BR112016028591B1 - COMPOUND INHIBITING LP-PLA2 ACTIVITY, PHARMACEUTICAL COMPOSITION COMPRISING SAID COMPOUND AND USE THEREOF TO TREAT NEURODEGENERATIVE DISEASE - Google Patents

Abstract

COMPOUNDS The present invention relates to new compounds that inhibit Lp-PLA2 activity, processes for their preparation, compositions containing them and their use in the treatment of diseases associated with Lp-PLA2 activity, for example atherosclerosis, Alzheimer's disease.

Description

RELATED REQUEST

[001] The present application claims priority from PCT International Application No. PCT/CN2014/000695 filed on July 22, 2014 with the State Intellectual Property Office of the People's Republic of China.

FIELD OF TECHNIQUE

[002] The present invention relates to new tricyclic imidazo-pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy for the treatment of Lp-mediated diseases -PLA2.

BASICS OF THE INVENTION

[003] Lipoprotein-associated phospholipase A2 (Lp-PLA2), formerly known as platelet-activating factor acetyl hydrolase (PAF-AH), is a phospholipase A2 enzyme involved in the hydrolysis of lipoprotein lipids or phospholipids. Lp-PLA2 travels with low-density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules derived from LDL oxidation. (See, for example, Zalewski A, et al., Arterioscler. Thromb. Vasc. Biol., 25, 5, 923 to 931 (2005)). Lp-PLA2 hydrolyzes the sn-2 ester of oxidized phosphatidylcholines to yield lipid mediators, lyso-phosphatidylcholine (lysoPC) and oxidized nonesterified fatty acids (NEFA). It has been observed that lysoPC and NEFAs provoke inflammatory responses. (See, for example, Zalewski A, et al. (2005)).

[004] Various Lp-PLA2 inhibitors and/or their uses have been previously described. (See, for example, published patent applications WO 96/13484, WO 96/19451, WO 97/02242, WO 97/12963, WO 97/21675, WO 97/21676, WO 97/41098, WO 97/41099 , WO 99/24420, WO 00/10980, WO 00/66566, WO 00/66567, WO 00/68208, WO 01/60805, WO 02/30904, WO 02/30911, WO 03/015786, WO 03/016287 , WO 03/041712, WO 03/042179, WO 03/042206, WO 03/042218, WO 03/086400, WO 03/87088, WO 08/048867, US 2008/0103156, US 2008/0090851/ 0090852 , and WO 08/048866). Described uses include the treatment of diseases involving or associated with endothelial dysfunction, diseases involving lipid oxidation in conjunction with Lp-PLA2 activity (e.g., associated with the formation of lysophosphatidylcholine and oxidized free fatty acids) , and diseases that involve activated monocytes, macrophages, or lymphocytes or that are associated with increased involvement of monocytes, macrophages, or lymphocytes. Examples of diseases include atherosclerosis (e.g., peripheral vascular atherosclerosis and cerebrovascular atherosclerosis), diabetes, hypertension, angina pectoris, post ischemia and reperfusion, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's disease, various neuropsychiatric diseases such as schizophrenia, myocardial infarction, ischemia, reperfusion injury, sepsis, acute and chronic inflammation and psoriasis.

[005] Lp-PLA2 inhibitors and/or their uses are also referred to, for example, in PCT Publications Nos. WO 05/003118 (and its Canadian family member CA 2530816A1); WO 06/063811; WO 06/063813 and WO 2008/141176; JP 200188847; and in Published Patent Application Nos. US 2008/0279846 A1, US 2010/0239565 A1 and US 2008/0280829 A1.

[006] Other researchers have studied the effects related to Lp-PLA2 and its inhibitors. For example, research data also indicated that LysoPC promotes atherosclerotic plaque development, which can lead to the formation of a necrotic core. (See, for example, Wilensky et al., Current Opinion in Lipidology, 20, 415 to 420 (2009)). In addition, the effect of Lp-PLA2 inhibitors on atherosclerotic plaque composition was demonstrated in a diabetic and hypercholesterolemic swine model of accelerated coronary atherosclerosis. (See, for example, Wilensky et al., Nature Medicine, 10, 1015 to 1016 (2008)). These research results provided further evidence that Lp-PLA2 inhibitors can be used to treat atherosclerosis.

[007] Additional studies indicate that high Lp-PLA2 activity is associated with a high risk of dementia, including Alzheimer's disease (AD) (see, for example, Van Oijen, et al., Annals of Neurology, 59, 139 (2006)). Higher levels of oxidized LDL have also been observed in patients with AD (See, for example, Kassner et al., Current Alzheimer Research, 5, 358 to 366 (2008), Dildar et al., Alzheimer Dis Assoc Disord, 24, April-June (2010), Sinem, et al., Current Alzheimer Research, 7, 463 to 469 (2010)). Furthermore, studies show that neuroinflammation is present in AD patients and multiple cytotoxic inflammatory cytokines are induced in AD patients. (See, for example, Colangelo, et al., Journal of Neuroscience Research, 70, 462 to 473 (2002), Wyss-Coray, Nature Medicine, 12, September (2006)). Research has shown that LysoPC functions as a pro-inflammatory factor that induces the release of multiple cytotoxic inflammatory cytokines (see Shi et al., Atherosclerosis, 191, 54 to 62 (2007)). Therefore, these studies provide additional evidence that Lp-PLA2 inhibitors can be used to treat AD by inhibiting Lp-PLA2 activity and reducing lysoPC production.

[008] In addition, the use of an Lp-PLA2 inhibitor in a diabetic and hypercholesterolemic swine model demonstrated that blood-brain barrier leakage and brain amyloid beta (Aβ) protein burden burden the pathological features of Alzheimer's disease. reduced. (See U.S. Patent Application Publication No. 2008/0279846). This publication describes several uses of Lp-PLA2 inhibitors for the treatment of diseases associated with blood-brain barrier leakage, including, for example, Alzheimer's disease and vascular dementia.

[009] Furthermore, neuroinflammation, including the release of multiple cytotoxic cytokines, is a common feature of all neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc. (See for example, Perry, Acta Neuropathol, 120, 277 to 286)). As discussed above, Lp-PLA2 inhibitors can reduce inflammation, for example, by reducing the release of multiple cytokines by suppressing lysoPC production. (See e.g., Shi, et al., Atherosclerosis 191, 54 to 62 (2007)). Thus, inhibition of Lp-PLA2 is a potential therapeutic treatment for neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, etc.

[0010] In addition to the inflammatory effect, LysoPC has been implicated in the activation of leukocytes, the induction of apoptosis and the mediation of endothelial dysfunction (See, for example, Wilensky et al., Current Opinion in Lipidology, 20, 415 to 420 (2009) ). Therefore, it is believed that Lp-PLA2 inhibitors may be used to treat tissue damage associated with diabetes by reducing the production of lysoPC, which can cause an ongoing cycle of vascular inflammation and increased production of reactive oxygen species ( ROS). Given the inflammatory roles of Lp-PLA2 and the association between localized inflammatory processes and diabetic retinopathy, it is postulated that Lp-PLA2 can be used to treat diabetic eye disease.

[0011] Glaucoma and age-related macular degeneration (AMD) are neurodegenerative diseases of the retina. Studies suggest that inflammation, including TNF-alpha signaling, may play an important role in the pathogenesis of glaucoma and AMD (See, for example, Buschini et al., Progress in Neurobiology, 95, 14 to 25 (2011), Tezel , Progress in Brain Research, vol. 173, ISSN0079-6123, Chapter 28). Thus, considering the function of Lp-PLA2 inhibitors to block the release of inflammatory cytokines (see, e.g., Shi et al., Atherosclerosis, 191, 54 to 62 (2007)), it is believed that Lp-PLA2 inhibitors may provide a potential therapeutic application for glaucoma and AMD.

[0012] 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. Although a number of these compounds have been described in the art, there remains a continuing need for Lp-PLA2 inhibitors that can be used in the treatment of a variety of conditions.

SUMMARY OF THE INVENTION

[0013] In a first aspect, this invention relates to compounds with a structure of

[0014] and their salts (for example, pharmaceutically acceptable salts thereof).

[0015] In another aspect, the invention relates to compounds with a structure of

[0016] and their salts (for example, pharmaceutically acceptable salts thereof).

[0017] In another aspect, the invention relates to compounds with a structure of

[0018] and salts thereof (for example, a pharmaceutically acceptable salt thereof).

[0019] This invention also relates to a pharmaceutical composition comprising compounds described in this invention and a pharmaceutically acceptable excipient.

[0020] The invention also relates to methods of treating or preventing a disease associated with Lp-PLA2 activity, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound of the invention described herein. The disease may be associated with 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.

[0021] This invention also provides methods of treating or preventing a disease by inhibiting the activity of Lp-PLA2. Exemplified diseases include, but are not limited to, neurodegeneration disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), atherosclerosis, stroke, bone metabolic disorder (e.g., bone marrow abnormalities). bone), dyslipidemia, Paget's disease, type II diabetes, metabolic syndrome, insulin resistance and hyperparathyroidism, diabetic eye disorder (e.g., macular edema, diabetic retinopathy, and posterior uveitis), macular edema, wound healing, rheumatoid arthritis, disease chronic obstructive pulmonary disease (COPD), psoriasis and multiple sclerosis. The methods comprise administering a therapeutically effective amount of a compound of this invention to an individual in need thereof. The present invention is not intended to be limited to any particular stage of the disease (e.g., early or advanced).

[0022] This invention also provides methods for treating or preventing Alzheimer's disease. The methods comprise administering to an individual in need thereof a therapeutically effective amount of a compound of this invention.

[0023] This invention also provides methods for treating or preventing atherosclerosis. The methods comprise administering to an individual in need thereof a therapeutically effective amount of a compound of this invention.

[0024] This invention also provides methods for decreasing the accumulation of amyloid beta (also called “Aβ”) in an individual's brain. The methods comprise administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention. In certain embodiments, the amyloid beta is Abeta-42.

[0025] This invention also provides methods for treating or preventing eye diseases through the administration of a compound of this invention. In certain embodiments, this invention provides methods for treating macular edema, which comprise administering to the subject a therapeutically effective amount of a compound of this invention. In certain embodiments, macular edema is associated with diabetic eye disease, e.g., diabetic macular edema or diabetic retinopathy. In one embodiment, macular edema is associated with posterior uveitis.

[0026] This invention also provides a use of compounds of this invention in the manufacture of a medicament for treating or preventing diseases described herein.

[0027] This invention also provides compounds of this invention for use in the treatment or prevention described herein.

DETAILED DESCRIPTION

[0028] As used in the description of the embodiments of the invention and the attached claims, the singular forms “a”, “an” and “the”, “a” are intended to also include the plural forms, unless the context indicates clearly the opposite. Also, as used herein, “and/or” is intended to encompass any and all possible combinations of one or more of the associated listed items. It will be further understood that the terms “comprises” and/or “comprising” when used in this specification, specify the presence of features, integers, steps, operations, elements and/or components, but do not preclude the presence or addition of one or more other characteristics, integers, steps, stages, elements, components and/or groups thereof.

