatible with the other ingredients or components of the pharmaceutical composition when commingled, such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a subject and interactions which would result in a pharmaceutical composition that is not pharmaceutically acceptable are avoided.

[0029] The compound of the invention and the one or more pharmaceutically acceptable excipients may be formulated into a dosage form adapted for administration to the subject by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration (including buccal or sublingual) such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets, (2) parenteral administration (including subcutaneous, intramuscular, intravenous or intradermal) such as sterile solutions, suspensions, and powders for reconstitution, (3) transdermal administration such as transdermal patches, (4) rectal administration such as suppositories, (5) nasal inhalation such as dry powders, aerosols, suspensions, and solutions, and (6) topical administration (including buccal, sublingual or transdermal) such as creams, ointments,lotions, solutions, pastes, sprays, foams, and gels. Such compositions may be prepared by any methods known in the art of pharmacy, for example, by bringing into association a compound of the invention with one or more excipients.

[0030] Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0031] Suitable pharmaceutically acceptable excipients may vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate carrying or transporting the compound or compounds of the invention once administered to the subject from an organ, or a portion of the body, to another organ, or a portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

[0032] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much the excipient is present in the formulation and what other ingredients are present in the formulation.

[0033] Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington' s Pharmaceutical Sciences (Mack Publishing Company), The Handbook of PharmaceuticalAdditives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0034] The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0035] In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. com starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

[0036] In some embodiments, 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl)oxy)-7, 8,8a,9-tetrahydro- lH,6H-pyrrolo[ 1 ',2' : 3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 - one, or a pharmaceutically acceptable salt thereof, is formulated with microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. In some embodiments, 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro- lH,6H-pyrrolo[T,2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof, is present in an amount of 0.5% to 90%, e.g., 0.5%, 2.5%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a percent within a range defined by any two of the aforementioned values, by weight based on the weight of the total formulation. In some embodiments, microcrystalline cellulose is present in an amount of 5% to 71% by weight based on the weight of the total formulation, mannitol is present in an amount of 20% to 30%, e.g., 25%, by weight based on the weight of the total formulation, croscarmellose sodium is present in an amount of 1% to 5%, e.g., 3%, by weight based on the weight of the total formulation, and magnesium stearate is present in an amount of 0.1% to 1%, e.g., 0.5%, by weight based on the weight of the total formulation.

[0037] In some embodiments, the formulation is encapsulated in hydroxypropyl methylcellulose (i.e., hypromellose) capsules.ASPECTS OF THE DISCLOSURE

[0038] Aspects, including embodiments, of the invention described herein may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below:

[0039] (1) A method for treating a neurodegenerative disease in a human subject in need thereof, comprising administering to the human subject a dosage of 1 mg to 180 mg of a compound 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9- tetrahydro-lH,6H-pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof, wherein the dosage can be administered once daily, twice daily, or three times daily.

[0040] (2) The method of aspect (1), wherein the dosage is 1 to 30 mg.

[0041] (3) The method of aspect (1), wherein the dosage is 60 to 90 mg.

[0042] (4) The method of aspect (1), wherein the dosage is 120 to 180 mg.

[0043] (5) The method of aspect (1), wherein the dosage is 1 mg and is administered once daily.

[0044] (6) The method of aspect (1), wherein the dosage is 1 mg and is administered twice daily.

[0045] (7) The method of aspect (1), wherein the dosage is 1 mg and is administered three times daily.

[0046] (8) The method of aspect (1), wherein the dosage is 5 mg and is administered once daily.

[0047] (9) The method of aspect (1), wherein the dosage is 5 mg and is administered twice daily.

[0048] (10) The method of aspect (1), wherein the dosage is 5 mg and is administered three times daily.

[0049] (11) The method of aspect (1), wherein the dosage is 20 mg and is administered once daily.

[0050] (12) The method of aspect (1), wherein the dosage is 20 mg and is administered twice daily.

[0051] (13) The method of aspect (1), wherein the dosage is 20 mg and is administered three times daily.

