The present invention relates to novel tetrahydrofurooxazine compounds, their use as selective BACE1 inhibitors, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds.

The present invention is in the field of treatment of Alzheimer’s disease and other diseases and disorders involving amyloid E (Abeta) peptide, a neurotoxic and highly aggregatory peptide segment of the amyloid precursor protein (APP). Alzheimer’s disease is a devastating neurodegenerative disorder that affects millions of patients worldwide. In view of the currently approved agents on the market which afford only transient, symptomatic benefits to the patient rather than halting, slowing, or reversing the disease, there is a significant unmet need in the treatment of Alzheimer’s disease.

Alzheimer’s disease is characterized by the generation, aggregation, and deposition of Abeta in the brain. Complete or partial inhibition of E-secretase (ȕ-site amyloid precursor protein-cleaving enzyme; BACE) has been shown to have a significant effect on plaque-related and plaque-dependent pathologies in mouse models suggesting that even small reductions in Abeta peptide levels might result in a long-term significant reduction in plaque burden and synaptic deficits, thus providing significant therapeutic benefits, particularly in the treatment of Alzheimer’s disease. In addition, two homologs of BACE have been identified which are referred to as BACE1 and BACE2, and it is believed that BACE1 is the most clinically important to development of Alzheimer’s disease. BACE1 is mainly expressed in the neurons while BACE2 has been shown to be expressed primarily in the periphery (See D. Oehlrich, Bioorg. Med. Chem. Lett., 24, 2033-2045 (2014)). In addition, BACE2 may be important to pigmentation as it has been identified as playing a role in the processing of pigment cell-specific melanocyte protein (See L. Rochin, et al., Proc. Natl. Acad. Sci. USA, 110(26), 10658-10663 (2013)). BACE inhibitors with central nervous system (CNS) penetration, particularly inhibitors that are selective for BACE1 over BACE2 are desired to provide treatments for Abeta peptide-mediated disorders, such as Alzheimer’s disease.

United States Patent No.9,079, 914 discloses certain fused aminodihydro-oxazine derivatives having BACE1 inhibitory effect useful in treating certain neurodegenerative diseases caused by Abeta protein, such as Alzheimer-type dementia. In addition, United States Patent No.8,940,734 discloses certain fused aminodihydrothiazine derivatives which possess BACE1 inhibitory activity and are further disclosed as useful therapeutic agents for a neurodegenerative disease caused by Abeta peptide, such as Alzheimer’s type dementia.

The present invention provides certain novel compounds that are inhibitors of BACE1. In addition, the present invention provides certain novel compounds that are selective inhibitors of BACE1 over BACE2. Furthermore, the present invention provides certain novel compounds which penetrate the CNS. The present invention also provides certain novel compounds which have the potential for an improved side-effect profile, for example, through selective inhibition of BACE1 over BACE2.

Accordin l the resent invention rovides a compound of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a compound of Formula Ia:

formula It

or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating Alzheimer’s disease in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of Formulas I or Ia, or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating the progression of mild cognitive impairment to Alzheimer’s disease in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of Formulas I or Ia, or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of inhibiting BACE in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of Formulas I or Ia, or a pharmaceutically acceptable salt thereof. The present invention also provides a method for inhibiting BACE-mediated cleavage of amyloid precursor protein, comprising administering to a patient in need of such treatment an effective amount of a compound of Formulas I or Ia, or a pharmaceutically acceptable salt thereof. The invention further provides a method for inhibiting production of Abeta peptide, comprising administering to a patient in need of such treatment an effective amount of a compound of Formulas I or Ia, or a pharmaceutically acceptable salt thereof.

Furthermore, this invention provides a compound of Formulas I or Ia, or a pharmaceutically acceptable salt thereof for use in therapy, in particular for use in the treatment of Alzheimer’s disease or for use in preventing the progression of mild cognitive impairment to Alzheimer’s disease. Even furthermore, this invention provides the use of a compound of Formulas I or Ia, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Alzheimer’s disease.

