# Patent

## Title
Iminothiadiazine dioxides containing a thioamide, amidine, or amide oxime group as BACE inhibitors, compositions, and their use

## Abstract

In its many embodiments, the present invention provides certain C2-ring-substituted iminothiadiazine compounds, or a tautomers thereof, and pharmaceutically acceptable salts of said compounds and said tautomers. The novel compounds of the invention are as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed.

## Background
FIELD OF THE INVENTION
This invention provides certain iminothiadiazine dioxide compounds containing a thioamide, amidine, or amide oxime group, 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's disease, Down's syndrome, Parkinson's disease, memory loss (including memory loss associated with Alzheimer's disease and Parkinson's disease), attention deficit symptoms (including attention deficit symptoms associated with Alzheimer's disease (“AD”), Parkinson's disease, and Down's syndrome), dementia (including pre-senile dementia, senile dementia, dementia associated with Alzheimer's disease, Parkinson's disease, and Down's syndrome), progressive supranuclear palsy, cortical basal degeneration, neurodegeneration, olfactory impairment (including olfactory impairment associated with Alzheimer's disease, Parkinson's disease, and Down'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'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 β-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'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's disease and cognitive decline in the elderly without Alzheimer'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'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'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's syndrome. The gene encoding APP is found on chromosome 21, which is also the chromosome found as an extra copy in Down's syndrome. Down's syndrome patients tend to acquire AD at an early age, with almost all those over 40 years of age showing Alzheimer'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'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's type pathology in Down'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 are expected to be of therapeutic value are discussed further hereinbelow.
SUMMARY OF THE INVENTION
The present invention provides certain iminothiadiazine dioxide compounds having a thioamide, amidine, or amide oxime group, which are collectively or individually referred to herein as “compound(s) of the invention”, as described herein. The compounds of the invention are inhibitors of BACE-1 and/or BACE-2, and may be useful for treating or preventing diseases or pathologies related thereto.
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:
-L1- is a divalent moiety selected from the group consisting of —C(S)NH—, —NHC(S)—, —C(NR10)NH—, and —NHC(NR10)—;
R1 is selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, is optionally substituted with one or more halogen;
R2 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;
R3 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;
R4 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 and heteroaryl;
m is 0 or more;
each RA (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF5, —OSF5, —Si(R5)3, —N(R6)2, —OR6, —SR6, 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 RA are each optionally independently unsubstituted or substituted with one or more groups independently selected from R8;
    
    


RL is selected from the group consisting of alkyl and heteroalkyl, wherein said alkyl and heteroalkyl of RL are each optionally unsubstituted or substituted with one or more halogen;
or, alternatively, RL is a moiety having the formula




wherein q is 0 or 1;
-LB- (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, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
p is 0 or more; and
each RB (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF5, —OSF5, —Si(R5)3, —N(R6)2, —NR7C(O)R6, —NR7S(O)2R6, —NR7S(O)2N(R6)2, —NR7C(O)N(R6)2, —NR7C(O)OR6, —C(O)R6, —C(O)OR6, —C(O)N(R6)2, —S(O)R6, —S(O)2R6, —S(O)2N(R6)2, —OR6, —SR6, 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 RB are each optionally independently unsubstituted or substituted with one or more groups independently selected from R9;
    
    


each R5 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl,

    
    
        wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl of R5 is unsubstituted or substituted with one or more halogen;
    
    


each R6 (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 R6 is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, and haloalkoxy;
    
    


each R7 (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 R7 is unsubstituted or substituted with one or more halogen;
    
    


each R8 (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 R8 is optionally substituted with halogen;
each R9 (when present) is independently selected from the group consisting of halogen, —OH, —CN, —SF5, —OSF5, 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; and
R10 (when present) is selected from the group consisting of H, —CN, alkyl, heteroalkyl, alkoxy, and —O-heteroalkyl wherein each alkyl, heteroalkyl, alkoxy, and —O-heteroalkyl of R10 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.


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 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′):
R1 is selected from the group consisting of H, methyl, ethyl, cyclopropyl, —CH2-cyclopropyl, and —CH2OCH3.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
R1 is selected from the group consisting of H and methyl.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
R1 is methyl.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R2 is selected from the group consisting of H, fluoro, methyl, ethyl, propyl, butyl, cyclopropyl, —CH2-cyclopropyl, and —CH2OCH3.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R2 is selected from the group consisting of H and methyl.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R2 is H.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R3 is selected from the group consisting of H, fluoro, methyl, ethyl, propyl, butyl, cyclopropyl, —CH2-cyclopropyl, and —CH2OCH3.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R3 is selected from the group consisting of H and methyl.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R3 is H.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R2 is selected from the group consisting of H, fluoro, methyl, ethyl, propyl, butyl, cyclopropyl, —CH2-cyclopropyl, and —CH2OCH3; and R3 is H.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R2 is selected from the group consisting of H and methyl; and R3 is H.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R2 is H and R3 is H.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R4 is selected from the group consisting of H, methyl, ethyl, cyclopropyl, —CH2-cyclopropyl, —CHF2, —CF3, and —CH2OCH3.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R4 is selected from the group consisting of methyl, cyclopropyl, —CH2F, and —CHF2.
In one embodiment, in each of Formulas (I), (IA), and (IA′), R4 is selected from the group consisting of methyl and —CHF2.
In one embodiment, in each of Formulas (I), (IA), and (IA′):
R4 is selected from the group consisting of methyl and —CHF2; and one of R2 and R3 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′):
R4 is selected from the group consisting of methyl and —CHF2;
R2 is selected from the group consisting of H and methyl; and
R3 is H.
In one embodiment, in each of Formulas (I), (IA), and (IA′):
R4 is selected from the group consisting of methyl and —CHF2;
R2 is H; and
R3 is H.
The following alternatives of ring A are applicable to any of the embodiments described hereinabove.
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 RA (when present) is independently selected from the group consisting of halogen, oxo, —CN, —SF5, —NHCH3, —N(CH3)2, —OCH3, —OCH2CH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —CH2OCH3, —S(CH3), methyl, ethyl, cyclopropyl, —CH2-cyclopropyl, —CF3, —CHF2, —CH2F, —OCF3, and —OCHF2.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
each RA (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —OCH3, —CH2OCH3, methyl, cyclopropyl, —CF3, —CHF2, —CH2F, —OCF3, and —OCHF2.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
each RA (when present) is independently selected from the group consisting of fluoro, chloro, —CN, —OCH3, —CH2OCH3, methyl, cyclopropyl, —CF3, —CHF2, and —CH2F.
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 RA (when present) is independently selected from the group consisting of halogen, oxo, —CN, —SF5, —NHCH3, —N(CH3)2, —OCH3, —OCH2CH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —CH2OCH3, —S(CH3), methyl, ethyl, cyclopropyl, —CH2-cyclopropyl, —CF3, —CHF2, —CH2F, —OCF3, and —OCHF2.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
ring A is selected from the group consisting of phenyl, wherein m is 0, 1, 2, or 3, and pyridyl wherein m is 0, 1, or 2; and
each RA (when present) is independently selected from the group consisting of halogen, oxo, —CN, —SF5, —NHCH3, —N(CH3)2, —OCH3, —OCH2CH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —CH2OCH3, —S(CH3), methyl, ethyl, cyclopropyl, —CH2-cyclopropyl, —CF3, —CHF2, —CH2F, —OCF3, and —OCHF2.
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 RA 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 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 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, p 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.
The following alternatives of RL are applicable to any of the embodiments described hereinabove.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
RL is selected from the group consisting of lower alkyl and lower heteroalkyl, wherein said lower alkyl and lower heteroalkyl of RL are each optionally unsubstituted or substituted with one or more halogen.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
RL is selected from the group consisting of methyl, ethyl, propyl, butyl, —CF3, —CHF2, —CH2F, —CH2CF3, —CF2CH3, —CH2OCH3, —CH2OCH2CH3, —CH2CH2OCH3, —CH2SCH3, —CH2SCH2CH3, —CH2CH2SCH3, —CH2N(CH3)2, —CH2NHCH3, —CH2CH2N(CH3)2, —CH2OCF3, and —CH2OCHF2.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): RL is selected from the group consisting of methyl, ethyl, —CF3, —CHF2, —CH2F, —CH2CF3, —CF2CH3, —CH2OCH3, —CH2OCH2CH3, —CH2SCH3, —CH2N(CH3)2, —CH2OCF3, and —CH2OCHF2.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): RL is selected from the group consisting of methyl, ethyl, —CF3, —CHF2, —CH2F, —CH2CF3, —CF2CH3, —CH2OCH3, CH2OCF3, and —CH2OCHF2.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
RL is a moiety having the formula




