Patent Publication Number: US-9422255-B2

Title: S-imino-S-oxo-iminothiazine compounds as BACE inhibitors, compositions, and their use

Description:
FIELD OF THE INVENTION 
     This invention provides certain S-imino-S-oxo iminothiazine compounds, and compositions comprising these compounds, as inhibitors of BACE, which may be useful for treating or preventing pathologies related thereto. 
     BACKGROUND 
     Amyloid beta peptide (“Aβ”) is a primary component of β amyloid fibrils and plaques, which are regarded as having a role in an increasing number of pathologies. Examples of such pathologies include, but are not limited to, Alzheimer&#39;s disease, Down&#39;s syndrome, Parkinson&#39;s disease, memory loss (including memory loss associated with Alzheimer&#39;s disease and Parkinson&#39;s disease), attention deficit symptoms (including attention deficit symptoms associated with Alzheimer&#39;s disease (“AD”), Parkinson&#39;s disease, and Down&#39;s syndrome), dementia (including pre-senile dementia, senile dementia, dementia associated with Alzheimer&#39;s disease, Parkinson&#39;s disease, and Down&#39;s syndrome), progressive supranuclear palsy, cortical basal degeneration, neurodegeneration, olfactory impairment (including olfactory impairment associated with Alzheimer&#39;s disease, Parkinson&#39;s disease, and Down&#39;s syndrome), β-amyloid angiopathy (including cerebral amyloid angiopathy), hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysis (β2-microglobulins and complications arising therefrom), neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeld-Jakob disease, traumatic brain injury and the like. 
     Aβ peptides are short peptides which are made from the proteolytic break-down of the transmembrane protein called amyloid precursor protein (“APP”). Aβ peptides are made from the cleavage of APP by β-secretase activity at a position near the N-terminus of Aβ, and by gamma-secretase activity at a position near the C-terminus of Aβ. (APP is also cleaved by α-secretase activity, resulting in the secreted, non-amyloidogenic fragment known as soluble APPα.) Beta site APP Cleaving Enzyme (“BACE-1”) is regarded as the primary aspartyl protease responsible for the production of Aβ by β-secretase activity. The inhibition of BACE-1 has been shown to inhibit the production of Aβ. 
     AD is estimated to afflict more than 20 million people worldwide and is believed to be the most common cause of dementia. AD is a disease characterized by degeneration and loss of neurons and also by the formation of senile plaques and neurofibrillary tangles. Presently, treatment of Alzheimer&#39;s disease is limited to the treatment of its symptoms rather than the underlying causes. Symptom-improving agents approved for this purpose include, for example, N-methyl-D-aspartate receptor antagonists such as memantine (Namenda®, Forest Pharmaceuticals, Inc.), cholinesterase inhibitors such as donepezil (Aricept®, Pfizer), rivastigmine (Exelon®, Novartis), galantamine (Razadyne Reminyl®), and tacrine (Cognex®). 
     In AD, Aβ peptides, formed through Aβ-secretase and gamma-secretase activity, can form tertiary structures that aggregate to form amyloid fibrils. Aβ peptides have also been shown to form Aβ oligomers (sometimes referred to as “Aβ aggregates” or “Abeta oligomers”). Aβ oligomers are small multimeric structures composed of 2 to 12 Aβ peptides that are structurally distinct from Aβ fibrils. Amyloid fibrils can deposit outside neurons in dense formations known as senile plaques, neuritic plaques, or diffuse plaques in regions of the brain important to memory and cognition. Aβ oligomers are cytotoxic when injected in the brains of rats or in cell culture. This Aβ plaque formation and deposition and/or Aβ oligomer formation, and the resultant neuronal death and cognitive impairment, are among the hallmarks of AD pathophysiology. Other hallmarks of AD pathophysiology include intracellular neurofibrillary tangles comprised of abnormally phosphorylated tau protein, and neuroinflammation. 
     Evidence suggests that Aβ, Aβ fibrils, aggregates, oligomers, and/or plaque play a causal role in AD pathophysiology. (Ohno et al., Neurobiology of Disease, No. 26 (2007), 134-145). Mutations in the genes for APP and presenilins 1/2 (PS1/2) are known to cause familial AD and an increase in the production of the 42-amino acid form of Aβ is regarded as causative. Aβ has been shown to be neurotoxic in culture and in vivo. For example, when injected into the brains of aged primates, fibrillar Aβ causes neuronal cell death around the injection site. Other direct and circumstantial evidence of the role of Aβ in Alzheimer etiology has also been published. 
     BACE-1 has become an accepted therapeutic target for the treatment of Alzheimer&#39;s disease. For example, McConlogue et al., J. Bio. Chem., Vol. 282, No. 36 (September 2007), have shown that partial reductions of BACE-1 enzyme activity and concomitant reductions of Aβ levels lead to a dramatic inhibition of Aβ-driven AD-like pathology, making β-secretase a target for therapeutic intervention in AD. Ohno et al. Neurobiology of Disease, No. 26 (2007), 134-145, report that genetic deletion of BACE-1 in 5XFAD mice abrogates Aβ generation, blocks amyloid deposition, prevents neuron loss found in the cerebral cortex and subiculum (brain regions manifesting the most severe amyloidosis in 5XFAD mice), and rescues memory deficits in 5XFAD mice. The group also reports that Aβ is ultimately responsible for neuron death in AD and concludes that BACE-1 inhibition has been validated as an approach for the treatment of AD. Roberds et al., Human Mol. Genetics, 2001, Vol. 10, No. 12, 1317-1324, established that inhibition or loss of β-secretase activity produces no profound phenotypic defects while inducing a concomitant reduction in Aβ. Luo et al., Nature Neuroscience, Vol. 4, No. 3, March 2001, report that mice deficient in BACE-1 have normal phenotype and abolished β-amyloid generation. 
     More recently, Jonsson, et al. have reported in Nature, Vol. 488, pp. 96-99 (August 2012), that a coding mutation (A673T) in the APP gene protects against Alzheimer&#39;s disease and cognitive decline in the elderly without Alzheimer&#39;s disease. More specifically, the A allele of rs63750847, a single nucleotide polymorphism (SNP), results in an alanine to threonine substitution at position 673 in APP (A673T). This SNP was found to be significantly more common in a healthy elderly control group than in an Alzheimer&#39;s disease group. The A673T substitution is adjacent to the aspartyl protease beta-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in a heterologous cell expression system in vitro. Jonsson, et al. report that an APP-derived peptide substrate containing the A673T mutation is processed 50% less efficiently by purified human BACE1 enzyme when compared to a wild-type peptide. Jonsson et al. indicate that the strong protective effect of the APP-A673T substitution against Alzheimer&#39;s disease provides proof of principle for the hypothesis that reducing the beta-cleavage of APP may protect against the disease. 
     BACE-1 has also been identified or implicated as a therapeutic target for a number of other diverse pathologies in which Aβ or Aβ fragments have been identified to play a causative role. One such example is in the treatment of AD-type symptoms of patients with Down&#39;s syndrome. The gene encoding APP is found on chromosome 21, which is also the chromosome found as an extra copy in Down&#39;s syndrome. Down&#39;s syndrome patients tend to acquire AD at an early age, with almost all those over 40 years of age showing Alzheimer&#39;s-type pathology. This is thought to be due to the extra copy of the APP gene found in these patients, which leads to overexpression of APP and therefore to increased levels of Aβ causing the prevalence of AD seen in this population. Furthermore, Down&#39;s patients who have a duplication of a small region of chromosome 21 that does not include the APP gene do not develop AD pathology. Thus, it is thought that inhibitors of BACE-1 could be useful in reducing Alzheimer&#39;s type pathology in Down&#39;s syndrome patients. 
     Another example is in the treatment of glaucoma (Guo et al., PNAS, Vol. 104, No. 33, Aug. 14, 2007). Glaucoma is a retinal disease of the eye and a major cause of irreversible blindness worldwide. Guo et al. report that Aβ colocalizes with apoptotic retinal ganglion cells (RGCs) in experimental glaucoma and induces significant RGC cell loss in vivo in a dose- and time-dependent manner. The group report having demonstrated that targeting different components of the Aβ formation and aggregation pathway, including inhibition of β-secretase alone and together with other approaches, can effectively reduce glaucomatous RGC apoptosis in vivo. Thus, the reduction of Aβ production by the inhibition of BACE-1 could be useful, alone or in combination with other approaches, for the treatment of glaucoma. 
     Another example is in the treatment of olfactory impairment. Getchell et al., Neurobiology of Aging, 24 (2003), 663-673, have observed that the olfactory epithelium, a neuroepithelium that lines the posterior-dorsal region of the nasal cavity, exhibits many of the same pathological changes found in the brains of AD patients, including deposits of Aβ, the presence of hyperphosphorylated tau protein, and dystrophic neurites among others. Other evidence in this connection has been reported by Bacon A W, et al., Ann NY Acad Sci 2002; 855:723-31; Crino P B, Martin J A, Hill W D, et al., Ann Otol Rhinol Laryngol, 1995; 104:655-61; Davies D C, et al., Neurobiol Aging, 1993; 14:353-7; Devanand D P, et al., Am J Psychiatr, 2000; 157:1399-405; and Doty R L, et al., Brain Res Bull, 1987; 18:597-600. It is reasonable to suggest that addressing such changes by reduction of Aβ by inhibition of BACE-1 could help to restore olfactory sensitivity in patients with AD. 
     For compounds which are inhibitors of BACE-2, another example is in the treatment of type-II diabetes, including diabetes associated with amyloidogenesis. BACE-2 is expressed in the pancreas. BACE-2 immunoreactivity has been reported in secretory granules of beta cells, co-stored with insulin and IAPP, but lacking in the other endocrine and exocrine cell types. Stoffel et al., WO2010/063718, disclose the use of BACE-2 inhibitors in the treatment of metabolic diseases such as Type-II diabetes. The presence of BACE-2 in secretory granules of beta cells suggests that it may play a role in diabetes-associated amyloidogenesis. (Finzi, G. Franzi, et al., Ultrastruct Pathol. 2008 November-December; 32(6):246-51.) 
     Other diverse pathologies characterized by the formation and deposition of Aβ or fragments thereof, and/or by the presence of amyloid fibrils, oligomers, and/or plaques, include neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, traumatic brain injury (“TBI”), Creutzfeld-Jakob disease and the like, type II diabetes (which is characterized by the localized accumulation of cytotoxic amyloid fibrils in the insulin producing cells of the pancreas), and amyloid angiopathy. In this regard reference can be made to the patent literature. For example, Kong et al., US2008/0015180, disclose methods and compositions for treating amyloidosis with agents that inhibit Aβ peptide formation. As another example, Loane, et al. report the targeting of amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. (Loane et al., “Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury”, Nature Medicine, Advance Online Publication, published online Mar. 15, 2009.) Still other diverse pathologies characterized by the inappropriate formation and deposition of Aβ or fragments thereof, and/or by the presence of amyloid fibrils, and/or for which inhibitor(s) of BACE-1 is expected to be of therapeutic value are discussed further hereinbelow. 
     SUMMARY OF THE INVENTION 
     The present invention provides certain S-imino-S-oxo iminothiazine compounds, which are collectively or individually referred to herein as “compound(s) of the invention”, as described herein. The compounds of the invention are useful as inhibitors of BACE-1 and/or BACE-2. 
     In one embodiment, the compounds of the invention have the structural Formula (I): 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof having the structural Formula (I′): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt thereof, wherein: 
     R N  is selected from the group consisting of alkyl, haloalkyl, and heteroalkyl, wherein said heteroalkyl is optionally substituted with halogen; 
     R 1A  is independently selected from the group consisting of: H, halogen, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
         wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 1A  is optionally unsubstituted or substituted with one or more halogen;       

     R 1B  is selected from the group consisting of H, halogen, alkyl, and heteroalkyl, wherein said alkyl and heteroalkyl of R 1B  are each optionally unsubstituted or substituted with one or more halogen; 
     or, alternatively, R 1B  is a moiety having the formula 
     
       
         
         
             
             
         
       
     
     wherein k is 0 or 1; 
     -L C - (when present) is a divalent moiety selected from the group consisting of lower alkyl and lower heteroalkyl, wherein each said lower alkyl and lower heteroalkyl is optionally substituted with one or more halogen; 
     ring C (when present) is selected from the group consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and a multicyclic group; 
     n is 0 or more; and 
     each R C  (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF 5 , —OSF 5 , —Si(R 5C ) 3 , —N(R 6C ) 2 , —NR 7C C(O)R 6C , —NR 7C S(O) 2 R 6C , —NR 7C S(O) 2 N(R 6C ) 2 , —NR 7C C(O)N(R 6C ) 2 , —NR 7C C(O)OR 6C , —C(O)R 6C , —C(O) 2 R 6C , —C(O)N(R 6C ) 2 , —S(O)R 6C , —S(O) 2 R 6C , —S(O) 2 N(R 6C ) 2 , —OR 6C , —SR 6C , alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
         wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, of R C  are each optionally independently unsubstituted or substituted with one or more groups independently selected from R 8 ;       

     R 2  is selected from the group consisting of H, halogen, alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl is optionally substituted with one or more halogen; 
     R 3  is selected from the group consisting of H, halogen, alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl is optionally substituted with one or more halogen; 
     R 4  is selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl is optionally substituted with one or more halogen; 
     ring A is selected from the group consisting of aryl, monocyclic heteroaryl, and a multicyclic group; 
     m is 0 or more; 
     each R A  (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF 5 , —OSF 5 , —Si(R 5A ) 3 , —N(R 6A ) 2 , —OR 6A , —SR 6A , alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
         wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R A  are each optionally independently unsubstituted or substituted with one or more groups independently selected from R 8 ;       

     -L 1 - is a divalent moiety selected from the group consisting of —NHC(O)— and —C(O)NH—; 
     R L  is selected from the group consisting of alkyl and heteroalkyl, wherein said alkyl and heteroalkyl of R L  are each optionally unsubstituted or substituted with one or more halogen; 
     or, alternatively, R L  is a moiety having the formula 
     
       
         
         
             
             
         
