WO2016012916A1 - 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 - Google Patents

1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by 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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French (fr)
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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.

Abstract

The present invention relates to novel compounds that inhibit Lp‐PLA2 activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases or disorders associated with the activity of Lp‐PLA2.

Description

1 ,2,3,5-TETRAHYDROIMIDAZO[1 ,2-C]PYRIMIDINE DERIVATIVES USEFUL IN THE TREATMENT OF DISEASES AND
DISORDERS MEDIATED BY LP-PLA2
FIELD OF THE INVENTION
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-PLA2.
BACKGROUND OF THE INVENTION
Lipoprotein-associated phospholipase A2 (Lp-PLA2) previously known as platelet-activating factor acetylhydrolase (PAF-AH), is a phospholipase A2 enzyme involved in hydrolysis of lipoprotein lipids or phospholipids. Lp-PLA2 travels with low-density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules derived from the oxidation of LDL. (See e.g., Zalewski A, et al., Arterioscler. Thromb. Vase. Biol., 25, 5, 923-31 (2005)). Lp-PLA2 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)).
A number of Lp-PLA2 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,
WO03/015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/87088, WO08/048867, US 2008/0103156, US 2008/0090851, US
2008/0090852, and WO08/048866. Disclosed uses include treating disease that involves or is associated with endothelial dysfunction, disease that involves lipid oxidation in conjunction with Lp-PLA2 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. Examples of disclosed 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-PLA2 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-PLA2 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" Biochem J 1999; 338: 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 2006, 6: 154-161; Zalewski A, et al. "Role of lipoprotein-associated phospholipase A2 in atherosclerosis" Arterioscler Thromb Vase Biol 2005; 25: 923-31. For example, research data has indicated that 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)).
In addition, products of 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. (2008) "Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques" Stroke 39:1448-55; Herrmann, J., et al. (2009) "Expression of lipoprotein-associated phospholipase A2 in carotid artery plaques predicts long-term cardiac outcome" European Heart Journal, 30: 2930-2938; and Gongalves, I., et al. (2012) "Evidence supporting a key role of Lp-PLA2-generated
lysophosphatidylcholine in human atherosclerotic plaque inflammation" Arteriosclerosis, Thrombosis, and Vascular Biology, 32: 1505-1512. For example, the effect of Lp-PLA2 inhibitors on atherosclerotic plaque composition was demonstrated in a diabetic and hypercholesterolemic porcine model of accelerated coronary atherosclerosis. (See e.g., Wilensky et al., Nature Medicine, 10, 1015-1016 (2008)).
Other research indicates an association between circulating Lp-PLA2 and risk of coronary heart disease. See e.g., Garza CA, et al. "Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review" Mayo Clin Proc 2007; 82: 159- 165); and The Lp-PLA2 Studies Collaboration "Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies" Lancet. 2010;375:1536-1544.
These research results provided further evidence that Lp-PLA2 inhibitors may be useful to treat atherosclerosis and diseases associated with atherosclerosis.
Clinical studies relating to use of Lp-PLA2 inhibitors in atherosclerosis-related disease have also been reported. See e.g. The STABILITY Investigators "Effect of Darapladib on Prevention of Ischemic Events in Stable Coronary Heart Disease" N Engl J Med.2014; 370(18):1702-1711 (see further, Clinicaltrials.gov Identifier NCT00799903 re study LPL100601); Serruys PW, et al. for the Integrated Biomarker and Imaging Study-2 Investigators "Effects of the Direct Lipoprotein- Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque" Circulation 2008;118:1172-1182 (see further, Clinicaltrials.gov Identifier NCT00268996 re study SB-480848/026); Mohler ER III, et al., for the Darapladib Investigators "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 2008; 51; 1632-1641 (see further, Clinicaltrials.gov Identifier NCT00269048 re study LPL104884); Johnson JL, et al. "Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial" PLoS One, 2014 Feb 20; 9(2):e89034. Doi: 10.1371/journal.pone.0089034.
Additional studies indicate that high Lp-PLA2 activity is associated with high risk of dementia, including Alzheimer's disease (AD) (See e.g., Van Oijen, et al. Annals of Neurology, 59,139 (2006)). Higher levels of 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
(2010)). Further, studies show that neuroinflammation is present in AD patients and multiple cytotoxic inflammatory cytokines are up-regulated in AD patients. (See e.g., Colangelo, et al., Journal of Neuroscience Research, 70, 462-473 (2002); Wyss-Coray, Nature Medicine, 12, Sept. (2006)). Research has shown that LysoPC function is a pro-inflammatory factor inducing multiple cytotoxic inflammatory cytokine release (See Shi, et al. Atherosclerosis, 191, 54-62 (2007)). Therefore, these studies provide additional evidence that inhibitors of Lp-PLA2 may be useful to treat AD by inhibiting activity of Lp-PLA2 and reducing lysoPC production.
In addition, use of an Lp-PLA2 inhibitor in a diabetic and hypercholesterolemia swine model demonstrated that blood-brain-barrier leakage and brain amyloid beta protein (Αβ) burden, the pathological hallmarks of Alzheimer's disease, were reduced. See e.g., 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. 2013; 35(l):179-98. Doi: 10.3233/JAD-122254. See also U.S. Patent Application Publication No.
2008/0279846 and WO 2008/140449, which describes several uses of Lp-PLA2 inhibitors for treating neurodegenerative diseases, e.g., associated with blood-brain-barrier leakage, including, e.g., Alzheimer's disease and vascular dementia.
Further, neuroinflammation, including multiple cytotoxic cytokine release, is a common feature of all neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc. (See e.g., Perry, Acta Neuropathol, 120, 277-286 (2010)). As discussed above, Lp-PLA2 inhibitors can reduce inflammation, for example, reducing multiple cytokine release by suppressing lysoPC production. (See e.g., Shi, et al.
Atherosclerosis 191, 54-62 (2007)). Thus, inhibiting Lp-PLA2 is a potential therapeutic treatment approach for neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc.
A clinical study relating to the effect of an Lp-PLA2 inhibitor on biomarkers related to
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.
In addition to the inflammatory effect, LysoPC has been implicated in leukocyte activation, induction of apoptosis and mediation of endothelial dysfunction (See, e.g., Wilensky et al., Current Opinion in Lipidology, 20, 415-420 (2009)). Therefore, it is believed that Lp-PLA2 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. In light of the inflammatory roles of Lp-PLA2 and the association between localized inflammatory processes and diabetic retinopathy, it is postulated that Lp-PLA2 can be used to treat diabetic ocular disease.
Glaucoma and age-related macular degeneration (AMD) are retina neurodegenerative diseases. Studies suggest that 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). Thus, considering Lp-PLA2 inhibitors' function of blocking inflammatory cytokine release (See e.g., Shi, et al. Atherosclerosis, 191, 54-62 (2007)), it is believed that Lp-PLA2 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. 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.
A clinical study relating to use of an Lp-PLA2 inhibitor in diabetic macular edema (DME) has also been reported. See e.g. http://www.gsk-clinicalstudyregister.eom/study/115403#rs, Clinicaltrials.gov Identifier NCT01506895, which describes study DM2115403. This study was a phase 2 randomized, double-masked, placebo-controlled, parallel-group study of repeat oral administration of 160 mg darapladib once daily for 3 months in adult subjects with DME with centre involvement. Subjects were randomized to receive darapladib:placebo in a 2:1 ratio, respectively. 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.
The potential beneficial effects of Lp-PLA2 inhibitors on diseases associated with macrophage polarization, e.g., M1/M2 macrophage polarization, has been described. See e.g. WO2012/076435 and WO2013/014185. These publications describe studies supporting the potential utility of 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.
WO2008/141176 and US2010/0239565 describe the use of Lp-PLA2 inhibitors for treating or preventing skin ulcers. WO2008/140450 and US20080280829 describe the use of Lp-PLA2 inhibitors for treating or preventing metabolic bone disorders, including e.g., bone marrow abnormalities, osteoporosis, and osteopenia.
In view of the number of pathological responses that are mediated by Lp-PLA2, attempts have been made to prepare compounds that inhibit its activity. Though a number of such compounds have been disclosed in the art, there remains a continuing need for inhibitors of Lp- PLA2 which can be used in the treatment of a variety of conditions.
SUMMARY OF THE INVENTION
In a first aspect, this invention relates to compounds of Formula (I) and salts thereof, including pharmaceutically acceptable salts thereof:
Figure imgf000007_0001
Formula (I)
wherein:
1 and R2 are independently CH3 or H;
R3 is H or C(i_3)alkyl; and R4 is
Figure imgf000008_0001
wherein
Ra is H or F,
Rb is -O-Y wherein Y is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are substituted with one CH3 substituent; and
Rc 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.
The invention also relates to methods of treating a disease or disorder associated with the activity of Lp-PLA2, 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).
This invention also provides methods of treating a disease or disorder by inhibiting Lp-
PLA2 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).
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. 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 retina;
diseases or disorders which involve and/or are associated with: (1) endothelial dysfunction (2) lipid oxidation in conjunction with enzyme activity, and/or (3) activated or increased involvement of monocytes, macrophages or lymphocytes, such as: 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;
neurodegenerative diseases or disorders, neurological diseases or disorders associated with an abnormal blood brain barrier (BBB) function (e.g. permeable BBB), inflammation, and/or microglia activation, diseases or disorders associated with blood brain barrier (BBB) leakage, and/or diseases or disorders associated with abnormal beta amyloid ("Αβ") accumulation in the brain, such as: 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;
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);
skin ulcers; and
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.
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 "Αβ") 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).
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.
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.
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. BRIEF DESCRIPTION OF THE DRAWINGS
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.
DETAILED DESCRIPTION OF THE INVENTION
Certain terms employed in the entire application (including the specification, examples, and appended claims) are defined herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used in the description of the embodiments of the invention and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, "and/or" refers to any and all possible combinations of one or more of the associated listed items. It will be further understood that the terms "comprises" and/or "comprising" when used in this specification, specify the presence of the associated listed items (e.g., the stated features, integers, steps, operations, elements, and/or components), but do not preclude the presence or addition of one or more other items.
All patents, patent applications and publications referred to herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification is controlling. This invention is directed, in a first aspect, to compounds of Formula I:
Figure imgf000011_0001
Formula (I)
wherein:
R1 and R2 are independently CH3 or H;
R3 is H or C(i_3)alkyl; and
R4 is
Figure imgf000011_0002
wherein
Ra is H or F,
Rb is -O-Y wherein Y is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl wherein pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are substituted with one CH3 substituent; and
Rc is F or CN;
and salts (e.g. pharmaceutically acceptable salts) thereof.
The alternative definitions for the various groups and substituent groups of Formula (I) provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group and substituent group definitions. The compounds of the invention are only those which are contemplated to be chemically stable as will be appreciated by those skilled in the art.
"Alkyl" refers to a monovalent, saturated, straight or branched hydrocarbon group having the specified number of carbon atoms. For example, 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. As used herein, "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. It should be understood that the term "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). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted.
The term "independently" means that where more than one substituent or group is selected from a number of possible substituents/groups, those substituents/groups may be the same or different.
In some embodiments of the compounds of the invention, 1 and R2 are each CH3.
In some embodiments of the compounds of the invention, R3 is H or CH3. In some embodiments, R3 is CH3.
In some embodiments of the compounds of the invention, Y of Rb is pyridinyl.
In some embodiments of the compounds of the invention, Y of Rb 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 CH3 substituent. In some embodiments, Y of Rb 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).
In some embodiments of the compounds of the invention, Ra is fluoro.
In some embodiments of the compounds of the invention, Rc is fluoro.
In some embodiments of the compounds of the invention, each of Ra and Rc is fluoro. In some embodiments of the compounds of the invention, Ra is fluoro and Rc is CN.
In some embodiments of the compounds of the invention, R1 and R2 are each CH3; R3 is H or CH3 (in more particular embodiments, CH3); Y of Rb 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 CH3 substituent; and Ra and/or Rc is fluoro (in more particular embodiments, Ra is fluoro and Rc is fluoro or CN). In some such embodiments, Y of Rb 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).
In some embodiments of the compounds of the invention, R1 and R2 are each CH3; R3 is H or CH3 (in more particular embodiments, CH3); Y of Rb is pyridinyl substituted by one CH3 substituent; and a and/or Rc is fluoro (in more particular embodiments, Ra is fluoro and Rc is fluoro or CN). In some such embodiments, Y of Rb 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. As used herein, 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. In some embodiments of the various aspects of the invention disclosed herein, the compound(s) of the invention is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in any physical form.
Accordingly, within the present invention are the compounds of Formula (I), as defined herein, in any salt or non-salt form and any physical form thereof, and mixtures of various forms. While such are included within the present invention, it will be understood that the compounds of Formula (I), as defined herein, in any salt or non-salt form, and in any physical form thereof, may have varying levels of activity, different bioavailabilities and different handling properties for formulation purposes.
It will be appreciated that the present invention encompasses compounds of Formula (I) as the free base and as salts thereof, for example as a pharmaceutically acceptable salt thereof. In one embodiment the invention relates to compounds of Formula (I) in the form of a free base. In another embodiment the invention relates to compounds of Formula (I) in the form of a salt, particularly, a pharmaceutically acceptable salt. It will be further appreciated that, in one embodiment, the invention relates to compounds of the Examples in the form of a free base. In another embodiment the invention relates to compounds of the Examples in the form of a salt, particularly, a pharmaceutically acceptable salt.
In particular embodiments, 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. Accordingly, 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). In another embodiment, 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). In some embodiments 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.
The skilled artisan will appreciate that 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. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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.
Because of their potential use in medicine, the salts and/or solvates of the compounds of Formula (I) are preferably pharmaceutically acceptable.
As used herein, the term "pharmaceutically acceptable" means a compound or other material (e.g. composition, dosage form) which is suitable for pharmaceutical (medicinal) use. For example, 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) which are suitable for use in medicine are those wherein 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 pKa 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. Examples of 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), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hippurate, hydrobromide, hydrochloride, hydroiodide, isobutyrate, lactate, lactobionate, laurate, maleate, malate, malonate, mandelate, methanesulfonate
(mesylate), naphthalene-l,5-disulfonate (napadisylate), naphthalene-sulfonate (napsylate), nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, phosphate, diphosphate, proprionate, pyroglutamate, salicylate, sebacate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate (tosylate; 4-methylbenzenesulfonate), undecylenate, l-hydroxy-2-naphthoate, 2,2-dichloroacetate, 2-hydroxyethanesulfonate (isethionate), 2-oxoglutarate, 4- acetamidobenzoate, and 4-aminosalicylate.
The compounds of this invention may contain an asymmetric center (also referred to as a chiral center), such as a chiral carbon. 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.
Individual 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. The skilled artisan will appreciate that where the desired
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. Alternatively, 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.
When a disclosed compound or its salt is named or depicted by structure, it is to be understood that 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.
In some embodiments, 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- imidazolidino[l,2-c]pyrimidin-5-one, characterized by having an XRPD pattern substantially in accordance with that of Figure 1 provided herein. In some embodiments, 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
characterized by having diffraction angles (expressed in °2Θ) 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.
It is well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining an XRPD pattern may cause some variability in the appearance, intensities, and positions of the lines in the diffraction pattern. 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. For example, 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. For example, 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. If the XRPD pattern is substantially in accordance with 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. Similarly, a person skilled in the art is capable of determining if a given diffraction angle (expressed in °2Θ) 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. For example, 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 D20 or methanol-d3). In some embodiments, 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. Examples of 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 3H, nC, 14C and 18F. Such isotopically-labeled forms of the compounds of the invention are useful in drug and/or substrate tissue distribution assays. For example, nC and 18F 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.
Because 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.
SYNTHETIC M ETHODS
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.
Names for the intermediate and final compounds described herein were generated using the software naming program Chem Draw Ultra vl2.0 available from Perkin Elmer, 940 Winter Street, Waltham, Massachusetts, 02451, USA. (http://www.perkinelmer.com/).
It will be appreciated by those skilled in the art that in certain instances this program may name a structurally depicted compound as a tautomer of that compound. It is to be understood that any reference to a named compound or a structurally depicted compound is intended to encompass all tautomers of such compounds and any mixtures or tautomers thereof.
Unless otherwise stated, all temperatures are reported in degrees Celsius.
Abbreviations which are not specifically defined below have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
General Synthetic Scheme 1
Figure imgf000019_0001
1, R2, R3, R4 and A are as defined in Formula (I).
General Synthetic Scheme 1 provides an exemplary synthesis for compounds 6 and 7. The starting material or reagents for Scheme 1 are commercially available (for example Aldrich or other vendors) or are made from commercially available starting materials using methods known to those skilled in the art.
Step (i) may be carried out by reacting H2NC(R1)(R2) C(R5)2OH 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.
Step (ii) may use appropriate reagents such as methanesulfonyl chloride (MsCI) and triethylamine (NEt3) 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 (K2C03) 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 (NEt3) in a suitable solvent such as THF at a suitable temperature such as 25 °C.
Step (iv) Where 3 = H, 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.
Step (v) may be carried out by reacting compound 5 with R4-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.
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.
The skilled artisan will appreciate that the intermediate R4-A-OH, can be prepared by using nucleophilic aromatic substitution chemistry to prepare the R4-A species with a base such as potassium carbonate (K2C03) 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.