The invention further provides a pharmaceutical composition, comprising a compound of Formulas I or Ia, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients. The invention further provides a process for preparing a pharmaceutical composition, comprising admixing a compound of Formulas I or Ia, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients. This invention also encompasses novel intermediates and processes for the synthesis of the compounds of Formulas I and Ia.

Mild cognitive impairment has been defined as a potential prodromal phase of dementia associated with Alzheimer’s disease based on clinical presentation and on progression of patients exhibiting mild cognitive impairment to Alzheimer’s dementia over time. (Morris, et al., Arch. Neurol., 58, 397-405 (2001); Petersen, et al., Arch.

Neurol., 56, 303-308 (1999)). The term“preventing the progression of mild cognitive impairment to Alzheimer’s disease” includes restraining, slowing, stopping, or reversing the progression of mild cognitive impairment to Alzheimer’s disease in a patient.

As used herein, the terms“treating” or“to treat” includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.

As used herein, the term "patient" refers to a human.

The term“inhibition of production of Abeta peptide” is taken to mean decreasing of in vivo levels of Abeta peptide in a patient.

As used herein, the term“effective amount” refers to the amount or dose of compound of the invention, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.

An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a patient, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

The compounds of the present invention are generally effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.01 to about 20 mg/kg of body weight. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed with acceptable side effects, and therefore the above dosage range is not intended to limit the scope of the invention in any way.

The compounds of the present invention are preferably formulated as

pharmaceutical compositions administered by any route which makes the compound bioavailable, including oral and transdermal routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for

preparing same are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy, L.V. Allen, Editor, 22nd Edition, Pharmaceutical Press, 2012).

The compounds of Formulas I and Ia, or pharmaceutically acceptable salts thereof are particularly useful in the treatment methods of the invention, but certain groups, substituents, and configurations are preferred. The following paragraphs describe such preferred groups, substituents, and configurations. It will be understood that these preferences are applicable both to the treatment methods and to the new compounds of the invention.

Further compounds of the present invention include:

,

and pharmaceutically acceptable salts thereof.

The compound of Formula I wherein the fused bicyclic ring is in the cis configuration, or pharmaceutically acceptable salt thereof, is preferred. For example, one of ordinary skill in the art will appreciate that the hydrogen at position 4a is in the cis configuration relative to the substituted phenyl at position 7a as shown in Scheme A below. In addition, the preferred relative configuration for positions 4a, 5, and 7a are also shown in Scheme A wherein the 1,1-difluoroethyl substituent at position 5 is in the cis configuration relative to the hydrogen at position 4a and the substituted phenyl at position 7a:

Although the present invention contemplates all individual enantiomers and diasteromers, as well as mixtures of the enantiomers of said compounds, including racemates, the compounds with the absolute configuration as set forth below are particularly preferred:

N-[3-[(4aR,5S,7aS)-2-amino-5-(1,1-difluoroethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]oxazin-7a-yl]-4-fluoro-phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide, and pharmaceutically acceptable salts thereof; and

N-[3-[(4aR,5S,7aS)-2-amino-5-(1,1-difluoroethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]oxazin-7a-yl]-4-fluoro-phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide 4-methylbenzenesulfonate

The crystalline form of N-[3-[(4aR,5S,7aS)-2-amino-5-(1,1-difluoroethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]oxazin-7a-yl]-4-fluoro-phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide 4-methylbenzenesulfonate which is characterized by a substantial peak in the X-ray diffraction spectrum, at diffraction angle 2-theta of 4.9° in combination with one or more of the peaks selected from the group consisting of 9.8°, 28.0°, and 14.7°, with a tolerance for the diffraction angles of 0.2 degrees, is further preferred.

One of ordinary skill in the art will appreciate that compounds of the invention can exist in tautomeric forms, as depicted below in Scheme B. When any reference in this application to one of the specific tautomers of the compounds of the invention is given, it is understood to encompass both tautomeric forms and all mixtures thereof.