wherein q, LB, ring B, p, and RB 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, -LB- is absent; RL is a moiety having the formula




and ring B and -L1- are directly connected as shown:





In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):
q is 1; and
RL is a moiety having the formula




wherein:

-LB- is a divalent moiety selected from the group consisting of —CH2—, —CF2—, —CH2CH2—, —CH2O—, and —CF2O—.
In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):
q is 1; and
RL is a moiety having the formula




wherein:

-LB- is a divalent moiety selected from the group consisting of —CH2—, —CF2—, and —CH2CH2—.
In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):
q is 1; and
RL is a moiety having the formula




wherein:

-LB- is —CH2—.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
RL 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′):
RL 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′):
RL 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′):
RL 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′):
RL is a moiety having the formula




wherein:

each RB group (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, —SF5, —NH2, —NH(CH3), —N(CH3)2, —NHC(O)CH3, —N(CH3)C(O)CH3, —NHS(O)2CH3, —N(CH3)S(O)2C H3, —C(O)OCH3, —C(O)OCH2CH3, —C(O)N(CH3)2, —C(O)NHCH3, —S(O)2CH3, —S(O)2N(CH3)2, —S(O)2NHCH3, —OCH3, —OCH2CH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, —S(CH3), methyl, ethyl, propyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —CH2OCH2CH3, —C≡CH3, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCH2CF3, —OCHF2, —OCH2F, —OCH2CH2F, 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, —CH3, —OCH3, and —CF3.
    
    


In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
RL is a moiety having the formula




wherein:

each RB group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —OH, —CN, —SF5, —NH2, —NH(CH3), —N(CH3)2, —NHC(O)CH3, —N(CH3)C(O)CH3, —NHS(O)2CH3, —N(CH3)S(O)2C H3, —C(O)OCH3, —C(O)OCH2CH3, —C(O)N(CH3)2, —C(O)NHCH3, —S(O)2CH3, —S(O)2N(CH3)2, —S(O)2NHCH3, —OCH3, —OCH2CH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, —S(CH3), methyl, ethyl, propyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —CH2OCH2CH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCH2CF3, —OCHF2, —OCH2F, and —OCH2CH2F.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
RL is a moiety having the formula




wherein:

each RB group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O)2CH3, —OCH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, methyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, and —OCH2CH2F.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
RL is a moiety having the formula




wherein:

q is 0 or 1;
-LB- (when present) is a divalent moiety selected from the group consisting of —CH2—, —CF2—, —CH2CH2—, —CH2O—, and —CF2O—;
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 RB group (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, —SF5, —NH2, —NH(CH3), —N(CH3)2, —NHC(O)CH3, —N(CH3)C(O)CH3, —NHS(O)2CH3, —N(CH3)S(O)2C H3, —C(O)OCH3, —C(O)OCH2CH3, —C(O)N(CH3)2, —C(O)NHCH3, —S(O)2CH3, —S(O)2N(CH3)2, —S(O)2NHCH3, —OCH3, —OCH2CH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, —S(CH3), methyl, ethyl, propyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —CH2OCH2CH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCH2CF3, —OCHF2, —OCH2F, —OCH2CH2F, 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, —CH3, —OCH3, and —CF3.
    
    


In an alternative of the immediately preceding embodiment, q is 0.
In another alternative of the immediately preceding embodiment, q is 1; and
-LB- is a divalent moiety selected from the group consisting of —CH2—, —CF2—, and —CH2CH2—.
In another alternative of the immediately preceding embodiment, q is 1; and
-LB- is —CH2—.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
RL 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;
p is 0 or more; and
each RB group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —OH, —CN, —SF5, —NH2, —NH(CH3), —N(CH3)2, —NHC(O)CH3, —N(CH3)C(O)CH3, —NHS(O)2CH3, —N(CH3)S(O)2C H3, —C(O)OCH3, —C(O)OCH2CH35—C(O)N(CH3)2, —C(O)NHCH3, —S(O)2CH3, —S(O)2N(CH3)2, —S(O)2NHCH3, —OCH3, —OCH2CH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, —S(CH3), methyl, ethyl, propyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —CH2OCH2CH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCH2CF3, —OCHF2, —OCH2F, and —OCH2CH2F.
In an alternative of the immediately preceding embodiment, q is 0.
In another alternative of the immediately preceding embodiment, q is 1; and
-LB- is a divalent moiety selected from the group consisting of —CH2—, —CF2—, and —CH2CH2—.
In another alternative of the immediately preceding embodiment, q is 1; and
-LB- is —CH2—.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
RL is a moiety having the formula




wherein:

q is 1;
-LB- (when present) is a divalent moiety selected from the group consisting
of —CH2—, —CF2—, and —CH2CH2—;
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 RB group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O)2CH3, —OCH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, methyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, and —OCH2CH2F.
In an alternative of the immediately preceding embodiment, -LB- is —CH2—.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
q is 0; and RL is a moiety having the formula




wherein:

ring B is selected from the group consisting of isoxazoyl, oxadiazoyl, oxazolyl, phenyl, pyridinyl, pyridyl, pyrazinyl, pyrimidinyl, and pyrazolyl;
p is 0 or more; and
each RB group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O)2CH3, —OCH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, methyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, and —OCH2CH2F.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
q is 0; and RL is a moiety having the formula




wherein:

ring B is selected from the group consisting of phenyl and pyridyl;
p is 0 or 1; and
each RB group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O)2CH3, —OCH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, methyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, and —OCH2CH2F.
In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):
q is 0; and RL is a moiety having the formula




wherein:

ring B is selected from the group consisting of pyridyl and pyrazinyl;
p is 0 or 1; and
each RB group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O)2CH3, —OCH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, methyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, and —OCH2CH2F.
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 RB 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 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 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 above embodiments, -L1- is selected from the group consisting of —C(S)NH—, —NHC(S)—, —C(NR10)NH—, and —NHC(NR10)—, wherein R10 (when present) is selected from the group consisting of H and alkoxy.
The following alternatives of -L1- are applicable to any of the embodiments described hereinabove.
In one alternative of each of the above embodiments, -L1- is selected from the group consisting of —C(S)NH—, —NHC(S)—, —C(NR10)NH—, and —NHC(NR10)—, wherein R10 (when present) is selected from the group consisting of H and —OMe.
In another alternative of each of the above embodiments, -L1- is selected from the group consisting of —C(NR10)NH— and —NHC(NR10)—, wherein R10 is selected from the group consisting of H and —OMe.
In another alternative of each of the above embodiments, -L1- is selected from the group consisting of —C(S)NH— and —NHC(S)—.
In another alternative of each of the above embodiments, -L1- is selected from the group consisting of —C(S)NH— and —C(NR10)NH—, wherein R10 (when present) is selected from the group consisting of H and —OMe.
In another alternative of each of the above embodiments, -L1- is —C(NR10)NH—, wherein R10 is selected from the group consisting of H and —OMe.
In another alternative of each of the above embodiments, -L1- is —C(S)NH—.
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's disease and/or drugs that may be useful for treating one or more symptoms of Alzheimer'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's Disease, Down's syndrome, Parkinson's disease, memory loss, memory loss associated with Alzheimer's disease, memory loss associated with Parkinson's disease, attention deficit symptoms, attention deficit symptoms associated with Alzheimer's disease (“AD”), Parkinson's disease, and/or Down's syndrome, dementia, stroke, microgliosis and brain inflammation, pre-senile dementia, senile dementia, dementia associated with Alzheimer's disease, Parkinson's disease, and/or Down's syndrome, progressive supranuclear palsy, cortical basal degeneration, neurodegeneration, olfactory impairment, olfactory impairment associated with Alzheimer's disease, Parkinson's disease, and/or Down's syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysis complications (from β2 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., m1 agonists (such as acetylcholine, oxotremorine, carbachol, or McNa343), or m2 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; GABAA 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 pharmaceutically acceptable salt thereof, 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 thereof, 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 thereof, or pharmaceutically acceptable salt of said compound 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 Aft Non-limiting examples of pathologies which may be associated with Aβ include: Alzheimer's Disease, Down's syndrome, Parkinson's disease, memory loss, memory loss associated with Alzheimer's disease, memory loss associated with Parkinson's disease, attention deficit symptoms, attention deficit symptoms associated with Alzheimer's disease (“AD”), Parkinson's disease, and/or Down's syndrome, dementia, stroke, microgliosis and brain inflammation, pre-senile dementia, senile dementia, dementia associated with Alzheimer's disease, Parkinson's disease, and/or Down's syndrome, progressive supranuclear palsy, cortical basal degeneration, neurodegeneration, olfactory impairment, olfactory impairment associated with Alzheimer's disease, Parkinson's disease, and/or Down's syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysis complications (from β2 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 thereof, or pharmaceutically acceptable salt of said compound 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'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 thereof, or pharmaceutically acceptable salt of said compound or said tautomer), optionally in further combination with one or more additional therapeutic agents which may be effective to treat Alzheimer'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 thereof, or pharmaceutically acceptable salt of said compound 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'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's disease. Thus, such methods comprise administering, prior to the onset of symptoms or clinical or biological evidence of MCI or Alzheimer's disease (e.g., from several months to several years 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 thereof, or pharmaceutically acceptable salt of said compound 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's syndrome, comprising administering an effective (i.e., therapeutically effective) amount of one or more compounds of the invention (or a tautomer thereof, or pharmaceutically acceptable salt or solvate of said compound 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 thereof, or pharmaceutically acceptable salt of said compound 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'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 herein.
In another embodiment, the invention provides methods of treating a disease or pathology, wherein said disease or pathology is Alzheimer's disease, olfactory impairment associated with Alzheimer's disease, Down's syndrome, olfactory impairment associated with Down's syndrome, Parkinson's disease, olfactory impairment associated with Parkinson's disease, stroke, microgliosis brain inflammation, pre-senile dementia, senile dementia, progressive supranuclear palsy, cortical basal degeneration, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma, amyloidosis, type II diabetes, diabetes-associated amyloidogenesis, scrapie, bovine spongiform encephalitis, traumatic brain injury, or Creutzfeld-Jakob disease, said method comprising administering a compound according to any one of claim 1 or claim 9, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, to a patient in need thereof in an amount effective to treat said disease or pathology.
In another embodiment, the invention provides for the use of any of the compounds of the invention for use as a medicament, or in medicine, or in therapy.
In another embodiment, the invention provides for use of a compound of the invention for the manufacture of a medicament for the treatment of a disease or pathology, wherein said disease or pathology is Alzheimer's disease, olfactory impairment associated with Alzheimer's disease, Down's syndrome, olfactory impairment associated with Down's syndrome, Parkinson's disease, olfactory impairment associated with Parkinson's disease, stroke, microgliosis brain inflammation, pre-senile dementia, senile dementia, progressive supranuclear palsy, cortical basal degeneration, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma, amyloidosis, type II diabetes, diabetes-associated amyloidogenesis, scrapie, bovine spongiform encephalitis, traumatic brain injury, or Creutzfeld-Jakob disease.
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, comprising 1 to about 10 carbon atoms. “Lower alkyl” means a straight or branched alkyl group comprising 1 to about 4 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, 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 10 carbon atoms in the straight or branched chain. Branched means that one or more lower alkyl groups such as methyl, ethyl propyl, ethenyl or propenyl are attached to a linear or branched alkenyl chain. “Lower alkenyl” means about 2 to about 4 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, heterocycloalkyl, etc. indicates a divalent moiety, e.g., —CH2CH2— 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 10 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, or lower alkenyl or lower alkynyl groups, are attached to a linear alkynyl chain. “Lower alkynyl” means about 2 to about 4 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(CH3)═CH—, and —CH═CHCH2—.
“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, pyridonyl, 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, cycloheptenyl, 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 pyrrolidinone (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 heterocycloalkenyl 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.