EXAMPLES
The following synthetic processes and examples are provided to more specifically illustrate the invention. These examples are not intended to limit the scope of the invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds,
compositions, and methods of the invention. While particular embodiments of the invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention. Abbreviations Meaning
NM R Nuclear magnetic resonance
LC-MS Liquid chromatography-mass spectrometry
HPLC High-performance liquid chromatography
DMSO-d6 Dimethyl sulfoxide- deuterated
CDCI3 Deuterated chloroform
RT or rt Room temperature
tR Retention time
ACN Acetonitrile
THF Tetrahydrofuran
MeOH Methanol
EtOAc Ethyl acetate
DMF A/,/\/-Dimethyl formamide
DCM Dichloromethane
TEA or NEt3 Triethyl amine
DIPEA Diisopropyl ethyl amine
DMAP 4-A/,/\/-Dimethyl amino pyridine
K2C03 Potassium carbonate
NaHC03 Sodium bicarbonate
NaH Sodium hydride
LAH or UAIH4 Lithium aluminum hydride
DIBALH Diisobutylaluminum hydride
NaBH4 Sodium borohydride
Na2S04 Sodium sulphate
MsCI Methane sulfonyl chloride
Pd2dba3 tris(Dibenzylideneacetone)dipalladium (0)
DPPF l,l'-bis(Diphenylphosphino)ferrocene
NM R
All NMR experiments were recorded in 400 MHz Varian instrument. Solvents used to record NMR experiments are DMSO-d6 (Cambridge Isotope Laboratories, CIL) & CDCI3 (CIL) and TMS was used as internal standard. All results were interpreted using VNM RJ 3.2 version. LCMS
Method A: Column: Acquity BEH C18 (50mm x 2.1mm) 1.7 μ; Mobile Phase: A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile gradient time (min) /%B: 0/3, 0.4/3, 3.2/98, 3.8/98, 4.2/3, 4.5/3; column temperature: 35 °C, Flow Rate: 0.6 ml/min
Method B: Column: Acquity BEH C18 (50 x 2.1mm) 1.7 μ; Mobile Phase:=A 0.1% formic acid in water; B=0.1% formic acid in acetonitrile gradient time (min) /%B: 0/3, 1.5/100,1.9/100,2/3; column temperature: 40 °C, Flow Rate: 1.0 ml/min
Method C: Column: XBridge C18 (50 x 4.6mm) 2.5 μ; Mobile Phase: C= acetonitrile;
D= 5mM ammonium acetate in water; gradient time (min) /%C: 0/5, 0.5/5, 1/15, 3.3/98, 5.2/98, 5.5/5, 6/5; column temperature: 35 °C, Flow Rate: 1.3 ml/min
Method D: Column: XBridge C18 (50 x 4.6mm) 2.5 μ; mobile phase: A= 5mM ammonium bicarbonate in water (pH-10); B= acetonitrile; gradient time (min) /%D: 0/5, 0.5/5, 1/15, 3.3/98, 5.2/98, 5.5/5, 6/5; column temperature: 35 °C, Flow Rate: 1.3 ml/min
Method E: Column: XBridge C18 (50 x 2.1 mm) 2.5 μ; mobile phase: C= 0.1% formic acid in acetonitrile; D= 0.1% formic acid in water; gradient time (min) /%C: 0/5, 0.5/5, 1/15, 3.3/98, 5.2/98, 5.5/5, 6/5; column temperature: 35 °C, Flow Rate: 1.3 ml/min
Method F: Column: Acquity BEH C18 (100 x 2.1 mm) 1.7 μ; mobile phase: A=0.1% trifluoroacetic acid in water; B=0.1% trifluoroacetic acid in acetonitrile; gradient time (min) /%B: 0/3, 8.5/100, 9.0/100, 9.5/3, 10.01/3; column temperature: 50 °C, Flow Rate: 0.55 ml/min
Analytical HPLC
Method A: Column: YMC PAL DIOL (250 x 4.6 mm) 5 μ; mobile phase: A=hexane; B=ethanol; isocratic; column temperature: 50 °C, Flow Rate: 2.0 ml/min
Chiral HPLC
Method A: Column: Chiralpak IA (4.6 x 250mm) 5μ; mobile phase B= 0.1% diethylamine in hexane: A= Ethanol, isocratic, 70:30; ambient temperature, flow rate: 1.0 mL/min; Sample loading solvent : ethanol and hexane
Preparative HPLC
Method A: Column: XBridge C18 (150 x 30 mm) 5 μ; mobile phase A= 10mm NH4HC03; B= acetonitrile (40:60); ambient temperature; flow rate, 30 ml/min; Sample loading solvent, acetonitrile; fraction volume, 150 ml. Method B : Column: Denali C18 (250 x 20 mm) 5 μ; mobile phase A, 10mm NH4HC03; B, acetonitrile (40:60); ambient temperature; flow rate, 30 ml/min; Sample loading solvent, acetonitrile; fraction volume, 250 ml
Method C: Column: X Terra C18 (250 x 19mm) 10 μ mobile phase, A=0.1% ammonium bicarbonate (63%) and B=acetonitrile (37%); flow rate, 18 ml/min; Sample loading solvent acetonitrile + MeOH; fraction volume 200 mL
Method D : Column : XBridge C18 (100 x 19mm) 5 μ; mobile phase, A= 0.1% ammonium bicarbonate, B= Acetonitrile gradient time (min)/% B : 0/10, 1/10, 15/60; column temperature °C : Ambient; flow rate, 30 ml/min, Sample loading solvent acetonitrile + MeOH; fraction volume, 100 ml
Method E : Column : X Terra C18 (100 x 19 mm) 10 μ; mobile phase, A= 0.1% ammonium bicarbonate (63%), B= acetonitrile (37%), column temperature : ambient temperature; Flow rate, 18 ml/min, Sample loading solvent acetonitrile + MeOH; Fraction volume, 250 ml
Method F : Column : XBridge C18 (150 x 30mm) 5 μ; mobile phase, A= 0.1% formic acid in water, B= Acetonitrile gradient time(min)/% B : 0/10, 2/10, 15/60, 18/90; column temperature °C :
Ambient; Flow rate, 30 ml/min, Sample loading solvent acetonitrile + THF; fraction volume, 150 ml
Method G : Column : Sunfire C18 (150 x 30mm) 5 μ; mobile phase, A= 0.1% formic acid in water, B= Acetonitrile gradient time(min)/% B : 0/10, 1/10, 15/60; column temperature °C : Ambient; Flow rate, 30 ml/min, Sample loading solvent acetonitrile + methanol; fraction volume, 150 ml
A) Intermediates
Synthetic Scheme for Intermediates 1-3:
Figure imgf000024_0001
Intermediate 1
Figure imgf000024_0002
Intermediate 2 Intermediate 3
Intermediate 1: 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-l-ol
Figure imgf000024_0003
To a suspension of 2-amino-2-methylpropan-l-ol (50 g, 561 mmol, Aldrich) and K2C03 (310 g, 2.24 mol) in acetonitrile (1000 mL) was added 2,4,6-trichloropyrimidine (103 g, 5.61 mol, Avra) at 0 °C drop wise for 5 min and stirred at RT for 18 h. The reaction mixture was filtered to remove the inorganic solids and the filtrate was concentrated under reduced pressure to afford the title compound (55 g) as a white solid.
*H NMR (400 MHz, DMSO-d6) δ: 7.74 (1H, s), 6.61 (1H, s), 4.86 (1H, t), 3.52 (2H, d), 1.25 (6H, s).
Intermediate 2: 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000024_0004
To a solution of 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-l-ol (60 g, 254 mmol) in THF (600 mL) was added triethylamine (106 mL, 762 mmol) and the reaction mixture stirred at 0 °C for 5 min. Methanesulfonyl chloride (29.7 mL, 381 mmol) was added at the same temperature and reaction stirred at RT for 2 h. 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.
*H NMR (400 MHz, DMSO-d6) δ: 8.84 (1H, s), 5.60 (1H, s), 3.74 (2H, s), 1.34 (6H, s).
Intermediate 3: tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo [l,2-c]pyrimidine-l (5H)-carboxylate
Figure imgf000025_0001
To a solution of 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (25 g, 125 mmol) in THF (500 mL) was added triethylamine (50 ml, 359 mmol), Boc20 (50 ml, 215 mmol) and DMAP (1 g, 8.19 mmol) at 0 °C. Then reaction mixture was stirred at RT for 3 h. The precipitated solid in the reaction mixture was filtered and then dried under vacuum to give the title compound (25 g) as a white solid.
*H NMR (400 MHz, DMSO-d6) δ: 6.57 (1H, s), 3.87 (2H, s), 1.57 (6H, s), 1.53 (9H, s)
Synthetic Scheme for Intermediates 4-6:
Figure imgf000025_0002
Intermediate 5 Intermediate 6 Intermediate 4: (5)-2-((2,6-dichloropyrimidin-4-yl)amino)propa
Figure imgf000026_0001
To a stirred solution of ('Sj-2-aminopropan-l-ol (100 g, 1.33 mol, AK Scientific in DM F (1000 mL) was added potassium carbonate (754 g, 5.46 mol) and the mixture stirred for 10 min. A solution of 2,4,6-trichloropyrimidine (244 g, 1.33 mol, Avra) in DMF (200 mL) was added at 0 QC and stirring continued at T for 16 h. The reaction mixture was partitioned between ethyl acetate (1000 mL) and water (1000 mL), the organic layer separated and washed with brine, dried over Na2S04 and evaporated under reduced pressure to afford a thick gum (300 g). The crude material was dissolved in ethyl acetate (500 mL), stirred for lh, and the precipitated solid was filtered to give the title compound (70 g).
H NMR (400 MHz, DMSO-d6) δ: 8.06 (1H, d), 6.52 (1H, s), 4.84-4.78 (1H, m), 4.06-4.00 (1H, m), 3.43-3.34 (2H, m), 1.15 (3H, d).
Intermediate 5: (S)-7-chloro-2-methyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000026_0002
To a stirred solution of (Sj-2-((2,6-dichloropyrimidin-4-yl)amino)propan-l-ol (80 g, 360 mmol) in THF (300 mL), cooled to 0 QC, was added triethylamine (151 mL, 1.08 mol). Methanesulfonyl chloride (42.1 mL, 540 mmol) was added slowly and the reaction mixture stirred at RT for 3 h and then concentrated under reduced pressure to give the mesylate as a crude product (150 g) which was used directly in the next step.
To a stirred solution of this material in water (1000 mL) was added triethylamine (209 mL, 1499 mmol) and the mixture heated at 100 °C for 5 h. The reaction mixture was filtered and then dried under vacuum to afford the title compound (39 g) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 8.75 (1H, s), 5.62 (1H, s), 4.24-4.12 (1H, m), 4.08 (1H, t), 3.56-3.51 (1H, m), 1.25 (3H, d). Intermediate 6: (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine- l(5H)-carboxylate
Figure imgf000027_0001
To a stirred solution of (Sj-7-chloro-2-methyl-2,3-dihydroimidazo[l,2-c]pyrimidin -5(l/-/)-one (120 g, 647 mmol) in THF (400 mL) and water (400 mL), cooled to 0 QC, was added sodium bicarbonate (136 g, 1616 mmol) and after 10 min di-ieri-butyl dicarbonate (180 mL, 776 mmol) was added and the reaction mixture stirred at T for 16 h. The reaction mixture as diluted with water (100 ml) and extracted with ethyl acetate (800 ml). The organic layer was separated and washed with brine solution (400 ml), dried over anhydrous Na2S04 and the solvent removed reduced pressure to give crude material that was purified by column chromatography using 100-200 mesh silica gel and 60% EtOAc/n-hexane as eluent. The product containing fractions were evaporated to afford the title compound (28 g) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 6.51 (1H, s), 4.56-4.51 (1H, m), 4.17 (1H, t), 3.70-3.66 (1H, m), 1.52 (9H, s), 1.38 (3H, d).
Synthetic Scheme for Intermediate 7:
Figure imgf000027_0002
Intermediate 5 Intermediate 7
Intermediate 7: (S)-7-chloro-l,2-dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000027_0003
To a solution of Sj-7-chloro-2-methyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (2 g, 10.78 mmol) in acetone (20 mL) was added K2C03 (2.98 g, 21.55 mmol) and Mel (0.674 mL, 10.78 mmol) and the reaction mixture stirred at RT for 18 h. The reaction mixture was evaporated under reduced pressure to give crude material (4.2 g) which was purified by column chromatography using 5% MeOH/DCM as eluent. The product containing fractions were evaporated to give the title compound (1.2 g) as an off-white solid.
*H NM (400 MHz, DMSO-d6) δ: 5.88 (1H, s), 4.16-4.09 (2H, m), 3.55-3.51 (1H, m), 2.88 (3H, s), 1.29 (3H, d).
Synthetic Scheme for Intermediates 8-10:
Figure imgf000028_0001
Intermediate 9 Intermediate 10
Intermediate 8: (/?)-2-((2,6-dichloropyrimidin-4-yl)amino)propan-l-ol)
Figure imgf000028_0002
To a suspension of (/?J-2-aminopropan-l-ol (100 g, 1.33 mmol Combiblock) and K2C03 (736 g, 5.33 mol) in DMF (1000 mL) was added a solution of 2,4,6-trichloropyrimidine (244 g, 1.33 mol, Avra) in DMF (100 mL) at 0 °C drop wise over 30 min and stirred at RT for 18 h. The reaction mixture was partitioned between ethyl acetate (1000 mL) and water (1000 mL) and the two layers were separated. The organic layer was washed with brine and dried over Na2S04. The solvent was evaporated under reduced pressure to give a crude thick gummy material (300 g). This material was dissolved in ethyl acetate (500 mL) and stirred for 1 h. The solid that precipitated was filtered to afford 40 g of the title compound and the above procedure was repeated on the filtrate to afford an additional 60 g of the title compound (100 g in total).
*H NMR (400 MHz, DMSO-d6) δ: 8.05 (1H, d), 6.51 (1H, s), 4.83 (1H, t), 4.05-4.00 (1H, m), 3.44-3.34 (2H, m), 1.11 (3H, d). Intermediate 9: ^-7-chloro-2-methyl- -dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000029_0001
To a solution of ( ?J-2-((2,6-dichloropyrimidin-4-yl)amino)propan-l-ol (50 g, 225 mmol)) in THF (500 mL) was added triethylamine (94 mL, 675 mmol) and the reaction mixture stirred at 0 °C for 5 min. Then methanesulfonyl chloride (26.3 mL, 338 mmol) was added at same temperature and the reaction stirred at RT for 2 h. The reaction mixture was filtered through a Celite bed and the filtrate was completely evaporated to give the crude mesylate (60 g).
A solution of the mesylate (60 g, 200 mmol) in a mixture of triethylamine (84 mL, 600 mmol) and water (500 mL) was heated to 100 °C for 5 h. The reaction mixture was cooled to RT and the precipitated solid was filtered to afford the title compound (30 g) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ: 8.78 (IH, s), 5.62 (IH, s), 4.22-4.17 (IH, m), 4.14 (IH, t), 3.56-3.51 (IH, m), 1.25 (3H, d).
Intermediate 10: (R)-te rt-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l (5H)-carboxylate
Figure imgf000029_0002
To a solution of ?J-7-chloro-2-methyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (30 g, 162 mmol) in THF (600 mL) was added triethylamine (56.3 mL, 404 mmol) and 4-DMAP (0.987 g, 8.08 mmol) the reaction mixture was stirred at 0 °C for 10 min. Then di-ferf-butyl carbonate (37.5 mL, 162 mmol) was added at the same temperature and the reaction mixture stirred for 3 h at RT. The reaction mixture was diluted with ethyl acetate (2 x 100 mL) and water (150 mL). The organic layer was separated, dried over anhydrous Na2S04 and evaporated under reduced pressure to give the title compound (22 g) as an off-white solid.
*H NMR (400 MHz, DMSO-d6) δ: 6.51 (IH, s), 4.57-4.52 (IH, m), 4.12 (IH, t), 3.70-3.66 (IH, m), 1.52 (9H, s), 1.38 (3H, d). Synthetic Scheme for Intermediate 11:
Figure imgf000030_0001
Intermediate 9 Intermediate 11
Intermediate 11: W-7-chloro-l,2-dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000030_0002
To a solution of ?J-7-chloro-2-methyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one (1.0 g, 5.39 mmol) in acetone (20 mL) was added K2C03 (1.489 g, 10.78 mmol) and Mel (0.337 mL, 5.39 mmol) and the reaction mixture stirred at RT for 42 h. The reaction mixture was filtered through a Celite bed and the filtrate was evaporated under reduced pressure to give the title compound (0.6 g) as a pale yellow solid.
H NMR (400 MHz, DMSO-d5) 5: 5.88 (1H, s), 4.16-4.03 (2H, m), 3.52-3.51 (1H, m), 2.88 (3H, s), 1.29 (3H, d).
Synthetic Scheme for Intermediates 12-15:
Figure imgf000030_0003
Intermediate 12 Intermediate 13
Figure imgf000030_0004
Intermediate 12: tert-butyl (l-hydroxy-2-methylpropan-2-yl)carbamate - Preparation 1
Figure imgf000031_0001
To a mixture of 2-amino-2-methylpropan-l-ol (467 g, 5.24 mol, Alfa), Na2C03 (9.44 g, 89 mmol) and sodium bicarbonate (9.68 g, 115 mmol) in 1,4-dioxane (3.8 L) and water (900 mL), stirred at 0 QC was added slowly di-ferf-butyl dicarbonate (1.460 L, 6.29 mol). The reaction mixture was stirred at T for 6 h. The reaction mixture was concentrated under reduced pressure at 50 °C to afford a residue which was poured in water (3 L). The aqueous layer was extracted with ethyl acetate (3 X 2 L) and the organic layers were dried over anhydrous Na2S04 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.
H NMR (400 MHz, DMSO-d6) δ: 6.05 (1H, s), 4.69-4.66 (1H, m), 3.29 (2H, d), 1.37 (9H, s), 1.13 (6H, s).
Intermediate 12: tert-butyl (l-hydroxy-2-meth lpropan-2-yl)carbamate - Preparation 2
To a solution of 2-amino-2-methylpropan-l-ol (500 g, 5.61 mol, Alfa) in THF (3.0 L) and water (1.0 L) was added Na2C03 (10.11 g, 95 mmol) and sodium bicarbonate (10.37 g, 123 mmol) and stirring continued at 0 QC. di-ferf-Butyl dicarbonate (1.56 L, 6.7 mol) was added. The reaction mixture was stirred at RT for 18 h. The THF layer was separated and the aqueous layer extracted with ethyl acetate (1.5 L). The combined organic layers were washed with brine solution (2 x 2 L), were dried over anhydrous Na2S04 and then concentrated under reduced pressure to afford crude title compound. The crude material was dissolved in petroleum ether (750 mL) and cooled to -50 °C. The resulting solid was filtered and washed with petroleum ether to give the title compound (750 g) as a white solid.
*H NMR (400 MHz, DMSO-d6) δ: 6.08 (1H, s), 4.67 (1H, t), 3.29 (2H, s), 1.37 (9H, s), 1.13 (6H, s). Intermediate 13: 2-methyl-2-(methylamino ropan-l-ol
Figure imgf000032_0001
To a stirred mixture of lithium aluminium hydride (301 g, 7.93 mol) in THF (5 L) under nitrogen in at 0 QC was added a solution of ieri-butyl (l-hydroxy-2-methylpropan-2-yl) carbamate (500 g, 2.62 mol) in THF (1 L) drop wise. The reaction mixture was stirred under reflux for 18 h. The reaction mixture was quenched with saturated Na2S04 solution (600 mL) and filtered through a Celite bed, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the title compound (200g) as a yellow solid.
H NM (300 MHz, DMSO-d6) δ: 4.41 (1H, bs), 3.13 (2H, s), 2.14 (3H, s), 1.11 (1H, s), 0.89 (6H, s).
Intermediate 14: 2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)-2-methylpropan-l-ol - Preparation 1
Figure imgf000032_0002
To a stirred mixture of 2,4,6-trichloropyrimidine (264 g, 1.44 mol, Avra), K2C03 (743 g, 5.38 mol) in DMF (1.5 L) was added 2-methyl-2-(methylamino)propan-l-ol (135 g, 1.31 mol) in DMF (700 mL) drop wise at RT and the mixture stirred for 18 h. The reaction mixture was concentrated, and then EtOAc (2 x 1.8 L) was added and the organic phase was washed with water (2 x 1.5 L), and saturated brine (1.5 L), dried over Na2S04 and concentrated under reduced pressure to give the crude title compound (1.3 kg). 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.
*H NMR (400 MHz, DMSO-d6) δ: 6.81 (1H, s), 4.80 (1H, bs), 3.73 (2H, s), 3.01 (3H, s), 1.42 (6H, s). Intermediate 14: 2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)-2-methylpropan-l-ol -
Preparation 2
Figure imgf000033_0001
To a stirred solution of 2-methyl-2-(methylamino)propan-l-ol (500 g, 4.84 mol) in acetone (5000 mL), was added K2C03 (1.34 Kg, 9.69 mol) and the mixture cooled to 0 ^c. A solution of 2,4,6- trichloropyrimidine (474 mL, 3.88 mol) in acetone (2.0 L), was added drop wise at the same temperature and the mixture stirred at T for 18 h. The reaction mixture was filtered, and the residue washed with EtOAc (2 x 2.0 L) and the filtrate concentrated under reduced pressure to give the crude title compound (900 g). The crude product was purified by silica gel (100-200 mesh) column chromatography, using ethyl acetate as eluent. The pure product containing fractions were combined and evaporated to give the title compound (325 g) as a pale yellow solid.
LCMS Method C: m/z [M+H]+ 250, tR 3.21 min
Intermediate 15: 7-chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one - Preparation 1
Figure imgf000033_0002
To a stirred solution of 2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)-2-methylpropan-l-ol (95 g) and triethylamine (159 mL, 1.14 mol) in THF (2.2 L), stirred at 0Q C, was added methanesulfonyl chloride (44 mL, 570 mmol) drop wise. The reaction mixture was stirred at 25Q C for 3 h. The reaction mixture was diluted with THF (1 Lit) and stirred for 30 min, and filtered to remove the salts. The filtrate was concentrated and the residue was dissolved in dichloromethane. Hexane was added, and the resulting suspension filtered, washed with further hexane (500 mL) and the solid dried under vacuum to afford the title compound (55 g) as a yellow solid.