[0029] Generally, the nomenclature used here and the laboratory procedures in organic chemistry, medicinal chemistry, biology described here are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as understood by one skilled in the art to which this description belongs. In the event that there are a plurality of definitions for a term used herein, those in this section prevail, unless otherwise indicated.

A. Definitions

[0030] As used herein, unless otherwise indicated, “disease” refers to any change in the state of the body or some of the organs, interrupting or disturbing the performance of functions and/or causing symptoms such as discomfort, dysfunction, distress or even death to the afflicted person or to those in contact with a person. An illness can also include an intemperance, affliction, inconvenience, pain, disturbance, sickness, illness, complaint, interdisposition and/or malingering.

[0031] As used herein, unless otherwise indicated, “neurodegenerative disease”, as used herein, refers to a variety of disorders of the central nervous system characterized by gradual and progressive loss of neural tissue and/or brain function. neural tissue. A neurodegenerative disease is a class of neurological disease where the neurological disease is characterized by a gradual and progressive loss of neural tissue and/or an altered neurological function, typically reducing neurological function as a result of a gradual and progressive loss of neural tissue. In certain embodiments, the neurodegenerative diseases described herein include neurodegenerative diseases where there is a defective blood-brain barrier, e.g., a leaky blood-brain 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.

[0032] As used herein, unless otherwise indicated, “vascular dementia” is also called “multi-infarct dementia”, which refers to a group of syndromes caused by different mechanisms, which result in vascular lesions in the brain. The main subtypes of vascular dementia are, for example, vascular mild cognitive dysfunction, multi-infarct dementia, vascular dementia due to a single strategic infarct, (affecting the thalamus, anterior cerebral artery, parietal lobes or cingulate gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (including, for example, vascular dementia due to lacunar lesions and Binswanger's disease) and mixed dementia.

[0033] As used herein, unless otherwise indicated, “blood brain barrier” or “BBB” are used interchangeably in this document and are used to refer to the permeable barrier that exists in blood vessels as they course through brain tissue which restricts and tightly regulates what is exchanged between blood and brain tissue. Components of the blood-brain barrier include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that are structurally correlated with the BBB, the basement membrane of the endothelial cells, and the expanded foot process of nearby astrocytes that cover almost the entire exposed outer surface of the blood vessel.

[0034] As used herein, unless otherwise indicated, "metabolic bone disease", as used herein, refers to a variety of bone diseases characterized by gradual and progressive loss of bone tissue. The metabolic bone diseases described here are metabolic bone diseases where there is a condition of diffusely decreased bone density and/or decreased bone strength. Such diseases are characterized by their histological appearance. Exemplified metabolic bone diseases include, but are not limited to, osteoporosis which is characterized by decreased mineral and bone matrix, and osteomalacia which is characterized by decreased mineral but intact bone matrix.

[0035] As used herein, unless otherwise indicated, “osteopenic diseases” or “osteopenia” are used interchangeably in this document, and refer to conditions with decreased calcification and/or bone density, and is a descriptive term used to refer to all skeletal systems where calcification and/or decreased bone density is observed. Osteopenia also refers to reduced bone mass due to inadequate osteoid synthesis.

[0036] As used herein, unless otherwise indicated, “osteoporosis” refers to conditions in which mineral and/or bone matrix is decreased and/or bone mass is reduced.

[0037] As used herein, unless otherwise indicated, “treating”, “treating” or “treatment” in reference to a disease means: (1) improving the disease or one or more of the biological manifestations of the disease, ( 2) 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) alleviate one or more of the symptoms or effects associated with the disease, (4) slow the progression of the disease or one or more of the biological manifestations of the disease and/or (5) decrease the likelihood of severity of a disease or biological manifestations of the disease. In one embodiment, “treating,” “treating,” or “treatment” in reference to Alzheimer's disease means: slowing the progression of decline in cognitive function.

[0038] As used herein, unless otherwise indicated, “preventing”, “preventing” or “prevention” means the prophylactic administration of a drug to decrease the likelihood of the onset or delay the onset of a disease or manifestation its biological nature.

[0039] As used herein, unless otherwise indicated, "individual" means a mammalian individual (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.) and particularly human beings including individuals of the male and female and including neonatal, infant, juvenile, adolescent, adult, and geriatric individuals, and including various races and ethnicities, including, but not limited to, white, black, Asian, American Indian, and Hispanic.

[0040] As used herein, unless otherwise indicated, “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the compound in question and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0041] As used herein, unless otherwise indicated, the term “therapeutically effective amount” means any amount that, compared to a corresponding individual who did not receive such amount, results in the treatment or prevention of a disease, but sufficiently low to avoid serious side effects (with a reasonable risk/benefit ratio) within the scope of sound medical judgment. A therapeutically effective amount of a compound will vary with the particular compound chosen (e.g., considering the potency, efficacy, and half-life of the compound); the chosen route of administration; the disease being treated; the severity of the disease being treated; the age, size, weight and physical condition of the patient being treated; the medical history of the patient being treated; the duration of treatment; the nature of concomitant therapy; the desired therapeutic effect; and similar factors, but can, however, be routinely determined by one skilled in the art.

B. Compounds

[0042] One aspect of the present invention provides compounds with the structure of 3 - ((3, 5-difluoro-4 - ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7,8, 8a,9- tetrahydropyrrolo [1',2':3,4] imidazo [1,2-c] pyrimidin-1 (6H) -one

[0043] and its salts.

[0044] Another aspect of the present invention provides compounds with the structure of 3 - ((3, 5-difluoro-4 - ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7,8, 8a, 9- tetrahydropyrrolo [1',2': 3,4] imidazo [1,2-c] pyrimidin-1 (6H) -one

[0045] and its pharmaceutically acceptable salts.

[0046] In one embodiment, this invention relates to compounds with the structure of (R) -3 - ((3, 5-difluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl )oxy) - 7,8a,9-tetrahydropyrrolo [1',2': 3,4] imidazo [1,2-c] pyrimidin-1 (6H) -one

[0047] and its salts.

[0048] In one embodiment, this invention relates to compounds with the structure of (R) -3 - ((3, 5-difluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl )oxy) - 7,8a,9-tetrahydropyrrolo [1',2': 3,4] imidazo [1,2-c] pyrimidin-1 (6H) -one o

[0049] and its pharmaceutically acceptable salts.

[0050] In another embodiment, the invention relates to a compound with the structure of (R) -3 - ((3,5-difluoro-4 - ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) 7,8,8a,9-tetrahydropyrrolo [1',2': 3,4] imidazo [1,2- c] pyrimidin-1 (6H) -one o

[0051] In one embodiment, the invention relates to a compound with the structure of a pharmaceutically acceptable salt of (R) -3 - ((3,5-difluoro-4 - ((2- (trifluoromethyl) pyridin-4 -yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetrahydropyrrolo [1',2':3,4]

[0052] In another embodiment, the invention relates to a compound with the structure of (S) -3 - ((3, 5-difluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) 7, 8, 8a, 9-tetrahydropyrrolo [1',2':3,4] imidazo [1,2- c] pyrimidin-1 (6H) - one

[0053] and its salts.

[0054] In another embodiment, the invention refers to a compound with the structure of (S) -3 - ((3, 5-difluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl)oxy) - 7, 8, 8a, 9-tetrahydropyrrolo [1', 2': 3,4] imidazo [1,2- c] pyrimidin-1 (6H) - one

[0055] and its pharmaceutically acceptable salts.

[0056] In one embodiment, the invention relates to a compound with the structure of (S) -3 - ((3, 5-difluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl)oxy) - 7, 8, 8a, 9-tetrahydropyrrolo [1',2': 3,4] imidazo [1,2-c] pyrimidin-1 (6H) - one

[0057] In one embodiment, the invention relates to a compound having the structure of a pharmaceutically acceptable salt of (S) -3 - ((3, 5-difluoro-4 - ((2- (trifluoromethyl) pyridin-4 -yl) oxy) benzyl) oxy) -7, 8, 8a, 9-tetrahydropyrrolo [1',2':3,4] imidazo [1,2- c] pyrimidin-1 (6H) - one

[0058] The compounds described above, salts (e.g., pharmaceutically acceptable salts) thereof may exist in stereoisomeric forms (e.g., contain one or more asymmetric carbon atoms). Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention. The scope of the present invention includes purified enantiomers or enantiomerically/diastereomerically enriched mixtures. The different isomeric forms can be separated or resolved from each other by conventional methods (e.g. chiral HPLC), or any given isomer can be obtained by conventional synthetic methods, e.g. stereospecific or asymmetric syntheses.

[0059] The invention also includes various deuterated forms of compounds described above, and salts (e.g., pharmaceutically acceptable salts) thereof. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. One skilled in the art will know how to synthesize deuterated forms of the compounds described above and salts (e.g., pharmaceutically acceptable salts) thereof. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds described above and salts (e.g., pharmaceutically acceptable salts) thereof, or can be synthesized using conventional techniques employing deuterated reagents (e.g., aluminum deuteride and lithium).

[0060] In addition to the free base of the compounds described here, the salt form of the compounds is also within the scope of the present invention. Pharmaceutically acceptable salts or salts of the compounds described herein can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable base or acid, respectively. For reviews on suitable pharmaceutical salts see Berge et al., J. Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33 (1986), 201 to 217; and Bighley et al., Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, pages 453 to 497.

[0061] In certain embodiments, the compounds of the present invention may contain a basic group and are therefore capable of forming pharmaceutically acceptable acid addition salts upon treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. These salts can be crystalline or amorphous. Examples of pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate (tosylate), and naphthalene-2- sulfonate. In some embodiments, pharmaceutically acceptable salts include L-tartrate, ethanedisulfonate (edisylate), sulfate, phosphate, p-toluenesulfonate (tosylate), hydrochloride salt, methanesulfonate, citrate, fumarate, benzenesulfonate, maleate, hydrobromide, L-lactate, malonate , and S-camphor-10-sulfonate. Some of these salts form solvates, some are crystalline.

[0062] The compounds described herein, their salts (e.g., pharmaceutically acceptable salts), deuterated forms, solvates or hydrates thereof, may exist in one or more polymorphic forms. Therefore, in a further aspect, the invention provides a polymorph of a compound defined herein, salts thereof (e.g. pharmaceutically acceptable salts) or a polymorph of a solvate or hydrate of a compound described herein or a salt (e.g. pharmaceutically acceptable salt).

[0063] The compounds described above and the salts (including their pharmaceutically acceptable salts) can be in the form of a solvate. For solvates of the compounds described above, including solvates of salts of the compounds described above, which are in crystalline form, one skilled in the art will appreciate that pharmaceutically acceptable solvates can be formed where solvent molecules are incorporated into the crystalline structure during crystallization. Solvates may involve non-aqueous solvents such as ethanol, isopropanol, dimethyl sulfoxide, acetic acid, ethanolamine and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystal structure. Solvates, where water is the solvent that is incorporated into the crystal structure, are typically called “hydrates”. Solvates include stoichiometric solvates as well as compositions containing varying amounts of the incorporated solvent(s), for example, a hydrate includes stoichiometric hydrates and compositions containing varying amounts of water.