Additionally, certain intermediates described in the following preparations may contain one or more nitrogen protecting groups. It is understood that protecting groups may be varied as appreciated by one of skill in the art depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example“Greene’s Protective Groups in Organic Synthesis”, Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc.2007).

Individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994).

A pharmaceutically acceptable salt of the compounds of the invention, such as a hydrochloride salt, can be formed, for example, by reaction of an appropriate free base of a compound of the invention and an appropriate pharmaceutically acceptable acid such as hydrochloric acid, p-toluenesulfonic acid, or malonic acid in a suitable solvent such as diethyl ether under standard conditions well known in the art. Additionally, the formation of such salts can occur simultaneously upon deprotection of a nitrogen protecting group. The formation of such salts is well known and appreciated in the art. See, for example, Gould, P.L.,“Salt selection for basic drugs,” International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R.J., et al.“Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4: 427-435 (2000); and Berge, S.M., et al.,“Pharmaceutical Salts,” Journal of

Pharmaceutical Sciences, 66: 1-19, (1977).

Certain abbreviations are defined as follows:“APP” refers to amyloid precursor protein;“AUC” refers to area under the curve;“BSA” refers to Bovine Serum Albumin; “CDI” refers to 1,1’-carbonyldiimidazole;“cDNA” refers to complementary

deoxyribonucleic acid;“CSF” refers to cerebrospinal fluid;“DCC” refers to 1,3-dicyclohexylcarbodiimide;“Deoxo-Fluor®” refers to bis(2-methoxyethyl)aminosulfur trifluoride;“DIC” refers to 1,3-diisopropylcarbodiimide;“DMAP” refers to 4-dimethylaminopyridine;“DMSO” refers to dimethyl sulfoxide;“EBSS” refers to Earle’s Balanced Salt Solution;“EDCI” refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;“ELISA” refers to enzyme-linked immunosorbent assay;“F12” refers to Ham’s F12 medium;“FBS” refers to Fetal Bovine Serum;“Fc” refers to fragment crystallizable;“FLUOLEAD™” refers to 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride;“FRET” refers to fluorescence resonance energy transfer;“HATU” refers to (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate;“HBTU” refers to (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminium

hexafluorophosphate;“HEK” refers to human embryonic kidney;“HF-pyridine” refers to hydrogen fluoride pyridine or Olah’s reagent or poly(pyridine fluoride);“HOAt” refers to 1-hydroxy-7-azabenzotriazole;“HOBT” refers to 1-hydroxylbenzotriazole hydrate;

“IC50” refers to the concentration of an agent that produces 50% of the maximal inhibitory response possible for that agent;“IgG1” refers to immunoglobulin-like domain Fc-gamma receptor;“MEM” refers to Minimum Essential Medium;“PBS” refers to phosphate buffered saline;“p.o.” refers to orally dosing;“PyBOP” refers to (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate);“PyBrOP” refers to bromo-tris-pyrrolidino phosphoniumhexafluorophosphate;“RFU” refers to relative fluorescence unit;“RT-PCR” refers to reverse transcription polymerase chain reaction;“SDS-PAGE” refers to sodium dodecyl sulfate polyacrylamide gel electrophoresis;“SFC” refers to super critical chromatography;“T3P®” refers to propylphosphonic anhydride;“THF” refers to tetrahydrofuran;“TEMPO” refers to (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl; “TMEM” refers to transmembrane protein;“Tris” refers to

tris(hydroxymethyl)aminomethane;“trityl” refers to a group of the formula“(Ph)3C-where Ph refers to a phenyl group;“XtalFluor-E® or DAST difluorosulfinium salt” refers to (diethylamino)difluorosulfonium tetrafluoroborate or N,N-diethyl-S,S-

difluorosulfiliminium tetrafluoroborate; and“XtalFluor-M® or morpho-DAST difluorosulfinium salt” refers to difluoro(morpholino)sulfonium tetrafluoroborate or difluoro-4-morpholinylsulfonium tetrafluoroborate.

The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures known to one of ordinary skill in the art, some of which are illustrated in the schemes, preparations, and examples below. One of ordinary skill in the art recognizes that the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds of the invention, or salts thereof. The products of each step in the schemes below can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention.

In Scheme 1, step A, trimethylsulfonium iodide is treated with an organic base such as n-butyllithium at a temperature of about -50 °C in a solvent such as THF. A protected oxymethyl oxirane, protected with a suitable protecting group, such as a trityl group, is then added to the basic solution at -10 °C and allowed to stir for about 2 hours to give the protected product of Scheme 1, Step A.“PG” is a protecting group developed for the amino group or oxygen group such as carbamates, amides, or ethers. Such protecting groups are well known and appreciated in the art. Alternatively, a diol such as (2S)-but-2-ene-1,2-diol can be selectively protected on one hydroxy using

triphenylmethyl chloride and organic bases such as DMAP and triethylamine in a solvent such as dichloromethane to give the protected product of Scheme 1, Step A. The protected product of Step A is reacted with an Į-haloester such as tert-butoxy

bromoacetate using tetra-N-butylammonium sulfate or other quaternary ammonium salt phase transfer catalysts in a solvent such as toluene and an aqueous inorganic base such as sodium hydroxide at about room temperature to give the compound of Scheme 1, Step B. Such alkylations are well known in the art. Alternatively a base such as 60% sodium hydride in oil with solvents such as N,N-dimethylformamide or THF and a temperature range of 0 to 100 °C can be used to give the protected product of Step B. The tert-butoxy carbonyl acetate is converted to an oxime over a 2-step procedure. A reducing agent such as isobutylaluminum hydride in hexanes is added dropwise at a temperature of about -70 °C followed by the dropwise addition of an aqueous acid such as hydrochloric acid at a temperature of about -60 °C. The work-up is accomplished with an organic extraction to give the intermediate material. This material is dissolved in an organic solvent such as dichloromethane and treated with sodium acetate followed by hydroxylamine

hydrochloride to give the oxime product of Step C. The oxime product of Scheme 1, Step C can be converted to the bicyclic 4,5-dihydroisoxazole product of Step D in a 3+2 cyclization by several methods such as using an aqueous solution of sodium hypochlorite or an alternative oxidant such as N-chlorosuccinimide and in a solvent such as tert-butyl methyl ether, toluene, dichloromethane, or xylene at a temperature of about 10-15 °C or with heating. The 2-fluoro-5-bromo phenyl group can be added to the dihydroisoxazole by generating the organometallic reagent. The organometallic reagent can be generated from 4-bromo-1-fluoro-2-iodo-benzene using halogen-metal exchange with reagents such as n-butyllithium or isopropylmagnesium chloride lithium chloride complex and dropwise addition at a temperature range of about -78 °C to 15 °C in a solvent such as THF. A Lewis acid such as boron trifluoride diethyl etherate is then added to give the product of Scheme 1, Step E.

Alternatively in Scheme 2, the protected product of Scheme 1, Step A, can be treated with 4-(2-chloroacetyl)morpholino and a base such as tetrabutyl ammonium hydrogen sulfate in a solvent such as toluene at a temperature of about 5 °C to give the product of Scheme 2, Step A. The morpholino group can then serve as a leaving group in Scheme 2, Step B. For example, the product of Scheme 2, Step A can be treated with the appropriate Grignard reagent which can be prepared in situ from isopropyl magnesium chloride lithium chloride complex and 4-bromo-1-fluoro-2-iodobenzene or if the appropriate Grignard reagent is available, the reagent can be added directly to the product of Scheme 2, Step A at a temperature of about 5 °C to give the product of Scheme 2, Step B. The carbonyl acetate can be converted to an oxime with hydroxylamine hydrochloride and sodium acetate with heating to about 50 °C to give the product of Scheme 2, Step C. The oxime product of Scheme 2, Step C can then be converted to the product of Scheme 2, Step D (the same product as Scheme 1, Step E) using hydroquinone in a solvent such as toluene and heating to reflux. The amine product of Scheme 2, Step D can be protected with an acetyl using acetyl chloride using an organic base such as DMAP and pyridine in a solvent such as dichloromethane at a temperature of about 0-5 °C to give the product of Scheme 2, Step E. The product of Scheme 2, Step E can then be converted to the product of Scheme 3, Step A as discussed below.

The product of Scheme 2, Step E, can be selectively deprotected at the hydroxy using acidic conditions such as adding p-toluenesulfonic acid monohydrate or formic acid in solvents such as methanol and dichloromethane to give the product of Scheme 3, Step A. In an alternate route, the isoxazole nitrogen of the compound of Scheme 2, Step D, can be protected with an acetyl group and the protecting group of the hydroxy methyl can be removed in a two-step procedure. For example, the compound of Scheme 2, Step D is treated with an organic base such as DMAP and pyridine in a solvent such as

dichloromethane and acetyl chloride is added. The temperature is maintained below about 10 °C and then allowed to stir at about room temperature. The reaction is diluted with water and extracted with a solvent such as dichloromethane. The organic extracts are washed with an aqueous acid such as 1 N hydrochloric acid and the aqueous extracted again with a solvent such as dichloromethane followed by an aqueous wash. The organic solvent can be partially removed and an acid such as formic acid or p-toluenesulfonic acid monohydrate in solvents such as dichloromethane and methanol can added to deprotect the hydroxy methyl. The mixture can be stirred at room temperature or heated to a temperature of about 40 °C until deprotection of the hydroxy is complete to give the compound of Scheme 3, Step A. The hydroxy methyl product of Scheme 3, Step A can be oxidized to the carboxylic acid product of Scheme 3, Step B using oxidizing agents such as 2-iodoxxybenzoic acid (IBX) at temperatures of 0-22 °C in a solvent such as DMSO or addition of (diacetoxyiodo)benzene portionwise or all at once in a solvent such as acetonitrile or acetonitrile and water with stirring at a temperature of about 5-25 °C to give the product of Scheme 3, Step B. TEMPO can also be used as a catalyst in the oxidation if preferred. The Weinreb amide can be prepared in Scheme 3, Step C using a coupling agent such as CDI in a portionwise addition or adding at once with a solvent such as dichloromethane, cooling to -20 °C and stirring for about 1 hour and adding N,O-dimethylhydroxylamine hydrochloride portionwise or all at once. An organic base such as triethylamine can also be used to promote the reaction. Further additions of CDI and N,O-dimethylhydroxylamine can be added until complete reaction is observed to give the Weinreb amide product of Scheme 3, Step C. Other coupling agents that could be used include carbodiimides such as DCC, DIC, or EDCI or other uronium or phosphonium salts of non-nucleophilic anions, such as HATU, HBTU, PyBOP, and PyBrOP. The ketone of Scheme 3, Step D can be formed from the Weinreb amide using an

organometallic reagent such as a Grignard reagent or an organolithium reagent in a solvent such as THF. The appropriate Grignard reagent can be added as a solution in

solvents such as ether or 2-methyltetrahydrofuran to the Weinreb amide at a temperature of about -78 °C to 0 °C to give the ketone of Scheme 3, Step D. The ketone of Step D can be converted to a difluoro-methyl group by adding the ketone to XtalFluor-M® in a solvent such as dichloromethane at about -78 °C to room temperature followed by the addition of triethylamine trihydrofluoride dropwise to give the compound of Scheme 3, Step E. Alternatively, the fluorinating reagent such as XtalFluor-M® can be added portionwise to the ketone product of Scheme 3, Step D at a temperature of about -20 °C to 10 °C and followed by the addition of triethylamine trihydrofluoride dropwise to give the product of Scheme 3, Step E. Another alternate procedure using Deoxo-Fluor® and trifluoride diethyl etherate in a solvent such as dichloromethane with stirring for about 2 hours followed by the addition of the ketone of Scheme 3, Step D and triethylamine trihydrofluoride gives the product of Scheme 3, Step E. Other fluorinating agents that may be used which are well known in the art are, diethylaminosulfur trifluoride (also referred to as“DAST”) and XtalFluor-E® with an additive such as triethylamine trihydrofluoride or FLUOLEAD™ using an additive such as HF-pyridine. The acetyl tetrahydroisoxazole can deprotected under acidic conditions well known in the art such as using hydrochloric acid and heating to about 100 °C to give the product of Scheme 3, Step F. The bicyclic tetrahydroisoxazole can be treated with zinc in acetic acid to form the ring opened product of Scheme 3, Step G in a manner analogous to the procedure described in Scheme 1, Step F. The oxazine product of Scheme 3, Step H can be prepared using cyanogen bromide in a solvent such as ethanol and heating to about 85 °C to form the amino oxazine ring product of Step H. The 5-bromo of the phenyl can be displaced with an amino group using copper (I) iodide, L-hydroxyproline, an inorganic base such as potassium carbonate and nitrogen gas with ammonium hydroxide to give the product of Scheme 3, Step I.

In Scheme 4, Step A, the aniline product of Scheme 3, Step I can be coupled with a heteroaromatic carboxylic acid utilizing coupling conditions well known in the art. One skilled in the art will recognize that there are a number of methods and reagents for amide formation resulting from the reaction of carboxylic acids and amines. For example, the reaction of an appropriate aniline with an appropriate acid in the presence of a coupling reagent and an amine base such as diisopropylethylamine or triethylamine, will give a compound of Scheme 4, Step A, Formula I. Coupling reagents include carbodiimides such as DCC, DIC, EDCI, and aromatic oximes such as HOBt and HOAt. Additionally, uronium or phosphonium salts of non-nucleophilic anions such as HBTU, HATU, PyBOP, and PyBrOP or a cyclic phosphoric anhydride such as T3P® can be used in place of the more traditional coupling reagents. Additives such as DMAP may be used to enhance the reaction. Alternatively, the aniline amine can be acylated using the appropriate aromatic acid chloride in the presence of a base such as triethylamine or pyridine to give compounds of Formula Ia.

WE CLAIM:

A compound of the formula:

or a pharmaceutically acceptable salt thereof.

2. The compound or salt according to claim 1 wherein the hydrogen at position 4a is in the cis configuration relative to the substituted phenyl at position 7a:

3. The compound or salt according to either claim 1 or claim 2 wherein the 1,1- difluoroethyl at position 5 is in the cis configuration relative to the hydrogen at position 4a and the substituted phenyl at position 7a:

.

4. The compound or salt thereof according to any one of claims 1 to 3 wherein the compound is N-[3-[(4aR,5S,7aS)-2-amino-5-(1,1-difluoroethyl)-4,4a,5,7- tetrahydrofuro[3,4-d][1,3]oxazin-7a-yl]-4-fluoro-phenyl]-5- (trifluoromethyl)pyridine-2-carboxamide.

5. The salt according to claim 4 which is N-[3-[(4aR,5S,7aS)-2-amino-5-(1,1- difluoroethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]oxazin-7a-yl]-4-fluoro-

phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide 4- methylbenzenesulfonate.

6. The salt according to claim 5 which is crystalline.

7. The salt according to either claim 5 or claim 6 which is characterized by a substantial peak in the X-ray diffraction spectrum, at diffraction angle 2-theta of 4.9° in combination with one or more of the peaks selected from the group consisting of 9.8°, 28.0°, and 14.7°, with a tolerance for the diffraction angles of 0.2 degrees.

8. A method of treating Alzheimer’s disease in a patient in need of such

treatment, comprising administering to the patient an effective amount of a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof.

9. A method of treating the progression of mild cognitive impairment to

Alzheimer’s disease in a patient in need of such treatment, comprising

administering to the patient an effective amount of a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof.

10. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7 for use in therapy.

11. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7 for use in the treatment of Alzheimer’s disease.

12. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7 for use in treating the progression of mild cognitive impairment to Alzheimer’s disease.

13. A pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 with one or more pharmaceutically acceptable carriers, diluents, or excipients.

14. A process for preparing a pharmaceutical composition, comprising admixing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 with one or more pharmaceutically acceptable carriers, diluents, or excipients.