LCMS Method A: m/z [M+H]+ 214/216, tR 1.12 min. Intermediate 15: 7-chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one - Preparation 2
Figure imgf000034_0001
To a stirred solution of 2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)-2-methylpropan-l-ol (325 g, 1.3 mol) in THF (3.5 L) at 0 was added a triethylamine (543 mL, 3.90 mol). After 20 min, methanesulfonyl chloride (152 mL, 1.95 mol) was added at 0 QC. The reaction mixture was stirred at RT for 3 h. The reaction mixture was filtered through a Celite bed which was washed with ethyl acetate. The filtrate was concentrated and the residue was purified by column chromatography using 60-120 mesh silica gel and ethyl acetate as the eluent to give the title compound (225 g). 1H NMR (400 MHz, DMSO-d6) δ: 5.85 (1H, s), 3.78 (2H, s), 2.83 (3H, s), 1.33 (6H, s).
Synthetic Scheme for Intermediates 16-17
Figure imgf000034_0002
Intermediate 16 Intermediate 17 Intermediate 16: 3,5-difluoro-4-((6- nzaldehyde - Preparation 1
Figure imgf000034_0003
To a solution of 3,4,5-trifluorobenzaldehyde (10 g, 62.5 mmol, Fluorochem) and 6-methylpyridin- 3-ol (6.82 g, 62.5 mmol, Alfa) in acetonitrile (100 mL) was added K2C03 (17.27 g, 125 mmol) at RT. The reaction was stirred at RT for 48 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL), washed with brine solution (100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to give the title compound (12 g) as a white solid.
LCMS Method A: m/z [M+H]+ 250, tR 1.81 min. Intermediate 16: 3,5-difluoro-4-((6- nzaldehyde - Preparation 2
Figure imgf000035_0001
To a stirred solution of 6-methylpyridin-3-ol (500 g, 4.58 mol, Frappa) in acetonitrile (5.0 L) was added K2C03 (1.90 Kg, 13.7 mol) at 0°C and stirred for 30 min. Then 3,4,5-trifluorobenzaldehyde (1.10 Kg, 6.9 mol, Tractus) was added and stirred the reaction mixture at 60 °C for 48h. The reaction mixture was diluted with ethyl acetate and water; the organic layer was separated and dried over Na2S04. The solvent was removed under reduced pressure to afford crude title compound (1.15 kg) as pale yellow syrup.
^ NM (400 MHz, CDCI3) δ: 9.92 (1H, t), 8.28 (1H, d), 7.59-7.53 (2H, m), 7.20-7.17 (1H, m), 7.13- 7.10 (1H, m), 2.54 (3H, s).
Intermediate 17: (3,5-difluoro-4-(( -methylpyridin-3-yl)oxy)phenyl)methanol - Preparation 1
Figure imgf000035_0002
To a stirred solution of 3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzaldehyde (12 g, 48.2 mmol) in methanol (100 mL) at 0 °C was added NaBH4 (2.19 g, 57.8 mmol) and stirring continued at same temperature under nitrogen for 30 min. The reaction mixture was slowly quenched with ice cold water (100 mL) and methanol removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with DCM (2 x 200 mL), washed with brine solution (100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the title compound (10 g) as a white solid.
LCMS Method A: m/z [M+H]+ 252, fR 1.53 min.
Intermediate 17: (3,5-difluoro-4-(( -methylpyridin-3-yl)oxy)phenyl)methanol - Preparation 2
Figure imgf000035_0003
A solution of 3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzaldehyde (650 g, 2.61 mol) in methanol (6.5 L) was cooled to 0 °C and NaBH4 (49.3 g, 1.30 mol) was added slowly at same temperature for 30 min and the reaction mixture stirred for 30 min at 0 °C. The reaction mixture was quenched with ice (800 g), the methanol evaporated under reduced pressure to give crude material which was dissolved in ethyl acetate (3.0 L) and water (2.0 L). The organic layer was separated, dried over Na2S04 and evaporated under reduced pressure to afford the crude product. The crude product was triturated with petroleum ether (3.0 L), the resulting solid was filtered and then dried under vacuum to afford to give the title compound (600 g) as off white solid. A mixture of this solid (10 g) in diethyl ether (50 mL) was stirred for lh, and filtered and then dried under vacuum to give an analytical sample of the title compound as a white solid. LCMS Method F: m/z [M+H]+ 252, tR 2.78 min. nthetic Scheme for Intermediates 18-21
Figure imgf000036_0001
Intermediate 18 Intermediate 19
DIBALH, THF
0°C-RT, 1 h
Figure imgf000036_0002
Intermediate 21
Intermediate 20
Intermediate 18: methyl 3-bromo-4,5-difluorobenzoate
Figure imgf000036_0003
To a stirred solution of 3-bromo-4,5-difluorobenzoic acid (9.5 g, 40.1 mmol, IS Pharma) in methanol (20 mL) and diethyl ether (80 mL) at 0 °C, was added a 1M solution of
trimethylsilyldiazomethane in THF (50 mL, 50 mmol). The reaction mixture was stirred for 2 h at RT and then the solvent was removed under reduced pressure to afford the title compound (9.0 g) as a yellow solid.
^NMR (400 MHz, DMSO-d6) δ: 8.06-8.04 (1H, m), 7.83-7.79 (1H, m), 3.93 (3H, s). Intermediate 19: Methyl 3-bromo-5-fluoro-4- 6-methylpyridin-3-yl)oxy)benzoate
Figure imgf000037_0001
To a stirred solution of methyl 3-bromo-4,5-difluorobenzoate (4.5 g) in DMF (30 mL), was added 6-methylpyridin-3-ol (2.15 g, 19.7 mmol, Alfa) and K2C03 (2.48 g, 17.9 mmol) and the mixture heated at 85 °C for 18 h The reaction mixture was quenched with ice water (10ml), and extracted with ethyl acetate (2 x 100 ml), washed with brine solution (2 x 100ml), dried over anhydrous Na2S04, and the solvent removed under reduced pressure to afford the title compound (5.0 g) as a colorless liquid.
LCMS Method B: m/z [M+H]+ 340, tR 0.98 min.
Intermediate 20: (3-bromo-5-fluoro-4- 6-methylpyridin-3-yl)oxy)phenyl)methanol
Figure imgf000037_0002
To a stirred solution of methyl 3-bromo-5-fluoro-4-((6-methylpyridin-3-yl)oxy)benzoate (3.8 g) in THF (50 mL), was added a 1.0 M solution of DIBAL-H in toluene (30 mL, 30.0 mmol) at 0 °C and the reaction mixture was stirred for lh at T. The reaction mixture was quenched with saturated NH4CI solution (30ml) at 0 °C and filtered through a Celite bed. The compound was extracted with ethyl acetate (2 x 100ml), washed with brine solution (2 x 50ml), dried over anhydrous Na2S04, and the solvent removed under reduced pressure to afford the title compound (3 g) as a brown solid.
LCMS Method B: m/z [M+H]+ 214, tR 0.67 min.
Intermediate 21: 3-fluoro-5-(hydrox methyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile
Figure imgf000037_0003
To a stirred solution of (3-bromo-5-fluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol (6.6 g, 21.14 mmol) in DMF (60 mL) in a sealable tube was added zinc cyanide (2.5 g, 21.14 mmol) at RT. The mixture was degassed for 30 min with argon and then were added
tris(dibenzylideneacetone)dipalladium (0) (0.120 g, 0.131 mmol) and 1,1'- bis(diphenylphosphino)ferrocene (0.500 g, 0.902 mmol). The mixture was again degassed for 30min with argon. The tube was sealed and heated at 180 °C for 3 h. The reaction mixture was diluted with ethyl acetate (100 ml), filtered through a Celite bed and the filtrate layer was washed with brine solution (2 x 100 ml) and dried over anhydrous Na2S04. The solvent was removed under reduced pressure to afford 7 g of crude product. This was purified by column
chromatography using 100-200 silica gel by eluting with 30% ethyl acetate in hexane to give the title compound (3.6 g) as a brown solid.
LCMS Method A: m/z [M+H]+ 259, tR 0.1.41 min.
Synthetic Scheme for Intermediates 22-23:
Figure imgf000038_0001
To a mixture of 2-fluoro-5-formylbenzonitrile (10 g, 67.1 mmol, AK Scientific) and 2-methylpyridin- 4-ol (7.32 g, 67.1 mmol, IS Pharma) in acetonitrile (200 mL) was added K2C03 (18.54 g, 134 mmol) and the mixture stirred at 80 °C for 18 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL) and washed with brine solution (100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the title compound (12 g) as a brown solid which was used in the next step without further purification
LCMS Method A: m/z [M+H]+ 239, fR.1.15 min.
Intermediate 23: 5-(hydroxymethy -2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000038_0002
To a stirred solution of 5-formyl-2-((2-methylpyridin-4-yl)oxy)benzonitrile (12 g, 50.4 mmol) in methanol (100 mL) was added NaBH4 (2.287 g, 60.4 mmol) at 0 °C and the reaction mixture stirred at the same temperature under nitrogen for 30 min. The reaction mixture was slowly quenched with ice cold water (100 mL) and the methanol removed under reduced pressure. The crude material, thus obtained, was diluted with water (100 mL) and extracted with DCM (2 x 200 mL) and washed with brine solution (100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude title product which was purified by column chromatography using 100-200 silica gel, eluting with 50% EtOAc/petroleum ether. The product containing fractions were concentrated under reduced pressure to afford the title compound (5 g) as a yellow solid.
LCMS Method A: m/z [M+H]+ 241, tR 1.12 min.
Figure imgf000039_0001
Intermediate 24: 3,5-difluoro-4-((2- nzaldehyde
Figure imgf000039_0002
To a mixture of 3,4,5-trifluorobenzaldehyde (10 g, 62.5 mmol, Avra) and 2-methylpyridin-4-ol (6.82 g, 62.5 mmol, IS Pharma) in acetonitrile (200 mL) was added K2C03 (17.27 g, 125 mmol) and the mixture stirred at 80 °C for 18 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL) and washed with brine solution (100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to give the title compound (13 g) as yellow liquid.
LCMS Method A: m/z [M+H]+ 250, tR 1.24 min. Intermediate 25: 3,5-difluoro-4-((2 nyl)methanol
Figure imgf000040_0001
To a stirred solution of 3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzaldehyde (13 g, 52.2 mmol) in methanol (100 mL) at at 0 °C was added NaBH4 (2.368 g, 62.6 mmol) and the mixture stirred at same temperature under nitrogen for 30 min. The reaction mixture was slowly quenched with ice cold water (100 mL) and methanol removed under reduced pressure. The material thus obtained, was diluted with water (100 mL) and extracted with DCM (2 x 200 mL), washed with brine solution (100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude product. This material was purified by column chromatography using 100-200 mesh silica gel, eluting with 50% EtOAc/petroleum ether The product containing fractions were concentrated under reduced pressure to afford the title compound (5 g) as a white solid.
LCMS Method A: m/z [M+H]+ 252, tR 1.19 min.
Synthetic Scheme for Intermediates 26-30:
Figure imgf000041_0001
Intermediate 26 Intermediate 27
Figure imgf000041_0002
Intermediate 28 Intermediate 29 Intermediate 30
Intermediate 26: methyl 3-fluoro-4-hydroxybenzoate
Figure imgf000041_0003
To a stirred solution of 3-fluoro-4-hydroxybenzoic acid (25 g, 160 mmol, Combiblocks) in methanol (250 mL), was added SOCI2 (25 ml, 343 mmol) at 0 °C and the mixture stirred at 65 °C for 18 h. The solvent was removed under reduced pressure and the residue diluted with diethyl ether (500 ml). The mixture was washed with cold saturated NaHC03 solution (3 x 500 ml), brine solution (2 x 500 ml), dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give the title compound as a brown solid (21 g) which was used in the next step without further purification.
LCMS Method B: m/z [M-H]" 169, tR 0.73 min. Intermediate 27: Methyl 3-bromo-5-fluoro-4-hydroxybenzoate
Figure imgf000041_0004
To a stirred solution of methyl 3-fluoro-4-hydroxybenzoate (21.0 g, 123 mmol) in DCM (120 mL) and acetic acid (120 mL) was added bromine (8.0 mL, 155 mmol) at 0 °C drop wise within 30 min. The reaction mixture was stirred for 48 h at RT and then diluted with ethyl acetate (500 ml). The mixture was washed with saturated Na2S203 solution (3 x 500 ml), brine solution (3 x 500ml) and dried over anhydrous Na2S04. The solvent was removed under reduced pressure to afford the title compound (30 g) as a yellow solid which was used without further purification.
LCMS Method B: m/z [M-H]+ 247, tR 0.98 min. Intermediate 28: Methyl 3-bromo- -fluoro-4-((2-methylpyridin-4-yl)oxy)benzoate
Figure imgf000042_0001
To a stirred solution of methyl 3-bromo-5-fluoro-4-hydroxybenzoate (22.0 g, 88 mmol) in xylene (220 mL) was added 4-bromo-2-methylpyridine (18.24 g, 106 mmol, Combiblocks), K2C03 (15.87 g, 115 mmol) and copper powder (0.841 g, 13.25 mmol), then the mixture was heated at 150 °C for 24 h. the reaction mass was cooled to 0 QC, diluted with water (200 ml) and EtOAc (300 ml). The mixture was filtered through a Celite bed which was washed with additional EtOAc (100 ml). The organic layer was separated, washed with brine solution (200 ml) and dried over anhydrous Na2S04. The solvent was evaporated to give crude product (200 g) which was wet with xylene. This material was purified by column chromatography using silica gel (100-200) and product containing fraction were collected and evaporated to give the title compound (7.2 g) as a brown liquid.
^NM (400 MHz, DMSO-d6) δ: 8.38 (1H, s), 8.14 (1H, m), 7.98 (1H, d), 6.84 (1H, s), 6.82-6.78 (1H, m), 3.90 (3H, s), 2.42 (3H, s). Intermediate 29: (3-bromo-5-fluor -4-((2-methylpyridin-4-yl)oxy)phenyl)methanol
Figure imgf000042_0002
To a stirred solution of methyl 3-bromo-5-fluoro-4-((2-methylpyridin-4-yl)oxy)benzoate (7.2 g, 21.17 mmol) in THF (100 mL) at 0 °C was added a 1.0 M solution of DIBAL-H in toluene (40 mL, 40.0 mmol) and the mixture stirred at RT for 1 h. The reaction mixture was quenched with aqueous NH4CI solution (100 ml), filtered through a Celite bed and washed with EtOAc (200 ml). The filtrate was extracted with EtOAc (500 ml), the organic layer washed with brine solution (200 ml), dried over anhydrous Na2S04 and evaporated to give the title compound (5.7 g) as a white solid which was used without further purification.
LCMS Method A: m/z [M+H]+ 312, tR 1.23 min Intermediate 30: 3-fluoro-5-(hydro din-4-yl)oxy)benzonitrile
Figure imgf000043_0001
To a stirred solution of (3-bromo-5-fluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol (5.7 g, 18.26 mmol) in DMF (70 mL) in a sealable tube was added zinc cyanide (2.137 g, 18.26 mmol) at T and the mixture degassed for 30 min with argon. tris(dibenzylideneacetone)dipalladium(0) (0.167 g, 0.183 mmol) and l,l'-bis(diphenylphosphino)ferrocene (2.03 g, 3.65 mmol) were added and the mixture degassed again for 30 min with argon. 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 Na2S04. 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)
LCMS Method A: m/z [M+H]+ 259, tR 2.82 min)
Synthetic Scheme for Intermediate 31: tert-butyl 7-((3,5-difluoro-4-((6-methylpyridin-3- yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000043_0002
Intermediate 3 Intermediate 17 Intermediate 31
Intermediate 31: tert-butyl 7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2,2- dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000043_0003
To a mixture of NaH (64.0 mg, 2.67 mmol) in THF (10 mL) was added (3,5-difluoro-4-((6- methylpyridin-3-yl)oxy)phenyl)methanol (168 mg, 0.667 mmol) in THF (10 mL) at 0 °C and the reaction mixture stirred for 10 min. ferf-Butyl 7-chloro-2,2-dimethyl-5-oxo-2,3- dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (200 mg, 0.667 mmol) was added and stirring continued for an additional 2 h at 0 °C. After completion of reaction, ice cold water (10 mL) was added as a quench and the mixture extracted with EtOAc (2 x 10 mL). The organic layers were washed with brine solution and concentrated under reduced pressure to afford the title compound (300 mg) as white solid which was used without further purification.
*H NM (400 MHz, DMSO-d6) δ: 8.23 (1H, s), 7.40-7.20 (4H, m), 6.10 (1H, s), 5.38 (2H, s), 3.81 (2H, s), 2.41 (3H, s), 1.30 (9H, s). Synthetic Scheme for Intermediate 32: tert-butyl 7-((3-cyano-5-fluoro-4-((6-methylpyridin-3- yl)oxy)benzyl)oxy)- -dimethyl-5-oxo-2,3-dihydroimidazo[l, -c]pyrimidine-l(5H)-carboxylate
Figure imgf000044_0001
Intermediate 3 nterme ate
Intermediate 32: tert-butyl 7-((3-cyano-5-fluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2,2- dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate (1)
Figure imgf000044_0002
To a stirred suspension of NaH (186 mg, 4.65 mmol) in THF (10 mL), was added 3-fluoro-5- (hydroxymethyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile (300mg, 1.16 mmol) in THF (10 mL) drop wise at 0 °C and stirred for 30 min at 0 °C. A solution of ferf-butyl 7-chloro-2,2-dimethyl-5- oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (348 mg, 1.16 mmol) in THF (10 mL) was then added at 0 °C, The reaction mixture stirred for 2 h at RT. The reaction was quenched with ice water (5 ml) at 0 °C, diluted with ethyl acetate (100 ml), and the ethyl acetate layer separated. The organic layer was with washed with brine solution (2 x 50ml), dried over anhydrous Na2S04 and the solvent removed under reduced pressure to afford the title compound (600 mg) as a brown solid. LCMS indicated this material was a mixture of the desired material and the de-protected product. LCMS Method A: m/z [M+H]+ 522, tR 1.14 mins
Synthetic Scheme for Intermediate 33: (/?)-tert-butyl 7-((3-cyano-5-fluoro-4-((6-methylpyridin-
3-yl)oxy)benzyl)oxy)-2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000045_0001
Intermediate 10 Intermediate 21 Intermediate 33
Intermediate 33: (/?)-tert-butyl 7-((3-cyano-5-fluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2- methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000045_0002
To a suspension of NaH (76 mg, 1.75 mmol) in THF (10 mL) was added 3-fluoro-5-
(hydroxymethyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile (271 mg, 1.05 mmol) in THF (5 mL) at 0 °C, the reaction mixture was then stirred at the same temperature for 10 min, and then (R)-tert- butyl 7-chloro-2-methyl-5-oxo-2,3- dihydroimidazo [l,2-c]pyrimidine-l(5/-/)-carboxylate (200 mg, 0.70 mmol) in THF (5 mL) was added and stirring continued for 3 h at 0 °C. 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 Na2S04 and evaporated under reduced pressure to give the crude title compound (280 mg) as brown gummy oil that was used without further purification LCMS Method D: m/z [M+H]+ 508, tR 3.68 mins
Synthetic Scheme for Intermediate 34: tert-butyl 7-((3-cyano-5-fluoro-4-((2-methylpyridin-4- yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000046_0001
Intermediate 3 Intermediate 30 Intermediate 34
Intermediate 34: tert-butyl 7-((3-cyano-5-fluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy) -2,2- dimethyl-5 -oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5r/)-carboxylate
Figure imgf000046_0002
To a mixture of NaH (96 mg, 4.00 mmol) in THF (10 mL) was added 3-fluoro-5-(hydroxymethyl)-2- ((2-methylpyridin-4-yl)oxy)benzonitrile (258 mg, 1.00 mmol) in THF (10 mL) at 0 °C and stirred for 10 min, the reaction mixture was then treated with ferf-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3- dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (300 mg, 1.00 mmol) and stirred for additional 2 h at 0 °C. After completion of the reaction, the mixture was quenched with ice cold water (10 mL) and extracted with EtOAc (2 x 10 mL) and then washed with brine solution. The organic layers were concentrated under reduced pressure to afford crude title compound (400 mg) as a white solid which was used without further purification.