       
     
     wherein q is 0 or 1; 
     -L B - (when present) is a divalent moiety selected from the group consisting of lower alkyl and lower heteroalkyl, wherein each said lower alkyl and lower heteroalkyl is optionally substituted with one or more halogen; 
     ring B is selected from the group consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and a multicyclic group; 
     p is 0 or more; and 
     each R B  (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF 5 , —OSF 5 , —Si(R 5B ) 3 , —N(R 6B ) 2 , —NR 7B C(O)R 6B , —NR 7B S(O) 2 R 6B , —NR 7B S(O) 2 N(R 6B ) 2 , —NR 7B C(O)N(R 6B ) 2 , —NR 7B C(O)OR 6B , —C(O)R 6B , —C(O)OR 6B , —C(O)N(R 6B ) 2 , —S(O)R 6B , —S(O) 2 R 6B , —S(O) 2 N(R 6B ) 2 , —OR 6B , —SR 6B , alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,
         wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, of R B  are each optionally independently unsubstituted or substituted with one or more groups independently selected from R 9 ;       

     each R 5A , R 5B , and R 5C  (when present) is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
         wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 5A , R 5B , and R 5C  is unsubstituted or substituted with one or more halogen;       

     each R 6A  and R 6C  (when present) is independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl 
     wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R 6A  and R 6C  is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, and haloalkoxy; 
     each R 6B  (when present) is independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,
         wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R 6B  is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, and haloalkoxy;       

     each R 7B  and R 7C  (when present) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
         wherein each said alkyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 7B  and R 7C  is unsubstituted or substituted with one or more halogen;       

     each R 8  (when present) is independently selected from the group consisting of halogen, lower alkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, and lower heterocycloalkyl, wherein each said lower alkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, and lower heterocycloalkyl of R 8  is optionally substituted with halogen; and 
     each R 9  (when present) is independently selected from the group consisting of halogen, —OH, —CN, —SF 5 , —OSF 5 , alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and —O-alkyl-heterocycloalkyl, wherein each said alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and —O-alkyl-heterocycloalkyl are optionally substituted with one or more halogen. 
     In other embodiments, the invention provides compositions, including pharmaceutical compositions, comprising one or more compounds of the invention (e.g., one compound of the invention), or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound(s) and/or said tautomer(s), optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent. 
     In other embodiments, the invention provides various methods of treating, preventing, ameliorating, and/or delaying the onset of an Aβ pathology and/or a symptom or symptoms thereof, comprising administering a composition comprising an effective amount of one or more compounds of the invention, or a tautomer thereof, or pharmaceutically acceptable salt or solvate of said compound(s) and/or said tautomer(s), to a patient in need thereof. Such methods optionally additionally comprise administering an effective amount of one or more additional therapeutic agents, simultaneously or sequentially, suitable for treating the patient being treated. 
     These and other embodiments of the invention, which are described in detail below or will become readily apparent to those of ordinary skill in the art, are included within the scope of the invention. 
     In other embodiments, the invention provides compositions, including pharmaceutical compositions, comprising one or more compounds of the invention (e.g., one compound of the invention), or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound(s) and/or said tautomer(s), optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent. 
     Additional embodiments in which the compounds of the invention may be useful include various methods of treating, preventing, ameliorating, and/or delaying the onset of an Aβ pathology and/or a symptom or symptoms thereof, comprising administering a composition comprising an effective amount of one or more compounds of the invention, or a tautomer thereof, or pharmaceutically acceptable salt or solvate of said compound(s) and/or said tautomer(s), to a patient in need thereof. Such methods optionally additionally comprise administering an effective amount of one or more additional therapeutic agents suitable for treating the patient being treated. 
     These and other embodiments of the invention, which are described in detail below or will become readily apparent to those of ordinary skill in the art, are included within the scope of the invention. 
    
    
     DETAILED DESCRIPTION 
     For each of the following embodiments, any variable not explicitly defined in the embodiment is as defined in Formula (I) or (IA). In each of the embodiments described herein, each variable is selected independently of the other unless otherwise noted. 
     In one embodiment, the compounds of the invention a structural formula according to Formula (I) or Formula (I′) above, or a pharmaceutically acceptable salt thereof. 
     In one embodiment, the compounds of the invention have the structural Formula (IA): 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof having the structural Formula (IA′): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt thereof, wherein each variable is as described in Formula (I). 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R N  is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, and —(C 1-6 alkyl)-cycloalkyl, wherein said heteroalkyl is optionally substituted with halogen. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R N  is selected from the group consisting of —(C 1-6 alkyl), —(C 1-6 alkyl)-cycloalkyl, —(C 1-6 haloalkyl), and —(C 1-6  alkyl)-O—(C 1-6 alkyl). 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R N  is selected from the group consisting of methyl and ethyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R N  is selected from the group consisting of methyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1A  is selected from the group consisting of H, fluorine, methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , and —CH 2 OCH 3 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1A  is selected from the group consisting of H, fluorine, methyl —CH 2 F, —CHF 2 , and —CF 3 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is selected from the group consisting of H, halogen, lower alkyl and lower heteroalkyl, wherein said lower alkyl and lower heteroalkyl of R 1B  are each optionally unsubstituted or substituted with one or more halogen. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is selected from the group consisting of H, fluoro, methyl, ethyl, propyl, butyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 SCH 3 , —CH 2 SCH 2 CH 3 , —CH 2 CH 2 SCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 OCF 3 , and —CH 2 OCHF 2 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is selected from the group consisting of H, fluoro, methyl, ethyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 SCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 OCF 3 , and —CH 2 OCHF 2 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is selected from the group consisting of H, fluoro, methyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OCH 3 , and —CH 2 N(CH 3 ) 2 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1A  is selected from the group consisting of H, fluorine, methyl —CH 2 F, —CHF 2 , and —CF 3 ; and 
     R 1B  is selected from the group consisting of H, fluoro, methyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OCH 3 , and —CH 2 N(CH 3 ) 2 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1A  is methyl; and 
     R 1B  is methyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is a moiety having the formula 
     
       
         
         
             
             
         
       
         
         
           
             wherein k, L C , ring C, n, and R C  are each as defined in Formula (I). 
           
         
       
    
     In some embodiments, in each of Formulas (I), (I′), (IA), and (IA′): 
     k is 0. In such embodiments, -L C - is absent; and R 1B  is a moiety having the formula 
     
       
         
         
             
             
         
       
     
     In some embodiments in each of Formulas (I), (I′), (IA), (IA′), (II), (II′), (III), (III′), (IV): 
     k is 1; and 
     R 1B  is a moiety having the formula 
                         
wherein:
 
     -L C - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —, —CH 2 O—, and —CF 2 O—. 
     In some embodiments in each of Formulas (I), (I′), (IA), (IA′), (II), (II′), (III), (III′), (IV): 
     k is 1; and 
     R 1B  is a moiety having the formula 
                         
wherein:
         -L C - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, and —CH 2 CH 2 —.       

     In some embodiments in each of Formulas (I), (I′), (IA), (IA′), (II), (II′), (III), (III′), (IV): 
     k is 1; and 
     R 1B  is a moiety having the formula 
                         
wherein:
 
     -L C - is —CH 2 —. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is a moiety having the formula 
                         
and
 
     ring C is selected from the group consisting of azetidinyl, benzimidazolyl, benzoisothiazolyl, benzoisoxazoyl, benzothiazolyl, benzoxazoyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, dihydroindenyl, dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl, imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl, thiomorpholinyl dioxide, and triazolyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is a moiety having the formula 
                         
and
 
     ring C is selected from the group consisting of azetidinyl, cyclopropyl, cyclobutyl, dihydrooxazolyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyl, thiomorpholinyl dioxide, and triazolyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is a moiety having the formula 
                         
and
 
     ring C is selected from the group consisting of azetidinyl, cyclopropyl, cyclobutyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, and thienyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is a moiety having the formula 
                         
and
 
     ring C is selected from the group consisting of azetidinyl, cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, and tetrahydropyranyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is a moiety having the formula 
                         
and
 
     each R C  (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, —SF 5 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)CH 3 , —N(CH 3 )C(O)CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 NHCH 3 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —S(CH 3 ), methyl, ethyl, propyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CH 2 F. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is a moiety having the formula 
                         
and
 
     each R C  (when present) is independently selected from the group consisting of fluoro, chloro, bromo, oxo, —OH, —CN, —SF 5 , —NH(CH 3 ), —N(CH 3 ) 2 , —S(O) 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —S(CH 3 ), methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is a moiety having the formula 
                         
and
 
     each R C  (when present) is independently selected from the group consisting of fluoro, chloro, —CN, —S(O) 2 CH 3 , —OCH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, methyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CH 2 F. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1B  is a moiety having the formula 
                         
and
 
     ring C is selected from the group consisting of azetidinyl, cyclopropyl, cyclobutyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, and thienyl;
         n is 0 or more; and       

     each R C  (when present) is independently selected from the group consisting of fluoro, chloro, bromo, oxo, —OH, —CN, —SF 5 , —NH(CH 3 ), —N(CH 3 ) 2 , —S(O) 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —S(CH 3 ), methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F. 
     In an alternative of the immediately preceding embodiment, k is 0. 
     In another alternative of the immediately preceding embodiment, k is 1; and 
     -L C - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —, —CH 2 O—, and —CF 2 O—. 
     In another alternative of the immediately preceding embodiment, k is 1; and 
     -L C - is a divalent moiety selected from the group consisting of —CH 2 —, —C 2 —, —CH 2 CH 2 —. 
     In another alternative of the immediately preceding embodiment, k is 1; and 
     -L C - is —CH 2 —. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     k is 1; and R 1B  is a moiety having the formula 
                         
wherein:
 
     -L C - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —, —CH 2 O—, and —CF 2 O—. 
     ring C is selected from the group consisting of azetidinyl, cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, and tetrahydropyranyl; 
     n is 0 or more; and 
     each R C  (when present) is independently selected from the group consisting of fluoro, chloro, —CN, —S(O) 2 CH 3 , —OCH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, methyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CH 2 F. 
     In another alternative of the immediately preceding embodiment, -L C - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —. 
     In another alternative of the immediately preceding embodiment, -L C - is —CH 2 —. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     k is 0; and R 1B  is a moiety having the formula 
     
       
         
         
             
             
         
       
     
     ring C is selected from the group consisting of azetidinyl, cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl, tetrahydrofuranyl, and tetrahydropyranyl; 
     n is 0 or more; and 
     each R C  (when present) is independently selected from the group consisting of fluoro, chloro, —CN, —S(O) 2 CH 3 , —OCH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, methyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CH 2 F. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1A  is methyl; and 
     R 1B  is selected from the group consisting of methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, and fluorophenyl. 
     It shall be understood that the phrase “n is 0 or more” means n is an integer from 0 up to the number that corresponds to the maximum number of substitutable hydrogen atoms of the ring to which R C  is shown attached. 
     Thus, in embodiments wherein ring C is a moiety having 4 substitutable hydrogen atoms, n is 0, 1, 2, 3, or 4. In an alternative of such embodiments wherein ring C is a moiety having 4 substitutable hydrogen atoms, n is 0, 1, 2, or 3. In an alternative of such embodiments wherein ring C is a moiety having 4 substitutable hydrogen atoms, n is 0, 1, or 2. In an alternative of such embodiments wherein ring C is a moiety having 4 substitutable hydrogen atoms, n is 0 or 1. In alternative of such embodiments wherein ring C is a moiety having 4 substitutable hydrogen atoms, n is 0. 
     In embodiments wherein ring C is a moiety having 3 substitutable hydrogen atoms, n is 0, 1, 2, or 3. In an alternative of such embodiments wherein ring C is a moiety having 3 substitutable hydrogen atoms, n is 0, 1, or 2. In an alternative of such embodiments wherein ring C is a moiety having 3 substitutable hydrogen atoms, n is 0 or 1. In alternative of such embodiments wherein ring C is a moiety having 3 substitutable hydrogen atoms, n is 0. 
     In embodiments wherein ring C is a moiety having 2 substitutable hydrogen atoms, n is 0, 1, or 2. In an alternative of such embodiments wherein ring C is a moiety having 2 substitutable hydrogen atoms, n is 0 or 1. In alternative of such embodiments wherein ring C is a moiety having 2 substitutable hydrogen atoms, n is 0. 
     In embodiments wherein ring C is a moiety having 1 substitutable hydrogen atom, n is 0 or 1. In an alternative of such embodiments wherein ring C is a moiety having 1 substitutable hydrogen atoms, n is 0. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 2  is selected from the group consisting of H, fluoro, methyl, ethyl, propyl, butyl, cyclopropyl, —CH 2 -cyclopropyl, and —CH 2 OCH 3 . 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 2  is selected from the group consisting of H and methyl. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 2  is H. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 3  is selected from the group consisting of H, fluoro, methyl, ethyl, propyl, butyl, cyclopropyl, —CH 2 -cyclopropyl, and —CH 2 OCH 3 . 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 3  is selected from the group consisting of H and methyl. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 3  is H. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 2  is selected from the group consisting of H, fluoro, methyl, ethyl, propyl, butyl, cyclopropyl, —CH 2 -cyclopropyl, and —CH 2 OCH 3 ; and R 3  is H. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 2  is selected from the group consisting of H and methyl; and R 3  is H. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 2  is H and R 3  is H. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 4  is selected from the group consisting of H, methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 F, —CHF 2 , —CF 3 , and —CH 2 OCH 3 . 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 4  is selected from the group consisting of methyl, cyclopropyl, —CH 2 F, and —CHF 2 . 
     In one embodiment, in each of Formulas (I), (IA), and (IA′), R 4  is selected from the group consisting of methyl and —CHF 2 . 
     In one embodiment, in each of Formulas (I), (IA), and (IA′): 
     R 4  is selected from the group consisting of methyl and —CHF 2 ; and 
     one of R 2  and R 3  is H and the other is selected from the group consisting of H and methyl. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′): 
     R 4  is selected from the group consisting of methyl and —CHF 2 ; 
     R 2  is selected from the group consisting of H and methyl; and 
     R 3  is H. 
     In one embodiment, in each of Formulas (I), (IA), and (IA′): 
     R 4  is selected from the group consisting of methyl and —CHF 2 ; 
     R 2  is H; and 
     R 3  is H. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1A  is H, H fluorine, methyl —CH 2 F, —CHF 2 , and —CF 3 ; and 
     R 1B  is selected from the group consisting of H, fluoro, methyl, ethyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OCH 3 , —CH 2 N(CH 3 ) 2 , cyclopropyl, —CH 2 -cyclopropyl, and fluorophenyl; 
     R 4  is selected from the group consisting of methyl and —CHF 2 ; 
     R 2  is selected from the group consisting of H and methyl; and 
     R 3  is H. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R 1A  is methyl; and 
     R 1B  is selected from the group consisting of methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, and fluorophenyl; 
     R 2  is H; 
     R 3  is H; 
     R 4  is methyl; and 
     R N  is selected from the group consisting of —(C 1-6 alkyl), —(C 1-2 alkyl)-cyclopropyl, fluoroethyl, and —(C 1-6 alkyl)-O—(C 1-6 alkyl). 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     ring A is selected from the group consisting of phenyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     ring A is selected from the group consisting of phenyl, pyridazinyl, pyridyl, pyrimidinyl, and pyrazinyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     ring A is selected from the group consisting of phenyl and pyridyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     each R A  (when present) is independently selected from the group consisting of halogen, oxo, —CN, —SF 5 , —NHCH 3 , —N(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —CH 2 OCH 3 , —S(CH 3 ), methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , and —OCHF 2 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     each R A  (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —OCH 3 , —CH 2 OCH 3 , methyl, cyclopropyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , and —OCHF 2 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     each R A  (when present) is independently selected from the group consisting of fluoro, chloro, —CN, —OCH 3 , —CH 2 OCH 3 , methyl, cyclopropyl, —CF 3 , —CHF 2 , and —CH 2 F. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     ring A is selected from the group consisting of phenyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl; 
     m is 0, 1, or 2; and 
     each R A  (when present) is independently selected from the group consisting of halogen, oxo, —CN, —SF 5 , —NHCH 3 , —N(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —CH 2 OCH 3 , —S(CH 3 ), methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , and —OCHF 2 . 
     It shall be understood that the phrase “m is 0 or more” means m is an integer from 0 up to the number that corresponds to the maximum number of substitutable hydrogen atoms of the ring to which R A  is shown attached. 
     Thus, in embodiments wherein ring A is a moiety having 4 substitutable hydrogen atoms, m is 0, 1, 2, 3, or 4. In an alternative of such embodiments wherein ring A is a moiety having 4 substitutable hydrogen atoms, m is 0, 1, 2, or 3. In an alternative of such embodiments wherein ring A is a moiety having 4 substitutable hydrogen atoms, m is 0, 1, or 2. In an alternative of such embodiments wherein ring A is a moiety having 4 substitutable hydrogen atoms, m is 0 or 1. In alternative of such embodiments wherein ring A is a moiety having 4 substitutable hydrogen atoms, m is 0. 
     In embodiments wherein ring A is a moiety having 3 substitutable hydrogen atoms, m is 0, 1, 2, or 3. In an alternative of such embodiments wherein ring A is a moiety having 3 substitutable hydrogen atoms, m is 0, 1, or 2. In an alternative of such embodiments wherein ring A is a moiety having 3 substitutable hydrogen atoms, m is 0 or 1. In alternative of such embodiments wherein ring A is a moiety having 3 substitutable hydrogen atoms, m is 0. 
     In embodiments wherein ring A is a moiety having 2 substitutable hydrogen atoms, m is 0, 1, or 2. In an alternative of such embodiments wherein ring A is a moiety having 2 substitutable hydrogen atoms, m is 0 or 1. In alternative of such embodiments wherein ring A is a moiety having 2 substitutable hydrogen atoms, m is 0. 
     In embodiments wherein ring A is a moiety having 1 substitutable hydrogen atom, m is 0 or 1. In an alternative of such embodiments wherein ring A is a moiety having 1 substitutable hydrogen atoms, m is 0. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is selected from the group consisting of lower alkyl and lower heteroalkyl, wherein said lower alkyl and lower heteroalkyl of R L  are each optionally unsubstituted or substituted with one or more halogen. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is selected from the group consisting of methyl, ethyl, propyl, butyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 SCH 3 , —CH 2 SCH 2 CH 3 , —CH 2 CH 2 SCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 OCF 3 , and —CH 2 OCHF 2 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): R L  is selected from the group consisting of methyl, ethyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 SCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 OCF 3 , and —CH 2 OCHF 2 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): R L  is selected from the group consisting of methyl, ethyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OCH 3 , CH 2 OCF 3 , and —CH 2 OCHF 2 . 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
     
       
         
         
             
             
         
       
     
     wherein q, L B , ring B, p, and R B  are each as defined in Formula (I). 
     In some embodiments, in each of Formulas (I), (I′), (IA), and (IA′): 
     q is 0. In such embodiments, -L B - is absent; R L  is a moiety having the formula 
                         
and ring B and -L 1 - are directly connected as shown:
 
     
       
         
         
             
             
         
       
     
     In some embodiments in each of Formulas (I), (I′), (IA), and (IA′): 
     q is 1; and 
     R L  is a moiety having the formula 
                         
wherein:
 
     -L B - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —, —OCH 2 —, and —OCF 2 —. 
     In some embodiments in each of Formulas (I), (I′), (IA), and (IA′): 
     q is 1; and 
     R L  is a moiety having the formula 
                         
wherein:
 
     -L B - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, and —CH 2 CH 2 —. 
     In some embodiments in each of Formulas (I), (I′), (IA), and (IA′): 
     q is 1; and 
     R L  is a moiety having the formula 
                         
wherein:
 
     -L B  is —CH 2 —. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
                         
wherein:
 
     ring B is selected from the group consisting of azetidinyl, benzimidazolyl, benzoisothiazolyl, benzoisoxazoyl, benzothiazolyl, benzoxazoyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, dihydroindenyl, dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl, imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl, thiomorpholinyl dioxide, and triazolyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
                         
wherein:
 
     ring B is selected from the group consisting of cyclobutyl, cyclopropyl, furanyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, and thienyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
                         
wherein:
 
     ring B is selected from the group consisting of furanyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, and thienyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
                         
wherein:
 
     ring B is selected from the group consisting of isoxazoyl, oxadiazoyl, oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
                         
wherein:
 
     each R B  group (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, —SF 5 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)CH 3 , —N(CH 3 )C(O)CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 NHCH 3 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , —S(CH 3 ), methyl, ethyl, propyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CH 2 F, phenyl, pyridyl, oxadiazoyl, isoxazoyl, oxazoyl, and pyrrolyl,
         wherein each said phenyl, pyridyl, oxadiazoyl, isoxazoyl, oxazoyl, and pyrrolyl is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of F, Cl, —CN, —CH 3 , —OCH 3 , and —CF 3 .       

     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
                         
wherein:
 
     each R B  group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —OH, —CN, —SF 5 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)CH 3 , —N(CH 3 )C(O)CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 NHCH 3 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , —S(CH 3 ), methyl, ethyl, propyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
                         
wherein:
 
     each R B  group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O) 2 CH 3 , —OCH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , methyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
                         
wherein:
 
     q is 0 or 1; 
     -L B - (when present) is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —, —OCH 2 —, and —OCF 2 —; 
     ring B is selected from the group consisting of azetidinyl, benzimidazolyl, benzoisothiazolyl, benzoisoxazoyl, benzothiazolyl, benzoxazoyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, dihydroindenyl, dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl, imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl, thiomorpholinyl dioxide, and triazolyl; 
     p is 0 or more; and 
     each R B  group (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, —SF 5 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)CH 3 , —N(CH 3 )C(O)CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 NHCH 3 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , —S(CH 3 ), methyl, ethyl, propyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —C≡O—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CH 2 F, phenyl, pyridyl, oxadiazoyl, isoxazoyl, oxazoyl, and pyrrolyl,
         wherein each said phenyl, pyridyl, oxadiazoyl, isoxazoyl, oxazoyl, and pyrrolyl is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of F, Cl, CN, —CH 3 , —OCH 3 , and —CF 3 .       

     In an alternative of the immediately preceding embodiment, q is 0. 
     In another alternative of the immediately preceding embodiment, q is 1; and 
     -L B - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, and —CH 2 CH 2 —. 
     In another alternative of the immediately preceding embodiment, q is 1; and 
     -L B  is —CH 2 —. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     R L  is a moiety having the formula 
                         
wherein:
         q is 0 or 1;       

     -L B - (when present) is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —, —OCH 2 —, and —OCF 2 —; 
     ring B is selected from the group consisting of cyclobutyl, cyclopropyl, furanyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, and thienyl; 
     p is 0 or more; and 
     each R B  group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —OH, —CN, —SF 5 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)CH 3 , —N(CH 3 )C(O)CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 NHCH 3 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , —S(CH 3 ), methyl, ethyl, propyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F. 
     In an alternative of the immediately preceding embodiment, q is 0. 
     In another alternative of the immediately preceding embodiment, q is 1; and 
     -L B - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, and —CH 2 CH 2 —. 
     In another alternative of the immediately preceding embodiment, q is 1; and 
     -L B - is —CH 2 —. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     q is 1; and R L  is a moiety having the formula 
                         
wherein:
 
     -L B - (when present) is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —, —OCH 2 —, and —OCF 2 —. 
     ring B is selected from the group consisting of isoxazoyl, oxadiazoyl, oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl; 
     p is 0 or more; and 
     each R B  group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O) 2 CH 3 , —OCH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , methyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F. 
     In an alternative of the immediately preceding embodiment, -L B - is a divalent moiety selected from the group consisting of —CH 2 —, —CF 2 —, and —CH 2 CH 2 —. 
     In another alternative of the immediately preceding embodiment, -L B - is —CH 2 —. 
     In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): 
     q is 0; and R L  is a moiety having the formula 
                         
wherein:
 
     ring B is selected from the group consisting of isoxazoyl, oxadiazoyl, oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl; 
     p is 0 or more; and 
     each R B  group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O) 2 CH 3 , —OCH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , methyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F. 
     It shall be understood that the phrase “p is 0 or more” means p is an integer from 0 up to the number that corresponds to the maximum number of substitutable hydrogen atoms of the ring to which R B  is shown attached. 
     Thus, in embodiments wherein ring B is a moiety having 4 substitutable hydrogen atoms, p is 0, 1, 2, 3, or 4. In an alternative of such embodiments wherein ring B is a moiety having 4 substitutable hydrogen atoms, p is 0, 1, 2, or 3. In an alternative of such embodiments wherein ring B is a moiety having 4 substitutable hydrogen atoms, p is 0, 1, or 2. In an alternative of such embodiments wherein ring B is a moiety having 4 substitutable hydrogen atoms, p is 0 or 1. In alternative of such embodiments wherein ring B is a moiety having 4 substitutable hydrogen atoms, p is 0. 
     In embodiments wherein ring B is a moiety having 3 substitutable hydrogen atoms, p is 0, 1, 2, or 3. In an alternative of such embodiments wherein ring B is a moiety having 3 substitutable hydrogen atoms, p is 0, 1, or 2. In an alternative of such embodiments wherein ring B is a moiety having 3 substitutable hydrogen atoms, p is 0 or 1. In alternative of such embodiments wherein ring B is a moiety having 3 substitutable hydrogen atoms, p is 0. 
     In embodiments wherein ring B is a moiety having 2 substitutable hydrogen atoms, p is 0, 1, or 2. In an alternative of such embodiments wherein ring B is a moiety having 2 substitutable hydrogen atoms, p is 0 or 1. In alternative of such embodiments wherein ring B is a moiety having 2 substitutable hydrogen atoms, p is 0. 
     In embodiments wherein ring B is a moiety having 1 substitutable hydrogen atom, p is 0 or 1. In an alternative of such embodiments wherein ring B is a moiety having 1 substitutable hydrogen atoms, p is 0. 
     In an alternative of each of the embodiments described above, -L 1 - is —C(O)NH—. 
     As noted above, -L 1 - (and -L B - when present) represent divalent moieties. The orientation of such divalent moieties in the formula is the same as the orientation of the moiety as written. Thus, for example, when R L  is the moiety 
                         
and -L 1 - is a — C(O)NH— group, the moiety
 
                         
has the formula:
 
     
       
         
         
             
             
         
       
     
     In an alternative of the above embodiments, in each of Formulas (I), (IA), and (IA′), ring A is phenyl, m is 1 or 2, R A  is fluoro; -L 1 - is —C(O)NH—; ring B is selected from the group consisting of phenyl, pyridyl, and pyrazinyl, p is 0, 1, or 2, and each R B  (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —OH, —CN, —SF 5 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)CH 3 , —N(CH 3 )C(O)CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 NHCH 3 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , —S(CH 3 ), methyl, ethyl, propyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCH 2 CF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F. 
     In an alternative of the immediately preceding embodiment, each R B  group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O) 2 CH 3 , —OCH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , methyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, and —OCH 2 CH 2 F. 
     It shall be noted that all four stereoisomers about the chiral center 
                         
in the compounds of the invention as shown in the Formulas (I), (I′), (IA), and (IA′) are contemplated as being within the scope of the invention:
 
     
       
         
         
             
             
         
       
     
     Specific non-limiting examples of compounds of the invention are shown in the table of examples below. While only one tautomeric form of each compound is shown in the tables, it shall be understood that all tautomeric forms of the compounds are contemplated as being within the scope of the non-limiting examples. 
     In another embodiment, 1 to 3 carbon atoms of the compounds of the invention may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied. 
     In another embodiment, there is provided a composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent. 
     Another embodiment provides a composition comprising a compound of the invention, either as the sole active agent, or optionally in combination with one or more additional therapeutic agents, and a pharmaceutically acceptable carrier or diluent. Non-limiting examples of additional therapeutic agents which may be useful in combination with the compounds of the invention include those selected from the group consisting of: (a) drugs that may be useful for the treatment of Alzheimer&#39;s disease and/or drugs that may be useful for treating one or more symptoms of Alzheimer&#39;s disease, (b) drugs that may be useful for inhibiting the synthesis Aβ, (c) drugs that may be useful for treating neurodegenerative diseases, and (d) drugs that may be useful for the treatment of type II diabetes and/or one or more symptoms or associated pathologies thereof. 
     Non-limiting examples of additional therapeutic agents which may be useful in combination with the compounds of the invention include drugs that may be useful for the treatment, prevention, delay of onset, amelioration of any pathology associated with Aβ and/or a symptom thereof. Non-limiting examples of pathologies associated with Aβ include: Alzheimer&#39;s Disease, Down&#39;s syndrome, Parkinson&#39;s disease, memory loss, memory loss associated with Alzheimer&#39;s disease, memory loss associated with Parkinson&#39;s disease, attention deficit symptoms, attention deficit symptoms associated with Alzheimer&#39;s disease (“AD”), Parkinson&#39;s disease, and/or Down&#39;s syndrome, dementia, stroke, microgliosis and brain inflammation, pre-senile dementia, senile dementia, dementia associated with Alzheimer&#39;s disease, Parkinson&#39;s disease, and/or Down&#39;s syndrome, progressive supranuclear palsy, cortical basal degeneration, neurodegeneration, olfactory impairment, olfactory impairment associated with Alzheimer&#39;s disease, Parkinson&#39;s disease, and/or Down&#39;s syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysis complications (from β 2  microglobulins and complications arising therefrom in hemodialysis patients), scrapie, bovine spongiform encephalitis, and Creutzfeld-Jakob disease, comprising administering to said patient at least one compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, in an amount effective to inhibit or treat said pathology or pathologies. 
     Non-limiting examples of additional therapeutic agents for that may be useful in combination with compounds of the invention include: muscarinic antagonists (e.g., m 1  agonists (such as acetylcholine, oxotremorine, carbachol, or McNa343), or m 2  antagonists (such as atropine, dicycloverine, tolterodine, oxybutynin, ipratropium, methoctramine, tripitamine, or gallamine)); cholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors such as donepezil (Aricept®, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride), galantamine (Razadyne®), and rivastigimine (Exelon®); N-methyl-D-aspartate receptor antagonists (e.g., Namenda® (memantine HCl, available from Forrest Pharmaceuticals, Inc.); combinations of cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists; gamma secretase modulators; gamma secretase inhibitors; non-steroidal anti-inflammatory agents; anti-inflammatory agents that can reduce neuroinflammation; anti-amyloid antibodies (such as bapineuzemab, Wyeth/Elan); vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; antibiotics; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABA A  inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors; Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); Tau aggregation inhibitors (e.g., Rember®); RAGE inhibitors (e.g., TTP 488 (PF-4494700)); anti-Abeta vaccine; APP ligands; agents that upregulate insulin, cholesterol lowering agents such as HMG-CoA reductase inhibitors (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin) and/or cholesterol absorption inhibitors (such as Ezetimibe), or combinations of HMG-CoA reductase inhibitors and cholesterol absorption inhibitors (such as, for example, Vytorin®); fibrates (such as, for example, clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate); combinations of fibrates and cholesterol lowering agents and/or cholesterol absorption inhibitors; nicotinic receptor agonists; niacin; combinations of niacin and cholesterol absorption inhibitors and/or cholesterol lowering agents (e.g., Simcor® (niacin/simvastatin, available from Abbott Laboratories, Inc.); LXR agonists; LRP mimics; H3 receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors; 5-HT4 agonists (e.g., PRX-03140 (Epix Pharmaceuticals)); 5-HT6 receptor antagonists; mGluR1 receptor modulators or antagonists; mGluR5 receptor modulators or antagonists; mGluR2/3 antagonists; Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; agents that can induce Abeta efflux such as gelsolin; Metal-protein attenuating compound (e.g, PBT2); and GPR3 modulators; and antihistamines such as Dimebolin (e.g., Dimebon®, Pfizer). 
     Another embodiment provides a method of preparing a pharmaceutical composition comprising the step of admixing at least one compound of the invention, or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer, and a pharmaceutically acceptable carrier or diluent. 
     Another embodiment provides a method of inhibiting β-secretase comprising exposing a population of cells expressing β-secretase to at least one compound of the invention, or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer, in an amount effective to inhibit β-secretase. In one such embodiment, said population of cells is in vivo. In another such embodiment, said population of cells is ex vivo. In another such embodiment, said population of cells is in vitro. 
     Additional embodiments in which the compounds of the invention may be useful include: a method of inhibiting β-secretase in a patient in need thereof. A method of inhibiting the formation of Aβ from APP in a patient in need thereof. A method of inhibiting the formation of Aβ plaque and/or Aβ fibrils and/or Aβ oligomers and/or senile plaques and/or neurofibrillary tangles and/or inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), in a patient in need thereof. Each such embodiment comprises administering at least one compound of the invention, or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer, in a therapeutically effective amount to inhibit said pathology or condition in said patient. 
     Additional embodiments in which the compounds of the invention may be useful include: a method of treating, preventing, and/or delaying the onset of one or more pathologies associated with Aβ and/or one or more symptoms of one or more pathologies associated with Aβ. Non-limiting examples of pathologies which may be associated with Aβ include: Alzheimer&#39;s Disease, Down&#39;s syndrome, Parkinson&#39;s disease, memory loss, memory loss associated with Alzheimer&#39;s disease, memory loss associated with Parkinson&#39;s disease, attention deficit symptoms, attention deficit symptoms associated with Alzheimer&#39;s disease (“AD”), Parkinson&#39;s disease, and/or Down&#39;s syndrome, dementia, stroke, microgliosis and brain inflammation, pre-senile dementia, senile dementia, dementia associated with Alzheimer&#39;s disease, Parkinson&#39;s disease, and/or Down&#39;s syndrome, progressive supranuclear palsy, cortical basal degeneration, neurodegeneration, olfactory impairment, olfactory impairment associated with Alzheimer&#39;s disease, Parkinson&#39;s disease, and/or Down&#39;s syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysis complications (from β 2  microglobulins and complications arising therefrom in hemodialysis patients), scrapie, bovine spongiform encephalitis, and Creutzfeld-Jakob disease, said method(s) comprising administering to said patient in need thereof at least one compound of the invention, or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer, in an amount effective to inhibit said pathology or pathologies. 
     Another embodiment in which the compounds of the invention may be useful includes a method of treating Alzheimer&#39;s disease, wherein said method comprises administering an effective (i.e., therapeutically effective) amount of one or more compounds of the invention (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer), optionally in further combination with one or more additional therapeutic agents which may be effective to treat Alzheimer&#39;s disease or a disease or condition associated therewith, to a patient in need of treatment. In embodiments wherein one or more additional therapeutic agents are administered, such agents may be administered sequentially or together. Non-limiting examples of associated diseases or conditions, and non-limiting examples of suitable additional therapeutically active agents, are as described above. 
     Another embodiment in which the compounds of the invention may be useful includes a method of treating mild cognitive impairment (“MCI”), wherein said method comprises administering an effective (i.e., therapeutically effective) amount of one or more compounds of the invention (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) to a patient in need of treatment. In one such embodiment, treatment is commenced prior to the onset of symptoms. 
     Another embodiment in which the compounds of the invention may be useful includes a method of preventing, or alternatively of delaying the onset, of mild cognitive impairment or, in a related embodiment, of preventing or alternatively of delaying the onset of Alzheimer&#39;s disease. In such embodiments, treatment can be initiated prior to the onset of symptoms, in some embodiments significantly before (e.g., from several months to several years before) the onset of symptoms to a patient at risk for developing MCI or Alzheimer&#39;s disease. Thus, such methods comprise administering, prior to the onset of symptoms or clinical or biological evidence of MCI or Alzheimer&#39;s disease (e.g., from several months to several yeards before, an effective (i.e., therapeutically effective), and over a period of time and at a frequency of dose sufficient for the therapeutically effective degree of inhibition of the BACE enzyme over the period of treatment, an amount of one or more compounds of the invention (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) to a patient in need of treatment. 
     Another embodiment in which the compounds of the invention may be useful includes a method of treating Down&#39;s syndrome, comprising administering an effective (i.e., therapeutically effective) amount of one or more compounds of the invention (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) to a patient in need of treatment. 
     Another embodiment in which the compounds of the invention may be useful includes a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of the invention (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient, the combined quantities of the compound of the invention and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer&#39;s disease, or (b) inhibit the deposition of amyloid protein in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) inhibit the activity of BACE-1 and/or BACE-2. 
     In various embodiments, the compositions and methods disclosed above and below wherein the compound(s) of the invention is a compound or compounds selected from the group consisting of the exemplary compounds of the invention described below. 
     In another embodiment, the invention provides for the use of a compound of the invention, or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer, in the manufacture of a medicament which may be useful in: the treatment, the delay of onset, and/or the prevention of one or more Aβ pathologies and/or in the treatment, the delay of onset, and/or the prevention of one or more symptoms of one or more Aβ pathologies. 
     DEFINITIONS 
     The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names and chemical structures may be used interchangeably to describe that same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portion of “hydroxyalkyl”, “haloalkyl”, arylalkyl-, alkylaryl-, “alkoxy” etc. 
     It shall be understood that, in the various embodiments of the invention described herein, any variable not explicitly defined in the context of the embodiment is as defined in Formula (I). All valences not explicitly filled are assumed to be filled by hydrogen. 
     “Patient” includes both human and non-human animals. Non-human animals include those research animals and companion animals such as mice, primates, monkeys, great apes, canine (e.g., dogs), and feline (e.g., house cats). 
     “Pharmaceutical composition” (or “pharmaceutically acceptable composition”) means a composition suitable for administration to a patient. Such compositions may contain the neat compound (or compounds) of the invention or mixtures thereof, or salts, solvates, prodrugs, isomers, or tautomers thereof, or they may contain one or more pharmaceutically acceptable carriers or diluents. The term “pharmaceutical composition” is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said “more than one pharmaceutically active agents”. The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units. 
     “Halogen” (or “halo”) means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine. 
     “Alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. 
     “Haloalkyl” means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above. 
     “Heteroalkyl” means an alkyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of attachment to the remainder of the molecule is through a carbon atom of the heteroalkyl radical. Suitable such heteroatoms include O, S, S(O), S(O) 2 , and —NH—, —N(alkyl)-. Non-limiting examples include ethers, thioethers, amines, and the like. 
     “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. 
     “Alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. More generally, the suffix “ene” on alkyl, aryl, hetercycloalkyl, etc. indicates a divalent moiety, e.g., —CH 2 CH 2 — is ethylene, and 
                         
is para-phenylene.
 
     “Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. 
     “Alkenylene” means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above. Non-limiting examples of alkenylene include —CH═CH—, —C(CH 3 )═CH—, and —CH═CHCH 2 —. 
     “Aryl” means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. “Monocyclic aryl” means phenyl. 
     “Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more substituents, which may be the same or different, as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. “Heteroaryl” may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term “monocyclic heteroaryl” refers to monocyclic versions of heteroaryl as described above and includes 4- to 7-membered monocyclic heteroaryl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, O, and S, and oxides thereof. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heteroaryl moities include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridoneyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof. 
     “Cycloalkyl” means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 3 to about 6 carbon atoms. The cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of multicyclic cycloalkyls include [1.1.1]-bicyclopentane, 1-decalinyl, norbornyl, adamantyl and the like. 
     
       
         
         
             
             
         
       
     
     “Cycloalkenyl” means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contain at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. The term “monocyclic cycloalkenyl” refers to monocyclic versions of cycloalkenyl groups described herein and includes non-aromatic 3- to 7-membered monocyclic cycloalkyl groups which contains one or more carbon-carbon double bonds. Non-limiting examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohetpenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. 
     “Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any —NH in a heterocyclyl ring may exist protected such as, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-dioxide. “Heterocyclyl” also includes rings wherein ═O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such ═O groups may be referred to herein as “oxo.” An example of such a moiety is pyrrolidinone (or pyrrolidone): 
                         
As used herein, the term “monocyclic heterocycloalkyl” refers monocyclic versions of the heterocycloalkyl moities described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O) 2 . The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. Non-limiting examples of lower alkyl-substituted oxetanyl include the moiety:
 
     
       
         
         
             
             
         
       
     
     “Heterocycloalkenyl” (or “heterocyclenyl”) means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl” also includes rings wherein ═O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Example of such moiety is pyrrolidenone (or pyrrolone): 
                         
As used herein, the term “monocyclic heterocycloalkenyl” refers to monocyclic versions of the heterocycloalkenyl moities described herein and include 4- to 7-membered monocyclic heterocycloalkenyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O) 2 . The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocyloalkenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, dihydrothiophenyl, and dihydrothiopyranyl, and oxides thereof.
 
     It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. 
                         
there is no —OH attached directly to carbons marked 2 and 5.
 
     As used herein, the term “multicyclic group” refers to a fused ring system comprising two (bicyclic), three (tricyclic), or more fused rings, wherein each ring of the fused ring system is independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, and monocyclic heterocycloalkenyl, as defined above. The point of attachment to the parent moiety is to any available ring carbon or (if present) ring heteroatom on any of the fused rings. It shall be understood that each of the following multicyclic groups pictured may be unsubstituted or substituted, as described herein. Only the point of attachment to the parent moiety is shown by the wavy line. 
     The term multicyclic group includes bicyclic aromatic groups. Non-limiting examples of multicyclic groups which are bicyclic aromatic groups include: 
                         
The term multicyclic group thus includes bicyclic heteroaromatic groups comprising from 1 to 3 ring heteroatoms, each said ring heteroatom being independently selected from the group consisting of N, O, and S, S(O), S(O) 2 , and oxides of N, O, and S, and oxides thereof.
 
     The term multicyclic group includes saturated bicyclic cycloalkyl groups. Non-limiting examples of multicyclic groups which are saturated bicyclic cycloalkyl groups include the following: 
     
       
         
         
             
             
         
       
     
     The term multicyclic group includes partially unsaturated bicyclic cycloalkyl groups. Non-limiting examples of multicyclic groups which comprise partially unsaturated bicyclic cycloalkyl groups include the following: 
     
       
         
         
             
             
         
       
     
     The term multicyclic groups includes partially or fully saturated bicyclic groups comprising from 1 to 3 ring heteroatoms, each said ring heteroatom is independently selected from the group consisting of N, O, and S, S(O), S(O) 2 , and oxides of N, O, and S. 
     The term multicyclic group includes aromatic tricyclic groups, cycloalkyl tricyclic groups, as well as heteroaromatic and partially and fully saturated tricyclic groups. For tricyclic groups comprising ring heteroatoms, said tricyclic groups comprise one or more (e.g., from 1 to 5) ring heteroatoms, wherein each said ring heteroatom is independently selected from N, O, and S, S(O), S(O) 2 , and oxides of N, O, and S: 
     “Arylalkyl” (or “aralkyl”) means an aryl-alkyl-group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl. The term (and similar terms) may be written as “arylalkyl-” (or as “-alkyl-aryl”) to indicate the point of attachment to the parent moiety. Similarly, “heteroarylalkyl”, “cycloalkylalkyl”, “cycloalkenylalkyl”, “heterocycloalkylalkyl”, “heterocycloalkenylalkyl”, etc., mean a heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, etc. as described herein bound to a parent moiety through an alkyl group. Preferred groups contain a lower alkyl group. Such alkyl groups may be straight or branched, unsubstituted and/or substituted as described herein. 
     “Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl. 
     “Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprising an oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can be substituted, provided that substituents adjacent to the ring oxygen do not include halo or substituents joined to the ring through an oxygen, nitrogen or sulfur atom. 
     “Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl, adamantylpropyl, and the like. 
     “Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like. 
     “Heteroarylalkyl” means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like. 
     “Heterocyclylalkyl” (or “heterocycloalkylalkyl”) means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like. 
     “Heterocyclenylalkyl” means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. 
     “Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. 
     “Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl. 
     “Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. 
     “Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. 
     “Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as defined herein. The bond to the parent moiety is through the alkyl. 
     Any of the foregoing functional groups may be unsubstituted or substituted as described herein. The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom&#39;s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound’ or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. 
     The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties. 
     Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylfused cycloalkylalkyl-moiety or the like includes substitution on any ring portion and/or on the alkyl portion of the group. 
     When a variable appears more than once in a group, e.g., R 6  in —N(R 6 ) 2 , or a variable appears more than once in a structure presented herein, the variables can be the same or different. 
     The line   as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry. For example: 
                         
means containing both
 
                         
The wavy line   as used herein, indicates a point of attachment to the rest of the compound. Lines drawn into the ring systems, such as, for example:
 
                         
indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.
 
     “Oxo” is defined as a oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e.g., 
     
       
         
         
             
             
         
       
         
         
           
             In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be any adjacent oxygen and/or sulfur present in said ring system. 
             As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example: 
           
         
       
    
     
       
         
         
             
             
         
       
     
     In another embodiment, the compounds of the invention, and/or compositions comprising them, are present in isolated and/or purified form. The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be suitable for in vivo or medicinal use and/or characterizable by standard analytical techniques described herein or well known to the skilled artisan. 
     When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al,  Protective Groups in organic Synthesis  (1991), Wiley, New York. 
     Those skilled in the art will recognize those instances in which the compounds of the invention may be converted to prodrugs and/or solvates, another embodiment of the present invention. A discussion of prodrugs is provided in T. Higuchi and V. Stella,  Pro - drugs as Novel Delivery Systems  (1987) 14 of the A.C.S. Symposium Series, and in  Bioreversible Carriers in Drug Design , (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. 
     One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms where they exist. “Solvate” means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H 2 O. 
     “Effective amount” or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect. 
     Those skilled in the art will recognize those instances in which the compounds of the invention may form salts. In such instances, another embodiment provides pharmaceutically acceptable salts of the compounds of the invention. Thus, reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes any of the following: acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also potentially useful. Salts of the compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. 
     Exemplary acid addition salts which may be useful include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.)  Handbook of Pharmaceutical Salts. Properties, Selection and Use . (2002) Zurich: Wiley-VCH; S. Berge et al,  Journal of Pharmaceutical Sciences  (1977) 66(1) 1-19; P. Gould,  International J. of Pharmaceutics  (1986) 33 201-217; Anderson et al,  The Practice of Medicinal Chemistry  (1996), Academic Press, New York; and in  The Orange Book  (Food &amp; Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. 
     Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. 
     All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered as potentially useful alternatives to the free forms of the corresponding compounds for purposes of the invention. 
     Another embodiment which may be useful includes pharmaceutically acceptable esters of the compounds of the invention. Such esters may include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1-4 alkyl, or C 1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C 1-20  alcohol or reactive derivative thereof, or by a 2,3-di(C 6-24 )acyl glycerol. 
     As mentioned herein, under certain conditions the compounds of the invention may form tautomers. Such tautomers, when present, comprise another embodiment of the invention. It shall be understood that all tautomeric forms of such compounds are within the scope of the compounds of the invention. For example, all keto-enol and imine-enamine forms of the compounds, when present, are included in the invention. Thus, a compound of the invention conforming to the formula: 
                         
and its tautomer, which can be depicted as:
 
                         
are both contemplated as being within the scope of the compounds of the invention. As noted above, while only one said tautomeric form of each compound is shown in the tables, it shall be understood that all tautomeric forms of the compounds are contemplated as being within the scope of the non-limiting example compounds of the invention.
 
     The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. 
     Where various stereoisomers of the compounds of the invention are possible, another embodiment provides for diastereomeric mixtures and individual enantiomers of the compounds of the invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher&#39;s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. 
     All stereoisomers (for example, geometric isomers, optical isomers and the like) of the compounds of the invention (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated as embodiments within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention). 
     Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. 
     Another embodiment which may be useful include isotopically-labelled compounds of the invention. Such compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as  2 H,  3 H,  11 C,  13 C,  14 C,  15 N,  18 O,  17 O,  31 P,  32 P,  35 S,  18 F, and  36 Cl, respectively. 
     In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates. 
     Polymorphic forms of the compounds of the invention, and of the salts, solvates, esters and prodrugs of the compounds of the invention, are intended to be included in the present invention. 
     Another embodiment provides suitable dosages and dosage forms of the compounds of the invention. Suitable doses for administering compounds of the invention to patients may readily be determined by those skilled in the art, e.g., by an attending physician, pharmacist, or other skilled worker, and may vary according to patient health, age, weight, frequency of administration, use with other active ingredients, and/or indication for which the compounds are administered. Doses may range from about 0.001 to 500 mg/kg of body weight/day of the compound of the invention. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg of body weight/day of a compound of the invention, or a pharmaceutically acceptable salt or solvate of said compound. In another embodiment, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. In another embodiment, a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses. 
     When used in combination with one or more additional therapeutic agents, the compounds of this invention may be administered together or sequentially. When administered sequentially, compounds of the invention may be administered before or after the one or more additional therapeutic agents, as determined by those skilled in the art or patient preference. 
     If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range. 
     Accordingly, another embodiment provides combinations comprising an amount of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional agents described above. 
     Another embodiment provides for pharmaceutically acceptable compositions comprising a compound of the invention, either as the neat chemical or optionally further comprising additional ingredients. For preparing pharmaceutical compositions from the compounds of the invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.),  Remington&#39;s Pharmaceutical Sciences,  18 th  Edition, (1990), Mack Publishing Co., Easton, Pa. 
     Liquid form preparations include solutions, suspensions and emulsions. Non-limiting examples which may be useful include water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. 
     Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. 
     Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. 
     Another embodiment which may be useful includes compositions comprising a compound of the invention formulated for transdermal delivery. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. 
     Other embodiment which may be useful includes compositions comprising a compound of the invention formulated for subcutaneous delivery or for oral delivery. In some embodiments, it may be advantageous for the pharmaceutical preparation comprising one or more compounds of the invention be prepared in a unit dosage form. In such forms, the preparation may be subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Each of the foregoing alternatives, together with their corresponding methods of use, are considered as included in the various embodiments of the invention. 
     Preparative Examples 
     Compounds of the invention can be made using procedures known in the art. The following reaction schemes show typical procedures, but those skilled in the art will recognize that other procedures can also be suitable. Reactions may involve monitoring for consumption of starting material, and there are many methods for said monitoring, including but not limited to thin layer chromatography (TLC) and liquid chromatography mass spectrometry (LCMS), and those skilled in the art will recognize that where one method is specified, other non-limiting methods may be substituted. 
     Mass spectra for synthetic intermediates were obtained on a Agilent LCMS using General LCMS conditions 1. 
     
       
         
           
               
               
             
               
                   
                   
               
             
            
               
                   
                 Acetic acid: AcOH 
               
               
                   
                 Acetonitrile: MeCN 
               
               
                   
                 Aqueous: aq. 
               
               
                   
                 Atmospheric pressure chemical ionization: APCI 
               
               
                   
                 Benzyl: Bn 
               
               
                   
                 Chloramine-T: N-chloro 4-methylbenzenesulfonamide, sodium salt 
               
               
                   
                 3-chloroperbenzoic acid: mCPBA 
               
               
                   
                 1,8-Diazabicycloundec-7-ene: DBU 
               
               
                   
                 Dichloromethane: DCM 
               
               
                   
                 Di-tert-butyldicarbonate: Boc 2 O 
               
               
                   
                 Diisopropylethylamine: DIPEAor iPr 2 NEt 
               
               
                   
                 Dimethylformamide: DMF 
               
               
                   
                 Dimethylsulfoxide: DMSO 
               
               
                   
                 Electrospray: ES 
               
               
                   
                 Ethyl: Et 
               
               
                   
                 Ethyl acetate: AcOEt or EtOAc 
               
               
                   
                 Example: Ex. 
               
               
                   
                 Gas chromatography-mass spectrometry: GCMS 
               
               
                   
                 Grams: g 
               
               
                   
                 Hexanes: hex 
               
               
                   
                 High performance liquid chromatography: HPLC 
               
               
                   
                 Inhibition: Inh. 
               
               
                   
                 Liquid chromatography mass spectrometry: LCMS 
               
               
                   
                 Lithium bis(trimethylsilyl)amide: LHMDS 
               
               
                   
                 Meta-chloroperoxybenzoic acid: m-CPBA 
               
               
                   
                 Methanesulfonyl chloride: MeSO 2 Cl 
               
               
                   
                 Methanol: MeOH 
               
               
                   
                 Methyl: Me 
               
               
                   
                 Methoxyethoxymethyl: MEM 
               
               
                   
                 Methyl chloromethyl ether: MOMCl 
               
               
                   
                 Methyl iodide: MeI 
               
               
                   
                 Methyl magnesium bromide: MeMgBr 
               
               
                   
                 Microliters: μl or μL 
               
               
                   
                 Milligrams: mg 
               
               
                   
                 Milliliters: mL 
               
               
                   
                 Millimoles: mmol 
               
               
                   
                 Minutes: min 
               
               
                   
                 n-Butyllithium: nBuLi or n-BuLi 
               
               
                   
                 Nuclear magnetic resonance spectroscopy: NMR 
               
               
                   
                 Number: no. or No. 
               
               
                   
                 Petroleum ether: PE 
               
               
                   
                 Retention time: t R   
               
               
                   
                 Reverse Phase: RP 
               
               
                   
                 Room temperature (ambient, about 25° C.): rt or RT 
               
               
                   
                 tert-Butoxycarbonyl: t-Boc or Boc 
               
               
                   
                 tert-Butyl: t-Bu or tBu 
               
               
                   
                 Temperature: temp. 
               
               
                   
                 Tetrahydrofuran: THF 
               
               
                   
                 Thin layer chromatography: TLC 
               
               
                   
                 Triethylamine: Et 3 N or TEA 
               
               
                   
                 Trifluoroacetic acid: TFA 
               
               
                   
                 Trifluoroacetic anhydride: TFAA 
               
               
                   
                 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane- 
               
               
                   
                 2,4-6-trioxide: T3P or T 3 P 
               
               
                   
                   
               
            
           
         
       
     
                                           
Step 1:
 
     To a solution of the acetophenone A1 (115 g, 628 mmol) in anhydrous THF (900 mL) was added (R)-t-butylsulfinimide (83.7 g, 691 mmol) and Ti(OEt) 4  (315 g, 1.38 mol). The resultant solution was heated to reflux for 20 hr. The solution was then cooled to RT and poured onto ice (3 kg). The resultant mixture was stirred for 20 min then filtered and the layers were separated. The organic layer washed with brine. The filter cake was washed with CH 2 Cl 2  (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified via flash chromatography (SiO 2 ; 15% EtOAc/heptane) to afford the ketimine A2. 
     Step 2: 
     To a stirred solution of A3 (13 g, 0.149 mol) in THF (200 mL) at −78° C. was added a solution of LiHMDS (745 mL, 1 M in THF, 0.745 mol). After stirring the solution at −78° C. for 1 h, methyl iodide (105.86 g, 0.745 mol) was added and stirring was continued for an additional 1 h. The reaction was quenched by addition of a saturated aqueous NH 4 Cl solution, and the resultant mixture was extracted with EtOAc. The combined organic layers were washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel eluting with 1:9 EtOAc:petroleum ether to afford A4.  1 H-NMR (DMSO-d 6 , 300 MHz): δ 2.25 (s, 3H), 1.59 (s, 6H). GCMS; m/z: 115.0 (M) +   
     Step 3: 
     To a solution of sulfide A4 (6 g, 0.052 mol) in MeOH (360 mL) at room temperature was added NaNHCN (5 g, 0.078 mol). To the solution was added NBS (14.8 g, 0.078 mol) in portions. The reaction mixture was stirred at RT for 2 hours. After that time, the reaction mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous solution of Na 2 S 2 O 3  and the mixture was extracted with CH 2 Cl 2 . The organic layer was washed with H 2 O and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel eluting with 5% methanol in dichloromethane to afford A5.  1 H-NMR (DMSO-d 6 , 300 MHz): δ 3.00 (s, 3H), 1.76 (s, 3H), 1.69 (s, 3H). m/z: 156.1 (M+H) +   
     Step 4: 
     To a stirred solution of A5 (6 g, 38.7 mmol) in EtOH (400 mL) at 0° C. was added K 2 CO 3  (16.02 g, 116 mmol) and mCPBA (ca. 70%; 9.98 g, 58 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours. After that time, the solvent was removed under reduced pressure. The residue was then partitioned between water and CH 2 Cl 2 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were washed with H 2 O and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel eluting with 1:1 EtOAc:petroleum ether to afford A6.  1 H-NMR (DMSO-d 6 , 300 MHz): δ 3.74 (s, 3H), 1.87 (s, 6H). m/z: 172.1 (M+H) +  Step 5: To a stirred solution of A6 (2.2 g, 12.8 mmol) in CH 2 Cl 2  (200 mL) at 0° C., was added TFAA (8.1 g, 38.5 mmol). The mixture was allowed to warm to room temperature and stirred overnight. After that time, the mixture was poured into water. The mixture was then extracted with CH 2 Cl 2 . The combined organic layers were washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel eluting with 1:3 EtOAc:petroleum ether to afford A7.  1 H-NMR (DMSO-d 6 , 400 MHz): δ 3.86 (s, 3H), 1.88 (s, 3H), 1.87 (s, 3H). m/z: 243.2 (M+H) +   
     Step 6: 
     To a stirred solution of A7 (2.0 g, 8.26 mmol) in methanol (100 mL) at RT was added K 2 CO 3  (5.7 g, 41.3 mmol). The resultant mixture was stirred at RT for 2 hours. After that time, the reaction mixture was filtered through a sintered funnel. The residue was washed with CH 2 Cl 2  and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography over silica gel eluting with 5% methanol in dichloromethane to afford A8.  1 H-NMR (DMSO-d 6 , 300 MHz): δ 4.63 (s, 1H), 3.05 (s, 3H), 1.62-1.61 (m, 6H). m/z: 147.2 (M+H) +   
     Step 7: 
     To a stirred solution of A8 (1.1 g, 6.84 mmol) in CH 2 Cl 2  (12 mL) was added trimethyloxonium tetrafluoroborate (1.00 g, 6.84 mmol). The reaction mixture was stirred for 15 min. After that time, anhydrous Na 2 CO 3  (3.77 g, 35.6 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the filtrate concentrated to yield the crude residue which was purified by flash chromatography over silica gel eluting with 3% methanol in dichloromethane to afford A9.  1 H-NMR (DMSO-d 6 , 400 MHz): δ 3.07 (s, 3H), 2.75 (s, 3H), 1.69-1.68 (m, 6H). m/z: 161.2 (M+H) +   
     Step 8: 
     To a solution of A9 (4.00 g, 25 mmol) in anhydrous THF (60 mL) at −78° C. under an atmosphere of N 2  was added dropwise a solution of n-BuLi (2.5 M in hexane, 15.6 mL, 25.0 mmol). The resultant solution was stirred at −78° C. for 1 h. To the solution was added a precooled (−78° C.) solution of A2 (4.29 g, 15.0 mmol) in THF (50 mL) via cannula. The resultant solution was stirred at −78° C. for 6 h. After that time, the reaction was quenched with a saturated aqueous solution of NH 4 Cl and the mixture was allowed to warm to RT. The mixture was then extracted with EtOAc and the layers were separated. The combined organic layers were washed with water, brine, dried over Na 2 SO 4  and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel eluting with a gradient of 50-60% EtOAc in petroleum ether as eluent to afford a product that contained A10. 
     Step 9: 
     To a solution of A10 (3.00 g) in CH 2 Cl 2  (30 mL) at 0° C. was added a solution of HCl in dioxane (3 mL, 4.5 M). The reaction mixture was stirred at 0° C. for 1 h. The volatiles were removed under reduced pressure and the crude residue was purified by preparative reverse phase HPLC [C 18  Waters Symmetry column, gradient elution 95:5 to 0:100 water (0.1% TFA):MeOH, 15 mL/min UV detection 215 nm] to afford A11 and A12. A11:  1 H-NMR (DMSO-d 6 , 400 MHz): δ 9.2, —9.10 (br peak, 2H), 8.46-8.38 (m, 2H), 7.65-7.60 (m, 1H), 4.18-4.08 (m, 2H), 2.57 (s, 3H), 1.78 (s, 3H), 1.68-1.66 (m, 6H). m/z: 343.2 (M+H) +   
     Step 10: 
     To a solution of A11 (0.100 g, 0.292 mmol) in ethanol (5 mL) at RT was added Cu(I)Cl (0.106 g, 1.07 mmol). The reaction mixture was then heated at reflux overnight. After that time, the volatiles were removed under reduced pressure. The residue was partitioned between 10% aqueous NaOH solution and CH 2 Cl 2 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layer were washed with water, brine, dried over Na 2 SO 4  and concentrated. The crude product was purified by flash chromatography over silica gel eluting with 3% methanol in dichloromethane to afford Aβ.  1 H-NMR (CDCl 3 , 400 MHz): δ 8.44-8.42 (m, 1H), 8.19-8.15 (m, 1H), 7.24-7.19 (m, 1H), 3.77 (d, J=15.3 Hz, 1H), 3.56 (d, J=15.3 Hz, 1H), 2.29 (s, 3H), 1.78-1.76 (m, 6H), 1.62 (s, 3H). m/z: 343.2 (M+H) +   
     Step 11: 
     To a stirred solution of A13 (0.100 g, 0.292 mmol) in dichloromethane (2 mL) was added DIPEA (0.2 mL, 1.46 mmol) and Boc 2 O (0.19 g, 0.8 mmol). The reaction mixture was stirred at RT for 2 h. Water was added to the reaction mixture and the mixture was extracted with dichloromethane and the layers were separated. The combined organic layers were washed with water, brine, dried over Na 2 SO 4  and concentrated. The crude product was purified by flash chromatography over silica gel eluting with 40% EtOAc in petroleum ether to afford A14. m/z: 443.4 (M+H) +   
     Step 12: 
     A stirred solution of A14 (90 mg, 0.203 mmol) in methanol (2 mL) was degassed by bubbling nitrogen through it for 3 min. To the solution was added Pd on carbon (20% w/w, 20 mg). The reaction mixture was then evacuated and back filled with hydrogen (balloon). The reaction mixture was stirred under the hydrogen atmosphere for 2 h. The mixture was then filtered through celite and the filtrate concentrated. The crude residue was purified by flash chromatography over silica gel eluting with 50% EtOAc in petroleum ether to afford A15. 
     Step 13: 
     To a solution of A15 (50 mg, 0.121 mmol) in THF (4 mL) at 0° C. was added 5-chloropyridine-2-carboxylic acid (22 mg, 0.145 mmol) and N,N-diisopropylethylamine (46 mg, 0.363 mmol) followed by a solution of T3P (50% in EtOAc, 53 mg, 0.169 mmol). The reaction mixture was then stirred for 2 h at RT. Water was added to the reaction and the mixture was stirred for 20 mins. After that time, the mixture was extracted with EtOAc and the layers were separated. The combined organic layers were washed with water and brine, dried over Na 2 SO 4  and concentrated. The crude residue was purified by flash chromatography over silica gel eluting with 40% EtOAc in petroleum ether to afford A16. m/z: 552.4 (M) +   
     Step 14: 
     To a solution of A16 (50 mg, 0.0905 mmol) in dichloromethane (3 mL) at 0° C. was added TFA (0.13 mL, 1.811 mmol). The reaction was stirred for 1 h at RT and then concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC [C 18  Waters Symmetry column, gradient elution 95:5 to 0:100 water (0.1% TFA):MeOH, 15 mL/min UV detection 215 nm] to afford Example 1a.  1 H-NMR (CD 3 OD, 400 MHz): δ. 8.74 (d, J=2.2 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.11 (dd, J=2.4 &amp; 8.4 Hz, 1H), 7.94-7.86 (m, 2H), 7.32-7.27 (m, 1H), 4.26 (d, J=15.8 Hz, 1H), 4.08 (d, J=15.8 Hz, 1H), 2.22 (s, 3H), 2.02 (s, 3H), 1.92 (s, 3H), 1.77 (s, 3H). 
     
       
         
         
             
             
         
       
     
     Intermediate A12 was converted to Example 1b using procedures similar to those described in Scheme A Steps 10-14. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 The following examples were prepared from either intermediate A11 or A12 following 
               
               
                 procedures similar to those described in Scheme A using the requisite carboxylic acid in Step 13. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 LCMS data 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 BACE 1 
                 BACE 2 
                 m/z 
                 t R   
                   
               
               
                 Ex 
                 Structure 
                 K i  (nM) 
                 K i  (nM) 
                 (MH + ) 
                 (min) 
                 Conditions 
               
               
                   
               
               
                 1a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                  3 
                 1 
                 452.2 
                 2.32 
                 1 
               
               
                   
               
               
                 1b 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                  8 
                 3 
                 452.2 
                 2.20 
                 1 
               
               
                   
               
               
                 2a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 10 
                 2 
                 436.2 
                 2.13 
                 1 
               
               
                   
               
               
                 2b 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 21 
                 6 
                 436.4 
                 2.10 
                 1 
               
               
                   
               
               
                 3a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 11 
                 5 
                 448.2 
                 2.12 
                 1 
               
               
                   
               
            
           
         
       
     
                                           
Step 1:
 
     A mixture of isobutyronitrile C1 (10 g, 145 mmol), N-bromosuccinimide (20.6 g, 116 mmol) and benzoyl peroxide (2.8 g, 11.6 mmol) was heated at 140° C. for 16 h. After that time, the reaction mixture was cooled to room temperature and filtered through a celite bed. The celite bed was washed thoroughly with diethyl ether. The mixture was concentrated to provide C2.  1 H NMR (CDCl 3 , 400 MHz): 2.10 (s, 6H). 
     Step 2: 
     To a stirred solution of trimethylsulfoxonium iodide (5.8 g, 26 mmol) in dry tetrahyrofuran (50 mL) was added a solution of potassiumbis(trimethysilyl)amide (20% in THF, 4.1 g, 20 mmol) dropwise via an addition funnel and the mixture was stirred for 2 h. After that time, the mixture was treated with a solution of C3 (5 g, 15 mmol) [C3 was prepared from 1-(2-fluoro-5-bromophenyl)ethanone following a procedure similar to that described in Scheme A step 1] in dry tetrahydrofuran (40 mL), followed by the dropwise addition of dimethylsulfoxide (2 mL). The reaction mixture was stirred at room temperature for 8 h under a nitrogen atmosphere. The reaction mixture was then added to saturated aqeuous citric acid solution and the resultant mixture was extracted with methyl tert-butyl ether. The combined organic layers were washed with water, dried over anhydrous Na 2 SO 4 , and concentrated. The crude product was purified by column chromatography over silica gel (gradient elution 5-8% ethyl acetate in petroleum ether) to obtain C4.  1 H-NMR (CD 3 OD, 400 MHz): δ 7.45-7.43 (m, 1H), 7.40-7.34 (m, 1H), 6.95-6.91 (m, 1H), 2.80 (s, 1H), 2.20 (s, 1H), 1.71 (s, 3H), 1.29 (s, 9H). 
     Step 3: 
     To a stirred solution of C4 (10 g, 30 mmol) in tetrahydrofuran (100 mL) at 0° C. was added DBU (6.8 g, 45 mmol) and thioacetic acid (4.5 g, 60 mmol). The reaction mixture was stirred at 60° C. for 16 h. After that time, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaHCO 3  solution and brine. The organic layer was then dried over Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography over silica gel (gradient elution 18-20% EtOAc in petroleum ether) to afford C5. MS (M+H) m/z 410.2/412.2.  1 H NMR (CD 3 OD, 400 MHz): δ 7.67-7.64 (m, 1H), 7.4053-7.49 (m, 1H), 7.08-7.03 (m, 1H), 5.45 (s, 1H), 3.64 (s, 1H), 2.31 (s, 3H), 1.79 (s, 3H), 1.23 (s, 9H). 
     Step 4: 
     To a solution of C5 (6.5 g, 16 mmol) in tetrahydrofuran (100 mL) at 0° C., was added a solution of sodium methoxide (7.6 mL, 23.78 mmol, 21% solution in methanol) and C2 (3.5 g, 23.78 mmol). The reaction mixture was allowed to warm from 0° C. to room temperature with stirring over 4 h. After that time, the reaction mixture was quenched with a saturated aqueous NH 4 Cl solution. The resultant mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4  and concentrated to afford C6 which was taken to the next step without further purification. MS (M+H) +  m/z 436.4. 
     Step 5: 
     To a solution of the C6 (7 g, 16 mmol) in dichloromethane (70 mL) was added a solution of 4 M HCl in dioxane (70 mL). The resultant solution was stirred at room temperature for 16 h. After that time, the solution was concentrated. The residue was then adjusted to approximately pH 8 with the addition of a saturated aqueous NaHCO 3  solution. The mixture was extracted with dichloromethane. The organic layer was washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated to afford C7 which was taken to the next step without further purification. MS m/z 333.0[M+H] +   
     Step 6: 
     To a slurry of C7 (6.5 g 20 mmol) in ethanol (70 mL) was added acetic acid (3 mL). The resultant mixture was heated to 80° C. for 16 h. After that time, the mixture was concentrated. The residue was then adjusted to ˜pH 8 with the addition of a saturated aqueous NaHCO 3  solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated to afford C8 which was taken to the next step without further purification. m/z 331.4 [M+H + ]. 
     Step 7: 
     To a solution of C8 (5 g, 15 mmol) in dichloromethane was added Boc 2 O (4.9 mL, 23 mmol) and triethylamine (3.1 mL, 23 mmol). The resultant mixture was stirred at room temperature for 16 h. The mixture was then diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated. The crude product was purified by flash column chromatography over silica gel (gradient elution 4-6% EtOAc in petroleum ether) to obtain C9. [M+H + ] m/z 431.2.  1 H NMR (CDCl 3  400 MHz): 10.99 (brs, 1H), 7.44-7.36 (m, 2H), 7.00-6.93 (m, 1H), 3.30 (d, 2H), 3.10 (d, 2H), 1.81 (s, 3H), 1.72 (s, 3H), 1.58 (s, 3H), 1.53 (s, 9H). 
     Step 8: 
     To a solution of C9 (5 g, 13 mmol) in DMF (60 mL) at 0° C. was added sodium hydride (1.6 g, 40 mmol, 60% in oil) and the mixture was stirred at 0° C. for 20 min. After that time, methoxyethoxymethyl chloride (4.9 g, 39.68 mmol) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was then poured into cold water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The crude residue was purified by flash chromatography over silica gel (gradient elution 6-9% EtOAc in petroleum ether) to afford C10. m/z: 519 (M+H) + 1 H NMR (CD 3 OD 400 MHz): 7.68-7.65 (m, 1H), 7.48-7.44 (m, 1H), 7.10-7.05 (m, 1H), 4.95 (s, 2H), 3.81-3.79 (m, 2H), 3.60-3.58 (m, 2H), 3.57 (s, 3H), 1.74 (s, 3H), 1.59 (s, 3H), 1.57 (s, 3H), 1.53 (s, 9H). 
     Step 9: 
     To a stirred solution of C10 (2 g, 4 mmol) in dichloromethane (30 mL) under an atmosphere of nitrogen were added magnesium oxide (620 mg, 15.414 mmol), cyanamide (404 mg, 9.63 mmol), (diacetoxyiodo)benzene (1.86 g, 5.78 mmol), and rhodium(II) acetate (340 mg, 0.77 mmol). The reaction mixture was stirred for 4 h at room temperature. The reaction was then quenched by adding ice water. The mixture was filtered through a celite pad and the layers were separated. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by flash chromatography over silica gel eluting with 56-59% EtOAc in petroleum ether to afford C11. m/z: 561.4 (M+H) +   
     Step 10: 
     To a solution of ruthenium (III) chloride (17 mg, 0.085 mmol) and sodium metaperiodate (1.2 g, 5.72 mmol) in water (10 mL) at 0° C. was added a solution of C11 (1.6 g, 2.9 mmol) in dichloromethane (20 mL) dropwise. The mixture was allowed to warm to room temperature and stirred for 4 hours. After that time, the volatiles were removed under reduced pressure. The residue was partitioned between water and dichloromethane. The layers were separated and the organic layer was washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The crude residue was purified by flash chromatography over silica gel eluting with 25-30% EtOAc in petroleum ether to afford C12 m/z: 575.4 (M+H) + . 
     Step 11: 
     To a stirred solution of C12 (6.5 g, 11 mmol) in dichloromethane (60 mL) at 0° C., was added TFAA (7.1 g, 34 mmol). The mixture was allowed to warm to room temperature and stir for 5 h. After that time, the reaction mixture was quenched by the addition of cold water and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo. To the crude residue was added methanol (50 mL) and potassium carbonate (1.9 g, 14 mmol). The reaction mixture was stirred for 5 h at room temperature. After that time, the mixture was filtered. The filter cake was washed repeatedly with dichloromethane and the combined filtrates were concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO 2 ; gradient elution 20-35% EtOAc in PE) to afford C13 and C14. C13:  1 H NMR (DMSO-d 6  400 MHz): 7.55-7.53 (m, 1H), 7.46-7.44 (m, 1H), 7.26-7.21 (m, 1H), 4.91-4.84 (m, 2H), 4.04-4.01 (m, 1H), 3.70-3.67 (m, 2H), 3.60-3.58 (m, 1H), 3.50-3.47 (m, 2H), 3.33 (s, 3H), 1.70 (s, 3H), 1.59 (s, 3H), 1.48 (s, 3H), 1.45 (s, 9H). 
     C14:  1 H NMR (DMSO-d 6  400 MHz): 7.56-7.52 (m, 1H), 7.45-7.44 (m, 1H), 7.24-7.22 (m, 1H), 5.02-5.00 (m, 1H), 4.82-4.79 (m, 1H), 4.05-4.02 (m, 1H), 3.75-3.66 (m, 2H), 3.56-3.52 (m, 1H), 3.50-3.48 (m, 1H), 3.33 (s, 3H), 1.70 (s, 3H), 1.59 (s, 3H), 1.48 (s, 3H), 1.45 (s, 9H). 
                                           
Step 1:
 
     To a solution of C13 (400 mg, 0.727 mmol) in dichloromethane (8 mL) at 0° C. was added trimethyloxonium tetrafluoroborate (161 mg, 1.09 mmol) and anhydrous sodium carbonate (231 mg, 2.18 mmol). The mixture was stirred at room temperature for 4 h. After that time, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo to afford D1. This material was carried on without further purification. m/z: 564.2 (M+H) + . 
     Step 2: 
     To a solution of D1 (400 mg, 0.708 mmol) in methanol (8 mL) were added sodium acetate (116 mg, 1.417 mmol) and 10% Pd/C (150 mg). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 4 h. After that time, the reaction mixture was filtered through celite and the filtrate was concentrated. The resultant residue was dissolved in ethyl acetate then washed with water and brine. The organic layer was dried over anhydrous Na 2 SO 4  and concentrated in vacuo to afford D2. This material was carried on to the next step without further purification. m/z: 486.4 (M+H) +   
     Step 3: 
     To a mixture of D2 (350 mg, 0.720 mmol) and conc. H 2 SO 4  (4 mL) at 0° C. was added fuming nitric acid (0.3 mL). The reaction mixture was stirred at 0° C. to room temperature for 2 h. After that time, the mixture was diluted with water and basified using a sodium carbonate solution. The resultant mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated to afford D3. This material was carried on to the next step without further purification. m/z: 343.4 (M+H) +   
     Step 4: 
     To the solution of D3 (200 mg, 0.584 mmol) and triethylamine (0.12 mL, 0.876 mmol) in dichloromethane (5 mL) was added Boc 2 O (0.19 mL, 0.876 mmol) and the reaction mixture was stirred at RT for 16 h. After that time, the volatiles were removed under reduced pressure to afford D4 which was carried on to the next step without further purification. m/z: 443.0 (M+H) +   
     Step 5: 
     To a solution of D4 (100 mg, 0.226 mmol) in methanol (5 mL) was added zinc (74 mg, 1.1 mmol) and ammonium chloride (60 mg, 1.1 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then filtered through celite, the filter cake was washed with a 1:1 mixture of methanol: dichloromethane and the filtrate was concentrated. The amine D5 was carried on to the next step without further purification. m/z: 413.4 (M+H) +   
     Step 6: 
     To a solution of 5-methoxypyrazine-2-carboxylic acid (21 mg, 0.133 mmol) in dichloromethane (3 mL) at room temperature under an atmosphere of nitrogen was added N,N-diisopropylethylamine (0.07 mL, 0.400 mmol) and a solution of T 3 P (50% in ethyl acetate, 0.26 mL, 0.400 mmol). The reaction mixture was stirred at room temperature for 15 min. After that time, a solution of D5 (55 mg, 0.133 mmol) in dichloromethane (2 mL) was then added slowly to the reaction and the mixture was stirred at room temperature for 3 h. After that time, the reaction was quenched by adding water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated. The crude residue was purified by flash column chromatography over silica gel using 30-32% ethyl acetate in PE to afford D6. m/z: 549.4 (M+H) +   
     Step 7: 
     To a solution of D6 (50 mg, 0.103 mmol) in dichloromethane (2 mL) at 0° C. was added TFA (1 mL) and the reaction mixture was allowed to warm to room temperature and stir for 1 h. The reaction mixture was concentrated under reduced pressure. The crude thus obtained purified by preparative HPLC (see Table 5 for conditions) to yield the pure Example 4a. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 The following examples were prepared from either intermediate C13 or C14 following 
               
               
                 procedures similar to those described in Scheme D using the requisite carboxylic acid in Step 6. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 LCMS data 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 BACE 1 
                 BACE 2 
                 m/z 
                 t R   
                   
               
               
                 Ex 
                 Structure 
                 K i  (nM) 
                 K i  (nM) 
                 (MH + ) 
                 (min) 
                 Conditions 
               
               
                   
               
               
                 4a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                  6 
                 12 
                 449.4 
                 2.14 
                 1 
               
               
                   
               
               
                 4b 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                  14 
                 32 
                 449.4 
                 2.12 
                 1 
               
               
                   
               
               
                 5a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 167 
                 10 
                 385.2 
                 1.81 
                 1 
               
               
                   
               
               
                 5b 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 228 
                 36 
                 385.2 
                 1.80 
                 1 
               
               
                   
               
            
           
         
       
     
                         
Step 1:
 
     Intermediate A8 was converted to E1 using a procedure similar to that described in Scheme A Step 7 using triethyloxonium tetrafluoroborate instead of trimethyloxonium tetrafluoroborate. 
     Steps 2-4: 
     Intermediate E1 was converted to a crude mixture containing E2 and E3 using procedures similar to those described in Scheme A Steps 8-10. The crude residue was purified by preparative HPLC (Column: Symmetry Prep C18 (19×300 mm) 7 μm; Column temp: ambient; mobile phase: A: 0.1% TFA in water, B: acetonitrile; gradient: 0-20 min 90:10 to 40:60 (A:B), 21-25 min 40:60 to 30:70 (A:B), from 25-26 min 30:70 to 0:100 (A:B), 26-30 min 0:100; flow rate: 15 mL/min; UV detection: 215 nm) to afford E2 and E3. E2: m/z: 357.2 (M+H) + . E3: m/z: 357.2 (M+H) + . 
     Steps 5-8: 
     Intermediate E2 was converted to Example 6a using procedures similar to those described in Scheme A Steps 11-14. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 The following examples were prepared from either intermediates E2 or E3 using procedures similar 
               
               
                 to those described in Scheme A Steps 11-14 using the requisite carboxylic acid in Step 13. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 LCMS data 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 BACE 1 
                 BACE 2 
                 m/z 
                 t R   
                   
               
               
                 Ex 
                 Structure 
                 K i  (nM) 
                 K i  (nM) 
                 (MH + ) 
                 (min) 
                 Conditions 
               
               
                   
               
               
                 6a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                  4 
                 1 
                 466.2 
                 2.40 
                 1 
               
               
                   
               
               
                 6b 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                  7 
                 5 
                 466.2 
                 2.31 
                 1 
               
               
                   
               
               
                 7a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 17 
                 3 
                 450.2 
                 2.34 
                 1 
               
               
                   
               
               
                 8a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                  4 
                 5 
                 457.4 
                 2.22 
                 1 
               
               
                   
               
            
           
         
       
     
                         
Step 1:
 
     To a stirred solution of A8 (2 g, 13.6 mmol) in acetonitrile (30 mL) was added (bromomethyl)cyclopropane (4.38 g, 32.4 mmol), cesium carbonate (10.9 g, 34.5 mmol), and n-tetrabutylammonium iodide (0.510 g, 1.36 mmol) at RT under nitrogen. The reaction mixture was then heated at reflux overnight. After that time, the solvents were removed under reduced pressure. To the crude residue was added water and the mixture was extracted with dichloromethane. The combined organic layers were washed with water and brine then dried over Na 2 SO 4  and concentrated. The crude residue was purified by flash chromatography over silica gel using a gradient elution of 50- 60% EtOAc in PE to afford F1. m/z: 201.4 (M+H) +   
     Steps 2-4: 
     Intermediate F1 was converted to diastereomers F2 and F3 using procedures similar to those described in Scheme A Steps 8-10 and purified using the preparative HPLC conditions described in Scheme C. F2: m/z: 383.2 (M+H) + . F3: m/z: 383.2 (M+H) + . 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 The following examples were prepared from either intermediates F2 or F3 using procedures similar 
               
               
                 to those described in Scheme A Steps 11-14 using the 5-chloropyridine carboxylic acid in Step 13. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 LCMS data 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 BACE 1 
                 BACE 2 
                 m/z 
                 t R   
                   
               
               
                 Ex 
                 Structure 
                 K i  (nM) 
                 K i  (nM) 
                 (MH + ) 
                 (min) 
                 Conditions 
               
               
                   
               
               
                 9a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3 
                 1 
                 493.2 
                 2.50 
                 1 
               
               
                   
               
               
                 9b 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4 
                 3 
                 493.2 
                 2.50 
                 1 
               
               
                   
               
            
           
         
       
     
                         
Step 1:
 
     To a stirred mixture of G1 (15 g, 111 mmol) in 50% aq. NaOH (220 mmol) at RT was added triethylbenzylammonium bromide (3.02 g, 11.11 mmol). The reaction mixture was heated to 70° C. with stirring for 15 min after which time methyl iodide (17.3 g, 1.221 mmol) was added over 20 min. The resultant mixture was stirred at 70° C. for an additional 6 h. The reaction mixture was then cooled to room temperature followed by the addition of ice water. The resultant mixture was extracted with EtOAc. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude residue was purified by flash chromatography over silica gel eluting with 3% EOAc in PE to afford G2.  1 H NMR (DMSO-d 6 , 400 MHz): δ. 7.48-7.45 (m, 2H), 7.28-7.22 (m, 2H), 4.35-4.30 (m, 1H), 1.53 (d, J=7.2 Hz, 3H). 
     Step 2: 
     To a solution of G2 (8 g, 54 mmol) in CCl 4  (80 mL) in a pressure tube, was added N-bromo succinimide (10.20 g, 53.69 mmol) and benzoylperoxide (1.29 g, 5.36 mmol). The tube was sealed and the reaction mixture was heated to 70° C. After that time, ice water was added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The crude residue was purified by flash chromatography over silica gel eluting with 3% EtOAc in PE to afford G3.  1 H NMR (DMSO-d 6 , 400 MHz): δ. 7.82-7.79 (m, 2H), 7.37-7.32 (m, 2H), 2.50 (s, 3H). 
     Step 3: 
     To a stirred solution of C5 (14 g, 34 mmol) in anhydrous tetrahydrofuran (200 mL) at 0° C. under an atmosphere of nitrogen was added sodium ethoxide (3.46 g, 51.00 mmol) and the mixture was stirred for 30 min. After that time, G3 (7.75 g, 34.2 mmol) was added and the reaction mixture was brought to room temperature with stirring for 3 h. To the mixture was then added ice water and the resultant mixture was extracted with EtOAc. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude residue was purified by flash chromatography over silica gel eluting with 3% EtOAc in PE to afford G4. m/z: 517.2 (MH) +   
     Step 4: 
     To a stirred solution of G4 (10 g, 19 mmol) in dichloromethane (150 mL) at 0° C. under an atmosphere of nitrogen was added a solution of HCl in dioxane (10 mL of 4.5 M). The reaction mixture was stirred for 1 h. After that time, the reaction was quenched with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4 , and concentrated to afford G5 which was carried on without further purification. m/z: 413.4 (MH) +   
     Step 5: 
     To a stirred solution of G5 (9.0 g, 22 mmol) in ethanol (100 mL) at room temperature under an atmosphere of nitrogen, was added 10 mL of acetic acid. The reaction mixture was then heated to reflux for 16 h. After that time, the solvents were removed under reduced pressure. The crude residue was basified with a saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo to afford G6 which was carried on without further purification. m/z: 413.4 (MH) +   
     Step 6: 
     To a stirred solution of G6 (7.5 g, 18 mmol) in dichloromethane (80 mL) at 0° C. under an atmosphere of nitrogen was added DIPEA (6.96 g, 54.2 mmol) followed by Boc 2 O (11.96 g, 54.8 mmol) and the reaction mixture was allowed to warm to room temperature and stir for 2 h. After that time, water was added to the reaction mixture and the resultant mixture was extracted with dichloromethane. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo. The crude residue was purified by flash chromatography over silica gel eluting with 3% EtOAc in PE as eluent to afford G7 and G8. G7:  1 H NMR (DMSO-d 6 , 400 MHz): δ 10.68 (s, 1H), 7.63-7.58 (m, 1H), 7.56-7.54 (m, 1H), 7.41-7.38 (m, 2H), 7.28-7.23 (m, 1H), 7.17-7.11 (m, 2H), 3.36-3.32 (m, 1H), 3.00 (d, J=14.4 Hz, 1H), 1.89 (s, 3H), 1.80 (s, 3H), 1.40 (s, 9H). G8:  1 H NMR (DMSO-d 6 , 400 MHz): δ 10.68 (s, 1H), 7.63-7.61 (m, 1H), 7.50-7.41 (m, 3H), 7.31-7.21 (m, 3H), 3.33-3.29 (m, 1H), 2.68 (d, J=14.8 Hz, 2H), 1.74 (s, 3H), 1.72 (s, 3H), 1.44 (s, 9H). 
                                           
Step 1:
 
     To a stirred solution of G7 (1.1 g, 2.2 mmol) in anhydrous DMF (15 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (258 mg, 6.46 mmol) slowly. After stirring at 0° C. for 10 min, 2-methoxyethoxymethyl chloride (0.80 g, 6.47 mmol) was added to the reaction and the mixture was stirred at room temperature for 2 h. After that time, the reaction was quenched with cold water and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated under reduced pressure. The crude residue was purified by flash column chromatography eluting with 10% EtOAc in PE to afford H1. m/z: 600.2 (MH + ). 
     Step 2: 
     To a stirred solution of H1 (2.35 g, 3.92 mmol) in ethanol (100 mL) at −10° C. was added m-CPBA (0.963 g, 3.92 mmol, 70% in water). The reaction mixture was stirred at −10° C. for 5 min. After that time, the reaction was quenched with an aqueous saturated NaHCO 3  solution and the resultant mixture was extracted with EtOAc. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel eluting with 20% EtOAc in PE to afford H2. m/z: 616.2 (MH + ). 
     Step 3: 
     To a solution of the H2 (1.55 g, 2.52 mmol) in dichloromethane (25 mL) at room temperature was added trifluoroacetamide (1.14 g, 10.09 mmol), magnesium oxide (0.8 g, 20.19 mmol), rhodium(II) acetate dimer (55.7 mg, 0.126 mmol) and iodobenzene diacetate (2.43 g, 7.57 mmol). The reaction mixture was stirred at for 16 h. After that time, the reaction mixture was filtered through celite, the filter pad was washed with dichloromethane and the filtrate was concentrated. The crude residue was purified by flash chromatography over silica gel eluting with 50% EtOAc in PE to afford H3. m/z 726.2 (MH + ). 
     Step 4: 
     To a stirred solution of H3 (1.0 g, 1.37 mmol) in methanol (15 mL) at room temperature was added K 2 CO 3  (0.95 g, 6.89 mmol). The resultant mixture was stirred at RT for 2 h. After that time, ice water was added to the reaction and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated. The crude residue was purified by silica gel column chromatography eluting with 50% EtOAc in PE to afford H4. m/z 631.2 (MH + ). 
     Step 5: 
     To a stirred solution of H4 (150 mg, 0.238 mmol) in N,N-dimethylformamide (5 mL) at 0° C., was added sodium hydride (23.8 mg, 0.593 mmol, 60% in paraffin oil). After stirring at 0° C. for 5 min, methyl iodide (84.0 mg, 0.596 mmol) was added slowly and then reaction mixture was stirred at 0° C. for an additional 30 min. After that time, the reaction mixture was quenched with ice water and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4  and concentrated under reduced pressure. The crude residue was purified by column chromatography eluting with 40% EtOAc in PE to afford H5. m/z: 644.2 (MH + ). 
     Step 6: 
     In a microwave vial, a stirred solution of H5 (30 mg, 0.0466 mmol) and sodium t-butoxide (13.4 mg, 0.139 mmol) in toluene (3 mL) was degassed with a flow of nitrogen. To the mixture was added (2-biphenylyl)di-tert-butylphosphine (2.77 mg, 0.00932 mmol), Pd 2 dba 3  (4.26 mg, 0.00466 mmol) and benzophenone imine (10.12 mg, 0.0559 mmol). The vial was purged with nitrogen for 3 min. Then reaction mixture was heated to 70° C. with stirring for 1 h. After that time, the reaction mixture was cooled to room temperature and filtered through celite. The celite bed was washed with ethyl acetate and the combined filtrate was concentrated to yield the crude imine. The residue was taken up in methanol (5 mL). To the solution was added sodium acetate (19.1 mg, 0.23 mmol) and hydroxylamine hydrochloride (16.1 mg, 0.233 mmol). The resultant solution was stirred at room temperature for 1 h. After that time, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated. The crude residue was purified by column chromatography eluting with 50% EtOAc in hexane to afford H6. m/z: 581.2 (MH + ). 
     Step 7: 
     To a solution of H6 (18 mg, 0.031 mmol) in THF (3 mL) at 0° C. was added the 5-chloropyridine-2-carboxylic acid (7.3 mg, 0.047 mmol), DIPEA (20 mg, 0.16 mmol) and a solution of T3P in ethyl acetate (50%, 39.4 mg, 0.062 mmol) respectively. The reaction mixture was stirred for 2 h at RT. After that time, the reaction was quenched with cold water and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated. The crude residue was purified by flash chromatography eluting with 40% EtOAc in PE to afford H7. m/z: 720.2 (MH + ). 
     Step 8: 
     To a solution of H7 (17 mg, 0.023 mmol) in dichloromethane (2 mL) at 0° C. was added a solution of HCl in dioxane (2 mL, 4.5M in dioxane). The mixture was stirred for 1 h at room temperature and then concentrated under reduced pressure. The residue thus obtained was purified by prep HPLC (column: Atlantis dC18 OBD (19×150 mm) 10 μm; column temp: ambient; mobile phase: A: 0.1% formic acid in water, B: acetonitrile; gradient: 0-20 min 90:10 to 40:60 (A:B), 21-25 min 40:60 to 30:70 (A:B), 25-26 min 30:70 to 0:100 (A:B), 26-30 min 0:100 (A:B); flow rate: 15 mL/min; UV detection: 215 nm) to afford Example 10a. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Examples 10b-1 and 10b-2 were prepared from intermediate G8 following 
               
               
                 procedures similar to those described in Scheme H. The diastereomers were  
               
               
                 separated by preparative HPLC (Column: Sunfire Prep C18 OBD (19 × 150 mm) 5μm;  
               
               
                 column temp: ambient; mobile phase: A: 0.1% TFA in water, B: acetonitrile; gradient:  
               
               
                 0-20 min 95:05 to 50:50 (A:B), 21-25 min 50:50 to 40:60 (A:B), 25-26 min 40:60 to  
               
               
                 0:100 (A:B), 26-30 min 0:100 (A:B); Flow rate: 15 mL/min; UV detection: 215 nm). 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 LCMS data 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 BACE 1 
                 BACE 2 
                 m/z 
                 t R   
                   
               
               
                 Ex 
                 Structure 
                 K i  (nM) 
                 K i  (nM) 
                 (MH + ) 
                 (min) 
                 Conditions 
               
               
                   
               
               
                 10a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 290 
                 106 
                 532.2 
                 2.56 
                 1 
               
               
                   
               
               
                 10b-1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 — 
                 532.2 
                 2.40 
                 1 
               
               
                   
               
               
                 10b-2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 — 
                 532.2 
                 2.41 
                 1 
               
               
                   
               
            
           
         
       
     
                         
Step 1:
 
     To a solution of C13 (300 mg, 0.545 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (33 mg, 0.818 mmol, 60% in oil) and tetrabutylammonium iodide (20 mg, 0.54 mmol). The mixture was stirred at 0° C. for 30 min. After that time, 1-bromo-2-fluoroethane (0.062 mL, 0.818 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with cold water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine then dried over anhydrous Na 2 SO 4  and concentrated in vacuo to afford I1 which was taken on without further purification. 
     Steps 2-7: 
     Intermediate I1 was converted to Example 11a following procedures similar to those described in Scheme D Steps 2-7 using 5-chloropyridine carboxylic acid in step 6. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 The below examples were prepared from either intermediate C13 or C14 and the 
               
               
                 requisite alkyl bromide following procedures similar to those described in Scheme I. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 LCMS data 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 BACE 1 
                 BACE 2 
                 m/z 
                 t R   
                   
               
               
                 Ex 
                 Structure 
                 K i  (nM) 
                 K i  (nM) 
                 (MH + ) 
                 (min) 
                 Conditions 
               
               
                   
               
               
                 11a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3 
                 1 
                 484.2 
                 2.32 
                 1 
               
               
                   
               
               
                 11b 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3 
                 2 
                 484.2 
                 2.32 
                 1 
               
               
                   
               
               
                 12a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3 
                 1 
                 496.2 
                 2.27 
                 1 
               
               
                   
               
               
                 12b 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4 
                 2 
                 496.2 
                 2.20 
                 1 
               
               
                   
               
            
           
         
       
     
                         
Step 1:
 
     LiHMDS (1.0 Min THF, 104 mL, 104 mmol) was added to a stirred −78° C. mixture of J1 (7.0 g, 86.0 mmol) in THF (70 mL) using an addition funnel, and the mixture was stirred at −78° C. for 45 min. To this mixture was added dimethyl disulfide (7.29 mL, 82 mmol) slowly, and the resulting mixture was then warmed up to rt slowly and stirred at rt overnight. The reaction mixture was quenched with sat. aq. NH 4 Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO 4  and concentrated in vacuo to give compound J2 that was used directly without further purification. 
     Step 2: 
     J2 was converted to J3 using conditions similar to those described in Scheme A steps 2. 
     Step 3: 
     To a stirred solution of J3 (2.0 g, 14 mmol) in ethanol (60 mL) at 0° C. was added m-CPBA (3.66 g, 42.4 mmol, 70% w/water). The reaction mixture was stirred at 0° C. for 2 h. After that time, the reaction was quenched with ice water and the resultant mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated. The crude residue was purified by flash chromatography over silica gel eluting with 50% EtOAc in PE to afford J4. m/z: 158 (MH + ). 
     Step 4: 
     To a solution of J4 (0.5 g, 3.18 mmol) in dichloromethane (10 mL) at room temperature was added 4-nitrobenzene sulfonamide (1.27 g, 6.32 mmol), magnesium oxide (0.53 g, 12.7 mmol), rhodium(II) acetate dimer (0.035 g, 0.079 mmol) and iodobenzene diacetate (2.05 g, 6.32 mmol). The reaction mixture was stirred at RT for 16 h. After that time, water was added to the reaction and the mixture was filtered through celite. The filter bed was washed with dichloromethane. The organic layer was separated, washed with brine, dried over anhydrous Na 2 SO 4  and concentrated. The crude residue was purified by flash chromatography over silica gel using gradient 50-100% EtOAc in PE to afford J5. m/z: 358.6 (MH + ). 
     Step 5: 
     To a stirred solution of J5 (0.2 g, 0.56 mmol) in methanol (10 mL) at room temperature was added potassium carbonate (0.16 g, 1.23 mmol) followed by N-acetyl-L-cysteine (0.2 g, 1.23 mmol) The reaction mixture was heated to reflux for 2 h. After that time, the reaction mixture was concentrated. The crude residue was partitioned between water and DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated. The crude residue was purified by flash chromatography over silica gel eluting with EtOAc to afford J6. m/z: 173 (M+H) +   
     Step 6: 
     Intermediate J6 was converted to J7 following a procedure similar to that described in Scheme A, Step 7. 
                         
Step 1:
 
     K1 is converted to K2 using conditions similar to those described in Scheme I step 1. 
     Steps 2-7: 
     K2 is converted to K8 using conditions similar to those described in Scheme A steps 2-7 respectively. 
                         
Step 1:
 
     To a pressure tube containing a mixture of L1 (1 g, 14.27 mmol) and trimethylsilyl cyanide (2.87 mL, 21.4 mmol) was added 18-crown-6 (0.226 g, 0.856 mmol) followed by potassium cyanide (0.111 g, 1.712 mmol). The tube was sealed and the mixture was heated at 140° C. for 1 h. The reaction mixture was cooled to room temperature and the mixture was added to water. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na 2 SO 4  and concentrated. The crude residue was purified by flash chromatography eluting with 10% EtOAc in PE to yield L2. 
     Step 2: 
     L2 (1.1 g, 6.50 mmol) was stirred in 1.5 N aqueous HCl (5.20 mL, 7.80 mmol) for 30 min at room temperature. The reaction mixture was cooled to 0° C., neutralized with a NaHCO 3  solution and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated. The crude residue was purified by flash chromatography eluting with 10% EtOAc in PE to afford L3.  1 H NMR (DMSO-d 6 , 400 MHz): δ 6.37 (d, J=6.5 Hz, 1H), 4.12 (t, J=6.8 Hz, 1H), 1.27-1.20 (m, 1H), 0.58-0.54 (m, 2H), 0.40-0.30 (m, 2H). 
     Step 3: 
     To a stirred solution of L3 (0.3 g, 3.09 mmol) in dichloromethane (10 mL) was added triphenylphosphine (1.215 g, 4.63 mmol) at 0° C. followed by tetrabromomethane (1.02 g, 3.09 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After that time, the volatiles were removed under reduced pressure. Diethyl ether was added to the residue. The resultant solid precipitate was isolated by filtration and washed with diethyl ether. This crude product was purified by flash chromatography eluting with 5% EtOAc in PE to afford L4.  1 H NMR (CDCl 3 , 300 MHz): δ 4.11 (d, J=7.8 Hz, 1H), 1.62-1.51 (m, 1H), 0.99-0.87 (m, 2H), 0.80-0.60 (m, 2H). 
     Step 4: 
     To a stirred solution of C5 (0.2 g, 0.487 mmol) in dry tetrahydrofuran (5 mL) at 0° C. was added sodium ethoxide (0.31 g, 0.975 mmol) under nitrogen. After stirring the reaction mixture for 15 min, L4 (0.117 g, 0.731 mmol) was added. The reaction mixture was brought to room temperature and stirred for 16 h. After that time, ice water was added to the reaction and the resultant mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na 2 SO 4 , and concentrated. The crude residue was purified by flash chromatography over silica gel eluting with 30% EtOAc in PE to afford L5. m/z: 447 (MH + ). 
     Step 5: 
     A solution of L5 in THF is treated with a solution of lithium bis(trimethylsilyl)amide. After 15 min, methyl iodide is added to the reaction and the solution is stirred for 2 hours. After that time, the reaction is quenched with water and the mixture is extracted with DCM. The organic layer is dried over Na 2 SO 4 , filtered and concentrated. The crude residue is purified by flash chromatography to afford L6. 
     Steps 6-16: 
     Intermediate L6 is converted to Example 13 following procedures similar to those described in Scheme G Steps 4-6 and Scheme H. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                   
                   
                   
                   
                 LCMS data 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 BACE 1 
                 BACE 2 
                 m/z 
                 t R   
                   
               
               
                 Ex 
                 Structure 
                 K i  (nM) 
                 K i  (nM) 
                 (MH + ) 
                 (min) 
                 Conditions 
               
               
                   
               
               
                 13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                   
               
            
           
         
       
     
     LCMS Conditions 
     Conditions 1: 
     Atlantis C18 (50×4.6 mm) 5.0 micron; Column temp: Ambient; Mobile phase: A: 0.1% Formic acid in water, B: 100% acetonitrile; Gradient: From 0 to 3 min 95:5 to 5:95 (A:B), from 3 to 4 min 5:95 (A:B), from 4 to 4.5 min 5:95 to 95:5 (A:B) from 4.5 to 6 mins 95:5 (A:B); Flow rate: 1.5 mL/min; UV detection: 215 nm; mass spectrometer: Agilent 6130 (Single) quadrupole. 
     Assays 
     Protocols that used to determine the recited potency values for the compounds of the invention are described below. 
     BACE1 HTRF FRET Assay 
     Reagents: 
     Na + -Acetate pH 5.0; 1% Brij-35; Glycerol; Dimethyl Sulfoxide (DMSO); Recombinant human soluble BACE1 catalytic domain (&gt;95% pure); APP Swedish mutant peptide substrate (QSY7-APP swe -Eu): QSY7-EISEVNLDAEFC-Europium-amide. 
     A homogeneous time-resolved FRET assay can be used to determine IC 50  values for inhibitors of the soluble human BACE1 catalytic domain. This assay monitors the increase of 620 nm fluorescence that resulted from BACE1 cleavage of an APPswedish APP swe  mutant peptide FRET substrate (QSY7-EISEVNLDAEFC-Europium-amide). This substrate contains an N-terminal QSY7 moiety that serves as a quencher of the C-terminal Europium fluorophore (620 nm Em). In the absence of enzyme activity, 620 nm fluorescence is low in the assay and increased linearly over 3 hours in the presence of uninhibited BACE1 enzyme Inhibition of BACE1 cleavage of the QSY7-APP swe -Eu substrate by inhibitors is manifested as a suppression of 620 nm fluorescence. 
     Varying concentrations of inhibitors at 3× the final desired concentration in a volume of 10 ul are preincubated with purified human BACE1 catalytic domain (3 nM in 10 μl) for 30 minutes at 30° C. in reaction buffer containing 20 mM Na-Acetate pH 5.0, 10% glycerol, 0.1% Brij-35 and 7.5% DSMO. Reactions are initiated by addition of 10 μl of 600 nM QSY7-APP swe -Eu substrate (200 nM final) to give a final reaction volume of 30 μl in a 384 well Nunc HTRF plate. The reactions are incubated at 30° C. for 1.5 hours. The 620 nm fluorescence is then read on a Rubystar HTRF plate reader (BMG Labtechnologies) using a 50 millisecond delay followed by a 400 millisecond acquisition time window Inhibitor IC 50  values are derived from non-linear regression analysis of concentration response curves. K i  values are then calculated from IC 50  values using the Cheng-Prusoff equation using a previously determined μm value of 8 μM for the QSY7-APP swe -Eu substrate at BACE1. 
     BACE-2 Assay 
     Inhibitor IC 50s  at purified human autoBACE-2 are determined in a time-resolved endpoint proteolysis assay that measures hydrolysis of the QSY7-EISEVNLDAEFC-Eu-amide FRET peptide substrate (BACE-HTRF assay). BACE-mediated hydrolysis of this peptide results in an increase in relative fluorescence (RFU) at 620 nm after excitation with 320 nm light Inhibitor compounds, prepared at 3× the desired final concentration in 1× BACE assay buffer (20 mM sodium acetate pH 5.0, 10% glycerol, 0.1% Brij-35) supplemented with 7.5% DMSO are pre-incubated with an equal volume of autoBACE-2 enzyme diluted in 1× BACE assay buffer (final enzyme concentration 1 nM) in black 384-well NUNC plates for 30 minutes at 30° C. The assay is initiated by addition of an equal volume of the QSY7-EISEVNLDAEFC-Eu-amide substrate (200 nM final concentration, K m =8 μM for 4 μM for autoBACE-2) prepared in 1× BACE assay buffer supplemented with 7.5% DMSO and incubated for 90 minutes at 30° C. DMSO is present at 5% final concentration in the assay. Following laser excitation of sample wells at 320 nm, the fluorescence signal at 620 nm is collected for 400 ms following a 50 μs delay on a RUBYstar HTRF plate reader (BMG Labtechnologies). Raw RFU data is normalized to maximum (1.0 nM BACE/DMSO) and minimum (no enzyme/DMSO) RFU values. IC 50s  are determined by nonlinear regression analysis (sigmoidal dose response, variable slope) of percent inhibition data with minimum and maximum values set to 0 and 100 percent respectively. Similar IC 50s  are obtained when using raw RFU data. The K i  values are calculated from the IC 50  using the Cheng-Prusoff equation.