[0064] The invention also includes isotopically labeled compounds and salts, which are identical to the compounds described above or their salts, but for the fact that one or more atoms are replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the compounds described above or their salts are isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3H, 11C, 14C and 18F. Such isotopically labeled compound described above or salts thereof are useful in drug and/or tissue substrate distribution assays. For example, the isotopes 11C and 18F are useful in PET (positron emission tomography). PET is useful in imaging the brain. The isotopically labeled compounds described above and their salts can generally be prepared by carrying out the procedures described below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In one embodiment, the compounds described above or their salts are not isotopically labeled.

[0065] As used herein, the terms “compound(s) of the invention” or “compound(s) of the present invention” mean a compound described above, as defined herein, in any form, that is, any saline form or not. saline (e.g., as a free base form, or as a salt, e.g., a pharmaceutically acceptable salt thereof), deuterated form, and any physical form thereof (e.g., including non-solid forms (e.g., liquid forms or semisolids), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvated forms, including hydrated forms (e.g., mono-, di-, and hemihydrates)) and mixtures of various forms. In the context of the composition pharmaceutical and treatment methods discussed herein, the terms “compounds of the invention” mean a compound described above, in the form of any pharmaceutically acceptable salt thereof or non-salt form (e.g., as a form of a free base), deuterated form and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semisolid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvated forms, including hydrated forms (e.g., mono -, di- and hemihydrates)), and mixtures of various forms.

[0066] Consequently, a compound of the invention includes a compound described above, or a salt thereof, for example, a pharmaceutically acceptable salt thereof. Representative compounds of this invention include the specific compounds described.

[0067] All temperatures are reported in degrees Celsius. All other abbreviations are as described in the ACS Style Guide (American Chemical Society, Washington, DC, 1986), unless abbreviations are specifically defined below.

[0068] LCMS conditions:

[0069]1) Acidic conditions:

[0070] Mobile phase: water containing 0.05% TFA/0.05% acetonitrile

[0071] Column: Agilent SB-C18 4.6 x 30 mm - 1.8 microns

[0072] Detection: MS and photodiode array (PDA) detector

[0073]2) Basic conditions:

[0074] Mobile phase: water containing 10 mmol NH4HCO3/acetonitrile

[0075] Column: XBridgeTM C18 4.6 x 50 mm - 3.5 microns

[0076] Detection: MS and photodiode array (PDA) detector

[0077] The chemical name of the compounds described in this application follows the principle of IUPAC nomenclature.

[0078] Abbreviations and Resource Sources

[0079] The following abbreviations and resources are used here below:

[0080]ISCO System - Teledyne ISCO (http://www.isco.com/html/seFlashChromatography.html)

[0081]r.t/rt/RT - ambient temperature

[0082] ACN - acetonitrile

[0083]Aq. - watery

[0084]CV - column volumes

[0085]DCM - dichloromethane

[0086]DMF - N, N-dimethylformamide

[0087]DMP - Dess-Martin periodinane

[0088]DMSO - dimethyl sulfoxide

[0089]EtOH - ethanol

[0090]EA/EtOAc - ethyl acetate

[0091] FC - flash chromatography (normally conducted on a silica gel column)

[0092] sat. - saturated

[0093] TEA or Et3N - triethylamine

[0094]THF - tetrahydrofuran

[0095]PE - petroleum ether

[0096]Examples

[0097] The following synthetic processes and examples are provided to more specifically illustrate the invention. These examples are not intended to limit the scope of the invention, but rather to provide guidance to one skilled in the art for preparing and using the compounds, compositions and methods of the invention. Although particular embodiments of the invention are described, one skilled in the art will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0098] In general, the compounds of the present invention can be prepared by conventional techniques known in the art and by known processes analogous to these. General methods for preparing the compounds of the present invention are set forth below. All starting materials and reagents described in the general experimental schemes below are commercially available.

[0099] In the procedures that follow, after each starting material, reference to an intermediate is typically provided. This is provided for assistance to the skilled chemist only. The starting material may not necessarily have been prepared from said batch. D1 (1- (2,6-Dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol

[00100] To the solution of 2, 4, 6-trichloropyrimidine (2.176 g, 11.86 mmol) and triethylamine (2.76 mL, 19.77 mmol) in acetonitrile (25 mL) was added pyrrolidin-2-yl-methanol (1.0 g, 9.89 mmol) in acetonitrile (5 mL) at 0° C. The mixture was stirred for 2 hours at room temperature and the solution was collected by filtration, concentrated in vacuo and the residue was purified through a column silica flash. After removing the solvent, a pale solid of (1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol (1.4 g, 5.64 mmol, 57.1% yield) was obtained. LC-MS (ESI): m/z 248 [M + H] +; 2.42 min (ret time). D2 3-Chloro-7,8,8a, 9-tetrahydropyrrolo [1', 2': 3,4] imidazo [1,2- c] pyrimidin-1 (6H) - one o

[00101] A solution of (1- (2,6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol (300 mg, 1.209 mmol) and triethylamine (0.506 mL, 3.63 mmol) in tetrahydrofuran (15 mL ) methanesulfonyl chloride (0.141 mL, 1.814 mmol) in tetrahydrofuran (5 mL) was added at 0°C and the mixture was stirred for a further 10 minutes at 0°C. The resulting mixture was concentrated in vacuo and the residue was acetonitrile (20.00 mL) and potassium carbonate (836 mg, 6.05 mmol) were added. The suspension was refluxed for 4 hours and filtered in vacuo, the filtrate was concentrated in vacuo to obtain the crude product 3-chloro-7, 8, 8a, 9-tetrahydropyrrole [1',2': 3.4] imidazo[1,2-c]pyrimidin-1(6H)-one (256 mg, 1.209 mmol, 100% yield). D3 (R) - (1- (2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol ci

[00102] The title compound was prepared by a procedure similar to that described for (1- (2,6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol starting from D-prolinol and 2, 4, 6-trichloropyrimidine.

[00103] An exemplary synthesis is provided: A solution of 2, 4, 6-trichloropyrimidine (3.26 g, 17.80 mmol) and triethylamine (4.13 mL, 29.7 mmol) in acetonitrile (25 mL) was D-prolinol (1.456 mL, 14.83 Mmol) in acetonitrile (5 mL) was added dropwise at 0°C. The mixture was stirred for 2 hours at room temperature and the solution was collected by filtration, concentrated in vacuo and the residue was purified through silica flash column. After removing the solvent, a pale solid of (R) - (1- (2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol (2.5 g, 10.08 mmol, 67.9% yield) was obtained. LC-MS (ESI): m/z 248 [M + H] +; 2.43 min (ret time). D4 (R) -3-chloro-7,8,8a,9-tetrahydropyrrolo [1',2': 3,4] imidazo [1,2- c] pyrimidin-1 (6H) - one

[00104] The title compound was prepared by a procedure similar to that described for 3-chloro-7,8,8a,9-tetrahydropyrrolo [1',2': 3,4] imidazo [1,2- c] pyrimidin- 1(6H)-one starting from (R)-(1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol.

[00105] The exemplary synthesis is presented below: To a solution of (R) - (1- (2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol (1.95 g, 7.86 mmol ) and triethylamine (3.29 mL, 23.58 mmol) in tetrahydrofuran (15 mL) was added dropwise methanesulfonyl chloride (0.919 mL, 11.79 mmol) in tetrahydrofuran (5 mL) at 0°C and the mixture was stirred for 10 min at 0°C. The resulting mixture was concentrated in vacuo and acetonitrile (20.00 mL) and potassium carbonate (3.26 g, 23.58 mmol) were added to the residue. The suspension was refluxed for 4 h and filtered under vacuum. The filtrate was concentrated in vacuo to obtain the title compound (1.663 mg, 7.86 mmol, 100% yield). LC-MS (ESI): m/z 212 [M + H] +; 1.33 min (ret time). D5 (S) - (1- (2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol

[00106] The title compound was prepared by a procedure similar to that described for (1- (2,6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol starting from L-prolinol and 2, 4, 6-trichloropyrimidine.

[00107] An exemplary process is provided: A solution of 2, 4, 6-trichloropyrimidine (3.26 g, 17.80 mmol) and triethylamine (4.13 mL, 29.7 mmol) in acetonitrile (5 mL) was L-prolinol (1.456 mL, 14.83 mmol) in acetonitrile (25 mL) was added dropwise at 0°C. The mixture was stirred for 2 hours at room temperature and the solution was collected by filtration, concentrated in vacuo and the residue was purified through silica flash column. The title compound was obtained (2.5 g, 10.08 mmol, 67.9% yield) as a pale solid. LC-MS (ESI): m/z 248 [M + H] +; 2.43 min (ret time). D6 (S) -3-chloro-7,8,8a,9-tetrahydropyrrolo [1',2': 3,4] imidazo [1,2- c] pyrimidin-1 (6H) - one

[00108] The title compound was prepared by a similar procedure to that described for 3-chloro-7,8,8a,9-tetrahydropyrrolo [1',2': 3,4] imidazo [1,2-c] pyrimidin-1 (6H) - one starting from (S) - (1- (2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol.

[00109] An exemplary process is provided: To the solution of (S) - (1- (2, 6- dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol (400 mg, 1.612 mmol) and triethylamine (0.674 mL, 4.84 mmol) in tetrahydrofuran (15 mL) was added dropwise methanesulfonyl chloride (0.188 mL, 2.418 mmol) in tetrahydrofuran (5 mL) at 0°C and the mixture was stirred for 10 min at 0°C. The resulting mixture was concentrated in vacuo and to the residue was added acetonitrile (20.00 mL) and potassium carbonate (668 mg, 4.84 mmol). The suspension was refluxed for 4 h and filtered under vacuum. The filtrate was concentrated in vacuo to provide the title compound (341 mg, 1.612 mmol, 100% yield), which was used in the next step directly. D7 3,5-Difluoro-4 - ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzaldehyde

[00110] A solution of 2- (trifluoromethyl) pyridin-4-ol (1.019 g, 6.25 mmol) and K2CO3 (1.727 g, 12.49 mmol) in acetonitrile (250 mL) stirred under nitrogen at 20° C A solution of 3,4,5-trifluorobenzaldehyde (1 g, 6.25 mmol) in acetonitrile (50 mL) was added dropwise over 5 min. The reaction mixture was stirred at 70°C for 18 h. The reaction mixture was diluted with ethyl acetate (20 mL) and the organic phase was washed with water (2 x 20 mL), saturated brine (20 mL), dried over sodium sulfate and evaporated in vacuo to obtain the title compound ( 2.0 g, 6.02 mmol, 96% yield) as a brown gum.

[00111]LC-MS (ESI): m/z 304 [M + H] +; 3.64 min (ret time).

[00112] An exemplary process is provided: A solution of 3,4,5-trifluorobenzaldehyde (2356 mg, 14.72 mmol) and 2-(trifluoromethyl) pyridin-4-ol (2000 mg, 12.26 mmol) in N,N-dimethylformamide (6 ML), K2CO3 (3390 mg, 24.53 mmol) was added. The mixture was irradiated with a microwave at 110°C and stirred for 3 h, and concentrated. The crude product was washed with EtOAc and then filtered. The organic phase was concentrated to obtain the title compound (4000 mg, 13.19 mmol, 55.9% yield) as an oil.

[00113]LC-MS (ESI): m/z 304 [M + H] +; 1.06 min (ret time). D8 (3,5-difluoro-4 - ((2- (trifluoromethyl) pyridin-4-yl) oxy) phenyl) methanol

[00114] To a solution of 3,5-difluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzaldehyde (50 g, 165 mmol) in methanol (400 mL) was added NaBH4 (3, 12 g, 82 mmol) at 0°C for 10 min. Reaction progress was monitored by TLC and the mobile phase was 30% EtOAc in PE. The reaction mixture was cooled with ice water (200 mL) and evaporated under reduced pressure to remove methanol and the crude product was diluted with ethyl acetate (200 mL) and water (200 mL), the organic layer was separated and washed with saline solution. of brine (100 mL), dried over NA2SO4 and evaporated completely to obtain 50 g of crude product, washed with PE and dried to obtain the title compound (45 g, 144 mmol, 88% yield).

[00115]LC-MS (ESI): m/z 306 [M + H] +; 2.13 min (ret time).

[00116] An exemplary process is provided: A solution of 3,5-difluoro-4 - ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzaldehyde (4 g, 13.19 mmol) in methanol (30 mL) NaBH4 (0.25 g, 6.60 mmol) was added at 0°C for 10 min in portions. The reaction mixture was stirred at 5°C for 0.5 h, concentrated and dissolved in water, then extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NA2SO4, filtered and concentrated. The crude product was purified by silica gel column (PE/EtOAc 5:1 to 1:1) to obtain the title compound (3.9 g, 12.61 mmol, 96% yield) as a white solid.

[00117]LC-MS (ESI): m/z 306 [M + H] +; 1.65 min (ret time). D9 3 - ((3, 5-Difluoro-4 - ((1-methyl-1H-pyrazol-4-yl) oxy) benzyl) oxy) -7,8,8a,9- tetrahydropyrrolo [1', 2': 3, 4] imidazo [1,2-c] pyrimidin-1 (6H) - one

[00118] To the solution of 3-chloro-7,8,8a,9-tetrahydropyrrolo [1',2':3,4] imidazo [1,2- c] pyrimidin-1 (6H) - one (85 mg, 0.402 mmol) and (3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl) methanol (96 mg, 0.402 mmol) in N,N-dimethylformamide (10 mL), Sodium hydride (48.2 mg, 1.205 mmol) was added at 0°C and stirred for an additional 10 minutes. The resulting mixture was cooled and purified via the C-18 flash column, the solvent was removed to give a white solid of 3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4- yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1',2':3.4]imidazo[1,2-c]pyrimidin-1(6H)-one (55 mg, 0.126 mmol, 31.3% yield).

[00119]LC-MS (ESI): m/z 416 [M + H] +; 3.55 min (ret time).

[00120]1H NMR (400 MHz, DMSO-d6): δ 7.61 (s, 1H), 7.32 - 7.27 (m, 3H), 5.34 (s, 1H), 5.30 - 5.23 (q, 2H), 4.10 - 4.01 (m, 2H), 3.89 - 3.85 (m, 1H), 3.73 (s, 3H), 3.40 - 3, 28 (m, 2H), 2.03 - 1.87 (m, 3H), 1.49 - 1.42 (m, 1H). Examples E1 (R) -3 - ((3, 5-difluoro-4 - ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9- tetrahydropyrrolo [1',2': 3.4] imidazo [1,2-c] pyrimidin-1 (6H) - one

[00121] To a solution of (R)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo [1',2': 3,4] imidazo [1,2- c] pyrimidin-1 (6H) - one (85 mg, 0.402 mmol) and (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl) methanol (123 mg, 0.402 mmol) in DMF (10 mL) was Sodium hydride (48.2 mg, 1.205 mmol) was added at 0°C and stirred for 10 min. The reaction mixture was cooled and purification via C-18 flash column yielded the title compound (50 mg, 0.099 mmol, 24.62% yield) as a blank.

[00122]LC-MS (ESI): m/z 481 [M + H] +; 2.83 min (ret time).

[00123]1H NMR (400 MHz, DMSO-d6): δ 8.70 - 8.68 (d, 1H), 7.67 - 7.66 (d, 1H), 7.47 - 7.45 (d , 2H), 7.33 - 7.31 (dd, 1H), 5.37 S, 1H), 5.37 - 3.30 (q, 2H), 4.10 - 4.02 (m, 2H) , 3.90 - 3.84 (m, 1H), 3.33 - 3.27 (m, 2H), 2.04 - 1.85 (m, 3H), 1.50 - 1.42 (m, 1H).

[00124]19F NMR (376 MHz, DMSO-d6): δ (ppm): - 66.65, - 126.83. E2 (S) -3 - ((3, 5-difluoro-4 - ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9- tetrahydropyrrole [1', 2':3.4] imidazo [1,2-c] pyrimidin-1 (6H) - one

[00125] The title compound was prepared by a procedure similar to that described for 3 - ((3, 5-difluoro-4 - ((1-methyl-1H-pyrazol-4-yl) oxy) benzyl) oxy) -7, 8, 8a, 9- tetrahydropyrrolo [1',2': 3,4] imidazo [1,2-c] pyrimidin-1 (6H) - one starting from (S) -3- chloro-7,8,8a, 9-tetrahydropyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and (3,5-difluoro-4-(2-(trifluoromethyl)pyridin-4- il) oxy) phenyl) methanol.

[00126]LC-MS (ESI): m/z 481 [M + H] +; 3.04 min (ret time).

[00127]1H NMR (400 MHz, DMSO-d6): δ 8.70 - 8.68 (d, 1H), 7.68 - 7.67 (d, 1H), 7.47 - 7.45 (d , 2H), 7.33 - 7.31 (dd, 1H), 5.37 (s, 2H), 5.33 (s, 1H), 4.08 - 4.02 (m, 2H), 3.889 - 3.86 (m, 1H), 3.33 - 3.27 (m, 2H), 2.04 - 1.85 (m, 3H) 1.45 (m, 1H).

[00128] An exemplary process is provided: A solution of (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrole [1',2': 3,4] imidazo [1,2- c] pyrimidin -16H)-one (57 mg, 0.269 mmol) and (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (82 mg, 0.269 mmol) in DMF (10 mL) was added sodium hydride (32.3 mg, 0.808 mmol) at 0°C and stirred for 10 min. The reaction mixture was cooled and C-18 flash column purification yielded the title compound (45.8 mg, 0.091 mmol, 33.6% yield) as a white solid.

[00129]LC-MS (ESI): m/z 481 [M + H] +; 3.04 min (ret time).

[00130]1H NMR (400 MHz, DMSO-d6): δ 8.70 - 8.68 (d, 1H), 7.68 - 7.67 (d, 1H), 7.47 - 7.45 (d , 2H), 7.33 - 7.31 (dd, 1H), 5.37 (s, 2H), 5.33 (s, 1H), 4.08 - 4.02 (m, 2H), 3, 88 - 3.86 (m, 1H), 3.31 - 3.29 (m, 2H), 2.04 - 1.85 (m, 3H), 1.50 - 1.45 (m, 1H).

[00131]19F NMR (376 MHz, DMSO-d6): δ (ppm): - 66.62, - 126.82.

C. Biological assays and data

[00132] The compounds of the present invention are inhibitors of Lp-PLA2 and may be useful in the treatment and prevention of diseases mediated by Lp-PLA2. The biological activities of the compounds of the present invention can be determined using any assay suitable for determining the activity of a compound as an inhibitor of Lp-PLA2, as well as tissue and in vivo models.

[00133] Biological activity data for each compound were either reported in at least one experiment or the average of multiple experiments. It is understood that the data described here may have reasonable variations depending on the specific conditions and procedures used by the person conducting the experiments. Lipoprotein-associated phospholipase A2 (Lp-PLA2) biochemical assay (1) Recombinant human Lp-PLA2 (rhLp-PLA2) assays - PED6 assay

[00134]N - ((6- (2,4-dinitrophenyl) amino) -hexanoyl) -2- (4,4-difluoro-5,7-dimethyl- 4-bora-3a, 4a-diaza-s- indacene -3-pentanoyl) -1-hexadecanoyl-sn-glycero-3- phosphoethanolamine, triethylammonium salt (PED6) is a commercially available fluorescently labeled phospholipid, which is commercially available from Invitrogene and Molecular Probes. There is a cooling para-nitro phenyl group (PNP) at the sn3 position and a Bodipy fluorescein group (FL) at the sn2 position. Upon cleavage with Lp-PLA2, the FL Bodipy group is released and can then result in an increase in fluorescence. Lp-PLA2 inhibitors thus prevent this cleavage and no increase in fluorescence is observed.

[00135] The PED6 assay was performed as a 10 μL uncooled assay. The source plate containing the compounds to be tested was prepared by making a 1:3 serial dilution (by volume) of the compounds within DMSO in a 384-well microplate. Then, 0.01 μL of the compounds in the compound source plate were transferred to Greiner 784076 384-well plates (black) using an ECHO liquid dispenser. 5 μL of human recombinant Lp-PLA2 enzyme (4 nM (or 110 pM) rhLp-PLA2 in 50 mM HEPES assay buffer, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to each well of the board. The plates were centrifuged for 10 seconds at 500 rpm. After 30 minutes of pre-incubation, 5 μL of substrate (4 μM (or 5 μM) PED6 [from 5 mM DMSO] in 50 mM HEPES assay buffer, pH 7.4, 150 mM NaCl, 1 mM CHAPS) were added to Greiner 784076 384-well plates (black). The plates were centrifuged for 10 seconds at 500 rpm. The plate was covered to protect it from light and incubated for 20 min at room temperature. Plates were read for fluorescence intensity at ex: 480/ em: 540 using a ViewLux microplate viewer for Envision spectrofluorimeters. pIC50 data, curve and QC analysis were conducted using the XL fitting module in Excel.

[00136] Examples 1 and 2 were tested in the PED6 assay. The pIC50 value for the tested compounds was either reported in at least one experiment or the average of multiple experiments. Example No. rhLp-PLA2 (pIC50) 1 9.8 2 9.5

[00137] For example, the pIC50 values of the recombinant human Lp-PLA2 assay for the following examples are: (2) PLA2 VIIB Assay

[00138]PLA2 VIIB (also known as Novel Serine Dependent Lipase, NSDL) is a serine hydrolase with 40% amino acid identity to human Lp-PLA2. Sequence comparisons indicate that the positions of the PLA VIIB active site catalytic triad are similar to those of Lp-PLA2. Similar to Lp-PLA2, it is capable of hydrolyzing oxidatively modified phospholipids and can be assayed using known Lp-PLA2 substrates.

[00139] Upon cleavage by a phopholipase, PLA2 VIIB releases a fluorescent Bodipy group. Recombinant human PLA2 VIIB is used as the source of phospholipase in this assay, and compounds are screened to test their degree of inhibition in this assay. The assay is used to determine the degree of selectivity of test compounds between PLA2 VIIB and Lp-PLA2.

[00140] The PLA2 VIIB assay was applied as a 10 μL uncooled assay. The source plate containing the compounds is prepared by making a 1:3 serial dilution (by volume) of the compounds with pure DMSO in a 384-well microplate. 0.01 μL of compounds in the compound source plate were transferred to Greiner 784076 384-well plates (black) by an ECHO liquid dispenser. 5 μL of Novel Serine Dependent Lipase (NSDL) enzyme (5 nM NSDL in 50 mM HEPES assay buffer, pH 7.4, 150 mM NaCl, 1 mM CHAPS) is added to each well. Alternatively, in some cases, this step was performed by adding 10 μL of recombinant human PLA2 VIIB (200 pM rhPLA2 VIIB in 50 mM HEPES assay buffer, pH 7.4, 150 mM NaCl, 1 mM CHAPS ) to each cavity. The plates were centrifuged for 10 seconds at 500 rpm. After 30 minutes of pre-incubation, 5 μL of substrate (5 μM PED6 [from 5 mM DMSO] in 50 mM HEPES assay buffer, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to low-volume 384-well (black) Greiner 784076 plates. Plates were read kinetically starting reading immediately after addition of PED6 at ex: 480/ at: 540 using ViewLux microplate reader or Envision spectrofluorimeters. IC50 data (which can be converted to pIC50 data), curve and QC analysis were conducted using the XLfit module in Excel.

[00141] Examples 1 and 2 were tested in the PLA2 VIIB assay described above. Both examples had at least 100-fold selectivity between recombinant human Lp-PLA2 and PLA2 VIIB.

[00142](3) Human plasma assay of lipoprotein-associated phospholipase A2 (Lp-PLA2) - Tio-PAF Assay

[00143] The human plasma assay uses a thioester analogue of PAF (phosphatidylcholine), where hydrolysis results in the formation of a phospholipid containing a free thiol group. The amount of thiol is quantified continuously by reaction with CPM (7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin), a maleimide that increases fluorescence upon Michael addition of thiols. This assay can detect Lp-PLA2 activity in human plasma, as determined by specific inhibition by Lp-PLA2 inhibitors.

[00144] The thio-PAF assay was performed as a 15 μL chilled assay. The compound source plate was prepared by making a 1:3 serial dilution (by volume) of the compounds in pure DMSO in a 384-well microplate. 0.01 μL of compounds in the compound source plate were transferred to low-volume Greiner 784076 384-well (black) plates via an ECHO liquid dispenser. 8 μL of pooled human plasma, which was previously aliquoted and frozen, was added. The plates were centrifuged for 10 seconds at 500 rpm. After 30 minutes of pre-incubation, 2 μL of substrate solution comprising 2.5 mM 2-thio-PAF [from ethanol stock], 32 μM CPM [from DMSO stock], and NEM at 3 .2 mM (N-ethylmaleimide) [made fresh daily in DMSO] in 50 mM HEPES assay buffer, pH 7.4, 150 mM NaCl, 1 mM CHAPS were added to 384-well Greiner 784076 plates (black ) low volume by a BRAVO liquid handling station. After 2 min, the reaction was quenched with 5 μL of 5% aqueous trifluoroacetic acid (TFA). The plates were covered to protect from light and incubated for 40 min at room temperature. Plates were read at ex: 380/ at: 485 using the Envision microplate reader. PIC50 data, curve and QC analysis were conducted using the XLFit module in Excel.

[00145] Examples 1 and 2 were tested in the Thio-PAF assay described above. The pIC50 values for the tested compounds were either reported from at least one experiment or the average of multiple experiments. The pIC50 value in the Lp-PLA2 human plasma assays for Example 1 was 8.1. The pIC50 value in the Lp-PLA2 human plasma assays for Example 2 was 7.7. D. Methods of Use

[00146] The compounds of the invention are Lp-PLA2 inhibitors. Therefore, these compounds can be used in therapy, for example, in the treatment or prevention of diseases associated with Lp-PLA2 activity, which comprises treating an individual in need thereof with a therapeutically effective amount of a Lp-PLA2 inhibitor. PLA2. Accordingly, one aspect of the invention is directed to methods of treating or preventing diseases associated with Lp-PLA2 activity. As will be appreciated by those skilled in the art, a particular disease or its treatment may involve one or more underlying mechanisms associated with Lp-PLA2 activity, including one or more of the mechanisms described herein.

[00147] In some embodiments, a Lp-PLA2 inhibitor according to the invention can be used in the treatment or prevention of any of the diseases described in the following published patent applications: WO 96/13484, WO 96/19451, WO 97/ 02242, WO 97/12963, WO 97/21675, WO 97/21676, WO 97/41098, WO 97/41099, WO 99/24420, WO 00/10980, WO 00/66566, WO 00/66567, WO 00/ 68208, WO 01/60805, WO 02/30904, WO 02/30911, WO 03/015786, WO 03/016287, WO 03/041712, WO 03/042179, WO 03/042206, WO 03/042218, WO 03/ 086400, WO 03/87088, WO 08/048867, US 2008/0103156, US 2008/0090851, US 2008/0090852, WO08/048866, WO05/003118 CA 2530816A1), WO06/0630811, WO 6/063813, WO 2008/141176 , JP 200188847, US 2008/0279846 A1, US 2010/0239565 A1, and US 2008/0280829 A1.

[00148] In certain embodiments, the compounds of the present invention can be used to treat or prevent any diseases involving endothelial dysfunction, for example, atherosclerosis (e.g., peripheral vascular atherosclerosis and cerebral vascular atherosclerosis), diabetes, hypertension, angina pectoris and after ischemia and reperfusion.

[00149] In certain embodiments, the compounds of the present invention can be used to treat or prevent any disease that involves lipid oxidation in conjunction with enzymatic activity, for example, in addition to conditions such as atherosclerosis and diabetes, other conditions such as arthritis rheumatoid, stroke, inflammatory conditions of the brain such as Alzheimer's disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.

[00150] In certain embodiments, the compounds of the present invention can be used to decrease the chances of having a cardiovascular event (such as a heart attack, myocardial infarction or stroke) in a patient with coronary disease.

[00151] In certain embodiments, the compounds of the present invention can be used to treat or prevent diseases involving activated monocytes, macrophages or lymphocytes, since all of these cell types express Lp-PLA2 including diseases involving activated macrophages such as M1, dendritic and/or other macrophages that generate oxidative stress. Exemplified diseases include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD), liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, Alzheimer's disease, and autoimmune diseases such as lupus.

[00152] In other embodiments, the compounds of the invention can be used for the primary or secondary prevention of acute coronary events, for example, caused by atherosclerosis; secondary therapy in the prevention of restenosis; or slow the progression of diabetic or hypertensive renal failure. Prevention includes treating an individual at risk for such conditions.

[00153] In certain embodiments, the present invention provides methods of treating or preventing a neurological disease associated with abnormal blood-brain barrier (BBB) function, inflammation, and/or activation of microglia in an individual in need of treatment. In some embodiments, the present invention provides methods of treating a neurological disease associated with abnormal blood-brain barrier (BBB) function, inflammation, and/or microglial activation in an individual in need of treatment. The methods comprise administering to the subject a therapeutically effective amount of a compound of the present invention. In another embodiment, the abnormal BBB is a leaky BBB. In yet a further embodiment, the disease is a neurodegenerative disease. Such neurodegenerative diseases are, for example, but are not limited to vascular dementia, Alzheimer's disease, Parkinson's disease and Huntington's disease. In one embodiment, the present invention provides methods of treating or preventing diseases associated with an individual with a leaky blood-brain barrier (BBB). In some embodiments, the present invention provides methods of treating diseases associated with an individual with a leaky blood-brain barrier (BBB). Exemplified diseases include, but are not limited to, cerebral hemorrhage, cerebral amyloid angiopathy. In one embodiment, the neurodegenerative disease is Alzheimer's disease. In one embodiment, the neurodegenerative disease is vascular dementia. In one embodiment, the neurodegenerative disease is multiple sclerosis (MS).

[00154] In one embodiment, the compounds of the present invention can be used to treat or prevent a neurodegenerative disease in an individual. The methods comprise administering to an individual in need of treatment a compound of the invention, for example, as a pharmaceutical composition comprising a compound of the invention. In one embodiment, the compounds of the present invention can be used to treat a neurodegenerative disease in an individual. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. In one embodiment, the neurodegenerative disease described herein is associated with an abnormal blood-brain barrier. In one embodiment, the individual administered an agent that inhibits Lp-PLA2 activity is a human.

[00155] In one embodiment, the present invention provides methods for treating or preventing an individual with or at risk for vascular dementia. The methods comprise administering to the subject a compound of the invention, for example, as a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. In one embodiment, the present invention provides methods of treating an individual with or at risk for vascular dementia. In one embodiment, vascular dementia is associated with Alzheimer's disease.

[00156] In certain embodiments, the present invention provides methods for decreasing amyloid beta, called “Aβ” accumulation in an individual's brain. The methods comprise administering to an individual in need of treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. In another embodiment, the amyloid beta is Abeta-42.

[00157] In certain embodiments, when an individual is administered a therapeutically effective amount of a compound of the present invention, the methods may further comprise administering to the individual another therapeutic agent that may be useful in treating the neurodegenerative disease for which the individual is suffering. being treated, or that it may be a co-morbidity. In one embodiment, the present invention provides methods of slowing or delaying the progression of cognitive and functional decline in patients with moderate Alzheimer's disease. In certain embodiments, the compounds of the present invention described herein can be used as an adjuvant to an agent that is used to provide symptomatic treatment to patients with Alzheimer's disease. For example, when the neurodegenerative disease is Alzheimer's disease or is similar to it, the individual may be treated with other agents targeting Alzheimer's disease such as ARICEPT® or donepezil, COGNEX® or tacrine, EXELON® or rivastigmine, REMINYL® or galantamine, anti-amyloid vaccine, Abeta-lowering therapies, mental exercise or stimulation. In certain embodiments, the present invention provides methods for delaying or slowing the progression of cognitive or functional decline in a patient with mild or moderate Alzheimer's disease and/or cerebrovascular disease (CVD), comprising administering a therapeutically effective amount of a compound of the present invention. invention to the patient who has been administered an agent used to provide symptomatic treatment of Alzheimer's disease (e.g., ARICEPT® or memantine) for 6 months or more.

[00158] In certain embodiments, the present invention relates to methods of treating or preventing metabolic bone diseases by administering to the individual in need of treatment a therapeutically effective amount of a compound of the present invention. In some embodiments, the present invention relates to methods of treating metabolic bone diseases by administering to the individual in need of treatment a therapeutically effective amount of a compound of the present invention. Exemplified metabolic bone diseases include diseases associated with loss of bone mass and density including, but are not limited to, osteoporosis and diseases related to osteopenia. Exemplified osteoporosis and osteopenia-related diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases. In another embodiment, the individual in need of treatment is a human being.

[00159] It is believed that the methods for preventing osteoporosis and/or osteopenic diseases described herein may be affected by inhibiting the expression of Lp-PLA2 and/or inhibiting the protein activity of Lp-PLA2. Accordingly, some embodiments of the present invention provide methods for inhibiting Lp-PLA2 by blocking enzymatic activity. In another embodiment, methods are provided for inhibiting Lp-PLA2 by reducing and/or repressing the expression of Lp-PLA2 RNA. In another embodiment, the prevention and/or reduction of bone mass loss and/or bone density loss leads to the prevention or reduction of symptoms associated with metabolic bone diseases such as osteoporosis and/or osteopenic diseases.

[00160] In certain embodiments, the methods further comprise administering to an individual in need of treatment additional therapeutic agents used in the treatment of metabolic bone diseases. For example, when the metabolic bone disease is osteoporosis, additional therapeutic agents such as bisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene), a selective estrogen modulator (SERM), estrogen therapy, hormone replacement therapy (ET/HRT) and teriparatide can be used.

[00161] One aspect of the present invention provides methods for treating and/or preventing ocular diseases by administering a therapeutically effective amount of a compound of the present invention. In some embodiments, the present invention provides methods for treating ocular diseases by administering a therapeutically effective amount of a compound of the present invention. The ocular diseases applicable to the present invention may be associated with degradation of the internal blood-retinal barrier (iBRB). The exemplified ocular diseases refer to diabetic ocular diseases, which include macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like. Furthermore, in one embodiment, the present invention relates to methods of treating ocular diseases by administering a compound of the present invention to inhibit Lp-PLA2. Exemplified ocular diseases include, but are not limited to, central retinal vein occlusion, branch retinal vein occlusion, Irvine-Gass syndrome (post-cataract and postsurgical), retinitis pigmentosa, pars planitis, Birdhot retinochororoidopathy, epiretinal membrane , choroidal tumors, cystic macular edema, parafoveal telandiectasia, tractional maculopathies, vitreomacular traction syndromes, retinal detachment, neuroretinitis, idiopathic macular edema and the like. More details on the use of the Lp-PLA2 inhibitor to treat ocular diseases are provided in WO2012/080497, which is incorporated herein by reference.

[00162] Furthermore, some embodiments of the present invention provide methods for treating or preventing diabetic macular edema in an individual. In some embodiments, the present invention provides methods for treating diabetic macular edema in an individual. The method comprises administering to an individual in need of treatment a therapeutically effective amount of a compound of the present invention.

[00163] In certain embodiments, the present invention provides methods of treating or preventing an individual with or at risk of having macular edema. In some embodiments, the present invention provides methods of treating an individual with or at risk for macular edema. The methods comprise administering to the subject a therapeutically effective amount of a compound of the present invention. In a further embodiment, macular edema is associated with diabetic eye disease, e.g., diabetic macular edema or diabetic retinopathy. In yet an additional embodiment, macular edema is associated with posterior uveitis.

[00164] In certain embodiments, the present invention provides methods for treating or preventing glaucoma or macular degeneration. In some embodiments, the present invention provides methods of treating glaucoma or macular degeneration. The methods comprise administering to the subject a therapeutically effective amount of a compound of the present invention.

[00165] In one embodiment, the present invention provides methods of treating or preventing a disease associated with degradation of the internal blood-retinal barrier in an individual in need of treatment. In one embodiment, the present invention provides methods of treating a disease associated with degradation of the internal blood-retinal barrier in a subject in need of treatment. The methods comprise administering to the subject a therapeutically effective amount of a compound of the present invention.

[00166] In one embodiment, systemic inflammatory diseases, such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic lupus erythematosus, Vogt-Koyanagi syndrome, Harada, Lyme disease, Bechet disease, ankylosing spondylitis, chronic granulomatous disease, enthesitis, may be the underlying cause of posterior uveitis affecting the retina, which may result in macular edema. The present invention relates to methods of treating or preventing posterior uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of a compound of the present invention. In one embodiment, the present invention provides methods for treating posterior uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of a compound of the present invention.

[00167] It is believed that Lp-PLA2 inhibitors may have beneficial effects on diseases associated with M1/M2 macrophage polarization. The belief is based on the following studies. A study was carried out by GSK to investigate the relationship between M1/M2 macrophage polarization and different diseases. 94 human markers described by Martinez FO and others that distinguished M1 and M2 phenotypes were used against a GeneLogic database submitted by GSK. (See Martinez FO et al. (2006) J Immunol 177, 7303 to 7311.) The Connectivity Map methodology described by Lamb J et al. was used to identify the fraction of samples in each disease state having expression characteristics consistent with a macrophage population favoring M1 or favoring M2. (See Lamb J et al. (2006) Science 313, 1929 to 1935) (PMID 17008526)). The study showed that liver cirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis and aortic aneurysm have M1/M2 imbalance.

[00168] An additional study was carried out to study the impact of Lp-PLA2 inhibitors on modulating M1/M2 imbalance. In this study, mice were induced to develop experimental autoimmune encephalomyelitis (EAE) by immunization with myelin basic protein (MBP) antigen and treated with a known Lp-PLA2 inhibitor: 5 - ((9-Methoxy-4-oxo-6, 7-dihydro-4H-pyrimido[6,1-a]isoquinolin-2-yl)oxy)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (see PCT application No. PCT/CN2011/001597). In this preventive treatment model, the compound was administered on day 0 (day of immunization) and continued to be administered until day 22. The study lasted 25 days. Rats were subsequently monitored for symptoms of EAE. Mice were immunized with MBP to develop EAE and symptoms were monitored daily. Plasma Lp-PLA2 activity, OxLDL and LysoPC concentration were determined at different time points throughout the course of EAE. The results showed that plasma Lp-PLA2 activity, OxLDL and LysoPC concentrations increased as clinical EAE disease progressed in the model, indicating that they played a role in the development of the pathology. Lp-PLA2 inhibitor treatment led to a reduction in clinical disease associated with decreased Lp-PLA2 activity and LysoPC levels in rat EAE plasma. Therefore, inhibition of Lp-PLA2 activity is beneficial to ameliorate the disease in the rat EAE model.

[00169] Ex vivo analysis of pro-inflammatory (M1) and anti-inflammatory (M2) markers in control and treated EAE rats treated with the compound. Splenic macrophages were harvested on day 13 post MBP immunization and assayed for expression of a variety of markers by real-time PCR. CNS-infiltrating cells were harvested and macrophages were analyzed for expression of M1 and M2 markers by real-time PCR. Compound treatment resulted in a decrease in M1 markers and an increase in M2 markers, which potentially indicated the possibility of anti-inflammation and tissue repair.

[00170] Thus, in certain embodiments, the present invention provides methods of treating or preventing diseases associated with macrophage polarization, for example, M1/M2 macrophage polarization. In some embodiments, the present invention provides methods of treating diseases associated with macrophage polarization, e.g., M1/M2 macrophage polarization. Exemplary diseases associated with macrophage polarization include, but are not limited to, liver cirrhosis, cutaneous psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis, and other autoimmune diseases that are associated with macrophage polarization.

[00171] Treatment and/or prevention of a disease associated with Lp-PLA2 activity can be achieved using a compound of this invention as a monotherapy or in dual or multiple combination therapy. For example, the compounds of the present invention can be used to treat or prevent the disease described herein in combination with an antihyperlipidemic, antiatherosclerotic, antidiabetic, antianginal, anti-inflammatory or antihypertensive agent or an agent for lowering lipoprotein. (a) (Lp (a)). Examples of the foregoing include, but are not limited to, cholesterol synthesis inhibitors such as statins, antioxidants such as probucol, insulin sensitizers, calcium channel antagonists, and anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs). . Examples of agents for lowering Lp(a) include the aminophosphonates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312. In one embodiment, the compounds of the present invention can be used with one or more statins. Statins are a well-known class of cholesterol-lowering agents and include atorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin, lovastatin, and rosuvastatin. In a certain embodiment, the compounds of the present invention can be used as an antidiabetic agent or an insulin sensitizer. In one embodiment, a compound of the present invention can be used with PPAR gamma activators, for example, GI262570 (GlaxoSmithKline) and the glitazone class of compounds such as rosiglitazone, troglitazone and pioglitazone. Such agents may be administered in therapeutically effective amounts, for example, as is known in the art, or in lesser or greater amounts than are known in the art, provided that the amount administered is therapeutically effective.

[00172] Combination therapy includes administering the therapeutic agents in separate dosage forms or together in a single dosage form. Combination therapy may involve simultaneous administration or separate administration of the therapeutic agents, which may be substantially simultaneous or substantially separate administration. Typically, combination therapy will involve administering each agent so that therapeutically effective amounts of each agent are present in the individual's body in at least one overlapping period.

[00173] One aspect of the present invention provides the use of a compound of the present invention for the preparation of a medicament for carrying out a method described herein.

[00174] In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment or prevention of diseases associated with Lp-PLA2 activity.

[00175] In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing any of the diseases described in the following published patent applications: WO 96/13484, WO 96/19451 , WO 97/02242, WO 97/12963, WO 97/21675, WO 97/21676, WO 97/41098, WO 97/41099, WO 99/24420, WO 00/10980, WO 00/66566, WO 00/66567 , WO 00/68208, WO 01/60805, WO 02/30904, WO 02/30911, WO 03/015786, WO 03/016287, WO 03/041712, WO 03/042179, WO 03/042206, WO 03/042218 , WO 03/086400, WO 03/87088, WO 08/048867, US 2008/0103156, US 2008/0090851, US 2008/0090852, WO08/048866, WO 05/003118 CA 2530816A1), WO 06/0 63811, WO 06 /063813, WO 2008/141176, JP 200188847, US 2008/0279846 A1, US 2010/0239565 A1, and US 2008/0280829 A1.

[00176] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing any diseases involving endothelial dysfunction, e.g., atherosclerosis (e.g., peripheral vascular atherosclerosis and cerebrovascular atherosclerosis ), diabetes, hypertension, angina pectoris and after ischemia and reperfusion.

[00177] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment or prevention of any disease involving lipid oxidation in conjunction with enzymatic activity, for example, in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischemia, reperfusion injury, sepsis and acute and chronic inflammation.

[00178] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament to reduce the chances of having a cardiovascular event (such as a heart attack, myocardial infarction or stroke) in a patient with coronary disease.

[00179] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament to treat or prevent diseases involving activated monocytes, macrophages or lymphocytes, since all of these cell types express Lp- PLA2 including diseases involving activated macrophages such as M1, dendritic and/or other macrophages that generate oxidative stress. Exemplified diseases include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD), liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis , Alzheimer's disease, and autoimmune diseases such as lupus.

[00180] In other embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the primary or secondary prevention of acute coronary events, for example, caused by atherosclerosis; secondary therapy in the prevention of restenosis; or slow the progression of diabetic or hypertensive renal failure. Prevention includes treating an individual at risk for such conditions.

[00181] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing a neurological disease associated with abnormal function of the blood-brain barrier (BBB), inflammation and/or activation of the microglia in an individual in need of treatment. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment of a neurological disease associated with abnormal blood-brain barrier (BBB) function, inflammation and/or microglial activation in a individual in need of treatment. In another embodiment, the abnormal BBB is a leaky BBB. In yet a further embodiment, the disease is a neurodegenerative disease. Such neurodegenerative diseases are, for example, but are not limited to vascular dementia, Alzheimer's disease, Parkinson's disease and Huntington's disease. In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment or prevention of diseases associated with an individual with a leaky blood-brain barrier (BBB). In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating diseases associated with an individual with a leaky blood-brain barrier (BBB). Exemplary diseases include, but are not limited to, cerebral hemorrhage, cerebral amyloid angiopathy. In one embodiment, the neurodegenerative disease is Alzheimer's disease. In one embodiment, the neurodegenerative disease is vascular dementia. In one embodiment, the neurodegenerative disease is multiple sclerosis (MS).

[00182] In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing a neurodegenerative disease in a subject. In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment of a neurodegenerative disease in an individual. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. In one embodiment, the neurodegenerative disease described herein is associated with an abnormal blood-brain barrier.

[00183] In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing an individual with or at risk of having vascular dementia. In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating an individual with or at risk for vascular dementia. In one embodiment, vascular dementia is associated with Alzheimer's disease.

[00184] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for decreasing amyloid beta, called “Aβ” accumulation in the brain of an individual. In another embodiment, the amyloid beta is Abeta-42.

[00185] In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for slowing or delaying the progression of decline in cognitive function in patients with mild Alzheimer's disease. In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament as an adjuvant to an agent that is used to provide symptomatic treatment to patients with Alzheimer's disease. For example, when the neurodegenerative disease is or is similar to Alzheimer's disease, the individual may be treated with other agents targeting Alzheimer's disease such as ARICEPT® or donepezil, COGNEX® or tacrine, EXELON® or rivastigmine, REMINYL® or galantamine , anti-amyloid vaccine, Abeta reduction therapies, mental exercise or stimulation. In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for slowing or delaying the progression of decline in cognitive function in a patient with mild or moderate Alzheimer's disease and/or cerebrovascular disease (CVD). ), where the patient was administered an agent used to provide symptomatic treatment of Alzheimer's disease (e.g., ARICEPT® or memantine) for 6 months or more. In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for slowing or delaying the progression of decline in cognitive function in a patient with mild or moderate Alzheimer's disease and cerebral small vessel disease ( SVD), where the patient has been administered an agent used to provide symptomatic treatment of Alzheimer's disease (e.g., ARICEPT® or memantine) for 6 months or more.

[00186] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment or prevention of metabolic bone diseases. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment of metabolic bone diseases. Exemplary metabolic bone diseases include diseases associated with loss of bone mass and density including, but not limited to, osteoporosis and osteopenic diseases. Examples of osteoporosis and osteopenic diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases. In another embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for preventing and/or reducing loss of bone mass and/or loss of bone density, leads to the prevention or reduction of associated symptoms to metabolic bone diseases such as osteoporosis and/or osteopenic diseases.

[00187] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment of metabolic bone diseases, where the medicament is used with additional therapeutic agents used in the treatment of metabolic bone diseases. For example, when the metabolic bone disease is osteoporosis, additional therapeutic agents such as bisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene), a selective estrogen modulator (SERM), estrogen therapy, hormone replacement therapy (ET/HRT) and teriparatide can be used.

[00188] One aspect of the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment and/or prevention of eye diseases. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating eye diseases. The ocular diseases applicable to the present invention may be associated with degradation of the inner blood-retinal barrier (iBRB). Exemplary ocular diseases refer to diabetic ocular diseases, which include macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like. Eye diseases include, but are not limited to, central retinal vein occlusion, branch retinal vein occlusion, Irvine-Gass syndrome (post-cataract and post-surgical), retinitis pigmentosa, pars planitis, Birdshot retinochoroidopathy, epiretinal membrane, choroidal tumors, macular edema, parafoveal telandiectasia, tractional maculopathies, vitreomacular traction syndromes, retinal detachment, neuroretinitis, idiopathic macular edema and the like. More details on the use of the Lp-PLA2 inhibitor to treat ocular diseases are provided in WO 2012/080497, which is incorporated herein by reference.

[00189] Furthermore, some embodiments of the present invention provide the use of a compound of the present invention for the preparation of a medicament for treating or preventing diabetic macular edema in an individual. In some embodiments, the present invention provides the use of a compound of the present invention for treating diabetic macular edema in an individual.

[00190] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing an individual with or at risk of having macular edema. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating an individual with or at risk of having macular edema. In a further embodiment, macular edema is associated with diabetic eye disease, e.g., diabetic macular edema or diabetic retinopathy. In yet an additional embodiment, macular edema is associated with posterior uveitis.

[00191] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating or preventing glaucoma or macular degeneration. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating glaucoma or macular degeneration.

[00192] In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment or prevention of a disease associated with degeneration of the internal blood-retinal barrier in an individual in need of treatment. In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment of a disease associated with degradation of the internal blood-retinal barrier in a subject in need of treatment.

[00193] In one embodiment, systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic lupus erythematosus, Vogt-Koyanagi syndrome -Harada, Lyme disease, Bechet disease, ankylosing spondylitis, chronic granulomatous disease, enthesitis, may be the underlying cause of posterior uveitis affecting the retina, which may result in macular edema. In one embodiment, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating posterior uveitis or any of these systemic inflammatory diseases.

[00194] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for the treatment or prevention of diseases associated with macrophage polarization, for example, M1/M2 macrophage polarization. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating diseases associated with macrophage polarization, for example, M1/M2 macrophage polarization. Exemplary diseases associated with macrophage polarization include, but are not limited to, liver cirrhosis, cutaneous psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis (ALS), cardiomyopathy ischemic disease, chronic heart failure after myocardial infarction (MI), and other autoimmune diseases that are associated with macrophage polarization.

[00195] Another aspect of the present invention provides a compound of the present invention for use in carrying out methods of treatment or prevention described herein. Another aspect of the present invention provides a compound described herein or a pharmaceutically acceptable salt thereof for use in therapy.

[00196] In some embodiments, the present invention provides a compound of the present invention for use in treating or preventing diseases associated with Lp-PLA2 activity.

[00197] In some embodiments, the present invention provides a compound of the present invention for use in the treatment or prevention of any of the diseases described in the following published patent applications: WO 96/13484, WO 96/19451, WO 97/02242, WO 97/12963, WO 97/21675, WO 97/21676, WO 97/41098, WO 97/41099, WO 99/24420, WO 00/10980, WO 00/66566, WO 00/66567, WO 00/68208, WO 01/60805, WO 02/30904, WO02/30911, WO 03/015786, WO 03/016287, WO 03/041712, WO 03/042179, WO 03/042206, WO 03/042218, WO 03/086400, WO 03/87088, WO 08/048867, US 2008/0103156, US 2008/0090851, US 2008/0090852, WO08/048866, WO05/003118 CA 2530816A1), WO06/063811, WO06/063813, WO 2008/141176, JP 200188847 , US 2008/0279846 A1, US 2010/0239565 A1, and US 2008/0280829 A1.

[00198] In certain embodiments, the present invention provides a compound of the present invention for use in the treatment or prevention of any diseases involving endothelial dysfunction, for example, atherosclerosis (e.g., peripheral vascular atherosclerosis and cerebral vascular atherosclerosis), diabetes, hypertension , angina pectoris and after ischemia and reperfusion.

[00199] In certain embodiments, the present invention provides a compound of the present invention for use in the treatment or prevention of any disease involving lipid oxidation in conjunction with enzymatic activity, for example, in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.

[00200] In certain embodiments, the present invention provides a compound of the present invention for use in reducing the chances of having a cardiovascular event (such as a heart attack, myocardial infarction or stroke) in a patient with coronary disease.

[00201] In certain embodiments, the present invention provides a compound of the present invention for use in the treatment or prevention of diseases involving activated monocytes, macrophages or lymphocytes, since all of these cell types express Lp-PLA2 including diseases involving activated macrophages such as M1, dendritic and/or other macrophages that generate oxidative stress. Exemplary diseases include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD), liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, Alzheimer's disease, autoimmune diseases such as lupus.

[00202] In other embodiments, the present invention provides a compound of the present invention for use in the primary or secondary prevention of acute coronary events, for example, caused by atherosclerosis; secondary therapy in the prevention of restenosis; or slow the progression of diabetic or hypertensive renal failure. Prevention includes treating an individual at risk for such conditions.

[00203] In certain embodiments, the present invention provides a compound of the present invention for use in treating or preventing a neurological disease associated with abnormal blood-brain barrier (BBB) function, inflammation and/or microglial activation in a subject in need. of treatment. In some embodiments, the present invention provides a compound of the present invention for use in treating a neurological disease associated with abnormal blood-brain barrier (BBB) function, inflammation, and/or microglial activation. In another embodiment, the abnormal BBB is a leaky BBB. In yet a further embodiment, the disease is a neurodegenerative disease. Such neurodegenerative diseases are, for example, but are not limited to vascular dementia, Alzheimer's disease, Parkinson's disease and Huntington's disease. In one embodiment, the present invention provides a compound of the present invention for use in treating or preventing diseases associated with an individual with a leaky blood-brain barrier (BBB). In some embodiments, the present invention provides a compound of the present invention for use in treating diseases associated with an individual with a leaky blood-brain barrier (BBB). Exemplary diseases include, but are not limited to, cerebral hemorrhage, cerebral amyloid angiopathy. In one embodiment, the neurodegenerative disease is Alzheimer's disease. In one embodiment, the neurodegenerative disease is vascular dementia. In one embodiment, the neurodegenerative disease is multiple sclerosis (MS).

[00204] In one embodiment, the present invention provides a compound of the present invention for use in treating or preventing a neurodegenerative disease in an individual. In one embodiment, the present invention provides a compound of the present invention for use in treating a neurodegenerative disease in an individual. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. In one embodiment, the neurodegenerative disease described herein is associated with an abnormal blood-brain barrier.

[00205] In one embodiment, the present invention provides a compound of the present invention for use in treating or preventing an individual with or at risk of having vascular dementia. In one embodiment, the present invention provides a compound of the present invention for use in treating an individual with or at risk for vascular dementia. In one embodiment, vascular dementia is associated with Alzheimer's disease.

[00206] In certain embodiments, the present invention provides a compound of the present invention for use in decreasing amyloid beta, called “Aβ” accumulation in a subject's brain. In another embodiment, the amyloid beta is Abeta-42.

[00207] In one embodiment, the present invention provides a compound of the present invention for use in delaying or slowing the progression of decline in cognitive function in patients with mild Alzheimer's disease. In certain embodiments, the present invention provides a compound of the present invention for use as an adjuvant to an agent that is used to provide symptomatic treatment to patients with Alzheimer's disease. For example, when the neurodegenerative disease is Alzheimer's disease or similar to it, the individual may be treated with other agents targeting Alzheimer's disease such as ARICEPT® or donepezil, COGNEX® or tacrine, EXELON® or rivastigmine, REMINYL® or galantamine, anti-amyloid vaccine, Abeta-lowering therapies, exercise or mental stimulation. In certain embodiments, the present invention provides a compound of the present invention for use in slowing or delaying the progression of decline in cognitive function in a patient with mild or moderate Alzheimer's disease and/or cerebrovascular disease (CVD), where the patient has been administered with an agent used to provide symptomatic treatment of Alzheimer's disease (e.g., ARICEPT® or memantine) for 6 months or longer. In certain embodiments, the present invention provides a compound of the present invention for use in slowing or delaying the progression of decline in cognitive function in a patient with mild or moderate Alzheimer's disease and cerebral small vessel disease (SVD), where the patient who has been administered with an agent used to provide symptomatic treatment of Alzheimer's disease (e.g., ARICEPT® or memantine) for 6 months or longer.

[00208] In certain embodiments, the present invention provides a compound of the present invention for use in the treatment or prevention of metabolic bone diseases. In some embodiments, the present invention provides a compound of the present invention for use in treating metabolic bone diseases. Examples of metabolic bone diseases include diseases associated with loss of bone mass and bone density including, but not limited to, osteoporosis and osteopenic diseases. Examples of osteoporosis and osteopenic diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases. In another embodiment, the present invention provides a compound of the present invention for use in preventing and/or reducing loss of bone mass and/or loss of bone density, leads to the prevention or reduction of symptoms associated with metabolic bone diseases such as osteoporosis. and/or osteopenic diseases.

[00209] In certain embodiments, the present invention provides a compound of the present invention for use in the treatment of metabolic bone diseases, where the medicament is used with additional therapeutic agents used in the treatment of metabolic bone diseases. For example, when the metabolic bone disease is osteoporosis, additional therapeutic agents such as bisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene), a selective estrogen modulator (SERM), estrogen therapy, hormone replacement therapy (ET/HRT) and teriparatide can be used.

[00210] One aspect of the present invention provides a compound of the present invention for use in the treatment and/or prevention of ocular diseases. In some embodiments, the present invention provides a compound of the present invention for use in treating ocular diseases. The ocular diseases applicable to the present invention may be associated with degradation of the internal blood-retinal barrier (iBRB). The exemplified ocular diseases refer to diabetic ocular diseases, which include macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like. More eye diseases include but are not limited to central retinal vein occlusion, branch retinal vein occlusion, Irvine-Gass syndrome (post-cataract and post-surgery), retinitis pigmentosa, pars planitis, birdshot retinochoroidopathy, epiretinal membrane, choroidal tumors, cystic macular edema, parafoveal telandiectasia, tractional maculopathies, vitreomacular traction syndromes, retinal detachment, neuroretinitis, idiopathic macular edema and the like. More details on the use of the Lp-PLA2 inhibitor to treat ocular diseases are provided in WO2012/080497, which is incorporated herein by reference.

[00211] Furthermore, some embodiments of the present invention provide a compound of the present invention for use in treating or preventing diabetic macular edema in an individual. In some embodiments, the present invention provides a compound of the present invention for use in treating diabetic macular edema in an individual.

[00212] In certain embodiments, the present invention provides a compound of the present invention for use in treating or preventing an individual with or at risk of having macular edema. In some embodiments, the present invention provides a compound of the present invention for use in treating an individual with or at risk for macular edema. In a further embodiment, macular edema is associated with diabetic eye disease, e.g., diabetic macular edema or diabetic retinopathy. In yet an additional embodiment, macular edema is associated with posterior uveitis.

[00213] In certain embodiments, the present invention provides a compound of the present invention for use in the treatment or prevention of glaucoma or macular degeneration. In some embodiments, the present invention provides a compound of the present invention for use in treating glaucoma or macular degeneration.

[00214] In one embodiment, the present invention provides a compound of the present invention for use in treating or preventing a disease associated with degradation of the internal blood-retinal barrier in an individual in need of treatment. In one embodiment, the present invention provides a compound of the present invention for use in treating a disease associated with degradation of the internal blood-retinal barrier in an individual in need of treatment.

[00215] In one embodiment, systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic lupus erythematosus, Vogt-Koyanagi syndrome- Harada, Lyme disease, Bechet disease, ankylosing spondylitis, chronic granulomatous disease, enthesitis, may be the underlying cause of posterior uveitis affecting the retina, which may result in macular edema. In one embodiment, the present invention provides a compound of the present invention for use in treating posterior uveitis or any of these systemic inflammatory diseases.

[00216] In certain embodiments, the present invention provides a compound of the present invention for use in treating or preventing diseases associated with macrophage polarization, for example, M1/M2 macrophage polarization. In some embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating diseases associated with macrophage polarization, for example, M1/M2 macrophage polarization. Exemplified diseases associated with macrophage polarization include, but are not limited to, liver cirrhosis, cutaneous psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis (ALS), cardiomyopathy ischemic disease, chronic heart failure after myocardial infarction (MI), and other autoimmune diseases that are associated with macrophage polarization.

E. Composition

[00217] The compounds of the present invention can be formulated into pharmaceutical compositions before administration to an individual. Accordingly, one aspect of the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient. According to another aspect of the invention, there is provided a process for preparing a pharmaceutical composition including mixing a compound described above or its salts, solvates, etc., with one or more pharmaceutically acceptable excipients.

[00218] Pharmaceutical compositions can be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.1 mg, 0.5 mg or 1 mg to 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, 750 mg or 1 g of a compound of the present invention, depending on the condition being treated, the route of administration and the age, weight and condition of the individual, or the pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. In other embodiments, unit dosage compositions are those that contain a daily dose or subdose as described herein, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions can be prepared by any of the methods well known to one skilled in the art.

[00219] A therapeutically effective amount of a compound of the present invention will depend on a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation and the route of administration and, as a last resort, it will be at the discretion of the attendant who prescribes the medication. However, a therapeutically effective amount of a compound of the present invention for treating the disease described herein will generally be in the range of 0.1 to 100 mg/kg of the recipient's body weight per day and more usually in the range of 1 to 10 mg. /kg of body weight per day. Thus, for example, for a 70 kg adult mammal, the actual amount per day would normally be 70 to 700 mg and this amount may be given in a single dose per day or in several subdoses per day such as two, three, four , five or six doses per day. Or dosing can be done intermittently, such as once every two days, once a week, or once a month. It is anticipated that similar dosages would be appropriate for the treatment of the other conditions noted above.

[00220] The pharmaceutical compositions of the invention may contain one or more compounds of the invention. In some embodiments, pharmaceutical compositions may contain more than one compound of the invention. For example, in some embodiments, pharmaceutical compositions may contain two or more compounds of the invention. Furthermore, the pharmaceutical compositions may optionally further comprise one or more additional pharmaceutically active compounds.

[00221] As used herein, “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or vehicle involved in giving the form or consistency to the pharmaceutical composition. Each excipient may be compatible with the other ingredients of the pharmaceutical composition when mixed in such a way that interactions that would substantially reduce the effectiveness of the compound of the invention when administered to an individual and interactions that would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. .

[00222] The compounds of the invention and the pharmaceutically acceptable excipient or excipients can be formulated in a dosage form adapted for administration to the individual 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, tablets, pills, powders, syrups, elixirs, suspensions, solutions, emulsions, and sachets; (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 association of a compound described above with the carrier(s) or excipient(s).

[00223] Pharmaceutical compositions adapted for oral administration can 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 creams; or liquid oil-in-water emulsions or liquid water-in-oil emulsions.

[00224] Suitable pharmaceutically acceptable excipients may vary depending on the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for the particular function 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. Some 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 transport of the compound or compounds of the invention once administered to the individual from one organ or part of the body to another organ or part of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to increase patient compliance.

[00225] 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, anti-cake forming agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents. One skilled in the art will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on the amount of the excipient that is present in the formulation and what other ingredients are present in the formulation.

[00226] Those skilled in the art have the knowledge and skills in the art to allow them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. Furthermore, there are a number of resources that are available to one skilled in the art that 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 Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[00227] The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods generally used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[00228] 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 pregelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate and dibasic calcium phosphate. The solid oral dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone and cellulose and its derivatives (e.g. cellulose microcrystalline). The solid oral dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid and sodium carboxymethyl cellulose. The solid oral dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

[00229] In certain embodiments, the present invention is directed to a pharmaceutical composition comprising 0.01 to 1000 mg of one or more compounds described above herein or a pharmaceutically acceptable salt thereof and 0.01 to 5 g of one or more pharmaceutically acceptable excipients .

[00230] In one embodiment, the present invention is directed to a pharmaceutical composition comprising 0.01 to 1000 mg (calculated as free base) of a compound having the structure of

[00231] or a pharmaceutically acceptable salt thereof and 0.01 to 5 g of one or more pharmaceutically acceptable excipients.

[00232] In one embodiment, the present invention is directed to a pharmaceutical composition comprising 0.01 to 1000 mg of a compound with the structure of

[00233] or a pharmaceutically acceptable salt thereof and 0.01 to 5 g of one or more pharmaceutically acceptable excipients.

[00234] In one embodiment, the present invention is directed to a pharmaceutical composition comprising 0.01 to 1000 mg (calculated as free base) of a compound with the structure of

[00235] or a pharmaceutically acceptable salt thereof and 0.01 to 5 g of one or more pharmaceutically acceptable excipients.

[00236] In another embodiment, the present invention is directed to a pharmaceutical composition for the treatment of neurodegenerative disease comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another embodiment, the present invention is directed to a pharmaceutical composition for the treatment of Alzheimer's disease comprising a compound described herein or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient thereof.

Claims (13)

1. Compound CHARACTERIZED by the fact that it is: or a salt thereof. 2. Compound, according to claim 1, CHARACTERIZED by the fact that it is: or a pharmaceutically acceptable salt thereof. 3. Compound, according to claim 1 or 2, CHARACTERIZED by the fact that it is (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy) benzyl)oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1(6H)-one: or a pharmaceutically acceptable salt thereof. 4. Compound according to any one of claims 1 to 3, CHARACTERIZED by the fact that it is (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl) oxy)benzyl)oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1(6H)-one: 5. Compound according to any one of claims 1 to 3, CHARACTERIZED by the fact that it is a pharmaceutically acceptable salt of (R)-3- ((3,5-difluoro-4-((2-(trifluoromethyl)pyridin -4-yl)oxy)benzyl)oxy)-7, 8, 8a, 9-tetrahydropyrrolo [1',2':3,4]imidazo[1,2-c]pyrimidin-1(6H)-one: 6. Compound, according to claim 1 or 2, CHARACTERIZED by the fact that it is (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy) benzyl)oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1(6H)-one: or a pharmaceutically acceptable salt thereof. 7. Compound, according to claim 1, 2 or 6, CHARACTERIZED by the fact that it is (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl) oxy)benzyl)oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1(6H)-one: 8. Compound, according to claim 1, 2 or 6, CHARACTERIZED by the fact that it is a pharmaceutically acceptable salt of (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridine -4-yl)oxy)benzyl)oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1',2':3,4]imidazo [1,2-c]pyrimidin-1(6H)-one: 9. Pharmaceutical composition CHARACTERIZED by the fact that it comprises a compound, as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 10. Compound, according to any one of claims 1 to 8, CHARACTERIZED by the fact that it is for use in the treatment of neurodegenerative disease. 11. Compound, according to claim 10, CHARACTERIZED by the fact that the neurodegenerative disease is Alzheimer's disease. 12. Use of a compound, as defined in any one of claims 1 to 8, CHARACTERIZED by the fact that it is for the manufacture of a medicine to treat neurodegenerative disease. 13. Use, according to claim 12, CHARACTERIZED by the fact that the neurodegenerative disease is Alzheimer's disease.