LCMS Method A: m/z [M+H]+ 522 fR 1.91 min
Synthetic Scheme for Intermediate 35: (/? -tert-butyl 7-((3-cyano-5-fluoro-4-((2-methylpyridin-4- yl)oxy)benzyl)oxy)-2- methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000046_0003
Intermediate 10 Intermediate 30 Intermediate 35 Intermediate 35: (R)-tert-buty\ 7-((3-cyano-5-fluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2- methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000047_0001
To a stirred solution of 60% NaH in mineral oil (200 mg, 5.00 mmol) in THF (10 mL), was added drop-wise at 0 °C, 3-fluoro-5-(hydroxymethyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile (300 mg, 1.16 mmol) in THF (10 mL). The mixture was stirred for 30 minutes at 0 °C, and then (/?J-ferf-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c] pyrimidine-l(5/-/)-carboxylate (332 mg, 1.16 mmol) in THF (10 mL) was added at 0 °C. The 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 Na2S04 and the solvent removed under reduced pressure to give the title compound (600 mg) as a brown solid which was used without further purification.
LCMS Method E: m/z [M+H]+ 508, fR 3.55 min
Synthetic Scheme for Intermediate 36: tert-butyl 7-((3-cyano-4-((2-methylpyridin-4- yl)oxy)benzyl)oxy)-2,2-dimethyl- 5-oxo-2,3- dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000047_0002
Intermediate 3 Intermediate 23 Intermediate 36 Intermediate 36: tert-Butyl 7-((3-cyano-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2,2-dimethyl- 5-oxo-2,3- dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000048_0001
To a mixture of NaH (96 mg, 4.00 mmol) in THF (10 mL) was added 5-(hydroxymethyl)-2-((2- methylpyridin-4-yl)oxy)benzonitrile (240 mg, 1.00 mmol) in THF (10.0 mL) at 0 °C and the mixture stirred for 10 min. The mixture was then treated with ferf-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3- dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (300 mg, 1.00 mmol) and stirred for additional 2 h at 0 °C. The reaction was quenched with ice cold water (10 mL) and extracted with EtOAc (2 x 10 mL) and washed with brine solution. The organic layers were concentrated under reduced pressure to give the title compound (400 mg) as a white solid which was used without further purification.
LCMS Method E: m/z [M+H]+ 504 tR 2.98 min
Synthetic Scheme for Intermediate 37: (S)-tert-buty\ 7-((3-cyano-4-((2-methylpyridin-4- yl)oxy)benzyl)oxy)-2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000048_0002
nterme ate nterme ate Intermediate 37
Intermediate 37: (S)-tert-bu y\ 7-((3-cyano-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2-methyl 5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000048_0003
To a suspension of NaH (33.6 mg, 1.40 mmol) in THF (10 mL) at 0 °C was added 5- (hydroxymethyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile (168 mg, 0.70 mmol) in THF (5 mL) and the reaction mixture stirred at the same temperature for 10 min. (S)-ferf-Butyl 7-chloro-2-methyl- 5-oxo-2,3-dihydroimidazo [l,2-c]pyrimidine-l(5/-/)-carboxylate (200 mg, 0.70 mmol) in THF (5 mL) was then added and the reaction mixture stirred for 16 h at T. The 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 Na2S04. The solvent was removed under reduced pressure to give crude material (400 mg) which was used directly in the next step without further purification.
LCMS Method E: m/z [M+H]+ 490 tR 2.93 min Synthetic Scheme for Intermediate 38: (R)-tert-buty\ 7-((3-cyano-4-((2-methylpyridin-4-
Figure imgf000049_0001
Intermediate 10 Intermediate 23 Intermediate 38
Intermediate 38: (R)-tert-buty\ 7-((3-cyano-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5 -oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000049_0002
To a suspension of 55% NaH in mineral oil (76 mg, 1.75 mmol) in THF (10 mL) at 0 °C was added 5-(hydroxymethyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile (252 mg, 1.05 mmol) in THF (5 mL), then the reaction mixture was stirred at the same temperature for 10 min. (R)-tert-Buty\ 7- chloro-2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (200 mg, 0.70 mmol) in THF (5 mL) was added and the reaction mixture was stirred for 3 h at 0 °C. 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 Na2S04 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.
LCMS Method A: m/z [M+H]+ 490 tR 1.96 min Synthetic Scheme for Intermediate 39: tert-butyl 7-((3,5-difluoro-4-((2-methylpyridin-4- yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000050_0001
Intermediate 3 Intermediate 25 Intermediate 39
Intermediate 39: tert-butyl 7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2,2- dimethyl-5-oxo -2,3-dihyd te
Figure imgf000050_0002
To a mixture of NaH (96 mg, 4.00 mmol) in THF (10 mL) at 0 °C was added (3,5-difluoro-4-((2- methylpyridin-4-yl)oxy)phenyl)methanol (251 mg, 1.00 mmol) in THF (10.00 mL) and stirred for 10 min, then ferf-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)- carboxylate (300 mg, 1.00 mmol) and stirred for additional 2 h at 0 °C.
The reaction was quenched with ice cold water (10 mL) and extracted with EtOAc (2 x 10 mL), washed with brine solution. The organic layers were concentrated under reduced pressure to give the title compound (400 mg) as white solid which was used in the next step without further purification.
LCMS Method A: m/z [M+H]+ 515 tR 2.09 min
Synthetic Scheme for Intermediate 40: (S)-tert-buty\ 7-((3,5-difluoro-4-((2-methylpyridin-4- yl)oxy)benzyl)oxy)-2-methyl -5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000051_0001
Intermediate 6 Intermediate 25 Intermediate 40
Intermediate 40: (S)-tert-bu y\ 7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2- methyl -5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000051_0002
To a suspension of NaH (33.6 mg, 1.40 mmol) in THF (10 mL) at 0 °C was added (3,5-difluoro-4-((2- methylpyridin-4-yl)oxy)phenyl)methanol (176 mg, 0.70 mmol) in THF (5 mL), and stirring continued at the same temperature for 10 min. (S)-tert-Buty\ 7-chloro-2-methyl-5-oxo-2,3- dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (200 mg, 0.70 mmol) in THF (5 mL) was added the reaction mixture stirred for 16 h at T . The reaction mixture was quenched with ice cold water (30 ml), extracted with ethyl acetate (2 x 30 ml); the organic layers were washed with brine solution (25 ml), dried over anhydrous Na2S04, and the solvent removed under reduced pressure to give crude title compound (450 mg) which was used directly in the next step without further purification
LCMS Method E: m/z [M+H]+ 501 tR 2.98 min nthetic Scheme for Intermediates 41-42:
Figure imgf000051_0003
Intermediate 41 Intermediate 42 Intermediate 41: 5-formyl-2-((6-me nitrile
Figure imgf000052_0001
To a solution of 3-cyano-4-fluorobenzaldehyde (25 g, 148 mmol, A K Scientific) and 6- methylpyridin-3-ol (18.3 g, 168 mmol, Alfa aesar) in acetonitrile (500 mL) was added K2C03 (46.3 g, 335 mmol) at T. The reaction was stirred at RT for 16 h. The solvent was removed under reduced pressure and then diluted with water (500 mL) and extracted with EtOAc (3 x 250 mL).The organic layers were washed with brine solution (200 mL). The organic layer was separated, dried over anhydrous IN^SC^ and concentrated under reduced pressure to give the title compound (39 g) as a white solid.
LCMS Method D: m/z [M+H]+ 239, tR 3.19 min.
Intermediate 42: 5-(hydroxymeth l)-2-((6-methylpyridin-3-yl)oxy)benzonitrile
Figure imgf000052_0002
To a stirred solution of 3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzaldehyde (41 g, 172 mmol) in methanol (500 mL) at 0 °C was added NaBH4 (7.81 g, 207 mmol) and stirring continued at same temperature under nitrogen for 30 min. The reaction mixture was quenched with ice cold water (100 mL) and methanol removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with DCM (2 x 200 mL), washed with brine solution (100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the title compound (40 g) as white solid.
LCMS Method A: m/z [M+H]+ 241, tR 1.26 min.
Synthetic Scheme for Intermediates 43-44:
Figure imgf000052_0003
Intermediate 43 Intermediate 44 Intermediate 43: 3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy) benzaldehyde
Figure imgf000053_0001
To a stirred solution of 3,4,5-trifluorobenzaldehyde (3.0 g, 18.7 mmol, Fluorochem) in acetonitrile (50 mL) at T were added K2C03 (3.88 g, 28.1 mmol) and 2-methylpyrimidin-5-ol (2.27 g, 20.6 mmol, Youchemicals Ltd.). The reaction mixture was heated to 90 °C and stirred for 18 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 200 mL), the organic layers were washed with brine solution (200 mL), separated and dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude title compound. This was purified by column chromatography using silica gel 100-200 mesh, eluting with 10% EtOAc/ hexane. The product containing fractions were combined and concentrated under reduced pressure to give the title compound (2.8 g) as a yellow solid.
LCMS Method C: m/z [M+H]+ 250, tR 3.02 min.
Intermediate 44: (3,5-difluoro-4-(( -methylpyrimidin-5-yl)oxy)phenyl)methanol
Figure imgf000053_0002
To a stirred solution of 3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzaldehyde (2.8 g, 11.2 mmol) in methanol (30 mL) at 0 °C, was added NaBH4 (0.212 g, 5.6 mmol) and stirring continued for 30 min. The reaction mixture was quenched with ice water (20 ml), and the mixture extracted with ethyl acetate (2 x 200ml). The organic layer was washed with brine solution (3 x 100ml), dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give the crude title compound as a brown solid which was purified by column chromatography using 100-200 mesh silica gel using 15% ethyl acetate/hexane as eluent. The product containing fractions were combined and the solvent removed under reduced pressure to give the title compound (2.150 g)) as an off white solid.
^ NMR (400 MHz, DMSO-d6) δ: 8.51 (2H, s), 7.26 (2H), 5.50 (1H, t), 4.54 (2H, d), 2.6 (3H, s). S nthetic Scheme for Intermediates 45-46:
Η(Τ %Γ 90 °C, 18 h 0°C, 10 min
Figure imgf000054_0001
T U N
Intermediate 45 Intermediate 46
Intermediate 45: 3,5-Difluoro-4-((5-meth lpyrazin-2-yl)oxy)benzaldehyde(
Figure imgf000054_0002
To a stirred solution 3,4,5-trifluorobenzaldehyde (3.0 g, 18.7 mmol) in acetonitrile (50 mL) at T, was added 5-methylpyrazin-2-ol (2.06 g, 18.7 mmol) and K2C03 (2.59 g, 18.7 mmol) and the mixture heated to 90 °C for 18h. The reaction mixture quenched with ice water (20 ml), and then extracted with ethyl acetate (2 x 200 ml), the organic layers were washed with brine solution (3 x 100 ml) and dried over anhydrous Na2S04. The solvent was removed under reduced pressure to give a brown solid which was purified by column chromatography using 100-200 mesh silica gel by eluting with 15% ethyl acetate/hexane. The product containing fractions were combined and the solvent removed under reduced pressure to give the title compound (300 mg) as an off white solid.
^ NMR (400 MHz, DMSO d6) δ: 9.97 (1H, s), 8.69 (1H, s), 8.06 (1H, s), 7.89-7.86 (2H, m), 2.48 (3H, s).
Intermediate 46: (3,5-difluoro-4-( -methylpyrazin-2-yl)oxy)phenyl)methanol
Figure imgf000054_0003
To a stirred solution of 3, 5-difluoro-4-((5-methylpyrazin-2-yl)oxy)benzaldehyde (300 mg, 1.20 mmol) in methanol (15 mL), was added NaBH4 (22.7 mg, 0.60 mmol) at 0 °C and the reaction mixture stirred for 30 minutes at 0 °C. The solvent was removed under reduced pressure and the residue treated with ice water (20 ml). The mixture was extracted with ethyl acetate (2 x 200 ml), the organic layers washed with brine solution (3 x 100 ml), dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give a brown solid. This was purified by column chromatography using 100-200 mesh silica gel by eluting with a mixture of 15% ethyl acetate/hexane. The product containing fractions were combined and the solvent removed under reduced pressure to give the title compound (200 mg) as an off white solid.
LCMS Method A: m/z [M+H]+ 253, tR 1.82 min. Synthetic Scheme for Intermediates 47-49:
Figure imgf000055_0001
n erme a e
Figure imgf000055_0002
Intermediate 49
Intermediate 48
Intermediate 47: methyl 3-bromo-5-fluoro-4-((5-methylpyrazin-2-yl) oxy)benzoate
Figure imgf000055_0003
To a stirred solution of methyl 3-bromo-4,5-difluorobenzoate (3.0 g, 12.0 mmol) in acetonitrile (50 mL), was added 6-methylpyridin-3-ol (1.45 g, 17.9 mmol, IS Pharma) and K2C03 (2.478 g, 17.93 mmol) and the mixture stirred at RT for 18 h .The reaction mixture was treated with water (100 ml), and extracted with ethyl acetate (3 x 100ml). The organic layers were washed with brine solution (150 ml), dried over anhydrous Na2S04, and the solvent removed under reduced pressure to afford the crude title compound (4 g). 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.
^ NMR (400 MHz, DMSO d6) δ: 8.67 (1H, s), 8.10 (1H, d), 8.06 (1H, s,), 7.96-7.93 (1H, m), 3.90 (3H, s), 2.47 (3H, s) Intermediate 48: 3-bromo-5-fluor -4-((5-methylpyrazin-2-yl)oxy)phenyl)methanol
Figure imgf000056_0001
To a stirred solution of methyl 3-bromo-5-fluoro-4-((6-methylpyrazin-3-yl)oxy)benzoate (1.0 g, 2.93 mmol) in THF (30 mL), was added a 25% solution of DIBAL-H in toluene (15 mL) at -20 °C and the reaction mixture was stirred for lhr at -20 °C. The reaction mixture was quenched with saturated NH4CI solution (10ml) at 0 °C and diluted with ethyl acetate (100ml), filtered through Celite. The organic layer was washed with brine solution (2 x 100ml), dried over anhydrous Na2S04, and the solvent removed under reduced pressure to afford the title compound (600 mg) as a brown solid.
*H NM (400 MHz, DMSO d6) δ: 8.59 (1H, d), 8.03 (1H, s), 7.52 (1H, s), 7.34 (1H, d), 5.45 (1H, t), 4.53 (2H, d), 2.45 (3H, s).
Intermediate 49: 3-fluoro-5-(hydro zin-2-yl)oxy)benzonitrile
Figure imgf000056_0002
To a stirred solution of (3-bromo-5-fluoro-4-((5-methylpyrazin-2-yl)oxy)phenyl)methanol (0.60 g, 1.92 mmol in DMF (20 mL) in sealable tube was added zinc cyanide (222 mg, 1.92 mmol) at RT. The mixture was degassed for 30 min under with argon and then were added
tris(dibenzylideneacetone)dipalladium (0) (0.120 g, 0.131 mmol) and 1,1'- bis(diphenylphosphino)ferrocene (0.212 g, 0.38 mmol) The mixture was again degassed for 30 min with argon. The tube was sealed and heated at 180 °C for 3 h. The reaction mixture was diluted with ethyl acetate (200 ml), filtered through a Celite bed and the filtrate layer was washed with brine solution (2 x 100 ml), dried over anhydrous Na2S04, the solvent was removed under reduced pressure to afford 700 mg of crude product. This was purified by column chromatography using 100-200 silica gel by eluting with 30% ethyl acetate/hexane to afford the title compound (250 mg) as a brown solid.
H NMR (400 MHz, DMSO d6) δ: 8.69 (1H, d), 8.08 (1H, s), 7.71 (2H, d), 5.54 (1H, t), 4.57 (2H, d), 2.49 (3H, s). nthetic Scheme for Intermediates 50-51:
Figure imgf000057_0001
Intermediate 50 Intermediate 51
Intermediate 50: 5-formyl-2-((6-me nitrile
Figure imgf000057_0002
To a solution of 2-fluoro-5-formylbenzonitrile (3.0 g, 20.1 mmol, AK Scientific) in acetonitrile (50 mL) in a sealable tube were added K2C03 (4.17 g, 30.2 mmol) and 2-methylpyrimidin-5-ol (2.44 g, 22.1 mmol, Bepharma) at T. The tube was sealed and the reaction was stirred at 90 °C for 16 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate (2 x 200 m L). The organic layers were washed with brine solution (3 x 100 m L). The organic layer was separated, dried over anhydrous Na2S04 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.
1H N M R (400 M Hz, DMSO d6) δ: 9.97 (1H, s), 8.57 (2H, s), 8.25 (1H, d, J = 2Hz), 8.05 (1H, s), 6.66 (1H, d), 2.82 (3H, s).
Intermediate 51: 5-(hydroxymeth l)-2-((2-methylpyrimidin-5-yl)oxy)benzonitrile
Figure imgf000057_0003
To a stirred solution of 5-formyl-2-((2-methylpyrimidin-5-yl)oxy)benzonitrile (2.5 g, 10.5 mmol) in methanol (30 m L) at 0 °C was added NaBH4 (198 mg, 5.23 mmol) and stirring continued at same temperature under nitrogen for 30 min. The methanol was removed under reduced pressure and the reaction mixture was quenched with ice cold water (100 mL). The mixture was extracted with ethyl acetate (2 x 200 m L), washed with brine solution (3 x 100 m L). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford crude material as a brown solid. This material was purified by column chromatography using 100- 200 mesh silica gel by eluting solvent 15% ethyl acetate/hexane. The product containing fractions were combined and solvent removed under reduced pressure to give the title compound (2.15 g) as an off white solid.
*H NM (400 MHz, DMSO d6) δ: 8.66 (2H, s), 7.80 (1H, s), 7.62 (1H, d), 7.10 (1H, d), 5.39 (1H, t), 4.50 (2H, d), 2 .65 (3H, s).
Synthetic Scheme for Intermediates 52-53:
Figure imgf000058_0001
Intermediate 52 Intermediate 53 Intermediate 52: 5-formyl-2-((5-methylpyrazin-2-yl)oxy)benzonitrile
Figure imgf000058_0002
To a solution of 2-fluoro-5-formylbenzonitrile (3.0 g, 20.1 mmol, AK Scientific) in acetonitrile (50 mL) in were added 2-methylpyrazin-2-ol (2.215 g, 20.12 mmol, IS Pharma) and K2C03 (4.17 g, 30.2 mmol) at RT and the reaction was stirred at 90 °C for 18 h. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layers were washed with brine solution (3 x 100 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to give the title compound (3.0 g) as a brown solid. The crude material was purified by column chromatography using 100-200 mesh silica gel and 15% ethyl acetate in hexane as eluent. The product containing fractions were combined and solvent removed under reduced pressure to give the title compound (1.5 g) as an off white solid.
*H NMR (400 MHz, DMSO d6) δ: 10.00 (1H, s), 8.66 (1H, s), 8.51 (1H, d), 8.24-8.21 (2H, m), 7.54 (1H, d), 2.45 (3H, s). Intermediate 53: 5-(hydroxymethyl)-2-((5-methylpyrazin-2-yl)oxy)benzonitrile
Figure imgf000059_0001
To a stirred solution of 5-formyl-2-((5-methylpyrazin-2-yl)oxy)benzonitrile (1.5 g, 6.27 mmol), in methanol (50 mL) at 0 °C was added NaBH4 (119 mg, 3.14 mmol) and stirring continued at same temperature for 30 min. The reaction mixture was quenched with ice cold water (100 mL) and the methanol was removed under reduced pressure. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL), washed with brine solution (200 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the title compound as a yellow solid.