[0052] (14) The method of aspect (1), wherein the dosage is 30 mg and is administered once daily.

[0053] (15) The method of aspect (1), wherein the dosage is 30 mg and is administered twice daily.

[0054] (16) The method of aspect (1), wherein the dosage is 30 mg and is administered three times daily.

[0055] (17) The method of aspect (1), wherein the dosage is 60 mg and is administered once daily.

[0056] (18) The method of aspect (1), wherein the dosage is 60 mg and is administered twice daily.

[0057] (19) The method of aspect (1), wherein the dosage is 60 mg and is administered three times daily.

[0058] (20) The method of aspect (1), wherein the dosage is 90 mg and is administered once daily.

[0059] (21) The method of aspect (1), wherein the dosage is 90 mg and is administered twice daily.

[0060] (22) The method of aspect (1), wherein the dosage is 90 mg and is administered three times daily.

[0061] (23) The method of aspect (1), wherein the dosage is 180 mg and is administered once daily.

[0062] (24) The method of aspect (1), wherein the dosage is 180 mg and is administered twice daily.

[0063] (25) The method of aspect (1), wherein the dosage is 180 mg and is administered three times daily.

[0064] (26) The method of any one of aspects ( 1 )-(25), wherein the compound is(7?)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H-pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof.

[0065] (27) The method of any one of aspects (l)-(26), wherein the neurodegenerative disease is Alzheimer’s disease.

[0066] (28) The method of aspect (27), wherein the Alzheimer’s disease is clinical, pre-clinical, or prodromal Alzheimer's disease.

[0067] (29 The method of any one of aspects (l)-(26), wherein the neurodegenerative disease is Down's syndrome.

[0068] (30) The method of any one of aspects (l)-(26), wherein the neurodegenerative disease is cerebral amyloid angiopathy.

[0069] (31) The method of aspect (30), wherein the cerebral amyloid angiopathy is clinical or pre-clinical cerebral amyloid angiopathy.

[0070] (32) The method of any one of aspects (l)-(26), wherein the neurodegenerative disease is vascular dementia.

[0071] (33) The method of any one of aspects (l)-(26), wherein the neurodegenerative disease is dementia caused by neurodegeneration.

[0072] (34) The method of any one of aspects (l)-(26), wherein the neurodegenerative disease is caused by deterioration of the blood-brain barrier.

[0073] (35) The method of any one of aspects (l)-(26), wherein the neurodegenerative disease is caused by adverse effects derived from LysoPC or NEFAs.

[0074] (36) A method for treating an ocular neovascular disease in a human subject in need thereof, comprising administering to the human subject a dosage of 1 mg to 180 mg of a compound 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9- tetrahydro-lH,6H-pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof, wherein the dosage can be administered once daily, twice daily, or three times daily.

[0075] (37) The method of aspect (36), wherein the dosage is 1 to 30 mg.

[0076] (38) The method of aspect (36), wherein the dosage is 60 to 90 mg.

[0077] (39) The method of aspect (36), wherein the dosage is 120 to 180 mg.

[0078] (40) The method of aspect (36), wherein the dosage is 1 mg and is administered once daily.

[0079] (41) The method of aspect (36), wherein the dosage is 1 mg and is administered twice daily.

[0080] (42) The method of aspect (36), wherein the dosage is 1 mg and is administered three times daily.

[0081] (43) The method of aspect (36), wherein the dosage is 5 mg and is administered once daily.

[0082] (44) The method of aspect (36), wherein the dosage is 5 mg and is administered twice daily.

[0083] (45) The method of aspect (36), wherein the dosage is 5 mg and is administered three times daily.

[0084] (46) The method of aspect (36), wherein the dosage is 20 mg and is administered once daily.

[0085] (47) The method of aspect (36), wherein the dosage is 20 mg and is administered twice daily.

[0086] (48) The method of aspect (36), wherein the dosage is 20 mg and is administered three times daily.

[0087] (49) The method of aspect (36), wherein the dosage is 30 mg and is administered once daily.

[0088] (50) The method of aspect (36), wherein the dosage is 30 mg and is administered twice daily.

[0089] (51) The method of aspect (36), wherein the dosage is 30 mg and is administered three times daily.

[0090] (52) The method of aspect (36), wherein the dosage is 60 mg and is administered once daily.

[0091] (53) The method of aspect (36), wherein the dosage is 60 mg and is administered twice daily.

[0092] (54) The method of aspect (36), wherein the dosage is 60 mg and is administered three times daily.

[0093] (55) The method of aspect (36), wherein the dosage is 90 mg and is administered once daily.

[0094] (56) The method of aspect (36), wherein the dosage is 90 mg and is administered twice daily.

[0095] (57) The method of aspect (36), wherein the dosage is 90 mg and is administered three times daily.

[0096] (58) The method of aspect (36), wherein the dosage is 180 mg and is administered once daily.

[0097] (59) The method of aspect (36), wherein the dosage is 180 mg and is administered twice daily.

[0098] (60) The method of aspect (36), wherein the dosage is 180 mg and is administered three times daily.

[0099] (61) The method of any one of aspects (36)-(60), wherein the compound is(7?)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro- lH,6H-pyrrolo[T,2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof.

[0100] (62) The method of any one of aspects (36)-(61), wherein the ocular neovascular disease is diabetic retinopathy, proliferative diabetic retinopathy, retinal vein occlusion, central retinal vein occlusion, branched retinal vein occlusion, diabetic retinal ischemia, ischemic retinopathy, or diabetic retinal edema.

[0101] (63) The method of any one of aspects (36)-(61), wherein the ocular neovascular disease is diabetic macular edema.EXAMPLES

[0102] These following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.EXAMPLE 1

[0103] This example evaluated the safety profile of (7?)-3-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one (compound) when administered to human subjects in a single ascending dose (SAD) study.

[0104] In this SAD study, 38 male and female participants were administered one single oral dose of either 1 mg, 5 mg, 20 mg, 60 mg, 180 mg, or a placebo. After receiving a respective dose, the incidence of any adverse events (AEs) was classified as being definitely not related, unlikely to be related, possibly related, probably related, or definitely related to the administered dosage.

[0105] A total of 22 (58%) participants had at least 1 treatment-emergent adverse effect (TEAE) during the SAD study, comprising 17 (59%) participants in the compound overallgroup and 5 (56%) participants in the placebo group. A total of 5 (13%) participants had at least 1 treatment-related TEAE, comprising 5 (17%) participants in the compound overall group and 0 participants in the placebo group. The most frequently reported TEAEs were catheter site pain, headache, and dermatitis contact. All AEs were mild or moderate in intensity. No apparent dose-dependent increase in the frequency and severity of AEs was observed.

[0106] A summary of adverse events is outlined in Table 1.Table 1 - Summary of Adverse Events in the SAD Study.

[0107] The results of this study indicated that single oral doses of up to 180 mg were safe and well tolerated.EXAMPLE 2

[0108] This example evaluated the safety profile of ( ?)-3-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin-l-one (compound) when administered to human subjects in a multiple ascending dose (MAD) study.

[0109] In this MAD study, 28 male and female participants were administered once daily oral doses of either 30 mg, 90 mg, 180 mg, or a placebo for 14 days. After the respective doses, the incidence of any adverse events (AEs) was classified as definitely not related, unlikely to be related, possibly related, probably related, or definitely related to the dosage.

[0110] A total of 20 (71%) participants had at least 1 TEAE, comprising 16 (70%) participants in the compound overall group and 4 (80%) participants in the placebo group. A total of 5 (18%) participants had at least 1 treatment-related TEAE, comprising 3 (13%) participants in the compound overall group and 2 (40%) participants in the placebo group. The most frequently reported TEAEs were headache, catheter site pain, catheter site swelling, and dizziness. All the reported AEs were mild or moderate in intensity and none of the AEs led to withdrawal from the study. No apparent dose-dependent increase in the frequency and severity of AEs was observed.[OHl] A summary of adverse events is outlined in Table 2.Table 2 - Summary of Adverse Events in the MAD Study.

[0112] The results of this study indicated that once daily repeated doses of up to 180 mg for 14 days were safe and well tolerated.EXAMPLE 3

[0113] This example evaluated the pharmacokinetic (PK) profile of ( ?)-3-((3,5-difluoro- 4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7, 8, 8a, 9-tetrahydro- 114,614- pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin-l-one when administered to human subjects in a single ascending dose (SAD) study.

[0114] Participants were administered a single oral dose of either 1 mg, 5 mg, 20 mg, 60 mg, or 180 mg, and PK plasma samples for concentration determination were collected atpre-dose (0 h) on Day 1 (DI) and at 0.5, 1, 2, 3, 4, 5, 6, 9, 12 h, 24 h (D2), 48 h (D3), 72 h (D4), and 96 h (D5) post dose. The plasma concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS / MS) method. The PK parameters including maximum plasma concentration (Cmax), the time it takes to reach the maximum concentration (Tmax), the area under the curve from the time of dosing to the last measureable concentration (AUCiast), the area under the curve from the time of dosing extrapolated to infinity (AUCO-INF), the half-life (T1 / 2), the volume of distribution based on the terminal elimination phase following extravascular administration (Vz / F), and the total body clearance following extravascular administration (CL / F) were determined by noncompartmental analysis.

[0115] The results of this study indicated that (R)-3-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one had low plasma clearance, moderate intersubject variability and suitable elimination half-life for once daily dosing in human subjects. A dose-proportional increase in exposure from 1 mg to 180 mg was observed.EXAMPLE 4

[0116] This example evaluated the pharmacokinetic (PK) profile of (7?)-3-((3,5-difluoro- 4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one when administered to human subjects in a multiple ascending dose (MAD) study.

[0117] Participants were administered once daily oral doses of either 30 mg, 90 mg, or 180 mg for 14 days, and plasma PK samples for concentration determination were collected at pre-dose (0 h) on Day 1 (DI), D2, D3, D5, D8, D12, and D14. Post-dose PK plasma samples were collected on DI and D14 at 0.5, 1, 2, 3, 4, 5, 6, 9, and 12 h post morning dose. In addition, PK plasma samples were collected on 24 h (DI 5), 48 h (DI 6), 72 h (DI 7), and 96 h (D18) post the D 14 morning dose. The plasma concentrations were determined by a validated LC-MS / MS method. PK parameters, including maximum concentration (Cmax), the time it takes to reach the maximum concentration (Tmax), the area under the curve over the dosing interval tau concentration (AUCo-tau), the half-life (T1 / 2), D14 / D1 observed accumulation ratio in exposure (Rac) were determined by non-compartmental analysis.

[0118] The results of this study indicated that (R)-3-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H-pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one had mild exposure accumulation (<1.5 folds) over repeated once daily dosing. In particular, a dose-proportional increase in exposure (AUCo-tau) from 30 mg to 90 mg and then a less than dose-proportional increase in AUCo-tau from 90 mg to 180 mg was observed after repeated once daily oral administration.EXAMPLE 5

[0119] This example evaluates the dose-dependent inhibition of plasma Lp-PLA2 activity of (A)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9- tetrahydro-lH,6H-pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin-l-one when administered to human subjects in a single ascending dose (SAD) study.

[0120] Participants were administered single oral doses of 1 mg, 5 mg, 20 mg, 60 mg, 180 mg, or placebo and the plasma samples for Lp-PLA2 activity were collected at pre-dose (0 h) on Day 1 (DI) and at 0.5, 1, 2, 3, 6, 12 h, 24 h (D2), 48 h (D3), 72 h (D4), and 96 h (D5) post dose. The plasma Lp-PLA2 activity was measured using the PLAC test and the percentage of Lp-PLA2 inhibition relative to the pre-dose baseline was calculated over a span of 96 h.

[0121] The results of this study indicated that (A)-3-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one had a dose- and concentration-dependent inhibition of plasma Lp-PLA2 activity. The percentage mean Lp-PLA2 inhibition was greater than 80% at 24 hours post dose in the participants administered doses of 5 mg, 20 mg, 60 mg, and 180 mg as compared to the pre-dose baseline (Table 3).Table 3 - The Percentage Mean Lp-PLAi Inhibition Versus Pre-dose Baseline at 24 Hours Post Dose in the SAD Study.EXAMPLE 6

[0122] This example evaluates the dose-dependent inhibition of plasma Lp-PLA2 activity of (7?)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9- tetrahydro-lH,6H-pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin-l-one when administered to human subjects in a multiple ascending dose (MAD) study.

[0123] Participants were administered once daily oral doses of 30 mg, 90 mg, or 180 mg, and the plasma samples for Lp-PLA2 activity were collected at pre-dose (0 h) on Day 1 (DI), D2, D3, D5, D8, D12, and D14. Post-dose plasma samples were collected on DI and D14 at 0.5, 1, 2, 3, 6, and 12 h post morning dose. In addition, plasma samples were collected on 24 h (D15), 48 h (D16), 72 h (D17), and 96 h (D18) post the D14 morning dose. The plasma Lp- PLA2 activity was measured using the PL AC test and the percentage of Lp-PLA2 inhibition relative to the Day 1 pre-dose baseline was calculated over a span of 432 h.

[0124] The resulting data indicated that all doses provided a higher percentage of Lp- PLA2 inhibition over 432 h. The percentage mean Lp-PLA2 inhibition was greater than 90% at trough at steady state in all doses as compared to the pre-dose baseline (Table 4).Table 4 - The Percentage Mean Lp-PLAi Inhibition Versus Pre-dose Baseline at Trough at Steady State in the MAD study.EXAMPLE 7

[0125] This example evaluates the cerebrospinal fluid (CSF) distribution of (7?)-3-((3 ,5- difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one when administered to human subjects.

[0126] Participants were administered an oral dose of 60 mg or placebo, and the CSF samples were taken at 2 h post administration by lumbar puncture. PK plasma samples for concentration determination were collected at pre-dose (0 h) on Day 1 (DI) and at 0.5, 1, 2, 3,4, 5, 6, 9, 12 h, and 24 h (D2) post dose. The CSF and plasma concentrations were determined by validated LC-MS / MS methods. The CSF-to-plasma unbound concentration ratio was calculated by correcting the CSF-to-plasma concentration ratio with plasma and brain tissue unbound fraction measured in vitro. The CSF Lp-PLA2 activity was measured by incubating CSF with probe substrate platelet-activating factor (PAF) for 60 minutes and the resultant hydrolyzed product lyso-PAF was quantified.

[0127] The CSF-to-plasma unbound concertation ratio was determined to be 1.2. The percentage mean Lp-PLA2 inhibition at approximately 2 hours post single oral dose of 60 mg was greater than 80% relative to that of the placebo group.

[0128] The results of this study indicated that (A)-3-((3,5-difluoro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin-l-one was brain penetrable and substantially inhibited Lp-PLA2 activity in the central nervous system.EXAMPLE 8

[0129] This example evaluates the effect of a high-fat breakfast on the pharmacokinetic (PK) parameters of (A)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)- 7, 8,8a,9-tetrahydro- lH,6H-pyrrolo[ l',2' : 3 ,4]imidazo[ 1 ,2-c]pyrimidin- 1 -one when administered to human subjects.

[0130] Participants were administered an oral dose of 60 mg under fasted and fed state conditions in a cross-over manner and PK plasma samples for concentration determination were collected at pre-dose (0 h) on Day 1 (DI) and at 0.5, 1, 2, 3, 4, 5, 6, 9, 12 h, 24 h (D2), 48 h (D3), 72 h (D4), and 96 h (D5) post dose. The plasma concentrations were determined by a validated LC-MS / MS method. The PK parameters including maximum plasma concentration (Cmax), the time it takes to reach the maximum concentration (Tmax), the area under the curve from the time of dosing to the last measurable concentration (AUCiast), the area under the curve from the time of dosing extrapolated to infinity (AUCO-INF), the half-life (T1 / 2), the volume of distribution based on the terminal elimination phase following extravascular administration (Vz / F), and the total body clearance following extravascular administration (CL / F) were determined by non-compartmental analysis.

