WO2016012916A1 - Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2 - Google Patents

Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2 Download PDF

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WO2016012916A1
WO2016012916A1 PCT/IB2015/055403 IB2015055403W WO2016012916A1 WO 2016012916 A1 WO2016012916 A1 WO 2016012916A1 IB 2015055403 W IB2015055403 W IB 2015055403W WO 2016012916 A1 WO2016012916 A1 WO 2016012916A1
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oxy
mmol
compound
methylpyridin
added
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PCT/IB2015/055403
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Vipulkumar Kantibhai Patel
Stefano Livia
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Glaxosmithkline Intellectual Property Development Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to novel bicyclic [5,6] imidazo pyrimidone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy for the treatment of diseases or disorders mediated by Lp-PLA 2 .
  • Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) previously known as platelet-activating factor acetylhydrolase (PAF-AH), is a phospholipase A2 enzyme involved in hydrolysis of lipoprotein lipids or phospholipids.
  • Lp-PLA 2 travels with low-density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules derived from the oxidation of LDL. (See e.g., Zalewski A, et al., Arterioscler. Thromb. Vase. Biol., 25, 5, 923-31 (2005)).
  • Lp-PLA 2 hydrolyzes the sn-2 ester of the oxidized phosphatidylcholines to give lipid mediators, lyso-phosphatidylcholine (lysoPC) and oxidized nonesterified fatty acids (NEFAs). It has been observed that lysoPC and NEFAs elicit inflammatory responses. (See e.g., Zalewski A, et al. (2005)).
  • Lp-PLA 2 inhibitors and/or uses thereof have been previously described. See e.g., published patent application nos. W096/13484, W096/19451, WO97/02242, W097/12963, W097/21675, W097/21676, WO 97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904, WO02/30911,
  • Disclosed uses include treating disease that involves or is associated with endothelial dysfunction, disease that involves lipid oxidation in conjunction with Lp-PLA 2 activity (e.g., associated with the formation of lysophosphatidylcholine and oxidized free fatty acids), and disease that involves activated monocytes, macrophages or lymphocytes or which is associated with increased involvement of monocytes, macrophages or lymphocytes.
  • diseases include atherosclerosis (e.g. peripheral vascular atherosclerosis and cerebrovascular atherosclerosis), diabetes, hypertension, angina pectoris, after ischaemia and reperfusion, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as
  • Alzheimer's Disease various neuropsychiatric disease such as schizophrenia, myocardial infarction, ischaemia, reperfusion injury, sepsis, acute and chronic inflammation, and psoriasis.
  • Lp-PLA 2 inhibitors and/or uses thereof are also reported, for example, in PCT Publication Nos. WO05/003118 (and its Canadian family member CA 2530816A1); WO06/063811; Other researchers have studied the effects related to Lp-PLA 2 and inhibitors thereof.
  • Products of Lp-PLA2 activity (lysophosphatidylcholine and oxidized fatty acids) promote atherosclerosis. See e.g., Macphee CH, et al.
  • Lipoprotein-associated phospholipase A2 platelet- activating factor acetylhydrolase, generates the oxidation of low-density lipoprotein: use of a novel inhibitor
  • Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target Current Opinion in Pharmacology 2006, 6: 154-161; Zalewski A, et al. "Role of lipoprotein-associated phospholipase A2 in atherosclerosis” Arterioscler Thromb Vase Biol 2005; 25: 923-31.
  • LysoPC promotes atherosclerotic plaque development, which can ultimately lead to the formation of a necrotic core (See e.g., Wilensky et al., Current Opinion in Lipidology, 20, 415-420 (2009)).
  • Lp-PLA2 activity are implicated in plaque vulnerability and pathology. See e.g. Kolodgie FD, et al. "Lipoproteinassociated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis” Arteriosclerosis Thrombosis and Vascular Biology, 2006;26:2523-9; Wilensky RL, et al. "Inhibition of
  • lipoproteinassociated phospholipase A2 reduces complex coronary atherosclerotic plaque development" Nature Medicine (21 Sep 2008), doi: 10.1038/nm.l870; Ferguson, J. F., et al. (2012) "Translational studies of lipoprotein-associated phospholipase A2 in inflammation and atherosclerosis” Journal of the American College of Cardiology, 59: 764-772; Chinetti-Gbaguidi, G. et al. (2011) "Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARy and LXRct pathways" Circulation Research, 108: 985-995; Mannheim D., et al.
  • Lp-PLA 2 inhibitors may be useful to treat atherosclerosis and diseases associated with atherosclerosis.
  • AD Alzheimer's disease
  • oxidized LDL have also been observed in AD patients (See e.g., Kassner et al. Current Alzheimer Research, 5, 358-366 (2008); Dildar, et al., Alzheimer Dis Assoc Disord, 24, April-June ( 2010); Sinem, et al. Current Alzheimer Research, 7, 463-469
  • Lp-PLA 2 inhibitors for treating neurodegenerative diseases, e.g., associated with blood-brain-barrier leakage, including, e.g., Alzheimer's disease and vascular dementia.
  • neuroinflammation including multiple cytotoxic cytokine release
  • neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc.
  • Lp-PLA 2 inhibitors can reduce inflammation, for example, reducing multiple cytokine release by suppressing lysoPC production.
  • Lp-PLA 2 inhibiting Lp-PLA 2 is a potential therapeutic treatment approach for neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc.
  • Alzheimer's disease and cognitive function has also been reported. See, e.g., http://www.gsk- ciinicaistudyregister.eom/study/114458#rs which describes Study LPZ114458, a phase 2a clinical study to evaluate the effect of the Lp-PLA2 inhibitor rilapladib on biomarkers related to the pathogenesis and progression of AD and cognitive function.
  • Subjects (with a diagnosis of possible AD with radiological evidence of cerebrovascular disease) took 250mg of rilapladib or placebo once daily for a period of 24 weeks in addition to their stable background therapy consisting of an acetylcholinesterase inhibitor (AChEI) and/or memantine.
  • Rilapladib exhibited approximately 80% inhibition of Lp-PLA2 throughout the treatment phase, and maintained cognitive performance around baseline levels after 24 weeks compared to a decline in the placebo group.
  • Lp-PLA 2 inhibitors can be used to treat tissue damage associated with diabetes by reducing the production of lysoPC, which can cause a continuous cycle of vascular inflammation and increased reactive oxygen species ( OS) production.
  • OS reactive oxygen species
  • Glaucoma and age-related macular degeneration are retina neurodegenerative diseases.
  • inflammation including TNF-alpha signaling, may play an important role in the pathogenesis of glaucoma and AMD (See e.g., Buschini et al., Progress in Neurobiology, 95, 14-25 (2011); Tezel, Progress in Brain Research, vol. 173, ISSN0079-6123, Chapter 28).
  • Lp-PLA 2 inhibitors their function of blocking inflammatory cytokine release (See e.g., Shi, et al. Atherosclerosis, 191, 54-62 (2007)), it is believed that Lp-PLA 2 inhibitors can provide a potential therapeutic application for neurodegenerative eye diseases and disorders such as retina neurodegenerative diseases, e.g. glaucoma and AMD.
  • WO2012/080497 describes the use of Lp-PLA2 inhibitors for treating or preventing eye conditions, including e.g. eye diseases or disorders associated with the breakdown of the inner blood-retinal barrier (iBRB), macular edema of any cause (e.g., macular edema associated with diabetic eye diseases (e.g. diabetic retinopathy), uveitis, or other causes such as retinal vein occlusion (RVO), inflammation, post-surgical, traction, and the like), age-related macular degeneration (AMD), uveitis, diabetic eye diseases and disorders (e.g.
  • iBRB inner blood-retinal barrier
  • macular edema of any cause e.g., macular edema associated with diabetic eye diseases (e.g. diabetic retinopathy), uveitis, or other causes such as retinal vein occlusion (RVO), inflammation, post-surgical, traction, and the like
  • AMD age-related macular de
  • diabetic macular edema diabetic retinopathy
  • central retinal vein occlusion branched retinal vein occlusion
  • Irvine-Gass syndrome post cataract and post-surgical
  • retinitis pigmentosa pars planitis
  • birdshot retinochoroidopathy epiretinal membrane
  • choroidal tumors cystic macular edema
  • parafoveal telengiectasis tractional maculopathies
  • vitreomacular traction syndromes retinal detachment
  • neuroretinitis idiopathic macular edema, and the like.
  • Subjects were stratified based on baseline visual acuity for balance between groups: >50 letters and ⁇ 50 letters. Eligibility for each subject was based only on one eye, which was designated as the study eye. The study eye was examined for changes over the life of the study. Administration of darapladib 160 mg for 3 months resulted in statistically significant improvements from baseline at Day 90 in vision as measured by by best-corrected visual acuity (BCVA) and macular edema as measured by spectral domain optical coherence tomography(SD- OCT) center subfield and center point.
  • BCVA best-corrected visual acuity
  • SD- OCT spectral domain optical coherence tomography
  • Lp-PLA 2 inhibitors on diseases associated with macrophage polarization, e.g., M1/M2 macrophage polarization, has been described. See e.g. WO2012/076435 and WO2013/014185.
  • Lp-PLA2 inhibitors in treating diseases or disorders associated with macrophage polarization (e.g., M1/M2 macrophage polarization), such as liver cirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis (ALS) and other autoimmune diseases that are associated with macrophage polarization.
  • diseases or disorders associated with macrophage polarization e.g., M1/M2 macrophage polarization
  • diseases or disorders associated with macrophage polarization e.g., M1/M2 macrophage polarization
  • diseases or disorders associated with macrophage polarization e.g., M1/M2 macrophage polarization
  • diseases or disorders associated with macrophage polarization e.g., M1/M2 macrophage polarization
  • WO2008/141176 and US2010/0239565 describe the use of Lp-PLA 2 inhibitors for treating or preventing skin ulcers.
  • WO2008/140450 and US20080280829 describe the use of Lp-PLA 2 inhibitors for treating or preventing metabolic bone disorders, including e.g., bone marrow abnormalities, osteoporosis, and osteopenia.
  • Lp-PLA 2 In view of the number of pathological responses that are mediated by Lp-PLA 2 , attempts have been made to prepare compounds that inhibit its activity. Though a number of such compounds have been disclosed in the art, there remains a continuing need for inhibitors of Lp- PLA 2 which can be used in the treatment of a variety of conditions.
  • this invention relates to compounds of Formula (I) and salts thereof, including pharmaceutically acceptable salts thereof:
  • R 1 and R 2 are independently CH 3 or H;
  • R 3 is H or C ( i_ 3) alkyl; and R 4 is
  • R a is H or F
  • R b is -O-Y wherein Y is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are substituted with one CH 3 substituent; and
  • R c is F or CN.
  • This invention also relates to pharmaceutical compositions comprising a compound of the invention (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof), and one or more pharmaceutically acceptable excipients.
  • a compound of the invention e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof
  • pharmaceutically acceptable excipients e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also relates to methods of treating a disease or disorder associated with the activity of Lp-PLA 2 , which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention described herein (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • a compound of the invention described herein e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also provides methods of treating a disease or disorder by inhibiting Lp-
  • PLA 2 activity which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention described herein (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • a compound of the invention described herein e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the methods of the invention may be used, e.g., for diseases or disorders such as:
  • ocular diseases or disorders including ocular diseases or disorders associated with the breakdown of the inner blood-retinal barrier (iBRB), and neurodegenerative eye diseases or disorders, such as: diabetic eye diseases or disorders (e.g., diabetic macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like), retinal vein occlusion (e.g.
  • diabetic eye diseases or disorders e.g., diabetic macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like
  • retinal vein occlusion e.g.
  • central retinal vein occlusion branched retinal vein occlusion
  • Irvine-Gass syndrome post cataract and post-surgical
  • retinitis pigmentosa pars planitis
  • birdshot retinochoroidopathy epiretinal membrane
  • choroidal tumors cystic macular edema
  • parafoveal telengiectasis tractional maculopathies
  • vitreomacular traction syndromes retinal detachment, neuroretinitis, macular edema (e.g., in addition to diabetic macular edema, macular edema associated with uveitis (particularly posterior uveitis), retinal vein occlusion, inflammation, post-surgical traction and the like, and idiopathic macular edema), glaucoma, macular degeneration (e.g. age-related macular degeneration) and the like, systemic inflammatory disease which may be the underlying cause of posterior uveitis affecting the
  • Atherosclerosis e.g.
  • peripheral vascular atherosclerosis and cerebrovascular atherosclerosis diabetes, hypertension, angina pectoris, after ischaemia and reperfusion, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischaemia, reperfusion injury, sepsis, acute inflammation and chronic inflammation, psoriasis, wound healing, chronic obstructive pulmonary disease (COPD), liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, multiple sclerosis, autoimmune diseases such as lupus, cardiovascular events (e.g. a heart attack, myocardial infarction or stroke), acute coronary events, restenosis, or diabetic or hypertensive renal insufficiency;
  • cardiovascular events e.g. a heart attack, myocardial infarction
  • BBB blood brain barrier
  • ⁇ abnormal beta amyloid
  • vascular dementia including vascular dementia associated with Alzheimer's disease, cerebrovascular disease, or small vessel disease
  • Alzheimer's disease Parkinson's disease
  • Huntington's disease amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • brain hemorrhage and cerebral amyloid angiopathy
  • cerebral amyloid angiopathy vascular dementia (including vascular dementia associated with Alzheimer's disease, cerebrovascular disease, or small vessel disease), Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), brain hemorrhage, and cerebral amyloid angiopathy;
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • metabolic bone diseases or disorders such as: diseases/disorders associated with loss of bone mass and density including osteoporosis and osteopenic related diseases (e.g., bone marrow abnormalities, dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases);
  • osteoporosis and osteopenic related diseases e.g., bone marrow abnormalities, dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases
  • diseases or disorders associated with macrophage polarization such as: liver cirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis (ALS) and other autoimmune diseases that are associated with macrophage polarization.
  • ALS amyotrophic lateral sclerosis
  • the present invention is not limited to any particular stage of the disease or disorder (e.g. early or advanced).
  • This invention also provides methods of decreasing beta amyloid (also referred to as " ⁇ ") accumulation in the brain of a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • a compound of the present invention e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also provides for use of the compounds of the invention (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating any disease or disorder described herein.
  • compounds of the invention e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof
  • the invention also provides compounds of the invention (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment of any disease or disorder described herein.
  • compounds of the invention e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof
  • This invention also provides compounds of the invention (e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in therapy, in particular in the treatment of any disease or disorder described herein.
  • compounds of the invention e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof
  • Figure 1 is an x-ray powder diffraction (X PD) pattern of a crystalline form of anhydrous 7- ( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H- imidazolidino[l,2-c]pyrimidin-5-one.
  • X PD x-ray powder diffraction
  • R 1 and R 2 are independently CH 3 or H;
  • R 3 is H or C ( i_ 3) alkyl
  • R a is H or F
  • R b is -O-Y wherein Y is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl wherein pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are substituted with one CH 3 substituent; and
  • R c is F or CN
  • salts e.g. pharmaceutically acceptable salts thereof.
  • Alkyl refers to a monovalent, saturated, straight or branched hydrocarbon group having the specified number of carbon atoms.
  • C ( i. 3) alkyl refers to an alkyl group having from 1 to 3 carbon atoms.
  • Exemplary C (1 . 3) alkyl groups include, but are not limited to, methyl, methylethyl, ethyl, n-propyl and isopropyl.
  • substituted in reference to a group indicates that one or more hydrogen atom attached to a member atom (e.g., carbon atom) within the group is replaced with a substituent selected from the group of defined substituents.
  • substituted includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture).
  • a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted.
  • 1 and R 2 are each CH 3 .
  • R 3 is H or CH 3 . In some embodiments, R 3 is CH 3 .
  • Y of R b is pyridinyl
  • Y of R b is selected from pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyridazin-3-yl (in more particular embodiments, pyridin-3-yl), each substituted by one CH 3 substituent.
  • Y of R b is 6-methyl-pyridin-3-yl, 2-methyl-pyridin-4-yl, 2-methyl-pyrimidin-5-yl, 5-methyl-pyrazin-2-yl, or 6-methylpyridazin-3-yl (in more particular embodiments, 6-methyl-pyridin-3-yl).
  • R a is fluoro
  • R c is fluoro
  • each of R a and R c is fluoro. In some embodiments of the compounds of the invention, R a is fluoro and R c is CN.
  • R 1 and R 2 are each CH 3 ;
  • R 3 is H or CH 3 (in more particular embodiments, CH 3 );
  • Y of R b is selected from pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl and pyridazin-3-yl (in more particular embodiments, pyridin-3-yl), each substituted by one CH 3 substituent; and
  • R a and/or R c is fluoro (in more particular embodiments, R a is fluoro and R c is fluoro or CN).
  • Y of R b is 6-methyl-pyridin-3-yl, 2- methyl-pyridin-4-yl, 2-methyl-pyrimidin-5-yl, 5-methyl-pyrazin-2-yl or 6-methylpyridazin-3-yl (in more particular embodiments, 6-methyl-pyridin-3-yl).
  • R 1 and R 2 are each CH 3 ;
  • R 3 is H or CH 3 (in more particular embodiments, CH 3 );
  • Y of R b is pyridinyl substituted by one CH 3 substituent; and a and/or R c is fluoro (in more particular embodiments, R a is fluoro and R c is fluoro or CN).
  • Y of R b is 6-methyl-pyridin-3-yl or 2-methyl-pyridin-4- yl, (in more particular embodiments, 6-methyl-pyridin-3-yl).
  • Representative compounds of this invention include the compounds of the Examples.
  • the terms "compound(s) of the invention”, “compound(s) of this invention” or the like mean a compound of Formula (I), as defined herein, in any form, i.e., any salt or non-salt form (e.g., as a free base form, or as a salt, e.g., a pharmaceutically acceptable salt thereof), and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
  • the compound(s) of the invention is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in any physical form.
  • the present invention encompasses compounds of Formula (I) as the free base and as salts thereof, for example as a pharmaceutically acceptable salt thereof.
  • the invention relates to compounds of Formula (I) in the form of a free base.
  • the invention relates to compounds of Formula (I) in the form of a salt, particularly, a pharmaceutically acceptable salt.
  • the invention relates to compounds of the Examples in the form of a free base.
  • the invention relates to compounds of the Examples in the form of a salt, particularly, a pharmaceutically acceptable salt.
  • this invention is directed to 7-( ⁇ 3,5-difluoro-4-[(6- methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H-imidazolidino[l,2- c]pyrimidin-5-one or a salt, particularly a pharmaceutically acceptable salt, thereof.
  • one particular compound of the invention is 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3- yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H-imidazolidino[l,2-c]pyrimidin-5-one (free base).
  • the compound of the invention is a salt of 7-( ⁇ 3,5-difluoro-4-[(6- methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H-imidazolidino[l,2- c]pyrimidin-5-one (in particular embodiments, a pharmaceutically acceptable salt thereof).
  • the compound of the invention is a mesylate or tosylate salt of 7-( ⁇ 3,5- difluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H- imidazolidino[l,2-c]pyrimidin-5-one.
  • solvates of a compound of Formula (I), or solvates of salts (e.g. pharmaceutically acceptable salts) of a compound of Formula (I), may be formed when solvent molecules are incorporated into the crystalline lattice during crystallization.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric solvate forms.
  • One or more solvents may form a solvate.
  • the solvent(s) which forms a solvate may be aqueous, e.g. water, and/or nonaqueous, e.g. ethanol, isopropanol, dimethylsulfoxide, acetic acid, ethanolamine, and/or ethyl acetate.
  • a the compound of the invention is a solvate, e.g. hydrate, of 7-( ⁇ 3,5-difluoro-4-[(6- methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H-imidazolidino[l,2- c]pyrimidin-5-one or a salt, particularly a pharmaceutically acceptable salt, thereof, including any of the particular salts described herein.
  • a the compound of the invention is an anhydrate, e.g. anhydrous 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H- imidazolidino[l,2-c]pyrimidin-5-one or a salt, particularly a pharmaceutically acceptable salt, thereof, including any of the particular salts described herein.
  • an anhydrous compound of the invention comprises 0.5 or less weight/weight% water (e.g. as measured by Karl Fischer titration)(in particular embodiments, 0.4, 0.3, 0.2 or 0.1 or less weight/weight% water), e.g. 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3- yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H-imidazolidino[l,2-c]pyrimidin-5-one or a salt, particularly a pharmaceutically acceptable salt, thereof, including any of the particular salts described herein, having any of the aforementioned water contents.
  • weight/weight% water e.g. as measured by Karl Fischer titration
  • 0.4, 0.3, 0.2 or 0.1 or less weight/weight% water e.g. 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3- yl)oxy]phenyl
  • the salts and/or solvates of the compounds of Formula (I) are preferably pharmaceutically acceptable.
  • pharmaceutically acceptable means a compound or other material (e.g. composition, dosage form) which is suitable for pharmaceutical (medicinal) use.
  • pharmaceutically acceptable compounds or other materials may include those which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Compounds of the invention in a salt and/or solvate form e.g. hydrates and hydrates of salts
  • the counterion or associated solvent is pharmaceutically acceptable. Salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their salts and solvates.
  • Salts may be prepared in situ during the final isolation and purification of a compound of Formula (I). If a basic compound of Formula (I) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.
  • This invention also provides for the conversion of one salt of a compound of this invention, e.g., a hydrochloride salt, into another salt of a compound of this invention, e.g., a sulfate salt.
  • Suitable pharmaceutically acceptable salts can include acid salts.
  • Salts of the compounds of Formula (I) containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, such as treatment of the free base with an acid.
  • suitable method known in the art, such as treatment of the free base with an acid.
  • pharmaceutically acceptable salts so formed include acetate, adipate, ascorbate, aspartate, benzenesulfonate, benzoate, camphorate, camphor-sulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), carbonate, bicarbonate, cinnamate, citrate, cyclamate, dodecylsulfate (estolate), ethane-l,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5- dihydroxybenzoate
  • the compounds of this invention may contain an asymmetric center (also referred to as a chiral center), such as a chiral carbon.