H NMR (400 MHz, DMSO d6) δ: 8.58 (IH, s), 8.11 (IH, s), 7.82 (IH, d), 7.71-7.69 (IH, m), 7.38 (IH, d), 5.41 (IH, t), 4.55 (2H, d), 2.48 (3H, s),
Synthetic Scheme for Intermediates 54-56:
Figure imgf000059_0002
Intermediate 54
Intermediate 18
Figure imgf000059_0003
Intermediate 56
Intermediate 55
Intermediate 54: methyl 3-bromo-5-fluoro-4-((2-methylpyrimidin-5-yl)oxy)benzoate
Figure imgf000059_0004
To a stirred solution of methyl 3-bromo-4,5-difluorobenzoate (3.0 g, 12.0 mmol) in acetonitrile (50 mL), was added K2C03 (2.48 g, 17.93 mmol) and 2-methylpyrimidin-5-ol (1.45 g, 13.2 mmol, Bepharm) and the mixture stirred at 90 °C for 18 h The reaction mixture was treated with water (200 ml), and extracted with ethyl acetate (2 x 200ml). The organic layers were washed with brine solution (200 ml), dried over anhydrous Na2S04, and the solvent removed under reduced pressure to afford the crude title compound (2.5 g) as a yellow solid which was used in the next step without further purification.
LCMS Method A: m/z [M+H]+ 341, tR 2.23 min
Intermediate 55: (3-bromo-5-fluor -4-((2-methylpyrimidin-5-yl)oxy)phenyl)methanol
Figure imgf000060_0001
To a stirred solution of methyl 3-bromo-5-fluoro-4-((6-methylpyrazin-3-yl)oxy)benzoate (2.0 g, 5.86 mmol) in THF (50 mL), was added a 20% w/v solution of DIBAL-H in toluene (14 mL, 19.7 mmol) at -20 °C and the reaction mixture was stirred for 30 min at -20 °C. The reaction mixture was quenched with NH4CI solution (50 ml) and diluted with water (100 mL) and extracted with ethyl acetate (100ml). The organic layer was washed with brine solution (200ml), dried over anhydrous Na2S04, and the solvent removed under reduced pressure to afford the title compound (800 mg) as a white solid which was used in the next step without further purification.
^ NM (400 MHz, DMSO d6) δ: 8.42 (2H, s), 7.57 (1H, s), 7.41 (1H, d), 5.50 (1H, t), 4.55 (2H, d), 2.60 (3H, s).
Intermediate 56: 3-fluoro-5-(hydro midin-5-yl)oxy)benzonitril
Figure imgf000060_0002
To a stirred solution of (3-bromo-5-fluoro-4-((5-methylpyrazin-2-yl)oxy)phenyl)methanol (0.80 g, 2.55 mmol in DMF (20 mL) in sealable tube was added zinc cyanide (295 mg, 2.55 mmol) at RT. The mixture was degassed for 30 min under with argon and then were added
tris(dibenzylideneacetone)dipalladium (0) (0.023 g, 0.026 mmol) and 1,1'- bis(diphenylphosphino)ferrocene (0.283 g, 0.51 mmol) The mixture was again degassed for 30min with argon. The tube was sealed and heated at 150 °C for 3 h. The reaction mixture was diluted with ethyl acetate (200ml), filtered through a Celite bed and the filtrate layer was washed with brine solution (2 x 100ml), dried over anhydrous Na2S04, the solvent was removed under reduced pressure to afford 700 mg of crude product. This was purified by column chromatography using 100-200 silica gel by eluting with 30% ethyl acetate/hexane to afford the title compound (300 m as brown solid.
LCMS Method A: m/z [M+H]+ 260, rR 1.61 min.
Figure imgf000061_0001
Intermediate 57 Intermediate 58
Figure imgf000061_0002
Intermediate 59
Intermediate 60
Pd2dba3 CHCI3, Zn(CN)2,
Figure imgf000061_0003
Intermediate 61
Intermediate 57: 3-Methoxy-4-((6-m thylpyridazin-3-yl)oxy)benzaldehyde
Figure imgf000061_0004
To a stirred solution of 4-hydroxy-3-methoxybenzaldehyde (10 g, 65.7 mmol, Loba Chem.) in DMF (50 mL) was added K2C03 (13.63 g, 99 mmol) and 3-chloro-6-methylpyridazine (8.45 g, 65.7 mmol, Amateck Chemical) and the reaction mixture was heated to 130 °C for 72 h. After completion of reaction ice water was added and extracted with EtOAc (3x200 mL), washed with ice water (2 x 200 mL), brine (100 mL), dried over Na2S04 and evaporated solvent to give crude material (16.5 g) which was purified by column chromatography using (100-200) silica gel and 20% EtOAc/n-hexane as eluant. The product containing fractions were evaporated to afford the title compound (2.6 g) as a pink coloured solid.
LCMS Method C: m/z [M+H]+ 245 rR 2.81 mins. Intermediate 58: 3-Hydroxy-4-((6-methylpyridazin-3-yl)oxy)benzaldehyde
Figure imgf000062_0001
To a stirred solution of 3-methoxy-4-((6-methylpyridazin-3-yl)oxy)benzaldehyde (2.6 g, 10.65 mmol) in dichloromethane (DCM) (30 mL) was added BBr3 (2.01 mL, 21.29 mmol) at 0 °C, and the reaction mixture was allowed to warm to 30 °C and stirred at that temperature for 16 h. After completion of reaction, the solvent was evaporated and the residue was dissolved in EtOAc (200 mL), washed with saturated NaHCO^ solution, brine (100 mL), dried over Na2S04 and the solvent evaporated to afford title compound (1.2g) as brown solid.
LCMS Method A: m/z [M+H]+ 231 tR 1.38 mins.
Intermediate 59: 5-Formyl-2-((6-meth lpyridazin-3-yl)oxy)phenyl trifluoromethanesulfonate
Figure imgf000062_0002
To a stirred mixture of NaH (0.250 g, 10.42 mmol) in THF (20 mL) was added solution of 3- hydroxy-4-((6-methylpyridazin-3-yl)oxy)benzaldehyde (1.2 g, 5.21 mmol) in THF (10 mL) at 0 °C, after 10 min a solution of l,l,l-trifluoro-/V-phenyl-N-
((trifluoromethyl)sulfonyl)methanesulfonamide (1.86 g, 5.21 mmol) in THF (10 mL) was added at same temperature. The reaction mixture was allowed to 25 °C for 2h. After completion of reaction, the mixture was quenched with 50 ml ice water, extracted with EtOAc (2 x 100 mL), the combined organic layer was washed with brine (50 mL), dried over Na2S04 and the solvent evaporated to give a crude product (1.9 g). This crude material was purified by column chromatography using (100-200) silica gel and 10% EtOAc/n-hexane as eluant. The product containing fractions were evaporated to afford the title compound (1.5 g) as an off white solid. LCMS Method A: m/z [M+H]+ 363 tR 2.22 mins.
Intermediate 60: 5-(Hydroxymethyl)-2-((6-methylpyridazin-3-yl)oxy)phenyl
trifluoromethanesulfonate
Figure imgf000062_0003
To a stirred solution of 5-formyl-2-((6-methylpyridazin-3-yl)oxy)phenyl trifluoromethanesulfonate (1.50 g, 4.14 mmol) in methanol (30 mL) at 0 °C was added NaBH4 (0.188 g, 4.97 mmol) and the mixture allowed to T and stirred for 3hr. After completion of the reaction, ice water 20 mL was added, the solvent was evaporated, the residue dissolved in EtOAc (200 mL), washed with water (100 mL), brine (50 mL), the organic layer over Na2S04 and the solvent evaporated to give the title compound (1.2 g) as anoff white solid.
LCMS Method A: m/z [M+H]+ 365 tR 2.02 mins.
Intermediate 61: 5-(Hydroxymeth -2-((6-methylpyridazin-3-yl)oxy)benzonitrile
Figure imgf000063_0001
To a stirred solution of 5-(hydroxymethyl)-2-((6-methylpyridazin-3-yl)oxy)phenyl
trifluoromethanesulfonate (100 mg, 0.275 mmol) in DMF (2 mL) in a sealable tube was added zinc cyanide (35.5 mg, 0.302 mmol) at RT and the mixture degassed for 30 min under an argon atmosphere. Pd2(dba)3.CHCI3 (12.57 mg, 0.014 mmol) and DPPF (7.61 mg, 0.014 mmol) were then added and the mixture again degassed for 30 min as before. The tube was sealed and the mixture was heated to 90 °C for 16 h. After completion of the reaction, ice water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (2 x 50 mL), the combined organic was washed with water (30 mL), brine (30 mL), dried over Na2S04 and the solvent evaporated to give crude product (63 mg). This crude material was purified by silica gel (100-200) column chromatography using 70% EtOAc/n-hexane as eluent. The product containing fractions were evaporated to afford the title compound (26 mg) as a brown solid.
LCMS Method A: m/z [M+H]+ 242 tR 1.43 mins.
B) Examples of Compounds of the Invention
Synthetic Scheme for Example 1
Figure imgf000064_0001
Intermediate 31 Example 1
Example 1: 7-((3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000064_0002
To a solution of ieri-butyl 7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy) benzyl)oxy)-2,2- dimethyl- 5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (300 mg, 0.58 mmol) in 1,4-dioxane (2 mL) was added 4 M HCI in 1,4-dioxane (10 mL) and the mixture stirred at RT for 18 h. The reaction mixture was concentrated and basified with NaHC03 solution (10 mL) and extracted with EtOAc (2 x 10 mL). The mixture was concentrated under reduced pressure to give the crude title compound which was purified by preparative HPLC Method A. The product containing fractions were collected and concentrated under reduced pressure to remove the acetonitrile and the precipitated solid was filtered and then dried under vaccum to give the title compound (160 mg) as a white solid.
*H NM R (400 MHz, DMSO-d6) δ: 8.25 (2H, d), 7.37-7.33 (2H, m), 7.29-7.22 (2H, m), 5.27 (2H, s), 5.04 (1H, s), 3.68 (2H, s), 2.43 (3H, s), 1.32 (6H, s).
LCMS Method C: m/z [M+H]+ 415, fR 3.23 min Synthetic Scheme Example 2: (S)-7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2-
Figure imgf000065_0001
Example 2: ^-7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2-methyl-2,3- dihydroimidazo[l,2-c]pyri
Figure imgf000065_0002
To a suspension of NaH (33.6 mg, 0.84 mmol) in THF (15 mL) was added (3,5-difluoro-4-((6- methylpyridin-3-yl)oxy)phenyl)methanol (106 mg, 0.42 mmol) in THF (5 mL) at 0 °C and the reaction mixture stirred at the same temperature for 10 min. Then a solution of (S)-ferf-butyl 7- chloro-2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (120 mg, 0.42 mmol) in THF (5 mL) was added and the reaction mixture stirred for a further 3 h at 0 °C. The reaction mixture was quenched with ice cold water (30 ml), extracted with ethyl acetate (2 x 30 ml), washed with brine solution (25 ml) and dried over anhydrous Na2S04. The solvent was removed under reduced pressure to give crude material (200 mg) which was purified by column chromatography using silica agel (100-200), eluting with 5% MeOH/DCM. The product containing fractions were collected and evaporated to give material to which was added ethyl acetate (5 mL). The mixture was stirred for 30 min, filtered and then dried to give the title compound (70 mg) as a white solid.
*H NM (400 MHz, DMSO-d6) δ: 8.25 (1H, d), 8.19 (1H, s), 7.36-7.34 (2H, m), 7.29-7.22 (2H, m), 5.27 (2H, s), 5.06 (1H, s), 4.15-4.01 (2H, m), 3.49-3.44 (lH,m), 2.43 (3H, s), 1.23 (3H, d).
LCMS Method A: m/z [M+H]+ 401, tR 1.41 min.
Chiral HPLC Method A: tR 6.28 min; 98.95% a/a Synthetic Scheme Example 3: (/?)-7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2- methyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000066_0001
Intermediate 10 Intermediate 17 Example 3 Example 3: ^-7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2-methyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000066_0002
To a stirred suspension of NaH (76 mg, 1.75 mmol) in THF (10 mL) at 0 °C was added (3,5-difluoro- 4-((6-methylpyridin-3-yl)oxy)phenyl)methanol (264 mg, 1.05 mmol) in THF (5 mL) and stirring continued at the same temperature for 10 min. Then a solution of (/?J-ferf-butyl 7-chloro-2- methyl-5-oxo-2,3-dihydroimidazo[l,2-c] pyrimidine-l(5H)-carboxylate (200 mg, 0.70 mmol) in THF (5 mL) was added and the reaction mixture stirred for 3 h at 0 °C. 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 Na2S04 and evaporated under reduced pressure to give crude material 250 mg. which was purified using preparative HPLC method B. The product containing fractions were collected and concentrated under reduced pressure to remove acetonitrile and obtained solid was filtered and then dried under vacuum to give the title compound (110 mg) as a white solid.
*H NM (400 MHz, DMSO-d6) δ: 8.26 (1H, d), 8.19 (1H, s), 7.37-7.33 (2H, m), 7.29-7.22 (2H, m), 5.27 (2H, s), 5.06 (1H, s), 4.15-4.02 (2H, m), 3.49-3.44 (lH,m), 2.43 (3H, s), 1.24 (3H, d).
LCMS Method A: m/z [M+H]+ 401, fR 1.41 min.
Chiral HPLC Method A: fR 7.22 min; 99.77% a/a Synthetic Scheme Example 4: ^-7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-l,2- dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000067_0001
Intermediate 7 Intermediate 17 Example 4
Example 4: ('S -7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-l,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000067_0002
To a stirred mixture of NaH (80 mg, 2.00 mmol) in THF (10 mL) at 0 °C was added (3,5-difluoro-4- ((6-methylpyridin-3-yl)oxy)phenyl)methanol (126 mg, 0.50 mmol) in THF (10 mL) and stirred for 15 min. Then Sj-7-chloro-l,2-dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (100 mg, 0.50 mmol) was added at 0 °C and the reaction mixture stirred for 2 h. After completion of reaction, ice cold water (10 mL) was added and the reaction mixture extracted with EtOAc (2 x 10 mL). The organic layer was concentrated under reduced pressure to afford crude product which was purified using preparative HPLC method A. The product containing fractions were collected and concentrated under reduced pressure to remove acetonitrile and the resulting solid was filtered and then dried under vacuum to give the title compound (47 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 8.25 (IH, d), 7.35 (2H, d), 7.29-7.22 (2H, m), 5.30 (2H, s), 5.24 (IH, s), 4.12-4.07 (2H, m), 3.99-3.93 (IH, m), 3.49-3.44 (IH, m), 2.82 (3H, s), 2.43 (3H, s), 1.27 (3H, d). LCMS Method A: m/z [M+H]+ 415, tR 1.50 min.
Synthetic Scheme Example 5: (/? -7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-l,2- dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000068_0001
Intermediate 11 Intermediate 17 Example 5 Example 5: ^-7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-l,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000068_0002
To a suspension of NaH (109 mg, 2.51 mmol) in THF (10 mL) was added (3,5-difluoro-4-((6- methylpyridin-3-yl)oxy)phenyl)methanol (378 mg, 1.50 mmol) in THF (5 mL) at 0 °C, then the reaction mixture stirred at same temperature for 10 min. Then a solution of f ?J-7-chloro-l,2- dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (200 mg, 1.00 mmol) in THF (5 mL) was added and the reaction mixture stirred for 3 h at 0 °C.
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 Na2S04, 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.
*H NM (400 MHz, DMSO-d6) δ: 8.25 (IH, d), 7.37-7.33 (2H, m), 7.30-7.22 (2H, m), 5.30 (2H, s), 5.24 (IH, s), 4.12-4.07 (IH, m), 3.99-3.95 (IH, m), 3.49-3.44 (IH, m), 2.82 (3H, s), 2.43 (3H, s), 1.27 (3H, d).
LCMS Method A: m/z [M+H]+ 415, tR 1.54 min. Synthetic Scheme Example 6: 3-fluoro-2-((6-methylpyridin-3-yl)oxy)-5-(((l,2,2-trimethyl-5-oxo- l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile
Figure imgf000069_0001
Intermediate 15 Intermediate 21 Example 6
Example 6: 3-fluoro-2-((6-methylpyridin-3-yl)oxy)-5-(((l,2,2-trimethyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile
Figure imgf000069_0002
To a suspension of NaH (186 mg, 4.65 mmol) in THF (10 mL), was added 3-fluoro-5- (hydroxymethyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile (300 mg, 1.16 mmol) in THF (10 mL drop wise at 0 °C and the reaction mixture stirred for 30 min at 0 °C. Then a solution of 7-chloro- l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one (248 mg, 1.16 mmol) in THF (10 mL) was added at 0 °C. The reaction mixture was stirred for 2 h at T.
After completion of the reaction, ice cold water (10 mL) was added and the mixture extracted with EtOAc (2 x 10 mL), the organic layer was washed with brine solution (2 x 50 ml), dried over anhydrous Na2S04 and the solvent was removed solvent under reduced pressure to afford 600 mg of crude material which was purified by using preparative HPLC method A.
The product containing fractions were concentrated under reduced pressure to remove acetonitrile and the resulting solid was filtered and then dried under vacuum to afford the title compound (45.9 mg) as an off white solid.
*H NMR (400 MHz, DMSO-d6) δ: 8.31 (1H, d), 7.85 (2H, dd), 7.30 (1H, d), 7.27 (1H, d), 5.31 (2H, s), 5.21 (1H, s), 3.73 (2H, s), 2.77 (3H, s), 2.51-2.45 (3H, m), 1.31 (6H, s)
LCMS Method A: m/z [M+H]+ 436, fR 1.61 min. Synthetic Scheme Example 7: 5-(((2,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c]pyrimidin-7-yl)oxy)methyl)-3-fluoro-2-((6-methylpyridin-3-yl)oxy)benzonitrile
Figure imgf000070_0001
Intermediate 32 Example 7
Example 7: 5-(((2,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7-yl)oxy) 3-fluoro-2-((6-methylpyridi -3-yl)oxy)benzonitrile
Figure imgf000070_0002
To a stirred solution of ferf-butyl 7-((3-cyano-5-fluoro-4-((6-methylpyridin-3-yl)oxy) benzyl)oxy)- 2,2-dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c] pyrimidine-l(5/-/)-carboxylate (600 mg, 1.15 mmol) in 1,4-dioxane (5 mL) was added 4.0 M HCI 1,4-dioxane (10 mL) and the mixture stirred for 16 h at T. The reaction mixture was evaporated under reduced pressure and neutralized (pH ~7) with NaHC03 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.
H NMR (400 MHz, DMSO-d6) δ: 8.30 (1H, d), 8.266 (lH,s), 7.87-7.86 (1H, m), 7.83 (1H, d), 7.37 (1H, d), 7.27 (1H, d), 5.05 (1H, s), 3.68 (2H,s), 2.51-2.50 (3H, m), 1.37 (6H, s).
LCMS Method A: m/z [M+H]+ 422, fR 1.46 min.