[0131] The results of this study indicated that the intake of high-fat food led to a minor increase in AUC exposure (26%), a slight decrease in peak concentration (20%), a delayed Tmax, and had no effect on the terminal half-life and exposure variability.EXAMPLE 9

[0132] This example evaluated the induction effect of (R)-3-((3,5-difhroro-4-((2- (trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one on metabolizing enzyme CYP3A when administered to human subjects in a multiple ascending dose (MAD) study.

[0133] Participants were administered once daily oral doses of either 30 mg, 90 mg, 180 mg, or a placebo and plasma samples for 4P-hydroxycholesterol (an endogenous marker of CYP3A activity in humans) concentration were collected at pre-dose on Day 1 (DI) and Day 14 (D14). The plasma concentrations of 4P-hydroxycholesterol were determined by a validated LC-MS / MS method. Treatment effect on plasma 4P-hydroxycholesterol will be assessed using an analysis of covariance model of log-transformed D14 / D1 concentration ratio.

[0134] The mean plasma Day 14 / Day 1 ratios of 4P-hydroxy cholesterol concentrations showed no difference between the 30 mg and placebo-treated participants. However, the mean plasma Day 14 / Day 1 ratios of 4P-hydroxy cholesterol concentrations were slightly greater for the 90 mg and 180 mg treated participants compared to the placebo-treated participants in a dose-dependent manner.

[0135] The results of this study indicated that once daily oral doses of 180 mg or less of (7?)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro- lH,6H-pyrrolo[r,2':3,4]imidazo[l,2-c]pyrimidin-l-one led to no CYP3A induction or low levels of CYP3 A induction.

[0136] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0137] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearlycontradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0138] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:

1. A method for treating a neurodegenerative disease in a human subject in need thereof, comprising administering to the human subject a dosage of 1 mg to 180 mg of a compound 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9- tetrahydro-lH,6H-pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof, wherein the dosage can be administered once daily, twice daily, or three times daily.

2. The method of claim 1, wherein the dosage is 1 to 30 mg.

3. The method of claim 1, wherein the dosage is 60 to 90 mg.

4. The method of claim 1, wherein the dosage is 120 to 180 mg.

5. The method of claim 1, wherein the dosage is 1 mg and is administered once daily.

6. The method of claim 1, wherein the dosage is 1 mg and is administered twice daily.

7. The method of claim 1, wherein the dosage is 1 mg and is administered three times daily.

8. The method of claim 1, wherein the dosage is 5 mg and is administered once daily.

9. The method of claim 1, wherein the dosage is 5 mg and is administered twice daily.

10. The method of claim 1, wherein the dosage is 5 mg and is administered three times daily.

11. The method of claim 1, wherein the dosage is 20 mg and is administered once daily.

12. The method of claim 1, wherein the dosage is 20 mg and is administered twice13. The method of claim 1, wherein the dosage is 20 mg and is administered three times daily.

14. The method of claim 1, wherein the dosage is 30 mg and is administered once daily.

15. The method of claim 1, wherein the dosage is 30 mg and is administered twice daily.

16. The method of claim 1, wherein the dosage is 30 mg and is administered three times daily.

17. The method of claim 1, wherein the dosage is 60 mg and is administered once daily.

18. The method of claim 1, wherein the dosage is 60 mg and is administered twice daily.

19. The method of claim 1, wherein the dosage is 60 mg and is administered three times daily.

20. The method of claim 1, wherein the dosage is 90 mg and is administered once daily.

21. The method of claim 1, wherein the dosage is 90 mg and is administered twice daily.

22. The method of claim 1, wherein the dosage is 90 mg and is administered three times daily.

23. The method of claim 1, wherein the dosage is 180 mg and is administered once daily.

24. The method of claim 1, wherein the dosage is 180 mg and is administered twice daily.

25. The method of claim 1, wherein the dosage is 180 mg and is administered three times daily.

26. The method of any one of claims 1-25, wherein the compound is (A)-3-((3,5- difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[T,2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 1-26, wherein the neurodegenerative disease is Alzheimer’s disease.