  • asymmetric center also referred to as a chiral center
  • the stereochemistry of the chiral carbon center present in compounds of this invention is generally represented in the compound names and/or in the chemical structures illustrated herein.
  • Compounds of this invention containing a chiral center may be present as racemic mixtures, diastereomeric mixtures, enantiomerically enriched mixtures, diastereomerically enriched mixtures, or as enantiomerically or diastereomerically pure individual stereoisomers.
  • stereoisomers of a compound of this invention may be resolved (or mixtures of stereoisomers may be enriched) using methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a stereoisomer-specific reagent for example by enzymatic oxidation or reduction
  • gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form.
  • specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compound or salt including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof.
  • the compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as
  • polymorphs it is to be understood that when named or depicted by structure, the disclosed compound or salt, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, I spectra, and X-ray powder diffraction (XRPD) patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
  • XRPD X-ray powder diffraction
  • the compound of the invention is a crystalline form of anhydrous
  • the compound of the invention is a crystalline form of anhydrous 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3-yl)oxy] phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H-imidaz
  • diffraction angles (expressed in °2 ⁇ ) obtained from an XRPD pattern at least at positions of about 6.4, 9.2, 9.9, 12.2, 13.1, 14.1, 14.4, 15.7, 16.2, 16.6, 18.6, 22.7, and 23.4 (in some embodiments, ⁇ 0.1 degrees with respect to each of the foregoing particular peaks), e.g. as shown in Table 1 herein.
  • an XRPD pattern that is "substantially in accordance" with that of the Figure 1 provided herein is an XRPD pattern that would be considered by one skilled in the art to represent a compound possessing the same crystal form as the compound that provided the XRPD pattern of the Figure.
  • the XRPD pattern may be identical to that of Figure 1, or more likely it may be somewhat different.
  • Such an XRPD pattern may not necessarily show each of the lines of the diffraction patterns presented herein, and/or may show a slight change in appearance, intensity, or a shift in position of said lines resulting from differences in the conditions involved in obtaining the data.
  • a person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or a different form from, a form disclosed herein by comparison of their XRPD patterns.
  • one skilled in the art can overlay an XRPD pattern of a sample of a crystalline form of anhydrous 7- ( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H- imidazolidino[l,2-c]pyrimidin-5-one (free base) with the XRPD pattern of Figure 1, and using expertise and knowledge in the art, readily determine whether the XRPD pattern of the sample is substantially in accordance with the XRPD pattern of Figure 1.
  • the sample form can be readily and accurately identified as having the same form as the crystalline form of anhydrous 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3- yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H-imidazolidino[l,2-c]pyrimidin-5-one (free base) described herein.
  • a person skilled in the art is capable of determining if a given diffraction angle (expressed in °2 ⁇ ) obtained from an XRPD pattern is at about the same position as a recited value.
  • the invention also includes various deuterated forms of the compounds of the invention.
  • One or more available hydrogen atoms attached to a carbon atom may be independently replaced with a deuterium atom.
  • a person of ordinary skill in the art will know how to synthesize deuterated forms of compounds of the invention.
  • commercially available deuterated starting materials may be employed in the preparation of deuterated forms of compounds of the invention. Employing such compounds may allow for the preparation of compounds in which the hydrogen atom at a chiral center is replaced with a deuterium atom.
  • Deuterated starting materials may alternatively be synthesized using conventional techniques employing deuterated reagents (e.g. by reduction using lithium aluminum deuteride or sodium borodeuteride or by metal-halogen exchange followed by quenching with D 2 0 or methanol-d 3 ).
  • compounds of the invention are not in a deuterated form.
  • the invention also includes isotopically-labeled forms of the compounds of the invention, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into isotopically-labeled forms of the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, and fluorine, such as 3 H, n C, 14 C and 18 F.
  • Such isotopically-labeled forms of the compounds of the invention are useful in drug and/or substrate tissue distribution assays.
  • n C and 18 F isotopes are useful in PET (positron emission tomography), which is useful in brain imaging.
  • Isotopically-labeled forms of the compounds of the invention can generally be prepared by carrying out the procedures disclosed below, by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent. In some embodiments, the compounds of the invention are not in and isotopically-labeled form.
  • the compounds of this invention are intended for use in pharmaceutical compositions it will be readily understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
  • the compounds of the invention may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the syntheses provided in these Schemes are applicable for producing compounds of the invention having a variety of different groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein.
  • Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See for example, "Protective groups in organic synthesis" by T.W. Green and P.G.M Wuts (Wiley & Sons, 1991) or “Protecting Groups” by P.J.Kocienski (Georg Thieme Verlag, 1994). Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with compounds of Formula (I), they are illustrative of processes that may be used to make the compounds of the invention.
  • R 2 , R 3 , R 4 and A are as defined in Formula (I).
  • Step (i) may be carried out by reacting H 2 NC(R 1 )(R 2 ) C(R 5 ) 2 OH with trichloropyrimidine using appropriate reagents such as potassium carbonate or triethylamine in an appropriate solvent such as acetonitrile under a suitable temperature such as room temperature to provide compound 2.
  • appropriate reagents such as potassium carbonate or triethylamine
  • an appropriate solvent such as acetonitrile
  • Step (ii) may use appropriate reagents such as methanesulfonyl chloride (MsCI) and triethylamine (NEt 3 ) in a suitable solvent such as THF at a suitable temperature such as RT.
  • Step (iii) may be taken place by reacting compound 3 with a suitable reagent such as potassium carbonate (K 2 C0 3 ) at an appropriate temperature such as 80 °C.
  • Steps (ii) and (iii) can be accomplished in a one pot procedure may use appropriate reagent such as methanesulfonyl chloride (MsCI) and triethylamine (NEt 3 ) in a suitable solvent such as THF at a suitable temperature such as 25 °C.
  • appropriate reagent such as methanesulfonyl chloride (MsCI) and triethylamine (NEt 3 ) in a suitable solvent such as THF at a suitable temperature such as 25 °C.
  • the pyrimidinone may be protected by using a reagent such as di- f-butyldicarbonate and a base such as triethylamine and a catalyst such as N,N- dimethylaminopyrimidine in a suitable solvent such as tetrahydrofuran (THF) at suitable temperature such as room temperature to provide protected compound 5.
  • a reagent such as di- f-butyldicarbonate and a base such as triethylamine and a catalyst such as N,N- dimethylaminopyrimidine in a suitable solvent such as tetrahydrofuran (THF) at suitable temperature such as room temperature to provide protected compound 5.
  • THF tetrahydrofuran
  • Step (v) may be carried out by reacting compound 5 with R 4 -A-OH in the presence of suitable base such as sodium hydride (NaH) in a suitable solvent such as A/,/ ⁇ /-dimethyformamide (DMF) at suitable temperature such as room temperature to provide the compounds 6 or 7 or 8.
  • suitable base such as sodium hydride (NaH)
  • suitable solvent such as A/,/ ⁇ /-dimethyformamide (DMF)
  • suitable temperature such as room temperature
  • Step (vi) A protecting group such as t-butoxycarbonyl may be removed from compound 8 by a reagent such as 4M hydrogen chloride in 1,4-dioxane or a strong acid such as trifluoroacetic acid at a temperature such as room temperature to provide de-protected compound 7.
  • a reagent such as 4M hydrogen chloride in 1,4-dioxane or a strong acid such as trifluoroacetic acid at a temperature such as room temperature to provide de-protected compound 7.
  • the intermediate R 4 -A-OH can be prepared by using nucleophilic aromatic substitution chemistry to prepare the R 4 -A species with a base such as potassium carbonate (K 2 C0 3 ) and a solvent such as acetonitrile at a temperature such as 80 °C.
  • A can be modified by standard function group manipulation, for example the reduction of an aldehyde or an ester by regents such as sodium borohydride or lithium aluminium hydride to furnish a primary alcohol.
  • A can be further modified by a replacement of an aromatic bromide with an aromatic nitrile using a reagent such as zinc cyanide and a catalyst mixture such as tris(dibenzylideneacetone)dipalladium(0) and l,l'-bis(diphenylphosphino)ferrocene in a solvent such as A/,/ ⁇ /-dimethylformamide at a temperature such as 150 °C.
  • a reagent such as zinc cyanide and a catalyst mixture
  • a catalyst mixture such as tris(dibenzylideneacetone)dipalladium(0) and l,l'-bis(diphenylphosphino)ferrocene
  • a solvent such as A/,/ ⁇ /-dimethylformamide
  • Method B Column: Denali C18 (250 x 20 mm) 5 ⁇ ; mobile phase A, 10mm NH 4 HC0 3 ; B, acetonitrile (40:60); ambient temperature; flow rate, 30 ml/min; Sample loading solvent, acetonitrile; fraction volume, 250 ml
  • the reaction mixture was filtered through a Celite bed and the filtrate was evaporated to give the mesylate (80 g) as a pale yellow liquid which was dissolved in a mixture of triethylamine (100 mL, 717 mmol) and water (500 mL). The mixture was heated to 100 °C for 5 h. and cooled to T and filtered. The solid was dried under vacuum to afford the title compound (25 g) as a pale yellow solid.
  • the aqueous layer was extracted with ethyl acetate (3 X 2 L) and the organic layers were dried over anhydrous Na 2 S0 4 and then concentrated under reduced pressure to afford the crude title compound.
  • the crude material was dissolved in petroleum ether (250 mL ) and cooled to -25 °C, stirred for 20 min to give a white solid, The solid was filtered and washed with 50 mL petroleum ether and dried under vacuum to title compound (700 g) as a white solid.
  • the crude product was purified by silica gel (100-200 mesh) column chromatography, using 20% ethyl acetate in petroleum ether as eluent. The pure product containing fractions were combined and evaporated to give the title compound (75 g) as a yellow solid.
  • the tube was sealed and the reaction mixture was heated to 150 °C for 1 h.
  • the reaction mixture was diluted with ethyl acetate (100ml), filtered through Celite bed and the bed washed with EtOAc (200 ml).
  • the filtrate was washed with brine solution (2 x 200ml), dried over anhydrous Na 2 S0 4 .
  • the solvent was removed under reduced pressure to give 8 g of crude product which was purified by column chromatography using 100-200 mesh silica gel. The product containing fractions were collected and then evaporated to give the title compound as a grey solid (3.4 g)
  • reaction mixture was stirred for 2 h at T and then quenched with ice water (5ml) at 0 °C, diluted with ethyl acetate (100ml), the ethyl acetate layer separated and washed with brine solution (2 x 50ml), dried over anhydrous Na 2 S0 4 and the solvent removed under reduced pressure to give the title compound (600 mg) as a brown solid which was used without further purification.
  • reaction mixture was quenched with ice cold water (30 ml), extracted with ethyl acetate (2 x 30 ml), washed with brine solution (25 ml), dried over anhydrous Na 2 S0 4 .
  • the solvent was removed under reduced pressure to give crude material (400 mg) which was used directly in the next step without further purification.
  • reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (15 mL), washed with brine solution (10 mL), dried over Na 2 S0 4 and evaporated under reduced pressure to give crude title compound (300 mg) as brown oil. This was used directly in the next step without further purification.
  • the crude compound was purified by column chromatography using silica gel 100-200 mesh, eluting with 15% EtOAc/hexane. The product containing fractions were combined and concentrated under reduced pressure to give the title compound (1.0 g) as a white solid.
  • the organic layer was separated, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to give the title compound (3.5 g) as a brown solid.
  • the crude material was purified by column chromatography using 100-200 mesh silica gel and 70% ethyl acetate/hexane as eluent. The product containing fractions were combined and solvent removed under reduced pressure to give the title compound (2.5 g) as an off white solid.
  • reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (15 mL), washed with brine solution (10 mL), dried over Na 2 S0 4 , evaporated under reduced pressure to give the crude product which was purified using preparative HPLC method B.
  • the product containing fractions were collected and concentrated under reduced pressure to remove acetonitrile and the resulting solid filtered and then dried under in vacuo to give the title compound (210 mg) as a white solid.
  • reaction mixture was evaporated under reduced pressure and neutralized (pH ⁇ 7) with NaHC0 3 solution (15 mL), extracted with ethyl acetate (20 mL), dried and the organic layer evaporated to give the crude product (280 mg) which was purified by using preparative HPLC conditions A.
  • the product containing fractions were collected and concentrated under reduced pressure to remove acetonitrile and resulting solid was filtered and washed with water (2 x 10ml) and dried under vacuum to give the title compound (47.4 mg) as an off white solid.
  • reaction mixture was quenched with ice cold water (30 ml), extracted with ethyl acetate (2 x 30 mL), washed with brine solution (25 ml), dried over anhydrous Na 2 S0 4 and the solvent removed under reduced pressure to give the crude material (300 mg) that was purified by using preparative HPLC method C.
  • the product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile, and the precipitated solid filtered and then dried under vacuum to give the title compound (165 mg) as a white solid.
  • reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (2 x 10 mL), washed with brine solution (10 mL), dried over Na 2 S0 4 and evaporated under reduced pressure to give crude material 300 mg which was purified using preparative HPLC method D. The product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile. The precipitated solid was filtered and then dried under vacuum to give the title compound (130 mg) as white solid.
  • reaction mixture was quenched with ice cold water (30 ml), extracted with ethyl acetate (2 x 50 ml), washed with brine solution (25 ml), dried over anhydrous Na 2 S0 4 and the solvent removed under reduced pressure to get crude material (500 mg) which was purified using preparative HPLC method E.
  • the product containing fractions were collected and concentrated under reduced pressure to remove acetonitrile, the solid precipitated filtered and then dried under vacuum to give the title compound as (96 mg) as a white solid.
  • the reaction mixture was stirred at RT for 18 h and then evaporated under reduced pressure and basified with NaHC0 3 solution (15 mL) and extracted with ethyl acetate (20 mL), dried and the organic layer evaporated to give the crude product 300 mg which was purified by preparative HPLC method F.
  • the product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile and the solution and basified with NaHC0 3 , extracted with DCM (20 mL) and dried over Na 2 S0 4 .
  • the solvent was evaporated under vacuum to give the crude title compound (60 mg) which was only 54% pure.
  • Example 12 3-fluoro-2-((2-methylpyridin-4-yl)oxy)-5-(((l,2,2-trimethyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile
  • Example 14 ⁇ -5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7- yl)oxy)methyl)-3-fluoro-2-((2-methylpyridin-4-yl)oxy)benzonitrile
  • reaction mixture was quenched with ice cold water (30 ml), extracted with ethyl acetate (2 x 30 ml), washed with brine solution (25 ml), dried over anhydrous Na 2 S0 4 and the solvent removed under reduced pressure to get crude (500 mg) which was purified using preparative HPLC method C.
  • the product containing fractions were collected and concentrated under reduced pressure to remove acetonitrile and the precipitated solid filtered and dried under vacuum to give the title compound (199 mg) as a white solid.
  • reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (2 x 10 mL), washed with brine solution (10 mL), dried over Na 2 S0 4 and evaporated under reduced pressure to give the crude product (350 mg) which was purified by preparative HPLC method C collecting 250 mL fractions. The product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile, the precipitated solid filtered and the solid dried under vacuum to give the title compound (250 mg) as a white solid.
  • reaction mixture was quenched with ice cold water (30 ml), extracted with ethyl acetate (2 x 50 ml), washed with brine solution (25 ml), dried over anhydrous Na 2 S0 4 , rand the solvent removed under reduced pressure to get crude (450 mg) which was purified using preparative HPLC method C collecting 250 mL fractions.
  • the product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile and the precipitated solid was filtered and dried under vacuum to give the title compound (119 mg) as a white solid.
  • reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (20 mL), washed with brine solution (15 mL), dried over Na 2 S0 4 and evaporated under reduced pressure to give the crude material (300 mg) which was purified using preparative HPLC method A collecting 200 mL fractions.
  • the product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile and the resulting solid was filtered and then dried under vacuum to give material which was triturated with ethyl acetate to give the title compound (110 mg) as a white solid.
  • the reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (15 mL), washed with brine solution (10 mL), dried over Na 2 S0 4 and evaporated under reduced pressure.
  • the crude material (350 mg) was purified using preparative HPLC method F.
  • the product fractions were combined and concentrated under reduced pressure to remove acetonitrile and basified with saturated NaHC0 3 solution (15 mL) and extracted with ethyl acetate (20 mL), dried over Na 2 S0 4 , evaporated under reduced pressure to give the title compound (140 mg) as a white solid.
  • reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 20 mL). The organic layers combined and dried over Na 2 S0 4 and concentrated under reduced pressure to get crude compound which was purified using preparative HPLC method A, collecting 200 mL fractions. The sample was loading using an acetonitrile/methanol mixture.
  • reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine solution (15 mL), dried over Na 2 S0 4 and evaporated under reduced pressure to give the crude product which was purified by using preparative HPLC method A. Product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile and the resulting solid was filtered and then dried under vacuum to give the title compound (250 mg) as a white solid.
  • reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine solution (15 mL), dried over Na 2 S0 4 and evaporated under reduced pressure to give crude product which was purified by using preparative HPLC method A.
  • Example 28 ⁇ -7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2-methyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
  • reaction mixture was quenched with ice cold water (10 mL) and the mixture was extracted with ethyl acetate (15 mL), washed with brine solution (10 mL), dried over Na 2 S0 4 and evaporated under reduced pressure give crude material that was purified using preparative HPLC method A.
  • the product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile and the resulting solid was filtered and then dried under vacuum to give the title compound (130 mg) as white a solid.
  • the reaction mixture was quenched with ice water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layers were separated, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to give crude product.
  • the crude product was purified by column chromatography using (100-200) silica gel and 3% methanol/DCM as eluent. The product containing fractions were concentrated under reduced pressure to give the title compound (10 g) which was further purified. It was washed with EtOAc (100 mL) and the resulting solid was dissolved in 100 mL EtOAc and warmed to 80°C for 10 min and cooled to T and stored for 16 h. Then solid was filtered and dried under vacuum to give crystalline title compound (7.0 g). The above process was repeated to give a solid which was kept under high vacuum to remove trapped ethyl acetate to give the title compound (5.12 g) as white solid.
  • the reaction mixture was quenched with ice cold water (2.0 L) and extracted with ethyl acetate (5.0 L) The organic layer was washed with brine solution (2.0 L), dried over Na 2 S0 4 and evaporated under reduced pressure to give the crude product as pale yellow oil.
  • the crude product was washed with pet ether (500 mL) and decanted. Then diethyl ether was added and stirred for 30 min. The precipitated solid was filtered and was dried under vacuum to give the title compound (200 g) as yellow solid.
  • the water content was 0.16 %w/w by oven Karl Fischer determination.
  • a sample of the product was characterized by XRPD.
  • the data were acquired on a PANalytical X'Pert Pro powder diffractometer, model PW3040/60 using an X'Celerator detector.
  • the acquisition conditions were: radiation: Cu Kct, generator tension: 40 kV, generator current: 45 mA, start angle: 2.0° 2 ⁇ , end angle: 40.0° 2 ⁇ , step size: 0.0167° 2 ⁇ , time per step: 31.75 seconds.
  • the sample was prepared by mounting a few milligrams of sample on a silicon wafer (zero background plate), resulting in a thin layer of powder.
  • the characteristic XRPD pattern is shown in Figure 1.
  • the characteristic XRPD angles and d-spacings are shown in Table 1.
  • the margin of error is approximately ⁇ 0.1° 2 ⁇ for each of the peak assignments. It should be noted that peak intensities may vary from sample to sample due to preferred orientation. Peak positions were measured using PANalytical Highscore Plus
  • Example 36 2-((5-methylpyrazin-2-yl)oxy)-5-(((l,2,2-trimethyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile
  • Example 37 (/?)-3-fluoro-5-(((2-methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7- yl)oxy)methyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile
  • the ethyl acetate layer was washed with brine (30 mL), dried over Na 2 S0 4 and concentrated under reduced pressure to afford crude product (120 mg).
  • the crude material was purified using preparative HPLC method A but loading the curding using a mixture of water, THF and acetonitrile and with a gradient [time (min)/%B: 0/60,12/60,12.1/100,18/100,18.1/60,24/100].
  • the compound containing fractions (100 mL) was lyophilized to afford the title compound (30 mg) as white solid.
  • the compounds of present invention are Lp-PLA 2 inhibitors, and therefore may be useful in the treatment of diseases or disorders associated with Lp-PLA 2 activity.
  • the biological activities of the compounds of present invention can be determined by using any suitable assay for determining the activity of a compound as an Lp-PLA 2 inhibitor, as well as tissue and in vivo models, including the assays described herein.
  • l-0-hexadecyl-2-deoxy-2-thio-S-acetyl-sn-glyceryl-3-phosphorylcholine (2-thio-PAF) is a substrate for PAF-hydrolases (PAF-AH) commercially available from Cayman Chemical.
  • PAF-AH PAF-hydrolases
  • CCM 7- diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin
  • CCM 7- diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin
  • This reaction results in an increase in fluorescence. Inhibitors of PLA2 therefore prevent this cleavage and no fluorescent increase is observed.
  • the Thio-PAF assay was run as an unquenched 20 ⁇ assay.
  • the source plate containing the compounds to be tested was prepared by making 1:3 (by volume) serial dilution of the compounds within DMSO on 384-well microplate. Then, 5 ⁇ ⁇ the compounds on compound source plate were transferred into 384 well Greiner 784076 (black) plates using STAR+ (Hamilton) liquid dispenser. ⁇ of recombinant human Lp-PLA2 enzyme (20 pM rhLp-PLA2 in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCI, 1 mM CHAPS) was added to each well of the plate.
  • the Thio-PAF assay was run as an unquenched 20 ⁇ assay.
  • the source plate containing the compounds to be tested was prepared by making 1:3 (by volume) serial dilution of the compounds within DMSO on 384-well microplate. Then, 5 ⁇ ⁇ the compounds on compound source plate were transferred into 384 well Greiner 784076 (black) plates using STAR+ (Hamilton) liquid dispenser. ⁇ of recombinant human PLA2 -VIIB enzyme (200 pM rhPLA2 -VIIB in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCI, 1 mM CHAPS) was added to each well of the plate.
  • substrate comprising 40 ⁇ 2-thio-PAF [from ethanol stock], 40 ⁇ CPM [from a DMSO stock] and 400 ⁇ NEM (N- ethylmaleimide) [made fresh daily in DMSO] in assay buffer (50 mM HEPES, pH 7.4, 150 mM NaCI, 1 mM CHAPS) was added to 384 well Greiner 784076 black plates. Plates were vortexed for 10 sec. The plate was covered to protect it from light and incubated for 20 min at 25 °C. The plates were read for fluorescence intensity at ex: 380nm / em: 485nm using Envision plate reader (Perkin Elmer). Raw data are transferred to Excel software and plC50 data, curve and QC analysis was conducted by using XL fit module in Excel.
  • Example compounds 1-38 exhibited a plC 50 ⁇ 5.5 according to this assay.
  • Lipoprotein-associated phospholipase A2 (Lp-PI_A2) Human Plasma assay
  • the human plasma assay utilizes the same thioester analog of PAF as described in the above
  • Recombinant human Lp-PLA2 assay may detect the activity of Lp-PI_A2 in human plasma, as determined by specific inhibition by Lp-PLA2 inhibitors.
  • the thio-PAF assay was run as a quenched 20 ⁇ assay.
  • Compounds source plate was prepared by making 1:3 (by volume) serial dilution of the compounds into pure DMSO on 96-well microplate. 5 ⁇ of compounds on compound source plate were transferred to 96-well Corning 3686 (black) low-volume plates by STAR+ (Hamilton) liquid dispenser. 10 ⁇ pooled human plasma, which was previously aliquoted and frozen, was added. Plates were centrifuged for 30 sec at 1000 rpm.
  • Example compounds 1-37 exhibited a plC 50 > 7.0 according to this assay.
  • the compounds of the invention are inhibitors of Lp-PLA 2 . Therefore, these compounds may be used in therapy, for example, in the treatment of diseases or disorders associated with the activity of Lp-PLA 2 , including for example treatment of diseases or disorders where inhibition of Lp-PLA 2 is of therapeutic benefit.
  • inhibition of Lp- PLA 2 may involve one or more mechanisms, and a particular disease or disorder or its treatment may involve one or more underlying mechanisms associated with Lp-PLA 2 activity, including those described herein.
  • the invention provides a method of inhibiting Lp-PLA 2 comprising contacting a biological material comprising the protein with a compound of the invention.
  • the contact is made in-vitro
  • the biological material is, e.g., cell culture or cellular tissue.
  • the contact is made in-vivo.
  • the invention also provides a method of treating a disease or disorder associated with Lp- PLA 2 activity, comprising administering a therapeutically effective amount of a compound of the invention, to a subject in need of such treatment.
  • This invention also provides a compound of the invention, for use in therapy.
  • This invention particularly provides for the use of a compound of the invention as an active therapeutic substance in the treatment of a disease or disorder associated with Lp-PLA 2 activity.
  • the invention also provides for the use of a compound of the invention in the
  • Treatment according to each of the methods of the invention comprises administering a therapeutically effective amount of a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt, to a subject in need thereof.
  • the subject in need of treatment has a disease or disorder disclosed herein. In some embodiments, the subject in need of treatment is at risk of having a disease or disorder disclosed herein. In some embodiments, the subject is a mammal, particularly a human.
  • Treatment according to any one or more of the methods of the invention applies to any of the diseases or disorders associated with Lp-PLA 2 activity disclosed herein, including any particular disease or disorder.
  • neurodegenerative disease or disorders refers to a varied assortment of central nervous system disorder characterized by gradual and progressive loss of neural tissue and/or neural tissue function.
  • Neurodegenerative diseases or disorders are a class of neurological disease/disorder where the neurological disease/disorder is characterized by a gradual and progressive loss of neural tissue, and/or altered neurological function, typically reduced neurological function as a result of a gradual and progressive loss of neural tissue.
  • the neurodegenerative diseases or disorders described herein include
  • neurodegenerative diseases and disorders where there is a defective blood brain barrier for example a permeable blood brain barrier.
  • vascular dementia refers to a group of syndromes caused by different mechanisms, which all result in vascular lesions in the brain.
  • the main subtypes of vascular dementia are, for example, vascular mild cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, (affecting the thalamus, the anterior cerebral artery, the parietal lobes or the cingulated gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (including, e.g. vascular dementia due to lacunar lesions and Binswanger disease), and mixed dementia.
  • blood-brain barrier or "BBB” are used interchangeably herein, and are used to refer to the permeability barrier that exists in blood vessels as they travel through the brain tissue that severely restricts and closely regulates what is exchanged between the blood and the brain tissue.
  • the blood brain barrier components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that are the structural correlate of the BBB, the basement membrane of endothelial cells and the expanded foot processes of nearby astrocytes which cover nearly all of the exposed outer surface of the blood vessel.
  • the BBB prevents most substances in the blood from entering brain tissue, including most large molecules such as Ig, antibodies, complement, albumin and drugs and small molecules.
  • inner blood-retinal barrier or “iB B” are used interchangeably herein, and are used to refer to the permeability barrier that exists in blood vessels as they travel through the retinal tissue that severely restricts and closely regulates what is exchanged between the blood and the retinal tissue.
  • the blood retinal barrier components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that are the structural correlate of the iBRB, the basement membrane of endothelial cells and the expanded foot processes of nearby astrocytic cells and pericytes, including glial cells, which cover nearly all of the exposed outer surface of the blood vessel.
  • the iBRB prevents most substances in the blood from entering retinal tissue, including most large molecules such as Ig, antibodies, complement, albumin and drugs and small molecules.
  • abnormal BBB is used to refer to a dysfunctional BBB, for example, where the BBB does not allow transit of molecules that normally transit a functional BBB, for example nutrients and sugars such as glucose.
  • An abnormal BBB can also refer to when the BBB is permeable to molecules that a normally functioning BBB would typically exclude, which is typically referred to "BBB permeability" herein.
  • abnormal inner BRB is used to refer to a dysfunctional iBRB, for example, where the iBRB does not allow transit of molecules that normally transit a functional iBRB, for example nutrients and sugars such as glucose.
  • An abnormal iBRB can also refer to when the iBRB is permeable to molecules that a normally functioning iBRB would typically exclude, which is typically referred to "iBRB permeability" herein.
  • BBB permeability or “permeable BBB” are commonly referred to by persons in the art as “leaky BBB”. The terms are used interchangeably herein to refer to impaired BBB integrity and increased vascular permeability.
  • a permeable BBB allows transit of molecules through the BBB that an intact BBB would normally exclude from the brain tissue, for example, Ig molecules, complement proteins, serum albumin and numerous other proteins.
  • An assay to determine the presence of a permeable BBB can be, for example, to assess the presence of extravascular Ig in the brain tissue which is normally restricted to the lumen of blood vessels when the BBB is functioning normally (i.e., when the BBB is not permeable), such as known in the art.
  • iBRB permeability or "permeable iBRB” are commonly referred to by persons in the art as “leaky iBRB”. The terms are used interchangeably herein to refer to impaired iBRB integrity and increased vascular permeability.
  • a permeable iBRB allows transit of molecules through the iBRB that an intact iBRB would normally exclude from the retinal tissue, for example, Ig molecules, complement proteins, serum albumin and numerous other proteins.
  • An assay to determine the presence of a permeable iBRB can be, for example, to assess the presence of extravascular Ig in the retinal tissue which is normally restricted to the lumen of blood vessels when the iBRB is functioning normally (i.e., when the BRB is not permeable), such as known in the art.
  • the disease or disorder is an ocular disease or disorder.
  • the ocular disease or disorder is associated with the breakdown of the inner blood-retinal barrier (iBRB).
  • the ocular disease or disorder is a neurodegenerative eye disease or disorder, e.g. a neurodegenerative retina eye disease or disorder.
  • Exemplary ocular diseases/disorders include diabetic eye diseases or disorders (e.g., diabetic macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion and the like), retinal vein occlusion (e.g.
  • central retinal vein occlusion central retinal vein occlusion, branched retinal vein occlusion), Irvine-Gass syndrome (post cataract and post-surgical), retinitis pigmentosa, pars planitis, birdshot retinochoroidopathy, epiretinal membrane, choroidal tumors, cystic macular edema, parafoveal telengiectasis, tractional maculopathies, vitreomacular traction syndromes, retinal detachment, neuroretinitis, macular edema (e.g., in addition to diabetic macular edema, macular edema associated with uveitis (particularly posterior uveitis), retinal vein occlusion, inflammation, post-surgical traction and the like, and idiopathic macular edema), glaucoma, macular degeneration (e.g. age-related macular degeneration) and the like.
  • macular degeneration e.g. age-
  • the disease is a systemic inflammatory disease which may be the underlying cause of posterior uveitis affecting the retina, which can result in macular edema, such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic lupus erythematosus, Vogt- Koyanagi-Harada syndrome, Lyme disease, Bechet's disease, ankylosing sponsylitis, chronic granulomatous disease, or enthesitis.
  • ocular diseases and disorders which may be treated by the methods of the invention herein are include those disclosed in WO2012/080497, which is incorporated by reference herein.
  • the disease or disorder is selected from the diseases or disorders disclosed in the following published patent applications:
  • the disease or disorder involves and/or is associated with: (1) endothelial dysfunction, for example, atherosclerosis, (e.g.
  • peripheral vascular atherosclerosis and cerebrovascular atherosclerosis diabetes, hypertension, angina pectoris and after ischaemia and reperfusion
  • lipid oxidation in conjunction with enzyme activity for example, atherosclerosis, diabetes, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischaemia, reperfusion injury, sepsis, acute inflammation and chronic inflammation
  • activated or increased involvement of monocytes, macrophages or lymphocytes as all of these cell types express Lp-PLA 2 including diseases involving activated macrophages such as Ml, dendritic and/or other macrophages which generate oxidative stress (e.g., psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD), liver cirrhosis, atopic dermatitis, pulmonary emphysem
  • COPD chronic
  • the disease or disorder is a cardiovascular event (e.g. a heart attack, myocardial infarction or stroke).
  • a cardiovascular event e.g. a heart attack, myocardial infarction or stroke.
  • compounds of the present invention may be used to lower the chances of having a cardiovascular event, e.g. in a patient with coronary heart disease.
  • the disease or disorder is an acute coronary event, restenosis, or diabetic or hypertensive renal insufficiency.
  • compounds of the invention may be used for the primary or secondary prevention of acute coronary events, e.g. caused by atherosclerosis; adjunctive therapy in the prevention of restenosis; or delaying the progression of diabetic or hypertensive renal insufficiency.
  • the disease or disorder is a neurological disease or disorder associated with an abnormal blood brain barrier (BBB) function, inflammation, and/or microglia activation.
  • BBB blood brain barrier
  • the abnormal BBB is a permeable BBB.