Synthetic Scheme Example 8: (S -5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-
Figure imgf000071_0001
Intermediate 7 Intermediate 21 Example 8 Example 8: ^-5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7- yl)oxy)methyl)-3-fluoro-2-((6-methylpyridin-3-yl)oxy)benzonitrile
Figure imgf000071_0002
To a suspension of NaH (80 mg, 2.00 mmol) in THF (15 mL) was added 3-fluoro-5-(hydroxymethyl)- 2-((6-methylpyridin-3-yl)oxy)benzonitrile (259 mg, 1.00 mmol) in THF (5 mL) at 0 °C and the mixture stirred at the same temperature for 10 min. Then a solution of (Sj-7-chloro-l,2-dimethyl- 2,3-dihydroimidazo[l,2-c] pyrimidin-5(l/-/)-one (200 mg, 1.00 mmol) in THF (5 mL) was added and the mixture stirred at T for 3 h. The 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 Na2S04 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. *H NMR (400 MHz, DMSO-d6) δ: 8.30 (IH, d), 7.86-7.83 (2H, m), 7.39-7.36 (IH, m), 7.27 (IH, d), 5.32 (2H, s), 5.25 (IH, s), 4.10 (IH, t), 3.99-3.95 (lH,m), 3.47 (IH, t), 2.825 (3H, s), 2.45 (3H, s), 1.27 (3H, d).
LCMS Method A: m/z [M+H]+ 422, fR 1.53 min.
Synthetic Scheme Example 9: ^-5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c]pyrimidin-7-yl)oxy)methyl)-3-fluoro-2-((6-methylpyridin-3-yl)oxy)benzonitrile
Figure imgf000072_0001
Intermediate 11 Intermediate 21 Example 9
Example 9: ^-5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7- yl)oxy)methyl)-3-fluoro-2-((6-methylpyridin-3-yl)oxy)benzonitrile
Figure imgf000072_0002
To a suspension of NaH (109 mg, 2.51 mmol) in THF (10 mL) was added 3-fluoro-5- (hydroxymethyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile (388 mg, 1.50 mmol) in THF (5 mL) at 0 °C, then the reaction mixture was stirred at same the temperature for 10 min, f/?J-7-chloro-l,2- dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (200 mg, 1.00 mmol) in THF (5 mL) was added and the reaction mixture stirred for 3 h at 0 °C. The 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 Na2S04 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.
H NM (400 MHz, DMSO-d6) δ: 8.30 (1H, d), 7.86-7.83 (2H, m), 7.39-7.360 (1H, m), 7.27 (1H, d), 5.32 (2H, s), 5.25 (1H, s), 4.10 (1H, t), 3.99-3.95 (1H, m), 3.48 (1H), 2.82 (3H, s), 2.45 (3H, s), 1.27 (3H, d).
LCMS Method A: m/z [M+H]+ 422, fR 1.53 min.
Synthetic Scheme Example 10: ^-3-fluoro-5-(((2-methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c]pyrimidin-7-yl)oxy)methyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile
Figure imgf000073_0001
Intermediate 6 Intermediate 21 Example 10
Example 10: ^-3-fluoro-5-(((2-methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7- yl)oxy)methyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile
Figure imgf000073_0002
To a suspension of NaH (56.0 mg, 1.40 mmol) in THF (15 mL) was added 3-fluoro-5- (hydroxymethyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile (181 mg, 0.70 mmol) in THF (5 mL) at 0 °C, the reaction mixture then stirred at the same temperature for 10 min, (S)-tert-butyl 7-chloro- 2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (200 mg, 0.70 mmol) in THF (5 mL) was then added and the reaction mixture stirred for 3 h at T. The 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 Na2S04 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.
*H NMR (400 MHz, DMSO-d6) δ: 8.30 (1H, d), 8.20 (1H, s), 7.86-7.83 (2H, m), 7.39-7.36 (1H, m), 7.26 (1H, d), 5.29 (2H, s), 5.07 (1H, s), 4.13-4.02 (2H, m), 3.49-3.45 (1H, m), 2.45 (3H, s), 1.23 (3H, d).
LCMS Method A: m/z [M+H]+ 408, tR 1.39 min.
Synthetic Scheme Example 11: (R)-tert-buty\ 7-((3-cyano-5-fluoro-4-((6-methylpyridin-3- yl)oxy)benzyl)oxy)- 2-methyl-5-oxo -2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000074_0001
Intermediate 33 Example 11
Example 11: (R)-tert-buty\ 7-((3-cyano-5-fluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2- methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5H)-carboxylate
Figure imgf000074_0002
To a solution of crude ( ?J-ferf-butyl 7-((3-cyano-5-fluoro-4-((6-methylpyridin-3-yl)oxy) benzyl)oxy)-2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (280 mg, 0.55 mmol) in 1,4-dioxane (5 mL) was added 4M HCI in 1,4-dioxane (1.38 mL) at 0 °C. The reaction mixture was stirred at RT for 18 h and then evaporated under reduced pressure and basified with NaHC03 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 NaHC03, extracted with DCM (20 mL) and dried over Na2S04. The solvent was evaporated under vacuum to give the crude title compound (60 mg) which was only 54% pure. This material was triturated with diethyl ether (4 x 5 mL) and the resulting solid was collected dried under vacuum and to give a white solid (32 mg). This material was blended with another batch prepared in a similar manner to give the title compound (62 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 8.30 (1H, d), 8.21 (1H, s), 7.86 (2H, m), 7.39-7.36 (1H, m), 7.26 (1H, d), 5.29 (2H, s), 5.08 (1H, s), 4.15-4.10 (1H, m), 4.04 (1H, t), 3.49-3.44 (1H, m), 2.45 (3H, s), 1.23 (3H, d).
LCMS Method A: m/z [M+H]+ 408, tR 1.39 min.
Synthetic Scheme 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
Figure imgf000075_0001
Intermediate 15 Intermediate 30 Example 12
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
Figure imgf000075_0002
To a mixture of NaH (74.9 mg, 1.87 mmol) in THF (5 mL) at 0 °C was added 3-fluoro-5- (hydroxymethyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile (242 mg, 0.94 mmol) in THF (5 mL) and the mixture stirred for 10 min at 0 °C. 7-Chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2- c]pyrimidin-5(l/-/)-one (200 mg, 0.94 mmol) was added and the reaction stirred for further 2 h at 0 °C. The reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2 x 20 mL), washed with brine solution (15 mL), the organic layer was then separated, dried over anhydrous Na2S04 and concentrated under reduced pressure to get crude compound (440 mg) was purified by preparative HPLC method E (200mL fractions and A= 0.01 M ammonium bicarbonate solution). The product containing fractions were collected and concentrated under reduced pressure to remove acetonitrile and the precipitated solid was filtered and then dried under vacuum to give the title compound (180 mg) as an off white solid.
*H NM (400 MHz, DMSO-d6) δ: 8.38 (1H, d), 7.92-7.89 (2H, m), 6.94 (1H, d), 6.88-6.85 (1H, m), 5.34 (2H, s), 5.22 (1H, s), 3.73 (2H, s), 2.78 (3H, s), 1.31 (6H, s).
LCMS Method A: m/z [M+H]+ 436, fR 1.35 min.
Synthetic Scheme Example 13: 5-(((2,2-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
Figure imgf000076_0001
Intermediate 34 Example 13
Example 13: 5-(((2,2-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)
Figure imgf000076_0002
To solution of ferf-butyl 7-((3-cyano-5-fluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2,2- dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (400 mg, 0.77 mmol) in 1,4-dioxane (5 mL) was added 4.0 M HCI in 1,4-dioxane (10 mL) and the mixture stirred at RT for 16 h. After completion of reaction, the mixture was concentrated and basified with NaHC03 solution (10 mL). The mixture was then extracted with EtOAc (2 x 10 mL) and then evaporated to give crude material that was purified by preparative HPLC method A. The product containing fractions were collected and concentrated under reduced pressure to remove acetonitrile and the precipitated solid was filtered and then dried under vacuum to give the title compound (55 mg) as a white solid.
*H NMR (400 MHz, DMSO-d6) δ: 8.38 (IH, d), 8.28 (IH, s), 7.92-7.88 (2H, m), 6.94 (IH, d), 6.86 (IH, dd), 5.32 (2H, s), 5.06 (IH, s), 3.69 (2H, s), 2.44 (3H, s), 1.32 (6H, s)
LCMS Method A: m/z [M+H]+ 422, tR 1.21 min.
Synthetic Scheme Example 14: (S -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
Figure imgf000077_0001
Intermediate 7 Intermediate 30 Example 14
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
Figure imgf000077_0002
To a suspension of NaH (80 mg, 2.00 mmol) in THF (15 mL) was added 3-fluoro-5-(hydroxymethyl)- 2-((2-methylpyridin-4-yl)oxy)benzonitrile (259 mg, 1.00 mmol) in THF (5 mL) at 0 °C, then the reaction mixture was stirred at the same temperature for 10 min, (Sj-7-chloro-l,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (200 mg, 1.00 mmol) in THF (5 mL) was then added and the reaction mixture reaction mixture for 3 h at T. The 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 Na2S04 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. *H NMR (400 MHz, DMSO-d6) δ: 8.38 (IH, d), 7.91-7.88 (2H, m), 6.94 (IH, d), 6.87-6.85 (IH, m), 5.34 (2H, s), 5.26 (IH, s), 4.13-4.08 (IH, m), 4.00-3.94 (IH, m), 3.50-3.45 (IH, m), 2.82 (3H, s), 2.44 (3H, s), 1.27 (3H, d).
LCMS Method A: m/z [M+H]+ 422, fR 1.29 min.
Synthetic Scheme Example 15: (/?)-5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimi
c]pyrimidin-7-yl)oxy)methyl)-3-fluoro-2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000078_0001
Intermediate 11 Intermediate 30 Example 15
Example 15: ^-5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyri
yl)oxy)methyl)-3-fluoro-2-(( -methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000078_0002
To a suspension of NaH (109 mg, 2.51 mmol) in THF (10 mL) was added 3-fluoro-5- (hydroxymethyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile (259 mg, 1.00 mmol) in THF (5 mL) at 0 °C, the reaction mixture was then stirred at the same temperature for 10 min, f/?J-7-chloro-l,2- dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (200 mg, 1.00 mmol) in THF (5 mL) was then added and the reaction mixture stirred for 3 h at T. The 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 Na2S04 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.
H NMR (400 MHz, DMSO-d6) δ: 8.38 (IH, d), 7.91-7.87 (2H, m), 6.94 (IH, d), 6.87-6.85 (IH, m), 5.34 (2H, s), 5.26 (IH, s), 4.13-4.07 (IH, m), 4.00-3.94 (IH, m), 3.50-3.45 (IH, m), 2.83 (3H, s), 2.44 (3H, s), 1.27 (3H, d).
LCMS Method A: m/z [M+H]+ 422, tR 1.29 min.
Synthetic Scheme Example 16: (S)-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
Figure imgf000079_0001
Intermediate 6 Intermediate 30 Example 16
Example 16: (S)-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
Figure imgf000079_0002
To a suspension of NaH (84 mg, 2.10 mmol) in THF (15 mL) was added 3-fluoro-5-(hydroxymethyl)- 2-((2-methylpyridin-4-yl)oxy)benzonitrile (271 mg, 1.05 mmol) in THF (5 mL) at 0 °C, then the reaction mixture was stirred at the same temperature for 10 min then (Sj-ferf-butyl 7-chloro-2- methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (300 mg, 1.05 mmol) in THF (5 mL) was added and the reaction mixture stirred for 3 h at T. The 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 Na2S04, 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.
*H NMR (400 MHz, DMSO-d6) δ: 8.38 (1H, d), 8.21 (1H, s) 7.91-7.88 (2H, m), 6.937 (2H, d), 6.87-85 (1H, m ), 5.32 (2H, s), 5.08 (1H, s), 4.14-4.02 (2H, m), 4.00-3.49 (1H, m), 2.44 (3H, s), 1.23 (3H). LCMS Method A: m/z [M+H]+ 408, fR 1.15 min.
Synthetic Scheme Example 17: 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
Figure imgf000080_0001
Intermediate 15 Intermediate 23 Example 17
Example 17: 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
Figure imgf000080_0002
To a mixture of NaH (74.9 mg, 1.87 mmol) in THF (5 mL) at 0 °C was added 5-(hydroxymethyl)-2- ((2-methylpyridin-4-yl)oxy)benzonitrile (225 mg, 0.94 mmol) in THF (5 mL) and the mixture stirred for 10 min at 0 °C. 7-Chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one (200 mg, 0.94 mmol) was added and the mixture was stirred for a further 2 h at 0 °C. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 x 15 mL), dried over Na2S04 and concentrated under reduced pressure to give the crude compound (350 mg). This was purified using preparative HPLC method B (acetonitrile/methanol was employed to load the material and 200 mL fractions collected). 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 (110 mg) as a white solid.
H NM (400 MHz, DMSO-d6) δ: 8.41 (1H, d), 7.99 (1H), 7.80 (1H, dd), 7.37 (1H, d), 6.95 (1H, d), 6.89-6.86 (1H, m), 5.31 (2H, s), 5.19 (1H, s), 3.72 (2H, s), 2.76 (3H, s), 2.45 (3H, s), 1.30 (6H, s). LCMS Method A: m/z [M+H]+ 418, fR 1.32 min
Synthetic Scheme for Example 18: 5-(((2,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c]pyrimidin-7-yl)oxy)methyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000081_0001
Intermediate 36 Example 18
Example 18: 5-(((2,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7- yl)oxy)methyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000081_0002
4.0 M HCI in 1,4-dioxane (10 mL) was added to ferf-butyl 7-((3-cyano-4-((2-methylpyridin-4- yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (400 mg, 0.79 mmol) and the mixture stirred at T for 16 h. The reaction mixture was
concentrated and basified with NaHC03 solution (10 mL) and then extracted with EtOAc (2 x 10 mL). These fractions were concentrated under reduced pressure to afford the crude product (400 mg) which was purified using preparative HPLC method A collecting 100 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 the title compound (80 mg) as a white solid.
*H NMR (400 MHz, DMSO-d6) δ: 8.40 (1H, d), 8.24 (1H, s), 7.99 (1H), 7.79 (1H, dd), 7.34 (1H, d), 6.95 (1H, d ), 6.88 (1H, dd), 5.29 (2H, s), 5.02 (1H, s), 3.68 (2H, s), 2.45 (3H, s), 1.32 (6H, s).
LCMS Method D: m/z [M+H]+ 404, tR 3.07 min
Synthetic Scheme for Example 19: (S -5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c rimidin-7-yl)oxy)methyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000081_0003
Intermediate 7 Intermediate 23 Example 19
Example 19: ^-5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7- yl)oxy)methyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000082_0001
To a suspension of NaH (80 mg, 2.00 mmol) in THF (10 mL) was added 5-(hydroxymethyl)-2-((2- methylpyridin-4-yl)oxy)benzonitrile (241 mg, 1.00 mmol) in THF (5 ml) at 0 °C, and the reaction mixture was stirred at the same temperature for 10 min. (Sj-7-Chloro-l,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (200 mg, 1.00 mmol) in THF (5 mL) was then added and the reaction mixture stirred for 2 h at 0 °C. The 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 Na2S04 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.
*H NM (400 MHz, DMSO-d6) δ: 8.41 (IH, d), 7.98 (H, d), 7.80-7.78 (IH, m), 7.35 (IH, d), 6.95 (IH, d), 6.88-6.86 (IH, m), 5.32 (2H, s), 5.23 (IH, s), 4.12-4.07 (IH, m), 3.99-3.93 (IH, m), 3.49-3.44 (IH, m), 2.82 (3H, s), 2.45 (3H, s), 1.27 (3H, d).
LCMS Method A: m/z [M+H]+ 404, tR 1.21 min
Synthetic Scheme for Example 20: (/?)-5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c]pyrimidin-7-yl)oxy)methyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000082_0002
Intermediate 11 Intermediate 23 Example 20
Example 20: (/?)-5-(((l,2-dimethyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7- yl)oxy)methyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000083_0001
To a suspension of NaH (109 mg, 2.51 mmol) in THF (10 mL) was added 5-(hydroxymethyl)-2-((2- methylpyridin-4-yl)oxy)benzonitrile (361 mg, 1.50 mmol) in THF (5 mL) at 0 °C, the reaction mixture was then stirred at the same temperature for 10 min and ( ?)-7-chloro-l,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (200 mg, 1.00 mmol) in THF (5 mL) was added and the reaction mixture stirred for 3 h at 0 °C. 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 Na2S04 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 NaHC03 solution (15 mL) and extracted with ethyl acetate (20 mL), dried over Na2S04, evaporated under reduced pressure to give the title compound (140 mg) as a white solid.
*H NM (400 MHz, DMSO-d6) δ: 8.41 (1H, d), 7.98 (1H, d), 7.79 (1H, dd), 7.35 (1H, d), 6.95 (1H, d), 6.89-6.86 (1H, m), 5.32 (2H, s), 5.22 (1H, s), 4.12-4.07 (1H, m), 3.99-3.94 (1H, m), 3.49-3.44 (1H, m), 2.82 (3H, s), 2.45 (3H, s), 1.27 (3H, d).
LCMS Method A: m/z [M+H]+ 404, tR 1.21 min Synthetic Scheme for Example 21: (S -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
Figure imgf000083_0002
Intermediate 37 Example 21 Example 21: ^-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
O
N^N
To a solution of (S)-tert-buty\ 7-((3-cyano-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy) -2-methyl-5- oxo -2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (400 mg, 0.82 mmol) was added 4.0M HCI in 1,4-dioxane (20 mL) at 0 °C and reaction mixture was stirred at T for 3 h. The reaction mixture was concentrated and basified with NaHC03 solution (10 mL) and then extracted with EtOAc (2 x 20 mL). The fractions were combined and concentrated under reduced pressure to give the crude product (400 mg) which was washed with diethyl ether (30 ml) then filtered and then dried to give material which was further purified using preparative HPLC method A with a flow rate 20 mL/min and collecting 250 mL fractions. The sample was loaded using an
acetonitrile/methanol mixture. 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 (70.2 mg) as a white solid.
^ NMR (400 MHz, DMSO-d6) δ: 8.41 (IH, d), 8.18 (IH, s), 7.98 (IH, d), 7.79 (IH, dd), 7.74 (IH, d), 6.95 (IH, d), 6.89-6.86 (IH, m), 5.30 (IH, s), 5.04 (IH, s), 4.13-4.01 (2H, m), 3.46 (IH, dd), 2.45 (3H, s), 1.23 (IH, d).
LCMS Method A: m/z [M+H]+ 390, fR 1.11 min Synthetic Scheme for Example 22: ^-5-(((2-methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c rimidin-7-yl)oxy)methyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000084_0001
Intermediate 38 Example 22 Example 22: ^-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
Figure imgf000085_0001
To a solution of ( ?J-ferf-butyl 7-((3-cyano-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy) -2-methyl-5- oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (300 mg, 0.61 mmol) in 1,4-dioxane (5 mL) at 0 °C was added 4.0 M HCI in 1,4-dioxane (0.77 mL). The reaction mixture was stirred at RT for 18 h. The reaction mixture was evaporated under reduced pressure and basified with NaHC03 solution (15 mL) and extracted with ethyl acetate (20 mL), the organic layer was evaporated to give the crude product (300 mg) which 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 (143 mg) as a white solid.
*H NMR (400 MHz, DMSO-d6) δ: 8.41 (1H, d), 8.19 (1H, s), 7.98 (2H, d), 7.79 (1H, dd), 7.34 (1H, d), 6.95 (1H, d), 6.87 (1H, dd ), 5.30 (2H, s), 5.04 (1H, s), 4.15-4.01 (2H, m), 3.49-3.44 (1H, m), 2.45 (3H, s), 1.23 (3H, d).
LCMS Method A: m/z [M+H]+ 390, tR 1.10 min
Synthetic Scheme for Example 23: 7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)- l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000085_0002
Intermediate 15 Intermediate 25 Example 23
Example 23: 7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000086_0001
To a mixture of NaH (74.9 mg, 1.87 mmol) in THF (5 mL) at 0 °C was added (3,5-difluoro-4-((2- methylpyridin-4-yl)oxy)phenyl)methanol (235 mg, 0.94 mmol) in THF (5 mL) and the mixture stirred for 10 min. 7-Chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (200 mg, 0.94 mmol) was added and the mixture stirred for a further 2 h at 0 °C.