“Arylalkyl” (or “aralkyl”) means an aryl-alkyl- group in which the aryl and alkyl are as previously described, except that in this context the “alkyl” portion of the “arylalkyl” (or “-alkyl-aryl”) group refers to a straight or branched lower alkyl group. 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. As indicated above, the “alkyl” group in this context represents a lower alkyl group, which may be straight or branched, or 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 propargylethyl.
“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'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., R6 in —N(R6)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 thereof, or pharmaceutically acceptable salt of said compound 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 H2O.
“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 & 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, C1-4alkyl, or C1-4alkoxy 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 C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)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.
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'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 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, 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 (1H) and deuterium (2H). 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's Pharmaceutical Sciences, 18th 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 comparing 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.
Techniques, solvents and reagents may be referred to by their abbreviations as follows:
Acetic acid: AcOH
Acetonitrile: MeCN
Aqueous: aq.
Atmospheric pressure chemical ionization: APCI
Benzyl: Bn
Bis(2-oxo-3-oxazolidinyl)phosphonic
chloride: BOPCl
tert-Butyl: t-Bu or tBu
Carbonyldiimidazole: CDI
Concentrated: conc.
Di-tert-butyldicarbonate: Boc2O
Dichloromethane: DCM
2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl: XPhos
Diisopropylethylamine: DIEA or iPr2Net
N,N-Dimethylaminopyridine: DMAP
Dimethylformamide: DMF
Dimethylsulfoxide: DMSO
Electrospray: ES
Ethanol: EtOH
Ether or diethyl ether: Et2O
Ethyl: Et
Ethyl acetate: AcOEt, EtOAc, or EA
Milligrams: mg
Example: Ex.
Grams: g
Hexanes: hex
High performance liquid chromatography: HPLC
Inhibition: Inh.
Liquid chromatography mass Spectrometry: LCMS
Liter: L
Lithium diisopropylamide: LDA
Methanesulfonyl chloride: MeSO2Cl
Methanol: MeOH
Methyl t-butyl ether: MTBE
Methyl chloromethyl ether: MOMCl
Methyl iodide: MeI
Methyl magnesium bromide: MeMgBr
Microliters: μl or μL
Milliliters: mL
Millimoles: mmol
Minutes: min
N-bromosuccinimide: NBS
nBuLi or n-BuLi
Normal: N
Nuclear magnetic resonance spectroscopy:
NMR Temperature: temp.
Number: no. or No.
Observed: Obs.
Palladium on carbon: Pd/C
Para-methoxy benzyl: PMB
Petroleum ether: PE
Retention time: tR 
Room temperature (ambient, about 25° C.): rt or RT
Saturated: sat
Silica gel: SiO2 
tert-Butoxycarbonyl: t-Boc or Boc
Chloro(2-di-t-butylphosphino-2′,4′,6′-tri-i-n-Butyllithium: propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)
t-Bu-Xphos palladacycle
Tetrahydrofuran: THF
Thin layer chromatography: TLC
Triethylamine: Et3N or TEA
Trifluoroacetic acid: TFA
2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4-6-trioxide: T3P
or T3P
Weight: w
Method A:







Step 1:

To a solution of acetophenone A1 (115 g, 628 mmol) in anhydrous THF (900 mL) was added (R)-t-butylsulfinimde (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. The mixture was then filtered and the filter cake was washed with CH2Cl2 (3×). The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified via flash chromatography (SiO2; 15% EtOAc/heptane) to afford the ketimine A2.
Step 2:
To a stirred solution of 4-methoxybenzyl amine A3 (199 g, 1.45 mol) in anhydrous pyridine (400 mL) at 0° C. was added dropwise via an addition funnel methanesulfonyl chloride (116 mL, 1.45 mol) over 45 min. After the addition was complete, the cooling bath was removed and the resultant solution was stirred at RT overnight. The reaction was concentrated in vacuo. The slurry was then taken up in DCM (1 L). The organic solution was washed with 1 N HCl (aq.) (2×1 L), sat. NaHCO3 (2×1 L) and brine (1×500 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford a solid. This solid was dissolved in 95% EtOH (430 mL) with warming The solution was allowed to cool, and the resulting solid precipitate was removed by filtration. The solid was then washed with cold EtOH (3×150 mL). A second crop of solid was similarly obtained after allowing the mother liquor to stir at RT overnight. This combined solids were dissolved in anhydrous DMF (3.0 L), cooled to 0° C. and placed under an atmosphere of N2. To this solution was added in small portions sodium hydride (60% in mineral oil, 60.2 g, 1.51 mol). After the addition was complete, the mixture was stirred for an additional 10 min. To this mixture was added dropwise via an addition funnel methyl iodide (250 g, 1.76 mol). After the addition was complete, the cooling bath was removed and the mixture was allowed to stir at RT overnight. After that time, the mixture was concentrated in vacuo to remove approximately 2.5 L of DMF. The mixture was then partitioned between 5 L ice water, 5 L Et2O and 500 mL of EtOAc. The organic layer was separated. The aqueous layer was extracted with Et2O (2×1 L). The combined organic layers were washed with brine (2×1 L), dried over Na2SO4, filtered and concentrated. The residue was stirred with hexanes, and the resulting solid was removed by filtration and washed with hexanes (2×250 mL). This solid was then dissolved in hexanes/EtOAc (1:1, 450 mL) with warming. The solid formed on cooling was filtered off to afford product A4. The remaining mother liquor was purified via silica gel chromatography (50% EtOAc/hexanes) to afford additional A4.
Step 3:
To a solution of sulfonamide A4 (38.0 g, 166 mmol) in anhydrous THF (500 mL) at −78° C. under an atmosphere of N2 was slowly added a solution of n-BuLi (1.6 M in hexanes, 104 mL, 166 mmol). The resultant solution was stirred at −78° C. for 30 min. After that time, a precooled (−78° C.) solution of ketimine A2 (23.7 g, 82.8 mmol) in anhydrous THF (200 mL) was added to the reaction mixture via cannula. The resulting mixture was allowed to stir at −78° C. for 1 hour. After that time, water and EtOAc were added to the reaction. The cooling bath was removed and the mixture was allowed to warm to RT. The aqueous layer was then separated and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified via flash chromatography (SiO2; gradient elution 100:0 to 40:60 hexanes:EtOAc) to afford A5.
Step 4:
To a solution of A5 (27.4 g, 53.1 mmol) in CH2Cl2: MeOH (3:1, 230 mL) was added a solution of HCl (4 M in dioxane, 80 mL, 319 mmol). The resultant solution was stirred at RT for 45 min. The solution was then concentrated. The crude residue was taken up in toluene (100 mL) and concentrated in vacuo (2×). The residue was dissolved in CH2Cl2 (230 mL). To this solution was added TFA (61.4 mL, 797 mmol) and 1,3-dimethoxybenzene (42 mL, 319 mmol). The resultant solution was stirred at RT overnight. The solution was then concentrated to approximately 1⁄4 the original volume. The solution was partitioned between 1 M HCl (aq.) (1 L) and Et2O (500 mL). The aqueous layer was separated and extracted with Et2O (2×500 mL). The organic layers were combined and back-extracted with 1 N HCl (1×250 mL). The aqueous layers were then combined, adjusted to approximately pH 10 with the slow addition of solid Na2CO3, and then extracted with CH2Cl2 (4×300 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford A6.
Step 5:
To a slurry of amine A6 (13.7 grams, 47 mmol) in n-butanol (150 mL) was added a solution of cyanogen bromide (5M in MeCN, 10.3 mL, 51 mmol). The resultant mixture was heated to reflux for 4 hours. The mixture was then concentrated to approximately 1⁄3 of the original volume. To the mixture was added Et2O (200 mL). The resultant solid was removed via filtration and the solid was washed with Et2O (2×). The solid was partitioned between EtOAc and sat. Na2CO3 (aq.). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford A7. This material was carried onto the next step without further purification.
Step 6:
To a solution of A7 (4.0 grams 11.6 mmol) in CH2Cl2 (100 mL) was added Et3N (2.26 mL, 16.2 mmol) and Boc2O (3.3 g, 15.1 mmol). The resultant solution was stirred at RT overnight. After that time, the solution was washed with sat. Na2CO3 (aq.). The aqueous layer was back-extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified via flash chromatography (SiO2, gradient elution 100:0 to 70:30 hexanes:EtOAc) to afford A8.
Step 7:
A solution of A8 (2.50 g, 6.0 mmol) in EtOH (150 mL) was purged with bubbling N2 for 3 min. To this solution was added Pd/C (10% w/w, 50% H2O, 698 mg). The atmosphere was evacuated and back-filled with H2 (3×). The resulting mixture was stirred at RT under a H2 balloon for 2 hrs. After that time, the mixture was purged with N2. The mixture was then filtered through Celite and concentrated. The residue was filtered through a small pad of silica gel eluting with EtOAc to afford A9. This material was used without further purification.
Step 8:
To a solution of 5-chloropicolinic acid (98 mg, 0.621 mmol) in tetrahydrofuran (3 mL) at room temperature was added N,N-diisopropylethylamine (0.27 mL, 1.554 mmol) and 50% solution of T3P in ethyl acetate (0.23 mL, 0.727 mmol). The reaction mixture was stirred at room temperature for 15 min. A solution of amine A9 (200 mg, 0.518 mmol) in tetrahydrofuran (3 mL) was then added slowly to the reaction, and the reaction mixture was stirred at room temperature for 3 h. After that time, the reaction was quenched by adding water. The mixture was then extracted with ethyl acetate and the layers were separated. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by flash column chromatography over silica gel (gradient elution: 22-25% ethyl acetate in petroleum ether) to afford A10. 1H NMR (DMSO-d6, 400 MHz): 10.84 (s, 1H), 10.33 (s, 1H), 8.78 (s, 1H), 8.22-8.20 (m, 1H), 8.13-8.11 (m, 1H), 7.97-7.92 (m, 2H), 7.29-7.24 (m, 1H), 4.40 (s, 2H), 3.04 (s, 3H), 1.81 (s, 3H), 1.46 (s, 9H).
Step 9:
To a stirred solution of A10 (200 mg, 0.436 mmol) in xylenes (5 mL) at room temperature (under nitrogen) was added phosphorus pentasulfide (126 mg, 0.578 mmol). The reaction mixture was heated at 80° C. for 5 h. After that time, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to reverse phase preparative HPLC [column: C18 19×300 mm 7 micron, gradient elution 5:95 to 100:0 MeOH in H2O (0.1% TFA) over 30 min, 15 mL/min] to yield Example 1. 1H NMR (DMSO-d6, 400 MHz): 10.29 (s, 1H), 8.74 (d, J=2.32 Hz, 1H), 8.65 (bs, 1H), 8.50 (d, J=8.64 Hz, 1H), 8.19 (d, J=2.36, Hz, J=8.56 Hz, 1H), 8.11-8.09 (m, 1H), 7.99-7.95 (m, 1H), 4.64 (d, J=14.76 Hz, 1H), 4.54 (d, J=14.62 Hz, 1H), 3.20 (s, 3H), 1.83 (s, 3H). MS: ES/APCI-MS [M+H+] m/z 442.2.
Examples 2-4c were prepared from A9 using procedures similar to those described in Method A steps 8-9 using the requisite carboxylic acid in Step 8 followed by heating at 100° C. for 5 hours (Examples 1-4), 110° C. for 6 hours (Examples 4a and 4b), or 130° C. for 6 hours (Example 4c) in Step 9.
















BACE1
BACE2
LCMS data















Ki
Ki
m/z
tR



Example
Structure
(nM)
(nM)
(M + H)+
(min)
Conditions





1




   9.1
1
442.2
2.42
1


 


2




 57
8
438.2
2.37
1


 


3




152
2
375.2
1.98
1


 


4




 83
7
381.4
2.07
1


 


4a




 18
7
476.2
2.48
1


 


4b




 25
2
426.2
2.24
1


 


4c




 3
4
439.2
2.18
1









Method B:





Step 1:

A mixture of compound B1 (98.0 g, 447 mmol), N,O-dimethylhydroxylamine hydrochloride (52.4 g, 537 mmol), and BOPCl (171 g, 671 mmol) in pyridine (490 mL) was stirred at room temperature for 3 h. After that time, the reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (2×1 L). The combined organic extracts were washed sequentially with 1 N HCl (aq.) (3×500 mL), saturated aqueous NaHCO3 (500 mL) and brine (1 L). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide B2. 1H NMR (300 MHz, CDCl3) δ 7.70-7.40 (m, 2H), 7.00 (d, J=8.8 Hz, 1H), 3.56 (br s, 3H), 3.35 (br s, 3H); ESI MS m/z 262 [M+H]+.
Step 2:
To a stirred solution of compound B2 (106 g, 404 mmol) in anhydrous THF (1.7 L) at 0° C. under nitrogen was added a solution of methyl magnesium bromide in diethyl ether (3.0 M, 270 mL, 808 mmol). After the addition was completed, the reaction mixture was stirred at 0° C. for 6.5 h. After that time, the solution was poured into to a cold solution of 2 N HCl (aq.) (1 L). The resulting mixture was warmed to room temperature and extracted with ethyl acetate (2×1 L). The combined organic extracts were washed with saturated aqueous NaHCO3 (500 mL) and brine (500 mL) then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford B3. 1H NMR (300 MHz, CDCl3) δ 7.98 (dd, J=6.4, 2.6 Hz, 1H), 7.61 (ddd, J=8.7, 4.3, 2.6 Hz, 1H), 7.05 (dd, J=10.4, 8.7, 1H), 2.64 (d, J=4.9, 3H); ESI MS m/z 217 [M+H]+.
Ketone B3 was converted to B4 using methods similar to those described in Method A steps 1 and 3-6. 1H NMR (300 MHz, CDCl3) δ 10.64 (s, 1H), 7.60-7.30 (m, 2H), 7.00 (dd, J=8.5, 1.7 Hz, 1H), 4.25 (d, J=14.0 Hz, 1H), 3.66 (d, J=14.0 Hz, 1H), 3.25 (s, 3H), 1.87 (s, 3H), 1.55 (s, 9H); ESI MS: m/z 450 [M+H]+.
Method C:




Step 1:

To a stirred solution of C1 (1.0 g, 8.5 mol) in H2O (15 mL) was added concentrated H2SO4 (4.2 mL, 0.085 mol). The reaction mixture was then cooled to 0° C. and a solution of NaNO2 (0.64 g, 0.0093 mol) in H2O (5.7 mL) was added dropwise. The reaction mixture was stirred for 30 min at 0° C. and then poured in to a refluxing mixture of water (11 mL) and conc. H2SO4 (1 mL). The mixture was stirred for 30 min at reflux and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate. The mixture was then washed with water.
The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (SiO2) using 20% ethyl acetate in petroleum ether as the eluent to afford C2. 1H NMR (DMSO-d6, 400 MHz): 11.2 (s, 1H), 8.25 (d, J=2.6 Hz, 1H), 7.85-7.83 (m, 1H), 7.30 (dd, J=2.8 & 8.6 Hz, 1H) MS: m/z: 121.0 (M+H)+
Step 2:
To a stirred solution of C2 (3.4 g, 0.028 mol) in DMF (40 mL) was added K2CO3 (4.3 g, 0.031 mol). The reaction mixture was stirred for 5 min and cooled to 0° C. Methyl iodide (2.8 mL, 0.043 mol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stir overnight. After that time, the volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (SiO2) using 20% ethyl acetate in petroleum ether as the eluent to yield C3. 1H NMR (CDCl3, 400 MHz): 8.39 (d, J=2.8 Hz, 1H), 7.67-7.65 (m, 1H), 7.27-7.24 (m, 1H), 3.94 (s, 3H). MS: m/z: 135.0 (M+H)+
Step 3:
A mixture of hydroxylamine hydrochloride (14.4 g, 0.208 mol) in DMSO (50 mL) was cooled to 5° C. under nitrogen. To this slurry was added potassium tert-butoxide (23.4 g, 0.208 mol) in portions. The mixture was stirred for 30 min at room temperature. Compound C3 (2.5 g, 0.0208 mol) was then added to the reaction mixture and the mixture stirred for 2 h. The reaction mixture was then poured slowly into ice-water and the mixture was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to yield the crude product. The crude product was then added to water. The resultant precipitate was isolated by filtration and dried under vacuum to afford C4. This material was used without further purification for the next step. 1H NMR (DMSO-d6, 400 MHz): 9.71 (s, 1H), 8.25 (d, J=2.7 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.42 (dd, J=2.9 & 8.9 Hz, 1H), 5.74 (s, 2H), 3.86 (s, 3H). MS: m/z: 168.2 (M+H)+
Step 4:
To a mixture of C4 (2.5 g, 11.9 mmol) in dioxane (20 mL) and 2 N aq. NaOH (15 mL) at 0° C. was slowly added dimethyl sulfate (3.4 mL, 36 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. After that time, water was added to the reaction and the mixture was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (SiO2) using 14% ethyl acetate in petroleum ether as the eluent to afford C5. 1H NMR (CDCl3, 300 MHz): 8.21 (d, J=2.8 Hz, 1H), 7.96-7.93 (m, 1H), 7.26-7.20 (m, 1H), 5.54 (bs, 2H), 3.93 (s, 3H), 3.89 (s, 3H). MS: m/z: 182.2 (M+H)+
Step 5:
To a microwave vial containing a solution of C5 (0.05 g, 0.276 mmol) in THF (5 mL), under nitrogen, was added B4 (0.12 g, 0.276 mmol) and potassium tert-butoxide (0.092 g, 0.828 mmol). The reaction mixture was then purged with nitrogen for 5 min. To the mixture was added t-BuXPhos palladacycle (0.038 g, 0.055 mmol) and the reaction mixture was further purged with nitrogen for 10 min. The vial was then sealed and heated in a microwave at 80° C. for 30 min. After that time, the mixture was cooled, the vial was opened, and the volatiles were removed in vacuo. The crude residue was purified by flash column chromatography (SiO2) eluting with a gradient of 20-60% ethyl acetate in petroleum ether to yield C6. MS: m/z: 551.2 (M+H)+
Step 6:
To a stirred solution of C6 (70 mg, 0.127 mmol) in dichloromethane (2 mL) at 0° C. was added TFA (0.2 mL). The reaction mixture was allowed to warm to RT and stirred for 2 h. The volatiles were removed under reduced pressure and the crude product was purified by preparative HPLC [C18 19×300 mm, 7 micron, gradient elution 5-100% MeOH in H2O (0.1% TFA) over 30 min, 15 mL/min] to afford Example 5. 1H NMR (DMSO d6, 400 MHz): 8.60 (bs, 1H), 8.14-8.13 (m, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.41 (dd, J=8.7 & 3 Hz, 1H), 6.98-6.93 (m, 1H), 6.69-6.67 (m, 1H), 6.62-6.58 (m, 1H), 4.40-4.10 (bs, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.12 (s, 3H), 1.63 (s, 3H). MS: m/z: 451.0 (M+H)+

















BACE2
LCMS data















BACE1
Ki
m/z
tR



Example
Structure
inhibition
(nM)
(M + H)+
(min)
Conditions





5




47% inh @ 10 uM
1450
451.0
2.08
1









Method D:





Step 1:

To a stirred solution of Example 1 (0.5 g, 1.13 mmol) in acetonitrile (10 mL) was added AgBF4 (0.64 g, 3.4 mmol), triethylamine (2.0 mL), and O-methyl hydroxylamine hydrochloride (0.93 g, 11.3 mmol). The reaction mixture was stirred at RT overnight. After that time, ice water was added to the reaction and the mixture was extracted with dichloromethane. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by preparative HPLC [C18 19×300 mm 7 micron, gradient elution 5-100% MeOH in H2O (0.1% TFA) over 30 min, 15 mL/min] to afford Example 6. 1H NMR (CD3OD, 400 MHz): 8.45 (d, J=2.2 Hz, 1H), 7.88 (dd, J=2.4 & 8.4 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.04-6.99 (m, 1H), 6.84-6.80 (m, 1H), 6.71-6.69 (m, 1H), 4.42 d, J=14.6 Hz, 1H), 4.17 (d, J=14.6 Hz, 1H), 3.94 (s, 3H), 3.30 (s, 3H), 1.84 (s, 3H). MS: m/z: 455.2 (M+H)+
