  • the disease is a neurodegenerative disease, e.g., vascular dementia (including vascular dementia associated with Alzheimer's disease, cerebrovascular disease, or small vessel disease), Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).
  • vascular dementia including vascular dementia associated with Alzheimer's disease, cerebrovascular disease, or small vessel disease
  • Alzheimer's disease Parkinson's disease
  • Huntington's disease Huntington's disease
  • MS amyotrophic lateral sclerosis
  • the disease or disorder is associated with blood brain barrier (BBB) leakage.
  • BBB blood brain barrier
  • diseases/disorders include, but are not limited to, brain hemorrhage and cerebral amyloid angiopathy.
  • the disease or disorder is associated with abnormal beta amyloid (" ⁇ ") accumulation in the brain.
  • treatment may be used to decrease ⁇ levels of a subject or to decrease accumulation of ⁇ in the brain of subject.
  • the beta amyloid is Abeta-42.
  • Examples of neurodegenerative diseases and disorders, and diseases and disorders associated with an abnormal BBB (e.g., permeable BBB) which may be treated by the methods of the invention include those disclosed in U.S. Patent Application Publication No. 2008/0279846 and WO2008/140449 , which are incorporated by reference herein.
  • the disease or disorder is a metabolic bone disease or disorder.
  • exemplary metabolic bone diseases/disorders include diseases/disorders associated with loss of bone mass and density including, but not limited to, osteoporosis and osteopenic related diseases (e.g., bone marrow abnormalities, dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases).
  • osteoporosis and osteopenic related diseases e.g., bone marrow abnormalities, dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism and related diseases.
  • Examples of metabolic bone diseases and disorders which may be treated by the methods of the invention include those disclosed in WO2008/140450 and US20080280829 , which are incorporated by reference herein.
  • the disease or disorder is a skin ulcer.
  • skin ulcers which may be treated by the methods of the invention include those disclosed in WO2008/141176 and US2010/0239565 , which are incorporated herein by reference.
  • the disease or disorder is associated with macrophage polarization, for example, M1/M2 macrophage polarization.
  • Exemplary diseases associated with macrophage polarization include, but are not limited to, liver cirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis (ALS) and other autoimmune diseases that are associated with macrophage polarization.
  • ALS amyotrophic lateral sclerosis
  • Treatment is intended to mean at least the mitigation of a disease or disorder in a subject.
  • the methods of treatment for mitigation of a disease or disorder include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy, improvement or cure of a disease or disorder.
  • treatment may involve at least the mitigation of one or more symptoms of a disease or disorder.
  • Treatment may involve: (1) to amelioration of the disease/disorder or one or more of the biological manifestations of the disease/disorder, (2) interference with (a) one or more points in the biological cascade that leads to or is responsible for the or (b) one or more of the biological manifestations of the disease/disorder, (3) alleviation one or more of the symptoms or effects associated with the disease/disorder, (4) slowing the progression of the disease/disorder or one or more of the biological manifestations of the disease/disorder, and/or (5) diminishing the likelihood of severity of a disease/disorder or biological manifestations of the disease/disorder.
  • treat includes “prevent”, “preventing” or “treatment” includes “prevent”, “preventing” or
  • prevention means the prophylactic administration of a drug to diminish the likelihood of the onset of or to delay the onset of a disease disorder or biological manifestation thereof, including administration to a subject at risk of having a disease or disorder.
  • a “therapeutically effective amount” is intended to mean that amount of a compound that, when administered to a subject in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof is a quantity of such agent that, when administered to a subject (e.g., human) in need thereof, is sufficient to modulate or inhibit the activity of Lp-PLA 2 such that a disease/disorder condition which is mediated or inhibited by that activity is reduced, alleviated or prevented.
  • the amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (plC 50 ) and the biological half-life of the particular compound), disease/disorder condition and its severity, and the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • the particular compound e.g., the potency (plC 50 ) and the biological half-life of the particular compound
  • disease/disorder condition and its severity e.g., age, size and weight
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the patient in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease/disorder and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • a therapeutically effective amount of a compound of the invention for the treatment of a disease or disorder described herein will generally be in the range of 0.1 to 100 mg/kg body weight of recipient per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or in a number of sub-daily doses per day as such as two, three, four, five or six doses per day.
  • the dosing can be done intermittently, such as once every other day, once a week, once a month, or frequencies therebetween.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal
  • Oral administration includes enteral (digestive tract) and buccal or sublingual administration. Parenteral
  • administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion into tissue or blood.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • Compounds of the invention may also be administered intradermal ⁇ or through transdermal implants.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, four or more times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the disease or disorder being treated, the severity of the disease or disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. In some embodiments, total daily dosages range from 1 mg to 2000 mg, e.g., total daily dosages may range from 1 mg to 250 mg.
  • the methods of the invention including methods of treating herein described may be achieved using a compound of this invention as a monotherapy, or in dual or multiple
  • Combination therapy includes administration of the therapeutic agents in separate dosage forms or together in a single dosage form. Combination therapy may involve
  • combination therapy will involve administration of each agent such that therapeutically effective amounts of each agent are present in the subject's body in at least an overlapping period.
  • the other therapeutic agent(s) used in combination therapy with a compound of the invention may be administered in therapeutically effective amounts, e.g., as is known in the art, or lesser or greater amounts than known in the art provided that the amount administered is therapeutically effective.
  • treatment can involve combination with other existing modes of treatment, e.g. existing agents and procedures for treatment of ocular diseases or disorders, such as anti VEGF therapeutics (e.g. Lucentis ® , Avastin ® and Aflibercept ® ),steroids, e.g., triamcinolone, and steroid implants containing fluocinolone acetonide, retinal focal laser photocoagulation, and pan-retinal photocoagulation,.
  • VEGF therapeutics e.g. Lucentis ® , Avastin ® and Aflibercept ®
  • steroids e.g., triamcinolone
  • steroid implants containing fluocinolone acetonide
  • retinal focal laser photocoagulation e.g., and pan-retinal photocoagulation
  • combination therapy may include treatment with one or more therapeutic actives for treating atherosclerosis, cardiovascular disease or coronary heart disease.
  • the compounds of the present invention may be used to treat the disease or disorder described herein in combination with an anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal, anti-inflammatory, or anti-hypertension agent or an agent for lowering Lipoprotein (a) (Lp(a)).
  • agents include, but are not limited to, cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitizers, calcium channel antagonists, and anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs).
  • agents for lowering Lp(a) include aminophosphonates, e.g. those described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312.
  • the compounds of the present invention may be used with one or more statins, e.g., atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin.
  • the compounds of the present invention may be used with an anti-diabetic agent or an insulin sensitizer.
  • a compound of the present invention may be used with a PPA gamma activator, for instance GI262570 (GlaxoSmithKline) and a compound from the glitazone class such as rosiglitazone, troglitazone and pioglitazone.
  • a PPA gamma activator for instance GI262570 (GlaxoSmithKline) and a compound from the glitazone class such as rosiglitazone, troglitazone and pioglitazone.
  • the other therapeutic agent is useful in treating a
  • the present invention provides methods of slowing or delaying the progression of cognitive and/or function decline in patients with Alzheimer's disease, e.g. mild or moderate Alzheimer's disease, cerebrovascular (CVD) disease, and/or similar disease.
  • the compounds of the present invention may be used as an adjunct to an agent that is used to provide symptomatic treatment to patients with such diseases.
  • the subject may be treated with other agents targeting Alzheimer's disease such as memantine, ARICEPT' or donepezil, COGNEX * or tacrine, EXELON * or rivastigmine, REMINYL * or galantamine, anti-amyloid vaccine, Abeta-lowering therapies, mental exercise or stimulation.
  • agents targeting Alzheimer's disease such as memantine, ARICEPT' or donepezil, COGNEX * or tacrine, EXELON * or rivastigmine, REMINYL * or galantamine, anti-amyloid vaccine, Abeta-lowering therapies, mental exercise or stimulation.
  • the additional therapeutic agent(s) is used in the treatment of skin ulcers, for example, anti-microbial therapy, anti-parasitic therapy, anti-obesity therapy, diabetes therapy, cardiovascular disease therapy, renal failure therapy, vasculitis therapy, venous insufficiency therapy, arterial insufficiency therapy, cancer therapy, immunosuppressant therapy, immunodeficiency therapy, steroid therapy, burn therapy, standard wound-care management, and/or bioengineered skin substitutes.
  • skin ulcers for example, anti-microbial therapy, anti-parasitic therapy, anti-obesity therapy, diabetes therapy, cardiovascular disease therapy, renal failure therapy, vasculitis therapy, venous insufficiency therapy, arterial insufficiency therapy, cancer therapy, immunosuppressant therapy, immunodeficiency therapy, steroid therapy, burn therapy, standard wound-care management, and/or bioengineered skin substitutes.
  • the additional therapeutic agent(s) is used in the treatment of metabolic bone diseases or disorders.
  • the metabolic bone disease is osteoporosis
  • additional therapeutic agent(s) such as bisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene), a selective estrogen modulator (SERM), estrogen therapy, hormone replacement therapy (ET/HRT) and teriparatide may be used.
  • bisphosphates e.g., alendronate, ibandromate, risedronate, calcitonin, raloxifene
  • SERM selective estrogen modulator
  • E/HRT hormone replacement therapy
  • teriparatide teriparatide
  • the compounds of the invention will be normally, but not necessarily, formulated into a pharmaceutical composition prior to administration to a subject. Accordingly, the invention is also directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl- lH,2H,3H,5H-imidazolidino[l,2-c]pyrimidin-5-one, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • 7-( ⁇ 3,5-difluoro- 4-[(6-methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H-imidazolidino[l,2- c]pyrimidin-5-one comprises crystalline anhydrous 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3- yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H-imidazolidino[l,2-c]pyrimidin-5-one characterized by having an XRPD pattern substantially in accordance with the XRPD pattern of Figure 1.
  • 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)- l,2,2-trimethyl-lH,2H,3H,5H-imidazolidino[l,2-c]pyrimidin-5-one comprises crystalline anhydrous 7-( ⁇ 3,5-difluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl ⁇ methoxy)-l,2,2-trimethyl-lH,2H,3H,5H- imidazolidino[l,2-c]pyrimidin-5-one characterized by having diffraction angles (expressed in °2 ⁇ ) obtained from a XRPD pattern at least at positions of about 6.4, 9.2, 9.9, 12.2, 13.1, 14.1, 14.4, 15.7, 16.2, 16.6, 18.6, 22.7, and 23.4 (in some embodiments, ⁇ 0.1 degrees with respect to each of the foregoing particular peaks), e.g.
  • the pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the subject such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (particularly, a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • the pharmaceutical compositions may contain from 0.1 mg to 1000 mg (e.g., 0.1 - 500 mg, 0.1 - 250 mg, or 0.1 - 100 mg) of a compound of this invention.
  • the pharmaceutical compositions contain from 1 mg to 1000 mg (e.g., 1 - 500 mg, 1 - 250, or 1 - 100 mg) of a compound of the invention.
  • Unit dosage form pharmaceutical compositions containing from 0.1 to 1000 mg of a compound of the invention may be administered one, two, three, four or more times per day, preferably one, two or three times per day, and more preferably one or two times a day, to effect treatment of an Lp-PLA 2 -mediated disease or disorder, e.g., as described herein.
  • the pharmaceutical composition may include one or more compounds of the invention and/or one or more pharmaceutically acceptable excipients.
  • the pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition or vehicle other than the active pharmaceutical ingredient(s) intended for treating a disease or disorder (e.g., a compound of the invention).
  • Pharmaceutically acceptable excipients are involved in providing a property or function useful to a pharmaceutical composition, for example an excipient may be involved in modifying physical, sensory, stability, or pharmaco-kinetic properties of the composition, for example in giving form or consistency to the composition, in bulking up the active ingredient (e.g. for convenient and accurate
  • each excipient will be involved in giving form or consistency to the composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention (or any other active ingredient, if present) when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
  • the compounds of the invention and the pharmaceutically acceptable excipient(s) will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms include those adapted for (1) oral administration (including buccal or sublingual) such as tablets, capsules, caplets, pills, lozenges, troches, powders, granules, syrups, elixirs, suspensions, solutions, edible foams or whips, emulsions, sachets, and cachets; (2) parenteral administration (including subcutaneous, intramuscular, intravenous or intradermal) such as sterile solutions, suspensions, lyophiles, microparticles, nanocarriers, implants, preformed implants and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions and solutions; and (6) topical administration such as creams, ointments, lotions
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain
  • pharmaceutically acceptable excipients may be chosen for their ability to: facilitate the production of uniform dosage forms, to facilitate the production of stable dosage forms, to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the subject from one organ, or portion of the body, to another organ, or portion of the body, and/or to enhance subject compliance.
  • 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-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, carriers, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press), including current and past editions.
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention provides a method of preparing a pharmaceutical composition
  • a method of preparing a pharmaceutical composition comprising the step of admixing a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients.
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a diluent or filler, and optionally a binder, disintegrant, and/or lubricant.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • Suitable binders include starch (e.g.
  • Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

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Abstract

La présente invention concerne de nouveaux composés qui inhibent l'activité de la Lp-PLA2, des procédés pour les préparer, des compositions les contenant, et leur utilisation pour le traitement maladies ou de troubles associés à l'activité de la Lp-PLA2.
PCT/IB2015/055403 2014-07-22 2015-07-16 Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2 WO2016012916A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112574221A (zh) * 2019-09-30 2021-03-30 上海纽思克生物科技有限公司 四环嘧啶酮类化合物、其制备方法、其组合物和用途
CN112778331A (zh) * 2019-11-09 2021-05-11 上海赛默罗生物科技有限公司 三环二氢咪唑并嘧啶酮衍生物、其制备方法、药物组合物和用途
CN113861220A (zh) * 2020-06-30 2021-12-31 上海纽思克生物科技有限公司 三环嘧啶酮类化合物、其制备方法、其组合物和用途
WO2022007810A1 (fr) * 2020-07-10 2022-01-13 上海纽思克生物科技有限公司 Composé de pyrimidinone tricyclique, son procédé de préparation, et composition et utilisation de celui-ci
WO2024027116A1 (fr) * 2022-08-04 2024-02-08 4B Technologies (Beijing) Co., Limited Composés de dihydroimidazo-pyrimidinone utiles en tant qu'inhibiteurs de lp-pla2 et leur utilisation
RU2820903C1 (ru) * 2020-06-30 2024-06-11 Неуско Биотек Лимитед Получение и применение трициклического пиримидинонового соединения и его композиции

Citations (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013484A1 (fr) 1994-10-29 1996-05-09 Smithkline Beecham Plc Derives d'azetidinone destines au traitement de l'atherosclerose
WO1996019451A1 (fr) 1994-12-22 1996-06-27 Smithkline Beecham Plc Azetidin-2-ones substituees, destinees au traitement de l'atherosclerose
WO1997002242A1 (fr) 1995-07-01 1997-01-23 Smithkline Beecham Plc Derives de l'azetidinone pour le traitement de l'atherosclerose
WO1997002037A1 (fr) 1995-06-30 1997-01-23 Symphar S.A. Composes et compositions pharmaceutiques les contenant
WO1997012963A2 (fr) 1995-09-29 1997-04-10 Smithkline Beecham Plc Paf-acetylhydrolase paf et son utilisation en therapie
WO1997021676A1 (fr) 1995-12-08 1997-06-19 Smithkline Beecham Plc Composes azetidinone destines au traitement de l'atherosclerose
WO1997021675A1 (fr) 1995-12-08 1997-06-19 Smithkline Beecham Plc Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose
WO1997041099A1 (fr) 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives d'azetidinone pour le traitement de l'atherosclerose
WO1997041098A1 (fr) 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives azetidinones destines au traitement de l'atherosclerose
WO1998028312A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques de l'acide aminophosphonique
WO1998028310A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques d'acide aminophosphonique
WO1998028311A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques d'acide aminophosphonique
WO1999024420A1 (fr) 1997-11-06 1999-05-20 Smithkline Beecham Plc Composes de pyrimidinone et compositions pharmaceutiques les renfermant
WO2000010980A1 (fr) 1998-08-21 2000-03-02 Smithkline Beecham Plc Derives de pyrimidinone destines au traitement de l'atherosclerose
WO2000066567A1 (fr) 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2000066566A1 (fr) 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes de pyrimidine
WO2000068208A1 (fr) 1999-05-05 2000-11-16 Smithkline Beecham Plc Derives pyrimidinones destines au traitement de l'atherosclerose
JP2001088847A (ja) 1999-09-22 2001-04-03 Toppan Printing Co Ltd 再封可能な開口維持部材付パウチ
WO2001060805A1 (fr) 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Derives de pyrimidine-4-one utilises comme inhibiteurs de ldl-pla¿2?
WO2002030911A1 (fr) 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives de pyrimidinone et leur utilisation dans le traitement de l'atherosclerose
WO2002030904A1 (fr) 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives pyridinone permettant de traiter l'atherosclerose
WO2003016287A2 (fr) 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Nouveaux procedes
WO2003015786A1 (fr) 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose
WO2003041712A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives de pyridone, pyridazone et triazone en tant qu'inhibiteurs de lp-pla2
WO2003042179A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives heterocycliques de glycinamide et leur utilisation medicale
WO2003042206A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Composes pyridinone et pyrimidinone
WO2003042218A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives condenses de pyrimidone en tant qu'inhibiteurs de lp-pla2 pour le traitement de l'atherosclerose
WO2003086400A1 (fr) 2002-04-10 2003-10-23 Glaxo Group Limited Derives de pyridinone et de pyrimidinone substitues en n a utiliser en tant qu'inhibiteurs de lp-pla2 dans le traitement de l'atherosclerose
WO2003087088A2 (fr) 2002-04-10 2003-10-23 Glaxo Group Limited Nouveaux composes
WO2005003118A1 (fr) 2003-07-02 2005-01-13 Bayer Healthcare Ag 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques
WO2006063813A2 (fr) 2004-12-18 2006-06-22 Bayer Healthcare Ag 1,2,4-triazone-5(2h)-ones substituees par 3-arylalkyle et 3-heteroarylalkyle
WO2006063811A2 (fr) 2004-12-18 2006-06-22 Bayer Healthcare Ag 1,2,4-triazin-5(2h)-ones substituees
US20080090852A1 (en) 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
US20080090851A1 (en) 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
WO2008048867A2 (fr) 2006-10-13 2008-04-24 Glaxo Group Limited Composés hétoroaromatiques bicycliques
WO2008048866A2 (fr) 2006-10-13 2008-04-24 Glaxo Group Limited Composés hétéroaromatiques bicycliques
US20080280829A1 (en) 2007-05-11 2008-11-13 Thomas Jefferson University Methods of treatment and prevention of metabolic bone diseases and disorders
US20080279846A1 (en) 2007-05-11 2008-11-13 Thomas Jefferson University Methods of treatment and prevention of neurodegenerative diseases and disorders
WO2008140450A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles osseux métaboliques
WO2008141176A1 (fr) 2007-05-11 2008-11-20 The Trustees Of The University Of Pennsylvania Procédés de traitement des ulcères de la peau
WO2008140449A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles neurodégénératifs
WO2012076435A1 (fr) 2010-12-06 2012-06-14 Glaxo Group Limited Composés de pyrimidinone utiles dans le traitement de maladies ou d'états pathologiques induits par la lp-pla2
WO2012080497A2 (fr) 2010-12-17 2012-06-21 Glaxo Group Limited Procédés de traitement et de prévention de maladies oculaires
WO2013014185A1 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Composés pyrimidones bicycliques
WO2013013503A1 (fr) * 2011-07-27 2013-01-31 Glaxo Group Limited Composés 2,3-dihydroimidazo[1,2-c]pyrimidin-5(1h)-one et utilisation en tant qu'inhibiteurs de lp-pla2
WO2014114694A1 (fr) * 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la phospholipase associée aux lipoprotéines a2 (lp-pla2) à base de 2,3-dihydro-imidazol[1,2-c]pyrimidin-5(1 h)-one

Patent Citations (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013484A1 (fr) 1994-10-29 1996-05-09 Smithkline Beecham Plc Derives d'azetidinone destines au traitement de l'atherosclerose
WO1996019451A1 (fr) 1994-12-22 1996-06-27 Smithkline Beecham Plc Azetidin-2-ones substituees, destinees au traitement de l'atherosclerose
WO1997002037A1 (fr) 1995-06-30 1997-01-23 Symphar S.A. Composes et compositions pharmaceutiques les contenant
WO1997002242A1 (fr) 1995-07-01 1997-01-23 Smithkline Beecham Plc Derives de l'azetidinone pour le traitement de l'atherosclerose
WO1997012963A2 (fr) 1995-09-29 1997-04-10 Smithkline Beecham Plc Paf-acetylhydrolase paf et son utilisation en therapie
WO1997021676A1 (fr) 1995-12-08 1997-06-19 Smithkline Beecham Plc Composes azetidinone destines au traitement de l'atherosclerose
WO1997021675A1 (fr) 1995-12-08 1997-06-19 Smithkline Beecham Plc Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose
WO1997041099A1 (fr) 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives d'azetidinone pour le traitement de l'atherosclerose
WO1997041098A1 (fr) 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives azetidinones destines au traitement de l'atherosclerose
WO1998028310A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques d'acide aminophosphonique
WO1998028312A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques de l'acide aminophosphonique
WO1998028311A1 (fr) 1996-12-20 1998-07-02 Symphar S.A. Derives pharmaceutiques d'acide aminophosphonique
WO1999024420A1 (fr) 1997-11-06 1999-05-20 Smithkline Beecham Plc Composes de pyrimidinone et compositions pharmaceutiques les renfermant
WO2000010980A1 (fr) 1998-08-21 2000-03-02 Smithkline Beecham Plc Derives de pyrimidinone destines au traitement de l'atherosclerose
WO2000066567A1 (fr) 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2000066566A1 (fr) 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes de pyrimidine
WO2000068208A1 (fr) 1999-05-05 2000-11-16 Smithkline Beecham Plc Derives pyrimidinones destines au traitement de l'atherosclerose
JP2001088847A (ja) 1999-09-22 2001-04-03 Toppan Printing Co Ltd 再封可能な開口維持部材付パウチ
WO2001060805A1 (fr) 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Derives de pyrimidine-4-one utilises comme inhibiteurs de ldl-pla¿2?
WO2002030911A1 (fr) 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives de pyrimidinone et leur utilisation dans le traitement de l'atherosclerose
WO2002030904A1 (fr) 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives pyridinone permettant de traiter l'atherosclerose
WO2003016287A2 (fr) 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Nouveaux procedes
WO2003015786A1 (fr) 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose
WO2003042179A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives heterocycliques de glycinamide et leur utilisation medicale
WO2003041712A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives de pyridone, pyridazone et triazone en tant qu'inhibiteurs de lp-pla2
WO2003042206A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Composes pyridinone et pyrimidinone
WO2003042218A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives condenses de pyrimidone en tant qu'inhibiteurs de lp-pla2 pour le traitement de l'atherosclerose
WO2003086400A1 (fr) 2002-04-10 2003-10-23 Glaxo Group Limited Derives de pyridinone et de pyrimidinone substitues en n a utiliser en tant qu'inhibiteurs de lp-pla2 dans le traitement de l'atherosclerose
WO2003087088A2 (fr) 2002-04-10 2003-10-23 Glaxo Group Limited Nouveaux composes
WO2005003118A1 (fr) 2003-07-02 2005-01-13 Bayer Healthcare Ag 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques
CA2530816A1 (fr) 2003-07-02 2005-01-13 Bayer Healthcare Ag 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques
WO2006063813A2 (fr) 2004-12-18 2006-06-22 Bayer Healthcare Ag 1,2,4-triazone-5(2h)-ones substituees par 3-arylalkyle et 3-heteroarylalkyle
WO2006063811A2 (fr) 2004-12-18 2006-06-22 Bayer Healthcare Ag 1,2,4-triazin-5(2h)-ones substituees
WO2008048866A2 (fr) 2006-10-13 2008-04-24 Glaxo Group Limited Composés hétéroaromatiques bicycliques
US20080090851A1 (en) 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
WO2008048867A2 (fr) 2006-10-13 2008-04-24 Glaxo Group Limited Composés hétoroaromatiques bicycliques
US20080090852A1 (en) 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
US20080103156A1 (en) 2006-10-13 2008-05-01 Leach Colin A Bicyclic Heteroaromatic Compounds
WO2008140450A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles osseux métaboliques
US20080279846A1 (en) 2007-05-11 2008-11-13 Thomas Jefferson University Methods of treatment and prevention of neurodegenerative diseases and disorders
US20080280829A1 (en) 2007-05-11 2008-11-13 Thomas Jefferson University Methods of treatment and prevention of metabolic bone diseases and disorders
WO2008141176A1 (fr) 2007-05-11 2008-11-20 The Trustees Of The University Of Pennsylvania Procédés de traitement des ulcères de la peau
WO2008140449A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles neurodégénératifs
US20100239565A1 (en) 2007-05-11 2010-09-23 The Trustees Of The University Of Pennsylvania Methods of treatment of skin ulcers
WO2012076435A1 (fr) 2010-12-06 2012-06-14 Glaxo Group Limited Composés de pyrimidinone utiles dans le traitement de maladies ou d'états pathologiques induits par la lp-pla2
WO2012080497A2 (fr) 2010-12-17 2012-06-21 Glaxo Group Limited Procédés de traitement et de prévention de maladies oculaires
WO2013014185A1 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Composés pyrimidones bicycliques
WO2013013503A1 (fr) * 2011-07-27 2013-01-31 Glaxo Group Limited Composés 2,3-dihydroimidazo[1,2-c]pyrimidin-5(1h)-one et utilisation en tant qu'inhibiteurs de lp-pla2
WO2014114694A1 (fr) * 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la phospholipase associée aux lipoprotéines a2 (lp-pla2) à base de 2,3-dihydro-imidazol[1,2-c]pyrimidin-5(1 h)-one

Non-Patent Citations (34)

* Cited by examiner, † Cited by third party
Title
"Effect of Darapladib on Prevention of Ischemic Events in Stable Coronary Heart Disease", N ENGL J MED., vol. 370, no. 18, 2014, pages 1702 - 1711
"Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies", LANCET, vol. 375, 2010, pages 1536 - 1544
"The Handbook of Pharmaceutical Additives", GOWER PUBLISHING LIMITED
"The Handbook of Pharmaceutical Excipients", THE AMERICAN PHARMACEUTICAL ASSOCIATION AND THE PHARMACEUTICAL PRESS
ACHARYA NK ET AL.: "Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib", J ALZHEIMERS DIS., vol. 35, no. 1, 2013, pages 179 - 98
BUSCHINI ET AL., PROGRESS IN NEUROBIOLOGY, vol. 95, 2011, pages 14 - 25
CHINETTI-GBAGUIDI, G. ET AL.: "Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARy and LXRa pathways", CIRCULATION RESEARCH, vol. 108, 2011, pages 985 - 995
COLANGELO ET AL., JOURNAL OF NEUROSCIENCE RESEARCH, vol. 70, 2002, pages 462 - 473
DILDAR ET AL., ALZHEIMER DIS ASSOC DISORD, vol. 24, April 2010 (2010-04-01)
FERGUSON, J. F. ET AL.: "Translational studies of lipoprotein-associated phospholipase A2 in inflammation and atherosclerosis", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 59, 2012, pages 764 - 772
GARZA CA ET AL.: "Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review", MAYO CLIN PROC, vol. 82, 2007, pages 159 - 165
GONÇALVES, I. ET AL.: "Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation", ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, vol. 32, 2012, pages 1505 - 1512
HERRMANN, J. ET AL.: "Expression of lipoprotein-associated phospholipase A2 in carotid artery plaques predicts long-term cardiac outcome", EUROPEAN HEARTJOURNAL, vol. 30, 2009, pages 2930 - 2938
JOHNSON JL ET AL.: "Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial", PLOS ONE, vol. 9, no. 2, 20 February 2014 (2014-02-20), pages E89034
KASSNER ET AL., CURRENT ALZHEIMER RESEARCH, vol. 5, 2008, pages 358 - 366
KOLODGIE FD ET AL.: "Lipoproteinassociated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis", ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, vol. 26, 2006, pages 2523 - 9
MACPHEE CH ET AL.: "Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates the oxidation of low-density lipoprotein: use of a novel inhibitor", BIOCHEM J, vol. 338, 1999, pages 479 - 87
MACPHEE CH ET AL.: "Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target", CURRENT OPINION IN PHARMACOLOGY, vol. 6, 2006, pages 154 - 161
MANNHEIM D. ET AL.: "Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques", STROKE, vol. 39, 2008, pages 1448 - 55
MOHLER ER III ET AL.: "The Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity and Cardiovascular Biomarkers in Patients With Stable Coronary Heart Disease or Coronary Heart Disease Risk Equivalent: The Results of a Multicenter, Randomized Double-Blind, Placebo-Controlled Study", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 51, 2008, pages 1632 - 1641
P.J.KOCIENSKI: "Protecting Groups", 1994, GEORG THIEME VERLAG
PERRY, ACTA NEUROPATHOL,, vol. 120, 2010, pages 277 - 286
SERRUYS PW ET AL.: "Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque", CIRCULATION, vol. 118, 2008, pages 1172 - 1182
SHI ET AL., ATHEROSCLEROSIS, vol. 191, 2007, pages 54 - 62
SINEM ET AL., CURRENT ALZHEIMER RESEARCH, vol. 7, 2010, pages 463 - 469
T.W. GREEN; P.G.M WUTS: "Protective groups in organic synthesis", 1991, WILEY & SONS
TEZEL, PROGRESS IN BRAIN RESEARCH, vol. 173
VAN OIJEN ET AL.: "Annals of Neurology", vol. 59, 2006, pages: 139
WILENSKY ET AL., CURRENT OPINION IN LIPIDOLOGY, vol. 20, 2009, pages 415 - 420
WILENSKY ET AL., NATURE MEDICINE, vol. 10, 2008, pages 1015 - 1016
WILENSKY RL ET AL.: "Inhibition of lipoproteinassociated phospholipase A2 reduces complex coronary atherosclerotic plaque development", NATURE MEDICINE, 21 September 2008 (2008-09-21)
WYSS-CORAY, NATURE MEDICINE, vol. 12, September 2006 (2006-09-01)
ZALEWSKI A ET AL., ARTERIOSCLER. THROMB. VASC. BIOL., vol. 25, no. 5, 2005, pages 923 - 31
ZALEWSKI A ET AL.: "Role of lipoprotein-associated phospholipase A2 in atherosclerosis", ARTERIOSCLER THROMB VASC BIOL, vol. 25, 2005, pages 923 - 31

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CN112574221B (zh) * 2019-09-30 2022-03-04 上海纽思克生物科技有限公司 四环嘧啶酮类化合物、其制备方法、其组合物和用途
CN112778331A (zh) * 2019-11-09 2021-05-11 上海赛默罗生物科技有限公司 三环二氢咪唑并嘧啶酮衍生物、其制备方法、药物组合物和用途
WO2021089032A1 (fr) * 2019-11-09 2021-05-14 上海赛默罗生物科技有限公司 Dérivé de dihydroimidazopyrimidone tricyclique, son procédé de préparation, composition pharmaceutique et son utilisation
CN114805389A (zh) * 2019-11-09 2022-07-29 上海赛默罗生物科技有限公司 三环二氢咪唑并嘧啶酮衍生物、其制备方法、药物组合物和用途
CN114805389B (zh) * 2019-11-09 2023-08-29 上海赛默罗生物科技有限公司 三环二氢咪唑并嘧啶酮衍生物、其制备方法、药物组合物和用途
CN113861220A (zh) * 2020-06-30 2021-12-31 上海纽思克生物科技有限公司 三环嘧啶酮类化合物、其制备方法、其组合物和用途
WO2022001881A1 (fr) * 2020-06-30 2022-01-06 上海纽思克生物科技有限公司 Composé de pyrimidinone tricyclique, son procédé de préparation et sa composition ainsi que son utilisation
AU2021301865B2 (en) * 2020-06-30 2023-12-14 Neusco Biotech Limited Tricyclic pyrimidinone compound, preparation method therefor, and composition and use thereof
RU2820903C1 (ru) * 2020-06-30 2024-06-11 Неуско Биотек Лимитед Получение и применение трициклического пиримидинонового соединения и его композиции
WO2022007810A1 (fr) * 2020-07-10 2022-01-13 上海纽思克生物科技有限公司 Composé de pyrimidinone tricyclique, son procédé de préparation, et composition et utilisation de celui-ci
WO2024027116A1 (fr) * 2022-08-04 2024-02-08 4B Technologies (Beijing) Co., Limited Composés de dihydroimidazo-pyrimidinone utiles en tant qu'inhibiteurs de lp-pla2 et leur utilisation

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