The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 20 mL). The organic layers combined and dried over Na2S04 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.
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 (88 mg) as a white solid.
*H NM (400 MHz, DMSO-d6) δ: 8.35 (1H, d), 7.41-7.37 (2H, m), 6.87 (1H, d), 6.82-6.80 (1H, m ),
5.31 (2H, s), 5.21 (1H, s), 3.73 (2H, s), 2.77 (3H, s), 2.43 (3H, s), 1.31 (6H, s).
LCMS Method A: m/z [M+H]+ 430, fR 1.39 min
Synthetic scheme for Example 24: 7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2,2- di
Figure imgf000086_0002
Intermediate 39 Example 24 Example 24: 7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000087_0001
4.0 M HCI in 1,4-Dioxane (10 mL) was added to ferf-butyl 7-((3,5-difluoro-4-((2-methylpyridin-4- yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (400 mg, 0.78 mmol) and the mixture stirred at T for 16 h. 1,4-Dioxane was removed and the residue basified with NaHC03 solution (10 mL). The mixture was then extracted with EtOAc (2 xlO mL). The combined layers were concentrated under reduced pressure to afford the crude product which was purified using preparative HPLC method A, collecting 100 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 the title compound (45 mg) as a white solid.
*H NMR (400 MHz, DMSO-d6) δ: 8.35 (1H), 8.26 (1H, s), 7.39 (2H, d), 6.87 (1H, d,), 6.81 (1H, dd), 5.29 (2H, s), 5.05 (1H, s), 3.68 (2H, s), 2.43 (3H, s), 1.32 (6H, s)
LCMS Method A: m/z [M+H]+ 415, tR 1.19 min
Synthetic Scheme for Example 25: (S)-7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)- l,2-dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000087_0002
Intermediate 7 Intermediate 25 Example 25
Example 25: (S)-7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-l,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyri
Figure imgf000087_0003
To a suspension of NaH (80 mg, 2.00 mmol) in THF (10 mL) at 0 °C was added (3,5-difluoro-4-((2- methylpyridin-4-yl)oxy)phenyl)methanol (252 mg, 1.00 mmol) in THF (10 mL) and the reaction mixture stirred at same temperature for 10 min. (S)-7-Chloro-l,2-dimethyl-2,3- dihydroimidazo[l,2-c] pyrimidin-5 (lH)-one (200 mg, 1.00 mmol) in THF (5 mL) was added and the reaction mixture stirred for 2 h at 0 °C. The 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 Na2S04 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.
*H NM (400 MHz, DMSO-d6) δ: 8.35 (IH, d,), 7.40-7.37 (2H, m), 6.87 (IH, d, ), 6.82-6.80 (IH, m), 5.32 (2H, s), 5.25 (IH, s), 4.12-4.07 (IH, m), 3.99-3.95 (IH, m), 3.49-3.45 (IH, m), 2.83 (3H, s), 2.43 (3H, s), 1.27 (3H, d).
LCMS Method A: m/z [M+H]+ 415, tR 1.34 min
Synthetic Scheme for Example 26: ^-7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)- l,2-dimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000088_0001
Intermediate 11 Intermediate 25 Example 26
Example 26: ^-7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-l,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyri
Figure imgf000088_0002
To a suspension of NaH (109 mg, 2.51 mmol) in THF (10 mL) at 0 °C was added (3,5-difluoro-4-((2- methylpyridin-4-yl)oxy)phenyl)methanol (378 mg, 1.50 mmol) in THF (5 mL). The reaction mixture was stirred at the same temperature for 10 min and (/?J-7-chloro-l,2-dimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (200 mg, 1.00 mmol) in THF (5 mL) was added and stirring continued for 3 h at 0 °C. The 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 Na2S04 and evaporated under reduced pressure to give 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 (240 mg) as a white solid.
H NM (400 MHz, DMSO-d6) δ: 8.35 (1H, d), 7.40-7.37 (2H, m), 6.87 (1H, d), 6.81 (1H), 5.32 (2H, s), 5.25 (1H, s), 4.12-4.07 (1H, m), 3.99-3.95 (1H, m), 3.49-3.45 (1H, m), 2.83 (3H, s), 2.43 (3H, s), 1.27 (3H, d).
LCMS Method A: m/z [M+H]+ 415, tR 1.30 min
Synthetic Scheme for Example 27:
Figure imgf000089_0001
Intermediate 40 Example 27
Example 27 ^-7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2-methyl-2,3- dihydroimidazo -c]pyrimidin-5(lH)-one
Figure imgf000089_0002
To (Sj-ferf-butyl 7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-2-methyl-5-oxo -2,3- dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (450 mg, 0.90 mmol) was added 4.0 M HCI in 1,4-dioxane (20 ml) at 0 °C. The reaction mixture was stirred at RT for 3 h and then concentrated and basified with NaHC03 solution (10 mL). The mixture was extracted with EtOAc (2 x 10 mL). The organic layers were combined and concentrated under reduced pressure to afford the crude product which was washed with diethyl ether (30 ml) then filtered and then dried to give material that was purified using preparative HPLC method G collecting 200 mL fractions. The product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile and basified with saturated NaHC03 solution (15 mL). The mixture was extracted with ethyl acetate (20 mL), dried over Na2S04, evaporated under reduced pressure to give the title compound (39.4 mg) as a white solid.
*H NM (400 MHz, DMSO-d6) δ: 8.35 (IH, d), 8.20 (IH, s) 7.39-7.37 (2H, m), 6.87-6.86 (IH, d ),
6.82-6.80 (IH, m ), 5.29 (2H, s), 5.07 (IH, s), 4.15-4.02 (2H, m), 3.49-3.45 (IH, m), 2.43 (3H, s), 1.23 (3H, d).
LCMS Method A: m/z [M+H]+ 401, fR 1.15 min
Synthetic Scheme for 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
Figure imgf000090_0001
Intermediate 10 Intermediate 25 Example 28
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
Figure imgf000090_0002
To a suspension of NaH (76 mg, 1.75 mmol) in THF (10 mL) at 0 °C was added (3,5-difluoro-4-((2- methylpyridin-4-yl)oxy)phenyl)methanol (264 mg, 1.05 mmol) in THF (5 mL), and stirring continued at the same temperature for 10 min. (R)-tert-Buty\ 7-chloro-2-methyl-5-oxo-2,3- dihydroimidazo [l,2-c]pyrimidine-l(5/-/)-carboxylate (200 mg, 0.70 mmol) in THF (5 mL) was added and the reaction mixture was stirred for 2 h at 0 °C. The 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 Na2S04 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. H NMR (400 MHz, DMSO-d6) δ: 8.35 (IH, d), 8.20 (IH, s) 7.41-7.36 (2H, m), 6.88 (IH, d), 6.82-6.80 (IH, m), 5.30 (2H, s), 5.07 (IH, s), 4.15-4.02 (2H, m), 3.49-3.45 (IH, m), 2.43 (3H, s), 1.23 (3H, d). LCMS Method A: m/z [M+H]+ 401, tR 1.20 min
Synthetic Scheme for Example 29: 2-((6-methylpyridin-3-yl)oxy)-5-(((l,2,2-trimethyl-5- -tetrahydroimidazo[l,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile
Figure imgf000091_0001
nterme ate nterme ate xamp e
Example 29: 2-((6-methylpyridin-3-yl)oxy)-5-(((l,2,2-trimethyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile
Figure imgf000091_0002
To a suspension of NaH (5.99 g, 150 mmol) in THF (100 mL) at 0 °C was added 5-(hydroxymethyl)- 2-((6-methylpyridin-3-yl)oxy)benzonitrile (9.90 g, 41.2 mmol) in THF (100 mL), and stirring continued at the same temperature for 15 min. 7-Chloro-l,2,2-trimethyl- 2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (8.0 g, 37.4 mmol) was added and the reaction mixture was stirred for 2 h at 0 °C. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3 x 250 mL), the organic layers washed with brine solution (250 mL), dried over Na2S04 and evaporated under reduced pressure give crude material that was purified using column chromatography using silica gel 100-200 mesh, using 5% Methanol in DCM as eluent. The product containing fractions were combined and concentrated under reduced pressure the resulting solid re-crystallized from a solution in ethyl acetate (90 mL) at 70 °C by addition of heptanes (100 mL) and storing the mixture for 2 h. The solid was filtered and dried under vacuum. The material was further purified by supercritical fluid chromatography:
Column: Pyridyl amide 250x30mm
Co-solvent Percentage: 20% of Methanol Total Flow: lOOgm/min
UV: 215nm
ABP : 120 bar
Stack time: 6 min
Load/injection: 17mg/inj
Compound loaded in: Methanol
Fraction volume: 11 L
The product containing fractions were combined and concentrated under reduced pressure. The resulting solid was stirred in n-heptane (200 mL) for 2 h and then filtered. The solid was suspended in ethyl acetate (100 mL) and heated to get a clear solution and then stored at room temperature for 16 h. The precipitated solid was filtered, washed with n-heptane (2 x 50 mL) and dried under reduced pressure to give the title compound (5.1g) as a white solid.
*H NMR (400MHz, CDCI3) δ: 8.34 (1H, d), 7.72 (1H, dd), 7.53 (1H, dd), 7.31 (1H, dd), 7.20 (1H, d), 6.82 (1H, d), 5.37 (2H, s), 4.94 (1H, s), 3.86 (2H, s), 2.77 (3H, s), 2.58 (3H, s), 1.37 (6H, s).
LCMS Method A: m/z [M+H]+ 418, tR 2.27 min
Synthetic Scheme for Example 30: 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
Figure imgf000092_0001
Intermediate 15 Intermediate 17 Example 30
Example 30 - Preparation 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
Figure imgf000092_0002
To a mixture of NaH (3.06 g, 127 mmol) in THF (50 mL) was added (3,5-difluoro-4-((6- methylpyridin-3-yl)oxy)phenyl)methanol (8.0 g, 31.8 mmol) in THF (50 mL) at 0 °C and stirring continued for 10 min. Then 7-chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(/-/)-one (6.80 g, 31.8 mmol) was added and the mixture stirred for additional 2 h at 0 °C. 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 Na2S04 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.
1HNMR (400 M Hz, CDCI3) δ: 8.28 (1H, d), 7.13-7.05 (4H, m), 5.39 (2H, s), 4.98 (1H, s), 3.88 (2H, s),
2.78 (3H, s), 2.51 (3H, s), 1.38 (6H, s).
LCMS Method F: m/z [M+H]+ 429, tR 2.41 min
Example 30 - Preparation 2 (hydrate): 7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)- l,2,2-trimethyl-2,3-dihydroimid hydrate
Figure imgf000093_0001
To a suspension of NaH (50.5 g, 1.26 mol) in THF (3.0 L) at 0 °C was added (3,5-difluoro-4-((6- methylpyridin-3-yl)oxy)phenyl)methanol (175 g, 695 mmol) in THF (1.0 L) and stirring continued for 10 min. Then a solution of 7-chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)- one (135 g, 632 mmol) in THF (2.0 L) was added at 0 °C and stirring continued for 3 h. 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 Na2S04 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.
Five batches (212 g, 220 g, 200 g, 10 g and lOg) each prepared in a similar manner to that above were combined and heated in ethyl acetate (10 L) at 80 °C for 6 h. The mixture was cooled to RT for 18 h. Ethyl acetate was removed by filtration and the solid compound was dried under vacuum to give the title compound (590 g) as yellow solid which had trapped ethyl acetate (confirmed by ^NMR). This batch and another batch (23 g) prepared in a similar manner to that above were combined, dissolved in methanol (3 L) and poured in to 15 L of water. The precipitated product was filtered through a Buchner funnel and dried under vacuum to give the title compound as a pale yellow solid ().
1H NMR (400 MHz, DMSO-d6) δ: 8.26 (1H, d), 7.39-7.33 (2H, m), 7.30-7.22 (2H, m), 5.30 (2H, s), 5.21 (1H, s), 3.73 (2H, s), 2.77 (3H, s), 2.44 (3H, s), 1.31 (6H, s).
LCMS Method F: m/z [M+H]+ 429, tR 2.29 min Example 30 - Preparation 3 (anhydrate): 7-((3,5-difluoro-4-((6-methylpyridin-3- yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000094_0001
7-((3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3-dihydroimidazo[l,2- c]pyrimidin-5(l/-/)-one hydrate (591 g) was transferred to a polythene lined steel tray and covered with a muslin cloth. The solid was dried in a vacuum oven at 50QC/100mbar with a nitrogen bleed for 21 hours 40 minutes. The dried solid was removed from the oven and transferred to bottles, total weight 542.9 g.
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° 2Θ, end angle: 40.0° 2Θ, step size: 0.0167° 2Θ, 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° 2Θ 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 software.
Table 1
2θ / ° d-spacings / A
6.4 13.9
9.2 9.6
9.9 8.9
12.2 7.3
13.1 6.8
14.1 6.3
14.4 6.2
15.7 5.7
16.2 5.5
16.6 5.4
18.6 4.8
22.7 3.9
23.4 3.8
Synthetic Scheme Example 31: 7-((3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzyl)oxy)- l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000095_0001
Intermediate 15 Intermediate 44 Example 31
Example 31: 7-((3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000095_0002
To a stirred suspension of NaH (138 mg, 2.31 mmol) in THF (5 mL) at 0 °C was added (3,5- difluoro-4-((2-methylpyrimidin-5-yl)oxy)phenyl)methanol (200 mg, 0.793
mmol) in THF drop wise, and stirring continued for 30 minutes at 0°C. 7-Chloro-l,2,2-trimethyl- 2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (169 mg, 0.79 mmol) in THF (5 mL) was then added. The reaction mixture stirred for 2 h at RT and then ice cold water (10 mL) was added. The mixture was extracted with EtOAc (2 x 10 mL), the organic layer washed with brine solution (2 x 50ml) and dried over anhydrous Na2S04. The solvent was removed under reduced pressure to give crude product that was purified using preparative HPLC method A with 50 mL fractions. The product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile. The resulting solid was filtered and washed with water (2 x 5ml) and n-hexane (2 x 5ml) and dried under vacuum to give the title compound (46 mg) as a white solid.
*H NMR (400MHz, DMSO-d6) δ: 8.54 (2H, s), 7.38 (2H, d), 5.28 (2H, s), 5.20 (1H, s,), 3.72 (2H, s), 2.78 (3H, s), 2.60 (3H, s), 1.30 (6H, s).
LCMS Method A: m/z [M+H]+ 430, fR 1.65 min
Synthetic Scheme for Example 32: 7-((3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzyl)oxy)- l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000096_0001
Intermediate 15 Intermediate 56 Example 32
Example 32: 7-((3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3 dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000096_0002
To a stirred suspension of NaH (101 mg, 2.31 mmol) in THF (5 mL) at 0 °C was added 3-fluoro-5- (hydroxymethyl)-2-((2-methylpyrimidin-5-yl)oxy)benzonitrile (150 mg, 0.58 mmol) in THF (5 mL) drop wise, and stirring continued for 30 minutes at 0°C. 7-Chloro-l,2,2-trimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (124 mg, 0.58 mmol) in THF (5 mL) was then added. The reaction mixture stirred for 2 h at RT and then ice cold water (10 mL) was added. The mixture was extracted with EtOAc (2 x 10 mL), the organic layer washed with brine solution (2 x 50ml) and dried over anhydrous Na2S04. The solvent was removed under reduced pressure to give crude product that was purified using preparative HPLC method A with 50 mL fractions. The product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile. The resulting solid was filtered and washed with water (2 x 5ml) and n-hexane (2 x 5ml) and then dried under vacuum to give the title compound (75.9 mg) as a white solid.
*H NMR (400 MHz, DMSO-d6) δ: 8.63 (2H, s), 7.87 (2H, d), 5.32 (2H, s), 5.21 (1H, s,), 3.73 (2H, s), 2.77 (3H, s), 2.62 (3H, s), 1.31 (6H, s).
LCMS Method A: m/z [M+H]+ 437, tR 1.64 min
Synthetic Scheme for Example 33: 7-((3,5-difluoro-4-((5-methylpyrazin-2-yl)oxy)benzyl)oxy)- l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000097_0001
Intermediate 15 Intermediate 46 Example 33
Example 33: 7-((3,5-difluoro-4-((5-methylpyrazin-2-yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one
Figure imgf000097_0002
To a stirred suspension of NaH (104 mg, 2.38 mmol) in THF (5 mL) at 0 °C, was added (3,5- difluoro-4-((5-methylpyrazin-2-yl)oxy)phenyl)methanol (150 mg, 0.56 mmol) in THF (5 mL) dropwise and stirred for 30 minutes. 7-Chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2- c]pyrimidin-5(l/-/)-one (127 mg, 0.60 mmol) in THF (5 mL) was added at 0 °C and then the reaction mixture was stirred for 2 h at RT. Ice cold water (10 mL) was added and the mixture extracted with EtOAc (2 x 10 mL), the organic layer was washed with brine solution (2 x 50ml), dried over anhydrous Na2S04 and solvent removed under reduced pressure to afford 300mg crude which was purified using preparative HPLC method A, collecting 50 mL fractions. The product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile, and the resulting solid was filtered and washed with water (2 x 5 ml) and n-hexane (2 x 10 ml) and then dried under vacuum to give the title compound (74.8 mg) as a white solid.
*H NM (400 MHz, DMSO-d6) δ: 8.63 (1H, d), 8.06 (1H, s), 7.32 (2H, d), 5.29 (2H, s), 5.210 (1H, s,), 3.72 (2H, s), 2.77 (3H, s), 2.46 (3H, s), 1.30 (6H, s).
LCMS Method A: m/z [M+H]+ 430, fR 1.85 min
Synthetic Scheme for Example 34: 3-fluoro-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)methy
Figure imgf000098_0001
Intermediate 15 Intermediate 49 Example 34
Example 34: 3-fluoro-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
Figure imgf000098_0002
To a stirred suspension of NaH (101 mg, 2.31 mmol) in THF (5 mL) at 0 °C, was added 3-fluoro-5- (hydroxymethyl)-2-((5-methylpyrazin-2-yl)oxy)benzonitrile (150 mg, 0.58 mmol) in THF (5 mL) drop wise and stirred for 30 minutes. 7-Chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2- c]pyrimidin-5(l/-/)-one (124 mg, 0.58 mmol) in THF (5 mL) was added at 0 °C and then the reaction mixture was stirred for 2 h at RT. Ice cold water (10 mL) was added and the mixture extracted with EtOAc (2 x 10 mL), the organic layer was washed with brine solution (2 x 50ml), dried over anhydrous Na2S04 and solvent removed under reduced pressure to afford 300 mg of crude material which was purified using preparative HPLC method A, collecting 50 mL fractions. The product containing fractions were combined and concentrated under reduced pressure to remove acetonitrile, and the resulting solid was filtered and washed with water (2 x 5 ml) and n-hexane (2 x 10 ml) and dried under vacuum to give the title compound (166 mg) as a white solid. H NMR (400 MHz, DMSO-d6) δ: 8.71 (IH, d), 8.09 (IH, s), 7.86-7.83 (2H, m), 5.32 (2H, s), 5.22 (IH, s), 3.73 (2H, s), 2.77 (3H, s), 2.48 (3H, s), 1.31 (6H, s).