BACE1
BACE2
LCMS data















Ki
Ki
m/z
tR



Example
Structure
(nM)
(nM)
(M + H)+
(min)
Conditions





6




340
58
455.2
2.21
1









Method E:





Step 1:

To a stirred solution of A9 (1.0 g, 2.69 mmol) in toluene (15 mL) at RT was added trimethylaluminium (2 M solution in toluene, 5.3 mL, 10.6 mmol). The reaction mixture was stirred for 10 min. After that time, a solution of E1 (700 mg, 3.84 mmol) dissolved in toluene (5 mL) was added drop-wise to the reaction mixture. The reaction mixture was then heated at 100° C. for 16 h. After that time, the reaction mixture was cooled to RT and the volatiles removed in vacuo. The crude residue was purified by preparative HPLC [C18 19×300 mm 7 micron, gradient elution 5-100% MeOH in H2O (0.1% TFA) over 30 min, 15 mL/min] to afford Example 7. 1H NMR (CD3OD, 400 MHz): 9.00 (d, J=1.9 Hz, 1H), 8.40 (dd, J=8.5 Hz & 2.3 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.62-7.56 (m, 2H), 7.46-7.44 (m, 1H), 4.60 (d, J=14.1 Hz, 1H), 4.34 (d, J=14.6 Hz, 1H), 3.32 (s, 3H), 1.99 (s, 3H). MS: m/z: 469.0 (M+H)+


















LCMS data















BACE1
BACE2
m/z
tR



Example
Structure
Ki (nM)
Ki (nM)
(M + H)+
(min)
Conditions





7




371
148
469.0
1.62
1









Method F:





Step 1:

To a solution of F1 (75 g, 474 mmol) in DCM (900 mL) was added CDI (92.3 g, 569 mmol) and the solution was heated to reflux for 50 min. The solution was then cooled to RT. To the solution was added N,O-dimethylhydroxylamine-HCl (51 g, 521 mmol) and DIEA (91 mL, 521 mmol). The resultant mixture was stirred at RT overnight. After that time, water was added to the mixture. The mixture then was extracted with DCM (2×). The combined organic layers were washed sequentially with an aqueous solution of 1 N HCl (2×), water and brine. The organic layer was then dried over MgSO4, filtered and concentrated. The resulting material was used without further purification.
Step 2:
To a solution of the F2 (455 mmol) in THF (1.6 L) at −78° C. was added a solution of MeMgBr (200 mL, 3 M in Et2O) over 30 min via cannula. The resultant mixture was allowed to warm to RT and stir overnight. After that time, the mixture was cooled to 0° C. The reaction mixture was then quenched with 1 M HClaq. (100 mL) and the mixture was further acidified with 6 M HClaq. (750 mL). The mixture was then extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over Na2SO4, filtered and concentrated to afford F3.
Steps 3-6:
F3 was converted to F4 using procedures similar to those described in Method A steps 1 and 3-5.
Step 7:
To a solution of F4 (11 mmol) in conc. H2SO4 (20 mL) at 0° C. was added via an addition funnel a mixture of conc H2SO4 (20 mL) and fuming HNO3 (10 mL) over 30 min and the resultant mixture was stirred for 1 hour at 0° C. After that time, the mixture was poured into ice/water. To the mixture was added solid NaOH until the aqueous layer was basic. The mixture was then extracted with EtOAc (3×). The combined organic layers were washed with water and brine, then dried over MgSO4, filtered and concentrated. The crude product was purified via flash chromatography (SiO2, gradient elution 0-7% MeOH in DCM) to afford F5.
Step 8:
To a solution of F5 (13.8 g, 41.3 mmol) in DCM (150 mL) was added Boc2O (19.8 g, 90.8 mmol) followed by Et3N (15 mL, 103 mmol) and DMAP (100 mg, 0.82 mmol). The resultant mixture was stirred at RT for 2.5 days. The mixture was washed with 0.5 M HCl (aq.) (3×) followed by sat. NaHCO3(aq.). The organic layer was then dried over MgSO4, filtered and concentrated. The crude product was purified via flash chromatography (SiO2, gradient elution 2-20% EtOAc in hexanes) to afford F6.
Step 9:
To a 3-neck round bottom flask equipped with a mechanical stirrer containing a solution of F6 (16.9 g, 31.6 mmol) in THF (254 mL) was added water (25.4 mL) and EtOH (68 mL). To the mixture was added Zn powder (20.7 g, 316 mmol) followed by NH4Cl (8.5 g, 158 mmol). The mixture was stirred at ambient temperature for 20 min after which time the mixture was heated to reflux for 5.25 hours. The mixture was then allowed to cool to RT and stir overnight. The mixture was filtered through Celite and the filter cake was washed with MeOH (150 mL). The filtrate was concentrated to about 1⁄4 of the original volume. To the solution was added water (150 mL). The resultant precipitate was removed via filtration and washed with water (50 mL). The solid was dried in the air for 2 hours followed by further drying in a vacuum oven (40° C.) for 1 hour to afford F7.
Method G:




Examples 8-14 were prepared from intermediate F7 following procedures similar to those described in Method A steps 8-9 using the requisite carboxylic acid in step 1 and the following conditions listed below for step 2.


















BACE1
BACE2
LCMS data















Step 2

Ki
Ki
m/z
tR



Example
conditions
Structure
(nM)
(nM)
(M + H)+
(min)
Conditions





 8
100° C. 6 hr Purification A




 9
 2
460.2
7.86
2


 


 9
130° C. 8 hr Purification B




 57
15
456.2
2.56
1


 


10
130° C. 8 hr Purification B




188
 6
393.2
1.78
3


 


11
130° C. 6 hr Purification B




 95
28
399.2
2.29
1


 


12
110° C. 6 hr Purification B




 17
 3
444.2
2.33
1


 


13
110° C. 6 hr Purification B




 30
21
494.2
2.52
1


 


14
130° C. 8 hr Purification B




 8
18
457.2
2.35
1









Purification A:

Preparative HPLC: Column: Sunfire Prep C18 OBD (19×150 mm) 5 micron; Column temp: ambient; mobile phase: A: 0.1% TFA in water, B: 100% methanol; gradient: from 0-20 min 95:05 to 40:60 (A:B), from 21-25 min 40:60 to 30:70 (A:B), from 25-26 min 30:70 to 0:100(A:B), from 26-30 min 0:100(A:B). Flow rate: 15 mL/min; UV: 215 nm.
Purification B:
Preparative HPLC: Column: Symmetry Prep C18 (19×300 mm) 7 micron; Column temp: ambient; mobile phase: A: 0.1% TFA in water, B: 100% methanol; gradient: from 0-20 min 95:05 to 30:70 (A:B), from 21-25 min 30:70 to 20:80 (A:B), from 25-26 min 20:80 to 0:100 (A:B), from 26 to 30 min 0:100 (A:B) to 0:100 (A:B). Flow rate: 15 mL/min; UV detection: 215 nm.
Analytical LCMS Conditions:
Conditions 1:
Column: 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 3-4 min 5:95 (A:B), from 4 to 4.5 min 5:95 to 95:5 (A:B), from 4.5 to 6 min 95:5 (A:B); Flow rate: 1.5 mL/min; UV detection: 215 nm; Mass spectrometer: Agilent 6130 (single) quadrupole.
Conditions 2:
Column: Xterra C18 (150×4.6 mm) 5.0 micron; Column temp: Ambient; Mobile Phase: A: 0.1% formic acid in water, B: 100% acetonitrile; Gradient: From 0 to 15 min 90:10 to 5:95 (A: B), from 15-20 mins 5:95 (A: B), from 20 to 23 mins 95:10(A:B); Flow rate: 0.8 mL/min; UV detection: 215 nm; Mass spectrometer: Agilent 6130 quadrupole.
Conditions 3:
Column: Zorbax XDBC18 (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 2.5 min 95:5 to 5:95 (A: B), from 2.5-4 mins 5:95 (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 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 (>95% pure); APP Swedish mutant peptide substrate (QSY7-APPswe-Eu): QSY7-EISEVNLDAEFC-Europium-amide.
A homogeneous time-resolved FRET assay can be used to determine IC50 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 APPswe 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-APPswe-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-APPswe-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 IC50 values are derived from non-linear regression analysis of concentration response curves. Ki values are then calculated from IC50 values using the Cheng-Prusoff equation using a previously determined μm value of 8 μM for the QSY7-APPswe-Eu substrate at BACE1. Observed Ki values for the non-limiting examples are reported in the tables above.
BACE-2 Assay
Inhibitor IC50s 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, Km=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. IC50s 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 IC50s are obtained when using raw RFU data. The Ki values are calculated from the IC50 using the Cheng-Prusoff equation.

## Claims

1. A compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I):



or a tautomer thereof having the structural Formula (I′):




or pharmaceutically acceptable salt thereof, wherein:
-L1- is a divalent moiety selected from the group consisting of —C(S)NH—, —NCH(S), —C(NR10)NH—, and —NHC(NR10)—;
R1 is selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, is optionally substituted with one or more halogen;
R2 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;
R3 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;
R4 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 and heteroaryl;
m is 0 or more;
each RA (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF5, —OSF5, —Si(R5)3, —N(R6)2, —OR6, —SR6, 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 RA are each optionally independently unsubstituted or substituted with one or more groups independently selected from R8;
RL is selected from the group consisting of alkyl and heteroalkyl, wherein said alkyl and heteroalkyl of RL are each optionally unsubstituted or substituted with one or more halogen;
or, alternatively, RL is a moiety having the formula




wherein q is 0 or 1;
-LB- (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, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
p is 0 or more; and
each RB (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF5, —OSF5, —Si(R5)3, —N(R6)2, —NR7C(O)R6, —NR7S(O)2R6, —NR7S(O)2N(R6)2, —NR7C(O)N(R6)2, —NR7C(O)OR6, —C(O)R6, —C(O)OR6, —C(O)N(R6)2, —S(O)R6, —S(O)2R6, —S(O)2N(R6)2, —OR6, —SR6, 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 RB are each optionally independently unsubstituted or substituted with one or more groups independently selected from R9;
each R5 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl of R5 is unsubstituted or substituted with one or more halogen;
each R6 (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 R6 is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, and haloalkoxy;
each R7 (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 R7 is unsubstituted or substituted with one or more halogen;
each R8 (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 R8 is optionally substituted with halogen;
each R9 (when present) is independently selected from the group consisting of halogen, —OH, —CN, —SF5, —OSF5, 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; and
R10 (when present) is selected from the group consisting of H, —CN, alkyl, heteroalkyl, alkoxy, and —O-heteroalkyl wherein each alkyl, heteroalkyl, alkoxy, and —O-heteroalkyl of R10 are optionally substituted with one or more halogen.

2. A compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R1 is selected from the group consisting of H, methyl, ethyl, cyclopropyl, —CH2-cyclopropyl, and —CH2OCH3.

3. A compound of claim 2, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R4 is selected from the group consisting of methyl and —CHF2; and
one of R2 and R3 is H and the other is selected from the group consisting of H and methyl.

4. A compound of claim 3, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
L1 is selected from the group consisting of —C(S)NH— and —C(NR10)NH— wherein R10 is selected from the group consisting of H and —OMe.

5. A compound of claim 4, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
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 RA (when present) is independently selected from the group consisting of halogen, oxo, —CN, —SF5, —NHCH3, —N(CH3)2, —OCH3, —OCH2CH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —CH2OCH3, —S(CH3), methyl, ethyl, cyclopropyl, —CH2-cyclopropyl, —CF3, —CHF2, —CH2F, —OCF3, and —OCHF2.

6. A compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
RL is selected from the group consisting of lower alkyl and lower heteroalkyl, wherein said lower alkyl and lower heteroalkyl of RL are each optionally unsubstituted or substituted with one or more halogen.

7. A compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
RL is a moiety having the formula





wherein:
q is 0 or 1;
-LB- (when present) is a divalent moiety selected from the group consisting of —CH2—, —CF2—, —CH2CH2—, —CH2O—, and —CF2O—;
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 RB group (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, —SF5, —NH2, —NH(CH3), —N(CH3)2, —NHC(O)CH3, —N(CH3)C(O)CH3, —NHS(O)2CH3, —N(CH3)S(O)2CH3, —C(O)OCH3, —C(O)OCH2CH3, —C(O)N(CH3)2, —C(O)NHCH3, —S(O)2CH3, —S(O)2N(CH3)2, —S(O)2NHCH3, —OCH3, —OCH2CH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, —S(CH3), methyl, ethyl, propyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —CH2OCH2CH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCH2CF3, —OCHF2, —OCH2F, —OCH2CH2F, 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, —CH3, —OCH3, and —CF3.

8. A compound of claim 7, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
q is 0; and RL is a moiety having the formula




ring B is selected from the group consisting of phenyl and pyridyl;
p is 0 or 1; and
each RB group (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —S(O)2CH3, —OCH3, —O-cyclopropyl, —O—CH2-cyclopropyl, —OCH2—C≡C—H, —OCH2—C≡C—CH3, methyl, cyclopropyl, —CH2-cyclopropyl, —CH2OCH3, —C≡CH, —C≡C—CH3, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, and —OCH2CH2F.

9. A compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound selected from the group consisting of:

10. A pharmaceutical composition comprising a compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent.