Patent Publication Number: US-9409924-B2

Title: Selective glycosidase inhibitors and uses thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is the U.S. National Stage filing under 35 U.S.C. §371 of International Application No. PCT/CA2012/050433, filed Jun. 27, 2012, which claims the benefit of U.S. Provisional Application No. 61/501,377, filed Jun. 27, 2011. 
    
    
     FIELD OF THE INVENTION 
     This application relates to compounds which selectively inhibit glycosidases and uses thereof. 
     BACKGROUND OF THE INVENTION 
     A wide range of cellular proteins, both nuclear and cytoplasmic, are post-translationally modified by the addition of the monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine) which is attached via an O-glycosidic linkage. 1  This modification is generally referred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzyme responsible for post-translationally linking β-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues of numerous nucleocytoplasmic proteins is O-GlcNAc transferase (OGT). 2-5  A second enzyme, known as glycoprotein 2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase) 6,7  removes this post-translational modification to liberate proteins making the O-GlcNAc-modification a dynamic cycle occurring several times during the lifetime of a protein. 8    
     O-GlcNAc-modified proteins regulate a wide range of vital cellular functions including, for example, transcription, 9-12  proteasomal degradation, 13  and cellular signaling. 14  O-GlcNAc is also found on many structural proteins. 15-17  For example, it has been found on a number of cytoskeletal proteins, including neurofilament proteins, 18,19  synapsins, 6,20  synapsin-specific clathrin assembly protein AP-3, 7  and ankyrinG. 14  O-GlcNAc modification has been found to be abundant in the brain. 21,22  It has also been found on proteins clearly implicated in the etiology of several diseases including Alzheimer&#39;s disease (AD) and cancer. 
     For example, it is well established that AD and a number of related tauopathies including Downs&#39; syndrome, Pick&#39;s disease, Niemann-Pick Type C disease, and amyotrophic lateral sclerosis (ALS) are characterized, in part, by the development of neurofibrillary tangles (NFTs). These NFTs are aggregates of paired helical filaments (PHFs) and are composed of an abnormal form of the cytoskeletal protein “tau”. Normally tau stabilizes a key cellular network of microtubules that is essential for distributing proteins and nutrients within neurons. In AD patients, however, tau becomes hyperphosphorylated, disrupting its normal functions, forming PHFs and ultimately aggregating to form NFTs. Six isoforms of tau are found in the human brain. In AD patients, all six isoforms of tau are found in NFTs, and all are markedly hyperphosphorylated. 23,24  Tau in healthy brain tissue bears only 2 or 3 phosphate groups, whereas those found in the brains of AD patients bear, on average, 8 phosphate groups. 25,26  A clear parallel between NFT levels in the brains of AD patients and the severity of dementia strongly supports a key role for tau dysfunction in AD. 27-29  The precise causes of this hyperphosphorylation of tau remain elusive. Accordingly, considerable effort has been dedicated toward: a) elucidating the molecular physiological basis of tau hyperphosphorylation; 30  and b) identifying strategies that could limit tau hyperphosphorylation in the hope that these might halt, or even reverse, the progression of Alzheimer&#39;s disease 31-34  Thus far, several lines of evidence suggest that up-regulation of a number of kinases may be involved in hyperphosphorylation of tau, 21,35,36  although very recently, an alternative basis for this hyperphosphorylation has been advanced. 21    
     In particular, it has emerged that phosphate levels of tau are regulated by the levels of O-GlcNAc on tau. The presence of O-GlcNAc on tau has stimulated studies that correlate O-GlcNAc levels with tau phosphorylation levels. The interest in this field stems from the observation that O-GlcNAc modification has been found to occur on many proteins at amino acid residues that are also known to be phosphorylated. 37-39  Consistent with this observation, it has been found that increases in phosphorylation levels result in decreased O-GlcNAc levels and conversely, increased O-GlcNAc levels correlate with decreased phosphorylation levels. 40  This reciprocal relationship between O-GlcNAc and phosphorylation has been termed the “Yin-Yang hypothesis” 41  and has gained strong biochemical support by the discovery that the enzyme OGT 4  forms a functional complex with phosphatases that act to remove phosphate groups from proteins. 42  Like phosphorylation, O-GlcNAc is a dynamic modification that can be removed and reinstalled several times during the lifespan of a protein. Suggestively, the gene encoding O-GlcNAcase has been mapped to a chromosomal locus that is linked to AD. 7,43  Hyperphosphorylated tau in human AD brains has markedly lower levels of O-GlcNAc than are found in healthy human brains. 21  It has been shown that O-GlcNAc levels of soluble tau protein from human brains affected with AD are markedly lower than those from healthy brain. 21  Furthermore, PHF from diseased brain was suggested to lack completely any O-GlcNAc modification whatsoever. 21  The molecular basis of this hypoglycosylation of tau is not known, although it may stem from increased activity of kinases and/or dysfunction of one of the enzymes involved in processing O-GlcNAc. Supporting this latter view, in both PC-12 neuronal cells and in brain tissue sections from mice, a nonselective N-acetylglucosamindase inhibitor was used to increase tau O-GlcNAc levels, whereupon it was observed that phosphorylation levels decreased. 21  The implication of these collective results is that by maintaining healthy O-GlcNAc levels in AD patients, such as by inhibiting the action of O-GlcNAcase, one should be able to block hyperphosphorylation of tau and all of the associated effects of tau hyperphosphorylation, including the formation of NFTs and downstream effects. However, because the proper functioning of the β-hexosaminidases is critical, any potential therapeutic intervention for the treatment of AD that blocks the action of O-GlcNAcase would have to avoid the concomitant inhibition of both hexosaminidases A and B. 
     Neurons do not store glucose and therefore the brain relies on glucose supplied by blood to maintain its essential metabolic functions. Notably, it has been shown that within brain, glucose uptake and metabolism decreases with aging. 44  Within the brains of AD patients marked decreases in glucose utilization occur and are thought to be a potential cause of neurodegeneration. 45  The basis for this decreased glucose supply in AD brain 46-48  is thought to stem from any of decreased glucose transport, 49,50  impaired insulin signaling, 51,52  and decreased blood flow. 53    
     In light of this impaired glucose metabolism, it is worth noting that of all glucose entering into cells, 2-5% is shunted into the hexosamine biosynthetic pathway, thereby regulating cellular concentrations of the end product of this pathway, uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc). 54  UDP-GlcNAc is a substrate of the nucleocytoplasmic enzyme O-GlcNAc transferase (OGT), 2-5  which acts to post-translationally add GlcNAc to specific serine and threonine residues of numerous nucleocytoplasmic proteins. OGT recognizes many of its substrates 55,56  and binding partners 42,57  through its tetratricopeptide repeat (TPR) domains. 58,59  As described above, O-GlcNAcase 6,7  removes this post-translational modification to liberate proteins making the O-GlcNAc-modification a dynamic cycle occurring several times during the lifetime of a protein. 8  O-GlcNAc has been found in several proteins on known phosphorylation sites 10,38,39,60,  including tau and neurofilaments. 61  Additionally, OGT shows unusual kinetic behaviour making it exquisitely sensitive to intracellular UDP-GlcNAc substrate concentrations and therefore glucose supply. 42    
     Consistent with the known properties of the hexosamine biosynthetic pathway, the enzymatic properties of OGT, and the reciprocal relationship between O-GlcNAc and phosphorylation, it has been shown that decreased glucose availability in brain leads to tau hyperphosphorylation. 45  Therefore the gradual impairment of glucose transport and metabolism, whatever its causes, leads to decreased O-GlcNAc and hyperphosphorylation of tau (and other proteins). Accordingly, the inhibition of O-GlcNAcase should compensate for the age related impairment of glucose metabolism within the brains of health individuals as well as patients suffering from AD or related neurodegenerative diseases. 
     These results suggest that a malfunction in the mechanisms regulating tau O-GlcNAc levels may be vitally important in the formation of NFTs and associated neurodegeneration. Good support for blocking tau hyperphosphorylation as a therapeutically useful intervention 62  comes from recent studies showing that when transgenic mice harbouring human tau are treated with kinase inhibitors, they do not develop typical motor defects 34  and, in another case, 33  show decreased levels of insoluble tau. These studies provide a clear link between lowering tau phosphorylation levels and alleviating AD-like behavioural symptoms in a murine model of this disease. Indeed, pharmacological modulation of tau hyperphosphorylation is widely recognized as a valid therapeutic strategy for treating AD and other neurodegenerative disorders. 63    
     Small-molecule O-GlcNAcase inhibitors, to limit tau hyperphosphorylation, have been considered for treatment of AD and related tauopathies. 64  Specifically, the O-GlcNAcase inhibitor thiamet-G has been implicated in the reduction of tau phosphorylation in cultured PC-12 cells at pathologically relevant sites. 64  Moreover, oral administration of thiamet-G to healthy Sprague-Dawley rats has been implicated in reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus. 64    
     There is also a large body of evidence indicating that increased levels of O-GlcNAc protein modification provides protection against pathogenic effects of stress in cardiac tissue, including stress caused by ischemia, hemorrhage, hypervolemic shock, and calcium paradox. For example, activation of the hexosamine biosynthetic pathway (HBP) by administration of glucosamine has been demonstrated to exert a protective effect in animals models of ischemia/reperfusion, 65-71  trauma hemorrhage, 72-74  hypervolemic shock, 75  and calcium paradox. 65,76  Moreover, strong evidence indicates that these cardioprotective effects are mediated by elevated levels of protein O-GlcNAc modification. 65,66,68,71,73,76-79  There is also evidence that the O-GlcNAc modification plays a role in a variety of neurodegenerative diseases, including Parkinson&#39;s disease and Huntington&#39;s disease. 80    
     Humans have three genes encoding enzymes that cleave terminal β-N-acetylglucosamine residues from glycoconjugates. The first of these encodes O-GlcNAcase. O-GlcNAcase is a member of family 84 of glycoside hydrolases that includes enzymes from organisms as diverse as prokaryotic pathogens to humans (for the family classification of glycoside hydrolases see Coutinho, P. M. &amp; Henrissat, B. (1999) Carbohydrate-Active Enzymes server at URL: http://afmb.cnrs-mrs.fr/CAZY/. 81,82  O-GlcNAcase acts to hydrolyse O-GlcNAc off of serine and threonine residues of post-translationally modified proteins. 1,6,7,83,84  Consistent with the presence of O-GlcNAc on many intracellular proteins, the enzyme O-GlcNAcase appears to have a role in the etiology of several diseases including type II diabetes, 14,85  AD, 16,21,86  and cancer. 22,87  Although O-GlcNAcase was likely isolated earlier on, 18,19  about 20 years elapsed before its biochemical role in acting to cleave O-GlcNAc from serine and threonine residues of proteins was understood. 6  More recently O-GlcNAcase has been cloned, 7  partially characterized, 20  and suggested to have additional activity as a histone acetyltransferase. 20  However, little was known about the catalytic mechanism of this enzyme. 
     The other two genes, HEXA and HEXB, encode enzymes catalyzing the hydrolytic cleavage of terminal β-N-acetylglucosamine residues from glycoconjugates. The gene products of HEXA and HEXB predominantly yield two dimeric isozymes, hexosaminidase A and hexosaminidase B, respectively. Hexosaminidase A (αβ), a heterodimeric isozyme, is composed of an α- and a β-subunit. Hexosaminidase B (ββ), a homodimeric isozyme, is composed of two β-subunits. The two subunits, α- and β-, bear a high level of sequence identity. Both of these enzymes are classified as members of family 20 of glycoside hydrolases and are normally localized within lysosomes. The proper functioning of these lysosomal β-hexosaminidases is critical for human development, a fact that is underscored by the tragic genetic illnesses, Tay-Sach&#39;s and Sandhoff diseases which stem from a dysfunction in, respectively, hexosaminidase A and hexosaminidase B. 88  These enzymatic deficiencies cause an accumulation of glycolipids and glycoconjugates in the lysosomes resulting in neurological impairment and deformation. The deleterious effects of accumulation of gangliosides at the organismal level are still being uncovered. 89    
     As a result of the biological importance of these β-N-acetyl-glucosaminidases, small molecule inhibitors of glycosidases 90,93  have received a great deal of attention, 94  both as tools for elucidating the role of these enzymes in biological processes and in developing potential therapeutic applications. The control of glycosidase function using small molecules offers several advantages over genetic knockout studies including the ability to rapidly vary doses or to entirely withdraw treatment. 
     However, a major challenge in developing inhibitors for blocking the function of mammalian glycosidases, including O-GlcNAcase, is the large number of functionally related enzymes present in tissues of higher eukaryotes. Accordingly, the use of non-selective inhibitors in studying the cellular and organismal physiological role of one particular enzyme is complicated because complex phenotypes arise from the concomitant inhibition of such functionally related enzymes. In the case of β-N-acetylglucosaminidases, many compounds that act to block O-GlcNAcase function are non-specific and act potently to inhibit the lysosomal β-hexosaminidases. 
     A few of the better characterized inhibitors of β-N-acetyl-glucosaminidases which have been used in studies of O-GlcNAc post-translational modification within both cells and tissues are streptozotocin (STZ), 2″-methyl-α- D -glucopyrano-[2,1-d]-Δ2′-thiazoline (NAG-thiazoline) and O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenylcarbamate (PUGNAc). 14,95-98    
     STZ has long been used as a diabetogenic compound because it has a particularly detrimental effect on β-islet cells. 99  STZ exerts its cytotoxic effects through both the alkylation of cellular DNA 99,100  as well as the generation of radical species including nitric oxide. 101  The resulting DNA strand breakage promotes the activation of poly(ADP-ribose) polymerase (PARP) 102  with the net effect of depleting cellular NAD+ levels and, ultimately, leading to cell death. 103,104  Other investigators have proposed instead that STZ toxicity is a consequence of the irreversible inhibition of O-GlcNAcase, which is highly expressed within β-islet cells. 95,105  This hypothesis has, however, been brought into question by two independent research groups. 106,107  Because cellular O-GlcNAc levels on proteins increase in response to many forms of cellular stress 108  it seems possible that STZ results in increased O-GlcNAc-modification levels on proteins by inducing cellular stress rather than through any specific and direct action on O-GlcNAcase. Indeed, Hanover and coworkers have shown that STZ functions as a poor and somewhat selective inhibitor of O-GlcNAcase 109  and although it has been proposed by others that STZ acts to irreversibly inhibit O-GlcNAcase, 110  there has been no clear demonstration of this mode of action. More recently, it has been shown that STZ does not irreversibly inhibit O-GlcNAcase. 111    
     NAG-thiazoline has been found to be a potent inhibitor of family 20 hexosaminidases, 93,112  and more recently, the family 84 O-GlcNAcases. 111  Despite its potency, a downside to using NAG-thiazoline in a complex biological context is that it lacks selectivity and therefore perturbs multiple cellular processes. 
     PUGNAc is another compound that suffers from the same problem of lack of selectivity, yet has enjoyed use as an inhibitor of both human O-GlcNAcase 6,113  and the family 20 human β-hexosaminidases. 114  This molecule, developed by Vasella and coworkers, was found to be a potent competitive inhibitor of the β-N-acetyl-glucosaminidases from  Canavalia ensiformis, Mucor rouxii , and the β-hexosaminidase from bovine kidney. 91  It has been demonstrated that administration of PUGNAc in a rat model of trauma hemorrhage decreases circulating levels of the pro-inflammatory cytokines TNF-α and IL-6. 115  It has also been shown that administration of PUGNAc in a cell-based model of lymphocyte activation decreases production of the cytokine IL-2. 116  Subsequent studies have indicated that PUGNAc can be used in an animal model to reduce myocardial infarct size after left coronary artery occlusions. 117  Of particular significance is the fact that elevation of O-GlcNAc levels by administration of PUGNAc, an inhibitor of O-GlcNAcase, in a rat model of trauma hemorrhage improves cardiac function. 115,118  In addition, elevation of O-GlcNAc levels by treatment with PUGNAc in a cellular model of ischemia/reperfusion injury using neonatal rat ventricular myocytes improved cell viability and reduced necrosis and apoptosis compared to untreated cells. 119    
     More recently, it has been suggested that the selective O-GlcNAcase inhibitor NButGT exhibits protective activity in cell-based models of ischemia/reperfusion and cellular stresses, including oxidative stress. 120  This study suggests the use of O-GlcNAcase inhibitors to elevate protein O-GlcNAc levels and thereby prevent the pathogenic effects of stress in cardiac tissue. 
     International patent applications PCT/CA2006/000300, filed 1 Mar. 2006, published under No. WO 2006/092049 on 8 Sep. 2006; PCT/CA2007/001554, filed 31 Aug. 2007, published under No. WO 2008/025170 on 6 Mar. 2008; PCT/CA2009/001087, filed 31 Jul. 2009, published under No. WO 2010/012106 on 4 Feb. 2010; PCT/CA2009/001088, filed 31 Jul. 2009, published under WO 2010/012107 on 4 Feb. 2010; PCT/CA2009/001302, filed 16 Sep. 2009, published under WO 2010/037207 on 8 Apr. 2010; PCT/CA2011/000548, filed 10 May 2011, published under No. WO 2011/140640 on 17 Nov. 2011; PCT/CA/2011/001241, filed 8 Nov. 2011, published under WO 2012/061927 on 18 May 2012; and PCT/US2011/059668, filed 8 Nov. 2011, published under WO 2012/064680 on 18 May 2012, describe selective inhibitors of O-GlcNAcase. 
     SUMMARY OF THE INVENTION 
     The invention provides, in part, compounds for selectively inhibiting glycosidases, prodrugs of the compounds, uses of the compounds and the prodrugs, pharmaceutical compositions including the compounds or prodrugs of the compounds, and methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, and/or accumulation or deficiency of O-GlcNAc. 
     In one aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where R 1  and R 2  may be independently H or F; R 3  may be OR 5  and R 4  may be H, or R 3  may be H and R 4  may be OR 5 ; each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F. 
     In alternative embodiments, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where R 1  may be H and R 2  may be F, or R 1  may be F and R 2  may be H; R 3  may be OR 5  and R 4  may be H, or R 3  may be H and R 4  may be OR 5 ; each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F. 
     In alternative embodiments, the invention provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where R 1  may be H and R 2  may be F, or R 1  may be F and R 2  may be H; each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F. 
     In alternative embodiments, the invention provides a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where R 1  and R 2  may be independently H or F; each R 5  may be independently H or C 1-6  acyl; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl. 
     In alternative embodiments, the invention provides a compound of Formula (Ic) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where each R 5  may be independently H or C 1-6  acyl; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl. 
     In alternative embodiments, the invention provides a compound of Formula (Id) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F. 
     In alternative embodiments, the invention provides a compound of Formula (Ie) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F. 
     In alternative embodiments, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where R 1  and R 2  may be independently H or F; R 3  may be OR 5  and R 4  may be H, or R 3  may be H and R 4  may be OR 5 ; each R 5  may be independently H or acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen optionally substituted from one up to the maximum number of substituents with fluoro and OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with fluoro and OH; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy; and two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring; where when R 6  is OR 5 , then R 7  is other than F. 
     In alternative embodiments, the compound may be a prodrug; the compound may selectively inhibit an O-glycoprotein 2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase); the compound may selectively bind an O-GlcNAcase (e.g., a mammalian O-GlcNAcase); the compound may selectively inhibit the cleavage of a 2-acetamido-2-deoxy-β-D-glucopyranoside (O-GlcNAc); the compound may not substantially inhibit a mammalian β-hexosaminidase. 
     In alternative embodiments, a compound according to Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Formula (Ie) may have enhanced permeability. 
     In alternative aspects, the invention provides a pharmaceutical composition including a compound according to the invention, in combination with a pharmaceutically acceptable carrier. 
     In alternative aspects, the invention provides methods of selectively inhibiting an O-GlcNAcase, or of inhibiting an O-GlcNAcase in a subject in need thereof, or of increasing the level of O-GlcNAc, or of treating a neurodegenerative disease, a tauopathy, cancer or stress, in a subject in need thereof, by administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where R 1  and R 2  may be independently H or F; R 3  may be OR 5  and R 4  may be H, or R 3  may be H and R 4  may be OR 5 ; each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F. The condition may be Alzheimer&#39;s disease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment (ALSci), Argyrophilic grain dementia, Bluit disease, Corticobasal degeneration (CBD), Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down&#39;s syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), Multiple system atrophy, Myotonic dystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigral degeneration, Parkinsonism-dementia complex of Guam, Pick&#39;s disease (PiD), Post-encephalitic parkinsonism (PEP), Prion diseases (including Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Fatal Familial Insomnia, and Kuru), Progressive supercortical gliosis, Progressive supranuclear palsy (PSP), Richardson&#39;s syndrome, Subacute sclerosing panencephalitis, Tangle-only dementia, Huntington&#39;s disease, Parkinson&#39;s disease, Schizophrenia, Mild Cognitive Impairment (MCI), Neuropathy (including peripheral neuropathy, autonomic neuropathy, neuritis, and diabetic neuropathy), or Glaucoma. The stress may be a cardiac disorder, e.g., ischemia; hemorrhage; hypovolemic shock; myocardial infarction; an interventional cardiology procedure; cardiac bypass surgery; fibrinolytic therapy; angioplasty; or stent placement. 
     In alternative aspects, the invention provides a method of treating an O-GlcNAcase-mediated condition that excludes a neurodegenerative disease, a tauopathy, cancer or stress, in a subject in need thereof, by administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where R 1  and R 2  may be independently H or F; R 3  may be OR 5  and R 4  may be H, or R 3  may be H and R 4  may be OR 5 ; each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F. In some embodiments, the condition may be inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, atherosclerosis, interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren&#39;s syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Guillain-Barré syndrome, systemic lupus erythematosus, myastenia gravis, glomerulonephritis, autoimmune thyroiditis, graft rejection, including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn&#39;s disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myotis, and eosiniphilic fasciitis; graft rejection, in particular but not limited to solid organ transplants, such as heart, lung, liver, kidney, and pancreas transplants (e.g. kidney and lung allografts); epilepsy; pain; fibromyalgia; stroke, e.g., neuroprotection following a stroke. 
     In alternative embodiments, R 1  and R 2  may be independently H or F; R 3  may be OR 5  and R 4  may be H, or R 3  may be H and R 4  may be OR 5 ; each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F. The administering may increase the level of O-GlcNAc in the subject. The subject may be a human. 
     In alternative aspects, the invention provides use of a compound of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     where R 1  and R 2  may be independently H or F; R 3  may be OR 5  and R 4  may be H, or R 3  may be H and R 4  may be OR 5 ; each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F, in the preparation of a medicament. The medicament may be for selectively inhibiting an O-GlcNAcase, for increasing the level of O-GlcNAc, for treating a condition modulated by an O-GlcNAcase, for treating a neurodegenerative disease, a tauopathy, a cancer, or stress. 
     In alternative aspects, the invention provides a method for screening for a selective inhibitor of an O-GlcNAcase, by a) contacting a first sample with a test compound; b) contacting a second sample with a compound of Formula (I) 
     
       
         
         
             
             
         
       
     
     where R 1  and R 2  may be independently H or F; R 3  may be OR 5  and R 4  may be H, or R 3  may be H and R 4  may be OR 5 ; each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F; c) determining the level of inhibition of the O-GlcNAcase in the first and second samples, where the test compound is a selective inhibitor of a O-GlcNAcase if the test compound exhibits the same or greater inhibition of the O-GlcNAcase when compared to the compound of Formula (I). 
     This summary of the invention does not necessarily describe all features of the invention. 
    
    
     DETAILED DESCRIPTION 
     The invention provides, in part, novel compounds that are capable of inhibiting an O-glycoprotein 2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase). In some embodiments, the O-GlcNAcase is a mammalian O-GlcNAcase, such as a rat, mouse or human O-GlcNAcase. 
     In some embodiments, one or more of the compounds according to the invention exhibit enhanced permeability. Permeability can be assessed using a variety of standard experimental techniques, including without limitation in situ perfusion, ex vivo tissue diffusion, in vitro cell monolayers (e.g. Caco-2 cells, MDCK cells, LLC-PK1 cells), and artificial cell membranes (e.g. PAMPA assay); suitable techniques for measuring effective permeability (P eff ) or apparent peameability (P app ) are reviewed for example by Volpe in  The AAPS Journal,  2010, 12(4), 670-678. In some embodiments, one or more of the compounds according to the invention show enhanced permeability when tested in one or more of these assays for determining P eff  or P app . In some embodiments, a compound that exhibits enhanced permeability exhibits greater oral absorption. In some embodiments, a compound that exhibits enhanced permeability exhibits greater brain penetrance when administered in vivo. In some embodiments, a compound that exhibits enhanced permeability achieves higher brain concentrations when administered in vivo. In some embodiments, a compound that exhibits enhanced permeability exhibits a higher brain/plasma concentration ratio when administered in vivo. In some embodiments, “enhanced permeability” means an increase in measured P eff  or P app  by any value between 10% and 100%, or of any integer value between 10% and 100%, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or over 100%, or an increase by 1-fold, 2-fold, or 3-fold, or more, as compared to a suitable reference compound disclosed in for example WO 2006/092049 or WO 2008/025170. A suitable reference compound may be, for example, (3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-2-propyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol, or (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol, or (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3 aH-pyrano[3,2-d]thiazole-6,7-diol. In some embodiments, “enhanced permeability” means a measurable P app  value (i.e. a value greater than zero) in the assay described below for determination of P app  in LLC-PK1 cells. In some embodiments, “enhanced permeability” means a P app  value greater than 2×10 −6  cm/s in the assay described below for determination of P app  in LLC-PK1 cells. In alternative embodiments, “enhanced permeability” means a P app  value in the range 2×10 −6  cm/s to 35×10 −6  cm/s in the assay described below for determination of P app  in LLC-PK1 cells. 
     In some embodiments, a compound according to the invention exhibits superior selectivity in inhibiting an O-GlcNAcase. In some embodiments, one or more of the compounds according to the invention are more selective for an O-GlcNAcase over a β-hexosaminidase. In some embodiments, one or more of the compounds selectively inhibit the activity of a mammalian O-GlcNAcase over a mammalian β-hexosaminidase. In some embodiments, a selective inhibitor of an O-GlcNAcase does not substantially inhibit a β-hexosaminidase. In some embodiments, the β-hexosaminidase is a mammalian β-hexosaminidase, such as a rat, mouse or human β-hexosaminidase. A compound that “selectively” inhibits an O-GlcNAcase is a compound that inhibits the activity or biological function of an O-GlcNAcase, but does not substantially inhibit the activity or biological function of a β-hexosaminidase. For example, in some embodiments, a selective inhibitor of an O-GlcNAcase selectively inhibits the cleavage of 2-acetamido-2-deoxy-β-D-glucopyranoside (O-GlcNAc) from polypeptides. In some embodiments, a selective inhibitor of an O-GlcNAcase selectively binds to an O-GlcNAcase. In some embodiments, a selective inhibitor of an O-GlcNAcase inhibits hyperphosphorylation of a tau protein and/or inhibits formations of NFTs. By “inhibits,” “inhibition” or “inhibiting” means a decrease by any value between 10% and 90%, or of any integer value between 30% and 60%, or over 100%, or a decrease by 1-fold, 2-fold, 5-fold, 10-fold or more. It is to be understood that the inhibiting does not require full inhibition. In some embodiments, a selective inhibitor of an O-GlcNAcase elevates or enhances O-GlcNAc levels e.g., O-GlcNAc-modified polypeptide or protein levels, in cells, tissues, or organs (e.g., in brain, muscle, or heart (cardiac) tissue) and in animals. By “elevating” or “enhancing” is meant an increase by any value between 10% and 90%, or of any integer value between 30% and 60%, or over 100%, or an increase by 1-fold, 2-fold, 5-fold, 10-fold, 15-fold, 25-fold, 50-fold, 100-fold or more. In some embodiments, a selective inhibitor of an O-GlcNAcase exhibits a selectivity ratio, as described herein, in the range 10 to 100000, or in the range 100 to 100000, or in the range 1000 to 100000, or at least 10, 20, 50, 100, 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 10,000, 25,000, 50,000, 75,000, or any value within or about the described range. 
     One or more of the compounds of the present invention elevate O-GlcNAc levels on O-GlcNAc-modified polypeptides or proteins in vivo specifically via interaction with an O-GlcNAcase enzyme, and are effective in treating conditions which require or respond to inhibition of O-GlcNAcase activity. 
     In some embodiments, one or more of the compounds of the present invention are useful as agents that produce a decrease in tau phosphorylation and NFT formation. In some embodiments, one or more of the compounds are therefore useful to treat Alzheimer&#39;s disease and related tauopathies. In some embodiments, one or more of the compounds are thus capable of treating Alzheimer&#39;s disease and related tauopathies by lowering tau phosphorylation and reducing NFT formation as a result of increasing tau O-GlcNAc levels. In some embodiments, one or more of the compounds produce an increase in levels of O-GlcNAc modification on O-GlcNAc-modified polypeptides or proteins, and are therefore useful for treatment of disorders responsive to such increases in O-GlcNAc modification; these disorders include without limitation neurodegenerative, inflammatory, cardiovascular, and immunoregulatory diseases. In some embodiments, a compound is also useful as a result of other biological activities related to their ability to inhibit the activity of glycosidase enzymes. In alternative embodiments, one or more of the compounds of the invention are valuable tools in studying the physiological role of O-GlcNAc at the cellular and organismal level. 
     In alternative embodiments, the invention provides methods of enhancing or elevating levels of protein O-GlcNAc modification in animal subjects, such as, veterinary and human subjects. In alternative embodiments, the invention provides methods of selectively inhibiting an O-GlcNAcase enzyme in animal subjects, such as, veterinary and human subjects. In alternative embodiments, the invention provides methods of inhibiting phosphorylation of tau polypeptides, or inhibiting formation of NFTs, in animal subjects, such as, veterinary and human subjects. 
     In specific embodiments, the invention provides compounds described generally by Formula (I) and the salts, prodrugs, and enantiomeric forms thereof: 
     
       
         
         
             
             
         
       
     
     As set forth in Formula (I): R 1  and R 2  may be independently H or F; R 3  may be OR 5  and R 4  may be H, or R 3  may be H and R 4  may be OR 5 ; each R 5  may be independently H or C 1-6  acyl; R 6  may be H, F, or OR 5 ; R 7  may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen and F optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; R 8  may selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH; or R 7  and R 8  and the carbon atom to which they are attached may join together to form vinyl; and each R 9  may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R 9  groups may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl; where when R 6  is OR 5 , then R 7  is other than F. 
     In some embodiments, R 1  as set forth in Formula (I) may be H or F. In some embodiments, R 1  may be F. 
     In some embodiments, R 2  as set forth in Formula (I) may be H or F. In some embodiments, R 2  may be F. 
     In some embodiments, R 3  as set forth in Formula (I) may be H, OH, or OC(O)R 10 , where R 10  may be H, C 1-6  alkyl, or C 3-6  cycloalkyl. In some embodiments, R 3  may be H or OH. In some embodiments, R 3  may be H. 
     In some embodiments, R 4  as set forth in Formula (I) may be H, OH, or OC(O)R 10 , where R 10  may be H, C 1-6  alkyl, or C 3-6  cycloalkyl. In some embodiments, R 4  may be H or OH. In some embodiments, R 4  may be OH. 
     In some embodiments, R 6  as set forth in Formula (I) may be H, F, OH, or OC(O)R 10 , where R 10  may be H, C 1-6  alkyl, or C 3-6  cycloalkyl. In some embodiments, R 6  may be H or OH. 
     In some embodiments, R 7  as set forth in Formula (I) may be selected from the group consisting of: H, F, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, each excluding hydrogen optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH. In some embodiments, R 7  may be H or CH 3 . 
     In some embodiments, R 8  as set forth in Formula (I) may be selected from the group consisting of: C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-6  cycloalkyl, aryl and heteroaryl, optionally substituted from one up to the maximum number of substituents with one or more of fluoro or OH. In some embodiments, R 8  may be CH 3  or CF 3 . 
     In some embodiments, R 7  and R 8  and the carbon atom to which they are attached as set forth in Formula (I) may join together to form vinyl. 
     In some embodiments, each R 9  as set forth in Formula (I) may be independently selected from the group consisting of: H, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, and C 1-6  alkoxy, where the C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, or C 1-6  alkoxy may be optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl. In some embodiments, each R 9  may be independently H, CH 3 , or CH 2 CH 3 . 
     In some embodiments, the two R 9  groups as set forth in Formula (I) may be connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl. 
     In some embodiments, NR 9   2  as set forth in Formula (I), may be optionally substituted 
                         
where X may be CR 11   2 , NR 11 , O, C═O, O(C═O), (C═O)O, NR 11 (C═O), or (C═O)NR 11 ; where each R 11  may be independently H or C 1-4  alkyl; and n may be an integer between 0 and 3. In some embodiments, NR 9   2  may be optionally substituted 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, morpholin-4-yl, 1-piperizinyl, azetidin-2-one-1-yl, pyrrolidin-2-one-1-yl, or piperid-2-one-1-yl. In some embodiments, NR 9   2  may be
 
     
       
         
         
             
             
         
       
     
     In specific embodiments of the invention, compounds according to Formula (I) include the compounds described in Table 1. 
     
       
         
           
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Example 
                 Name 
                 Structure 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 (3aR,5R,6R,7R,7aR)-7-fluoro-5-((S)- 1-hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2 
                 (3aR,5R,6R,7R,7aR)-7-fluoro-5-((R)- 1-hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3 
                 (3aR,5R,6R,7R,7aR)-2-(ethylamino)- 7-fluoro-5-((S)-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4 
                 (3aR,5R,6R,7R,7aR)-2-(ethylamino)- 7-fluoro-5-((R)-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 5 
                 (3aR,5R,6R,7R,7aR)-2- (dimethylamino)-7-fluoro-5-((S)-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 6 
                 (3aR,5R,6R,7R,7aR)-2- (dimethylamino)-7-fluoro-5-((R)-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7 
                 (3aR,5S,6R,7R,7aR)-2-(ethylamino)- 7-fluoro-5-((R)-2,2,2-trifluoro-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 8 
                 (3aR,5S,6R,7R,7aR)-2-(ethylamino)- 7-fluoro-5-((S)-2,2,2-trifluoro-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 9 
                 (3aR,5S,6R,7R,7aR)-7-fluoro-2- (methylamino)-5-((R)-2,2,2-trifluoro- 1-hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 10 
                 (3aR,5S,6R,7R,7aR)-7-fluoro-2- (methylamino)-5-((S)-2,2,2-trifluoro- 1-hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 11 
                 (3aR,5S,6R,7R,7aR)-2- (dimethylamino)-7-fluoro-5-((R)- 2,2,2-trifluoro-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 12 
                 (3aR,5S,6R,7R,7aR)-2- (dimethylamino)-7-fluoro-5-((S)- 2,2,2-trifluoro-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 13 
                 (3aR,5R,6S,7aR)-2-(ethylamino)-5- ((S)-1-hydroxyethyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 14 
                 (3aR,5R,6S,7aR)-2-(ethylamino)-5- ((R)-1-hydroxyethyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15 
                 (3aR,5R,6R,7R,7aR)-5-ethyl-7-fluoro- 2-(methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 16 
                 (3aR,5R,6S,7aR)-5-((S)-1- hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 17 
                 (3aR,5R,6S,7aR)-5-((R)-1- hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 18 
                 (3aR,5R,6S,7aR)-2-(dimethylamino)- 5-((S)-1-hydroxyethyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 19 
                 (3aR,5R,6S,7aR)-2-(dimethylamino)- 5-((R)-1-hydroxyethyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 20 
                 (3aR,5S,6S,7aR)-2-(methylamino)-5- ((R)-2,2,2-trifluoro-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 21 
                 (3aR,5S,6S,7aR)-2-(methylamino)-5- ((S)-2,2,2-trifluoro-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 22 
                 (3aR,5S,6S,7aR)-2-(dimethylamino)- 5-((R)-2,2,2-trifluoro-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 23 
                 (3aR,5S,6S,7aR)-2-(dimethylamino)- 5-((S)-2,2,2-trifluoro-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 24 
                 (3aR,5S,6R,7R,7aR)-7-fluoro-2- (methylamino)-5-((R)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 25 
                 (3aR,5S,6R,7R,7aR)-7-fluoro-2- (methylamino)-5-((S)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 26 
                 (3aR,5S,6R,7R,7aR)-2-(ethylamino)- 7-fluoro-5-((R)-1,1,1-trifluoro-2- hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 27 
                 (3aR,5S,6R,7R,7aR)-2-(ethylamino)- 7-fluoro-5-((S)-1,1,1-trifluoro-2- hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 28 
                 (3aR,5S,6R,7R,7aR)-2- (dimethylamino)-7-fluoro-5-(1,1,1- trifluoro-2-hydroxypropan-2-yl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 29 
                 (3aR,5S,6S,7aR)-2-(methylamino)-5- ((R)-1,1,1-trifluoro-2-hydroxypropan- 2-yl)-5,6,7,7a-tetrahydro-3aH- pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 30 
                 (3aR,5S,6S,7aR)-2-(methylamino)-5- ((S)-1,1,1-trifluoro-2-hydroxypropan- 2-yl)-5,6,7,7a-tetrahydro-3aH- pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 31 
                 (3aR,5R,6R,7R,7aR)-2-(azetidin-1- yl)-7-fluoro-5-((S)-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 32 
                 (3aR,5S,6R,7R,7aR)-2-(azetidin-1- yl)-7-fluoro-5-((R)-2,2,2-trifluoro-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 33 
                 (3aR,5R,6R,7R,7aR)-2-amino-7- fluoro-5-((S)-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 34 
                 (3aR,5R,6R,7S,7aR)-7-fluoro-5-((S)- 1-hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 35 
                 (3aR,5R,6R,7S,7aR)-7-fluoro-5-((R)- 1-hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 36 
                 (3aR,5R,6R,7S,7aR)-2-(ethylamino)- 7-fluoro-5-((S)-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 37 
                 (3aR,5R,6R,7S,7aR)-2-(ethylamino)- 7-fluoro-5-((R)-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 38 
                 (3aR,5S,6R,7S,7aR)-7-fluoro-2- (methylamino)-5-((R)-2,2,2-trifluoro- 1-hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 39 
                 (3aR,5S,6R,7S,7aR)-7-fluoro-2- (methylamino)-5-((S)-2,2,2-trifluoro- 1-hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 40 
                 (3aR,5S,6R,7S,7aR)-2-(ethylamino)- 7-fluoro-5-((R)-2,2,2-trifluoro-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 41 
                 (3aR,5S,6R,7S,7aR)-2-(ethylamino)- 7-fluoro-5-((S)-2,2,2-trifluoro-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 42 
                 (3aR,5R,6R,7S,7aR)-5-ethyl-7-fluoro- 2-(methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 43 
                 (3aR,5S,6R,7S,7aR)-7-fluoro-5-(2- hydroxypropan-2-yl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 44 
                 (3aR,5S,6R,7S,7aR)-7-fluoro-2- (methylamino)-5-((S)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 45 
                 (3aR,5S,6R,7S,7aR)-7-fluoro-2- (methylamino)-5-((R)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 46 
                 (3aR,5R,6S,7R,7aR)-7-fluoro-5-((S)- 1-hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 47 
                 (3aR,5R,6S,7R,7aR)-7-fluoro-5-((R)- 1-hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 48 
                 (3aR,5S,6S,7R,7aR)-7-fluoro-2- (methylamino)-5-((R)-2,2,2-trifluoro- 1-hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 49 
                 (3aR,5S,6S,7R,7aR)-7-fluoro-2- (methylamino)-5-((S)-2,2,2-trifluoro- 1-hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 50 
                 (3aR,5R,6S,7S,7aR)-7-fluoro-5-((S)- 1-hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 51 
                 (3aR,5R,6R,7aR)-5-((S)-1- hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 52 
                 (3aR,5R,6R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-((S)-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 53 
                 (3aR,5R,6R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-((R)-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 54 
                 (3aR,5S,6R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-((R)- 2,2,2-trifluoro-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 55 
                 (3aR,5S,6R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-((S)- 2,2,2-trifluoro-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 56 
                 (3aR,5S,6R,7S,7aR)-2-(ethylamino)- 7-fluoro-5-((R)-1,1,1-trifluoro-2- hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 57 
                 (3aR,5S,6R,7S,7aR)-2-(ethylamino)- 7-fluoro-5-((S)-1,1,1-trifluoro-2- hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 58 
                 (3aR,5S,6R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-(1,1,1- trifluoro-2-hydroxypropan-2-yl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 59 
                 (3aR,5R,6R,7S,7aR)-2-(azetidin-1- yl)-7-fluoro-5-((S)-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 60 
                 (3aR,5S,6R,7S,7aR)-2-(azetidin-1-yl)- 7-fluoro-5-((R)-2,2,2-trifluoro-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 61 
                 (3aR,5R,6R,7S,7aR)-7-fluoro-5-((S)- 1-hydroxyethyl)-2-(pyrrolidin-1-yl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 62 
                 (3aR,5S,6R,7S,7aR)-7-fluoro-2- (pyrrolidin-1-yl)-5-((R)-2,2,2- trifluoro-1-hydroxyethyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 63 
                 (3aR,5R,6R,7R,7aR)-7-fluoro-5-((R)- 2-fluoro-1-hydroxyethyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 64 
                 (3aR,5S,6R,7R,7aR)-5-((R)-2,2- difluoro-1-hydroxyethyl)-7-fluoro-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 65 
                 (3aR,5R,5R,7S,7aR)-7-fluoro-5-((R)- 2-fluoro-1-hydroxyethyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 66 
                 (3aR,5S,6R,7S,7aR)-5-((R)-2,2- difluoro-1-hydroxyethyl)-7-fluoro-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 67 
                 (3aR,5R,6R,7R,7aR)-7-fluoro-5-((S)- 1-hydroxypropyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 68 
                 (3aR,5R,6R,7R,7aR)-5-((S)-3,3- difluoro-1-hydroxypropyl)-7-fluoro-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 69 
                 (3aR,5R,6R,7R,7aR)-7-fluoro-2- (methylamino)-5-((S)-3,3,3-trifluoro- 1-hydroxypropyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 70 
                 (3aR,5R,6R,7R,7aR)-5-((S)- cyclopropyl(hydroxy)methyl)-7- fluoro-2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 71 
                 (3aR,5R,6R,7R,7aR)-5-((S)- cyclobutyl(hydroxy)methyl)-7-fluoro- 2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 72 
                 (3aR,5R,6R,7R,7aR)-5-((S)- cylcopentyl(hydroxy)methyl)-7- fluoro-2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 73 
                 (3aR,5R,6R,7S,7aR)-7-fluoro-5-((S)- 1-hydroxypropyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 74 
                 (3aR,5R,6R,7S,7aR)-5-((S)-3,3- difluoro-1-hydroxypropyl)-7-fluoro-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 75 
                 (3aR,5R,6R,7S,7aR)-7-fluoro-2- (methylamino)-5-((S)-3,3,3-trifluoro- 1-hydroxypropyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 76 
                 (3aR,5R,6R,7S,7aR)-5-((S)- cyclopropyl(hydroxy)methyl)-7- fluoro-2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 77 
                 (3aR,5R,6R,7S,7aR)-5-((S)- cyclobutyl(hydroxy)methyl)-7-fluoro- 2-(methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 78 
                 (3aR,5R,6R,7S,7aR)-5-((S)- cyclopentyl(hydroxy)methyl)-7- fluoro-2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 79 
                 (3aR,5R,6R,7S,7aR)-7-fluoro-2- (methylamino)-5-vinyl-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 80 
                 (3aR,5R,6S,7S,7aR)-7-fluoro-2- (methylamino)-5-(2,2,2- trifluoroethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     As will be appreciated by a person skilled in the art, Formula (I) above may also be represented alternatively as follows: 
     
       
         
         
             
             
         
       
     
     As used herein the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. For example, “a compound” refers to one or more of such compounds, while “the enzyme” includes a particular enzyme as well as other family members and equivalents thereof as known to those skilled in the art. 
     Throughout this application, it is contemplated that the term “compound” or “compounds” refers to the compounds discussed herein and includes precursors and derivatives of the compounds, including acyl-protected derivatives, and pharmaceutically acceptable salts of the compounds, precursors, and derivatives. The invention also includes prodrugs of the compounds, pharmaceutical compositions including the compounds and a pharmaceutically acceptable carrier, and pharmaceutical compositions including prodrugs of the compounds and a pharmaceutically acceptable carrier. 
     The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion. 
     “Alkyl” refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation and including, for example, from one to ten carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and which is attached to the rest of the molecule by a single bond. In alternative embodiments, the alkyl group may contain from one to eight carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In alternative embodiments, the alkyl group may contain from one to six carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specifically in the specification, the alkyl group may be optionally substituted by one or more substituents as described herein. Unless stated otherwise specifically herein, it is understood that the substitution can occur on any carbon of the alkyl group. 
     “Alkenyl” refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond and including, for example, from two to ten carbon atoms, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond. In alternative embodiments, the alkenyl group may contain from two to eight carbon atoms, such as 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In alternative embodiments, the alkenyl group may contain from three to six carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specifically in the specification, the alkenyl group may be optionally substituted by one or more substituents as described herein. Unless stated otherwise specifically herein, it is understood that the substitution can occur on any carbon of the alkenyl group. 
     “Alkynyl” refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond and including, for example, from two to ten carbon atoms. In alternative embodiments, the alkynyl group may contain from two to eight carbon atoms, such as 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In alternative embodiments, the alkynyl group may contain from three to six carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specifically in the specification, the alkynyl group may be optionally substituted by one or more substituents as described herein. 
     “Aryl” refers to a phenyl group, an aromatic ring including 6 carbon atoms. Unless stated otherwise specifically herein, the term “aryl” is meant to include aryl groups optionally substituted by one or more substituents as described herein. 
     “Heteroaryl” refers to a single aromatic ring group containing one or more heteroatoms in the ring, for example N, O, S, including for example, 5-6 members, such as 5 or 6 members. Examples of heteroaryl groups include furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, imidazole. Unless stated otherwise specifically herein, the term “heteroaryl” is meant to include heteroaryl groups optionally substituted by one or more substituents as described herein. 
     “Acyl” refers to a group of the formula —C(O)R a , where R a  is a C 1-10  alkyl or a C 1-6  alkyl group or a C 3-15  cycloalkyl group as described herein. The alkyl or cycloalkyl group(s) may be optionally substituted as described herein. 
     “Alkoxy” refers to a group of the formula —OR b , where R b  is a C 1-10  alkyl or a C 1-6  alkyl group as described herein. The alkyl group(s) may be optionally substituted as described herein. 
     “Cycloalkyl” refers to a stable monovalent monocyclic, bicyclic or tricyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having for example from 3 to 15 carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond. In alternative embodiments, the cycloalkyl group may contain from three to six carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless otherwise stated specifically herein, the term “cycloalkyl” is meant to include cycloalkyl groups which are optionally substituted as described herein. 
     In some embodiments, two R 9  groups as set forth in Formula (I) may be connected together with the nitrogen atom to which they are attached to form a ring. In these embodiments, “ring” refers to a stable nitrogen-containing monocyclic group having 3 to 6 members that may be saturated or monounsaturated. In alternative embodiments, the ring may include C, H and N atoms. In other embodiments, the ring may include heteroatoms, for example O and S. Examples of a ring in these embodiments include 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 2,5-dihydro-1H-pyrrol-1-yl, 1-piperidinyl, 1,2,3,6-tetrahydropyridin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 1-piperizinyl, azetidin-2-one-1-yl, pyrrolidin-2-one-1-yl, piperid-2-one-1-yl, 1,2-oxazetidin-2-yl, isoxazolidin-2-yl, and 1,2-oxazinan-2-yl. The ring in these embodiments may be optionally substituted as described herein. 
     “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs one or more times and instances in which it does not. For example, “optionally substituted alkyl” means that the alkyl group may or may not be substituted and that the description includes both substituted alkyl groups and alkyl groups having no substitution, and that said alkyl groups may be substituted one or more times. Examples of optionally substituted alkyl groups include, without limitation, methyl, ethyl, propyl, etc. and including cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; examples of optionally substituted alkenyl groups include allyl, crotyl, 2-pentenyl, 3-hexenyl, 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc. In some embodiments, optionally substituted alkyl and alkenyl groups include C 1-6  alkyls or alkenyls. 
     Therapeutic Indications 
     The invention provides methods of treating conditions that are modulated, directly or indirectly, by an O-GlcNAcase enzyme or by O-GlcNAc-modified protein levels, for example, a condition that is benefited by inhibition of an O-GlcNAcase enzyme or by an elevation of O-GlcNAc-modified protein levels. Such conditions include, without limitation, Glaucoma, Schizophrenia, tauopathies, such as Alzheimer&#39;s disease, neurodegenerative diseases, cardiovascular diseases, diseases associated with inflammation, diseases associated with immunosuppression and cancers. One or more of the compounds of the invention are also useful in the treatment of diseases or disorders related to deficiency or over-expression of O-GlcNAcase or accumulation or depletion of O-GlcNAc, or any disease or disorder responsive to glycosidase inhibition therapy. Such diseases and disorders include, but are not limited to, Glaucoma, Schizophrenia, neurodegenerative disorders, such as Alzheimer&#39;s disease (AD), or cancer. Such diseases and disorders may also include diseases or disorders related to the accumulation or deficiency in the enzyme OGT. Also included is a method of protecting or treating target cells expressing proteins that are modified by O-GlcNAc residues, the dysregulation of which modification results in disease or pathology. The term “treating” as used herein includes treatment, prevention, and amelioration. 
     In alternative embodiments, the invention provides methods of enhancing or elevating levels of protein O-GlcNAc modification in animal subjects, such as, veterinary and human subjects. This elevation of O-GlcNAc levels can be useful for the prevention or treatment of Alzheimer&#39;s disease; prevention or treatment of other neurodegenerative diseases (e.g. Parkinson&#39;s disease, Huntington&#39;s disease); providing neuroprotective effects; preventing damage to cardiac tissue; and treating diseases associated with inflammation or immunosuppression. 
     In alternative embodiments, the invention provides methods of selectively inhibiting an O-GlcNAcase enzyme in animal subjects, such as veterinary and human subjects. 
     In alternative embodiments, the invention provides methods of inhibiting phosphorylation of tau polypeptides, or inhibiting formation of NFTs, in animal subjects, such as, veterinary and human subjects. Accordingly, a compound of the invention may be used to study and treat AD and other tauopathies. 
     In general, the methods of the invention are effected by administering a compound according to the invention to a subject in need thereof, or by contacting a cell or a sample with a compound according to the invention, for example, a pharmaceutical composition comprising a therapeutically effective amount of the compound according to Formula (I). More particularly, they are useful in the treatment of a disorder in which the regulation of O-GlcNAc protein modification is implicated, or any condition as described herein. Disease states of interest include Alzheimer&#39;s disease (AD) and related neurodegenerative tauopathies, in which abnormal hyperphosphorylation of the microtubule-associated protein tau is involved in disease pathogenesis. In some embodiments, a compound may be used to block hyperphosphorylation of tau by maintaining elevated levels of O-GlcNAc on tau, thereby providing therapeutic benefit. 
     The effectiveness of a compound in treating pathology associated with the accumulation of toxic tau species (for example, Alzheimer&#39;s disease and other tauopathies) may be confirmed by testing the ability of a compound to block the formation of toxic tau species in established cellular 121-123  and/or transgenic animal models of disease. 33,34    
     Tauopathies that may be treated with a compound of the invention include: Alzheimer&#39;s disease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment (ALSci), Argyrophilic grain dementia, Bluit disease, Corticobasal degeneration (CBD), Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down&#39;s syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), Multiple system atrophy, Myotonic dystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigral degeneration, Parkinsonism-dementia complex of Guam, Pick&#39;s disease (PiD), Post-encephalitic parkinsonism (PEP), Prion diseases (including Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Fatal Familial Insomnia, and Kuru), Progressive supercortical gliosis, Progressive supranuclear palsy (PSP), Richardson&#39;s syndrome, Subacute sclerosing panencephalitis, Tangle-only dementia, and Glaucoma. 
     One or more of the compounds of this invention are also useful in the treatment of conditions associate with tissue damage or stress, stimulating cells, or promoting differentiation of cells. Accordingly, in some embodiments, a compound of this invention may be used to provide therapeutic benefit in a variety of conditions or medical procedures involving stress in cardiac tissue, including but not limited to: ischemia; hemorrhage; hypovolemic shock; myocardial infarction; an interventional cardiology procedure; cardiac bypass surgery; fibrinolytic therapy; angioplasty; and stent placement. 
     The effectiveness of a compound in treating pathology associated with cellular stress (including ischemia, hemorrhage, hypovolemic shock, myocardial infarction, and other cardiovascular disorders) may be confirmed by testing the ability of a compound to prevent cellular damage in established cellular stress assays, 108,119,120  and to prevent tissue damage and promote functional recovery in animal models of ischemia-reperfusion, 71,117  and trauma-hemorrhage. 73,115,118    
     Compounds that selectively inhibit O-GlcNAcase activity may be used for the treatment of diseases that are associated with inflammation, including but not limited to, inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, atherosclerosis, interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren&#39;s syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Guillain-Barré syndrome, systemic lupus erythematosus, myastenia gravis, glomerulonephritis, autoimmune thyroiditis, graft rejection, including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn&#39;s disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myotis, eosiniphilic fasciitis; and cancers. 
     In addition, compounds that affects levels of protein O-GlcNAc modification may be used for the treatment of diseases associated with immunosuppression, such as in individuals undergoing chemotherapy, radiation therapy, enhanced wound healing and burn treatment, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy) or combination of conventional drugs used in the treatment of autoimmune diseases and graft/transplantation rejection, which causes immunosuppression; or immunosuppression due to congenital deficiency in receptor function or other causes. 
     One or more of the compounds of the invention may be useful for treatment of neurodegenerative diseases, including Parkinson&#39;s disease and Huntington&#39;s disease. Other conditions that may be treated are those triggered, affected, or in any other way correlated with levels of O-GlcNAc post-translational protein modification. It is expected that one or more of the compounds of this invention may be useful for the treatment of such conditions and in particular, but not limited to, the following for which a association with O-GlcNAc levels on proteins has been established: graft rejection, in particular but not limited to solid organ transplants, such as heart, lung, liver, kidney, and pancreas transplants (e.g. kidney and lung allografts); cancer, in particular but not limited to cancer of the breast, lung, prostate, pancreas, colon, rectum, bladder, kidney, ovary; as well as non-Hodgkin&#39;s lymphoma and melanoma; epilepsy, pain, fibromyalgia, or stroke, e.g., for neuroprotection following a stroke. 
     Pharmaceutical &amp; Veterinary Compositions, Dosages, and Administration 
     Pharmaceutical compositions including compounds according to the invention, or for use according to the invention, are contemplated as being within the scope of the invention. In some embodiments, pharmaceutical compositions including an effective amount of a compound of Formula (I) are provided. 
     The compounds of Formula (I) and their pharmaceutically acceptable salts, enantiomers, solvates, and derivatives are useful because they have pharmacological activity in animals, including humans. In some embodiments, one or more of the compounds according to the invention are stable in plasma, when administered to a subject. 
     In some embodiments, a compound according to the invention, or for use according to the invention, may be provided in combination with any other active agents or pharmaceutical compositions where such combined therapy is useful to modulate O-GlcNAcase activity, for example, to treat neurodegenerative, inflammatory, cardiovascular, or immunoregulatory diseases, or any condition described herein. In some embodiments, a compound according to the invention, or for use according to the invention, may be provided in combination with one or more agents useful in the prevention or treatment of Alzheimer&#39;s disease. Examples of such agents include, without limitation,
         acetylcholine esterase inhibitors (AChEIs) such as Aricept® (Donepezil), Exelon® (Rivastigmine), Razadyne® (Razadyne ER®, Reminyl®, Nivalin®, Galantamine), Cognex® (Tacrine), Dimebon, Huperzine A, Phenserine, Debio-9902 SR (ZT-1 SR), Zanapezil (TAK0147), ganstigmine, NP7557, etc.;   NMDA receptor antagonists such as Namenda® (Axura®, Akatinol®, Ebixa®, Memantine), Dimebon, SGS-742, Neramexane, Debio-9902 SR (ZT-1 SR), etc.;   gamma-secretase inhibitors and/or modulators such as Flurizan™ (Tarenflurbil, MPC-7869, R-flurbiprofen), LY450139, MK 0752, E2101, BMS-289948, BMS-299897, BMS-433796, LY-411575, GSI-136, etc.;   beta-secretase inhibitors such as ATG-Z1, CTS-21166, MK-8931, etc.;   alpha-secretase activators, such as NGX267, etc;   amyloid-β aggregation and/or fibrillization inhibitors such as Alzhemed™ (3APS, Tramiprosate, 3-amino-1-propanesulfonic acid), AL-108, AL-208, AZD-103, PBT2, Cereact, ONO-2506PO, PPI-558, etc.;   tau aggregation inhibitors such as methylene blue, etc.;   microtubule stabilizers such as AL-108, AL-208, paclitaxel, etc.;   RAGE inhibitors, such as TTP488, etc.;   5-HT1a receptor antagonists, such as Xaliproden, Lecozotan, etc.;   5-HT4 receptor antagonists, such as PRX-03410, etc.;   kinase inhibitors such as SRN-003-556, amfurindamide, LiCl, AZD1080, NP031112, SAR-502250, etc.   humanized monoclonal anti-Aβ antibodies such as Bapineuzumab (AAB-001), LY2062430, RN1219, ACU-5A5, etc.;   amyloid vaccines such as AN-1792, ACC-001, etc.;   neuroprotective agents such as Cerebrolysin, AL-108, AL-208, Huperzine A, etc.;   L-type calcium channel antagonists such as MEM-1003, etc.;   nicotinic receptor antagonists, such as AZD3480, GTS-21, etc.;   nicotinic receptor agonists, such as MEM 3454, Nefiracetam, etc.;   peroxisome proliferator-activated receptor (PPAR) gamma agonists such as Avandia® (Rosglitazone), etc.;   phosphodiesterase IV (PDE4) inhibitors, such as MK-0952, etc.;   hormone replacement therapy such as estrogen (Premarin), etc.;   monoamine oxidase (MAO) inhibitors such as NS2330, Rasagiline (Azilect®), TVP-1012, etc.;   AMPA receptor modulators such as Ampalex (CX 516), etc.;   nerve growth factors or NGF potentiators, such as CERE-110 (AAV-NGF), T-588, T-817MA, etc.;   agents that prevent the release of luteinizing hormone (LH) by the pituitary gland, such as leuoprolide (VP-4896), etc.;   GABA receptor modulators such as AC-3933, NGD 97-1, CP-457920, etc.;   benzodiazepine receptor inverse agonists such as SB-737552 (S-8510), AC-3933, etc.;   noradrenaline-releasing agents such as T-588, T-817MA, etc.       

     It is to be understood that combination of compounds according to the invention, or for use according to the invention, with Alzheimer&#39;s agents is not limited to the examples described herein, but includes combination with any agent useful for the treatment of Alzheimer&#39;s disease. Combination of compounds according to the invention, or for use according to the invention, and other Alzheimer&#39;s agents may be administered separately or in conjunction. The administration of one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s). 
     In alternative embodiments, a compound may be supplied as a “prodrug” or protected forms, which release the compound after administration to a subject. For example, a compound may carry a protective group which is split off by hydrolysis in body fluids, e.g., in the bloodstream, thus releasing the active compound or is oxidized or reduced in body fluids to release the compound. Accordingly, a “prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term “prodrug” refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a subject. 
     The term “prodrug” is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention where a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and acetamide, formamide, and benzamide derivatives of amine functional groups in one or more of the compounds of the invention and the like. 
     A discussion of prodrugs may be found in “Smith and Williams&#39; Introduction to the Principles of Drug Design,” H. J. Smith, Wright, Second Edition, London (1988); Bundgard, H.,  Design of Prodrugs  (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113 191 (Harwood Academic Publishers, 1991); Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14; or in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated in full by reference herein. 
     Suitable prodrug forms of one or more of the compounds of the invention include embodiments in which one or more R 5  as set forth in Formula (I) is C(O)R, where R is optionally substituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl. In these cases the ester groups may be hydrolyzed in vivo (e.g. in bodily fluids), releasing the active compounds in which each R 5  is H. Preferred prodrug embodiments of the invention include compounds of Formula (I) where one or more R 5  is C(O)CH 3 . 
     Compounds according to the invention, or for use according to the invention, can be provided alone or in combination with other compounds in the presence of a liposome, an adjuvant, or any pharmaceutically acceptable carrier, diluent or excipient, in a form suitable for administration to a subject such as a mammal, for example, humans, cattle, sheep, etc. If desired, treatment with a compound according to the invention may be combined with more traditional and existing therapies for the therapeutic indications described herein. Compounds according to the invention may be provided chronically or intermittently. “Chronic” administration refers to administration of the compound(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. “Intermittent” administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature. The terms “administration,” “administrable,” or “administering” as used herein should be understood to mean providing a compound of the invention to the subject in need of treatment. 
     “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved, for example, by the United States Food and Drug Administration or other governmental agency as being acceptable for use in humans or domestic animals. 
     A compound of the present invention may be administered in the form of a pharmaceutically acceptable salt. In such cases, pharmaceutical compositions in accordance with this invention may comprise a salt of such a compound, preferably a physiologically acceptable salt, which are known in the art. In some embodiments, the term “pharmaceutically acceptable salt” as used herein means an active ingredient comprising compounds of Formula I used in the form of a salt thereof, particularly where the salt form confers on the active ingredient improved pharmacokinetic properties as compared to the free form of the active ingredient or other previously disclosed salt form. 
     A “pharmaceutically acceptable salt” includes both acid and base addition salts. A “pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. 
     A “pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. 
     Thus, the term “pharmaceutically acceptable salt” encompasses all acceptable salts including but not limited to acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartarate, mesylate, borate, methylbromide, bromide, methylnitrite, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutame, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydradamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like. 
     Pharmaceutically acceptable salts of a compound of the present invention can be used as a dosage for modifying solubility or hydrolysis characteristics, or can be used in sustained release or prodrug formulations. Also, pharmaceutically acceptable salts of a compound of this invention may include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. 
     Pharmaceutical formulations will typically include one or more carriers acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment. Suitable carriers are those known in the art for use in such modes of administration. 
     Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner. For parenteral administration, a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds such as those used for vitamin K. For enteral administration, the compound may be administered in a tablet, capsule or dissolved in liquid form. The table or capsule may be enteric coated, or in a formulation for sustained release. Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, gels, hydrogels, or solutions which can be used topically or locally to administer a compound. A sustained release patch or implant may be employed to provide release over a prolonged period of time. Many techniques known to skilled practitioners are described in  Remington: the Science  &amp;  Practice of Pharmacy  by Alfonso Gennaro, 20 th  ed., Williams &amp; Wilkins, (2000). Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of a compound. Other potentially useful parenteral delivery systems for modulatory compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. 
     A compound or a pharmaceutical composition according to the present invention may be administered by oral or non-oral, e.g., intramuscular, intraperitoneal, intravenous, intracisternal injection or infusion, subcutaneous injection, transdermal or transmucosal routes. In some embodiments, a compound or pharmaceutical composition in accordance with this invention or for use in this invention may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc. Implants may be devised which are intended to contain and release such compounds or compositions. An example would be an implant made of a polymeric material adapted to release the compound over a period of time. A compound may be administered alone or as a mixture with a pharmaceutically acceptable carrier e.g., as solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.; injections, drops, suppositories, pessaryies. In some embodiments, compounds or pharmaceutical compositions in accordance with this invention or for use in this invention may be administered by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. 
     A compound of the invention may be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats, and monkeys. However, a compound of the invention can also be used in other organisms, such as avian species (e.g., chickens). One or more of the compounds of the invention may also be effective for use in humans. The term “subject” or alternatively referred to herein as “patient” is intended to be referred to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. However, one or more of the compounds, methods and pharmaceutical compositions of the present invention may be used in the treatment of animals. Accordingly, as used herein, a “subject” may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. The subject may be suspected of having or at risk for having a condition requiring modulation of O-GlcNAcase activity. 
     An “effective amount” of a compound according to the invention includes a therapeutically effective amount or a prophylactically effective amount. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as inhibition of an O-GlcNAcase, elevation of O-GlcNAc levels, inhibition of tau phosphorylation, or any condition described herein. A therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as inhibition of an O-GlcNAcase, elevation of O-GlcNAc levels, inhibition of tau phosphorylation, or any condition described herein. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount. A suitable range for therapeutically or prophylactically effective amounts of a compound may be any integer from 0.1 nM-0.1 M, 0.1 nM-0.05 M, 0.05 nM-15 μM or 0.01 nM-10 μM. 
     In alternative embodiments, in the treatment or prevention of conditions which require modulation of O-GlcNAcase activity, an appropriate dosage level will generally be about 0.01 to 500 mg per kg subject body weight per day, and can be administered in singe or multiple doses. In some embodiments, the dosage level will be about 0.1 to about 250 mg/kg per day. It will be understood that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound used, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the patient undergoing therapy. 
     It is to be noted that dosage values may vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners. The amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. In general, compounds of the invention should be used without causing substantial toxicity, and as described herein, one or more of the compounds exhibit a suitable safety profile for therapeutic use. Toxicity of a compound of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be necessary to administer substantial excesses of the compositions. 
     In the compounds of generic Formula (I), 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 generic Formula (I). For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula (I) 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. 
     Other Uses and Assays 
     A compound of Formula (I) may be used in screening assays for compounds which modulate the activity of glycosidase enzymes, preferably the O-GlcNAcase enzyme. The ability of a test compound to inhibit O-GlcNAcase-dependent cleavage of O-GlcNAc from a model substrate may be measured using any assays, as described herein or known to one of ordinary skill in the art. For example, a fluoresence or UV-based assay known in the art may be used. A “test compound” is any naturally-occurring or artificially-derived chemical compound. Test compounds may include, without limitation, peptides, polypeptides, synthesised organic molecules, naturally occurring organic molecules, and nucleic acid molecules. A test compound can “compete” with a known compound such as a compound of Formula (I) by, for example, interfering with inhibition of O-GlcNAcase-dependent cleavage of O-GlcNAc or by interfering with any biological response induced by a compound of Formula (I). 
     Generally, a test compound can exhibit any value between 10% and 200%, or over 500%, modulation when compared to a compound of Formula (I) or other reference compound. For example, a test compound may exhibit at least any positive or negative integer from 10% to 200% modulation, or at least any positive or negative integer from 30% to 150% modulation, or at least any positive or negative integer from 60% to 100% modulation, or any positive or negative integer over 100% modulation. A compound that is a negative modulator will in general decrease modulation relative to a known compound, while a compound that is a positive modulator will in general increase modulation relative to a known compound. 
     In general, test compounds are identified from large libraries of both natural products or synthetic (or semi-synthetic) extracts or chemical libraries according to methods known in the art. Those skilled in the field of drug discovery and development will understand that the precise source of test extracts or compounds is not critical to the method(s) of the invention. Accordingly, virtually any number of chemical extracts or compounds can be screened using the exemplary methods described herein. Examples of such extracts or compounds include, but are not limited to, plant-, fungal-, prokaryotic- or animal-based extracts, fermentation broths, and synthetic compounds, as well as modification of existing compounds. Numerous methods are also available for generating random or directed synthesis (e.g., semi-synthesis or total synthesis) of any number of chemical compounds, including, but not limited to, saccharide-, lipid-, peptide-, and nucleic acid-based compounds. Synthetic compound libraries are commercially available. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant, and animal extracts are commercially available from a number of sources, including Biotics (Sussex, UK), Xenova (Slough, UK), Harbor Branch Oceanographic Institute (Ft. Pierce, Fla., USA), and PharmaMar, MA, USA. In addition, natural and synthetically produced libraries are produced, if desired, according to methods known in the art, e.g., by standard extraction and fractionation methods. Furthermore, if desired, any library or compound is readily modified using standard chemical, physical, or biochemical methods. 
     When a crude extract is found to modulate inhibition of O-GlcNAcase-dependent cleavage of O-GlcNAc, or any biological response induced by a compound of Formula (I), further fractionation of the positive lead extract is necessary to isolate chemical constituents responsible for the observed effect. Thus, the goal of the extraction, fractionation, and purification process is the careful characterization and identification of a chemical entity within the crude extract having O-GlcNAcase-inhibitory activities. The same assays described herein for the detection of activities in mixtures of compounds can be used to purify the active component and to test derivatives thereof. Methods of fractionation and purification of such heterogeneous extracts are known in the art. If desired, compounds shown to be useful agents for treatment are chemically modified according to methods known in the art. Compounds identified as being of therapeutic, prophylactic, diagnostic, or other value may be subsequently analyzed using a suitable animal model, as described herein on known in the art. 
     In some embodiments, one or more of the compounds are useful in the development of animal models for studying diseases or disorders related to deficiencies in O-GlcNAcase, over-expression of O-GlcNAcase, accumulation of O-GlcNAc, depletion of O-GlcNAc, and for studying treatment of diseases and disorders related to deficiency or over-expression of O-GlcNAcase, or accumulation or depletion of O-GlcNAc. Such diseases and disorders include neurodegenerative diseases, including Alzheimer&#39;s disease, and cancer. 
     Various alternative embodiments and examples of the invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention. 
     EXAMPLES 
     The following examples are intended to illustrate embodiments of the invention and are not intended to be construed in a limiting manner. 
     Abbreviations 
     ABCN=1,1′-azobis(cyclohexane-carbonitrile) 
     AcCl=acetyl chloride 
     AIBN=azobisisobutyronitrile 
     BCl 3 =boron trichloride 
     BnBr=benzyl bromide 
     Bu 4 NI=tetra-n-butylammonium iodide 
     Boc 2 O=di-tert-butyl dicarbonate 
     BzCl=benzoyl chloride 
     DAST=diethylaminosulfur trifluoride 
     DCM=dichloromethane 
     DIPEA=diisopropylethylamine 
     DMAP=4-dimethylaminopyridine 
     DMF=N,N-dimethylformamide 
     DMP=Dess-Martin periodinane 
     DMSO=dimethyl sulfoxide 
     Et 3 N=triethylamine 
     Et 2 O=diethyl ether 
     PMB=pentamethylbenzene 
     TBDMSCl=tert-butyldimethylsilyl chloride 
     TBAF=tetra-n-butylammonium fluoride 
     TMSCF 3 =(trifluoromethyl)trimethylsilane 
     TFA=2,2,2-trifluoroacetic acid 
     THF=tetrahydrofuran 
     thio-CDI=1,1′-thiocarbonyl diimidazole 
     Examples 1 &amp; 2 
     (3aR,5R,6R,7R,7aR)-7-fluoro-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5R,6R,7R,7aR)-7-fluoro-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a suspension of (3aR,5R,6S,7R,7aR)-2-(methylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (8.50 g, 37.0 mmol) in DMF (60 mL) was added DIPEA (2.0 mL), Boc 2 O (23.0 g, 105 mmol) and MeOH (2.0 mL). The mixture was stirred at room temperature for 3 h, and then MeOH (50 mL) was added. The reaction mixture was concentrated under reduced pressure at ˜35° C. The residue was purified on silica gel by flash column chromatography (MeOH/DCM, 1:8), followed by re-crystallization from EtOAc/hexanes, to afford tert-butyl ((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (11.8 g, 96%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.14 (d, J=6.9 Hz, 1H), 4.20 (d, J=6.4 Hz, 1H), 4.11 (d, J=5.6 Hz, 1H), 3.85-3.70 (m, 2H), 3.63-3.55 (m, 1H), 3.31 (s, 3H), 1.53 (s, 9H). 
     To a solution of the above material (11.7 g, 35.1 mmol), DIPEA (10.3 g, 80.0 mmol) and DMAP (0.040 g, 0.33 mmol) in DCM (180 mL), at 0° C., was added BzCl (10.1 g, 72.0 mmol) slowly. After addition the mixture was stirred at room temperature for 5 h. Saturated aqueous NH 4 Cl solution (100 mL) was added, and the organic layer was collected. The aqueous layer was further extracted with DCM (3×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:4 to 1:1), affording ((3aR,5R,6S,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(methyl)amino)-7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate as a white solid (4.20 g, 22%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.01-7.99 (m, 4H), 7.60-7.55 (m, 1H), 7.54-7.50 (m, 1H), 7.45-7.41 (m, 2H), 7.37-7.35 (m, 2H), 6.21 (d, J=7.1 Hz, 1H), 5.23-5.20 (m, 1H), 4.55-4.51 (m, 2H), 4.48-4.42 (m, 2H), 4.15-4.07 (m, 2H), 3.36 (s, 3H), 1.56 (s, 9H). 
     To a solution of the above material (7.91 g, 14.6 mmol) in anhydrous DCM (100 mL) at −78° C. under N 2 , was added DAST (11.8 g, 73.0 mmol). After addition the mixture was stirred at room temperature for 72 h. The reaction mixture was then cooled at −78° C., diluted with DCM (100 mL), and then quenched with saturated aqueous NaHCO 3  (150 mL). The organic layer was collected, and the aqueous was extracted with DCM (2×100 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:4), affording ((3aR,5R,6R,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(methyl)amino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate as a white solid (6.10 g, 77%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.01-7.98 (m, 4H), 7.60-7.56 (m, 1H), 7.56-7.52 (m, 1H), 7.45-7.41 (m, 2H), 7.38-7.35 (m, 2H), 6.19 (d, J=7.2 Hz, 1H), 5.52-5.46 (m, 1H), 5.40-5.28 (m, 1H), 4.61-4.56 (m, 1H), 4.52 (dd, J=3.6, 12.0 Hz, 1H), 4.43 (dd, J=5.7, 12.0 Hz, 1H), 4.03-3.99 (m, 1H), 3.36 (s, 3H), 1.56 (s, 9H). 
     A mixture of the above material (6.10 g, 11.2 mmol) and K 2 CO 3  (1.00 g, 7.25 mmol) in anhydrous MeOH (50 mL) was stirred at room temperature for 3 h. Dry ice was added, and the solvent was removed under reduced pressure. The residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 1:1 to 10:1), affording tert-butyl ((3aR,5R,6R,7R,7aR)-7-fluoro-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (3.25 g, 86%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.06 (d, J=6.8 Hz, 1H), 5.15 (ddd, J=2.4, 4.4, 45.7 Hz, 1H), 4.46-4.41 (m, 1H), 3.96-3.89 (m, 1H), 3.83 (dd, J=3.2, 11.8 Hz, 1H), 3.73 (dd, J=5.4, 11.8 Hz, 1H), 3.46-3.42 (m, 1H), 3.32 (s, 3H), 1.54 (s, 9H). 
     At 0° C., to a solution of the above material (0.880 g, 2.61 mmol) and imidazole (0.354 g, 5.20 mmol) in anhydrous DMF (15 mL) was added TBDMSCl (0.452 g, 3.00 mmol). The mixture was stirred at room temperature for 72 h and diluted with Et 2 O (100 mL) and brine (100 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (50 mL). The combined extract was washed with H 2 O (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:3), affording tert-butyl ((3aR,5R,6R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white foam (1.10 g, 93%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.06 (d, J=6.8 Hz, 1H), 5.19-5.02 (m, 1H), 4.43-4.38 (m, 1H), 3.98-3.93 (m, 1H), 3.85 (dd, J=5.0, 10.6 Hz, 1H), 3.73 (dd, J=5.2, 10.6 Hz, 1H), 3.45-3.43 (m, 1H), 3.34 (s, 3H), 1.54 (s, 9H), 0.89 (s, 9H), 0.08 (s, 6H). 
     At 0° C., to a solution of the above material (1.06 g, 2.35 mmol) and Bu 4 NI (0.087 g, 0.24 mmol) in anhydrous DMF (15 mL) was added NaH (60% in mineral oil, 0.118 g, 2.94 mmol). After addition of NaH, to the reaction mixture was added BnBr (0.703 g, 4.11 mmol). The mixture was stirred at room temperature for 16 h and diluted with Et 2 O (60 mL) and saturated NH 4 Cl (50 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (2×30 mL). The combined extract was washed with brine (40 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:4), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a sticky oil (1.22 g, 96%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.27 (m, 5H), 6.10 (d, J=7.0 Hz, 1H), 5.30-5.16 (m, 1H), 4.80 (d, J=11.0 Hz, 1H), 4.55 (d, J=11.0 Hz, 1H), 4.48-4.42 (m, 1H), 3.88-3.80 (m, 1H), 3.78-3.69 (m, 2H), 3.46-3.44 (m, 1H), 3.31 (s, 3H), 1.53 (s, 9H), 0.89 (s, 9H), 0.04 (s, 6H). 
     At 0° C., to a solution of the above material (1.22 g, 2.25 mmol) in THF (15 mL) was added TBAF (1.0 M in THF, 5.0 mL, 5.0 mmol). After addition the reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc (20 mL) and brine (50 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 1:2), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (0.96 g, 100%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.29 (m, 5H), 6.09 (d, J=6.7 Hz, 1H), 5.32 (ddd, J=1.8, 3.6, 45.4 Hz, 1H), 4.80 (d, J=11.6 Hz, 1H), 4.55 (d, J=11.6 Hz, 1H), 4.53-4.48 (m, 1H), 3.81-3.72 (m, 2H), 3.61-3.55 (m, 1H), 3.49-3.45 (m, 1H), 3.31 (s, 3H), 1.53 (s, 9H). 
     To a solution of the above material (1.50 g, 3.52 mmol) in DCM (40 mL) was added DMP (2.20 g, 5.20 mmol). After stirring at room temperature for 1 h the reaction mixture was diluted with Et 2 O (20 mL), and then concentrated to dryness. Saturated aqueous NaHCO 3  (30 mL) with Na 2 S 2 O 3  (2 g) was added, and the mixture was extracted with EtOAc (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 1:2), affording tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (1.02 g, 68%).  1 H NMR (400 MHz, CDCl 3 ) δ 9.60 (s, 1H), 7.35-7.29 (m, 5H), 6.12 (d, J=7.0 Hz, 1H), 5.39-5.27 (m, 1H), 4.78 (d, J=11.4 Hz, 1H), 4.66 (d, J=11.4 Hz, 1H), 4.57-4.51 (m, 1H), 4.00-3.95 (m, 2H), 3.31 (s, 3H), 1.53 (s, 9H). 
     To a solution of the above material (0.150 g, 0.350 mmol) in anhydrous THF (10 mL) under N 2  was added MeMgBr (1.4 M in THF/toluene, 0.60 mL, 0.84 mmol). After addition the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH 4 Cl (10 mL), and then extracted with EtOAc (3×15 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording mixed tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R &amp; S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as an off-white foam (0.115 g, 75%) with a diastereomeric ratio of 1:3.2 based on  1 H NMR. 
     To the above material (0.115 g, 0.260 mmol) and PMB (0.115 g, 0.777 mmol) in anhydrous DCM (4 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 0.8 mL, 0.8 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath warmed to 0° C. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:12), affording a mixture of the title compounds as a pale yellow solid (0.055 g, 85%). The mixture was then separated on Agilent 1200 by Prep-HPLC (column, C18, 19×50 mm, 5 um; mobile phase, water with 0.03% NH 4 OH, and CH 3 CN (from 3% to 100% in 15 min); dectector, 220 nm), affording (3aR,5R,6R,7R,7aR)-7-fluoro-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (19 mg) and (3aR,5R,6R,7R,7aR)-7-fluoro-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (5.5 mg) both as white solids. Example 1:  1 H NMR (400 MHz, CD 3 OD) δ 6.34 (d, J=6.6 Hz, 1H), 4.83 (td, J=4.2 Hz, 45.4 Hz, 1H), 4.37-4.31 (m, 1H), 4.00-3.91 (m, 2H), 3.31-3.28 (m, 1H), 2.84 (s, 3H), 1.22 (d, J=6.6 Hz, 1H);  13 C NMR (100 MHz, CD 3 OD) δ 164.52 (d, J=1.6 Hz), 96.10 (d, J=177.3 Hz), 90.82 (d, J=3.0 Hz), 77.11 (d, J=3.0 Hz), 73.90 (d, J=25.3 Hz), 69.06 (d, J=23.5 Hz), 62.61, 30.63, 19.90; MS, (ES, m/z) [M+H] +  251.1. Example 2:  1 H NMR (400 MHz, D 2 O) δ 6.29 (d, J=6.9 Hz, 1H), 4.83 (td, J=4.2, 45.4 Hz, 1H), 4.44-4.29 (m, 1H), 4.08-3.91 (m, 1H), 3.89-3.78 (m, 1H), 3.61-3.50 (m, 1H), 2.76 (s, 3H), 1.10 (d, J=6.6 Hz, 3H); MS, (ES, m/z) [M+H] +  251.1. 
     Examples 3 &amp; 4 
     (3aR,5R,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5R,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a suspension of (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (35.0 g, 141 mmol) in DMF (300 mL) cooled at 15° C., was added DIPEA (6.0 mL), Boc 2 O (61.5 g, 282 mmol) and MeOH (6.0 mL). The mixture was stirred at room temperature for 16 h, and then MeOH (50 mL) was added. The reaction mixture was concentrated under reduced pressure at ˜35° C. The residue was purified on silica gel by flash column chromatography (EtOAc/hexanes 1:1, then MeOH/DCM, 1:5), followed by recrystallization from EtOAc/hexanes, to afford tert-butyl ((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate as a white solid (31.5 g, 64% yield).  1 H NMR (400 MHz, CDCl 3 ) δ 6.12 (d, J=6.8 Hz, 1H), 4.23-4.22 (m, 1H), 4.17-4.14 (m, 1H), 3.91-3.86 (m, 2H), 3.81-3.77 (m, 3H), 3.59-3.55 (m, 1H), 3.17-3.16 (m, 1H, OH), 1.53 (s, 9H), 1.16 (t, J=7.0 Hz, 3H). 
     To a solution of the above material (1.64 g, 4.73 mmol), DIPEA (1.34 g, 10.4 mmol) and DMAP (0.010 g, 0.082 mmol) in DCM (50 mL), at 0° C., was added BzCl (1.33 g, 9.50 mmol) slowly. After addition the mixture was stirred at room temperature overnight. Saturated aqueous NH 4 Cl solution (50 mL) was added, and the organic layer was collected. The aqueous layer was further extracted with DCM (2×40 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was separated on silica gel by flash column chromatography (EtOAc/hexanes, 1:4 to 1:2), affording ((3aR,5R,6S,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(ethyl)amino)-7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate as a white solid (0.67 g, 26%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J=8.1 Hz, 4H), 7.57-7.35 (m, 6H), 6.19 (d, J=7.1 Hz, 1H), 5.21 (dd, J=2.8, 9.2 Hz, 1H), 4.56-4.51 (m, 2H), 4.47-4.42 (m, 2H), 4.14-4.10 (m, 1H), 3.99-3.92 (m, 2H), 1.55 (s, 9H), 1.19 (t, J=7.2 Hz, 3H). 
     To a solution of the above material (3.00 g, 5.39 mmol) in anhydrous DCM (30 mL) at −78° C. under N 2 , was added DAST (5.44 g, 33.8 mmol). After addition the mixture was stirred at room temperature for 48 h. The reaction mixture was then cooled at −78° C., diluted with DCM (50 mL), and then quenched with saturated aqueous NaHCO 3  (70 mL). The organic layer was collected, and the aqueous was extracted with DCM (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:4), affording ((3aR,5R,6R,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(ethyl)amino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate as a white solid (2.15 g, 71%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.00-7.98 (m, 4H), 7.59-7.57 (m, 1H), 7.52-7.48 (m, 1H), 7.43-7.39 (m, 2H), 7.37-7.33 (m, 2H), 6.15 (d, J=7.2 Hz, 1H), 5.51-5.43 (m, 1H), 5.38-5.26 (m, 1H), 4.59-4.55 (m, 1H), 4.50 (dd, J=3.6, 12.0 Hz, 1H), 4.41 (dd, J=5.7, 12.0 Hz, 1H), 4.02-3.92 (m, 3H), 1.56 (s, 9H), 1.19 (t, J=7.0 Hz, 3H). 
     A mixture of the above material (2.15 g, 3.85 mmol) and K 2 CO 3  (0.531 g, 3.85 mmol) in anhydrous MeOH (40 mL) was stirred at room temperature for 3 h. Dry ice was added, and the solvent was removed under reduced pressure. The residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 1:1, then 10:1), affording tert-butyl ((3aR,5R,6R,7R,7aR)-7-fluoro-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate as a white solid (1.25 g, 93%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.05 (d, J=6.8 Hz, 1H), 5.24-5.12 (m, 1H), 4.48-4.43 (m, 1H), 3.99-3.82 (m, 4H), 3.73 (dd, J=5.5, 11.4 Hz, 1H), 3.45-3.41 (m, 1H), 1.54 (s, 9H), 1.18 (t, J=7.0 Hz, 3H). 
     At 0° C., to a solution of the above material (1.25 g, 3.58 mmol) and imidazole (0.488 g, 7.16 mmol) in anhydrous DMF (25 mL) was added TBDMSCl (0.583 g, 3.87 mmol). The mixture was stirred at room temperature for 72 h, and then diluted with Et 2 O (100 mL) and brine (100 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (50 mL). The combined extract was washed with H 2 O (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:3), affording tert-butyl ((3aR,5R,6R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate as a colorless sticky oil (1.66 g, 100%).  1 H NMR (500 MHz, CDCl 3 ) δ 6.03 (d, J=6.8 Hz, 1H), 5.10 (ddd, J=2.8, 4.2, 45.5 Hz), 4.43-4.40 (m, 1H), 3.99-3.88 (m, 3H), 3.85 (dd, J=5.0, 10.5 Hz, 1H), 3.71 (dd, J=5.6, 10.5 Hz, 1H), 3.41-3.38 (m, 1H), 2.39 (d, J=5.6 Hz, 1H), 1.54 (s, 9H), 1.17 (t, J=7.0 Hz, 3H), 0.89 (s, 9H), 0.080 (s, 3H), 0.078 (s, 3H). 
     At 0° C., to a solution of the above material (1.63 g, 3.51 mmol) and Bu 4 NI (0.13 g, 0.35 mmol) in anhydrous DMF (15 mL) was added NaH (60% in mineral oil, 0.182 g, 4.56 mmol). After addition of NaH, to the reaction mixture was added BnBr (1.20 g, 7.00 mmol). The mixture was stirred at room temperature for 16 h and diluted with Et 2 O (60 mL) and saturated NH 4 Cl (50 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (2×30 mL). The combined extract was washed with brine (40 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:4), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate as a sticky oil (1.90 g, 98%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.27 (m, 5H), 6.08 (d, J=7.0 Hz, 1H), 5.31-5.18 (m, 1H), 4.79 (d, J=11.5 Hz, 1H), 4.55 (d, J=11.5 Hz, 1H), 4.49-4.43 (m, 1H), 3.92-3.78 (m, 3H), 3.75 (dd, J=2.2, 11.5 Hz, 1H), 3.70 (dd, J=4.5, 11.5 Hz, 1H), 3.41-3.38 (m, 1H), 1.52 (s, 9H), 1.12 (t, J=7.0 Hz, 3H), 0.88 (s, 9H), 0.038 (s, 3H), 0.036 (s, 3H). 
     At 0° C., to a solution of the above material (1.89 g, 3.41 mmol) in THF (20 mL) was added TBAF (1.0 M in THF, 5.0 mL, 5.0 mmol). After addition the reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc (20 mL) and brine (50 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 1:2), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate as a white solid (1.43 g, 95%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.28 (m, 5H), 6.06 (d, J=7.1 Hz, 1H), 5.32 (ddd, J=1.3, 3.1, 45.2 Hz, 1H), 4.79 (d, J=11.6 Hz, 1H), 4.55 (d, J=11.6 Hz, 1H), 4.53-4.48 (m, 1H), 3.91-3.85 (m, 2H), 3.81-3.73 (m, 2H), 3.59-3.55 (m, 1H), 3.46-3.41 (m, 1H), 1.53 (s, 9H), 1.12 (t, J=7.0 Hz, 3H). 
     To a solution of the above material (0.441 g, 1.00 mmol) in DCM (10 mL) was added DMP (0.630 g, 1.49 mmol). After stirring at room temperature for 1.5 h the reaction mixture was diluted with Et 2 O (20 mL), and then concentrated to dryness. Saturated aqueous NaHCO 3  (20 mL) with Na 2 S 2 O 3  (2 g) was added, and the mixture was extracted with EtOAc (2×30 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 1:2), affording tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate as a white solid (0.36 g, 81%).  1 H NMR (400 MHz, CDCl 3 ) δ 9.60 (s, 1H), 7.36-7.27 (m, 5H), 6.11 (d, J=7.0 Hz, 1H), 5.39-5.26 (m, 1H), 4.76 (d, J=11.4 Hz, 1H), 4.66 (d, J=11.4 Hz, 1H), 4.57-4.51 (m, 1H), 3.99-3.93 (m, 1H), 3.93-3.91 (m, 1H), 3.89-3.83 (m, 2H), 1.52 (s, 9H), 1.08 (t, J=7.0 Hz, 3H). 
     To a solution of the above material (0.357 g, 0.85 mmol) in anhydrous THF (10 mL) under N 2  was added MeMgBr (1.4 M in THF/toluene, 1.4 mL, 2.0 mmol). After addition the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH 4 Cl (10 mL), and then extracted with EtOAc (3×15 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-(((R &amp; S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3 aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate was obtained as a white foam (0.22 g, 60%) with a diastereomeric ratio of 1:2.2 based on  1 H NMR. 
     To the above material (0.215 g, 0.473 mmol) and PMB (0.115 g, 0.777 mmol) in anhydrous DCM (4 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 0.8 mL, 0.8 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath warmed to 0° C. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:15), a mixture of the title compounds was obtained as a white solid (0.110 g, 88%). The mixture was then separated on Agilent 1200 Prep-HPLC (column, C18, 19×50 mm, 5 um; mobile phase, water with 0.03% NH 4 OH, and CH 3 CN (from 10% to 45% in 10 min); detector, 220 nm), affording (3aR,5R,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3 aH-pyrano[3,2-d]thiazol-6-ol (45 mg) as a white solid;  1 H NMR (400 MHz, D 2 O) δ 6.25 (d, J=6.6 Hz, 1H), 4.80 (td, J=4.2, 45.4 Hz, 1H), 4.43-4.35 (m, 1H), 4.94-3.83 (m, 2H), 3.27 (dd, J=3.9, 9.3 Hz, 1H), 3.19-3.11 (m, 2H), 1.12 (d, J=6.6 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H); MS, (ES, m/z) [M+H] +  265.0. Also isolated was (3aR,5R,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (30 mg) as a white solid;  1 H NMR (400 MHz, D 2 O) δ 6.28 (d, J=6.6 Hz, 1H), 4.80 (td, J=4.2, 45.4 Hz, 1H), 4.44-4.36 (m, 1H), 4.03-4.00 (m, 1H), 3.98-3.82 (m, 1H), 3.52 (dd, J=3.0, 12.3 Hz, 1H), 3.13-3.20 (m, 2H), 1.11 (d, J=6.9 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H); MS, (ES, m/z) [M+H] +  265.0. 
     Examples 5 &amp; 6 
     (3aR,5R,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5R,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     At 0° C., to a solution of (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5.20 g, 21.0 mmol) and imidazole (8.0 g, 117 mmol) in anhydrous DMF (65 mL) was added TBDMSCl (10.0 g, 66.3 mmol). The mixture was stirred at room temperature for 24 h and diluted with Et 2 O (100 mL) and brine (100 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (100 mL). The combined extract was washed with H 2 O (100 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 1:1), affording (3aR,5R,6R,7R,7aR)-7-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a colorless sticky oil (5.95 g, 60%).  1 H NMR (500 MHz, CDCl 3 ) δ 6.15 (d, J=5.9 Hz, 1H), 4.34-4.33 (m, 1H), 4.21-4.19 (m, 1H), 3.80-3.72 (m, 2H), 3.48-3.47 (m, 1H), 3.01 (s, 6H), 0.897 (s, 9H), 0.893 (s, 9H), 0.124 (s, 3H), 0.120 (s, 3H), 0.068 (s, 6H). 
     At 0° C., to a solution of the above material (5.95 g, 12.5 mmol) and DMAP (0.10 g, 0.81 mmol) in pyridine (50 mL) was added BzCl (3.00 g, 21.3 mmol). The mixture was stirred at room temperature for 24 h and diluted with EtOAc (100 mL) and saturated aqueous NaHCO 3  (100 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (100 mL). The combined extract was washed with H 2 O (100 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated with hexanes under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:4), affording (3aR,5R,6R,7R,7aR)-7-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-yl benzoate as a white solid (6.85 g, 88%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.05-8.02 (m, 2H), 7.56-7.52 (m, 1H), 7.43-7.39 (m, 2H), 6.27 (d, J=6.3 Hz, 1H), 5.06-5.03 (m, 1H), 4.40 (dd, J=2.2, 3.8 Hz, 1H), 4.32-4.30 (m, 1H), 3.82-3.79 (m, 1H), 3.71 (d, J=4.8 Hz, 2H), 3.03 (s, 6H), 0.89 (s, 9H), 0.85 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H), 0.02 (s, 3H), 0.00 (3H). 
     To a solution of the above material (9.30 g, 16.0 mmol) in MeOH (100 mL) was bubbled HCl (g) for 2 min. The reaction mixture was then stirred at room temperature for 2 h. The solvent was removed, and the residue was neutralized with saturated aqueous NaHCO 3  (150 mL). The aqueous was extracted with EtOAc (6×80 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure to afford (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-7-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-yl benzoate as a white solid (5.4 g, 96%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.03-8.01 (m, 2H), 7.56-7.53 (m, 1H), 7.44-7.39 (m, 2H), 6.37 (d, J=4.5 Hz, 1H), 5.12-5.09 (m, 1H), 4.41-4.37 (m, 2H), 3.92-3.89 (m, 1H), 3.78-3.73 (m, 1H), 3.69-3.65 (m, 1H), 3.00 (s, 6H). 
     At 0° C., to a solution of the above material (5.35 g, 15.2 mmol) and DMAP (0.050 g, 0.41 mmol) in pyridine (50 mL) was added BzCl (2.88 g, 15.8 mmol). The mixture was stirred at room temperature for 4 h and diluted with EtOAc (100 mL) and saturated aqueous NaHCO 3  (100 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated with hexanes under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 10:1), affording ((3aR,5R,6S,7R,7aR)-6-(benzoyloxy)-2-(dimethylamino)-7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate as a white solid (4.20 g, 67%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.04-8.00 (m, 4H), 7.58-7.50 (m, 2H), 7.44-7.37 (m, 4H), 6.38 (d, J=6.6 Hz, 1H), 5.23-5.20 (m, 1H), 4.56 (dd, J=3.2, 12.0 Hz, 1H), 4.48-4.41 (m, 3H), 4.27-4.22 (m, 1H), 3.03 (s, 6H). 
     The above material (0.410 g, 0.898 mmol) was converted to the corresponding fluoride via treatment with DAST, using the procedure described for Example 3. The reaction mixture was stirred at room temperature for 16 h. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:3 to 1:2), ((3aR,5R,6R,7R,7aR)-6-(benzoyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate was obtained as a white foam (0.380 g, 92%).  1 H NMR (500 MHz, CDCl 3 ) δ 8.03-8.00 (m, 4H), 7.58-7.55 (m, 1H), 7.44-7.41 (m, 1H), 7.44-7.41 (m, 2H), 7.39-7.36 (m, 2H), 6.36 (d, J=6.8 Hz, 1H), 5.51-5.45 (m, 1H), 5.28-5.19 (m, 1H), 4.69-4.67 (m, 1H), 4.51 (dd, J=3.4, 12.0 Hz, 1H), 4.40 (dd, J=5.9, 12.0 Hz, 1H), 4.13-4.10 (m, 1H), 3.05 (s, 6H). 
     The above material (0.375 g, 0.818 mmol) was deprotected using the procedure described for Example 3. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:12), (3aR,5R,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.190 g, 93%).  1 H NMR (400 MHz, CD 3 OD) δ 6.35 (d, J=6.7 Hz, 1H), 4.78 (td, J=5.0 Hz, 48.1 Hz, 1H), 4.34-4.28 (m, 1H), 3.79 (dd, J=2.0, 12.0 Hz, 1H), 3.77-3.64 (m, 2H), 3.61-3.57 (m, 1H), 3.01 (s, 6H). 
     The above material (1.30 g, 5.19 mmol) was converted to the corresponding silyl ether using the procedure described for Example 3. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:1), (3aR,5R,6R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (1.84 g, 97%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.22 (d, J=6.3 Hz, 1H), 5.07 (ddd, J=2.2, 4.2, 45.8 Hz, 1H), 4.52-4.49 (m, 1H), 3.86-3.81 (m, 1H), 3.78 (d, J=4.8 Hz, 2H), 3.50-3.46 (m, 1H), 3.02 (s, 6H), 0.089 (s, 9H), 0.07 (s, 6H). 
     The above material (1.80 g, 4.94 mmol) was benzyl-protected then the silyl ether was cleaved, using the procedure described for Example 3. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 2:3 to 5:1), ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methanol was obtained as a white solid (2.02 g, 91% over 2 steps).  1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.28 (m, 5H), 6.27 (d, J=6.7 Hz, 1H), 5.21 (ddd, J=2.5, 3.9, 46.1 Hz, 1H), 4.82 (d, J=11.6 Hz, 1H), 4.59-4.53 (m, 1H), 3.77-3.69 (m, 2H), 3.66-3.57 (m, 2H), 3.00 (s, 6H). 
     To a solution of DMSO (0.172 g, 2.20 mmol) in anhydrous DCM (10 mL) at −78° C. under N 2  was added oxalyl chloride (0.261 g, 2.06 mmol) slowly, and the mixture was stirred at ˜−30° C. for 45 min. The mixture was then cooled at −78° C., and a solution of the above material (0.290 g, 0.852 mmol) in anhydrous DCM (5 mL) was added slowly. After stirring at ˜−30° C. for 2 h the reaction mixture was cooled back at −78° C., and Et 3 N (0.334 g, 3.31 mmol) was added. The mixture was stirred at ˜−1-30° C. for another 30 min, and then quenched with H 2 O (20 mL). The organic layer was collected, and the aqueous was extracted with DCM (2×10 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure to give the crude (3aR,5S,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde as pale yellow foam. Under N 2  this aldehyde was dissolved in anhydrous THF (20 mL), and MeMgBr (1.4 M in THF/toluene, 1.5 mL, 2.1 mmol) was added. After addition the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCO 3  (20 mL), and then extracted with EtOAc (3×30 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 2:3 to 5:1), affording mixed (R &amp; S)-1-((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol as a pale yellow solid (0.24 g, 79%) with a diastereomeric ratio of 1:4 based on  1 H NMR. 
     The above material (0.240 g, 0.677 mmol) was deprotected with BCl 3  using the procedure described for Example 3. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:12), a mixture of the title compounds was obtained as a white solid (0.161 g, 90%). The mixture was then separated by Prep-Chiral-HPLC (column, Chiralpak IC (SFC), 2×25 cm, 5 um, Chiral-P(IC)002S09IC00CJ-MI001; mobile phase, phase A, hexane; phase B, ethanol with 0.1% DEA (10% ethanol, 30 min); detector, 220 nm), affording (3aR,5R,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (68 mg) as a white solid;  1 H NMR (400 MHz, D 2 O) δ 6.24 (d, J=6.9 Hz, 1H), 4.79 (td, J=4.2, 45.4 Hz, 1H), 4.41-4.36 (m, 1H), 3.93-3.83 (m, 2H), 3.29-3.24 (m, 1H), 2.90 (s, 6H), 1.13 (d, J=6.6 Hz, 3H); MS, (ES, m/z) [M+H] +  265.0. Also isolated was (3aR,5R,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3 aH-pyrano[3,2-d]thiazol-6-ol (22 mg), as a white solid;  1 H NMR (400 MHz, D 2 O) δ 6.26 (d, J=6.9 Hz, 1H), 4.78 (td, J=4.2, 45.4 Hz, 1H), 4.42-4.34 (m, 1H), 3.99-3.95 (m, 1H), 3.89-3.80 (m, 1H), 3.54-3.50 (m, 1H), 2.91 (s, 6H), 1.14 (d, J=6.6 Hz, 3H). MS, (ES, m/z) [M+H] +  265.0. 
     Examples 7 &amp; 8 
     (3aR,5S,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5R,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.410 g, 0.936 mmol) and TMSCF 3  (0.266 g, 1.87 mmol) in anhydrous THF (8 mL) was added TBAF (1.0 M in THF, 0.040 mL, 0.040 mmol). After addition the reaction mixture was stirred at room temperature for 2 h. Another batch of TBAF (1.0 M in THF, 1.5 mL, 1.5 mmol) was added, and the mixture was stirred at room temperature for another 16 h. The reaction solution was then diluted with EtOAc (20 mL) and brine (30 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (20 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:3), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R &amp; S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate as a pale yellow oil (0.355 g, 75%) with a diastereomeric ratio of 1:1.05 based on  1 H NMR. 
     The above material (0.350 g, 0.688 mmol) was deprotected with BCl 3  using the procedure described for Example 3. Purification and separation on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:15) afforded (3aR,5S,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (0.082 g, 37%) as a white solid;  1 H NMR (400 MHz, CD 3 OD) δ 6.34 (d, J=6.6 Hz, 1H), 4.93-4.78 (m, 1H), 4.39-4.33 (m, 1H), 4.26-4.20 (m, 1H), 4.07-4.00 (m, 1H), 3.79 (d, J=9.6 Hz, 1H), 3.34-3.23 (m, 2H), 1.18 (t, J=7.2 Hz, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 163.67, 126.42 (q, J=281.0 Hz), 96.08 (d, J=177.7 Hz), 90.22 (d, J=1.3 Hz), 73.66 (d, J=25.4 Hz), 71.74-71.67 (m), 69.08 (q, J=30.3 Hz), 68.00 (d, J=24.1 Hz), 39.77, 14.87; MS, (ES, m/z) [M+H] +  319.1. Also isolated was (3aR,5S,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (0.074 g, 34%), as a white solid;  1 H NMR (400 MHz, CD 3 OD) δ 6.28 (d, J=6.6 Hz, 1H), 4.98-4.84 (m, 1H), 4.49-4.43 (m, 1H), 4.12-4.04 (m, 2H), 3.75 (dd, J=5.4, 8.8 Hz, 1H), 3.34-3.23 (m, 2H), 1.18 (t, J=7.2 Hz, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 163.43, 126.14 (q, J=280.8 Hz), 94.24 (d, J=176.5 Hz), 89.42 (d, J=1.4 Hz), 73.84 (d, J=26.3 Hz), 72.91-72.88 (m), 72.10 (q, J=29.9 Hz), 69.74 (d, J=24.7 Hz), 39.87, 14.93; MS, (ES, m/z) [M+H] +  319.1. 
     The following examples were synthesized according to procedures analogous to those described for Examples 7 and 8. 
     
       
         
           
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Example 
                 Structure 
                 Name 
               
               
                   
               
             
            
               
                  9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (3aR,5S,6R,7R,7aR)-7-fluoro-2-(methylamino)-5- ((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
               
               
                   
               
            
           
           
               
            
               
                   1 H NMR (400 MHz, CD 3 OD) δ 6.34 (d, J = 6.5 Hz, 1H), 4.84 (td, J = 4.7, 47.7 Hz, 1H), 
               
               
                 4.34 (td, J = 5.6, 14.0 Hz, 1H), 4.22-4.19 (m, 1H), 4.06-3.97 (m, 1H), 3.77 (d, J = 9.6 
               
               
                 Hz, 1H), 2.85 (s, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 164.48, 126.41 (q, J = 281.2 
               
               
                 Hz), 96.18 (d, J = 177.8 Hz), 90.61 (d, J = 3.4 Hz), 73.81 (d, J = 25.3 Hz), 71.75-71.68 
               
               
                 (m), 69.07 (q, J = 30.3 Hz), 68.00 (d, J = 24.2 Hz), 30.60; MS, (ES, m/z) [M + H] +  305.1. 
               
               
                   
               
            
           
           
               
               
               
            
               
                 10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (3aR,5S,6R,7R,7aR)-7-fluoro-2-(methylamino)-5- ((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
               
               
                   
               
            
           
           
               
            
               
                   1 H NMR (400 MHz, CD 3 OD) δ 6.28 (d, J = 6.6 Hz, 1H), 4.96-4.82 (m, 1H), 4.47-4.42 
               
               
                 (m, 1H), 4.11-4.02 (m, 2H), 3.73 (dd, J = 5.3, 8.8 Hz, 1H), 2.85 (s, 3H);  13 C NMR (100 
               
               
                 MHz, CD 3 OD) δ 164.31, 126.16 (q, J = 280.1 Hz), 94.39 (d, J = 176.6 Hz), 89.78 (d, J = 
               
               
                 1.6 Hz), 74.03 (d, J = 19.9 Hz), 73.01-72.96 (m), 72.06 (q, J = 29.9 Hz), 69.71 (d, J = 
               
               
                 24.7 Hz), 30.74; MS, (ES, m/z) [M + H] +  305.1. 
               
               
                   
               
            
           
         
       
     
     Examples 11 &amp; 12 
     (3aR,5S,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5S,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methanol (0.290 g, 0.852 mmol) was subjected to Swern oxidation as described for Example 5 to provide crude (3aR,5S,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde, which was treated with TMSCF 3  as described for Example 9. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 2:3 to 4:1), tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R &amp; S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(dimethyl)carbamate was obtained as a pale yellow solid (0.230 g, 66%) with a diastereomeric ratio of 1.4:1 based on  1 H NMR. 
     The above material (0.230 g, 0.563 mmol) was deprotected with BCl 3  using the procedure described for Example 3. Purification and separation on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:16) afforded (3aR,5S,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (0.060 g, 33%) as a white solid;  1 H NMR (400 MHz, CD 3 OD) δ 6.36 (d, J=6.6 Hz, 1H), 4.84 (td, J=4.8, 47.8 Hz, 1H), 4.45 (td, J=4.5, 14.0 Hz, 1H), 4.25-4.19 (m, 1H), 4.05-3.97 (m, 1H), 3.76 (d, J=9.6 Hz, 1H), 3.01 (s, 6H);  13 C NMR (100 MHz, CD 3 OD) δ 166.08, 126.42 (q, J=281.1 Hz), 96.22 (d, J=177.9 Hz), 91.23 (d, J=3.5 Hz), 74.13 (d, J=25.3 Hz), 71.87-71.80 (m), 69.04 (q, J=30.3 Hz), 67.97 (d, J=24.1 Hz), 40.38; MS, (ES, m/z) [M+H] +  319.1. Also isolated was (3aR,5S,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (0.074 g, 41%) as a white solid;  1 H NMR (400 MHz, CD 3 OD) δ 6.32 (d, J=6.4 Hz, 1H), 4.90 (ddd, J=3.2, 4.3, 46.2 Hz, 1H), 4.51-4.45 (m, 1H), 4.14-4.04 (m, 2H), 3.74 (dd, J=4.9, 8.8 Hz, 1H), 3.04 (s, 6H);  13 C NMR (100 MHz, CD 3 OD) δ 165.93 (d, J=2.7 Hz), 126.13 (q, J=280.8 Hz), 94.28 (d, J=176.7 Hz), 90.28 (d, J=1.6 Hz), 74.07 (d, J=26.3 Hz), 73.09-73.05 (m), 71.97 (q, J=29.9 Hz), 69.63 (d, J=24.9 Hz), 40.50; MS, (ES, m/z) [M+H] +  319.1. 
     Examples 13 &amp; 14 
     (3aR,5R,6S,7aR)-2-(ethylamino)-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5R,6S,7aR)-2-(ethylamino)-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     A mixture of ((3aR,5R,6S,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(ethyl)amino)-7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate (2.60 g, 4.68 mmol) and thio-CDI (90% tech, 2.0 g, 10.0 mmol) in toluene (60 mL) was stirred at 95° C. for 16 h. After cooling the solvent was removed under reduced pressure, and the residue was purified on automatic flash column chromatography (EtOAc/hexanes, 1:3 to 2:3), affording (3aR,5R,6S,7R,7aR)-7-((1H-imidazole-1-carbonothioyl)oxy)-5-((benzoyloxy)methyl)-2-((tert-butoxycarbonyl)(ethyl)amino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-yl benzoate as a yellow solid (3.00 g, 96%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.76 (s, 1H), 8.08-7.94 (m, 4H), 7.70 (s, 1H), 7.57-7.37 (m, 6H), 7.18 (s, 1H), 6.36 (dd, J=1.9, 3.7 Hz, 1H), 6.17 (d, J=7.1 Hz, 1H), 5.54 (td, J=1.2, 9.2 Hz, 1H), 4.70-4.67 (m, 1H), 4.60 (dd, J=3.2, 12.1 Hz, 1H), 4.42 (dd, J=5.1, 12.1 Hz, 1H), 4.11-4.08 (m, 1H), 4.05-3.97 (m, 2H), 1.56 (s, 9H), 1.22 (t, J=7.2 Hz, 3H). 
     A mixture of the above material (3.00 g, 4.50 mmol), tributyltin hydride (2.91 g, 10.0 mmol) and ABCN (0.085 mg, 0.35 mmol) in mixed anhydrous toluene/THF (30/40 mL) was stirred at reflux for 4 h. After cooling the solvent was removed under reduced pressure, and the residue was purified on automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:3), affording ((3aR,5R,6S,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(ethyl)amino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate as a white solid (1.60 g, 66%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.03-7.94 (m, 4H), 7.57-7.52 (m, 2H), 7.44-7.35 (m, 4H), 6.07 (d, J=7.2 Hz, 1H), 5.44-5.40 (m, 1H), 4.52-4.41 (m, 3H), 4.06-3.96 (m, 3H), 2.70-2.64 (m, 1H), 2.47-2.40 (m, 1H), 1.56 (s, 9H), 1.18 (t, J=7.2 Hz, 3H). 
     The above material (1.6 g, 3.0 mmol) was benzoyl-deprotected with K 2 CO 3  using the procedure described for Example 3. After purification on silica gel by flash column chromatography (MeOH/DCM, 1:20), tert-butyl ethyl((3aR,5R,6S,7aR)-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate (0.86 g, 87%) was obtained as a white solid. 
     The above material (0.820 g, 2.48 mmol) was mono-TBDMS protected using the procedure described for Example 3. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 1:2), tert-butyl ((3aR,5R,6S,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.71 g, 64%) was obtained as a white solid. 
     The above material (0.710 g, 2.24 mmol) was benzyl protected using the procedure described for Example 3. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:4), tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.77 g, 64%) was obtained as a colorless sticky oil. 
     The above material (0.770 g, 1.43 mmol) was silyl-deprotected with TBAF using the procedure described for Example 3. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 1:1), tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate was obtained as a colorless sticky foam (0.61 g, 100%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.33-7.25 (m, 5H), 5.97 (d, J=7.2 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.38 (d, J=11.6 Hz, 1H), 4.36-4.33 (m, 1H), 3.86 (q, J=7.0 Hz, 2H), 3.75-3.71 (m, 2H), 3.60-3.56 (m, 1H), 3.60-3.50 (m, 1H), 2.53-2.49 (m, 1H), 2.06-2.01 (m, 1H), 1.90 (t, J=6.7 Hz, 1H), 1.52 (s, 9H), 1.10 (t, J=7.0 Hz, 3H). 
     At 0° C., to a mixture of the above material (0.098 g, 0.24 mmol), tetrabutylammonium bromide (TBAB) (5.3 mg, 0.017 mmol), 2,2,6,6-tetramethylpiperidine-N-oxyl) (TEMPO) (2.6 mg, 0.017 mmol), NaHCO 3  (0.12 g, 1.2 mmol) in H 2 O/DCM (3/5 mL) was added N-bromosuccinimide (NBS) (0.054 g, 0.30 mmol). The mixture was stirred at ˜12° C. for 30 min, and extracted with DCM (2×10 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:1), affording tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate as an off-white foam (0.075 g, 75%).  1 H NMR (400 MHz, CDCl 3 ) δ 9.61 (s, 1H), 7.35-7.26 (m, 5H), 6.00 (d, J=7.2 Hz, 1H), 4.67 (d, J=11.6 Hz, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.40-4.37 (m, 1H), 4.01-3.98 (m, 2H), 3.85 (q, J=7.0 Hz, 2H), 2.62-2.59 (m, 1H), 2.05-2.01 (m, 1H), 1.52 (s, 9H), 1.08 (t, J=7.0 Hz, 3H). 
     The above material (0.065 g, 0.15 mmol) was treated with MeMgBr using the procedure described for Example 3. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-((R &amp; S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate was obtained as a white foam (0.046 g, 70%) with a diastereomeric ratio of 1:1.3 based on  1 H NMR. 
     The above material (0.170 g, 0.389 mmol) was deprotected with BCl 3  using the procedure described for Example 3. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:14), a mixture of the title compounds was obtained as a white solid (0.084 g, 88%). The mixture was then separated on Agilent 1200 Prep-HPLC (column, C18, 19×50 mm, 5 um; mobile phase, water with 0.03% NH 4 OH, and CH 3 CN (from 10% to 70% in 8 min); detector, 220 nm), affording (3aR,5R,6S,7aR)-2-(ethylamino)-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (26 mg) as a white solid;  1 H NMR (400 MHz, D 2 O) δ 6.20 (d, J=6.3 Hz, 1H), 4.33-4.28 (m, 1H), 3.93-3.85 (m, 2H), 3.40 (dd, J=3.9, 7.8 Hz, 1H), 3.33-3.20 (m, 2H), 2.14-2.04 (m, 2H), 1.20 (d, J=6.6 Hz, 3H), 1.17 (t, J=7.2 Hz, 3H); MS, (ES, m/z) [M+H] +  247.0. Also isolated was (3aR,5R,6S,7aR)-2-(ethylamino)-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (22 mg) as a white solid;  1 H NMR (400 MHz, D 2 O) δ 6.20 (d, J=6.3 Hz, 1H), 4.33-4.31 (m, 1H), 3.95-3.87 (m, 2H), 3.33-3.32 (m, 1H), 3.31-3.19 (m, 2H), 2.12 (t, J=4.8 Hz, 2H), 1.20 (d, J=6.6 Hz, 3H), 1.17 (t, J=7.2 Hz, 3H); MS, (ES, m/z) [M+H] +  247.0. 
     Example 15 
     (3aR,5R,6R,7R,7aR)-5-ethyl-7-fluoro-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     A diastereomeric mixture of tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R &amp; S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.560 g, 1.27 mmol), obtained as described for Example 1, and thio-CDI (90% tech, 0.60 g, 3.3 mmol) in anhydrous DMF (20 mL) was stirred at 95° C. for 5 h. After cooling the solvent was removed under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:3 to 1:1), affording a pale yellow sticky oil. A mixture of the sticky oil, Bu 3 SnH (0.873 g, 3.00 mmol) and ABCN (0.030 g, 0.12 mmol) in anhydrous THF (20 mL) was stirred at reflux for 4 h. After cooling the solvent was removed under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:4), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-5-ethyl-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a colorless oil (0.28 g, 52%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.35-7.27 (m, 5H), 6.09 (d, J=7.3 Hz, 1H), 5.32-5.19 (m, 1H), 4.79 (d, J=11.5 Hz, 1H), 4.52 (d, J=11.5 Hz, 1H), 4.50-4.46 (m, 1H), 3.54-3.47 (m, 1H), 3.31 (s, 3H), 3.30-3.26 (m, 1H), 1.76-1.70 (m, 1H), 1.53 (s, 9H), 1.45-1.37 (m, 1H), 0.89 (t, J=7.4 Hz, 3H). 
     To a solution of the above material (0.280 g, 0.660 mmol) and PMB (0.30 g, 2.0 mmol) in anhydrous DCM (10 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 2.5 mL, 2.5 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath warmed to 0° C. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:15), affording (3aR,5R,6R,7R,7aR)-5-ethyl-7-fluoro-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.099 g, 64%).  1 H NMR (400 MHz, CD 3 OD) δ 6.30 (d, J=6.6 Hz, 1H), 4.72 (dt, J=4.9, 48.0 Hz, 1H), 4.32-4.25 (m, 1H), 3.57-3.49 (m, 1H), 3.42 (dt, J=2.8, 8.8 Hz, 1H), 2.84 (s, 3H), 1.89-1.82 (m, 1H), 1.50-1.42 (m, 1H), 0.94 (t, J=7.4 Hz, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 164.64 (d, J=1.3 Hz), 96.39 (d, J=177.2 Hz), 91.16 (d, J=3.7 Hz), 75.20 (d, J=4.7 Hz), 73.79 (d, J=24.7 Hz), 72.94 (d, J=22.3 Hz), 30.53, 26.30, 10.11; MS, (ES, m/z) [M+H] +  235.1 
     Examples 16 &amp; 17 
     (3aR,5R,6S,7aR)-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5R,6S,7aR)-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     The material described above, 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.180 g, 0.558 mmol), was deprotected with BCl 3  using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:12), (3aR,5R,6S,7aR)-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3 aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.105 g, 81%) and as a mixture of diastereomers. 
     The diastereomeric mixture from above (95 mg, 0.41 mmol) was separated by Prep-HPLC under the following conditions: [(Agilent 1200): Column, X-Bridge C18; mobile phase, 50 mmol/L NH 4 HCO 3  in water with 0.05% NH 4 OH and CH 3 CN(CH 3 CN 5% up to 20% in 10 min); detector, 220 nm UV] to afford (3aR,5R,6S,7aR)-5-(S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (faster eluting isomer, 33.8 mg) as white solid. (ES, m/z): [M+H] +  233.0;  1 H NMR (300 MHz, D 2 O) δ 6.12 (d, J=6.6 Hz, 1H), 4.34-4.39 (m, 1H), 3.88-3.94 (m, 1H), 3.77-3.85 (m, 1H), 3.12-3.16 (m, 1H), 2.76 (s, 3H), 2.04-2.08 (m, 2H), 1.12 (d, J=6.6 Hz, 3H). (3aR,5R,6S,7aR)-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (slower eluting isomer, 21.7 mg) as white solid. (ES, m/z): [M+H] +  233.0;  1 H NMR (300 MHz, D 2 O) δ 6.15 (d, J=6.6 Hz, 1H), 4.36-4.40 (m, 1H), 3.90-3.99 (m, 2H), 3.35-3.39 (m, 1H), 2.78 (s, 3H), 2.01-2.09 (m, 2H), 1.09 (d, J=6.6 Hz, 3H). 
     Examples 18 &amp; 19 
     (3aR,5R,6S,7aR)-2-(dimethylamino)-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5R,6S,7aR)-2-(dimethylamino)-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of (3aR,5S,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde (1.04 g) in anhydrous THF (30 mL) at 0° C. was added a solution of MeMgBr (1.4 M in 1:3 THF/toluene, 5.80 mL, 8.13 mmol) dropwise. The reaction was then stirred at room temperature for 20 h. The mixture was diluted with H 2 O (50 mL), extracted with EtOAc (2×40 mL). The combined extract was dried over anhydrous Na 2 SO 4 . The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 2%-5% 2 M NH 3  MeOH solution in DCM to give 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.840 g, 77%) as a pale yellow foam. MS m/z 337.2 (M+1, 100%);  1 H NMR (400 MHz, CDCl 3 ) shown this was a mixture of two diastereomers with a ratio ˜60:40. 
     To a solution of the above material (0.260 g, 0.774 mmol) in DCM (5 mL) at −78° C. was added a solution of BCl 3  in DCM (1.0 M, 1.55 mL, 1.55 mmol). The mixture was slowly warmed up to room temperature and stirred for 17 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (2 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 2%-5% 2 M NH 3  MeOH solution in DCM to give (3aR,5R,6S,7aR)-2-(dimethylamino)-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (0.086 g, 45%) as a white solid. MS m/z 247.1 (M+1, 100%);  1 H NMR (400 MHz, MeOD) shown this was a mixture of two diastereomers with a ratio ˜60:40. 
     The above mixture (77.3 mg) was separated by Prep-HPLC with the following conditions [(Agilent 1200 prep HPLC; Column: Sun Fire Prep C18, 19*50 mm 5 um; mobile phase: Water with 0.03% NH 4 OH and CH 3 CN (5% CH 3 CN up to 35% in 10 min; dectector: UV 220 nm))] to give (3aR,5R,6S,7aR)-2-(dimethylamino)-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (faster eluting isomer) as a white solid (26.3 mg); [M+H] +  247.1;  1 H NMR (300 MHz, D 2 O) δ 6.22 (d, J=6.9 Hz, 1H), 4.43-4.48 (m, 1H), 3.93-3.97 (m, 1H), 3.80-3.85 (m, 1H), 3.16-3.20 (m, 1H), 3.04 (s, 6H), 2.05-2.12 (m, 2H), 1.13 (d, J=6.6 Hz, 3H); and (3aR,5R,6S,7aR)-2-(dimethylamino)-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (slower eluting isomer) as a white solid (18 mg). [M+H] +  247.1;  1 H NMR (300 MHz, D 2 O) δ 6.23 (d, J=6.9 Hz, 1H), 4.47-4.49 (m, 1H), 3.95-4.05 (m, 1H), 3.91-3.94 (m, 1H), 3.38-3.41 (m, 1H), 3.06 (s, 6H), 1.97-2.12 (m, 2H), 1.08 (d, J=6.3 Hz, 3H). 
     Examples 20 &amp; 21 
     (3aR,5S,6S,7aR)-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5S,6S,7aR)-2-(methylamino)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     A mixture of ((3aR,5R,6S,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(methyl)amino)-7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate (5.00 g, 9.21 mmol) and thio-CDI (90% tech, 3.40 g, 19.1 mmol) in anhydrous DMF (30 mL) was stirred at 95° C. for 4 h. After cooling the solvent was removed under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), affording (3aR,5R,6S,7R,7aR)-7-((1H-imidazole-1-carbonothioyl)oxy)-5-((benzoyloxy)methyl)-2-((tert-butoxycarbonyl)(methyl)amino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-yl benzoate as a pale yellow solid (5.60 g, 93%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.76 (s, 1H), 8.03-8.01 (m, 2H), 7.97-7.95 (m, 2H), 7.64-7.60 (m, 1H), 7.54-7.50 (m, 1H), 7.45 (t, J=7.7 Hz, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.02 (s, 1H), 6.38-6.37 (m, 1H), 6.15 (d, J=7.1 Hz, 1H), 5.56 (td, J=1.2, 9.2 Hz, 1H), 4.70-4.67 (m, 1H), 4.58 (dd, J=3.2, 12.1 Hz, 1H), 4.42 (dd, J=5.1, 12.1 Hz, 1H), 4.08-4.03 (m, 1H), 3.43 (s, 3H), 1.56 (s, 9H). 
     A mixture of the above material (5.60 g, 8.58 mmol), Bu 3 SnH (5.84 g, 17.0 mmol) and ABCN (0.15 g, 0.60 mmol) in mixed anhydrous toluene/THF (50/50 mL) was stirred at 90° C. for 16 h. After cooling the solvent was removed under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording ((3aR,5R,6S,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(methyl)amino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate as a white solid (3.20 g, 71%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.03-7.98 (m, 4H), 7.58-7.49 (m, 2H), 7.44-7.40 (m, 4H), 6.08 (d, J=7.3 Hz, 1H), 5.44-5.40 (m, 1H), 4.49-4.40 (m, 3H), 4.07-4.03 (m, 1H), 3.35 (s, 3H), 2.64-2.59 (m, 1H), 2.44-2.37 (m, 1H), 1.56 (s, 9H). 
     A mixture of the above material (3.20 g, 6.08 mmol) and K 2 CO 3  (0.840 g, 6.08 mmol) in anhydrous MeOH (40 mL) was stirred at room temperature for 3 h. Dry ice was added, and the solvent was removed under reduced pressure. The residue was purified on silica gel by flash column chromatography (MeOH/DCM, 1:50 to 1:20), affording tert-butyl ((3aR,5R,6S,7aR)-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (1.82 g, 94%).  1 H NMR (400 MHz, CDCl 3 ) δ 5.91 (d, J=6.9 Hz, 1H), 4.36-4.32 (m, 1H), 3.89-3.85 (m, 1H), 3.81-3.75 (m, 1H), 3.65-3.59 (m, 1H), 3.38-3.34 (m, 1H), 3.33 (s, 3H), 2.48-2.43 (m, 1H), 2.32 (d, J=10.7 Hz, 1H), 2.17-2.11 (m, 1H), 1.84 (t, J=6.3 Hz, 1H), 1.54 (s, 9H). 
     At 0° C., to a solution of the above material (1.82 g, 5.72 mmol) and imidazole (1.17 g, 17.2 mmol) in anhydrous DMF (30 mL) was added TBDMSCl (0.952 g, 6.32 mmol). The mixture was stirred at room temperature for 16 h and diluted with Et 2 O (100 mL) and brine (100 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (50 mL). The combined extract was washed with H 2 O (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl ((3aR,5R,6S,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a colorless sticky oil (2.30 g, 93%).  1 H NMR (400 MHz, CDCl 3 ) δ 5.92 (d, J=6.8 Hz, 1H), 4.31-4.28 (m, 1H), 3.92-3.90 (m, 1H), 3.73 (d, J=4.6 Hz, 2H), 3.35-3.31 (m, 1H), 3.33 (s, 3H), 2.41 (d, J=9.4 Hz, 1H), 2.41-2.36 (m, 1H), 2.18-2.12 (m, 1H), 1.54 (s, 9H), 0.89 (s, 9H), 0.06 (s, 6H). 
     At 0° C., to a solution of the above material (2.78 g, 6.45 mmol) and Bu 4 NI (0.238 g, 0.645 mmol) in anhydrous DMF (25 mL) was added NaH (60% in mineral oil, 0.335 g, 8.38 mmol). After addition of NaH, to the reaction mixture was added BnBr (1.93 g, 11.3 mmol). The mixture was stirred at room temperature for 16 h, and diluted with Et 2 O (100 mL) and saturated NH 4 Cl (100 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (2×40 mL). The combined extract was washed with brine (80 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:4), affording tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a colorless sticky oil (2.76 g, 82%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.27 (m, 5H), 6.02 (d, J=7.1 Hz, 1H), 4.67 (d, J=11.6 Hz, 1H), 4.40 (d, J=11.6 Hz, 1H), 4.34-4.30 (m, 1H), 3.83-3.78 (m, 1H), 3.77-3.69 (m, 2H), 3.53-3.50 (m, 1H), 3.29 (s, 3H), 2.44-2.39 (m, 1H), 2.14-2.08 (m, 1H), 1.52 (s, 9H), 0.88 (s, 9H), 0.04 (s, 6H). 
     At 0° C., to a solution of the above material (2.7 g, 5.2 mmol) in THF (20 mL) was added TBAF (1.0 M in THF, 12.0 mL, 12.0 mmol). After addition the reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc (40 mL) and brine (80 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 1:1), affording tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a colorless sticky foam (2.0 g, 94%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.27 (m, 5H), 6.01 (d, J=7.2 Hz, 1H), 4.69 (d, J=11.6 Hz, 1H), 4.40 (d, J=11.6 Hz, 1H), 4.36-4.34 (m, 1H), 3.77-3.72 (m, 2H), 3.62-3.54 (m, 2H), 3.30 (s, 3H), 2.53-2.48 (m, 1H), 2.09-2.02 (m, 1H), 1.71 (t, J=6.3 Hz, 1H), 1.53 (s, 9H). 
     At 0° C., to a solution of the above material (0.663 g, 1.62 mmol) in DCM (20 mL) was added DMP (1.17 g, 2.76 mmol). After stirring at room temperature for 1.5 h the reaction mixture was diluted with Et 2 O (30 mL), and then concentrated to dryness. Saturated aqueous NaHCO 3  solution (30 mL) with Na 2 S 2 O 3  (2 g) was added, and the mixture was extracted with EtOAc (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), affording tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white foam (0.57 g, 86%).  1 H NMR (500 MHz, CDCl 3 ) δ 9.63 (s, 1H), 7.36-7.27 (m, 5H), 6.04 (d, J=7.2 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.50 (d, J=11.5 Hz, 1H), 4.43-4.39 (m, 1H), 4.07 (d, J=8.0 Hz), 4.02-3.99 (m, 1H), 3.29 (s, 3H), 2.64-2.59 (m, 1H), 2.10-2.03 (m, 1H), 1.53 (s, 9H). 
     To a solution of the above material (0.17 g, 0.42 mmol) and TMSCF 3  (0.12 g, 0.84 mmol) in anhydrous THF (6 mL) was added TBAF (1.0 M in THF, 0.020 mL, 0.020 mmol). After addition the reaction mixture was stirred at room temperature for 2 h. Another batch of TBAF (1.0 M in THF, 0.60 mL, 0.60 mmol) was added, and the mixture was stirred at room temperature for another 16 h. The reaction solution was then diluted with EtOAc (20 mL) and brine (30 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (20 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:4 to 1:1), affording tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.060 g, 30%) as a pale yellow oil;  1 H NMR (400 MHz, CDCl 3 ) δ 7.33-7.27 (m, 5H), 6.01 (d, J=7.4 Hz, 1H), 4.69 (d, J=11.0 Hz, 1H), 4.43-4.35 (m, 2H), 4.08-3.99 (m, 2H), 3.75 (dd, J=5.6, 7.9 Hz, 1H), 3.26 (s, 3H), 2.63-2.57 (m, 1H), 2.09-2.03 (m, 1H), 1.52 (s, 9H). Also isolated was tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.052 g, 26%) as pale yellow oil;  1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.27 (m, 5H), 6.05 (d, J=7.2 Hz, 1H), 4.79 (d, J=11.5 Hz, 1H), 4.41 (d, J=11.5 Hz, 1H), 4.35-4.31 (m, 1H), 4.03-3.98 (m, 1H), 3.93-3.89 (m, 1H), 3.77 (d, J=8.6 Hz, 1H), 3.29 (s, 3H), 2.45-2.39 (m, 1H), 2.15-2.09 (m, 1H), 1.52 (s, 9H). 
     To tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.052 g, 0.11 mmol) and PMB (0.10 g, 0.67 mmol) in anhydrous DCM (5 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 0.60 mL, 0.60 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath warmed to 0° C. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:12), affording (3aR,5S,6S,7aR)-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.023 g, 74%).  1 H NMR (400 MHz, CD 3 OD) δ 6.21 (d, J=6.4 Hz, 1H), 4.29-4.24 (m, 1H), 4.21-4.15 (m, 1H), 4.01-3.96 (m, 1H), 3.70 (d, J=8.8 Hz, 1H), 2.83 (s, 3H), 2.22-2.16 (m, 1H), 2.08-2.01 (m, 1H);  13 C NMR (100 MHz, CD 3 OD) δ 163.69, 126.47 (q, J=281.2 Hz), 91.73, 73.5 (br.), 69.62 (q, J=30.1 Hz), 69.34, 64.60, 35.16, 30.60; MS, (ES, m/z) [M+H] +  287.1. 
     To tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.060 g, 0.13 mmol) and PMB (0.10 g, 0.67 mmol) in anhydrous DCM (4 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 0.60 mL, 0.60 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath warmed to 0° C. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:12), affording (3aR,5S,6S,7aR)-2-(methylamino)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.030 g, 82%).  1 H NMR (400 MHz, CD 3 OD) δ 6.15 (d, J=6.5 Hz, 1H), 4.38-4.34 (m, 1H), 4.11-4.07 (m, 1H), 4.05-3.98 (m, 1H), 3.68 (dd, J=5.6, 7.1 Hz), 2.84 (s, 3H), 2.20-2.09 (m, 2H);  13 C NMR (100 MHz, CD 3 OD) δ 163.99, 126.24 (q, J=280.7 Hz), 91.08, 75.0 (br.), 72.12 (q, J=29.7 Hz), 70.17, 67.00, 33.65, 30.80; MS, (ES, m/z) [M+H] +  287.1. 
     Examples 22 &amp; 23 
     (3aR,5S,6S,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5S,6S,7aR)-2-(dimethylamino)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of (3aR,5S,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde (0.650 g) in anhydrous THF (15 mL) at room temperature was TMSCF 3  (0.750 mL, 5.08 mmol) followed by TBAF (1.0 M in THF, 0.10 mL, 0.10 mmol). The reaction was stirred at room temperature for 2 h. Another 2.50 mL of TBAF (1.0 M in THF) was added and the mixture was stirred at room temperature for 18 h. The solution was diluted with saturated aqueous NaHCO 3  (30 mL), extracted with EtOAc (2×20 mL). The combined extract was dried over anhydrous Na 2 SO 4 . The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 1%-3% 2 M NH 3  MeOH solution in DCM to give 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)-2,2,2-trifluoroethanol (0.274 g, 35%) as a pale yellow foam. MS m/z 391.1 (M+1, 100%). An estimation ratio of the two diastereomers was 70:30 based on its  1 H NMR (400 MHz, CDCl 3 ) spectrum. 
     To a solution of the above material (0.260 g, 0.774 mmol) in DCM (5 mL) at −78° C. was added a solution of BCl 3  in DCM (1.0 M, 1.34 mL, 1.34 mmol). The mixture was slowly warmed up to room temperature and stirred for 17 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (2 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 2%-5% 2 M NH 3  MeOH solution in DCM to give (3aR,5S,6S,7aR)-2-(dimethylamino)-5-(2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (0.044 g, 22%) as a pale yellow foam. MS m/z 301.1 (M+1, 100%). An estimation ratio of the two diastereomers was 70:30 based on its  1 H NMR (400 MHz, MeOD) spectrum. 
     Examples 24 &amp; 25 
     (3aR,5S,6R,7R,7aR)-7-fluoro-2-(methylamino)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5S,6R,7R,7aR)-7-fluoro-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.930 g, 2.19 mmol) in anhydrous THF (15 mL), at 0° C. and under N 2 , was added MeMgBr (1.4 M in THF/toluene, 3.0 mL, 5.2 mmol). After addition the mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous NaHCO 3  solution (30 mL), and then extracted with EtOAc (3×30 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (40 mL) and Boc 2 O (2.0 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentration the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as an off-white foam (0.767 g, 80%), which contained two diastereomers. 
     The above material (0.767 g, 1.74 mmol) was oxidized with DMP using the procedure described for Example 29. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), tert-butyl ((3aR,5S,6R,7R,7aR)-5-acetyl-6-(benzyloxy)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate was obtained as a white foam (0.39 g, 51%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.27 (m, 5H), 6.14 (d, J=7.2 Hz, 1H), 5.37-5.25 (m, 1H), 4.76 (d, J=11.2 Hz, 1H), 4.65 (d, J=11.2 Hz, 1H), 4.57-4.55 (m, 1H), 4.07-4.00 (m, 1H), 3.86 (d, J=8.5 Hz, 1H), 3.26 (s, 3H), 2.19 (s, 3H), 1.53 (s, 9H). 
     The above material (0.375 g, 0.856 mmol) was subjected to TMSCF 3  addition as described for Example 29. The product mixture was purified and separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:20 to 1:4), affording tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.13 g, 30%) as a white foam;  1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.29 (m, 5H), 6.18 (d, J=7.3 Hz, 1H), 5.55-5.44 (m, 1H), 4.84 (d, J=10.6 Hz, 1H), 4.65-4.62 (m, 1H), 4.49 (d, J=10.6 Hz, 1H), 4.08-4.01 (m, 1H), 3.63 (d, J=8.5 Hz, 1H), 3.32 (s, 3H), 3.14 (s, 1H), 1.53 (s, 9H), 1.32 (s, 3H). Also isolated was tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.20 g, 46%) as a white foam;  1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.30 (m, 5H), 6.15 (d, J=7.2 Hz, 1H), 5.57-5.46 (m, 1H), 4.83 (d, J=10.6 Hz, 1H), 4.64-4.62 (m, 1H), 4.52 (d, J=10.6 Hz, 1H), 4.08-4.01 (m, 1H), 3.64 (d, J=8.6 Hz, 1H), 3.34 (s, 3H), 3.00 (s, 1H), 1.54 (s, 9H), 1.34 (s, 3H). 
     The above material, tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3 aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.130 g, 0.256 mmol), was deprotected with BCl 3  using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:15), (3aR,5S,6R,7R,7aR)-7-fluoro-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.073 g, 90%).  1 H NMR (400 MHz, CD 3 OD) δ 6.32 (d, J=6.8 Hz, 1H), 5.04-4.91 (m, 1H), 4.55-4.50 (m, 1H), 4.20-4.13 (m, 1H), 3.61 (d, J=8.5 Hz, 1H), 2.86 (s, 3H), 1.36 (s, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 164.36 (d, J=2.5 Hz), 127.43 (q, J=285.3 Hz), 93.67 (d, J=177.4 Hz), 89.21, 75.77 (q, J=27.0 Hz), 74.71 (d, J=1.4 Hz), 73.70 (d, J=26.7 Hz), 68.14 (d, J=25.0 Hz), 30.90, 18.90 (q, J=2.1 Hz); MS, (ES, m/z) [M+H] +  318.1. 
     The above material, tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.200 g, 0.394 mmol), was deprotected with BCl 3  using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:15), (3aR,5S,6R,7R,7aR)-7-fluoro-2-(methylamino)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.114 g, 91%).  1 H NMR (400 MHz, CD 3 OD) δ 6.29 (d, J=6.8 Hz, 1H), 5.05-4.93 (m, 1H), 4.55-4.51 (m, 1H), 4.15-4.08 (m, 1H), 3.73 (d, J=8.6 Hz, 1H), 2.85 (s, 3H), 1.34 (s, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 164.35 (d, J=2.7 Hz), 127.35 (q, J=284.3 Hz), 93.14 (d, J=175.8 Hz), 89.65, 75.73 (q, J=27.3 Hz), 73.40 (d, J=27.2 Hz), 72.90, 68.88 (d, J=25.6 Hz), 30.85, 16.75 (q, J=1.3 Hz); MS, (ES, m/z) [M+H] +  318.1. 
     Examples 26 &amp; 27 
     (3aR,5S,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5S,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     The aldehyde tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.42 g, 0.96 mmol) was subjected to MeMgBr addition as described for Example 24. After purification on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate was obtained as a white foam (0.30 g, 69%), which contained two diastereomers. 
     The above material (0.30 g, 0.66 mmol) was oxidized with DMP using the procedure described for Example 29. After purification on silica gel by automatic flash column chromatography ((EtOAc/hexanes, 1:10 to 1:2), tert-butyl ((3aR,5S,6R,7R,7aR)-5-acetyl-6-(benzyloxy)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate was obtained as a clear oil (0.20 g, 67%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.27 (m, 5H), 6.14 (d, J=7.2 Hz, 1H), 5.43-5.32 (m, 1H), 4.77 (d, J=11.1 Hz, 1H), 4.65 (d, J=11.1 Hz, 1H), 4.60-4.55 (m, 1H), 4.07-4.00 (m, 1H), 3.92-3.85 (m, 2H), 3.84 (d, J=8.3 Hz, 1H), 2.19 (s, 3H), 1.53 (s, 9H), 1.08 (t, J=7.0 Hz, 3H). 
     The above material (0.200 g, 0.442 mmol) was subjected to TMSCF 3  addition as described for Example 29. The product mixture was purified and separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:20 to 1:4), affording tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.057 g, 25%) as a white foam;  1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.28 (m, 5H), 6.13 (d, J=7.4 Hz, 1H), 5.45-5.33 (m, 1H), 4.77 (d, J=10.9 Hz, 1H), 4.62-4.58 (m, 1H), 4.52 (d, J=10.9 Hz, 1H), 4.05-3.98 (m, 1H), 3.86-3.81 (m, 2H), 3.58 (d, J=8.7 Hz, 1H), 3.20 (s, 1H), 1.53 (s, 9H), 1.32 (s, 3H), 1.05 (t, J=7.0 Hz, 3H). Also isolated was tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.10 g, 43%) as a white foam;  1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.29 (m, 5H), 6.09 (d, J=7.4 Hz, 1H), 5.46-5.34 (m, 1H), 4.78 (d, J=10.9 Hz, 1H), 4.62-4.57 (m, 1H), 4.53 (d, J=10.9 Hz, 1H), 4.06-3.99 (m, 1H), 3.91-3.79 (m, 2H), 3.57 (d, J=8.9 Hz, 1H), 3.15 (s, 1H), 1.53 (s, 9H), 1.34 (s, 3H), 1.06 (t, J=7.0 Hz, 3H). 
     The above material, tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.057 g, 0.11 mmol), was deprotected with BCl 3  using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:17), (3aR,5S,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.031 g, 85%).  1 H NMR (400 MHz, CD 3 OD) δ 6.30 (d, J=6.8 Hz, 1H), 5.03-4.90 (m, 1H), 4.54-4.49 (m, 1H), 4.20-4.13 (m, 1H), 3.61 (d, J=8.5 Hz, 1H), 3.30-3.22 (m, 2H), 1.36 (s, 3H), 1.17 (t, J=7.2 Hz, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 163.48 (d, J=1.7 Hz), 127.48 (q, J=285.5 Hz), 93.70 (d, J=177.4 Hz), 88.94, 75.79 (q, J=27.0 Hz), 74.76 (d, J=1.4 Hz), 73.79 (d, J=26.7 Hz), 68.15 (d, J=25.1 Hz), 40.02, 18.92 (q, J=2.2 Hz), 14.95; MS, (ES, m/z) [M+H] +  333.1. 
     The above material, tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.100 g, 0.191 mmol), was deprotected with BCl 3  using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:17), (3aR,5S,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.053 g, 84%).  1 H NMR (400 MHz, CD 3 OD) δ 6.26 (d, J=6.8 Hz, 1H), 5.04-4.92 (m, 1H), 4.54-4.50 (m, 1H), 4.15-4.07 (m, 1H), 3.73 (d, J=8.6 Hz, 1H), 3.34-3.21 (m, 2H), 1.33 (s, 3H), 1.17 (t, J=7.2 Hz, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 163.47 (d, J=2.2 Hz), 127.40 (q, J=284.2 Hz), 93.11 (d, J=175.6 Hz), 89.36, 75.75 (q, J=27.3 Hz), 73.50 (d, J=27.2 Hz), 72.90, 68.94 (d, J=25.7 Hz), 39.95, 16.72 (q, J=1.5 Hz), 14.98; MS, (ES, m/z) [M+H] +  333.1. 
     Example 28 
     (3aR,5S,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of DMSO (0.275 g, 3.50 mmol) in anhydrous DCM (5 mL) at −78° C. under N 2  was added oxalyl chloride (0.422 g, 3.32 mmol) dropwise. The mixture was stirred at ˜−30° C. for 30 min and cooled to −78° C. again. A solution of ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yflmethanol (0.465 g, 1.37 mmol) in anhydrous DCM (5 mL) was added. After stirring at ˜−30° C. for 2 h the reaction mixture was cooled back to −78° C. and Et 3 N (0.624 g, 6.18 mmol) was added. The mixture was stirred at ˜−30° C. for another 30 min, and then quenched with H 2 O (20 mL). The organic layer was collected and the aqueous was extracted with DCM (2×10 mL). The combined extracts were dried over anhydrous Na 2 SO 4 . The solvent was evaporated under reduced pressure to give the crude aldehyde. This was purified by silica gel column chromatography, eluted with 30%-60% EtOAc in hexanes to give (3aR,5S,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde (0.190 g, 41%) as a pale yellow foam. MS m/z 339.1 (M+1, 100%). 
     To a solution of above aldehyde (0.170 g, 0.503 mmol) in anhydrous THF (5 mL) at 0° C. was added a solution of MeMgBr (1.4 M in 1:3 THF/toluene, 0.90 mL, 1.26 mmol) dropwise. The reaction was then stirred at room temperature for 2 h. The mixture was diluted with H 2 O (10 mL), extracted with EtOAc (2×10 mL). The combined extracts were dried over anhydrous Na 2 SO 4 . The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 1%-2% 2 M NH 3  MeOH solution in DCM to give 1-((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.115 g, 65%) as a pale yellow foam. MS m/z 355.2 (M+1, 100%);  1 H NMR (400 MHz, CDCl 3 ) showed this was a mixture of two diastereomers with a ratio ˜4:1. 
     To a solution of the above material (0.110 g, 0.311 mmol) in dry DCM (3 mL) at 0° C. was added DMP (0.198 g, 0.467 mmol). The mixture was then stirred at room temperature for 4 h. The reaction was diluted with saturated aqueous NaHCO 3  (10 mL) and 1 M Na 2 S 2 O 3  (3 mL) and extracted with DCM (2×10 mL). The extracts were dried over Na 2 SO 4  and the solvents were evaporated to give the crude product. This was purified by column chromatography on silica gel, eluted with 1% NH 4 OH in 1:1 hexanes-EtOAc to provide 1-((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yflethanone (0.0786 g, 72%) as a white foam. This material was used directly in the next step without further purification. MS m/z 353.1 (M+1, 100%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.28-7.38 (m, 2H), 6.32 (d, J=6.7 Hz, 1H), 5.29 (d, J=44.3 Hz, 1H), 4.81 (d, J=11.3 Hz, 1H), 4.66 (m, 1H), 4.64 (d, J=11.3 Hz, 1H), 3.95-4.03 (m, 2H), 3.01 (s, 6H), 2.16 (s, 3H). 
     To a solution of the above material (0.074 g, 0.21 mmol) in anhydrous THF (4 mL) at room temperature was TMSCF 3  (0.075 g, 0.53 mmol) followed by TBAF (1.0 M in THF, 0.03 mL, 0.03 mmol). The reaction was stirred at room temperature for 2 h. Another 0.24 mL of TBAF (1.0 M in THF) was added and the mixture was stirred at room temperature for 5 h. The solution was diluted with saturated aqueous NaHCO 3  (10 mL), extracted with EtOAc (2×10 mL). The combined extract was dried over anhydrous Na 2 SO 4 . The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 30% EtOAc in hexanes to give 2-((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-2-(dimethylamino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)-1,1,1-trifluoropropan-2-ol (0.055 g, 62%) as a pale yellow syrup. MS m/z 423.1 (M+1, 100%).  1 H NMR (400 MHz, CDCl 3 ) spectrum shown this was a mixture of the two diastereomers with a ratio ˜56:44. 
     To a solution of the above material (0.055 g, 0.13 mmol) in DCM (2 mL) at −78° C. was added a solution of BCl 3  in DCM (1.0 M, 0.16 mL, 0.16 mmol). The mixture was slowly warmed up to room temperature and stirred for 5 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (1 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 30%400% EtOAc in hexanes to give (3aR,5S,6R,7R,7aR)-2-(dimethylamino)-7-fluoro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (0.0344 g, 80%) as a white solid. MS m/z 333.1 (M+1, 100%);  1 H NMR (400 MHz, MeOD) spectrum shown this was a mixture of the two diastereomers with a ratio ˜56:44. 
     Examples 29 &amp; 30 
     (3aR,5S,6S,7aR)-2-(methylamino)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5S,6S,7aR)-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.920 g, 2.26 mmol) in anhydrous THF (20 mL) at 15° C. was added a solution of MeMgBr (1.4 M in THF/toluene, 4.1 mL, 5.7 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 h, and then quenched with saturated aqueous NaHCO 3  solution (30 mL). The mixture was extracted with EtOAc (2×30 mL), and the combined extracts were dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (MeOH/DCM, 0:4 to 1:4), affording tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.350 g, 37%) as a white foam;  1 H NMR (400 MHz, CDCl 3 ) for this material indicated that it contained two diastereomers with a ratio of 1:2. Also isolated was the deprotected side product 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.300 g, 41%) as a white solid;  1 H NMR (400 MHz, CDCl 3 ) for this material indicated that it contained two diastereomers with a ratio of 1:1.4. 
     To a solution of tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.406 g, 0.961 mmol) in dry DCM (20 mL) was added DMP (0.615 g, 1.45 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated. The residue was diluted with saturated aqueous NaHCO 3  solution (20 mL) and 1 M Na 2 S 2 O 3  aqueous solution (5 mL), and extracted with EtOAc (2×20 mL). The combined extract was dried over Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:4 to 2:3), affording tert-butyl ((3aR,5S,6S,7aR)-5-acetyl-6-(benzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.32 g), which was impure and used in the next step without further purification. 
     To a solution of the above material and TMSCF 3  (0.251 g, 1.77 mmol) in anhydrous THF (15 mL) was added TBAF (1.0 M in THF, 0.030 mL, 0.030 mmol). After addition the reaction mixture was stirred at room temperature for 16 h. Another batch of TBAF (1.0 M in THF, 1.2 mL, 1.2 mmol) was added, and the mixture was stirred at room temperature for another 3 h. The reaction solution was then diluted with EtOAc (20 mL) and brine (30 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (20 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:4 to 1:1), affording tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.11 g, 23% over two steps) as a pale yellow oil;  1 H NMR (400 MHz, CDCl 3 ) δ 7.35-7.27 (m, 5H), 6.06 (d, J=7.7 Hz, 1H), 4.70 (d, J=10.8 Hz, 1H), 4.46-4.42 (m, 1H), 4.32 (d, J=10.8 Hz, 1H), 4.08-4.05 (m, 1H), 3.67 (d, J=7.8 Hz, 1H), 3.26 (s, 3H), 2.70-2.66 (m, 1H), 1.98-1.92 (m, 1H), 1.52 (s, 9H), 1.31 (s, 3H). Also isolated was tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.16 g, 34% over two steps), as a pale yellow oil;  1 H NMR (400 MHz, CDCl 3 ) δ 7.34-7.27 (m, 5H), 6.05 (d, J=7.6 Hz, 1H), 4.71 (d, J=10.8 Hz, 1H), 4.45-4.42 (m, 1H), 4.35 (d, J=10.8 Hz, 1H), 4.08-4.05 (m, 1H), 3.69 (d, J=8.0 Hz, 1H), 3.27 (s, 3H), 2.71-2.67 (m, 1H), 2.03-1.98 (m, 1H), 1.53 (s, 9H), 1.32 (s, 3H). 
     The protected material, tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.105 g, 0.214 mmol), was deprotected using BCl 3 , as described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:12), (3aR,5S,6S,7aR)-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.051 g, 79%).  1 H NMR (400 MHz, CD 3 OD) δ 6.18 (d, J=6.8 Hz, 1H), 4.46-4.42 (m, 1H), 4.20-4.17 (m, 1H), 3.53 (d, J=7.2 Hz, 1H), 2.85 (s, 3H), 2.32-2.27 (m, 1H), 2.09-2.02 (m, 1H), 1.33 (s, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 164.34, 127.46 (q, J=285.3 Hz), 91.10, 77.04, 75.83 (q, J=26.9 Hz), 70.56, 66.52, 33.66, 30.94, 18.67 (q, J=2.2 Hz); MS, (ES, m/z) [M+H] +  301.1. 
     The protected material, tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.160 g, 0.326 mmol), was deprotected using BCl 3 , as described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:12), (3aR,5S,6S,7aR)-2-(methylamino)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.072 g, 73%).  1 H NMR (400 MHz, CD 3 OD) δ 6.18 (d, J=6.8 Hz, 1H), 4.44-4.41 (m, 1H), 4.19-4.15 (m, 1H), 3.67 (d, J=7.4 Hz, 1H), 2.85 (s, 3H), 2.29-2.24 (m, 1H), 2.09-2.03 (m, 1H), 1.31 (s, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 164.14, 127.51 (q, J=284.3 Hz), 91.42, 75.71 (q, J=27.0 Hz), 75.53, 70.18, 66.58, 33.47, 30.89, 16.96 (q, J=1.5 Hz); MS, (ES, m/z) [M+H] +  301.1. 
     The following examples were synthesized according to procedures analogous to the schemes and examples outlined above. 
     
       
         
           
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Example 
                 Structure 
                 Name 
               
               
                   
               
             
            
               
                 31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (3aR,5R,6R,7R,7aR)-2-(azetidin-1-yl)-7-fluoro- 5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol 
               
               
                   
               
            
           
           
               
            
               
                   1 H NMR (300 MHz, D 2 O) δ 6.36 (d, J = 7.5 Hz, 1H), 4.80 (td, J = 3.3, 34.8 Hz, 1H), 
               
               
                 4.43-4.37 (m, 1H), 3.97 (t, J = 5.7 Hz, 4H), 3.94-3.85 (m, 2H), 3.31-3.25 (m, 1H), 
               
               
                 2.32-2.24 (m, 2H), 1.17 (d, J = 6.0 Hz, 3H); (ES, m/z) [M + H] +  277.0. 
               
               
                   
               
            
           
           
               
               
               
            
               
                 32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (3aR,5S,6R,7R,7aR)-2-(azetidin-1-yl)-7-fluoro- 5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
               
               
                   
               
            
           
           
               
            
               
                   1 H NMR (300 MHz, D 2 O) δ 6.34 (d, J = 5.1 Hz, 1H), 4.86 (td, J = 3.3, 38.4 Hz, 1H), 
               
               
                 4.44-4.38 (m, 1H), 4.34-4.28 (m, 1H), 4.08-4.02 (m, 1H), 3.98 (t, J = 6.0 Hz, 4H), 3.76 
               
               
                 (d, J = 6.9 Hz, 1H), 2.33-2.25 (m, 2H); (ES, m/z): [M + H] +  331.0. 
               
               
                   
               
            
           
         
       
     
     Example 33 
     (3aR,5R,6R,7R,7aR)-2-amino-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a suspension of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-aminotetrahydro-2H-pyran-2,4,5-triyltriacetate hydrochloride (14.0 g, 36.5 mmol) in MeCN (160 mL) was added DIPEA (5.16 g, 40.0 mmol) and allyl isothiocyanate (7.92 g, 79.9 mmol). After the mixture was stirred at 80° C. for 3 h, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:2 to 2:1), affording a white foam (16.7 g). The white foam was dissolved in DCM (120 mL) and TFA (8.5 mL) was added. The mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure. The residue was diluted with DCM (60 mL) and washed with saturated aqueous NaHCO 3  (60 mL). The organic layer was collected and aqueous layer was extracted with DCM once (40 mL). The combined organic extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in DCM (160 mL), and Boc 2 O (21.8 g, 100 mmol) was added as well as DIPEA (3.0 mL). The mixture was stirred at room temperature for 16 h. The solvent was then evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), affording a white foam. The white foam was dissolved in dry MeOH (150 mL), into which was bubbled NH 3  (g) for 5 min. After stirring at room temperature for 3 h the mixture was concentrated, and the residue was purified by re-crystallization from MeOH/EtOAc to give tert-butyl allyl((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate as a white solid (9.02 g, 69% over 4 steps).  1 H NMR (400 MHz, CD 3 OD) δ 6.12 (d, J=6.2 Hz, 1H), 5.88-5.79 (m, 1H), 5.18-5.12 (m, 2H), 4.54-4.41 (m, 2H), 4.30-4.26 (m, 2H), 3.84 (dd, J=2.8, 11.9 Hz, 1H), 3.74-3.67 (m, 2H), 3.50-3.46 (m, 1H), 2.37 (s, br. 1H), 2.22 (s, br. 1H), 2.00 (s, br. 1H), 1.53 (s, 9H). 
     To a solution of the above material (7.02 g, 19.4 mmol), DIPEA (6.29 g, 48.7 mmol) and DMAP (0.040 g, 0.33 mmol) in DCM (150 mL), at 15° C., was added BzCl (6.03 g, 42.9 mmol) slowly. After addition the mixture was stirred at room temperature for 5 h. Saturated aqueous NH 4 Cl solution (40 mL) was added, and the organic layer was collected. The extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), affording (3aR,5R,6S,7R,7aR)-2-(allyl(tert-butoxycarbonyl)amino)-5-((benzoyloxy)methyl)-7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-yl benzoate as a white solid (2.80 g, 25%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.01-7.99 (m, 4H), 7.59-7.56 (m, 1H), 7.54-7.50 (m, 1H), 7.44-7.40 (m, 2H), 7.39-7.35 (m, 2H), 6.20 (d, J=7.0 Hz, 1H), 5.88-5.81 (m, 1H), 5.17-5.07 (m, 3H), 4.54-4.48 (m, 4H), 4.45-4.40 (m, 2H), 4.12-4.06 (m, 1H), 2.70 (d, J=6.4 Hz, 1H), 1.53 (s, 9H). 
     To a solution of the above material (2.40 g, 4.22 mmol) in anhydrous DCM (30 mL), at −78° C. under N 2 , was added DAST (4.32 g, 2.68 mmol). After addition the mixture was stirred at room temperature for 2 days. At −78° C., the reaction mixture was diluted with DCM (20 mL), and then quenched by adding saturated aqueous NaHCO 3  dropwise. The organic layer was collected, and the aqueous was extracted with DCM (2×30 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:20 to 1:4), affording (3aR,5R,6R,7R,7aR)-2-(allyl(tert-butoxycarbonyl)amino)-5-((benzoyloxy)methyl)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-yl benzoate as a white solid (1.70 g, 70%).  1 H NMR (400 MHz, CDCl 3 ) δ 8.00-7.98 (m, 4H), 7.60-7.56 (m, 1H), 7.53-7.50 (m, 1H), 7.44-7.40 (m, 2H), 7.38-7.34 (m, 2H), 6.17 (d, J=7.1 Hz, 1H), 5.92-5.82 (m, 1H), 5.46 (dd, J=9.4, 21.3 Hz, 1H), 5.36-5.25 (m, 1H), 5.16-5.08 (m, 2H), 4.59-4.44 (m, 4H), 4.40 (dd, J=6.0, 12.0 Hz, 1H), 3.99-3.95 (m, 1H), 1.53 (s, 9H). 
     A mixture of the above material (1.70 g, 2.98 mmol) and K 2 CO 3  (0.40 g, 2.9 mmol) in anhydrous MeOH (30 mL) was stirred at room temperature for 3 h. Dry ice was added, and the solvent was removed under reduced pressure. The residue was purified on silica gel by flash column chromatography (MeOH/DCM, 1:20), affording tert-butyl allyl((3aR,5R,6R,7R,7aR)-7-fluoro-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate as a white solid (1.07 g, 99%).  1 H NMR (400 MHz, CD 3 OD) δ 6.12 (d, J=6.6 Hz, 1H), 5.95-5.85 (m, 1H), 5.16-5.10 (m, 2H), 5.00-4.86 (m, 1H), 4.54-4.37 (m, 3H), 3.81-3.73 (m, 2H), 3.60 (d, J=6.0, 12.1 Hz, 1H), 3.39-3.34 (m, 1H), 1.51 (s, 9H). 
     At 0° C., to a solution of the above material (1.06 g, 2.94 mmol) and imidazole (0.600 g, 8.82 mmol) in anhydrous DMF (15 mL) was added TBDMSCl (0.478 g, 3.17 mmol). The mixture was stirred at room temperature for 5 h and diluted with Et 2 O (100 mL) and brine (100 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (50 mL). The combined extract was washed with H 2 O (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl allyl((3aR,5R,6R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate as a white solid (1.36 g, 97%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.05 (d, J=6.8 Hz, 1H), 5.90-5.80 (m, 1H), 5.18-5.04 (m, 3H), 4.51-4.39 (m, 3H), 3.93-3.84 (m, 1H), 3.81-3.72 (m, 2H), 3.31-3.26 (m, 1H), 2.14 (d, J=8.1 Hz, 1H), 1.53 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H). 
     At 0° C., to a solution of the above material (0.720 g, 1.51 mmol) and Bu 4 NI (0.056 g, 0.151 mmol) in anhydrous DMF (8 mL) was added NaH (60% in mineral oil, 0.078 g, 1.96 mmol) and subsequently added allyl bromide (0.365 g, 3.02 mmol). The mixture was stirred at room temperature for 5 h, diluted with Et 2 O (50 mL) and washed with saturated NaHCO 3  (50 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (30 mL). The combined extract was washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:20 to 1:4), affording tert-butyl allyl((3aR,5R,6R,7R,7aR)-6-(allyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate as a pale yellow sticky oil (0.675 g, 87%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.08 (d, J=7.0 Hz, 1H), 5.93-5.82 (m, 2H), 5.30-5.08 (m, 5H), 4.46-4.40 (m, 3H), 4.22 (dd, J=5.3, 12.6 Hz, 1H), 4.03 (dd, J=5.8, 12.6 Hz, 1H), 3.80-3.70 (m, 3H), 3.39-3.35 (m, 1H), 1.51 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H). 
     At 0° C., to a solution of the above material (0.675 g, 1.31 mmol) in THF (10 mL) was added TBAF (1.0 M in THF, 2.5 mL, 2.5 mmol). After addition the reaction mixture was stirred at room temperature for 3 h and diluted with EtOAc (30 mL) and brine (30 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (20 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 1:2), affording tert-butyl allyl((3aR,5R,6R,7R,7aR)-6-(allyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yflcarbamate as a colorless oil (0.53 g, 100%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.07 (d, J=7.1 Hz, 1H), 5.92-5.82 (m, 2H), 5.31-5.10 (m, 5H), 4.52-4.40 (m, 3H), 4.22 (dd, J=5.2, 12.6 Hz, 1H), 4.03 (dd, J=5.9, 12.6 Hz, 1H), 3.82-3.77 (m, 1H), 3.74-3.61 (m, 2H), 3.42-3.38 (m, 1H), 1.52 (s, 9H). 
     At 0° C., to a solution of the above material (0.53 g, 1.3 mmol) in DCM (25 mL) was added DMP (0.81 g, 1.9 mmol). After stirring at room temperature for 1.5 h the reaction mixture was diluted with Et 2 O (30 mL), and then concentrated to dryness. Saturated NaHCO 3  aqueous solution (30 mL) with Na 2 S 2 O 3  (2 g) was added, and the mixture was extracted with EtOAc (2×30 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:4 to 2:3), affording the corresponding aldehyde as a colorless oil (0.47 g). To this material in anhydrous THF (15 mL) at 0° C. was added a solution of MeMgBr (1.4 M in THF/toluene, 2.5 mL, 3.5 mmol). The reaction mixture was stirred at room temperature for 3 h, and then quenched with saturated NaHCO 3  solution (30 mL). The mixture was extracted with EtOAc (2×30 mL), and the combined extracts were dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl allyl((3aR,5R,6R,7R,7aR)-6-(allyloxy)-7-fluoro-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yflcarbamate (0.29 g, 53%), as a mixture of two diastereomers in a ratio of 2.6:1, as indicated by  1 H NMR. 
     Under Ar, to the above material (0.168 g, 0.403 mmol) in 1,4-dioxane (10 mL) was added Et 3 N (0.164 g, 1.62 mmol), HCOOH (0.118 g, 2.43 mmol). To the solution was bubbled with Ar for 30 sec, and Pd(PPh 3 ) 4  (0.187 g, 0.162 mmol) was added. After stirring at 60° C. for 16 h, the reaction mixture was concentrated, and the residue was purified on silica gel by automatic flash column chromatography (MeOH/DCM, 1:40 to 1:20), affording tert-butyl ((3aR,5R,6R,7R,7aR)-7-fluoro-6-hydroxy-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate as an off-white solid (0.083 g, 85%).  1 H NMR (400 MHz, CD 3 OD) δ 6.21 (d, J=7.1 Hz, 1H), 4.90 (td, J=3.8, 46.7 Hz, 1H), 4.35-4.31 (m, 1H), 4.01-3.90 (m, 2H), 3.14 (dd, J=3.0, 9.6 Hz, 1H), 1.49 (s, 9H), 1.22 (d, J=6.6 Hz, 1H);  13 C NMR (100 MHz, CD 3 OD) δ 162.83, 155.73, 94.85 (d, J=177.4 Hz), 87.24 (d, J=1.4 Hz), 82.88, 77.22 (d, J=3.3 Hz), 69.29 (d, J=27.8 Hz), 68.92 (d, J=24.1 Hz), 67.08, 28.54, 19.77; MS, (ES, m/z) [M+Na] +  359.1. 
     To a solution of the above material (0.0562 g, 0.167 mmol) in dry MeOH (5 mL) was bubbled with HCl(g) for 30 sec. After stirring at room temperature for 5 h the reaction mixture was concentrated to dryness. The residue was neutralized with 1.0 M NH 3  in MeOH, and purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:5) to afford (3aR,5R,6R,7R,7aR)-2-amino-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.0387 g, 98%).  1 H NMR (400 MHz, CD 3 OD) δ 6.36 (d, J=7.0 Hz, 1H), 4.85 (td, J=4.2, 47.1 Hz, 1H), 4.38-4.32 (m, 1H), 4.00-3.92 (m, 2H), 3.28 (dd, J=2.7, 9.3 Hz, 1H), 1.21 (d, J=6.6 Hz, 1H);  13 C NMR (100 MHz, CD 3 OD) δ 165.10 (d, J=2.3 Hz), 95.64 (d, J=177.3 Hz), 91.13 (d, J=2.5 Hz), 77.17 (d, J=3.8 Hz), 73.41 (d, J=26.0 Hz), 69.02 (d, J=23.8 Hz), 66.73, 19.88; MS, (ES, m/z) [M+H] +  237.1. 
     Example 34 
     (3aR,5R,6R,7S,7aR)-7-fluoro-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     At 0° C., to a solution of tert-butyl ((3aR,5R,6R,7R,7aR)-7-fluoro-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (9.00 g, 26.8 mmol) and imidazole (9.09 g, 133 mmol) in anhydrous DMF (60 mL) was added TBDMSCl (14.1 g, 93.5 mmol). The mixture was stirred at room temperature for 16 h, diluted with Et 2 O (200 mL) and washed with brine (2×200 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (2×100 mL). The combined extract was washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 0 to 1:6), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a colorless oil (16.0 g, 100%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.10 (d, J=6.9 Hz, 1H), 4.89 (td, J=4.3, 47.3 Hz, 1H), 4.38-4.31 (m, 1H), 4.01-3.93 (m, 1H), 3.81-3.70 (m, 2H), 3.41-3.37 (m, 1H), 3.32 (s, 3H), 1.53 (s, 9H), 0.89 (s, 18H), 0.144 (s, 3H), 0.087 (s, 3H), 0.048 (s, 6H). 
     At 0° C., to a solution of the above material (16.0 g) in mixed DCM/MeOH (100 mL, 1:4) was added AcCl (0.32 g, 4.1 mmol). After the mixture was stirred at room temperature for 24 h, NaHCO 3  powder (1 g) was added, and the suspension was stirred for 30 min. The solvent was then evaporated under reduced pressure, and the residue was dissolved in DCM (100 mL) and washed with saturated aqueous NaHCO 3  (50 mL). The organic layer was collected, and the aqueous was extracted with DCM (2×80 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the filtrate was treated with Boc 2 O (4.0 g, 18 mmol) for 3 h. Then the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:3), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-((tert-butyldimethylsilyl)oxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white foam (11.6 g, 96%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.10 (d, J=7.1 Hz, 1H), 4.99 (ddd, J=2.7, 4.1, 46.0 Hz, 1H), 4.46-4.40 (m, 1H), 3.96-3.88 (m, 1H), 3.78 (dd, J=2.3, 11.8 Hz, 1H), 3.62 (dd, J=5.2, 11.8 Hz, 1H), 3.46-3.41 (m, 1H), 3.32 (s, 3H), 1.54 (s, 9H), 0.89 (s, 9H), 0.16 (s, 3H), 0.09 (s, 3H). 
     To a solution of the above material (11.3 g, 25.1 mmol) in DCM (200 mL) at 0° C. was added DMP (14.8 g, 34.9 mmol). After stirring at room temperature for 2 h the reaction solution was concentrated at room temperature to around 100 mL, and then diluted with Et 2 O (300 mL). The resulting suspension was filtered through a Celite cake, and the filtrate was concentrated to dryness at room temperature. The residue was extracted with Et 2 O (200 mL) and the solid was filtered off. The ether solution was washed with saturated aqueous NaHCO 3  (200 mL), and the aqueous was extracted with Et 2 O (2×50 mL). The combined extract was dried over anhydrous MgSO 4 . After filtration the solvent was evaporated under reduced pressure to give crude tert-butyl ((3aR,5S,6R,7R,7aR)-6-((tert-butyldimethylsilyl)oxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (11.8 g). This crude material was used in the next step without further purification. 
     To a solution of the above material (11.8 g) in anhydrous THF (200 mL) under N 2  at 0° C. was added MeMgBr (1.4 M in THF/toluene, 42.0 mL, 58.8 mmol). After addition the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCO 3  (200 mL), and the reaction mixture was extracted with EtOAc (200 mL) and DCM (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure. The residue was dissolved in DCM (100 mL) and treated with Boc 2 O (3 g) for 3 h. The solvent was then evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc/hexane, 0 to 1:4) to afford tert-butyl ((3aR,5R,6R,7R,7aR)-6-((tert-butyldimethylsilyl)oxy)-7-fluoro-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a mixture of two diastereomers (6.60 g, 57% two steps). 
     To a solution of the above material (6.60 g, 14.2 mmol) in anhydrous THF (80 mL) at 0° C. was added TBAF (1.0 M in THF, 28.0 mL, 28.0 mmol). The mixture was stirred at room temperature for 3 h. The reaction was diluted with brine (100 mL), and then extracted with EtOAc (3×80 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc/hexane/25% DCM, 1:2 to 1:1/) to afford tert-butyl ((3aR,5R,6R,7R,7aR)-7-fluoro-6-hydroxy-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (3.77 g, 76%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.09 (d, J=6.9 Hz, 1H), 5.24-5.12 (m, 1H), 4.48-4.43 (m, 1H), 3.97-3.87 (m, 2H), 3.34 (s, 3H), 3.15 (dd, J=5.0, 8.0 Hz, 1H), 2.12 (s, br., 2H, (OH)), 1.55 (s, 9H), 1.26 (d, J=6.5 Hz, 3H). 
     At 0° C., to a solution of the above material (0.930 g, 2.65 mmol) and imidazole (0.726 g, 10.7 mmol) in anhydrous DMF (20 mL) was added TBDMSCl (0.502 g, 3.33 mmol). The mixture was stirred at room temperature for 16 h, diluted with Et 2 O (100 mL) and washed with brine (2×100 mL). The organic layer was collected, and the aqueous was extracted with Et 2 O (50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 0 to 1:3), affording tert-butyl ((3aR,5S,6R,7R,7aR)-5-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white foam (0.919 g, 75%).  1 H NMR (500 MHz, CDCl 3 ) δ 6.09 (d, J=6.9 Hz, 1H), 5.04 (td, J=4.0, 46.8 Hz, 1H), 4.41-4.36 (m, 1H), 4.08-4.03 (m, 2H), 3.32 (s, 3H), 3.32-3.30 (m, 1H), 2.64 (s, br., 1H, (OH)), 1.54 (s, 9H), 1.20 (d, J=6.4 Hz, 3H), 0.89 (s, 9H), 0.087 (s, 3H), 0.083 (s, 3H). 
     To a solution of the above material (0.900 g, 1.94 mmol) in DCM (30 mL) was added DMP (1.23 g, 2.91 mmol). After stirring at room temperature for 45 min the reaction was diluted with Et 2 O (100 mL). The resulting suspension was filtered through a Celite cake, and the filtrate was concentrated to dryness at room temperature. The residue was loaded onto a silica gel plug and the product was eluted with (EtOAc/hexanes, 1:4), affording tert-butyl ((3aR,5R,7R,7aR)-5-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-7-fluoro-6-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white foam (0.90 g, 100%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.47 (d, J=6.9 Hz, 1H), 5.11 (dd, J=5.5, 48.4 Hz, 1H), 4.68-4.61 (m, 1H), 4.54-4.49 (m, 1H), 3.90-3.89 (m, 1H), 3.32 (s, 3H), 1.54 (s, 9H), 1.26 (d, J=6.5 Hz, 3H), 0.84 (s, 9H), 0.074 (s, 3H), 0.043 (s, 3H). 
     To a solution of the above material (0.900 g, 1.94 mmol) in dry MeOH (25 mL) was added NaH (60% in mineral oil, 0.0155 g, 0.388 mmol), and the mixture was stirred at room temperature for 10 min (followed by TLC). The reaction mixture was then cooled at 0° C., and NaBH 4  (0.140 g, 3.70 mmol) was added. After the mixture was stirred at 0° C. for 20 min a chip of dry ice was added and the solvent was evaporated. The residue was dissolved in DCM (50 mL), and washed with saturated aqueous NH 4 Cl (50 mL). The organic layer was collected, and the aqueous was extracted with DCM (2×20 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:5), affording tert-butyl ((3aR,5S,6R,7S,7aR)-5-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white foam (0.793 g, 88%).  1 H NMR (500 MHz, CDCl 3 ) δ 6.11 (d, J=6.9 Hz, 1H), 4.99 (td, J=4.3, 47.2 Hz, 1H), 4.48-4.42 (m, 1H), 4.15-4.09 (m, 1H), 4.02-3.96 (m, 1H), 3.48-3.45 (m, 1H), 3.37 (s, 3H), 2.80 (s, br., 1H, (OH)), 1.55 (s, 9H), 1.22 (d, J=6.4 Hz, 3H), 0.89 (s, 9H), 0.084 (s, 3H), 0.075 (s, 3H). 
     To a solution of the above material (0.780 g, 1.68 mmol) in dry MeOH (20 mL) was bubbled HCl(g) for 30 sec. The mixture was stirred at room temperature for 6 h. After the solvent was evaporated under reduced pressure, the residue was neutralized with 1.0 M NH 3  in MeOH and purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:10), affording (3aR,5R,6R,7S,7aR)-7-fluoro-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.410 g, 98%).  1 H NMR (500 MHz, CD 3 OD) δ 6.41 (d, J=6.7 Hz, 1H), 4.84 (td, J=3.6 Hz, 50.1 Hz, 1H), 4.40-4.34 (m, 1H), 4.04-3.93 (m, 2H), 3.60 (dd, J=2.7, 8.6 Hz, 1H), 2.86 (s, 3H), 1.22 (d, J=6.6 Hz, 1H);  13 C NMR (100 MHz, CD 3 OD) δ 165.56, 91.07 (d, J=183.5 Hz), 90.92 (d, J=4.4 Hz), 76.33 (d, J=3.2 Hz), 71.56 (d, J=16.2 Hz), 67.39 (d, J=17.2 Hz), 66.88, 30.58, 19.70; MS, (ES, m/z) [M+H] +  251.1. 
     Example 35 
     (3aR,5R,6R,7S,7aR)-7-fluoro-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.35 g, 0.83 mmol) in anhydrous THF (15 mL), at 0° C. and under N 2 , was added MeMgBr (1.4 M in THF/toluene, 3.0 mL, 4.2 mmol). After addition the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO 3  aqueous solution (30 mL), and then extracted with EtOAc (30 mL) and DCM (3×30 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was dried under high vacuum. To the residue and PMB (0.50 g, 3.4 mmol) in dry DCM (8 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 3.0 mL, 3.0 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:10), affording (3aR,5R,6R,7S,7aR)-7-fluoro-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.039 g, 19%).  1 H NMR (400 MHz, CD 3 OD) δ 6.40 (d, J=6.7 Hz, 1H), 4.78 (td, J=3.6, 49.3 Hz, 1H), 4.40 (ddd, J=3.6, 6.6, 18.0 Hz, 1H), 4.00-3.89 (m, 2H), 3.79 (dd, J=3.2, 8.0 Hz, 1H), 2.86 (s, 3H), 1.19 (d, J=6.6 Hz, 1H);  13 C NMR (100 MHz, CD 3 OD) δ 165.99, 91.11 (d, J=5.31 Hz), 90.74 (d, J=184.1 Hz), 76.85 (q, J=3.7 Hz), 71.64 (d, J=16.4 Hz), 68.64, 68.22 (d, J=16.9 Hz), 30.55, 17.74; MS, (ES, m/z) [M+H] +  251.1. 
     Example 36 &amp; 37 
     (3aR,5R,6R,7S,7aR)-2-(ethylamino)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5R,6R,7S,7aR)-2-(ethylamino)-7-fluoro-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl (3aR,5R,6R,7S,7aR)-6-(tert-butyldimethylsilyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate (600 mg, 1.3 mmol) in DCM (30 mL) was added DMP (806 mg, 1.9 mmol) at 0° C. After stirring at room temperature for 2 h, the reaction was quenched with mixed saturated aqueous NaHCO 3  (20 mL) and Na 2 S 2 O 3  (20 mL). The resulting solution was extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum to give the crude aldehyde. The aldehyde was dissolved in THF (30 mL), treated with MeMgC1 (3 M in THF, 1.1 mL, 3.3 mmol) at 0° C.˜25° C. for 3 h. The reaction was then quenched with H 2 O (50 mL) and extracted with EtOAc (3×40 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 3%-30% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7S,7aR)-6-(tert-butyldimethylsilyloxy)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a yellow oil (355 mg, 57% of 2 steps). (ES, m/z) [M+H] +  479.0;  1 H NMR (300 MHz, CDCl 3 ) δ 6.20-6.14 (m, 1H), 4.95-4.65 (m, 1H), 4.44-4.25 (m, 2H), 4.08-3.79 (m, 4H), 1.51 (s, 9H), 1.25-1.14 (m, 6H), 0.87 (s, 9H), 0.12-0.06 (m, 6H). 
     A solution of the above material (350 mg, 0.73 mmol) in MeOH (saturated with HCl gas) (10 mL) was stirred for 3 h at room temperature. Volatiles were distilled out to afford a residue, which was dissolved in MeOH (5 mL). The pH value of the solution was adjusted to 9 with saturated aqueous K 2 CO 3 . The resulting solution was extracted with THF(3×10 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions [(Agilent 1200): Column, X-Bridge Prep-C18; mobile phase, water with 0.05% ammonia and 3% acetonitrile up to 13% acetonitrile in 10 mins; dectector, 220,254 nm] to afford (3aR,5R,6R,7S,7aR)-2-(ethylamino)-7-fluoro-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (63 mg, 32%); (ES, m/z): [M+H] +  265.0;  1 H NMR (300 MHz, D 2 O) δ 6.25 (d, J=6.6 Hz, 1H), 4.78 (td, J=3.9, 48.3 Hz, 1H), 4.42-4.33 (m, 1H), 4.00-3.91 (m, 2H), 3.71-3.68 (m, 1H), 3.22-3.05 (m, 2H), 1.07 (d, J=6.6 Hz, 3H), 1.02 (d, J=7.2 Hz, 3H) and (3aR,5R,6R,7S,7aR)-2-(ethylamino)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (77 mg, 39%); (ES, m/z): [M+H] +  265.0;  1 H NMR (300 MHz, D 2 O) δ 6.20 (d, J=6.6 Hz, 1H), 4.85 (td, J=3.6, 49.2 Hz, 1H), 4.41-4.31 (m, 1H), 3.98-3.89 (m, 2H), 3.47-3.43 (m, 1H), 3.17-3.09 (m, 2H), 1.10 (d, J=6.6 Hz, 3H), 1.02 (d, J=7.2 Hz, 3H). 
     Example 38 
     (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5R,6R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (9.28 g, 20.6 mmol) in DCM (150 mL) was added DMP (13.1 g, 30.9 mmol). After stirring at room temperature for 1 h the reaction was diluted with Et 2 O (400 mL). The resulting suspension was filtered through Celite cake, and the filtrate was concentrated to dryness at room temperature. The residue was loaded onto a layered NaHCO 3 /silica gel plug, and the product was eluted with (EtOAc/hexanes, 1:4), affording tert-butyl ((3aR,5R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white crystalline solid (8.96 g, 97%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.29 (d, J=7.0 Hz, 1H), 5.09 (dd, J=4.7, 48.4 Hz, 1H), 4.75-4.69 (m, 1H), 4.12-4.05 (m, 2H), 3.96-3.93 (m, 1H), 3.28 (s, 3H), 1.54 (s, 9H), 0.86 (s, 9H), 0.056 (s, 3H), 0.050 (s, 3H). 
     To a solution of the above material (8.96 g, 20.0 mmol) in dry MeOH (250 mL) was added NaH (60% in mineral oil, 0.158 g, 3.95 mmol), and the mixture was stirred at room temperature for 15 min (followed by TLC). The reaction mixture was then cooled at 0° C., and NaBH 4  (1.32 g, 34.9 mmol) was added. After the mixture was stirred at 0° C. for 20 min a chip of dry ice was added and the solvent was evaporated. The residue was dissolved in DCM (100 mL), and washed with saturated aqueous NH 4 Cl (100 mL). The organic layer was collected, and the aqueous was extracted with DCM (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:5), affording tert-butyl ((3aR,5R,6R,7S,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white foam (6.84 g, 76%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.06 (d, J=6.7 Hz, 1H), 5.01 (td, J=4.3, 46.8 Hz, 1H), 4.49-4.44 (m, 1H), 4.17-4.13 (m, 1H), 3.80-3.79 (m, 2H), 3.66-3.63 (m, 1H), 3.38 (s, 3H), 2.72 (s, br., 1H, (OH)), 1.54 (s, 9H), 0.89 (s, 9H), 0.062 (s, 3H), 0.057 (s, 3H). 
     At 0° C., to a solution of the above material (1.30 g, 2.89 mmol) and Bu 4 NI (0.107 g, 0.290 mmol) in anhydrous DMF (12 mL) was added NaH (60% in mineral oil, 0.145 g, 3.63 mmol). After addition of NaH, BnBr (0.989 g, 5.78 mmol) was added. After stirring at 0° C. for 30 min and then at room temperature overnight the mixture was diluted with Et 2 O (100 mL). The mixture was washed with saturated aqueous NH 4 Cl (2×50 mL). The aqueous was extracted with Et 2 O (2×40 mL). The combined extract was washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:20 to 1:4), affording tert-butyl ((3aR,5R,6R,7S,7aR)-6-(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a sticky oil (1.44 g, 92%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.27 (m, 5H), 6.21 (d, J=7.2 Hz, 1H), 5.30-5.16 (m, 1H), 4.80 (d, J=11.4 Hz, 1H), 4.56 (d, J=11.4 Hz, 1H), 4.50-4.42 (m, 1H), 3.95-3.78 (m, 4H), 3.44 (s, 3H), 1.54 (s, 9H), 0.89 (s, 9H), 0.049 (s, 6H). 
     At 0° C., to a solution of the above material (1.44 g, 2.66 mmol) in THF (25 mL) was added TBAF (1.0 M in THF, 3.5 mL, 3.5 mmol). After addition the reaction mixture was stirred at room temperature for 2 h and diluted with brine (50 mL). The mixture was extracted with EtOAc (2×40 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:2 to 1:1), affording tert-butyl ((3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (1.08 g, 95%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.27 (m, 5H), 6.18 (d, J=7.4 Hz, 1H), 5.17-5.04 (m, 1H), 4.84 (d, J=11.6 Hz, 1H), 4.55 (d, J=11.6 Hz, 1H), 4.50-4.43 (m, 1H), 3.95-3.91 (m, 1H), 3.88 3.82 (m, 1H), 3.79-3.75 (m, 1H), 3.71-3.67 (m, 1H), 3.37 (s, 3H), 1.53 (s, 9H). 
     To a solution of the above material (2.57 g, 6.03 mmol) in DCM (60 mL) at 0° C. was added DMP (3.82 g, 9.00 mmol). After stirring at room temperature for 1 h the reaction mixture was diluted with Et 2 O (100 mL). The resulting suspension was filtered through a Celite cake, and the filtrate was concentrated to dryness at room temperature. The residue was extracted with EtOAc (3×50 mL), and the solid was filtered off. The extract was washed mixed saturated aqueous NaHCO 3  (30 mL) and Na 2 S 2 O 3  (5 mL). The extract was collected and dried over anhydrous MgSO 4 . After filtration the solvent was evaporated under reduced pressure to give crude tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate. This crude material was used in the next step without further purification.  1 H NMR (400 MHz, CDCl 3 ) δ 9.65 (s, 1H), 7.39-7.29 (m, 5H), 6.04 (d, J=7.0 Hz, 1H), 5.08 (td, J=4.2, 46.7 Hz, 1H), 4.84 (d, J=11.4 Hz, 1H), 4.64 (d, J=11.4 Hz, 1H), 4.55-4.49 (m, 1H), 4.31 (d, J=7.5 Hz, 1H), 4.19-4.15 (m, 1H), 3.30 (s, 3H), 1.52 (s, 9H).) 
     To a solution of the above material (1.94 g, 4.57 mmol) and TMSCF 3  (1.80 g, 12.7 mmol) in anhydrous THF (50 mL) was added TBAF (1.0 M in THF, 0.75 mL, 0.75 mmol). After addition the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled at 0° C., and another batch of TBAF (1.0 M in THF, 11.0 mL, 11.0 mmol) was added. The mixture was stirred at room temperature for another 2 h, and then diluted with EtOAc (100 mL) and brine (100 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), affording tert-butyl ((3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a pale yellow solid (0.761 g, 34%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.28 (m, 5H), 6.20 (d, J=7.5 Hz, 1H), 5.06 (td, J=3.5, 49.5 Hz, 1H), 4.80 (d, J=11.6 Hz, 1H), 4.57 (d, J=11.6 Hz, 1H), 4.38-4.30 (m, 1H), 4.23 (d, J=8.8 Hz, 1H), 4.15-4.10 (m, 1H), 3.91-3.84 (m, 1H), 3.32 (s, 3H), 2.96 (d, J=10.1 Hz, 1H(OH)), 1.52 (s, 9H). 
     To a solution of the above material (0.760 g, 1.54 mmol) and PMB (0.70 g, 4.7 mmol) in anhydrous DCM (10 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 10.0 mL, 10.0 mmol). The mixture was stirred for ˜5 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:8), affording (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-(R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as an off-white solid (0.373 g, 80%).  1 H NMR (400 MHz, CD 3 OD) δ 6.43 (d, J=6.7 Hz, 1H), 4.86 (ddd, J=2.9, 3.6, 51.5 Hz, 1H), 4.34-4.26 (m, 2H), 4.17 (d, J=9.3 Hz, 1H), 3.99-3.90 (m, 1H), 2.85 (s, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 165.65, 126.48 (q, J=281.2 Hz), 91.27 (d, J=183.2 Hz), 90.42 (d, J=2.2 Hz), 70.54 (d, J=16.2 Hz), 69.70-69.65 (m), 69.20 (d, J=30.4 Hz), 65.91 (d, J=17.6 Hz), 30.37; MS, m/z=305.1 (M+1). 
     Example 39 
     (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.352 g, 0.829 mmol) and TMSCF 3  (0.290 g, 2.04 mmol) in anhydrous THF (15 mL) was added TBAF (1.0 M in THF, 0.050 mL, 0.050 mmol). After addition the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled at 0° C., and another batch of TBAF (1.0 M in THF, 1.5 mL, 1.5 mmol) was added. The mixture was stirred at room temperature for another 2 h, and then diluted with EtOAc (20 mL) and brine (50 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (20 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 2:3), affording tert-butyl ((3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a pale yellow solid (0.141 g, 34%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.28 (m, 5H), 6.14 (d, J=7.5 Hz, 1H), 5.09 (td, J=4.1, 46.4 Hz, 1H), 4.87 (d, J=10.8 Hz, 1H), 4.38-4.30 (m, 1H), 4.50 (d, J=10.8 Hz, 1H), 4.25-4.22 (m, 1H), 4.10-4.06 (m, 2H), 3.27 (s, 3H), 1.52 (s, 9H). 
     To a solution of the above material (0.141 g, 0.285 mmol) and PMB (0.20 g, 1.3 mmol) in anhydrous DCM (6 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 2.5 mL, 2.5 mmol). The mixture was stirred for ˜4 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:10), affording (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as an off-white solid (0.076 g, 78%).  1 H NMR (400 MHz, CD 3 OD) δ 6.34 (d, J=6.6 Hz, 1H), 4.85 (td, J=3.8, 48.2 Hz, 1H), 4.52-4.46 (m, 1H), 4.20-4.14 (m, 2H), 4.02 (dd, J=4.3, 7.5 Hz, 1H), 2.87 (s, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 166.00, 126.09 (q, J=280.7 Hz), 90.39 (d, J=6.2 Hz), 89.99 (d, J=185.0 Hz), 74.54 (d, J=4.7 Hz), 72.12 (d, J=16.6 Hz), 71.40 (q, J=30.0 Hz), 67.57 (d, J=17.0 Hz), 30.72; MS, m/z=305.1 (M+1). 
     Examples 40 &amp; 41 
     (3aR,5S,6R,7S,7aR)-2-(ethylamino)-7-fluoro-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5S,6R,7S,7aR)-2-(ethylamino)-7-fluoro-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a suspension of (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (88 g, 358 mmol) in MeOH (500 mL) was added Et 3 N (48.9 g, 484 mmol) and Boc 2 O (139 g, 637 mmol) in sequence at 25° C. After stirring for 10 h, volatiles were distilled out to afford a residue, which was purified by a silica gel column, eluted with 1%˜3% MeOH in DCM to give the crude product as a syrup. The syrup was re-crystallized from EtOAc/petroleum ether (1:3) to afford tert-butyl (3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a white solid (90 g, 73%). (ES, m/z): [M+H] +  349.0;  1 H NMR (300 MHz, CDCl 3 ) δ 6.13 (d, J=6.6 Hz, 1H), 4.23-4.22 (m, 1H), 4.17-4.14 (m, 1H), 3.91-3.86 (m, 2H), 3.81-3.77 (m, 3H), 3.59-3.55 (m, 1H), 3.16-3.17 (m, 1H, OH), 1.53 (s, 9H), 1.15 (t, J=7.5 Hz, 3H). 
     A solution of the above material (80 g, 230 mmol) and imidazole (62.5 g, 919 mmol) in DMF (300 mL) was treated with TBDMSCl (76 g, 506 mmol) for 3 h at 50° C. The reaction was quenched with saturated aqueous NaHCO 3  solution (1 L) and extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine (3×300 mL), dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 3%-10% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7R,7aR)-7-(tert-butyldimethylsilyloxy)-5-((tert-butyldimethylsilyloxy)methyl)-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a yellow oil (78 g, 59%). (ES, m/z): [M+H] +  577.0;  1 H NMR (300 MHz, CDCl 3 ) δ 5.95 (d, J=6.0 Hz, 1H), 4.25-4.21 (m, 1H), 4.01-4.09 (m, 1H), 3.98-3.83 (m, 2H), 3.81-3.65 (m, 3H), 3.45-3.35 (m, 1H), 1.50 (s, 9H), 1.15 (t, J=7.5 Hz, 3H), 0.92 (s, 9H), 0.89 (s, 9H), 0.15 (s, 6H), 0.08 (s, 6H). 
     To a solution of the above material (75 g, 130 mmol) in pyridine (200 mL) was added DMAP (1.6 g, 13 mmol), and BzCl (36.5 g, 261 mmol) at 0° C. After stirring for 6 h at 25° C., the reaction was quenched with saturated aqueous NaHCO 3  solution (600 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine (3×200 mL), dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The crude residue was purified by a silica gel column, eluted with 1%-5% EtOAc in petroleum ether to give (3aR,5R,6R,7R,7aR)-2-(tert-butoxycarbonyl)-7-(tert-butyldimethylsilyloxy)-5-((tert-butyldimethyl silyloxy)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ylbenzoate as a yellow oil (80 g, 90%). (ES, m/z): [M+H] +  681.0;  1 H NMR (300 MHz, CDCl 3 ) δ 8.03 (d, J=6.0 Hz, 2H), 7.57-7.54 (m, 1H), 7.44-7.39 (m, 2H), 6.06 (d, J=4.8 Hz, 1H), 5.17 (d, J=6.9 Hz, 1H), 4.49 (s, 1H), 4.19-4.16 (m, 1H), 3.95 (q, J=4.8 Hz, 2H), 3.74-3.73 (m, 1H), 3.71-3.68 (m, 2H), 1.55 (s, 9H), 1.15 (t, J=4.8 Hz, 3H), 0.92 (s, 9H), 0.87 (s, 9H), 0.20 (s, 3H), 0.16 (s, 3H), 0.03 (s, 6H). 
     The above material (80 g, 117 mmol) was treated with 1.5 M solution of HCl (g) in MeOH (300 mL) at room temperature for 12 h. The solvent was removed at room temperature under vacuum to give a residue, which was dissolved into MeOH (500 mL), followed by the addition of Et 3 N (23.5 g, 232 mmol) and Boc 2 O (50.8 g, 233 mmol) at room temperature. After additional 10 h, volatiles were distilled out to afford a residue, which was purified by a silica gel column, eluted with 10%-20% EtOAc in DCM to give (3aR,5R,6S,7R,7aR)-2-(tert-butoxycarbonyl)-7-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-yl benzoate as a yellow oil (47 g, 88%). (ES, m/z): [M+H] +  453.0;  1 H NMR (300 MHz, CDCl 3 ) δ 8.03 (d, J=6.0 Hz, 2H), 7.57-7.54 (m, 1H), 7.44-7.39 (m, 2H), 6.17 (d, J=7.2 Hz, 1H), 5.13 (d, J=8.4 Hz, 1H), 4.56-4.55 (m, 1H), 4.39-4.37 (m, 1H), 3.95 (q, J=4.8 Hz, 2H), 3.80-3.60 (m, 3H), 1.55 (s, 9H), 1.15 (t, J=4.8 Hz, 3H). 
     To a solution of the above material (47 g, 104 mmol) and DMAP (0.6 g, 4.9 mmol) in pyridine (300 mL) was added BzCl (11.6 g, 82 mmol) at −10° C. After stirring for 12 h at room temperature, the reaction was quenched with saturated aqueous NaHCO 3  solution (800 mL) and extracted with EtOAc (3×500 mL). The combined organic layer was washed with brine (3×300 mL), dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The crude residue was purified by a silica gel column, eluted with 10%-20% EtOAc in petroleum ether to give [(3aR,5R,6S,7R,7aR)-6-(benzoyloxy)-2-{[(tert-butoxy)carbonyl](ethyl)amino}-7-hydroxy-3aH,5H,6H,7H,7aH-pyrano[3,2-d][1,3]thiazol-5-yl]methyl benzoate as a yellow syrup (35 g, 61%). (ES, m/z): [M+H] +  557.0;  1 H NMR (300 MHz, CDCl 3 ) δ 8.03-8.01 (m, 4H), 7.61-7.52 (m, 2H), 7.45-7.37 (m, 4H), 6.20 (d, J=5.4 Hz, 1H), 5.19-5.17 (m, 1H), 4.57-4.53 (m, 2H), 4.48-4.43 (m, 2H), 4.17-4.13 (m, 1H), 4.00-3.90 (m, 2H), 1.57 (s, 9H), 1.19 (t, J=5.4 Hz, 3H). 
     A solution of the above material (20 g, 36 mmol) in DCM (200 mL) was treated with DAST (23.2 g, 144 mmol) at −78° C. After stirring for 36 h at 25° C., the reaction was quenched with saturated NaHCO 3  solution (400 mL) and extracted with DCM (3×200 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The crude residue was purified by a silica gel column, eluted with 1%-5% EtOAc in petroleum ether to give [(3aR,5R,6R,7R,7aR)-6-(benzoyloxy)-2-{[(tert-butoxy)carbonyl](ethyl)amino}-7-fluoro-3aH,5H,6H,7H,7aH-pyrano[3,2-d][1,3]thiazol-5-yl]methyl benzoate as a yellow oil (14 g, 70%). (ES, m/z): [M+H] +  559.0;  1 H NMR (300 MHz, CDCl 3 ) δ 8.02-8.00 (m, 4H), 7.61-7.51 (m, 2H), 7.45-7.36 (m, 4H), 6.18 (d, J=5.4 Hz, 1H), 5.54-5.40 (m, 1H), 5.35 (d, J=36 Hz, 1H), 4.61-4.59 (m, 1H), 4.57-4.41 (m, 2H), 4.03-3.94 (m, 3H), 1.57 (s, 9H), 1.21 (t, J=5.1 Hz, 3H). 
     A solution of the above material (26 g, 46.5 mmol) in MeOH (200 mL) was treated with K 2 CO 3  (0.7 g, 5 mmol) for 3 h at 25° C. The resulting solution was neutralized with acetic acid and the solvent was removed at room temperature under vacuum. The crude residue was purified by a silica gel column, eluted with 1%-3% MeOH in DCM to give tert-butyl ethyl((3aR,5R,6R,7R,7aR)-7-fluoro-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate as a white solid (15 g, 92%). (ES, m/z): [M+H] +  351.0;  1 H NMR (300 MHz, CDCl 3 ) δ 6.10 (d, J=5.1 Hz, 1H), 4.95 (td, J=4.3, 45 Hz, 1H), 4.43-4.37 (m, 1H), 3.96-3.87 (m, 2H), 3.80-3.73 (m, 2H), 3.62-3.57 (m, 1H), 3.38-3.35 (m, 1H), 1.53 (s, 9H), 1.13 (t, J=5.1 Hz, 3H). 
     To a solution of the above material (3 g, 8.5 mmol) in DCM (50 mL) was added Et 3 N (1.3 g, 13 mmol), DMAP (0.2 g, 1.7 mmol) and TBDMSCl (1.93 g, 12.7 mmol) at room temperature. After stirring for 10 h, the reaction was quenched with saturated aqueous NaHCO 3  solution (50 mL) and extracted with DCM (2×30 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 10%-20% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7R,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a yellow oil (3.6 g, 90%). (ES, m/z): [M+H] +  465.0;  1 H NMR (300 MHz, CDCl 3 ) δ 5.98 (d, J=6.6 Hz, 1H), 4.96 (td, J=4.9, 48 Hz, 1H), 4.45-4.37 (m, 2H), 3.96-3.87 (m, 2H), 3.88-3.75 (m, 1H), 3.64-3.55 (m, 1H), 3.38-3.35 (m, 1H), 1.51 (s, 9H), 1.15 (t, J=5.1 Hz, 3H), 0.85 (s, 9H), 0.02 (s, 6H). 
     To a solution of the above material (2.2 g, 4.7 mmol) in DCM (40 mL) was added DMP (3 g, 7.1 mmol) at 0° C. After stirring at room temperature for 2 h, the reaction was quenched with mixed saturated aqueous NaHCO 3  (20 mL) and Na 2 S 2 O 3  (20 mL). The resulting solution was extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 2%-15% EtOAc in petroleum ether to give tert-butyl (3aR,5R,7R,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-7-fluoro-6-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a yellow solid (1.9 g, 89%). (ES, m/z): [M+H] +  463.0;  1 H NMR (300 MHz, CDCl 3 ) δ 6.24 (d, J=6.9 Hz, 1H), 5.05 (dd, J=4.5, 48.6 Hz, 1H), 4.75-4.68 (m, 1H), 4.11-4.06 (m, 1H), 4.04-3.99 (m, 1H), 3.93-3.79 (m, 3H), 1.51 (s, 9H), 1.07 (t, J=6.9 Hz, 3H), 0.84 (s, 9H), 0.03 (s, 6H). 
     To a solution of the above material (1.8 g, 3.9 mmol) in MeOH (30 mL) was added NaH (70% in mineral oil, 11 mg, 0.3 mmol). After stirring at room temperature for 40 min, the reaction mixture was then cooled to 0° C., and NaBH 4  (296 mg, 7.8 mmol) was added. After additional 1 hour, the reaction was quenched with ice-water (30 mL) and extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 3%-20% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7S,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a yellow solid (1.2 g, 67%). (ES, m/z): [M+H] +  465.0;  1 H NMR (300 MHz, CDCl 3 ) δ 6.01 (d, J=6.6 Hz, 1H), 4.93 (td, J=4.3, 46.8 Hz, 1H), 4.44-4.35 (m, 2H), 4.17-4.08 (m, 1H), 3.96-3.87 (m, 1H), 3.86-3.77 (m, 1H), 3.56-3.47 (m, 1H), 3.42-3.37 (m, 1H), 1.51 (s, 9H), 1.13 (t, J=5.1 Hz, 3H), 0.85 (s, 9H), 0.02 (s, 6H). 
     To a solution of the above material (2.6 g, 5.6 mmol) in DCM (50 mL) was added imidazole (816 mg, 12 mmol) and TBDMSCl (1.3 g, 8.4 mmol) at room temperature. After stirring for 6 h, the reaction was quenched with saturated aqueous NaHCO 3  solution (50 mL) and extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The residue was purified by a short silica gel column, eluted with 1%-20% EtOAc in petroleum ether to give crude tert-butyl (3aR,5R,6R,7S,7aR)-6-(tert-butyldimethylsilyloxy)-5-((tert-butyldimethylsilyloxy)methyl)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a yellow oil, which was used in next step directly; (ES, m/z): [M+H] +  579.1. 
     To a solution of the above crude material in DCM (10 mL) and MeOH (20 mL) was added AcCl (2 mL) slowly at 0° C. After stirring for 30 min at 20° C. (followed by TLC), the pH value of the solution was adjusted to 8-9 with Et 3 N. The solvent was removed at room temperature under vacuum. The residue was purified by a silica gel column, eluted with 3%-20% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7S,7aR)-6-(tert-butyldimethylsilyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3 aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a yellow oil (1.3 g, 50% of 2 steps). (ES, m/z): [M+H] +  465.1;  1 H NMR (300 MHz, CDCl 3 ) δ 6.17 (d, J=6.3 Hz, 1H), 4.99-4.82 (m, 1H), 4.22-4.13 (m, 1H), 4.09-4.03 (m, 1H), 3.88-3.75 (m, 2H), 3.73-3.67 (m, 1H), 3.55-3.41 (m, 1H), 3.38-3.35 (m, 1H), 1.55 (s, 9H), 1.17 (t, J=5.1 Hz, 3H), 0.91 (s, 9H), 0.09 (s, 6H). 
     To a solution of the above material (1.3 g, 2.8 mmol) in DCM (30 mL) was added DMP (1.8 g, 4.2 mmol) at 0° C. After stirring at room temperature for 2 h, the reaction was quenched with mixed saturated aqueous NaHCO 3  (20 mL) and Na 2 S 2 O 3  (20 mL). The resulting solution was extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum to give the crude aldehyde. The aldehyde was dissolved in THF (30 mL), treated with TMSCF 3  (2 g, 14 mmol) and TBAF (350 mg, 1.1 mmol) and 4 A molecular sieve at 0° C.˜25° C. for 12 h, then additional TBAF (1.3 g, 4.2 mmol) was added. After an additional 2 h, the reaction was diluted with H 2 O (50 mL) and extracted with EtOAc (3×40 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 3%-30% EtOAc in petroleum ether to give tert-butyl ethyl((3aR,5S,6R,7S,7aR)-7-fluoro-6-hydroxy-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate as a yellow oil (970 mg, 39% of 2 steps). (ES, m/z): [M+H] +  419.1;  1 H NMR (300 MHz, CDCl 3 ) δ 6.26-6.13 (m, 1H), 5.01-4.80 (m, 1H), 4.39-4.23 (m, 2H), 4.21-3.99 (m, 2H), 3.68-3.52 (m, 2H), 1.55 (s, 9H), 1.19-1.13 (m, 3H). 
     To a solution of the above material (380 mg, 0.9 mmol) in DCM (20 mL) was added TFA (4 mL). After 2 h at room temperature, volatiles were distilled out to give a residue, which was dissolved into MeOH (3 mL) and neutralized with concentrated ammonia. After concentrating under vacuum, the crude mixture was purified by Prep-HPLC with the following conditions [(Agilent 1200):Column, X-Bridge Prep-C18; mobile phase, water with 0.05% ammonia and 10% acetonitrile up to 22% acetonitrile in 10 mins; detector, 220 nm, 254 nm] to afford (3aR,5S,6R,7S,7aR)-2-(ethylamino)-7-fluoro-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (70.3 mg, 24%); (ES, m/z): [M+H] +  319.0;  1 H NMR (300 MHz, D 2 O) δ 6.15 (d, J=6.6 Hz, 1H), 4.89 (td, J=4.2, 44.1 Hz, 1H), 4.48-4.39 (m, 1H), 4.32-4.16 (m, 2H), 3.95-3.90 (m, 1H), 3.20-3.10 (m, 2H), 1.02 (t, J=7.5 Hz, 3H); and (3aR,5S,6R,7S,7aR)-2-(ethylamino)-7-fluoro-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (81.9 mg, 28%); (ES, m/z): [M+H] +  319.0;  1 H NMR (300 MHz, D 2 O) δ 6.24 (d, J=6.6 Hz, 1H), 4.92 (ddd, J=2.7, 4.2, 50.7 Hz, 1H), 4.37-4.26 (m, 2H), 4.09-3.97 (m, 2H), 3.19-3.07 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). 
     Example 42 
     (3aR,5R,6R,7S,7aR)-5-ethyl-7-fluoro-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (500 mg, 1.17 mmol) in DCM (20 mL) was added DMP (746 mg, 1.76 mmol) at 0° C. After stirring at room temperature for 2 h, the reaction was quenched with mixed saturated aqueous NaHCO 3  (10 mL) and Na 2 S 2 O 3  (10 mL). The resulting solution was extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum to give the crude aldehyde tert-butyl (3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(methyl)carbamate. This crude aldehyde was used in the next step without further purification.  1 H NMR (400 MHz, CDCl 3 ) δ 9.65 (s, 1H), 7.39-7.29 (m, 5H), 6.04 (d, J=7.0 Hz, 1H), 5.08 (td, J=4.2, 46.7 Hz, 1H), 4.84 (d, J=11.4 Hz, 1H), 4.64 (d, J=11.4 Hz, 1H), 4.55-4.49 (m, 1H), 4.31 (d, J=7.5 Hz, 1H), 4.19-4.15 (m, 1H), 3.30 (s, 3H), 1.52 (s, 9H). 
     A solution of the above crude material (1.17 mmol) in THF (20 mL) was treated with MeMgC1 (1 M, 2.34 mL, 2.34 mmol) for 3 h at 10° C. The reaction was then quenched with H 2 O (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 5%-20% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(methyl)carbamate as a light yellow oil (273 mg, 53% over 2 steps). (ES, m/z) [M+H] +  441.1;  1 H NMR (300 MHz, CDCl 3 ) δ 7.40-7.31 (m, 5H), 6.21-6.03 (m, 1H), 5.12-4.93 (m, 2H), 4.65-4.42 (m, 2H), 4.35-4.15 (m, 2H), 3.96-3.65 (m, 1H), 3.38-3.29 (m, 3H), 1.57-1.54 (m, 9H), 1.34-1.29 (m, 3H). 
     To a solution of the above material (150 mg, 0.34 mmol) in DCM (15 mL) was added pyridine (107 mg, 1.36 mmol) and O-phenyl carbonochloridothioate (248 mg, 1.45 mmol) slowly at 0° C. After stirring at room temperature for 24 h, the reaction was quenched with saturated aqueous NaHCO 3  (20 mL). The resulting solution was extracted with DCM (3×50 mL). The combined organic layer was dried over anhydrous Na 2 SO 4  and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 2%-5% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1-(phenoxycarbonothioyloxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(methyl)carbamate as a yellow oil (116 mg, 59%). (ES, m/z) [M+H] +  577.0;  1 H NMR (300 MHz, CDCl 3 ) δ 7.46-7.29 (m, 8H), 7.20-7.10 (m, 2H), 6.23 (d, J=7.5 Hz, 1H), 5.58-5.52 (m, 1H), 5.19-5.00 (m, 1H), 4.93 (d, J=11.1 Hz, 1H), 4.68-4.60 (m, 1H), 4.57 (d, J=11.1 Hz, 1H), 4.10-3.98 (m, 2H), 3.29 (s, 3H), 1.55 (s, 9H), 1.38-1.34 (m, 3H). 
     To a solution of the above material (110 mg, 0.19 mmol) in toluene (10 mL) was added SnBu 3 H (277 mg, 0.95 mmol), AIBN (31 mg, 0.19 mmol). After stirring for 2 h at 80° C., the solvent was distilled out to give a residue, which was purified by a silica gel column, eluted with 2%-10% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7S,7aR)-6-(benzyloxy)-5-ethyl-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-ylmethyl)carbamate as a light yellow oil (57 mg, 70%). (ES, m/z) [M+H] +  425.0;  1 H NMR (300 MHz, CDCl 3 ) δ 7.38-7.31 (m, 5H), 6.12 (d, J=7.5 Hz, 1H), 5.19-5.01 (m, 1H), 4.88 (d, J=11.1 Hz, 1H), 4.54 (d, J=11.4 Hz, 1H), 4.50-4.44 (m, 1H), 3.73-3.64 (m, 2H), 3.33 (s, 3H), 1.58-1.49 (m, 2H), 1.51 (s, 9H), 0.93 (t, J=7.5 Hz, 3H). 
     A solution of the above material (110 mg, 0.26 mmol) in DCM (10 mL) was treated with BCl 3  (1M, 1.3 mL, 1.3 mmol) at −78° C.˜−30° C. for 2 h. The reaction was then quenched with MeOH (10 mL). Volatiles were distilled out to give a residue, which was dissolved into MeOH (3 mL) and neutralized with concentrated ammonia. After concentrating under vacuum, the crude product was purified by Prep-HPLC with the following conditions [(Agilent 1200):Column, X-Bridge Prep-C18; mobile phase, water with 0.05% ammonia and 18% acetonitrile up to 38% acetonitrile in 8 mins; detector, 220 nm, 254 nm] to afford (3aR,5R,6R,7S,7aR)-5-ethyl-7-fluoro-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (60.9 mg, 55%); (ES, m/z): [M+H] +  235.0;  1 H NMR (300 MHz, D 2 O) δ 6.19 (d, J=6.3 Hz, 1H), 4.89 (td, J=3.3, 53.4 Hz, 1H), 4.40-4.31 (m, 1H), 3.83-3.70 (m, 2H), 2.78 (s, 3H), 1.74-1.65 (m, 1H), 1.60-1.49 (m, 1H), 0.85 (t, J=7.5 Hz, 3H). 
     Example 43 
     (3aR,5S,6R,7S,7aR)-7-fluoro-5-(2-hydroxypropan-2-yl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (2.0 g, 4.7 mmol) in anhydrous THF (40 mL), at 0° C. and under N 2 , was added MeMgBr (1.4 M in THF/toluene, 8.0 mL, 11.2 mmol). After addition the mixture was stirred at room temperature for 3 h. The reaction was diluted with Et 2 O (50 mL) and then quenched with saturated NaHCO 3  aqueous solution (50 mL). The organic layer was collected, and the aqueous was extracted with DCM (3×40 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (40 mL) and Boc 2 O (2.0 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentration the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:2 to 3:2), affording tert-butyl ((3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (1.0 g, 48%), as a mixture of diastereomers. 
     To a solution of the above material (1.0 g, 2.3 mmol) in dry DCM (20 mL) was added DMP (1.2 g, 2.8 mmol). The reaction mixture was stirred at room temperature for 1.5 h, and then was diluted with Et 2 O (80 mL). After filtration through a celite cake the filtrate was washed with saturated NaHCO 3  aqueous solution (30 mL), and collected. The aqueous was extracted with EtOAc (2×40 mL). The combined extract was dried over Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:8 to 1:2), affording tert-butyl ((3aR,5S,6R,7S,7aR)-5-acetyl-6-(benzyloxy)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.49 g, 49%) as a white solid.  1 H NMR (500 MHz, CDCl 3 ) δ 7.39-7.37 (m, 2H), 7.34-7.31 (m, 2H), 7.31-7.29 (m, 1H), 6.02 (d, J=7.1 Hz, 1H), 5.15-5.04 (m, 1H), 4.84 (d, J=11.1 Hz, 1H), 4.62 (d, J=11.1 Hz, 1H), 4.54-4.51 (m, 1H), 4.25-4.20 (m, 2H), 3.33 (s, 3H), 2.23 (s, 3H), 1.54 (s, 9H). 
     To a solution of the above material (0.153 g, 0.348 mmol) in anhydrous THF (10 mL), under N 2 , was added MeMgBr (1.4 M in THF/toluene, 0.50 mL, 0.70 mmol). After addition the mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated NaHCO 3  aqueous solution (20 mL), and then extracted with DCM (2×20 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was dried under high vacuum. To a solution of the residue and PMB (0.15 g, 1.0 mmol) in dry DCM (4 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 2.6 mL, 2.6 mmol). The mixture was stirred for ˜5 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:12), affording (3aR,5S,6R,7S,7aR)-7-fluoro-5-(2-hydroxypropan-2-yl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.073 g, 79%).  1 H NMR (400 MHz, CD 3 OD) δ 6.15 (d, J=6.5 Hz, 1H), 4.38-4.34 (m, 1H), 4.11-4.07 (m, 1H), 4.05-3.98 (m, 1H), 3.68 (dd, J=5.6, 7.1 Hz), 2.84 (s, 3H), 2.20-2.09 (m, 2H);  13 C NMR (100 MHz, CD 3 OD) δ 163.99, 126.24 (q, J=280.7 Hz), 91.08, 75.0 (br.), 72.12 (q, J=29.7 Hz), 70.17, 67.00, 33.65, 30.80; MS, (ES, m/z) [M+H] +  265.1. 
     Examples 44 &amp; 45 
     (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-5-acetyl-6-(benzyloxy)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.310 g, 0.704 mmol) and TMSCF 3  (0.299 g, 2.10 mmol) in anhydrous THF (12 mL) was added TBAF (1.0 M in THF, 0.040 mL, 0.040 mmol). After addition the reaction mixture was stirred at room temperature for 16 h. Another batch of TBAF (1.0 M in THF, 1.2 mL, 1.2 mmol) was added at 0° C., and the mixture was stirred at room temperature for another 2 h. The reaction solution was then diluted with brine (50 mL), and extracted with EtOAc (2×30 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.178 g, 50%) as a white foam,  1 H NMR (major isomer) (400 MHz, CDCl 3 ) δ 7.37-7.28 (m, 5H), 6.18 (d, J=7.7 Hz, 1H), 5.08 (td, J=4.3, 45.6 Hz, 1H), 4.92 (d, J=10.7 Hz, 1H), 4.67-4.60 (m, 1H), 4.49 (d, J=10.7 Hz, 1H), 4.27-4.22 (m, 1H), 3.66-3.92 (m, 1H), 3.28 (s, 3H), 3.05 (s, br. 1H), 1.54 (s, 9H), 1.38 (s, 3H); and tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.136 g, 38%) as a white foam,  1 H NMR (minor isomer) (400 MHz, CDCl 3 ) δ 7.37-7.28 (m, 5H), 6.19 (d, J=7.7 Hz, 1H), 5.05 (td, J=4.3, 45.7 Hz, 1H), 4.94 (d, J=10.7 Hz, 1H), 4.64-4.60 (m, 1H), 4.49 (d, J=10.7 Hz, 1H), 4.26-4.24 (m, 1H), 3.90 (d, J=7.5 Hz, 1H), 3.29 (s, 3H), 3.25 (s, br. 1H), 1.54 (s, 9H), 1.37 (s, 3H). The stereochemistry for each isomer was assigned randomly. 
     To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (major isomer from the TMSCF 3  addition step) (0.18 g, 0.35 mmol) and PMB (0.15 g, 1.0 mmol) in dry DCM (5 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 2.0 mL, 2.0 mmol). The mixture was stirred for ˜4 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:13), affording (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.086 g, 77%).  1 H NMR (600 MHz, CD 3 OD) δ 6.37 (d, J=6.7 Hz, 1H), 4.83 (ddd, J=3.5, 4.6, 46.7 Hz, 1H), 4.61-4.57 (m, 1H), 4.33-4.30 (m, 1H), 3.90 (d, J=6.9 Hz), 2.88 (s, 3H), 1.34 (s, 3H);  13 C NMR (150.9 MHz, CD 3 OD) δ 165.55, 127.29 (q, J=286.0 Hz), 90.86 (d, J=8.4 Hz), 89.66 (d, J=186.5 Hz), 76.23 (d, J=4.0 Hz), 75.41 (q, J=27.4 Hz), 72.65 (d, J=16.6 Hz), 67.79 (d, J=16.6 Hz), 30.84, 17.28; MS, (ES, m/z) [M+H] +  319.1. 
     To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (minor isomer from the TMSCF 3  addition step) (0.136 g, 0.277 mmol) and PMB (0.10 g, 0.68 mmol) in dry DCM (5 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 2.0 mL, 2.0 mmol). The mixture was stirred for ˜4 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:13), affording (3aR,5S,6R,7S,7aR)-7-fluoro-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.081 g, 92%).  1 H NMR (600 MHz, CD 3 OD) δ 6.34 (d, J=6.7 Hz, 1H), 4.84 (ddd, J=3.5, 5.0, 46.3 Hz, 1H), 4.63-4.60 (m, 1H), 4.36-4.33 (m, 1H), 3.75 (d, J=6.9 Hz), 2.88 (s, 3H), 1.35 (s, 3H);  13 C NMR (150.9 MHz, CD 3 OD) δ 165.25, 127.26 (q, J=287.0 Hz), 90.46 (d, J=9.1 Hz), 89.55 (d, J=186.4 Hz), 79.12 (d, J=4.0 Hz), 75.77 (q, J=27.3 Hz), 73.26 (d, J=16.6 Hz), 67.35 (d, J=16.9 Hz), 30.96, 18.72; MS, (ES, m/z) [M+H] +  319.1. 
     Examples 46 &amp; 47 
     (3aR,5R,6S,7R,7aR)-7-fluoro-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]ithiazol-6-ol and (3aR,5R,6S,7R,7aR)-7-fluoro-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (2.57 g, 5.72 mmol) in dry MeOH (50 mL), at 0° C., was added NaBH 4  (0.295 g, 7.80 mmol). After the mixture was stirred at 0° C. for 20 min a chip of dry ice was added, and the solvent was evaporated. The residue was dissolved in DCM (50 mL) and washed with satd. aqueous NaHCO 3  (50 mL). The organic layer was collected, and the aqueous was extracted with DCM (2×30 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 1:10 to 1:3), affording tert-butyl ((3aR,5R,6S,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.95 g, 37%), as a sticky oil.  1 H NMR (400 MHz, CDCl 3 ) δ 6.11 (d, J=6.7 Hz, 1H), 4.84 (ddd, J=3.2, 6.7, 48.2 Hz, 1H), 4.45 (td, J=6.7, 16.6 Hz, 1H), 4.32-4.29 (m, 1H), 4.00-3.93 (m, 2H), 3.90-3.86 (m, 1H), 3.36 (s, 3H), 3.19 (s, br., 1H, (OH)), 1.53 (s, 9H), 0.90 (s, 9H), 0.093 (s, 3H), 0.087 (s, 3H). 
     At 0° C., to a solution of the above material (0.852 g, 1.89 mmol) and Bu 4 NI (0.070 g, 0.189 mmol) in anhydrous DMF (8 mL) was added NaH (60% in mineral oil, 0.945 g, 2.36 mmol). After addition of NaH, to the reaction mixture was added BnBr (0.646 g, 3.78 mmol). After stirring at room temperature for 16 h the mixture was diluted with brine (60 mL) and extracted with Et 2 O (2×60 mL). The combined extract was washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:5), affording tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a colorless sticky oil (0.980 g, 95%).  1 H NMR (500 MHz, CDCl 3 ) δ 7.38-7.29 (m, 5H), 5.98 (d, J=6.0 Hz, 1H), 4.89 (ddd, J=2.1, 7.1, 48.6 Hz, 1H), 4.87 (d, J=11.8 Hz, 1H), 4.64 (d, J=11.8 Hz, 1H), 4.43 (td, J=6.6, 18.1 Hz, 1H), 4.17-4.10 (m, 1H), 4.01-3.98 (m, 1H), 3.81 (dd, J=7.0, 10.5 Hz, 1H), 3.77-3.73 (m, 1H), 3.36 (s, 3H), 1.52 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H). 
     At 0° C., to a solution of the above material (0.980 g, 1.81 mmol) in THF (10 mL) was added TBAF (1.0 M in THF, 3.0 mL, 3.0 mmol). After stirring at room temperature for 2 h the reaction mixture diluted with brine (50 mL) and extracted with EtOAc (2×50 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:5 to 2:3), affording tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (0.79 g, 100%).  1 H NMR (400 MHz, CDCl 3 ) δ 7.39-7.32 (m, 5H), 5.98 (d, J=5.88 Hz, 1H), 5.11 (ddd, J=2.9, 6.2, 48.6 Hz, 1H), 4.88 (d, J=11.6 Hz, 1H), 4.61 (d, J=11.6 Hz, 1H), 4.45 (td, J=6.0, 15.9 Hz, 1H), 4.08-3.98 (m, 2H), 3.92-3.88 (m, 1H), 3.70 (dd, J=4.6, 11.6 Hz, 1H), 1.51 (s, 9H). 
     To a solution of the above material (0.790 g, 1.85 mmol) in DCM (10 mL) was added DMP (1.14 g, 2.69 mmol). After stirring at room temperature for 1 h the reaction mixture was diluted with Et 2 O (100 mL), and filtered through a celite cake. The filtrate was concentrated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 1:5 to 1:2), affording tert-butyl ((3aR,5S,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (0.73 g, 93%).  1 H NMR (400 MHz, CDCl 3 ) δ 9.76 (d, J=3.1 Hz, 1H), 7.39-7.31 (m, 5H), 5.93 (d, J=4.3 Hz, 1H), 5.39 (ddd, J=1.8, 4.5, 48.7 Hz, 1H), 4.85 (d, J=11.6 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.28-4.20 (m, 3H), 3.33 (s, 3H), 1.53 (s, 9H). 
     To a solution of the above material (0.390 g, 0.919 mmol) in anhydrous THF (8 mL) under N 2  was added MeMgBr (1.4 M in THF/toluene, 3.0 mL, 4.2 mmol). After addition the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCO 3  (30 mL), and then extracted with EtOAc (40 mL) and DCM (2×30 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (5 mL). Boc 2 O (0.38 g, 1.7 mmol) was added, and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.116 g, 29%) as a white solid,  1 H NMR (500 MHz, CDCl 3 ) δ 7.39-7.33 (m, 5H), 6.00 (d, J=6.2 Hz, 1H), 5.00 (ddd, J=2.8, 6.2, 48.4 Hz, 1H), 4.94 (d, J=11.5 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.48 (td, J=6.6, 16.7 Hz, 1H), 4.26-4.22 (m, 1H), 4.08-4.04 (m, 1H), 3.56 (dd, J=3.1, 8.3 Hz, 1H), 3.36 (s, 3H), 1.51 (s, 9H), 1.20 (d, J=6.3 Hz, 3H); also isolated was tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.186 g, 46%) as a white solid,  1 H NMR (500 MHz, CDCl 3 ) δ 7.38-7.30 (m, 5H), 6.12 (d, J=6.3 Hz, 1H), 5.10-4.99 (m, 1H), 4.96 (d, J=11.8 Hz, 1H), 4.61 (d, J=11.8 Hz, 1H), 4.54 (td, J=6.6, 17.2 Hz, 1H), 4.15-4.07 (m, 2H), 3.60 (dd, J=3.1, 6.3 Hz, 1H), 3.48 (s, 3H), 1.54 (s, 9H), 1.08 (d, J=6.3 Hz, 3H). 
     To a solution of tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.116 g, 0.264 mmol) and PMB (0.20 g, 1.3 mmol) in anhydrous DCM (6 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 1.2 mL, 1.2 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:10), affording (3aR,5R,6S,7R,7aR)-7-fluoro-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.064 g, 97%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.43 (dd, J=1.4, 6.5 Hz, 1H), 4.51 (ddd, J=3.2, 8.2, 48.2 Hz, 1H), 4.35-4.32 (m, 1H), 4.30-4.22 (m, 1H), 4.03-3.96 (m, 1H), 3.57 (d, J=8.2 Hz, 1H), 2.86 (s, 3H), 1.20 (d, J=6.3 Hz, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 164.40, 95.50 (d, J=183.3 Hz), 92.85 (d, J=8.6 Hz), 78.33 (d, J=6.2 Hz), 69.39 (d, J=20.8 Hz), 66.14 (d, J=16.5 Hz), 65.95 (d, J=8.4 Hz), 30.23, 20.71; MS, (ES, m/z) [M+H] +  251.1. 
     To a solution of tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.180 g, 0.409 mmol) and PMB (0.20 g, 1.3 mmol) in anhydrous DCM (6 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 2.0 mL, 2.0 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:10), affording (3aR,5R,6S,7R,7aR)-7-fluoro-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.092 g, 90%).  1 H NMR (400 MHz, CDCl 3 ) δ 6.45 (dd, J=1.1, 6.4 Hz, 1H), 4.59 (ddd, J=3.2, 8.1, 48.0 Hz, 1H), 4.30-4.22 (m, 1H), 4.18-4.14 (m, 1H), 4.08-4.02 (m, 1H), 3.66 (d, J=7.4 Hz, 1H), 2.83 (s, 3H), 1.22 (d, J=6.8 Hz, 3H);  13 C NMR (100 MHz, CD 3 OD) δ 164.73, 95.14 (d, J=183.0 Hz), 92.31 (d, J=8.7 Hz), 79.15 (d, J=6.2 Hz), 69.62 (d, J=20.7 Hz), 67.98 (d, J=2.9 Hz), 67.56 (d, J=16.7 Hz), 30.28, 18.92; MS, (ES, m/z) [M+H] +  251.1. 
     Examples 48 &amp; 49 
     (3aR,5S,6S,7R,7aR)-7-fluoro-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol and (3aR,5S,6S,7R,7aR)-7-fluoro-2-(methylamino)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl ((3aR,5S,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.320 g, 0.754 mmol) and TMSCF 3  (0.208 g, 1.46 mmol) in anhydrous THF (8 mL) was added TBAF (1.0 M in THF, 0.030 mL, 0.030 mmol). After addition the reaction mixture was stirred at room temperature for 2 h. Another batch of TBAF (1.0 M in THF, 1.0 mL, 1.0 mmol) was added, and the mixture was stirred at room temperature for another 2 h. The reaction solution was then diluted with EtOAc (20 mL) and brine (30 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (20 mL). The combined extract was dried over anhydrous Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a pale yellow foam, with a 6.8:1 mixture of diastereomers based on  1 H NMR. To a solution of the yellow foam and PMB (0.20 g, 1.3 mmol) in anhydrous DCM (6 mL) at −78° C. under N 2 , was added BCl 3  (1.0 M in DCM, 2.0 mL, 2.0 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH 3  in MeOH/DCM, 1:10), affording (3aR,5S,6S,7R,7aR)-7-fluoro-2-(methylamino)-5-(R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.118 g, 77%) with a diastereomeric ratio of 6.8:1 based on  1 H NMR. This mixture was separated by Prep-HPLC with the following conditions: Column, XBridge Prep. C18, 19×150 mm; mobile phase, water with 0.05% NH 4 OH and CH 3 CN (from 5% to 25% in 10 min); Dectector, UV 220 nm, to give (3aR,5S,6S,7R,7aR)-7-fluoro-2-(methylamino)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (the faster eluting isomer) as white solid (65 mg, 28% overall yield),  1 H NMR (300 MHz, CD 3 OD) δ 6.46 (d, J=6.3 Hz, 1H), 4.66 (td, J=3.0, 48.3 Hz, 1H), 4.44-4.42 (m, 3H), 4.12 (d, J=6.0 Hz, 1H), 2.85 (s, 3H), MS, (ES, m/z) [M+H] +  305.0; and (3aR,5S,6S,7R,7aR)-7-fluoro-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (the slower eluting isomer) (6.5 mg, 2.8% overall yield),  1 H NMR (300 MHz, CD 3 OD) δ 6.41 (d, J=6.3 Hz, 1H), 4.63 (td, J=3.3, 48.0 Hz, 1H), 4.36-4.19 (m, 3H), 4.08-4.05 (m, 1H), 2.85 (s, 3H). (ES, m/z) [M+H] +  305.0. 
     The following examples may be synthesized according to procedures analogous to the schemes and examples outlined above. 
                             TABLE 4               Example   Name   Structure                  50   (3aR,5R,6S,7S,7aR)-7-fluoro-5-((S)- 1-hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol                                     51   (3aR,5R,6R,7aR)-5-((S)-1- hydroxyethyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol                                     52   (3aR,5R,6R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-((S)-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     53   (3aR,5R,R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-((R)-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     54   (3aR,5S,6R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-((R)- 2,2,2-trifluoro-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol                                     55   (3aR,5S,6R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-((S)- 2,2,2-trifluoro-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol                                     56   (3aR,5S,6R,7S,7aR)-2-(ethylamino)- 7-fluoro-5-((R)-1,1,1-trifluoro-2- hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol                                     57   (3aR,5S,6R,7S,7aR)-2-(ethylamino)- 7-fluoro-5-((S)-1,1,1-trifluoro-2- hydroxypropan-2-yl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol                                     58   (3aR,5S,6R,7S,7aR)-2- (dimethylamino)-7-fluoro-5-(1,1,1- trifluoro-2-hydroxypropan-2-yl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol                                     59   (3aR,5R,6R,7S,7aR)-2-(azetidin-1- yl)-7-fluoro-5-((S)-1-hydroxyethyl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol                                     60   (3aR,5S,6R,7S,7aR)-2-(azetidin-1-yl)- 7-fluoro-5-((R)-2,2,2-trifluoro-1- hydroxyethyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     61   (3aR,5R,6R,7S,7aR)-7-fluoro-5-((S)- 1-hydroxyethyl)-2-(pyrrolidin-1-yl)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol                                     62   (3aR,5S,6R,7S,7aR)-7-fluoro-2- (pyrrolidin-1-yl)-5-((R)-2,2,2- trifluoro-1-hydroxyethyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol                                     63   (3aR,5R,6R,7R,7aR)-7-fluoro-5-((R)- 2-fluoro-1-hydroxyethyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     64   (3aR,5S,6R,7R,7aR)-5-((R)-2,2- difluoro-1-hydroxyethyl)-7-fluoro-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     65   (3aR,5R,6R,7S,7aR)-7-fluoro-5-((R)- 2-fluoro-1-hydroxyethyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     66   (3aR,5S,6R,7S,7aR)-5-((R)-2,2- difluoro-1-hydroxyethyl)-7-fluoro-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     67   (3aR,5R,6R,7R,7aR)-7-fluoro-5-((S)- 1-hydroxypropyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol                                     68   (3aR,5R,6R,7R,7aR)-5-((S)-3,3- difluoro-1-hydroxypropyl)-7-fluoro-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     69   (3aR,5R,6R,7R,7aR)-7-fluoro-2- (methylamino)-5-((S)-3,3,3-trifluoro- 1-hydroxypropyl)-5,6,7,7a-tetrahydro- 3aH-pyrno[3,2-d]thiazol-6-ol                                     70   (3aR,5R,6R,7R,7aR)-5-((S)- cyclopropyl(hydroxy)methyl)-7- fluoro-2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol                                     71   (3aR,5R,6R,7R,7aR)-5-((S)- cyclobutyl(hydroxy)methyl)-7-fluoro- 2-(methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     72   (3aR,5R,6R,7R,7aR)-5-((S)- cyclopentyl(hydroxy)methyl)-7- fluoro-2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol                                     73   (3aR,5R,6R,7S,7aR)-7-fluoro-5-((S)- 1-hydroxypropyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazol-6-ol                                     74   (3aR,5R,6R,7S,7aR)-5-((S)-3,3- difluoro-1-hydroxypropyl)-7-fluoro-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     75   (3aR,5R,6R,7S,7aR)-7-fluoro-2- (methylamino)-5-((S)-3,3,3-trifluoro- 1-hydroxypropyl)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     76   (3aR,5R,6R,7S,7aR)-5-((S)- cyclopropyl(hydroxy)methyl)-7- fluoro-2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol                                     77   (3aR,5R,6R,7S,7aR)-5-((S)- cyclobutyl(hydroxy)methyl)-7-fluoro- 2-(methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                     78   (3aR,5R,6R,7S,7aR)-5-((S)- cyclopentyl(hydroxy)methyl)-7- fluoro-2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol                                     79   (3aR,5R,6R,7S,7aR)-7-fluoro-2- (methylamino)-5-vinyl-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 6-ol                                     80   (3aR,5R,6S,7S,7aR)-7-fluoro-2- (methylamino)-5-(2,2,2- trifluoroethyl)-5,6,7,7-tetrahydro- 3aH-pyrano[3,2-d]thiazol-6-ol                                          
Biological Activity
 
     Assay for Determination of K I  Values for Inhibition of O-GlcNAcase Activity 
     Experimental Procedure for Kinetic Analyses: 
     Enzymatic reactions were carried out in a reaction containing 50 mM NaH 2 PO 4 , 100 mM NaCl and 0.1% BSA (pH 7.0) using 2 mM 4-Methylumbelliferyl N-acetyl-β-D-glucosaminide dihydrate (Sigma M2133) dissolved in ddH 2 O, as a substrate. The amount of purified human O-GlcNAcase enzyme used in the reaction was 0.7 nM. Test compound of varying concentrations was added to the enzyme prior to initiation of the reaction. The reaction was performed at room temperature in a 96-well plate and was initiated with the addition of substrate. The production of fluorescent product was measured every 60 sec for 45 min with a Tecan Infinite M200 plate-reader with excitation at 355 nM and emission detected at 460 nM, with 4-Methylumbelliferone (Sigma M1381) used to produce a standard curve. The slope of product production was determined for each concentration of compound tested and plotted, using standard curve fitting algorithms for sigmoidal dose response curves. The values for a four parameter logistic curve fit of the data were determined. 
     K I  values were determined using the Cheng-Prusoff equation; the K m  of O-GlcNAcase for substrate was 0.2 mM. 
     Examples 1 to 49 were tested in the above described assay and exhibited K I  values for inhibition of O-GlcNAcase in the range 0.1 nM-10 μM. 
     Assay for Determination of K I  Values for Inhibition of β-Hexosaminidase Activity 
     Experimental Procedure for Kinetic Analyses: 
     Enzymatic reactions were carried out in a reaction containing 50 mM NaH 2 PO 4 , 100 mM NaCl and 0.1% BSA (pH 7.0) using 2 mM 4-Methylumbelliferyl N-acetyl-β-D-glucosaminide dihydrate (Sigma M2133) dissolved in ddH 2 O, as a substrate. The amount of purified human β-hexosaminidase enzyme used in the reaction was 24 nM. Test compound of varying concentrations was added to the enzyme prior to initiation of the reaction. The reaction was performed at room temperature in a 96-well plate and was initiated with the addition of substrate. The production of fluorescent product was measured every 60 sec for 45 min with a Tecan Infinite M200 plate-reader with excitation at 355 nM and emission detected at 460 nM, with 4-Methylumbelliferone (Sigma M1381) used to produce a standard curve. The slope of product production was determined for each concentration of compound tested and plotted, using standard curve fitting algorithms for sigmoidal dose response curves. The values for a four parameter logistic curve fit of the data were determined. 
     K I  values were determined using the Cheng-Prusoff equation. 
     When tested in this assay, many of the compounds described herein exhibit K I  values for inhibition of β-hexosaminidase in the range 10 nM to greater than 100 uM. 
     The selectivity ratio for inhibition of O-GlcNAcase over β-hexosaminidase is defined here as:
 
K I (β-hexosaminidase)/K I (O-GlcNAcase)
 
     In general, the compounds described herein exhibited a selectivity ratio in the range of about 10 to 100000. Thus, many compounds of the invention exhibit high selectivity for inhibition of O-GlcNAcase over β-hexosaminidase. 
     Assay for Determination of Cellular Activity for Compounds that Inhibit O-GlcNAcase Activity 
     Inhibition of O-GlcNAcase, which removes O-GlcNAc from cellular proteins, results in an increase in the level of O-GlcNAcylated protein in cells. An increase in O-GlcNAcylated protein can be measured by an antibody, such as RL-2, that binds to O-GlcNAcylated protein. The amount of O-GlcNAcylated protein:RL2 antibody interaction can be measured by enzyme linked immunosorbant assay (ELISA) procedures. 
     A variety of tissue culture cell lines, expressing endogenous levels of O-GlcNAcase, can be utilized; examples include rat PC-12, and human U-87, or SK—N—SH cells. In this assay, rat PC-12 cells were plated in 96-well plates with approximately 10,000 cells/well. Compounds to be tested were dissolved in DMSO, either 2 or 10 mM stock solution, and then diluted with DMSO and water in a two-step process using a Tecan workstation. Cells were treated with diluted compounds for 24 h (5.4 μL into 200 μL 1 well volume) to reach a final concentration of inhibitor desired to measure a compound concentration dependent response, typically, ten 3 fold dilution steps, starting at 10 μM were used to determine a concentration response curve. To prepare a cell lysate, the media from compound treated cells was removed, the cells were washed once with phosphate buffered saline (PBS) and then lysed for 5 minutes at room temperature in 50 μL of Phosphosafe reagent (Novagen Inc, Madison, Wis.) with protease inhibitors and PMSF. The cell lysate was collected and transferred to a new plate, which was then either coated to assay plates directly or frozen −80° C. until used in the ELISA procedure. If desired, the total protein concentration of samples was determined using 20 μL of the sample using the BCA method. 
     The ELISA portion of the assay was performed in a black Maxisorp 96-well plate that was coated overnight at 4° C. with 100 μL/well of the cell lysate (1:10 dilution of the lysate with PBS containing protease inhibitors, phosphatase inhibitors, and PMSF). The following day the wells were washed 3 times with 300 μL/well of Wash buffer (Tris-buffered saline with 0.1% Tween 20). The wells were blocked with 100 μL/well Blocking buffer (Tris buffered saline w/0.05% Tween 20 and 2.5% Bovine serum albumin). Each well was then washed two times with 300 μL/well of wash buffer. The anti O-GlcNAc antibody RL-2 (Abcam, Cambridge, Mass.), diluted 1:1000 in blocking buffer, was added at 100 μL/well. The plate was sealed and incubated at 37° C. for 2 h with gentle shaking. The wells were then washed 3-times with 300 μL/well wash buffer. To detect the amount of RL-2 bound horse-radish peroxidase (HRP) conjugated goat anti-mouse secondary antibody (diluted 1:3000 in blocking buffer) was added at100 μL/well. The plate was incubated for 60 min at 37° C. with gentle shaking. Each well was then washed 3-times with 300 μL/well wash buffer. The detection reagent was added, 100 μL/well of Amplex Ultra RED reagent (prepared by adding 30 μL of 10 mM Amplex Ultra Red stock solution to 10 mL PBS with 18 μL 3% hydrogen peroxide, H 2 O 2 ). The detection reaction was incubated for 15 minutes at room temperature and then read with excitation at 530 nm and emission at 590 nm. 
     The amount of O-GlcNAcylated protein, as detected by the ELISA assay, was plotted for each concentration of test compound using standard curve fitting algorithms for sigmoidal dose response curves. The values for a four parameter logistic curve fit of the data were determined, with the inflection point of the curve being the potency value for the test compound. 
     Assay for Determination of Apparent Permeability (P app ) 
     Bi-directional transport was evaluated in LLC-PK1 cells in order to determine apparent permeability (P app ). LLC-PK1 cells can form a tight monolayer and therefore can be used to assess vectorial transport of compounds from basolateral to apical (B→A) and from apical to basolateral (A→B). 
     To determine P app , LLC-PK1 cells were cultured in 96-well transwell culture plates (Millipore). Solutions containing the test compounds (1 μM) were prepared in Hank&#39;s Balanced Salt Solution with 10 mM HEPES. Substrate solution (150 μL) was added to either the apical (A) or the basolateral (B) compartment of the culture plate, and buffer (150 μL) was added to the compartment opposite to that containing the compound. At t=3 h, 50 μL samples were removed from both sides of monolayers dosed with test compound and placed in 96 well plates, scintillant (200 μL) or internal standard (100 μL labetolol 1 μM) was added to the samples and concentration was determined by liquid scintillation counting in a MicroBeta Wallac Trilux scintillation counter (Perkin Elmer Life Sciences, Boston, Mass.) or by LCMS/MS (Applied Biosystems SCIEX API 5000 triple quadruple mass spectrometer). [ 3 H]Verapamil (1 μM) was used as the positive control. The experiment was performed in triplicate. 
     The apparent permeability, P app , was calculated by the following formula for samples taken at t=3 h: 
               P   app     =         Volume   ⁢           ⁢   of   ⁢           ⁢   Receptor   ⁢           ⁢   Chamber   ⁢           ⁢     (   mL   )           [     Area   ⁢           ⁢   of   ⁢           ⁢   membrane   ⁢           ⁢     (     cm   2     )       ]     ⁡     [     Initial   ⁢           ⁢   Concentration   ⁢           ⁢     (   μM   )       ]         ×       Δ   ⁢           ⁢   in   ⁢           ⁢   Concentration   ⁢           ⁢     (   μM   )         Δ   ⁢           ⁢   in   ⁢           ⁢   Time   ⁢           ⁢     (   s   )                 
Where: Volume of Receptor Chamber was 0.15 mL; Area of membrane was 0.11 cm 2 ; the Initial Concentration is the sum of the concentration measured in the donor plus concentration measured in receiver compartments at t=3 h; A in Concentration is concentration in the receiver compartment at 3 h; and Δ in Time is the incubation time (3×60×60=10800 s). P app  was expressed as 10 −6  cm/s. The P app  (LLC-PK1 cells) are the average of the P app  for transport from A to B and P app  for transport from B to A at t=3 h:
 
     
       
         
           
             
               
                 P 
                 app 
               
               ⁡ 
               
                 ( 
                 
                   LLC 
                   - 
                   
                     PK 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     1 
                     ⁢ 
                     Cells 
                   
                 
                 ) 
               
             
             = 
             
               
                 
                   
                     P 
                     app 
                   
                   ⁡ 
                   
                     ( 
                     
                       A 
                       → 
                       B 
                     
                     ) 
                   
                 
                 + 
                 
                   
                     P 
                     app 
                   
                   ⁡ 
                   
                     ( 
                     
                       B 
                       → 
                       A 
                     
                     ) 
                   
                 
               
               2 
             
           
         
       
     
     Representative data from the binding, cell-based, and permeability assays described above are shown in the following table. Certain compounds of the invention exhibited superior potency or permeability in one or more of these assays. For comparison, the first two table entries show data for compounds (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol and (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol, disclosed in WO 2008/025170. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 5 
               
               
                   
               
               
                   
                   
                 Cell-based 
                 Fluorescence- 
                 Papp LLC-PK1 
               
               
                   
                   
                 ELISA 
                 based hOGA 
                 cells 
               
               
                 Example 
                 Structure 
                 EC 50  (nM) 
                 Ki (nM) 
                 (10 −6  cm/s) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 13 
                 0.4 
                 &lt;1.0 
               
               
                   
               
               
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 10 
                 0.3 
                 &lt;1.0 
               
               
                   
               
               
                  1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 13 
                 1.1 
                 3.3 
               
               
                   
               
               
                  3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 12 
                 5.2 
               
               
                   
               
               
                  5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 16 
                 14 
               
               
                   
               
               
                  7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 16 
                 15 
               
               
                   
               
               
                  9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 74 
                 3.5 
                 6.6 
               
               
                   
               
               
                 11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 9.5 
                 23 
               
               
                   
               
               
                 13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 26 
                 2.3 
               
               
                   
               
               
                 15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 156 
                 34 
               
               
                   
               
               
                 20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 50 
                 3.5 
                 3.4 
               
               
                   
               
               
                 29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 492 
                 ND 
               
               
                   
               
               
                 32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 13 
                 21 
               
               
                   
               
               
                 34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5.2 
                 0.3 
                 1.9 
               
               
                   
               
               
                 37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 266 
                 2.1 
               
               
                   
               
               
                 38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 9.1 
                 0.7 
                 3.7 
               
               
                   
               
               
                 42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 50 
                 ND 
               
               
                   
               
               
                 43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 390 
                 2.4 
               
               
                   
               
               
                 46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ND 
                 562 
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     The present invention has been described with regard to one or more embodiments. However, it will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims. 
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