LCMS Method A: m/z [M+H]+ 437, fR 1.83 min
Synthetic Scheme for Example 35: 2-((2-methylpyrimidin-5-yl)oxy)-5-(((l,2,2-trimethyl-5-oxo- l,2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7-yl)oxy)methyl)be
Figure imgf000099_0001
Intermediate 15 Intermediate 51 Example 35
Example 35: 2-((2-methylpyrimidin-5-yl)oxy)-5-(((l,2,2-trimethyl-5-oxo-l,2,3,5- tetrahydroimidazo[l,2-c]p
Figure imgf000099_0002
To a suspension of NaH (59.7 mg, 2.49 mmol) in THF (5.0 mL) at 0 °C was added 5-
(hydroxymethyl)-2-((2-methylpyrimidin-5-yl)oxy) benzonitrile (150 mg, 0.62 mmol) in THF (5 mL) drop wise, and stirring continued at the same temperature for 30 min. A solution of 7-chloro- l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one (133 mg, 0.62 mmol) in THF (5.0 mL) was added and the reaction mixture was stirred for 2 h at RT. Ice cold water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3 x 10 mL), the organic layers washed with brine solution (2 x 50 mL), dried over Na2S04 and evaporated under reduced pressure give crude material that was purified using preparative HPLC method A, collecting 50 mL fractions. The product containing fractions were combined and concentrated under reduced pressure. The resulting solid was washed with water (2 x 5 mL) and n-hexane (2 x 10 mL) and dried under reduced pressure to give the title compound (123 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 8.70 (2H, s), 7.95 (IH, d), 7.70-7.68 (IH, m), 7.22 (IH, d), 5.27 (2H, s), 5.16 (IH, s), 3.71 (2H, s), 2.75 (3H, s), 2.66 (3H, s), 1.30 (6H, s).
LCMS Method A: m/z [M+H]+ 419, tR 1.53 min Synthetic Scheme for Example 36: 2-((5-methylpyrazin-2-yl)oxy)-5-(((l,2,2-trimethyl-5- l 2,3,5-tetrahydroimidazo[l,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile
Figure imgf000100_0001
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
Figure imgf000100_0002
To a suspension of NaH (265 mg, 6.63 mmol) in THF (5.0 mL) at 0 °C was added 5- (hydroxymethyl)-2-((5-methylpyrazin-2-yl)oxy)benzonitrile (400 mg, 1.66 mmol) in TH F (5 mL) dropwise, and stirring continued at the same temperature for 30 min. A solution of 7-chloro- l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(lH)-one (354 mg, 1.66 mmol) in THF (5.0 mL) was added and the reaction mixture was stirred for 2 h at RT. Ice cold water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (2 x 10 m L), the organic layers washed with brine solution (2 x 50 mL), dried over Na2S04 and evaporated under reduced pressure give crude material that was purified using preparative H PLC method A, collecting 50 mL fractions. The product containing fractions were combined and concentrated under reduced pressure. The resulting solid was washed with water (2 x 5 mL) and n-hexane (2 x 10 m L) and dried under reduced pressure to give the title compound (292 mg) as a white solid.
*H N M R (400 M Hz, DMSO-d6) δ: 8.60 (IH, s), 8.12 (IH, d), 7.96 (IH, d), 7.80-7.77 (IH, m), 7.43 (IH, d), 5.31 (2H, s), 5.19 (IH, s), 3.72 (2H, s), 2.76 (3H, s), 2.48 (3H, s), 1.30 (6H, s)
LCMS Method A: m/z [M+H]+ 419, fR 1.63 min Synthetic Scheme Example 37: (/?)-3-fluoro-5-(((2-methyl-5-oxo-l,2,3,5-tetrahydroimidazo[l,2- c rimidin-7-yl)oxy)methyl)-2-((2-methylpyridin-4-yl)oxy)benzonitrile
Figure imgf000101_0001
Intermediate 35 Example 37 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
Figure imgf000101_0002
To a stirred solution of ( ?J-ferf-butyl 7-((3-cyano-5-fluoro-4-((2-methylpyridin-4-yl)
oxy)benzyl)oxy)-2-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidine-l(5/-/)-carboxylate (600 mg, 1.18 mmol) in 1,4-dioxane (5 mL) was added 4.0 M solution of HCI in 1,4-dioxane (15 mL) at RT and the mixture was stirred for 18 h. The reaction mixture was evaporated under reduced pressure and neutralized (pH 7) with NaHC03 solution (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried and evaporated to give crude product 250mg which was purified using preparative HPLC method B. The product containing fractions were collected and concentrated under reduced pressure to remove acetonitrile and the solid that was obtained was filtered and washed with water (2 x 10ml), dried under vacuum to afford the title compound (50.2 mg) as a white solid.
*H NMR (400 MHz, DMSO-d6) δ: 8.38 (IH, d), 8.21 (IH, s), 7.91 (IH, d), 7.89-7.88 (IH, m), 6.93 (IH, d), 6.86 (IH, dd), 5.32 (2H, s), 5.08 (2H, s), 4.15-4.01 (2H, m), 3.47 (3H, d).
LCMS Method A: m/z [M+H]+ 408, tR 1.17 min. Synthetic Scheme for Example 38: 5-(hydroxymethyl)-2-((6-methylpyridazin-3- yl)oxy)benzonitrile
Figure imgf000102_0001
Intermediate 15 Intermediate 61
Example 38: 5-(hydroxymethyl)-2-((6-methylpyridazin-3-yl)oxy)benzonitrile
Figure imgf000102_0002
To a stirred solution of 5-(hydroxymethyl)-2-((6-methylpyridazin-3-yl)oxy)benzonitrile (100 mg, 0.42 mmol) in THF (5 mL) was added NaH (33.2 mg, 0.83 mmol) at 0 °C and the reaction mixture stirred for 10 min. Then 7-chloro-l,2,2-trimethyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (70.9 mg, 0.33 mmol) was added and the mixture stirred for 2 h at 0 °C. After completion of the reaction, ice water was added, and the mixture extracted with EtOAc (2 x 50 mL). The ethyl acetate layer was washed with brine (30 mL), dried over Na2S04 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.
*H NM (400 MHz, DMSO-d6) δ: 7.97 (1H, d), 7.75 (1H, d), 7.59 (1H, d), 7.46-7.43 (2H, m), 5.36 (2H, s), 5.19 (1H, s), 3.70 (2H, s), 2.75 (3H, s), 2.57 (3H, s), 1.29 (6H, s).
LCMS Method A: m/z [M+H]+ 419 fR 1.52 mins. Example 39: 7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one methanesulfonate
Figure imgf000103_0001
A suspension of 7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (500 mg, 1.17 mmol) in acetone (3 mL) was heated at 51 QC for 45 min. A solution of methanesulfonic acid (0.076 mL, 1.17 mmol) in acetone (2 mL) was added and the mixture then stirred at RT for 2 h. The resulting solid material was filtered with a sinter funnel and then collected and dried under high vacuum at RT for 8 h to give the title compound as a white solid (510 mg).
*H NMR (400 MHz, DMSO-d6) δ: 8.39 (1H, d), 7.52-7.46 (2H, m), 7.41 (1H, d), 7.33-7.31 (1H, m), 6.01 (1H, s), 5.42 (2H, s), 3.89 (2H, s), 3.05 (3H, s), 2.50 (3H, s), 2.32 (3H, s), 1.41 (6H, s)
LCMS Method A: m/z [M+H]+ 429 fR 1.60 mins.
Example 40: 7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(lH)-one 4-methylbenzenesulfonate
Figure imgf000103_0002
A suspension of 7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-l,2,2-trimethyl-2,3- dihydroimidazo[l,2-c]pyrimidin-5(l/-/)-one (500 mg, 1.17 mmol) in acetone (3 mL) was heated at 51 QC for 50 min. p-Toluenesulfonic acid (222 mg, 1.17 mmol) in acetone (2 mL) was added and the mixture then stirred at RT for 4 h. The resulting solid material was filtered with a sinter funnel and then collected and dried under high vacuum at RT for 8 h to give the title compound as a white solid (530 mg).
*H NMR (400 MHz, DMSO-d6) δ: 8.31 (1H, d), 7.48-7.38 (4H, m), 7.39-7.38 (1H, m), 7.33 (1H, d), 7.11 (2H, d), 5.89 (1H, s), 5.39 (2H, s), 3.86 (2H, s), 3.00 (3H, s), 2.49 (3H, s), 2.28 (3H, s), 1.39 (6H, s). LCMS Method A: m/z [M+H]+ 429
HPLC Method A: tR 5.39 mins.
Biological assays
The compounds of present invention are Lp-PLA2 inhibitors, and therefore may be useful in the treatment of diseases or disorders associated with Lp-PLA2 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-PLA2 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. Upon cleavage with PAF-AH, the free thiol is released at the sn-2 position and can then react with 7- diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) a thiol-reactive coumarin. This reaction (Michael addition) results in an increase in fluorescence. Inhibitors of PLA2 therefore prevent this cleavage and no fluorescent increase is observed.
The biological activity data for each tested Example compound was either reported in at least one experiment or the average of multiple experiments. The data described herein may have reasonable variations depending on the specific conditions and procedures used by the person conducting the experiments.
1} Recombinant human Lp-PLA2 assay
The Thio-PAF assay was run as an unquenched 20 μί 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 μί οί the compounds on compound source plate were transferred into 384 well Greiner 784076 (black) plates using STAR+ (Hamilton) liquid dispenser. ΙΟμί 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. 5 μΐ of substrate comprising 40 μΜ 2-thio-PAF [from ethanol stock], 40 μΜ CPM [from a DMSO stock] and 400 μΜ 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 plC50 > 6.2 according to this assay.
Recombinant human PLA2 VIIB assay
The Thio-PAF assay was run as an unquenched 20 μί 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 μί οί the compounds on compound source plate were transferred into 384 well Greiner 784076 (black) plates using STAR+ (Hamilton) liquid dispenser. ΙΟμί 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. 5 μΐ of substrate comprising 40 μΜ 2-thio-PAF [from ethanol stock], 40 μΜ CPM [from a DMSO stock] and 400 μΜ 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 plC50 < 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. This 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 μί 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 μί of compounds on compound source plate were transferred to 96-well Corning 3686 (black) low-volume plates by STAR+ (Hamilton) liquid dispenser. 10 μί pooled human plasma, which was previously aliquoted and frozen, was added. Plates were centrifuged for 30 sec at 1000 rpm. After 15 minutes preincubation at room temperature, 5 μί of substrate solution comprising 2 mM 2-thio-PAF [from ethanol stock], 52 μΜ CPM [from a DMSO stock] and 2.5 mM NEM (N- ethylmaleimide) [made fresh daily in DMSO] in assay buffer (50mM HEPES, pH 7.4, 150 mM NaCI, 1 mM CHAPS) was added to 96-well Corning 3686 (black) low-volume plates. After 3 mins, reaction was quenched with 10 μί of 5% aqueous trifluoroacetic acid (TFA). Plates were centrifuged 30 sec at 1000 rpm, covered to protect from light and incubated for 10 min at room temperature. Plates were read 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 1-37 exhibited a plC50 > 7.0 according to this assay. USES OF COMPOUNDS OF THE INVENTION
The compounds of the invention are inhibitors of Lp-PLA2. Therefore, these compounds may be used in therapy, for example, in the treatment of diseases or disorders associated with the activity of Lp-PLA2, including for example treatment of diseases or disorders where inhibition of Lp-PLA2 is of therapeutic benefit. As will be appreciated by those skilled in the art, inhibition of Lp- PLA2 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-PLA2 activity, including those described herein.
Thus, the invention provides a method of inhibiting Lp-PLA2 comprising contacting a biological material comprising the protein with a compound of the invention. In some embodiments the contact is made in-vitro, and the biological material is, e.g., cell culture or cellular tissue. In other embodiments, the contact is made in-vivo.
The invention also provides a method of treating a disease or disorder associated with Lp- PLA2 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-PLA2 activity.
The invention also provides for the use of a compound of the invention in the
manufacture of a medicament for use in the treatment of a disease or disorder associated with Lp-PLA2 activity.
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.
In some embodiments, 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-PLA2 activity disclosed herein, including any particular disease or disorder.
As used herein, "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. In some embodiments, 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.
As use herein "vascular dementia" (also referred to as "multi-infarct 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.
The terms "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.
The terms "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.
The term "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.
The term "abnormal inner BRB" ("abnormal iBRB")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.
The terms "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. For example, 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.
The terms "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. For example, 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.
In some embodiments of the methods of the invention, the disease or disorder is an ocular disease or disorder. In some embodiments, the ocular disease or disorder is associated with the breakdown of the inner blood-retinal barrier (iBRB). In some embodiments, 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, 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. In some
embodiments, 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. Examples of 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.
In some embodiments of the methods of the invention, the disease or disorder is selected from the diseases or disorders disclosed in the following published patent applications:
W096/13484, W096/19451, WO97/02242, W097/12963, W097/21675, W097/21676, WO 97/41098, WO97/41099, WO99/24420, WOOO/10980, WOOO/66566, WOOO/66567, WOOO/68208, WO01/60805, WO02/30904, WO02/30911, WO03/015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/87088, WO08/048867, US 2008/0103156, US 2008/0090851, US 2008/0090852, WO08/048866, WO05/003118 CA
2530816A1), WO06/063811, WO06/063813, WO 2008/141176, JP 200188847, US 2008/0279846 Al, US 2010/0239565 Al, and US 2008/0280829 Al. In some embodiments of the methods of the invention, 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; (2) 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; and/or (3) activated or increased involvement of monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA2 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 emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, Alzheimer's disease, and autoimmune diseases such as lupus).
In some embodiments of the methods of the invention, the disease or disorder is a cardiovascular event (e.g. a heart attack, myocardial infarction or stroke). For example, 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.
In some embodiments of the methods of the invention, the disease or disorder is an acute coronary event, restenosis, or diabetic or hypertensive renal insufficiency. For example, 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.
In some embodiments of the methods of the invention, the disease or disorder is a neurological disease or disorder associated with an abnormal blood brain barrier (BBB) function, inflammation, and/or microglia activation. In some embodiments, the abnormal BBB is a permeable BBB. In some embodiments, 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).
In some embodiments of the methods of the invention, the disease or disorder is associated with blood brain barrier (BBB) leakage. Exemplary such diseases/disorders include, but are not limited to, brain hemorrhage and cerebral amyloid angiopathy. In some embodiments of the methods of the invention, the disease or disorder is associated with abnormal beta amyloid ("Αβ") accumulation in the brain. For example, treatment may be used to decrease Αβ levels of a subject or to decrease accumulation of Αβ in the brain of subject. In some such embodiments, 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.
In some embodiments of the methods of the invention, 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). 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.
In some embodiments of the methods of the invention, the disease or disorder is a skin ulcer. Examples of 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.
In some embodiments of the methods of the invention, 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.
"Treat", "treating" or "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. Thus, 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.
As used herein, "treat", "treating" or "treatment" includes "prevent", "preventing" or
"prevention". As used herein, "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. Thus, for example, 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-PLA2 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 (plC50) 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. Likewise, the 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.
In some embodiments, 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. Thus, for example, for a 70kg adult mammal, 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. In some embodiments, 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
administration, rectal administration, and administration by inhalation. 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. In addition, 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 with one or more other therapeutic agents.
Combination therapy includes administration of the therapeutic agents in separate dosage forms or together in a single dosage form. Combination therapy may involve
simultaneous administration or separate administration of the therapeutic agents, which may be substantially simultaneous or substantially separate administration. Typically, combination therapy will involve 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.
In some embodiments, e.g. in the treatment of ocular diseases or disorders, 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,. Therapeutic agents to treat neurodegenerative diseases or disorders may also be useful as co-actives for treating an ocular disorder or disease.
In some embodiments, combination therapy may include treatment with one or more therapeutic actives for treating atherosclerosis, cardiovascular disease or coronary heart disease. In some embodiments, 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)). Examples of such 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). Examples of 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. In some embodiments, the compounds of the present invention may be used with one or more statins, e.g., atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin. In some embodiments, the compounds of the present invention may be used with an anti-diabetic agent or an insulin sensitizer. In some embodiments, 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.
In some embodiments, the other therapeutic agent is useful in treating a
neurodegenerative disease or disorder for which the subject is being treated, or that may be a comorbidity. In some embodiments, 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. In some embodiments, 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. For example, when the neurodegenerative disease is or is similar to Alzheimer's disease, 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.
In some embodiments, 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.
In some embodiments, the additional therapeutic agent(s) is used in the treatment of metabolic bone diseases or disorders. For example, when 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.
For use in therapy, 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.
In some particular embodiments, the invention provides 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. In some embodiments, 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. In some embodiments, 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 °2Θ) 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. as shown in Table 1 herein.
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. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form. For oral application, for example, one or more tablets or capsules may be administered. 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). When prepared in unit dosage form, 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. In some embodiments, 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-PLA2-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.
As used herein, "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
dispensation), in enhancing therapy (e.g. facilitating drug absorption or solubility, or other pharmacokinetic properties), in the manufacturing process (e.g. as a handling or processing aid), in stabilizing the composition, or in enhancing patient compliance (e.g., enhancing palatability or appearance of the composition). Typically at least one 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. In addition, 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, solutions, pastes, sprays, foams, gels, dermal patches, and transdermal patches or sprays.
Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain
pharmaceutically acceptable excipients may be chosen for their ability to: facilitate the production of uniform dosage forms, 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. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much 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. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press), including current and past editions.
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
Accordingly, in some embodiments the invention provides 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.
In one aspect, 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. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). 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.

Claims

What is claimed is:
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof,
Figure imgf000119_0001
Formula (I)
wherein:
R1 and R2 are independently CH3 or H;
R3 is H or C(i_3)alkyl; and
R4 is
Figure imgf000119_0002
wherein
Ra is H or F,
Rb is -O-Y wherein Y is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are substituted with one CH3 substituent; and
Rc is F or CN.
2. The compound according to claim 1, wherein R1 and R2 are each CH3.
3. The compound according to claim 1 or 2, wherein R is H or CH3.
4. The compound according to claim 3, wherein R is CH3.
5. The compound according to any preceding claim, wherein Y of R is pyridinyl substituted by one CH3 substituent.
6. The compound according to any one of claims 1-4, wherein Y of b is pyridin-3-yl, pyridin- 4-yl, pyrimidin-5-yl, pyrazin-2-yl or pyridazin-3-yl (in particular embodiments, pyridin-3-yl), each substituted by one CH3 substituent.
7. The compound according to claim 6, wherein Y of Rb 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 particular embodiments, 6-methyl-pyridin-3-yl).
8. The compound according to any preceding claim, wherein Ra is fluoro.
9. The compound according to claim 8, wherein Rc is fluoro.
10. The compound according to claim 8, wherein Rc is CN.
11. The compound according claim 1, wherein the compound is a compound of any one of Examples 1 to 38, or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, wherein the compound 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 or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1, wherein the compound 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.
14. The compound according to claim 1, wherein the compound is a crystalline form of
anhydrous 7-({3,5-difluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}methoxy)-l,2,2-trimethyl- 11-1,21-1, 3H,5H-imidazolidino[l,2-c]pyrimidin-5-one characterized by an XRPD pattern substantially in accordance with Figure 1.
15. The compound according to claim 1, wherein the compound is a crystalline form of
anhydrous 7-({3,5-difluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}methoxy)-l,2,2-trimethyl- 11-1,21-1, 3H,5H-imidazolidino[l,2-c]pyrimidin-5-one characterized by having diffraction angles (expressed in °2Θ) 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.
16. A pharmaceutical composition comprising the compound of Formula (I) or a
pharmaceutically acceptable salt thereof according to any one of the preceding claims, and one or more pharmaceutically acceptable excipients.
17. A method for treating a disease or disorder associated with Lp-PLA2 activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof according to any one of claims 1-15.
18. The method according to claim 17, wherein the subject is human.
19. A use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof
according to any one of claims 1 -15, in the manufacture of a medicament for treating a disease or disorder associated with Lp-PLA2 activity.
20. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 15 for use in the treatment of a disease or disorder associated with Lp-PLA2 activity.
21. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 -15 for use in therapy.
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