28. The method of claim 27, wherein the Alzheimer’s disease is clinical, pre-clinical, or prodromal Alzheimer's disease.

29. The method of any one of claims 1-26, wherein the neurodegenerative disease is Down's syndrome.

30. The method of any one of claims 1-26, wherein the neurodegenerative disease is cerebral amyloid angiopathy.

31. The method of claim 30, wherein the cerebral amyloid angiopathy is clinical or pre-clinical cerebral amyloid angiopathy.

32. The method of any one of claims 1-26, wherein the neurodegenerative disease is vascular dementia.

33. The method of any one of claims 1-26, wherein the neurodegenerative disease is dementia caused by neurodegeneration.

34. The method of any one of claims 1-26, wherein the neurodegenerative disease is caused by deterioration of the blood-brain barrier.

35. The method of any one of claims 1-26, wherein the neurodegenerative disease is caused by adverse effects derived from LysoPC or NEFAs.

36. A method for treating an ocular neovascular disease in a human subject in need thereof, comprising administering to the human subject a dosage of 1 mg to 180 mg of a compound 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9- tetrahydro-lH,6H-pyrrolo[l',2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceuticallyacceptable salt thereof, wherein the dosage can be administered once daily, twice daily, or three times daily.

37. The method of claim 36, wherein the dosage is 1 to 30 mg.

38. The method of claim 36, wherein the dosage is 60 to 90 mg.

39. The method of claim 36, wherein the dosage is 120 to 180 mg.

40. The method of claim 36, wherein the dosage is 1 mg and is administered once daily.

41. The method of claim 36, wherein the dosage is 1 mg and is administered twice daily.

42. The method of claim 36, wherein the dosage is 1 mg and is administered three times daily.

43. The method of claim 36, wherein the dosage is 5 mg and is administered once daily.

44. The method of claim 36, wherein the dosage is 5 mg and is administered twice daily.

45. The method of claim 36, wherein the dosage is 5 mg and is administered three times daily.

46. The method of claim 36, wherein the dosage is 20 mg and is administered once daily.

47. The method of claim 36, wherein the dosage is 20 mg and is administered twice daily.

48. The method of claim 36, wherein the dosage is 20 mg and is administered three times daily.

49. The method of claim 36, wherein the dosage is 30 mg and is administered once daily.

50. The method of claim 36, wherein the dosage is 30 mg and is administered twice daily.

51. The method of claim 36, wherein the dosage is 30 mg and is administered three times daily.

52. The method of claim 36, wherein the dosage is 60 mg and is administered once daily.

53. The method of claim 36, wherein the dosage is 60 mg and is administered twice daily.

54. The method of claim 36, wherein the dosage is 60 mg and is administered three times daily.

55. The method of claim 36, wherein the dosage is 90 mg and is administered once daily.

56. The method of claim 36, wherein the dosage is 90 mg and is administered twice daily.

57. The method of claim 36, wherein the dosage is 90 mg and is administered three times daily.

58. The method of claim 36, wherein the dosage is 180 mg and is administered once daily.

59. The method of claim 36, wherein the dosage is 180 mg and is administered twice daily.

60. The method of claim 36, wherein the dosage is 180 mg and is administered three times daily.

61. The method of any one of claims 36-60, wherein the compound is ( ?)-3-((3,5- difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro-lH,6H- pyrrolo[T,2':3,4]imidazo[l,2-c]pyrimidin-l-one, or a pharmaceutically acceptable salt thereof.

62. The method of any one of claims 36-61, wherein the ocular neovascular disease is diabetic retinopathy, proliferative diabetic retinopathy, retinal vein occlusion, central retinal vein occlusion, branched retinal vein occlusion, diabetic retinal ischemia, ischemic retinopathy, or diabetic retinal edema.

63. The method of any one of claims 36-61, wherein the ocular neovascular disease is diabetic macular edema.

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